Early Phase Clinical Trials

Greg PondPhD PStat

Escarpment Cancer Research InstituteDepartment of OncologyDepartment of Clinical Epidemiology and Biostatistics

6 November 2014

Learning Objectives

1 Understand clinical questions of interest

2 Understand statistical questions of interest

3 Understand different phases (12others)

4 Able to discuss designs for early phase clinical trials

My Background (biases)

bullDepartment of Oncology (associate appointment with Clin Epi amp Biostats)

bull13+ years in cancer clinical trials

bullMinimal involvement with other diseases

bullInteraction (questions) are good

Your Background

bullDoes anyone have experience designing an early phase trial

bullHow many have clinical trials experience What sort

bullWho is clinician statistician researcher other

Thought Experiment

bullYou (or collaborator) has new drug which showed astonishing activity in animals lab experiments Ultimately you want to apply for regulatory approval

bullYou need to convince financier to fund you to get to regulatory approval What processes will you use

Standard Drug Development Paradigm

bullPhase I ndash safety Find safe dose

bullPhase II ndash preliminary efficacy Is it active

bullPhase III ndash efficacy Is it superior to standard

bullPhase IV ndash effectiveness Is it beneficial in the real-world

Phase I

bullFDA Definition Phase 1 includes the initial introduction of an investigational new drug into humans These studies are closely monitored and may be conducted in patients but are usually conducted in healthy volunteer subjects These studies are designed to determine the metabolic and pharmacologic actions of the drug in humans the side effects associated with increasing doses and if possible to gain early evidence on effectiveness During Phase 1 sufficient information about the drugs pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled scientifically valid Phase 2 studies

Phase II

bullFDA Definition Phase 2 includes the early controlled clinical studies

conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition This phase of testing also helps determine the common short-term side effects and risks associated with the drug Phase 2 studies are typically well-controlled closely monitored and conducted in a relatively small number of patients usually involving several hundred people

Clinical Trial Phases

bullNIH Definition PHASE I TRIALS Initial studies to determine the metabolism and pharmacologic actions of drugs in humans the side effects associated with increasing doses and to gain early evidence of effectiveness may include healthy participants andor patients

PHASE II TRIALS Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks

PHASE III TRIALS Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling

Clinical Trial 1bull What question should be answered in first clinical trial

bull Is it safe to administer Is there any biological activity How much should we give

bull Give to small number of humans in a controlled environment (why) and check (side) effects

TGN1412 for RAbull Injected to six volunteers at sub-clinical dose on 13 March 2006 10 min apart in London UK

bull All lsquoimmediatelyrsquo hospitalised six with multi-organ failure due to lsquocytokine stormrsquo 1 ballooned up like lsquothe elephant manrsquo

bull Volunteers given ₤2000 All survived but may have long-term immune system issues

bull The company TeGenero went bankrupt within the year

Dose Levelsbull DL1 usually based on animal data (eg 110th LD50 in

mice)

bull Escalation of doses uses Fibonacci sequence (x2 x167 x15 x133 x133 hellip)

bull Oral medications based on availability of doses (ie if only come in 50 mg pills)

Penel N and Kramar A BMC Med Res Meth 12103 2012

Phase I Cancer (3+3)bull Give to 3 patients

bull If 03 have dose limiting toxicity - escalate

bull If 13 has DLT expand to 3 more patients

bull If 16 has DLT ndash escalate

bull If ge23 or ge26 ndash reached maximum tolerated dose (MTD)

bull DLT serious or life-threatening AE occurring in first cycle ndash not standard

Hansen Graham Pond Siu Phase I Trial Design Is 3+3 the Best Cancer Control 21(3) 2014

DLTsbull Serious or life-threatening AE occurring in first

cycle ndash not standard

bull Grade of AE (1=mild 2 3 4 5=death) Grade 3+

bull Leukemia patients almost all have grade 4 hematological AE

bull Attributable to drug

bull Chronic grade 2 AE (fatigue nausea etc)

Phase I Cancer (3+3)bull Recommended phase II dose is the dose below

MTD

bull Europe MTD=RP2D

bull DEFINE

Phase I Non-cancerbull Give drug to paid volunteers

bull How much would you need to be paid to take a drug with a 33 chance of giving you a seriouslife-threatening AE

bull What is compensation if 33 of volunteers get SAE

bull Luckily most treatments expected to have fewnone AE

Phase I Non-cancerbull How do you measure safetyoutcomes

bull Measure the effects on body (pharmacokinetics pharmacodynamics)

bull Ensure it is within acceptable limits

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Learning Objectives

1 Understand clinical questions of interest

2 Understand statistical questions of interest

3 Understand different phases (12others)

4 Able to discuss designs for early phase clinical trials

My Background (biases)

bullDepartment of Oncology (associate appointment with Clin Epi amp Biostats)

bull13+ years in cancer clinical trials

bullMinimal involvement with other diseases

bullInteraction (questions) are good

Your Background

bullDoes anyone have experience designing an early phase trial

bullHow many have clinical trials experience What sort

bullWho is clinician statistician researcher other

Thought Experiment

bullYou (or collaborator) has new drug which showed astonishing activity in animals lab experiments Ultimately you want to apply for regulatory approval

bullYou need to convince financier to fund you to get to regulatory approval What processes will you use

Standard Drug Development Paradigm

bullPhase I ndash safety Find safe dose

bullPhase II ndash preliminary efficacy Is it active

bullPhase III ndash efficacy Is it superior to standard

bullPhase IV ndash effectiveness Is it beneficial in the real-world

Phase I

bullFDA Definition Phase 1 includes the initial introduction of an investigational new drug into humans These studies are closely monitored and may be conducted in patients but are usually conducted in healthy volunteer subjects These studies are designed to determine the metabolic and pharmacologic actions of the drug in humans the side effects associated with increasing doses and if possible to gain early evidence on effectiveness During Phase 1 sufficient information about the drugs pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled scientifically valid Phase 2 studies

Phase II

bullFDA Definition Phase 2 includes the early controlled clinical studies

conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition This phase of testing also helps determine the common short-term side effects and risks associated with the drug Phase 2 studies are typically well-controlled closely monitored and conducted in a relatively small number of patients usually involving several hundred people

Clinical Trial Phases

bullNIH Definition PHASE I TRIALS Initial studies to determine the metabolism and pharmacologic actions of drugs in humans the side effects associated with increasing doses and to gain early evidence of effectiveness may include healthy participants andor patients

PHASE II TRIALS Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks

PHASE III TRIALS Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling

Clinical Trial 1bull What question should be answered in first clinical trial

bull Is it safe to administer Is there any biological activity How much should we give

bull Give to small number of humans in a controlled environment (why) and check (side) effects

TGN1412 for RAbull Injected to six volunteers at sub-clinical dose on 13 March 2006 10 min apart in London UK

bull All lsquoimmediatelyrsquo hospitalised six with multi-organ failure due to lsquocytokine stormrsquo 1 ballooned up like lsquothe elephant manrsquo

bull Volunteers given ₤2000 All survived but may have long-term immune system issues

bull The company TeGenero went bankrupt within the year

Dose Levelsbull DL1 usually based on animal data (eg 110th LD50 in

mice)

bull Escalation of doses uses Fibonacci sequence (x2 x167 x15 x133 x133 hellip)

bull Oral medications based on availability of doses (ie if only come in 50 mg pills)

Penel N and Kramar A BMC Med Res Meth 12103 2012

Phase I Cancer (3+3)bull Give to 3 patients

bull If 03 have dose limiting toxicity - escalate

bull If 13 has DLT expand to 3 more patients

bull If 16 has DLT ndash escalate

bull If ge23 or ge26 ndash reached maximum tolerated dose (MTD)

bull DLT serious or life-threatening AE occurring in first cycle ndash not standard

Hansen Graham Pond Siu Phase I Trial Design Is 3+3 the Best Cancer Control 21(3) 2014

DLTsbull Serious or life-threatening AE occurring in first

cycle ndash not standard

bull Grade of AE (1=mild 2 3 4 5=death) Grade 3+

bull Leukemia patients almost all have grade 4 hematological AE

bull Attributable to drug

bull Chronic grade 2 AE (fatigue nausea etc)

Phase I Cancer (3+3)bull Recommended phase II dose is the dose below

MTD

bull Europe MTD=RP2D

bull DEFINE

Phase I Non-cancerbull Give drug to paid volunteers

bull How much would you need to be paid to take a drug with a 33 chance of giving you a seriouslife-threatening AE

bull What is compensation if 33 of volunteers get SAE

bull Luckily most treatments expected to have fewnone AE

Phase I Non-cancerbull How do you measure safetyoutcomes

bull Measure the effects on body (pharmacokinetics pharmacodynamics)

bull Ensure it is within acceptable limits

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

My Background (biases)

bullDepartment of Oncology (associate appointment with Clin Epi amp Biostats)

bull13+ years in cancer clinical trials

bullMinimal involvement with other diseases

bullInteraction (questions) are good

Your Background

bullDoes anyone have experience designing an early phase trial

bullHow many have clinical trials experience What sort

bullWho is clinician statistician researcher other

Thought Experiment

bullYou (or collaborator) has new drug which showed astonishing activity in animals lab experiments Ultimately you want to apply for regulatory approval

bullYou need to convince financier to fund you to get to regulatory approval What processes will you use

Standard Drug Development Paradigm

bullPhase I ndash safety Find safe dose

bullPhase II ndash preliminary efficacy Is it active

bullPhase III ndash efficacy Is it superior to standard

bullPhase IV ndash effectiveness Is it beneficial in the real-world

Phase I

bullFDA Definition Phase 1 includes the initial introduction of an investigational new drug into humans These studies are closely monitored and may be conducted in patients but are usually conducted in healthy volunteer subjects These studies are designed to determine the metabolic and pharmacologic actions of the drug in humans the side effects associated with increasing doses and if possible to gain early evidence on effectiveness During Phase 1 sufficient information about the drugs pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled scientifically valid Phase 2 studies

Phase II

bullFDA Definition Phase 2 includes the early controlled clinical studies

conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition This phase of testing also helps determine the common short-term side effects and risks associated with the drug Phase 2 studies are typically well-controlled closely monitored and conducted in a relatively small number of patients usually involving several hundred people

Clinical Trial Phases

bullNIH Definition PHASE I TRIALS Initial studies to determine the metabolism and pharmacologic actions of drugs in humans the side effects associated with increasing doses and to gain early evidence of effectiveness may include healthy participants andor patients

PHASE II TRIALS Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks

PHASE III TRIALS Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling

Clinical Trial 1bull What question should be answered in first clinical trial

bull Is it safe to administer Is there any biological activity How much should we give

bull Give to small number of humans in a controlled environment (why) and check (side) effects

TGN1412 for RAbull Injected to six volunteers at sub-clinical dose on 13 March 2006 10 min apart in London UK

bull All lsquoimmediatelyrsquo hospitalised six with multi-organ failure due to lsquocytokine stormrsquo 1 ballooned up like lsquothe elephant manrsquo

bull Volunteers given ₤2000 All survived but may have long-term immune system issues

bull The company TeGenero went bankrupt within the year

Dose Levelsbull DL1 usually based on animal data (eg 110th LD50 in

mice)

bull Escalation of doses uses Fibonacci sequence (x2 x167 x15 x133 x133 hellip)

bull Oral medications based on availability of doses (ie if only come in 50 mg pills)

Penel N and Kramar A BMC Med Res Meth 12103 2012

Phase I Cancer (3+3)bull Give to 3 patients

bull If 03 have dose limiting toxicity - escalate

bull If 13 has DLT expand to 3 more patients

bull If 16 has DLT ndash escalate

bull If ge23 or ge26 ndash reached maximum tolerated dose (MTD)

bull DLT serious or life-threatening AE occurring in first cycle ndash not standard

Hansen Graham Pond Siu Phase I Trial Design Is 3+3 the Best Cancer Control 21(3) 2014

DLTsbull Serious or life-threatening AE occurring in first

cycle ndash not standard

bull Grade of AE (1=mild 2 3 4 5=death) Grade 3+

bull Leukemia patients almost all have grade 4 hematological AE

bull Attributable to drug

bull Chronic grade 2 AE (fatigue nausea etc)

Phase I Cancer (3+3)bull Recommended phase II dose is the dose below

MTD

bull Europe MTD=RP2D

bull DEFINE

Phase I Non-cancerbull Give drug to paid volunteers

bull How much would you need to be paid to take a drug with a 33 chance of giving you a seriouslife-threatening AE

bull What is compensation if 33 of volunteers get SAE

bull Luckily most treatments expected to have fewnone AE

Phase I Non-cancerbull How do you measure safetyoutcomes

bull Measure the effects on body (pharmacokinetics pharmacodynamics)

bull Ensure it is within acceptable limits

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Your Background

bullDoes anyone have experience designing an early phase trial

bullHow many have clinical trials experience What sort

bullWho is clinician statistician researcher other

Thought Experiment

bullYou (or collaborator) has new drug which showed astonishing activity in animals lab experiments Ultimately you want to apply for regulatory approval

bullYou need to convince financier to fund you to get to regulatory approval What processes will you use

Standard Drug Development Paradigm

bullPhase I ndash safety Find safe dose

bullPhase II ndash preliminary efficacy Is it active

bullPhase III ndash efficacy Is it superior to standard

bullPhase IV ndash effectiveness Is it beneficial in the real-world

Phase I

bullFDA Definition Phase 1 includes the initial introduction of an investigational new drug into humans These studies are closely monitored and may be conducted in patients but are usually conducted in healthy volunteer subjects These studies are designed to determine the metabolic and pharmacologic actions of the drug in humans the side effects associated with increasing doses and if possible to gain early evidence on effectiveness During Phase 1 sufficient information about the drugs pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled scientifically valid Phase 2 studies

Phase II

bullFDA Definition Phase 2 includes the early controlled clinical studies

conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition This phase of testing also helps determine the common short-term side effects and risks associated with the drug Phase 2 studies are typically well-controlled closely monitored and conducted in a relatively small number of patients usually involving several hundred people

Clinical Trial Phases

bullNIH Definition PHASE I TRIALS Initial studies to determine the metabolism and pharmacologic actions of drugs in humans the side effects associated with increasing doses and to gain early evidence of effectiveness may include healthy participants andor patients

PHASE II TRIALS Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks

PHASE III TRIALS Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling

Clinical Trial 1bull What question should be answered in first clinical trial

bull Is it safe to administer Is there any biological activity How much should we give

bull Give to small number of humans in a controlled environment (why) and check (side) effects

TGN1412 for RAbull Injected to six volunteers at sub-clinical dose on 13 March 2006 10 min apart in London UK

bull All lsquoimmediatelyrsquo hospitalised six with multi-organ failure due to lsquocytokine stormrsquo 1 ballooned up like lsquothe elephant manrsquo

bull Volunteers given ₤2000 All survived but may have long-term immune system issues

bull The company TeGenero went bankrupt within the year

Dose Levelsbull DL1 usually based on animal data (eg 110th LD50 in

mice)

bull Escalation of doses uses Fibonacci sequence (x2 x167 x15 x133 x133 hellip)

bull Oral medications based on availability of doses (ie if only come in 50 mg pills)

Penel N and Kramar A BMC Med Res Meth 12103 2012

Phase I Cancer (3+3)bull Give to 3 patients

bull If 03 have dose limiting toxicity - escalate

bull If 13 has DLT expand to 3 more patients

bull If 16 has DLT ndash escalate

bull If ge23 or ge26 ndash reached maximum tolerated dose (MTD)

bull DLT serious or life-threatening AE occurring in first cycle ndash not standard

Hansen Graham Pond Siu Phase I Trial Design Is 3+3 the Best Cancer Control 21(3) 2014

DLTsbull Serious or life-threatening AE occurring in first

cycle ndash not standard

bull Grade of AE (1=mild 2 3 4 5=death) Grade 3+

bull Leukemia patients almost all have grade 4 hematological AE

bull Attributable to drug

bull Chronic grade 2 AE (fatigue nausea etc)

Phase I Cancer (3+3)bull Recommended phase II dose is the dose below

MTD

bull Europe MTD=RP2D

bull DEFINE

Phase I Non-cancerbull Give drug to paid volunteers

bull How much would you need to be paid to take a drug with a 33 chance of giving you a seriouslife-threatening AE

bull What is compensation if 33 of volunteers get SAE

bull Luckily most treatments expected to have fewnone AE

Phase I Non-cancerbull How do you measure safetyoutcomes

bull Measure the effects on body (pharmacokinetics pharmacodynamics)

bull Ensure it is within acceptable limits

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Thought Experiment

bullYou (or collaborator) has new drug which showed astonishing activity in animals lab experiments Ultimately you want to apply for regulatory approval

bullYou need to convince financier to fund you to get to regulatory approval What processes will you use

Standard Drug Development Paradigm

bullPhase I ndash safety Find safe dose

bullPhase II ndash preliminary efficacy Is it active

bullPhase III ndash efficacy Is it superior to standard

bullPhase IV ndash effectiveness Is it beneficial in the real-world

Phase I

bullFDA Definition Phase 1 includes the initial introduction of an investigational new drug into humans These studies are closely monitored and may be conducted in patients but are usually conducted in healthy volunteer subjects These studies are designed to determine the metabolic and pharmacologic actions of the drug in humans the side effects associated with increasing doses and if possible to gain early evidence on effectiveness During Phase 1 sufficient information about the drugs pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled scientifically valid Phase 2 studies

Phase II

bullFDA Definition Phase 2 includes the early controlled clinical studies

conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition This phase of testing also helps determine the common short-term side effects and risks associated with the drug Phase 2 studies are typically well-controlled closely monitored and conducted in a relatively small number of patients usually involving several hundred people

Clinical Trial Phases

bullNIH Definition PHASE I TRIALS Initial studies to determine the metabolism and pharmacologic actions of drugs in humans the side effects associated with increasing doses and to gain early evidence of effectiveness may include healthy participants andor patients

PHASE II TRIALS Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks

PHASE III TRIALS Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling

Clinical Trial 1bull What question should be answered in first clinical trial

bull Is it safe to administer Is there any biological activity How much should we give

bull Give to small number of humans in a controlled environment (why) and check (side) effects

TGN1412 for RAbull Injected to six volunteers at sub-clinical dose on 13 March 2006 10 min apart in London UK

bull All lsquoimmediatelyrsquo hospitalised six with multi-organ failure due to lsquocytokine stormrsquo 1 ballooned up like lsquothe elephant manrsquo

bull Volunteers given ₤2000 All survived but may have long-term immune system issues

bull The company TeGenero went bankrupt within the year

Dose Levelsbull DL1 usually based on animal data (eg 110th LD50 in

mice)

bull Escalation of doses uses Fibonacci sequence (x2 x167 x15 x133 x133 hellip)

bull Oral medications based on availability of doses (ie if only come in 50 mg pills)

Penel N and Kramar A BMC Med Res Meth 12103 2012

Phase I Cancer (3+3)bull Give to 3 patients

bull If 03 have dose limiting toxicity - escalate

bull If 13 has DLT expand to 3 more patients

bull If 16 has DLT ndash escalate

bull If ge23 or ge26 ndash reached maximum tolerated dose (MTD)

bull DLT serious or life-threatening AE occurring in first cycle ndash not standard

Hansen Graham Pond Siu Phase I Trial Design Is 3+3 the Best Cancer Control 21(3) 2014

DLTsbull Serious or life-threatening AE occurring in first

cycle ndash not standard

bull Grade of AE (1=mild 2 3 4 5=death) Grade 3+

bull Leukemia patients almost all have grade 4 hematological AE

bull Attributable to drug

bull Chronic grade 2 AE (fatigue nausea etc)

Phase I Cancer (3+3)bull Recommended phase II dose is the dose below

MTD

bull Europe MTD=RP2D

bull DEFINE

Phase I Non-cancerbull Give drug to paid volunteers

bull How much would you need to be paid to take a drug with a 33 chance of giving you a seriouslife-threatening AE

bull What is compensation if 33 of volunteers get SAE

bull Luckily most treatments expected to have fewnone AE

Phase I Non-cancerbull How do you measure safetyoutcomes

bull Measure the effects on body (pharmacokinetics pharmacodynamics)

bull Ensure it is within acceptable limits

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Standard Drug Development Paradigm

bullPhase I ndash safety Find safe dose

bullPhase II ndash preliminary efficacy Is it active

bullPhase III ndash efficacy Is it superior to standard

bullPhase IV ndash effectiveness Is it beneficial in the real-world

Phase I

bullFDA Definition Phase 1 includes the initial introduction of an investigational new drug into humans These studies are closely monitored and may be conducted in patients but are usually conducted in healthy volunteer subjects These studies are designed to determine the metabolic and pharmacologic actions of the drug in humans the side effects associated with increasing doses and if possible to gain early evidence on effectiveness During Phase 1 sufficient information about the drugs pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled scientifically valid Phase 2 studies

Phase II

bullFDA Definition Phase 2 includes the early controlled clinical studies

conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition This phase of testing also helps determine the common short-term side effects and risks associated with the drug Phase 2 studies are typically well-controlled closely monitored and conducted in a relatively small number of patients usually involving several hundred people

Clinical Trial Phases

bullNIH Definition PHASE I TRIALS Initial studies to determine the metabolism and pharmacologic actions of drugs in humans the side effects associated with increasing doses and to gain early evidence of effectiveness may include healthy participants andor patients

PHASE II TRIALS Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks

PHASE III TRIALS Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling

Clinical Trial 1bull What question should be answered in first clinical trial

bull Is it safe to administer Is there any biological activity How much should we give

bull Give to small number of humans in a controlled environment (why) and check (side) effects

TGN1412 for RAbull Injected to six volunteers at sub-clinical dose on 13 March 2006 10 min apart in London UK

bull All lsquoimmediatelyrsquo hospitalised six with multi-organ failure due to lsquocytokine stormrsquo 1 ballooned up like lsquothe elephant manrsquo

bull Volunteers given ₤2000 All survived but may have long-term immune system issues

bull The company TeGenero went bankrupt within the year

Dose Levelsbull DL1 usually based on animal data (eg 110th LD50 in

mice)

bull Escalation of doses uses Fibonacci sequence (x2 x167 x15 x133 x133 hellip)

bull Oral medications based on availability of doses (ie if only come in 50 mg pills)

Penel N and Kramar A BMC Med Res Meth 12103 2012

Phase I Cancer (3+3)bull Give to 3 patients

bull If 03 have dose limiting toxicity - escalate

bull If 13 has DLT expand to 3 more patients

bull If 16 has DLT ndash escalate

bull If ge23 or ge26 ndash reached maximum tolerated dose (MTD)

bull DLT serious or life-threatening AE occurring in first cycle ndash not standard

Hansen Graham Pond Siu Phase I Trial Design Is 3+3 the Best Cancer Control 21(3) 2014

DLTsbull Serious or life-threatening AE occurring in first

cycle ndash not standard

bull Grade of AE (1=mild 2 3 4 5=death) Grade 3+

bull Leukemia patients almost all have grade 4 hematological AE

bull Attributable to drug

bull Chronic grade 2 AE (fatigue nausea etc)

Phase I Cancer (3+3)bull Recommended phase II dose is the dose below

MTD

bull Europe MTD=RP2D

bull DEFINE

Phase I Non-cancerbull Give drug to paid volunteers

bull How much would you need to be paid to take a drug with a 33 chance of giving you a seriouslife-threatening AE

bull What is compensation if 33 of volunteers get SAE

bull Luckily most treatments expected to have fewnone AE

Phase I Non-cancerbull How do you measure safetyoutcomes

bull Measure the effects on body (pharmacokinetics pharmacodynamics)

bull Ensure it is within acceptable limits

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Phase I

bullFDA Definition Phase 1 includes the initial introduction of an investigational new drug into humans These studies are closely monitored and may be conducted in patients but are usually conducted in healthy volunteer subjects These studies are designed to determine the metabolic and pharmacologic actions of the drug in humans the side effects associated with increasing doses and if possible to gain early evidence on effectiveness During Phase 1 sufficient information about the drugs pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled scientifically valid Phase 2 studies

Phase II

bullFDA Definition Phase 2 includes the early controlled clinical studies

conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition This phase of testing also helps determine the common short-term side effects and risks associated with the drug Phase 2 studies are typically well-controlled closely monitored and conducted in a relatively small number of patients usually involving several hundred people

Clinical Trial Phases

bullNIH Definition PHASE I TRIALS Initial studies to determine the metabolism and pharmacologic actions of drugs in humans the side effects associated with increasing doses and to gain early evidence of effectiveness may include healthy participants andor patients

PHASE II TRIALS Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks

PHASE III TRIALS Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling

Clinical Trial 1bull What question should be answered in first clinical trial

bull Is it safe to administer Is there any biological activity How much should we give

bull Give to small number of humans in a controlled environment (why) and check (side) effects

TGN1412 for RAbull Injected to six volunteers at sub-clinical dose on 13 March 2006 10 min apart in London UK

bull All lsquoimmediatelyrsquo hospitalised six with multi-organ failure due to lsquocytokine stormrsquo 1 ballooned up like lsquothe elephant manrsquo

bull Volunteers given ₤2000 All survived but may have long-term immune system issues

bull The company TeGenero went bankrupt within the year

Dose Levelsbull DL1 usually based on animal data (eg 110th LD50 in

mice)

bull Escalation of doses uses Fibonacci sequence (x2 x167 x15 x133 x133 hellip)

bull Oral medications based on availability of doses (ie if only come in 50 mg pills)

Penel N and Kramar A BMC Med Res Meth 12103 2012

Phase I Cancer (3+3)bull Give to 3 patients

bull If 03 have dose limiting toxicity - escalate

bull If 13 has DLT expand to 3 more patients

bull If 16 has DLT ndash escalate

bull If ge23 or ge26 ndash reached maximum tolerated dose (MTD)

bull DLT serious or life-threatening AE occurring in first cycle ndash not standard

Hansen Graham Pond Siu Phase I Trial Design Is 3+3 the Best Cancer Control 21(3) 2014

DLTsbull Serious or life-threatening AE occurring in first

cycle ndash not standard

bull Grade of AE (1=mild 2 3 4 5=death) Grade 3+

bull Leukemia patients almost all have grade 4 hematological AE

bull Attributable to drug

bull Chronic grade 2 AE (fatigue nausea etc)

Phase I Cancer (3+3)bull Recommended phase II dose is the dose below

MTD

bull Europe MTD=RP2D

bull DEFINE

Phase I Non-cancerbull Give drug to paid volunteers

bull How much would you need to be paid to take a drug with a 33 chance of giving you a seriouslife-threatening AE

bull What is compensation if 33 of volunteers get SAE

bull Luckily most treatments expected to have fewnone AE

Phase I Non-cancerbull How do you measure safetyoutcomes

bull Measure the effects on body (pharmacokinetics pharmacodynamics)

bull Ensure it is within acceptable limits

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Phase II

bullFDA Definition Phase 2 includes the early controlled clinical studies

conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition This phase of testing also helps determine the common short-term side effects and risks associated with the drug Phase 2 studies are typically well-controlled closely monitored and conducted in a relatively small number of patients usually involving several hundred people

Clinical Trial Phases

bullNIH Definition PHASE I TRIALS Initial studies to determine the metabolism and pharmacologic actions of drugs in humans the side effects associated with increasing doses and to gain early evidence of effectiveness may include healthy participants andor patients

PHASE II TRIALS Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks

PHASE III TRIALS Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling

Clinical Trial 1bull What question should be answered in first clinical trial

bull Is it safe to administer Is there any biological activity How much should we give

bull Give to small number of humans in a controlled environment (why) and check (side) effects

TGN1412 for RAbull Injected to six volunteers at sub-clinical dose on 13 March 2006 10 min apart in London UK

bull All lsquoimmediatelyrsquo hospitalised six with multi-organ failure due to lsquocytokine stormrsquo 1 ballooned up like lsquothe elephant manrsquo

bull Volunteers given ₤2000 All survived but may have long-term immune system issues

bull The company TeGenero went bankrupt within the year

Dose Levelsbull DL1 usually based on animal data (eg 110th LD50 in

mice)

bull Escalation of doses uses Fibonacci sequence (x2 x167 x15 x133 x133 hellip)

bull Oral medications based on availability of doses (ie if only come in 50 mg pills)

Penel N and Kramar A BMC Med Res Meth 12103 2012

Phase I Cancer (3+3)bull Give to 3 patients

bull If 03 have dose limiting toxicity - escalate

bull If 13 has DLT expand to 3 more patients

bull If 16 has DLT ndash escalate

bull If ge23 or ge26 ndash reached maximum tolerated dose (MTD)

bull DLT serious or life-threatening AE occurring in first cycle ndash not standard

Hansen Graham Pond Siu Phase I Trial Design Is 3+3 the Best Cancer Control 21(3) 2014

DLTsbull Serious or life-threatening AE occurring in first

cycle ndash not standard

bull Grade of AE (1=mild 2 3 4 5=death) Grade 3+

bull Leukemia patients almost all have grade 4 hematological AE

bull Attributable to drug

bull Chronic grade 2 AE (fatigue nausea etc)

Phase I Cancer (3+3)bull Recommended phase II dose is the dose below

MTD

bull Europe MTD=RP2D

bull DEFINE

Phase I Non-cancerbull Give drug to paid volunteers

bull How much would you need to be paid to take a drug with a 33 chance of giving you a seriouslife-threatening AE

bull What is compensation if 33 of volunteers get SAE

bull Luckily most treatments expected to have fewnone AE

Phase I Non-cancerbull How do you measure safetyoutcomes

bull Measure the effects on body (pharmacokinetics pharmacodynamics)

bull Ensure it is within acceptable limits

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Clinical Trial Phases

bullNIH Definition PHASE I TRIALS Initial studies to determine the metabolism and pharmacologic actions of drugs in humans the side effects associated with increasing doses and to gain early evidence of effectiveness may include healthy participants andor patients

PHASE II TRIALS Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks

PHASE III TRIALS Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling

Clinical Trial 1bull What question should be answered in first clinical trial

bull Is it safe to administer Is there any biological activity How much should we give

bull Give to small number of humans in a controlled environment (why) and check (side) effects

TGN1412 for RAbull Injected to six volunteers at sub-clinical dose on 13 March 2006 10 min apart in London UK

bull All lsquoimmediatelyrsquo hospitalised six with multi-organ failure due to lsquocytokine stormrsquo 1 ballooned up like lsquothe elephant manrsquo

bull Volunteers given ₤2000 All survived but may have long-term immune system issues

bull The company TeGenero went bankrupt within the year

Dose Levelsbull DL1 usually based on animal data (eg 110th LD50 in

mice)

bull Escalation of doses uses Fibonacci sequence (x2 x167 x15 x133 x133 hellip)

bull Oral medications based on availability of doses (ie if only come in 50 mg pills)

Penel N and Kramar A BMC Med Res Meth 12103 2012

Phase I Cancer (3+3)bull Give to 3 patients

bull If 03 have dose limiting toxicity - escalate

bull If 13 has DLT expand to 3 more patients

bull If 16 has DLT ndash escalate

bull If ge23 or ge26 ndash reached maximum tolerated dose (MTD)

bull DLT serious or life-threatening AE occurring in first cycle ndash not standard

Hansen Graham Pond Siu Phase I Trial Design Is 3+3 the Best Cancer Control 21(3) 2014

DLTsbull Serious or life-threatening AE occurring in first

cycle ndash not standard

bull Grade of AE (1=mild 2 3 4 5=death) Grade 3+

bull Leukemia patients almost all have grade 4 hematological AE

bull Attributable to drug

bull Chronic grade 2 AE (fatigue nausea etc)

Phase I Cancer (3+3)bull Recommended phase II dose is the dose below

MTD

bull Europe MTD=RP2D

bull DEFINE

Phase I Non-cancerbull Give drug to paid volunteers

bull How much would you need to be paid to take a drug with a 33 chance of giving you a seriouslife-threatening AE

bull What is compensation if 33 of volunteers get SAE

bull Luckily most treatments expected to have fewnone AE

Phase I Non-cancerbull How do you measure safetyoutcomes

bull Measure the effects on body (pharmacokinetics pharmacodynamics)

bull Ensure it is within acceptable limits

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Clinical Trial 1bull What question should be answered in first clinical trial

bull Is it safe to administer Is there any biological activity How much should we give

bull Give to small number of humans in a controlled environment (why) and check (side) effects

TGN1412 for RAbull Injected to six volunteers at sub-clinical dose on 13 March 2006 10 min apart in London UK

bull All lsquoimmediatelyrsquo hospitalised six with multi-organ failure due to lsquocytokine stormrsquo 1 ballooned up like lsquothe elephant manrsquo

bull Volunteers given ₤2000 All survived but may have long-term immune system issues

bull The company TeGenero went bankrupt within the year

Dose Levelsbull DL1 usually based on animal data (eg 110th LD50 in

mice)

bull Escalation of doses uses Fibonacci sequence (x2 x167 x15 x133 x133 hellip)

bull Oral medications based on availability of doses (ie if only come in 50 mg pills)

Penel N and Kramar A BMC Med Res Meth 12103 2012

Phase I Cancer (3+3)bull Give to 3 patients

bull If 03 have dose limiting toxicity - escalate

bull If 13 has DLT expand to 3 more patients

bull If 16 has DLT ndash escalate

bull If ge23 or ge26 ndash reached maximum tolerated dose (MTD)

bull DLT serious or life-threatening AE occurring in first cycle ndash not standard

Hansen Graham Pond Siu Phase I Trial Design Is 3+3 the Best Cancer Control 21(3) 2014

DLTsbull Serious or life-threatening AE occurring in first

cycle ndash not standard

bull Grade of AE (1=mild 2 3 4 5=death) Grade 3+

bull Leukemia patients almost all have grade 4 hematological AE

bull Attributable to drug

bull Chronic grade 2 AE (fatigue nausea etc)

Phase I Cancer (3+3)bull Recommended phase II dose is the dose below

MTD

bull Europe MTD=RP2D

bull DEFINE

Phase I Non-cancerbull Give drug to paid volunteers

bull How much would you need to be paid to take a drug with a 33 chance of giving you a seriouslife-threatening AE

bull What is compensation if 33 of volunteers get SAE

bull Luckily most treatments expected to have fewnone AE

Phase I Non-cancerbull How do you measure safetyoutcomes

bull Measure the effects on body (pharmacokinetics pharmacodynamics)

bull Ensure it is within acceptable limits

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

TGN1412 for RAbull Injected to six volunteers at sub-clinical dose on 13 March 2006 10 min apart in London UK

bull All lsquoimmediatelyrsquo hospitalised six with multi-organ failure due to lsquocytokine stormrsquo 1 ballooned up like lsquothe elephant manrsquo

bull Volunteers given ₤2000 All survived but may have long-term immune system issues

bull The company TeGenero went bankrupt within the year

Dose Levelsbull DL1 usually based on animal data (eg 110th LD50 in

mice)

bull Escalation of doses uses Fibonacci sequence (x2 x167 x15 x133 x133 hellip)

bull Oral medications based on availability of doses (ie if only come in 50 mg pills)

Penel N and Kramar A BMC Med Res Meth 12103 2012

Phase I Cancer (3+3)bull Give to 3 patients

bull If 03 have dose limiting toxicity - escalate

bull If 13 has DLT expand to 3 more patients

bull If 16 has DLT ndash escalate

bull If ge23 or ge26 ndash reached maximum tolerated dose (MTD)

bull DLT serious or life-threatening AE occurring in first cycle ndash not standard

Hansen Graham Pond Siu Phase I Trial Design Is 3+3 the Best Cancer Control 21(3) 2014

DLTsbull Serious or life-threatening AE occurring in first

cycle ndash not standard

bull Grade of AE (1=mild 2 3 4 5=death) Grade 3+

bull Leukemia patients almost all have grade 4 hematological AE

bull Attributable to drug

bull Chronic grade 2 AE (fatigue nausea etc)

Phase I Cancer (3+3)bull Recommended phase II dose is the dose below

MTD

bull Europe MTD=RP2D

bull DEFINE

Phase I Non-cancerbull Give drug to paid volunteers

bull How much would you need to be paid to take a drug with a 33 chance of giving you a seriouslife-threatening AE

bull What is compensation if 33 of volunteers get SAE

bull Luckily most treatments expected to have fewnone AE

Phase I Non-cancerbull How do you measure safetyoutcomes

bull Measure the effects on body (pharmacokinetics pharmacodynamics)

bull Ensure it is within acceptable limits

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Dose Levelsbull DL1 usually based on animal data (eg 110th LD50 in

mice)

bull Escalation of doses uses Fibonacci sequence (x2 x167 x15 x133 x133 hellip)

bull Oral medications based on availability of doses (ie if only come in 50 mg pills)

Penel N and Kramar A BMC Med Res Meth 12103 2012

Phase I Cancer (3+3)bull Give to 3 patients

bull If 03 have dose limiting toxicity - escalate

bull If 13 has DLT expand to 3 more patients

bull If 16 has DLT ndash escalate

bull If ge23 or ge26 ndash reached maximum tolerated dose (MTD)

bull DLT serious or life-threatening AE occurring in first cycle ndash not standard

Hansen Graham Pond Siu Phase I Trial Design Is 3+3 the Best Cancer Control 21(3) 2014

DLTsbull Serious or life-threatening AE occurring in first

cycle ndash not standard

bull Grade of AE (1=mild 2 3 4 5=death) Grade 3+

bull Leukemia patients almost all have grade 4 hematological AE

bull Attributable to drug

bull Chronic grade 2 AE (fatigue nausea etc)

Phase I Cancer (3+3)bull Recommended phase II dose is the dose below

MTD

bull Europe MTD=RP2D

bull DEFINE

Phase I Non-cancerbull Give drug to paid volunteers

bull How much would you need to be paid to take a drug with a 33 chance of giving you a seriouslife-threatening AE

bull What is compensation if 33 of volunteers get SAE

bull Luckily most treatments expected to have fewnone AE

Phase I Non-cancerbull How do you measure safetyoutcomes

bull Measure the effects on body (pharmacokinetics pharmacodynamics)

bull Ensure it is within acceptable limits

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Phase I Cancer (3+3)bull Give to 3 patients

bull If 03 have dose limiting toxicity - escalate

bull If 13 has DLT expand to 3 more patients

bull If 16 has DLT ndash escalate

bull If ge23 or ge26 ndash reached maximum tolerated dose (MTD)

bull DLT serious or life-threatening AE occurring in first cycle ndash not standard

Hansen Graham Pond Siu Phase I Trial Design Is 3+3 the Best Cancer Control 21(3) 2014

DLTsbull Serious or life-threatening AE occurring in first

cycle ndash not standard

bull Grade of AE (1=mild 2 3 4 5=death) Grade 3+

bull Leukemia patients almost all have grade 4 hematological AE

bull Attributable to drug

bull Chronic grade 2 AE (fatigue nausea etc)

Phase I Cancer (3+3)bull Recommended phase II dose is the dose below

MTD

bull Europe MTD=RP2D

bull DEFINE

Phase I Non-cancerbull Give drug to paid volunteers

bull How much would you need to be paid to take a drug with a 33 chance of giving you a seriouslife-threatening AE

bull What is compensation if 33 of volunteers get SAE

bull Luckily most treatments expected to have fewnone AE

Phase I Non-cancerbull How do you measure safetyoutcomes

bull Measure the effects on body (pharmacokinetics pharmacodynamics)

bull Ensure it is within acceptable limits

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

DLTsbull Serious or life-threatening AE occurring in first

cycle ndash not standard

bull Grade of AE (1=mild 2 3 4 5=death) Grade 3+

bull Leukemia patients almost all have grade 4 hematological AE

bull Attributable to drug

bull Chronic grade 2 AE (fatigue nausea etc)

Phase I Cancer (3+3)bull Recommended phase II dose is the dose below

MTD

bull Europe MTD=RP2D

bull DEFINE

Phase I Non-cancerbull Give drug to paid volunteers

bull How much would you need to be paid to take a drug with a 33 chance of giving you a seriouslife-threatening AE

bull What is compensation if 33 of volunteers get SAE

bull Luckily most treatments expected to have fewnone AE

Phase I Non-cancerbull How do you measure safetyoutcomes

bull Measure the effects on body (pharmacokinetics pharmacodynamics)

bull Ensure it is within acceptable limits

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Phase I Cancer (3+3)bull Recommended phase II dose is the dose below

MTD

bull Europe MTD=RP2D

bull DEFINE

Phase I Non-cancerbull Give drug to paid volunteers

bull How much would you need to be paid to take a drug with a 33 chance of giving you a seriouslife-threatening AE

bull What is compensation if 33 of volunteers get SAE

bull Luckily most treatments expected to have fewnone AE

Phase I Non-cancerbull How do you measure safetyoutcomes

bull Measure the effects on body (pharmacokinetics pharmacodynamics)

bull Ensure it is within acceptable limits

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Phase I Non-cancerbull Give drug to paid volunteers

bull How much would you need to be paid to take a drug with a 33 chance of giving you a seriouslife-threatening AE

bull What is compensation if 33 of volunteers get SAE

bull Luckily most treatments expected to have fewnone AE

Phase I Non-cancerbull How do you measure safetyoutcomes

bull Measure the effects on body (pharmacokinetics pharmacodynamics)

bull Ensure it is within acceptable limits

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Phase I Non-cancerbull How do you measure safetyoutcomes

bull Measure the effects on body (pharmacokinetics pharmacodynamics)

bull Ensure it is within acceptable limits

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Phase I Non-cancerbull Statistical tests on differences in variability

bull Differences in mean less important (why)

bull How do you define sample size

bull Often want to ensure biodistribution

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Cancer Phase I Ethicsbull Often start lsquotoo lowrsquo for safety reasons

bull Suboptimal dose reduces chance of response

bull Phase I response rates quoted as ~5

bull Patients do not enter these trials altruistically

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Ethicsbull Should you allow intrapatient dose escalation

bull Chance of response for patient

bull How to evaluate late AE

bull How likely is it for a patient with worsening disease to stay on treatment for gt2 cycles

bull Generally No

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Ethicsbull Average patient survival may be a few months

bull What if drug requires weekly IV injections

bull How to assess long-term toxicities

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Correct RP2Dbull Too low reduced chance of efficacy in later

trials

bull Too high excess toxicity dose reductions

bull Based on 3+3=6 patients

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

httpjoneslabchemwsuedu

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Modified Designsbull Rapid early escalation and intra-patient

escalation permitted

bull 1 pt dose level until grade 2 AE then 3+3

bull Reduce of patients in trial (slightly) at suboptimal dose More likely to give patients too toxic dose

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Model-Based Designsbull lsquoRecentrsquo innovation

bull Specify dose-toxicity relationship

bull Update based on data

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Example dose-toxicity curve

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Othersbull EWOC ndash curve based on probability of

observing a SAE

bull TITE-CRM ndash time to event CRM

bull Mixed effects proportional odds model ndash odds of severe toxicity per cycle

bull Some gain in assessing accurate dose May use more patients (pre-define limit on sample size)

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Hansen AR1 Graham DM Pond GR Siu LL Phase 1 trial design is 3 + 3 the best Cancer Control 2014 Jul21(3)200-8

Secondary Outcomesbull Small numbers of patients

bull Want correlative (pKpDbiological effects)

bull Patients receive different doses

bull Many correlative outcomes are binaryordinal

bull Consider costbenefit

Secondary Outcomesbull Does biology change pre- to post-treatment

bull Is patient healthy enough post-treatment

bull Ethics of paired biopsies

bull What is accuracy of assay

Howeverhellipbull Some argue no reason to pursue development

of new drug if no marker of target

bull Molecularly targeted agents

bull Drug A targets marker X highly prevalent in cancer

bull If patient does not express X then drug useless

Targeted Agentsbull If 80 of patients with X respond but only

10 of patients have X and 0 of patients without X respond SOC is 5 response

bull Phase III RCT needs gt2250 patients without accurate assay

bull Phase III RCT needs 16 lsquoenrichedrsquo patients with accurate assay

bull Regulatory bodies asking for proof of mechanisms of action

Phase IIbull Is there any evidence of activity

bull Might this agent be potentially useful

bull Do not want to test if drug is lsquobetterrsquo than standard treatment (why not)

bull Proof of principle

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

Phase II non-cancerbull Compare efficacy ndash often of a surrogate

outcome

bull Small randomised trial

bull Does blood pressure go down ndash surrogate for MI

bull Do MS patients improve activity levels walk ndash long-term abilities

Placebo

5 mg

20 mg

10 mg

50 mg

R

Phase II non-cancerbull Size ndash few hundred

bull Multiple comparison adjustments

bull α=005 β=080

Phase II non-cancerbull Select optimal dose regimen

bull Highest dose may be unsafe not tolerable

bull Ideally want dose-response relationship

Phase II non-cancerbull Trial design standard statistical analyses

bull T-tests χ2 tests Wilcoxon rank-sum Fisherrsquos exact tests

bull Estimation of differences also important

bull Some subgroup analyses performed though power is small ndash pre-define

Phase II non-cancerbull Secondary outcomes safety tolerability

treatment completion rate

bull Preliminary evidence of OS (or phase III outcome)

bull Use for designing phase III trial

Phase II Cancerbull Placebo generally considered unethical

bull Any disease which is terminal or requires intervention of some sort (schizophrenia HIV)

bull Best supportive care may be given for palliation

Phase II Cancerbull How would you measure if there is lsquoany

evidence of activityrsquo

bull Most cancer drugs historically fail and have substantial side effects

bull Remember 33 have seriouslife-threatening AE in 1st 28 days alone and ~5 respond at all

bull Thoughts

Phase II Cancerbull Give to small numbers of patients (single-arm)

bull If anyone responds =gt evidence of activity

bull Add a few more patients and estimate RR

bull Gehan - 1960

Phase II Cancerbull Two stages formalize based on α and β

(Fleming 1982)

bull Optimal designs (Simon 1989)

bull Assuming drug is ineffective what is minimum number of patients needed

bull Reduces total sample size across all trials

Design Issuesbull Some advances ndash some patients respond to std

bull Ethically can not give novel therapy with less chance of response

bull Novel therapies designed not to shrink tumour but only prevent it from growing

bull How to proceed

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Secondary Outcomesbull Does biology change pre- to post-treatment

bull Is patient healthy enough post-treatment

bull Ethics of paired biopsies

bull What is accuracy of assay

Howeverhellipbull Some argue no reason to pursue development

of new drug if no marker of target

bull Molecularly targeted agents

bull Drug A targets marker X highly prevalent in cancer

bull If patient does not express X then drug useless

Targeted Agentsbull If 80 of patients with X respond but only

10 of patients have X and 0 of patients without X respond SOC is 5 response

bull Phase III RCT needs gt2250 patients without accurate assay

bull Phase III RCT needs 16 lsquoenrichedrsquo patients with accurate assay

bull Regulatory bodies asking for proof of mechanisms of action

Phase IIbull Is there any evidence of activity

bull Might this agent be potentially useful

bull Do not want to test if drug is lsquobetterrsquo than standard treatment (why not)

bull Proof of principle

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

Phase II non-cancerbull Compare efficacy ndash often of a surrogate

outcome

bull Small randomised trial

bull Does blood pressure go down ndash surrogate for MI

bull Do MS patients improve activity levels walk ndash long-term abilities

Placebo

5 mg

20 mg

10 mg

50 mg

R

Phase II non-cancerbull Size ndash few hundred

bull Multiple comparison adjustments

bull α=005 β=080

Phase II non-cancerbull Select optimal dose regimen

bull Highest dose may be unsafe not tolerable

bull Ideally want dose-response relationship

Phase II non-cancerbull Trial design standard statistical analyses

bull T-tests χ2 tests Wilcoxon rank-sum Fisherrsquos exact tests

bull Estimation of differences also important

bull Some subgroup analyses performed though power is small ndash pre-define

Phase II non-cancerbull Secondary outcomes safety tolerability

treatment completion rate

bull Preliminary evidence of OS (or phase III outcome)

bull Use for designing phase III trial

Phase II Cancerbull Placebo generally considered unethical

bull Any disease which is terminal or requires intervention of some sort (schizophrenia HIV)

bull Best supportive care may be given for palliation

Phase II Cancerbull How would you measure if there is lsquoany

evidence of activityrsquo

bull Most cancer drugs historically fail and have substantial side effects

bull Remember 33 have seriouslife-threatening AE in 1st 28 days alone and ~5 respond at all

bull Thoughts

Phase II Cancerbull Give to small numbers of patients (single-arm)

bull If anyone responds =gt evidence of activity

bull Add a few more patients and estimate RR

bull Gehan - 1960

Phase II Cancerbull Two stages formalize based on α and β

(Fleming 1982)

bull Optimal designs (Simon 1989)

bull Assuming drug is ineffective what is minimum number of patients needed

bull Reduces total sample size across all trials

Design Issuesbull Some advances ndash some patients respond to std

bull Ethically can not give novel therapy with less chance of response

bull Novel therapies designed not to shrink tumour but only prevent it from growing

bull How to proceed

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Howeverhellipbull Some argue no reason to pursue development

of new drug if no marker of target

bull Molecularly targeted agents

bull Drug A targets marker X highly prevalent in cancer

bull If patient does not express X then drug useless

Targeted Agentsbull If 80 of patients with X respond but only

10 of patients have X and 0 of patients without X respond SOC is 5 response

bull Phase III RCT needs gt2250 patients without accurate assay

bull Phase III RCT needs 16 lsquoenrichedrsquo patients with accurate assay

bull Regulatory bodies asking for proof of mechanisms of action

Phase IIbull Is there any evidence of activity

bull Might this agent be potentially useful

bull Do not want to test if drug is lsquobetterrsquo than standard treatment (why not)

bull Proof of principle

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

Phase II non-cancerbull Compare efficacy ndash often of a surrogate

outcome

bull Small randomised trial

bull Does blood pressure go down ndash surrogate for MI

bull Do MS patients improve activity levels walk ndash long-term abilities

Placebo

5 mg

20 mg

10 mg

50 mg

R

Phase II non-cancerbull Size ndash few hundred

bull Multiple comparison adjustments

bull α=005 β=080

Phase II non-cancerbull Select optimal dose regimen

bull Highest dose may be unsafe not tolerable

bull Ideally want dose-response relationship

Phase II non-cancerbull Trial design standard statistical analyses

bull T-tests χ2 tests Wilcoxon rank-sum Fisherrsquos exact tests

bull Estimation of differences also important

bull Some subgroup analyses performed though power is small ndash pre-define

Phase II non-cancerbull Secondary outcomes safety tolerability

treatment completion rate

bull Preliminary evidence of OS (or phase III outcome)

bull Use for designing phase III trial

Phase II Cancerbull Placebo generally considered unethical

bull Any disease which is terminal or requires intervention of some sort (schizophrenia HIV)

bull Best supportive care may be given for palliation

Phase II Cancerbull How would you measure if there is lsquoany

evidence of activityrsquo

bull Most cancer drugs historically fail and have substantial side effects

bull Remember 33 have seriouslife-threatening AE in 1st 28 days alone and ~5 respond at all

bull Thoughts

Phase II Cancerbull Give to small numbers of patients (single-arm)

bull If anyone responds =gt evidence of activity

bull Add a few more patients and estimate RR

bull Gehan - 1960

Phase II Cancerbull Two stages formalize based on α and β

(Fleming 1982)

bull Optimal designs (Simon 1989)

bull Assuming drug is ineffective what is minimum number of patients needed

bull Reduces total sample size across all trials

Design Issuesbull Some advances ndash some patients respond to std

bull Ethically can not give novel therapy with less chance of response

bull Novel therapies designed not to shrink tumour but only prevent it from growing

bull How to proceed

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Targeted Agentsbull If 80 of patients with X respond but only

10 of patients have X and 0 of patients without X respond SOC is 5 response

bull Phase III RCT needs gt2250 patients without accurate assay

bull Phase III RCT needs 16 lsquoenrichedrsquo patients with accurate assay

bull Regulatory bodies asking for proof of mechanisms of action

Phase IIbull Is there any evidence of activity

bull Might this agent be potentially useful

bull Do not want to test if drug is lsquobetterrsquo than standard treatment (why not)

bull Proof of principle

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

Phase II non-cancerbull Compare efficacy ndash often of a surrogate

outcome

bull Small randomised trial

bull Does blood pressure go down ndash surrogate for MI

bull Do MS patients improve activity levels walk ndash long-term abilities

Placebo

5 mg

20 mg

10 mg

50 mg

R

Phase II non-cancerbull Size ndash few hundred

bull Multiple comparison adjustments

bull α=005 β=080

Phase II non-cancerbull Select optimal dose regimen

bull Highest dose may be unsafe not tolerable

bull Ideally want dose-response relationship

Phase II non-cancerbull Trial design standard statistical analyses

bull T-tests χ2 tests Wilcoxon rank-sum Fisherrsquos exact tests

bull Estimation of differences also important

bull Some subgroup analyses performed though power is small ndash pre-define

Phase II non-cancerbull Secondary outcomes safety tolerability

treatment completion rate

bull Preliminary evidence of OS (or phase III outcome)

bull Use for designing phase III trial

Phase II Cancerbull Placebo generally considered unethical

bull Any disease which is terminal or requires intervention of some sort (schizophrenia HIV)

bull Best supportive care may be given for palliation

Phase II Cancerbull How would you measure if there is lsquoany

evidence of activityrsquo

bull Most cancer drugs historically fail and have substantial side effects

bull Remember 33 have seriouslife-threatening AE in 1st 28 days alone and ~5 respond at all

bull Thoughts

Phase II Cancerbull Give to small numbers of patients (single-arm)

bull If anyone responds =gt evidence of activity

bull Add a few more patients and estimate RR

bull Gehan - 1960

Phase II Cancerbull Two stages formalize based on α and β

(Fleming 1982)

bull Optimal designs (Simon 1989)

bull Assuming drug is ineffective what is minimum number of patients needed

bull Reduces total sample size across all trials

Design Issuesbull Some advances ndash some patients respond to std

bull Ethically can not give novel therapy with less chance of response

bull Novel therapies designed not to shrink tumour but only prevent it from growing

bull How to proceed

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Phase IIbull Is there any evidence of activity

bull Might this agent be potentially useful

bull Do not want to test if drug is lsquobetterrsquo than standard treatment (why not)

bull Proof of principle

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

Phase II non-cancerbull Compare efficacy ndash often of a surrogate

outcome

bull Small randomised trial

bull Does blood pressure go down ndash surrogate for MI

bull Do MS patients improve activity levels walk ndash long-term abilities

Placebo

5 mg

20 mg

10 mg

50 mg

R

Phase II non-cancerbull Size ndash few hundred

bull Multiple comparison adjustments

bull α=005 β=080

Phase II non-cancerbull Select optimal dose regimen

bull Highest dose may be unsafe not tolerable

bull Ideally want dose-response relationship

Phase II non-cancerbull Trial design standard statistical analyses

bull T-tests χ2 tests Wilcoxon rank-sum Fisherrsquos exact tests

bull Estimation of differences also important

bull Some subgroup analyses performed though power is small ndash pre-define

Phase II non-cancerbull Secondary outcomes safety tolerability

treatment completion rate

bull Preliminary evidence of OS (or phase III outcome)

bull Use for designing phase III trial

Phase II Cancerbull Placebo generally considered unethical

bull Any disease which is terminal or requires intervention of some sort (schizophrenia HIV)

bull Best supportive care may be given for palliation

Phase II Cancerbull How would you measure if there is lsquoany

evidence of activityrsquo

bull Most cancer drugs historically fail and have substantial side effects

bull Remember 33 have seriouslife-threatening AE in 1st 28 days alone and ~5 respond at all

bull Thoughts

Phase II Cancerbull Give to small numbers of patients (single-arm)

bull If anyone responds =gt evidence of activity

bull Add a few more patients and estimate RR

bull Gehan - 1960

Phase II Cancerbull Two stages formalize based on α and β

(Fleming 1982)

bull Optimal designs (Simon 1989)

bull Assuming drug is ineffective what is minimum number of patients needed

bull Reduces total sample size across all trials

Design Issuesbull Some advances ndash some patients respond to std

bull Ethically can not give novel therapy with less chance of response

bull Novel therapies designed not to shrink tumour but only prevent it from growing

bull How to proceed

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms by pharmaceutical sales (2005) by period during which compound first entered clinical testing

DiMasi J A and Grabowski H G JCO 200725209-216 copy2007 by American Society of Clinical Oncology

Phase II non-cancerbull Compare efficacy ndash often of a surrogate

outcome

bull Small randomised trial

bull Does blood pressure go down ndash surrogate for MI

bull Do MS patients improve activity levels walk ndash long-term abilities

Placebo

5 mg

20 mg

10 mg

50 mg

R

Phase II non-cancerbull Size ndash few hundred

bull Multiple comparison adjustments

bull α=005 β=080

Phase II non-cancerbull Select optimal dose regimen

bull Highest dose may be unsafe not tolerable

bull Ideally want dose-response relationship

Phase II non-cancerbull Trial design standard statistical analyses

bull T-tests χ2 tests Wilcoxon rank-sum Fisherrsquos exact tests

bull Estimation of differences also important

bull Some subgroup analyses performed though power is small ndash pre-define

Phase II non-cancerbull Secondary outcomes safety tolerability

treatment completion rate

bull Preliminary evidence of OS (or phase III outcome)

bull Use for designing phase III trial

Phase II Cancerbull Placebo generally considered unethical

bull Any disease which is terminal or requires intervention of some sort (schizophrenia HIV)

bull Best supportive care may be given for palliation

Phase II Cancerbull How would you measure if there is lsquoany

evidence of activityrsquo

bull Most cancer drugs historically fail and have substantial side effects

bull Remember 33 have seriouslife-threatening AE in 1st 28 days alone and ~5 respond at all

bull Thoughts

Phase II Cancerbull Give to small numbers of patients (single-arm)

bull If anyone responds =gt evidence of activity

bull Add a few more patients and estimate RR

bull Gehan - 1960

Phase II Cancerbull Two stages formalize based on α and β

(Fleming 1982)

bull Optimal designs (Simon 1989)

bull Assuming drug is ineffective what is minimum number of patients needed

bull Reduces total sample size across all trials

Design Issuesbull Some advances ndash some patients respond to std

bull Ethically can not give novel therapy with less chance of response

bull Novel therapies designed not to shrink tumour but only prevent it from growing

bull How to proceed

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Phase II non-cancerbull Compare efficacy ndash often of a surrogate

outcome

bull Small randomised trial

bull Does blood pressure go down ndash surrogate for MI

bull Do MS patients improve activity levels walk ndash long-term abilities

Placebo

5 mg

20 mg

10 mg

50 mg

R

Phase II non-cancerbull Size ndash few hundred

bull Multiple comparison adjustments

bull α=005 β=080

Phase II non-cancerbull Select optimal dose regimen

bull Highest dose may be unsafe not tolerable

bull Ideally want dose-response relationship

Phase II non-cancerbull Trial design standard statistical analyses

bull T-tests χ2 tests Wilcoxon rank-sum Fisherrsquos exact tests

bull Estimation of differences also important

bull Some subgroup analyses performed though power is small ndash pre-define

Phase II non-cancerbull Secondary outcomes safety tolerability

treatment completion rate

bull Preliminary evidence of OS (or phase III outcome)

bull Use for designing phase III trial

Phase II Cancerbull Placebo generally considered unethical

bull Any disease which is terminal or requires intervention of some sort (schizophrenia HIV)

bull Best supportive care may be given for palliation

Phase II Cancerbull How would you measure if there is lsquoany

evidence of activityrsquo

bull Most cancer drugs historically fail and have substantial side effects

bull Remember 33 have seriouslife-threatening AE in 1st 28 days alone and ~5 respond at all

bull Thoughts

Phase II Cancerbull Give to small numbers of patients (single-arm)

bull If anyone responds =gt evidence of activity

bull Add a few more patients and estimate RR

bull Gehan - 1960

Phase II Cancerbull Two stages formalize based on α and β

(Fleming 1982)

bull Optimal designs (Simon 1989)

bull Assuming drug is ineffective what is minimum number of patients needed

bull Reduces total sample size across all trials

Design Issuesbull Some advances ndash some patients respond to std

bull Ethically can not give novel therapy with less chance of response

bull Novel therapies designed not to shrink tumour but only prevent it from growing

bull How to proceed

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Placebo

5 mg

20 mg

10 mg

50 mg

R

Phase II non-cancerbull Size ndash few hundred

bull Multiple comparison adjustments

bull α=005 β=080

Phase II non-cancerbull Select optimal dose regimen

bull Highest dose may be unsafe not tolerable

bull Ideally want dose-response relationship

Phase II non-cancerbull Trial design standard statistical analyses

bull T-tests χ2 tests Wilcoxon rank-sum Fisherrsquos exact tests

bull Estimation of differences also important

bull Some subgroup analyses performed though power is small ndash pre-define

Phase II non-cancerbull Secondary outcomes safety tolerability

treatment completion rate

bull Preliminary evidence of OS (or phase III outcome)

bull Use for designing phase III trial

Phase II Cancerbull Placebo generally considered unethical

bull Any disease which is terminal or requires intervention of some sort (schizophrenia HIV)

bull Best supportive care may be given for palliation

Phase II Cancerbull How would you measure if there is lsquoany

evidence of activityrsquo

bull Most cancer drugs historically fail and have substantial side effects

bull Remember 33 have seriouslife-threatening AE in 1st 28 days alone and ~5 respond at all

bull Thoughts

Phase II Cancerbull Give to small numbers of patients (single-arm)

bull If anyone responds =gt evidence of activity

bull Add a few more patients and estimate RR

bull Gehan - 1960

Phase II Cancerbull Two stages formalize based on α and β

(Fleming 1982)

bull Optimal designs (Simon 1989)

bull Assuming drug is ineffective what is minimum number of patients needed

bull Reduces total sample size across all trials

Design Issuesbull Some advances ndash some patients respond to std

bull Ethically can not give novel therapy with less chance of response

bull Novel therapies designed not to shrink tumour but only prevent it from growing

bull How to proceed

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Phase II non-cancerbull Size ndash few hundred

bull Multiple comparison adjustments

bull α=005 β=080

Phase II non-cancerbull Select optimal dose regimen

bull Highest dose may be unsafe not tolerable

bull Ideally want dose-response relationship

Phase II non-cancerbull Trial design standard statistical analyses

bull T-tests χ2 tests Wilcoxon rank-sum Fisherrsquos exact tests

bull Estimation of differences also important

bull Some subgroup analyses performed though power is small ndash pre-define

Phase II non-cancerbull Secondary outcomes safety tolerability

treatment completion rate

bull Preliminary evidence of OS (or phase III outcome)

bull Use for designing phase III trial

Phase II Cancerbull Placebo generally considered unethical

bull Any disease which is terminal or requires intervention of some sort (schizophrenia HIV)

bull Best supportive care may be given for palliation

Phase II Cancerbull How would you measure if there is lsquoany

evidence of activityrsquo

bull Most cancer drugs historically fail and have substantial side effects

bull Remember 33 have seriouslife-threatening AE in 1st 28 days alone and ~5 respond at all

bull Thoughts

Phase II Cancerbull Give to small numbers of patients (single-arm)

bull If anyone responds =gt evidence of activity

bull Add a few more patients and estimate RR

bull Gehan - 1960

Phase II Cancerbull Two stages formalize based on α and β

(Fleming 1982)

bull Optimal designs (Simon 1989)

bull Assuming drug is ineffective what is minimum number of patients needed

bull Reduces total sample size across all trials

Design Issuesbull Some advances ndash some patients respond to std

bull Ethically can not give novel therapy with less chance of response

bull Novel therapies designed not to shrink tumour but only prevent it from growing

bull How to proceed

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Phase II non-cancerbull Select optimal dose regimen

bull Highest dose may be unsafe not tolerable

bull Ideally want dose-response relationship

Phase II non-cancerbull Trial design standard statistical analyses

bull T-tests χ2 tests Wilcoxon rank-sum Fisherrsquos exact tests

bull Estimation of differences also important

bull Some subgroup analyses performed though power is small ndash pre-define

Phase II non-cancerbull Secondary outcomes safety tolerability

treatment completion rate

bull Preliminary evidence of OS (or phase III outcome)

bull Use for designing phase III trial

Phase II Cancerbull Placebo generally considered unethical

bull Any disease which is terminal or requires intervention of some sort (schizophrenia HIV)

bull Best supportive care may be given for palliation

Phase II Cancerbull How would you measure if there is lsquoany

evidence of activityrsquo

bull Most cancer drugs historically fail and have substantial side effects

bull Remember 33 have seriouslife-threatening AE in 1st 28 days alone and ~5 respond at all

bull Thoughts

Phase II Cancerbull Give to small numbers of patients (single-arm)

bull If anyone responds =gt evidence of activity

bull Add a few more patients and estimate RR

bull Gehan - 1960

Phase II Cancerbull Two stages formalize based on α and β

(Fleming 1982)

bull Optimal designs (Simon 1989)

bull Assuming drug is ineffective what is minimum number of patients needed

bull Reduces total sample size across all trials

Design Issuesbull Some advances ndash some patients respond to std

bull Ethically can not give novel therapy with less chance of response

bull Novel therapies designed not to shrink tumour but only prevent it from growing

bull How to proceed

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Phase II non-cancerbull Trial design standard statistical analyses

bull T-tests χ2 tests Wilcoxon rank-sum Fisherrsquos exact tests

bull Estimation of differences also important

bull Some subgroup analyses performed though power is small ndash pre-define

Phase II non-cancerbull Secondary outcomes safety tolerability

treatment completion rate

bull Preliminary evidence of OS (or phase III outcome)

bull Use for designing phase III trial

Phase II Cancerbull Placebo generally considered unethical

bull Any disease which is terminal or requires intervention of some sort (schizophrenia HIV)

bull Best supportive care may be given for palliation

Phase II Cancerbull How would you measure if there is lsquoany

evidence of activityrsquo

bull Most cancer drugs historically fail and have substantial side effects

bull Remember 33 have seriouslife-threatening AE in 1st 28 days alone and ~5 respond at all

bull Thoughts

Phase II Cancerbull Give to small numbers of patients (single-arm)

bull If anyone responds =gt evidence of activity

bull Add a few more patients and estimate RR

bull Gehan - 1960

Phase II Cancerbull Two stages formalize based on α and β

(Fleming 1982)

bull Optimal designs (Simon 1989)

bull Assuming drug is ineffective what is minimum number of patients needed

bull Reduces total sample size across all trials

Design Issuesbull Some advances ndash some patients respond to std

bull Ethically can not give novel therapy with less chance of response

bull Novel therapies designed not to shrink tumour but only prevent it from growing

bull How to proceed

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Phase II non-cancerbull Secondary outcomes safety tolerability

treatment completion rate

bull Preliminary evidence of OS (or phase III outcome)

bull Use for designing phase III trial

Phase II Cancerbull Placebo generally considered unethical

bull Any disease which is terminal or requires intervention of some sort (schizophrenia HIV)

bull Best supportive care may be given for palliation

Phase II Cancerbull How would you measure if there is lsquoany

evidence of activityrsquo

bull Most cancer drugs historically fail and have substantial side effects

bull Remember 33 have seriouslife-threatening AE in 1st 28 days alone and ~5 respond at all

bull Thoughts

Phase II Cancerbull Give to small numbers of patients (single-arm)

bull If anyone responds =gt evidence of activity

bull Add a few more patients and estimate RR

bull Gehan - 1960

Phase II Cancerbull Two stages formalize based on α and β

(Fleming 1982)

bull Optimal designs (Simon 1989)

bull Assuming drug is ineffective what is minimum number of patients needed

bull Reduces total sample size across all trials

Design Issuesbull Some advances ndash some patients respond to std

bull Ethically can not give novel therapy with less chance of response

bull Novel therapies designed not to shrink tumour but only prevent it from growing

bull How to proceed

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Phase II Cancerbull Placebo generally considered unethical

bull Any disease which is terminal or requires intervention of some sort (schizophrenia HIV)

bull Best supportive care may be given for palliation

Phase II Cancerbull How would you measure if there is lsquoany

evidence of activityrsquo

bull Most cancer drugs historically fail and have substantial side effects

bull Remember 33 have seriouslife-threatening AE in 1st 28 days alone and ~5 respond at all

bull Thoughts

Phase II Cancerbull Give to small numbers of patients (single-arm)

bull If anyone responds =gt evidence of activity

bull Add a few more patients and estimate RR

bull Gehan - 1960

Phase II Cancerbull Two stages formalize based on α and β

(Fleming 1982)

bull Optimal designs (Simon 1989)

bull Assuming drug is ineffective what is minimum number of patients needed

bull Reduces total sample size across all trials

Design Issuesbull Some advances ndash some patients respond to std

bull Ethically can not give novel therapy with less chance of response

bull Novel therapies designed not to shrink tumour but only prevent it from growing

bull How to proceed

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Phase II Cancerbull How would you measure if there is lsquoany

evidence of activityrsquo

bull Most cancer drugs historically fail and have substantial side effects

bull Remember 33 have seriouslife-threatening AE in 1st 28 days alone and ~5 respond at all

bull Thoughts

Phase II Cancerbull Give to small numbers of patients (single-arm)

bull If anyone responds =gt evidence of activity

bull Add a few more patients and estimate RR

bull Gehan - 1960

Phase II Cancerbull Two stages formalize based on α and β

(Fleming 1982)

bull Optimal designs (Simon 1989)

bull Assuming drug is ineffective what is minimum number of patients needed

bull Reduces total sample size across all trials

Design Issuesbull Some advances ndash some patients respond to std

bull Ethically can not give novel therapy with less chance of response

bull Novel therapies designed not to shrink tumour but only prevent it from growing

bull How to proceed

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Phase II Cancerbull Give to small numbers of patients (single-arm)

bull If anyone responds =gt evidence of activity

bull Add a few more patients and estimate RR

bull Gehan - 1960

Phase II Cancerbull Two stages formalize based on α and β

(Fleming 1982)

bull Optimal designs (Simon 1989)

bull Assuming drug is ineffective what is minimum number of patients needed

bull Reduces total sample size across all trials

Design Issuesbull Some advances ndash some patients respond to std

bull Ethically can not give novel therapy with less chance of response

bull Novel therapies designed not to shrink tumour but only prevent it from growing

bull How to proceed

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Phase II Cancerbull Two stages formalize based on α and β

(Fleming 1982)

bull Optimal designs (Simon 1989)

bull Assuming drug is ineffective what is minimum number of patients needed

bull Reduces total sample size across all trials

Design Issuesbull Some advances ndash some patients respond to std

bull Ethically can not give novel therapy with less chance of response

bull Novel therapies designed not to shrink tumour but only prevent it from growing

bull How to proceed

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Design Issuesbull Some advances ndash some patients respond to std

bull Ethically can not give novel therapy with less chance of response

bull Novel therapies designed not to shrink tumour but only prevent it from growing

bull How to proceed

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Questionsbull Often novel therapies are given in addition to

standard of care

bull Outcome of response changed to time to progression

bull Randomization

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Histogram of number of randomized phase II cancer studies published from 1986 to 2002

Lee J J and Feng L JCO 2005234450-4457

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Randomized Phase II designsbull gt4x number of patients needed

bull Solutions look for massive effects inflate α and β

bull One suggestion is α=020 β=020 HR=06 ndash unrealistic

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Randomized Phase II Outcomesbull PFS instead of OS

bull PFS often a poor surrogate

bull May be difficult to run phase III if large differences observed

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Other designsbull lsquoPick-the-winnerrsquo

bull 21 allocation with control only to lsquoensure H0 is accuratersquo

bull No formal comparison different regimens

bull None widely accepted

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Statistical Design No Design categoriesemspemspemspemspSWE randomized phase II 13 106

emspemspemspemsp1-stage design 48 390

emspemspemspemspemspemspemspemsp1-sample binomial 14

emspemspemspemspemspemspemspemsp2-sample binomial 15

emspemspemspemspemspemspemspemsp2-sample continuous 12

emspemspemspemspemspemspemspemsp2-sample survival 7

emspemspemspemsp2-stage design 55 447

emspemspemspemspemspemspemspemspGehanrsquos 14

emspemspemspemspemspemspemspemspSimonrsquos optimal 14

emspemspemspemspemspemspemspemspSimonrsquos minimax 11

emspemspemspemspemspemspemspemspAd-hoc binomial 10

emspemspemspemspemspemspemspemspFlemingrsquos 3

emspemspemspemspemspemspemspemspMultinomial 2

emspemspemspemspemspemspemspemspLogistic 1

emspemspemspemsp3-stage design 4 33

emspemspemspemspemspemspemspemspEORTC binomial 3

emspemspemspemspemspemspemspemspEnsignrsquos binomial 1

emspemspemspemspOthers 3 24emspemspemspemspemspemspemspemspBayesian binomial 2

emspemspemspemspemspemspemspemspGroup sequential binomial 1

Design by type of primary end points

emspemspemspemspBinomial 102 829emspemspemspemspContinuous 12 98emspemspemspemspSurvival 7 57emspemspemspemspMultinomial 2 16Total 123 1000

Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)

Lee J J and Feng L JCO 2005234450-4457

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

lsquoNovelrsquo designsbull Randomised discontinuation trials

bull Treat all patients with agent for 1 cycle

bull Keep treating patients with a response

bull Stop treating patients who are progressing

bull Randomize patients with stable disease to treatment versus placebo

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Summary of phase II trial designs

Rubinstein L et al Clin Cancer Res 2009151883-1890

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

RDT Trialsbull Primary analysis is comparison of randomized

patients

bull Re-challenge placebo patients who progress

bull Ethics

bull Can fail miserably if of patients with SD is small

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Crossoverbull Trial is novel therapy versus BSC

bull Patients who fail BSC lsquocrossoverrsquo to receive novel therapy

bull Ethically all pts receive trt

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Crossoverbull Problem is study is really treat now or treat

later

bull All patients are progressing at start of study

bull Tumour grows and becomes more resistant

bull Cannot determine long-term OS advantage If trial is + and regulatory approval difficult for fundersinsurance (OHIP)

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Bayesian Response-Toxicity Curve

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Genetic Marker Designbull NSCLC pts primary outcome 8-week SDbull Genetic profiling improved primary outcome from 30

(expected) to 46 in BATTLE

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Bayesian Adaptive Designbull BATTLE randomize pts 1111 initially

bull As info increases allocate patients preferentially to treatmentmarker combination with best performance

bull Outcome is Prob(8 week SD|marker amp treatment)

bull Large complex need real-time datahistology

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Marker Designsbull I-SPY2 underway in breast cancer

bull Lots of information essentially many single-arm trials

bull May reject treatmentmarker combo with small numbers

bull Costs ~$27 million over 5 years for 800 patients

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Combined Phase Trialsbull Phase III trials

bull Include phase I patients in phase II analysis

bull Only pts treated at RP2D

bull Population must be the same thus may reduce s evaluable for phase I

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Combined Phase Trialsbull Phase IIIII

bull Do randomised phase II study using a surrogate endpoint

bull Stop at analysis 1 if lack of efficacy

bull Continue to phase III if some evidence

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Combined Phase Trialsbull Does not affect the α since interim analysis

based on different endpoint

bull However must be willing to commit resources for phase III study

bull Phase III tends to have large of institutions if stop at IA much work for little gain

bull 3-6 months to get study started

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Secondary Outcomesbull Safety toxicity cost QOL ease of

treatment

bull Many not known after phase I

bull May inform phase III design but may be added costs with no benefit if phase II fails

bull Can add support for regulatory approval of positive trials

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Basis of All Initial Approvals

Cytotoxic Drugs (n = 13 drugs in 34 indications)

Targeted Drugs (n = 11 drugs in 26 indications)

No No

Phase III data 30 88 20 77

Single-arm phase II data only

4dagger 12 4Dagger 15

Randomized phase II data only

0 0 2sect 8

Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through 2008 Inclusive

Hui K Gan Axel Grothey Gregory R Pond Malcolm J Moore Lillian L Siu and Daniel Sargent dArr Randomized Phase II Trials Inevitable or InadvisableJCO 28(15) 2641-2647 2010

Phase 0bull Looking for biological effects only

bull Give agent as a single-agent for 1 weekday

bull Evaluate biological markers only

bull Some then combine agent with standard in full trial

bull No clinical benefit

Phase 0bull Preferentially given as part of phase I study

(can identify dose effect)

bull Not necessarily given to all patients in study

bull Occasionally given in isolation (give 1 month of treatment to 5-10 patients)

bull Recruitment is a major issue

Additional Considerationsbull Benefit to patient is of concern

bull Considerable risk of harm

bull Small numbers of patients

bull Benefit is that may identify assay target

Additional Considerationsbull Phase I and II are supposed to be lsquoquickrsquo

bull Can take 2-3 years (or more) each

bull What will landscape look like in 10 years (when applying for regulatory approval)

Additional Considerationsbull Up to 1 year to get study activated after

protocol finalized

bull Research Ethics Boards

bull Legal contracts with all sites

bull Database data collection

bull Site scientific and finance reviews

Data Collectionbull Up to 1000 data items collected trial

bull Average of lt20 used (lt100 trial)

bull Massive wastage

OrsquoLeary Seow Julian Levine Pond Data collection in cancer clinical trials Too much of a good thing Clin Trials 10(4)624-632 Aug 2013

Data Collectionbull Clinical trials nurse collects databull Data manager enters databull Trial coordinator reviews data finds issuebull Coordinator sends DCF to data managerbull Data manager reviews with nursebull Data manager sends revised databull Trial coordinator re-reviews data bull Study investigator reviews and signs offbull Database is locked

bull All at gt$50 hour

Data Collectionbull Is it critical to the study

bull How likely will it be for planning future study

bull Data clarification is importantWeight=110 (kglbs)What date is 11614 How important is family history if half patients

answer=UNK

Privacybull Large restrictions on data captured due to

privacy

bull Date of birth diagnosis ndash restricted to year

bull Genetic markers

bull Want tissue sample sent to third party for QA review ndash did you specify in the consent

Consent Formbull Legal document describing procedures

goals information needed options for patient

bull Very detailed (I have seen gt30 page consents)

bull Sub-consents for biomarker research

bull Signed by patient personnel (not in position of authority)

Regulatory Burdenbull 296 distinct processes required to activate a phase III trial

bull Dilts DM Sandler AB Cheng S et al (2009) Steps and time to process clinical trials at the Cancer Therapy Evaluation Program J Clin Oncol 271761ndash1766

Area Processing Step Decision Point Loop Stopping Point

Concept (total) 106 21 5 6

emspemspemspemspCRM 76 13 2 4

emspemspemspemspTask force 71 19 4 5

Protocol 88 17 8 4

PMB 10 6 2 1

CDE 20 4 1 0

CIRB 34 9 5 2

Final review 16 3 3 0

Total CRM 244 52 21 11

Total task force 239 58 23 12

Comparison of Works Steps Decision Points Loops and Stopping Points by Major Stage of Development

Dilts D M et al JCO 2009271761-1766

Median of gt600 days from concept to activation

Procedure CostLife-Year Saved

Clinical trials regulations $2700000

Hemodialysis29 $43000-$104000

Statins for heart disease (moderate- to high-risk patients)30 $19000-$25000

Colorectal cancer screening by colonoscopy32 $14000

Adjuvant trastuzumab breast cancer31 $20000

Bevacizumab advanced nonndashsmall-cell lung cancer33 $380000

Paclitaxelcisplatin for advanced ovarian cancer34 $26000

David J Stewart Simon N Whitney Razelle Kurzrock Equipoise Lost Ethics Costs and the Regulation of Cancer Clinical Research JCO 28(17) 2925-2935 2010

Costs per Year of Life Gained by Selected Interventions

DSMBbull Debate about if they are needed

bull Phase I probably not

bull Cancer phase II ndash depends on design (randomized or single-arm of patients)

bull Non-cancer phase II - probably

DSMBbull 1-2 sites investigators know each patient

bull DSMB knows just numbers

bull Steering committee should meet before every stagedose escalation decision etc

bull Larger studiesmore sites may need independent review

Final thoughtsbull Early phase studies often have lsquosimplersquo

designs

bull More complex logistical practical issues than late stage designs

bull These must be incorporated in analysis design interpretation inference

Final thoughtsbull Must as a biostatistician have understanding

of non-statistical aspects and

bull Must be able to communicate effectively with non-statisticians (clinicians nurses CRA ethics regulatory pathologists radiologists lab technicians scientists IT geneticists hellip)

• Early Phase Clinical Trials
• Learning Objectives
• My Background (biases)
• Your Background
• Thought Experiment
• Standard Drug Development Paradigm
• Phase I
• Phase II
• Clinical Trial Phases
• Clinical Trial 1
• TGN1412 for RA
• Dose Levels
• Phase I Cancer (3+3)
• DLTs
• Slide 15
• Phase I Non-cancer
• Slide 17
• Slide 18
• Cancer Phase I Ethics
• Ethics
• Slide 21
• Correct RP2D
• PowerPoint Presentation
• Slide 24
• Modified Designs
• Model-Based Designs
• Example dose-toxicity curve
• Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74
• Others
• Slide 30
• Secondary Outcomes
• Slide 32
• Howeverhellip
• Targeted Agents
• Slide 35
• Slide 36
• Phase II non-cancer
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Phase II Cancer
• Slide 44
• Slide 45
• Slide 46
• Design Issues
• Questions
• Slide 49
• Randomized Phase II designs
• Randomized Phase II Outcomes
• Other designs
• Slide 53
• lsquoNovelrsquo designs
• Slide 55
• RDT Trials
• Crossover
• Slide 58
• Bayesian Response-Toxicity Curve
• Genetic Marker Design
• Bayesian Adaptive Design
• Marker Designs
• Combined Phase Trials
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Phase 0
• Slide 69
• Additional Considerations
• Slide 71
• Slide 72
• Data Collection
• Slide 74
• Slide 75
• Privacy
• Consent Form
• Regulatory Burden
• Slide 79
• Slide 80
• DSMB
• Slide 82
• Final thoughts
• Slide 84

Phase 0bull Preferentially given as part of phase I study

(can identify dose effect)

bull Not necessarily given to all patients in study

bull Occasionally given in isolation (give 1 month of treatment to 5-10 patients)

bull Recruitment is a major issue

Additional Considerationsbull Benefit to patient is of concern

bull Considerable risk of harm

bull Small numbers of patients

bull Benefit is that may identify assay target

Additional Considerationsbull Phase I and II are supposed to be lsquoquickrsquo

bull Can take 2-3 years (or more) each

bull What will landscape look like in 10 years (when applying for regulatory approval)

Additional Considerationsbull Up to 1 year to get study activated after

protocol finalized

bull Research Ethics Boards

bull Legal contracts with all sites

bull Database data collection

bull Site scientific and finance reviews

Data Collectionbull Up to 1000 data items collected trial

bull Average of lt20 used (lt100 trial)

bull Massive wastage

OrsquoLeary Seow Julian Levine Pond Data collection in cancer clinical trials Too much of a good thing Clin Trials 10(4)624-632 Aug 2013

Data Collectionbull Clinical trials nurse collects databull Data manager enters databull Trial coordinator reviews data finds issuebull Coordinator sends DCF to data managerbull Data manager reviews with nursebull Data manager sends revised databull Trial coordinator re-reviews data bull Study investigator reviews and signs offbull Database is locked

bull All at gt$50 hour

Data Collectionbull Is it critical to the study

bull How likely will it be for planning future study

bull Data clarification is importantWeight=110 (kglbs)What date is 11614 How important is family history if half patients

answer=UNK

Privacybull Large restrictions on data captured due to

privacy

bull Date of birth diagnosis ndash restricted to year

bull Genetic markers

bull Want tissue sample sent to third party for QA review ndash did you specify in the consent

Consent Formbull Legal document describing procedures

goals information needed options for patient

bull Very detailed (I have seen gt30 page consents)

bull Sub-consents for biomarker research

bull Signed by patient personnel (not in position of authority)

Regulatory Burdenbull 296 distinct processes required to activate a phase III trial

bull Dilts DM Sandler AB Cheng S et al (2009) Steps and time to process clinical trials at the Cancer Therapy Evaluation Program J Clin Oncol 271761ndash1766

Area Processing Step Decision Point Loop Stopping Point

Concept (total) 106 21 5 6

emspemspemspemspCRM 76 13 2 4

emspemspemspemspTask force 71 19 4 5

Protocol 88 17 8 4

PMB 10 6 2 1

CDE 20 4 1 0

CIRB 34 9 5 2

Final review 16 3 3 0

Total CRM 244 52 21 11

Total task force 239 58 23 12

Comparison of Works Steps Decision Points Loops and Stopping Points by Major Stage of Development

Dilts D M et al JCO 2009271761-1766

Median of gt600 days from concept to activation

Procedure CostLife-Year Saved

Clinical trials regulations $2700000

Hemodialysis29 $43000-$104000

Statins for heart disease (moderate- to high-risk patients)30 $19000-$25000

Colorectal cancer screening by colonoscopy32 $14000

Adjuvant trastuzumab breast cancer31 $20000

Bevacizumab advanced nonndashsmall-cell lung cancer33 $380000

Paclitaxelcisplatin for advanced ovarian cancer34 $26000

David J Stewart Simon N Whitney Razelle Kurzrock Equipoise Lost Ethics Costs and the Regulation of Cancer Clinical Research JCO 28(17) 2925-2935 2010

Costs per Year of Life Gained by Selected Interventions

DSMBbull Debate about if they are needed

bull Phase I probably not

bull Cancer phase II ndash depends on design (randomized or single-arm of patients)

bull Non-cancer phase II - probably

DSMBbull 1-2 sites investigators know each patient

bull DSMB knows just numbers

bull Steering committee should meet before every stagedose escalation decision etc

bull Larger studiesmore sites may need independent review

Final thoughtsbull Early phase studies often have lsquosimplersquo

designs

bull More complex logistical practical issues than late stage designs

bull These must be incorporated in analysis design interpretation inference

Final thoughtsbull Must as a biostatistician have understanding

of non-statistical aspects and

bull Must be able to communicate effectively with non-statisticians (clinicians nurses CRA ethics regulatory pathologists radiologists lab technicians scientists IT geneticists hellip)

• Early Phase Clinical Trials
• Learning Objectives
• My Background (biases)
• Your Background
• Thought Experiment
• Standard Drug Development Paradigm
• Phase I
• Phase II
• Clinical Trial Phases
• Clinical Trial 1
• TGN1412 for RA
• Dose Levels
• Phase I Cancer (3+3)
• DLTs
• Slide 15
• Phase I Non-cancer
• Slide 17
• Slide 18
• Cancer Phase I Ethics
• Ethics
• Slide 21
• Correct RP2D
• PowerPoint Presentation
• Slide 24
• Modified Designs
• Model-Based Designs
• Example dose-toxicity curve
• Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74
• Others
• Slide 30
• Secondary Outcomes
• Slide 32
• Howeverhellip
• Targeted Agents
• Slide 35
• Slide 36
• Phase II non-cancer
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Phase II Cancer
• Slide 44
• Slide 45
• Slide 46
• Design Issues
• Questions
• Slide 49
• Randomized Phase II designs
• Randomized Phase II Outcomes
• Other designs
• Slide 53
• lsquoNovelrsquo designs
• Slide 55
• RDT Trials
• Crossover
• Slide 58
• Bayesian Response-Toxicity Curve
• Genetic Marker Design
• Bayesian Adaptive Design
• Marker Designs
• Combined Phase Trials
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Phase 0
• Slide 69
• Additional Considerations
• Slide 71
• Slide 72
• Data Collection
• Slide 74
• Slide 75
• Privacy
• Consent Form
• Regulatory Burden
• Slide 79
• Slide 80
• DSMB
• Slide 82
• Final thoughts
• Slide 84

Additional Considerationsbull Benefit to patient is of concern

bull Considerable risk of harm

bull Small numbers of patients

bull Benefit is that may identify assay target

Additional Considerationsbull Phase I and II are supposed to be lsquoquickrsquo

bull Can take 2-3 years (or more) each

bull What will landscape look like in 10 years (when applying for regulatory approval)

Additional Considerationsbull Up to 1 year to get study activated after

protocol finalized

bull Research Ethics Boards

bull Legal contracts with all sites

bull Database data collection

bull Site scientific and finance reviews

Data Collectionbull Up to 1000 data items collected trial

bull Average of lt20 used (lt100 trial)

bull Massive wastage

OrsquoLeary Seow Julian Levine Pond Data collection in cancer clinical trials Too much of a good thing Clin Trials 10(4)624-632 Aug 2013

Data Collectionbull Clinical trials nurse collects databull Data manager enters databull Trial coordinator reviews data finds issuebull Coordinator sends DCF to data managerbull Data manager reviews with nursebull Data manager sends revised databull Trial coordinator re-reviews data bull Study investigator reviews and signs offbull Database is locked

bull All at gt$50 hour

Data Collectionbull Is it critical to the study

bull How likely will it be for planning future study

bull Data clarification is importantWeight=110 (kglbs)What date is 11614 How important is family history if half patients

answer=UNK

Privacybull Large restrictions on data captured due to

privacy

bull Date of birth diagnosis ndash restricted to year

bull Genetic markers

bull Want tissue sample sent to third party for QA review ndash did you specify in the consent

Consent Formbull Legal document describing procedures

goals information needed options for patient

bull Very detailed (I have seen gt30 page consents)

bull Sub-consents for biomarker research

bull Signed by patient personnel (not in position of authority)

Regulatory Burdenbull 296 distinct processes required to activate a phase III trial

bull Dilts DM Sandler AB Cheng S et al (2009) Steps and time to process clinical trials at the Cancer Therapy Evaluation Program J Clin Oncol 271761ndash1766

Area Processing Step Decision Point Loop Stopping Point

Concept (total) 106 21 5 6

emspemspemspemspCRM 76 13 2 4

emspemspemspemspTask force 71 19 4 5

Protocol 88 17 8 4

PMB 10 6 2 1

CDE 20 4 1 0

CIRB 34 9 5 2

Final review 16 3 3 0

Total CRM 244 52 21 11

Total task force 239 58 23 12

Comparison of Works Steps Decision Points Loops and Stopping Points by Major Stage of Development

Dilts D M et al JCO 2009271761-1766

Median of gt600 days from concept to activation

Procedure CostLife-Year Saved

Clinical trials regulations $2700000

Hemodialysis29 $43000-$104000

Statins for heart disease (moderate- to high-risk patients)30 $19000-$25000

Colorectal cancer screening by colonoscopy32 $14000

Adjuvant trastuzumab breast cancer31 $20000

Bevacizumab advanced nonndashsmall-cell lung cancer33 $380000

Paclitaxelcisplatin for advanced ovarian cancer34 $26000

David J Stewart Simon N Whitney Razelle Kurzrock Equipoise Lost Ethics Costs and the Regulation of Cancer Clinical Research JCO 28(17) 2925-2935 2010

Costs per Year of Life Gained by Selected Interventions

DSMBbull Debate about if they are needed

bull Phase I probably not

bull Cancer phase II ndash depends on design (randomized or single-arm of patients)

bull Non-cancer phase II - probably

DSMBbull 1-2 sites investigators know each patient

bull DSMB knows just numbers

bull Steering committee should meet before every stagedose escalation decision etc

bull Larger studiesmore sites may need independent review

Final thoughtsbull Early phase studies often have lsquosimplersquo

designs

bull More complex logistical practical issues than late stage designs

bull These must be incorporated in analysis design interpretation inference

Final thoughtsbull Must as a biostatistician have understanding

of non-statistical aspects and

bull Must be able to communicate effectively with non-statisticians (clinicians nurses CRA ethics regulatory pathologists radiologists lab technicians scientists IT geneticists hellip)

• Early Phase Clinical Trials
• Learning Objectives
• My Background (biases)
• Your Background
• Thought Experiment
• Standard Drug Development Paradigm
• Phase I
• Phase II
• Clinical Trial Phases
• Clinical Trial 1
• TGN1412 for RA
• Dose Levels
• Phase I Cancer (3+3)
• DLTs
• Slide 15
• Phase I Non-cancer
• Slide 17
• Slide 18
• Cancer Phase I Ethics
• Ethics
• Slide 21
• Correct RP2D
• PowerPoint Presentation
• Slide 24
• Modified Designs
• Model-Based Designs
• Example dose-toxicity curve
• Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74
• Others
• Slide 30
• Secondary Outcomes
• Slide 32
• Howeverhellip
• Targeted Agents
• Slide 35
• Slide 36
• Phase II non-cancer
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Phase II Cancer
• Slide 44
• Slide 45
• Slide 46
• Design Issues
• Questions
• Slide 49
• Randomized Phase II designs
• Randomized Phase II Outcomes
• Other designs
• Slide 53
• lsquoNovelrsquo designs
• Slide 55
• RDT Trials
• Crossover
• Slide 58
• Bayesian Response-Toxicity Curve
• Genetic Marker Design
• Bayesian Adaptive Design
• Marker Designs
• Combined Phase Trials
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Phase 0
• Slide 69
• Additional Considerations
• Slide 71
• Slide 72
• Data Collection
• Slide 74
• Slide 75
• Privacy
• Consent Form
• Regulatory Burden
• Slide 79
• Slide 80
• DSMB
• Slide 82
• Final thoughts
• Slide 84

Additional Considerationsbull Phase I and II are supposed to be lsquoquickrsquo

bull Can take 2-3 years (or more) each

bull What will landscape look like in 10 years (when applying for regulatory approval)

Additional Considerationsbull Up to 1 year to get study activated after

protocol finalized

bull Research Ethics Boards

bull Legal contracts with all sites

bull Database data collection

bull Site scientific and finance reviews

Data Collectionbull Up to 1000 data items collected trial

bull Average of lt20 used (lt100 trial)

bull Massive wastage

OrsquoLeary Seow Julian Levine Pond Data collection in cancer clinical trials Too much of a good thing Clin Trials 10(4)624-632 Aug 2013

Data Collectionbull Clinical trials nurse collects databull Data manager enters databull Trial coordinator reviews data finds issuebull Coordinator sends DCF to data managerbull Data manager reviews with nursebull Data manager sends revised databull Trial coordinator re-reviews data bull Study investigator reviews and signs offbull Database is locked

bull All at gt$50 hour

Data Collectionbull Is it critical to the study

bull How likely will it be for planning future study

bull Data clarification is importantWeight=110 (kglbs)What date is 11614 How important is family history if half patients

answer=UNK

Privacybull Large restrictions on data captured due to

privacy

bull Date of birth diagnosis ndash restricted to year

bull Genetic markers

bull Want tissue sample sent to third party for QA review ndash did you specify in the consent

Consent Formbull Legal document describing procedures

goals information needed options for patient

bull Very detailed (I have seen gt30 page consents)

bull Sub-consents for biomarker research

bull Signed by patient personnel (not in position of authority)

Regulatory Burdenbull 296 distinct processes required to activate a phase III trial

bull Dilts DM Sandler AB Cheng S et al (2009) Steps and time to process clinical trials at the Cancer Therapy Evaluation Program J Clin Oncol 271761ndash1766

Area Processing Step Decision Point Loop Stopping Point

Concept (total) 106 21 5 6

emspemspemspemspCRM 76 13 2 4

emspemspemspemspTask force 71 19 4 5

Protocol 88 17 8 4

PMB 10 6 2 1

CDE 20 4 1 0

CIRB 34 9 5 2

Final review 16 3 3 0

Total CRM 244 52 21 11

Total task force 239 58 23 12

Comparison of Works Steps Decision Points Loops and Stopping Points by Major Stage of Development

Dilts D M et al JCO 2009271761-1766

Median of gt600 days from concept to activation

Procedure CostLife-Year Saved

Clinical trials regulations $2700000

Hemodialysis29 $43000-$104000

Statins for heart disease (moderate- to high-risk patients)30 $19000-$25000

Colorectal cancer screening by colonoscopy32 $14000

Adjuvant trastuzumab breast cancer31 $20000

Bevacizumab advanced nonndashsmall-cell lung cancer33 $380000

Paclitaxelcisplatin for advanced ovarian cancer34 $26000

David J Stewart Simon N Whitney Razelle Kurzrock Equipoise Lost Ethics Costs and the Regulation of Cancer Clinical Research JCO 28(17) 2925-2935 2010

Costs per Year of Life Gained by Selected Interventions

DSMBbull Debate about if they are needed

bull Phase I probably not

bull Cancer phase II ndash depends on design (randomized or single-arm of patients)

bull Non-cancer phase II - probably

DSMBbull 1-2 sites investigators know each patient

bull DSMB knows just numbers

bull Steering committee should meet before every stagedose escalation decision etc

bull Larger studiesmore sites may need independent review

Final thoughtsbull Early phase studies often have lsquosimplersquo

designs

bull More complex logistical practical issues than late stage designs

bull These must be incorporated in analysis design interpretation inference

Final thoughtsbull Must as a biostatistician have understanding

of non-statistical aspects and

bull Must be able to communicate effectively with non-statisticians (clinicians nurses CRA ethics regulatory pathologists radiologists lab technicians scientists IT geneticists hellip)

• Early Phase Clinical Trials
• Learning Objectives
• My Background (biases)
• Your Background
• Thought Experiment
• Standard Drug Development Paradigm
• Phase I
• Phase II
• Clinical Trial Phases
• Clinical Trial 1
• TGN1412 for RA
• Dose Levels
• Phase I Cancer (3+3)
• DLTs
• Slide 15
• Phase I Non-cancer
• Slide 17
• Slide 18
• Cancer Phase I Ethics
• Ethics
• Slide 21
• Correct RP2D
• PowerPoint Presentation
• Slide 24
• Modified Designs
• Model-Based Designs
• Example dose-toxicity curve
• Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74
• Others
• Slide 30
• Secondary Outcomes
• Slide 32
• Howeverhellip
• Targeted Agents
• Slide 35
• Slide 36
• Phase II non-cancer
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Phase II Cancer
• Slide 44
• Slide 45
• Slide 46
• Design Issues
• Questions
• Slide 49
• Randomized Phase II designs
• Randomized Phase II Outcomes
• Other designs
• Slide 53
• lsquoNovelrsquo designs
• Slide 55
• RDT Trials
• Crossover
• Slide 58
• Bayesian Response-Toxicity Curve
• Genetic Marker Design
• Bayesian Adaptive Design
• Marker Designs
• Combined Phase Trials
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Phase 0
• Slide 69
• Additional Considerations
• Slide 71
• Slide 72
• Data Collection
• Slide 74
• Slide 75
• Privacy
• Consent Form
• Regulatory Burden
• Slide 79
• Slide 80
• DSMB
• Slide 82
• Final thoughts
• Slide 84

Additional Considerationsbull Up to 1 year to get study activated after

protocol finalized

bull Research Ethics Boards

bull Legal contracts with all sites

bull Database data collection

bull Site scientific and finance reviews

Data Collectionbull Up to 1000 data items collected trial

bull Average of lt20 used (lt100 trial)

bull Massive wastage

OrsquoLeary Seow Julian Levine Pond Data collection in cancer clinical trials Too much of a good thing Clin Trials 10(4)624-632 Aug 2013

Data Collectionbull Clinical trials nurse collects databull Data manager enters databull Trial coordinator reviews data finds issuebull Coordinator sends DCF to data managerbull Data manager reviews with nursebull Data manager sends revised databull Trial coordinator re-reviews data bull Study investigator reviews and signs offbull Database is locked

bull All at gt$50 hour

Data Collectionbull Is it critical to the study

bull How likely will it be for planning future study

bull Data clarification is importantWeight=110 (kglbs)What date is 11614 How important is family history if half patients

answer=UNK

Privacybull Large restrictions on data captured due to

privacy

bull Date of birth diagnosis ndash restricted to year

bull Genetic markers

bull Want tissue sample sent to third party for QA review ndash did you specify in the consent

Consent Formbull Legal document describing procedures

goals information needed options for patient

bull Very detailed (I have seen gt30 page consents)

bull Sub-consents for biomarker research

bull Signed by patient personnel (not in position of authority)

Regulatory Burdenbull 296 distinct processes required to activate a phase III trial

bull Dilts DM Sandler AB Cheng S et al (2009) Steps and time to process clinical trials at the Cancer Therapy Evaluation Program J Clin Oncol 271761ndash1766

Area Processing Step Decision Point Loop Stopping Point

Concept (total) 106 21 5 6

emspemspemspemspCRM 76 13 2 4

emspemspemspemspTask force 71 19 4 5

Protocol 88 17 8 4

PMB 10 6 2 1

CDE 20 4 1 0

CIRB 34 9 5 2

Final review 16 3 3 0

Total CRM 244 52 21 11

Total task force 239 58 23 12

Comparison of Works Steps Decision Points Loops and Stopping Points by Major Stage of Development

Dilts D M et al JCO 2009271761-1766

Median of gt600 days from concept to activation

Procedure CostLife-Year Saved

Clinical trials regulations $2700000

Hemodialysis29 $43000-$104000

Statins for heart disease (moderate- to high-risk patients)30 $19000-$25000

Colorectal cancer screening by colonoscopy32 $14000

Adjuvant trastuzumab breast cancer31 $20000

Bevacizumab advanced nonndashsmall-cell lung cancer33 $380000

Paclitaxelcisplatin for advanced ovarian cancer34 $26000

David J Stewart Simon N Whitney Razelle Kurzrock Equipoise Lost Ethics Costs and the Regulation of Cancer Clinical Research JCO 28(17) 2925-2935 2010

Costs per Year of Life Gained by Selected Interventions

DSMBbull Debate about if they are needed

bull Phase I probably not

bull Cancer phase II ndash depends on design (randomized or single-arm of patients)

bull Non-cancer phase II - probably

DSMBbull 1-2 sites investigators know each patient

bull DSMB knows just numbers

bull Steering committee should meet before every stagedose escalation decision etc

bull Larger studiesmore sites may need independent review

Final thoughtsbull Early phase studies often have lsquosimplersquo

designs

bull More complex logistical practical issues than late stage designs

bull These must be incorporated in analysis design interpretation inference

Final thoughtsbull Must as a biostatistician have understanding

of non-statistical aspects and

bull Must be able to communicate effectively with non-statisticians (clinicians nurses CRA ethics regulatory pathologists radiologists lab technicians scientists IT geneticists hellip)

• Early Phase Clinical Trials
• Learning Objectives
• My Background (biases)
• Your Background
• Thought Experiment
• Standard Drug Development Paradigm
• Phase I
• Phase II
• Clinical Trial Phases
• Clinical Trial 1
• TGN1412 for RA
• Dose Levels
• Phase I Cancer (3+3)
• DLTs
• Slide 15
• Phase I Non-cancer
• Slide 17
• Slide 18
• Cancer Phase I Ethics
• Ethics
• Slide 21
• Correct RP2D
• PowerPoint Presentation
• Slide 24
• Modified Designs
• Model-Based Designs
• Example dose-toxicity curve
• Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74
• Others
• Slide 30
• Secondary Outcomes
• Slide 32
• Howeverhellip
• Targeted Agents
• Slide 35
• Slide 36
• Phase II non-cancer
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Phase II Cancer
• Slide 44
• Slide 45
• Slide 46
• Design Issues
• Questions
• Slide 49
• Randomized Phase II designs
• Randomized Phase II Outcomes
• Other designs
• Slide 53
• lsquoNovelrsquo designs
• Slide 55
• RDT Trials
• Crossover
• Slide 58
• Bayesian Response-Toxicity Curve
• Genetic Marker Design
• Bayesian Adaptive Design
• Marker Designs
• Combined Phase Trials
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Phase 0
• Slide 69
• Additional Considerations
• Slide 71
• Slide 72
• Data Collection
• Slide 74
• Slide 75
• Privacy
• Consent Form
• Regulatory Burden
• Slide 79
• Slide 80
• DSMB
• Slide 82
• Final thoughts
• Slide 84

Data Collectionbull Up to 1000 data items collected trial

bull Average of lt20 used (lt100 trial)

bull Massive wastage

OrsquoLeary Seow Julian Levine Pond Data collection in cancer clinical trials Too much of a good thing Clin Trials 10(4)624-632 Aug 2013

Data Collectionbull Clinical trials nurse collects databull Data manager enters databull Trial coordinator reviews data finds issuebull Coordinator sends DCF to data managerbull Data manager reviews with nursebull Data manager sends revised databull Trial coordinator re-reviews data bull Study investigator reviews and signs offbull Database is locked

bull All at gt$50 hour

Data Collectionbull Is it critical to the study

bull How likely will it be for planning future study

bull Data clarification is importantWeight=110 (kglbs)What date is 11614 How important is family history if half patients

answer=UNK

Privacybull Large restrictions on data captured due to

privacy

bull Date of birth diagnosis ndash restricted to year

bull Genetic markers

bull Want tissue sample sent to third party for QA review ndash did you specify in the consent

Consent Formbull Legal document describing procedures

goals information needed options for patient

bull Very detailed (I have seen gt30 page consents)

bull Sub-consents for biomarker research

bull Signed by patient personnel (not in position of authority)

Regulatory Burdenbull 296 distinct processes required to activate a phase III trial

bull Dilts DM Sandler AB Cheng S et al (2009) Steps and time to process clinical trials at the Cancer Therapy Evaluation Program J Clin Oncol 271761ndash1766

Area Processing Step Decision Point Loop Stopping Point

Concept (total) 106 21 5 6

emspemspemspemspCRM 76 13 2 4

emspemspemspemspTask force 71 19 4 5

Protocol 88 17 8 4

PMB 10 6 2 1

CDE 20 4 1 0

CIRB 34 9 5 2

Final review 16 3 3 0

Total CRM 244 52 21 11

Total task force 239 58 23 12

Comparison of Works Steps Decision Points Loops and Stopping Points by Major Stage of Development

Dilts D M et al JCO 2009271761-1766

Median of gt600 days from concept to activation

Procedure CostLife-Year Saved

Clinical trials regulations $2700000

Hemodialysis29 $43000-$104000

Statins for heart disease (moderate- to high-risk patients)30 $19000-$25000

Colorectal cancer screening by colonoscopy32 $14000

Adjuvant trastuzumab breast cancer31 $20000

Bevacizumab advanced nonndashsmall-cell lung cancer33 $380000

Paclitaxelcisplatin for advanced ovarian cancer34 $26000

David J Stewart Simon N Whitney Razelle Kurzrock Equipoise Lost Ethics Costs and the Regulation of Cancer Clinical Research JCO 28(17) 2925-2935 2010

Costs per Year of Life Gained by Selected Interventions

DSMBbull Debate about if they are needed

bull Phase I probably not

bull Cancer phase II ndash depends on design (randomized or single-arm of patients)

bull Non-cancer phase II - probably

DSMBbull 1-2 sites investigators know each patient

bull DSMB knows just numbers

bull Steering committee should meet before every stagedose escalation decision etc

bull Larger studiesmore sites may need independent review

Final thoughtsbull Early phase studies often have lsquosimplersquo

designs

bull More complex logistical practical issues than late stage designs

bull These must be incorporated in analysis design interpretation inference

Final thoughtsbull Must as a biostatistician have understanding

of non-statistical aspects and

bull Must be able to communicate effectively with non-statisticians (clinicians nurses CRA ethics regulatory pathologists radiologists lab technicians scientists IT geneticists hellip)

• Early Phase Clinical Trials
• Learning Objectives
• My Background (biases)
• Your Background
• Thought Experiment
• Standard Drug Development Paradigm
• Phase I
• Phase II
• Clinical Trial Phases
• Clinical Trial 1
• TGN1412 for RA
• Dose Levels
• Phase I Cancer (3+3)
• DLTs
• Slide 15
• Phase I Non-cancer
• Slide 17
• Slide 18
• Cancer Phase I Ethics
• Ethics
• Slide 21
• Correct RP2D
• PowerPoint Presentation
• Slide 24
• Modified Designs
• Model-Based Designs
• Example dose-toxicity curve
• Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74
• Others
• Slide 30
• Secondary Outcomes
• Slide 32
• Howeverhellip
• Targeted Agents
• Slide 35
• Slide 36
• Phase II non-cancer
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Phase II Cancer
• Slide 44
• Slide 45
• Slide 46
• Design Issues
• Questions
• Slide 49
• Randomized Phase II designs
• Randomized Phase II Outcomes
• Other designs
• Slide 53
• lsquoNovelrsquo designs
• Slide 55
• RDT Trials
• Crossover
• Slide 58
• Bayesian Response-Toxicity Curve
• Genetic Marker Design
• Bayesian Adaptive Design
• Marker Designs
• Combined Phase Trials
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Phase 0
• Slide 69
• Additional Considerations
• Slide 71
• Slide 72
• Data Collection
• Slide 74
• Slide 75
• Privacy
• Consent Form
• Regulatory Burden
• Slide 79
• Slide 80
• DSMB
• Slide 82
• Final thoughts
• Slide 84

Data Collectionbull Clinical trials nurse collects databull Data manager enters databull Trial coordinator reviews data finds issuebull Coordinator sends DCF to data managerbull Data manager reviews with nursebull Data manager sends revised databull Trial coordinator re-reviews data bull Study investigator reviews and signs offbull Database is locked

bull All at gt$50 hour

Data Collectionbull Is it critical to the study

bull How likely will it be for planning future study

bull Data clarification is importantWeight=110 (kglbs)What date is 11614 How important is family history if half patients

answer=UNK

Privacybull Large restrictions on data captured due to

privacy

bull Date of birth diagnosis ndash restricted to year

bull Genetic markers

bull Want tissue sample sent to third party for QA review ndash did you specify in the consent

Consent Formbull Legal document describing procedures

goals information needed options for patient

bull Very detailed (I have seen gt30 page consents)

bull Sub-consents for biomarker research

bull Signed by patient personnel (not in position of authority)

Regulatory Burdenbull 296 distinct processes required to activate a phase III trial

bull Dilts DM Sandler AB Cheng S et al (2009) Steps and time to process clinical trials at the Cancer Therapy Evaluation Program J Clin Oncol 271761ndash1766

Area Processing Step Decision Point Loop Stopping Point

Concept (total) 106 21 5 6

emspemspemspemspCRM 76 13 2 4

emspemspemspemspTask force 71 19 4 5

Protocol 88 17 8 4

PMB 10 6 2 1

CDE 20 4 1 0

CIRB 34 9 5 2

Final review 16 3 3 0

Total CRM 244 52 21 11

Total task force 239 58 23 12

Comparison of Works Steps Decision Points Loops and Stopping Points by Major Stage of Development

Dilts D M et al JCO 2009271761-1766

Median of gt600 days from concept to activation

Procedure CostLife-Year Saved

Clinical trials regulations $2700000

Hemodialysis29 $43000-$104000

Statins for heart disease (moderate- to high-risk patients)30 $19000-$25000

Colorectal cancer screening by colonoscopy32 $14000

Adjuvant trastuzumab breast cancer31 $20000

Bevacizumab advanced nonndashsmall-cell lung cancer33 $380000

Paclitaxelcisplatin for advanced ovarian cancer34 $26000

David J Stewart Simon N Whitney Razelle Kurzrock Equipoise Lost Ethics Costs and the Regulation of Cancer Clinical Research JCO 28(17) 2925-2935 2010

Costs per Year of Life Gained by Selected Interventions

DSMBbull Debate about if they are needed

bull Phase I probably not

bull Cancer phase II ndash depends on design (randomized or single-arm of patients)

bull Non-cancer phase II - probably

DSMBbull 1-2 sites investigators know each patient

bull DSMB knows just numbers

bull Steering committee should meet before every stagedose escalation decision etc

bull Larger studiesmore sites may need independent review

Final thoughtsbull Early phase studies often have lsquosimplersquo

designs

bull More complex logistical practical issues than late stage designs

bull These must be incorporated in analysis design interpretation inference

Final thoughtsbull Must as a biostatistician have understanding

of non-statistical aspects and

bull Must be able to communicate effectively with non-statisticians (clinicians nurses CRA ethics regulatory pathologists radiologists lab technicians scientists IT geneticists hellip)

• Early Phase Clinical Trials
• Learning Objectives
• My Background (biases)
• Your Background
• Thought Experiment
• Standard Drug Development Paradigm
• Phase I
• Phase II
• Clinical Trial Phases
• Clinical Trial 1
• TGN1412 for RA
• Dose Levels
• Phase I Cancer (3+3)
• DLTs
• Slide 15
• Phase I Non-cancer
• Slide 17
• Slide 18
• Cancer Phase I Ethics
• Ethics
• Slide 21
• Correct RP2D
• PowerPoint Presentation
• Slide 24
• Modified Designs
• Model-Based Designs
• Example dose-toxicity curve
• Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74
• Others
• Slide 30
• Secondary Outcomes
• Slide 32
• Howeverhellip
• Targeted Agents
• Slide 35
• Slide 36
• Phase II non-cancer
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Phase II Cancer
• Slide 44
• Slide 45
• Slide 46
• Design Issues
• Questions
• Slide 49
• Randomized Phase II designs
• Randomized Phase II Outcomes
• Other designs
• Slide 53
• lsquoNovelrsquo designs
• Slide 55
• RDT Trials
• Crossover
• Slide 58
• Bayesian Response-Toxicity Curve
• Genetic Marker Design
• Bayesian Adaptive Design
• Marker Designs
• Combined Phase Trials
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Phase 0
• Slide 69
• Additional Considerations
• Slide 71
• Slide 72
• Data Collection
• Slide 74
• Slide 75
• Privacy
• Consent Form
• Regulatory Burden
• Slide 79
• Slide 80
• DSMB
• Slide 82
• Final thoughts
• Slide 84

Data Collectionbull Is it critical to the study

bull How likely will it be for planning future study

bull Data clarification is importantWeight=110 (kglbs)What date is 11614 How important is family history if half patients

answer=UNK

Privacybull Large restrictions on data captured due to

privacy

bull Date of birth diagnosis ndash restricted to year

bull Genetic markers

bull Want tissue sample sent to third party for QA review ndash did you specify in the consent

Consent Formbull Legal document describing procedures

goals information needed options for patient

bull Very detailed (I have seen gt30 page consents)

bull Sub-consents for biomarker research

bull Signed by patient personnel (not in position of authority)

Regulatory Burdenbull 296 distinct processes required to activate a phase III trial

bull Dilts DM Sandler AB Cheng S et al (2009) Steps and time to process clinical trials at the Cancer Therapy Evaluation Program J Clin Oncol 271761ndash1766

Area Processing Step Decision Point Loop Stopping Point

Concept (total) 106 21 5 6

emspemspemspemspCRM 76 13 2 4

emspemspemspemspTask force 71 19 4 5

Protocol 88 17 8 4

PMB 10 6 2 1

CDE 20 4 1 0

CIRB 34 9 5 2

Final review 16 3 3 0

Total CRM 244 52 21 11

Total task force 239 58 23 12

Comparison of Works Steps Decision Points Loops and Stopping Points by Major Stage of Development

Dilts D M et al JCO 2009271761-1766

Median of gt600 days from concept to activation

Procedure CostLife-Year Saved

Clinical trials regulations $2700000

Hemodialysis29 $43000-$104000

Statins for heart disease (moderate- to high-risk patients)30 $19000-$25000

Colorectal cancer screening by colonoscopy32 $14000

Adjuvant trastuzumab breast cancer31 $20000

Bevacizumab advanced nonndashsmall-cell lung cancer33 $380000

Paclitaxelcisplatin for advanced ovarian cancer34 $26000

David J Stewart Simon N Whitney Razelle Kurzrock Equipoise Lost Ethics Costs and the Regulation of Cancer Clinical Research JCO 28(17) 2925-2935 2010

Costs per Year of Life Gained by Selected Interventions

DSMBbull Debate about if they are needed

bull Phase I probably not

bull Cancer phase II ndash depends on design (randomized or single-arm of patients)

bull Non-cancer phase II - probably

DSMBbull 1-2 sites investigators know each patient

bull DSMB knows just numbers

bull Steering committee should meet before every stagedose escalation decision etc

bull Larger studiesmore sites may need independent review

Final thoughtsbull Early phase studies often have lsquosimplersquo

designs

bull More complex logistical practical issues than late stage designs

bull These must be incorporated in analysis design interpretation inference

Final thoughtsbull Must as a biostatistician have understanding

of non-statistical aspects and

bull Must be able to communicate effectively with non-statisticians (clinicians nurses CRA ethics regulatory pathologists radiologists lab technicians scientists IT geneticists hellip)

• Early Phase Clinical Trials
• Learning Objectives
• My Background (biases)
• Your Background
• Thought Experiment
• Standard Drug Development Paradigm
• Phase I
• Phase II
• Clinical Trial Phases
• Clinical Trial 1
• TGN1412 for RA
• Dose Levels
• Phase I Cancer (3+3)
• DLTs
• Slide 15
• Phase I Non-cancer
• Slide 17
• Slide 18
• Cancer Phase I Ethics
• Ethics
• Slide 21
• Correct RP2D
• PowerPoint Presentation
• Slide 24
• Modified Designs
• Model-Based Designs
• Example dose-toxicity curve
• Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74
• Others
• Slide 30
• Secondary Outcomes
• Slide 32
• Howeverhellip
• Targeted Agents
• Slide 35
• Slide 36
• Phase II non-cancer
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Phase II Cancer
• Slide 44
• Slide 45
• Slide 46
• Design Issues
• Questions
• Slide 49
• Randomized Phase II designs
• Randomized Phase II Outcomes
• Other designs
• Slide 53
• lsquoNovelrsquo designs
• Slide 55
• RDT Trials
• Crossover
• Slide 58
• Bayesian Response-Toxicity Curve
• Genetic Marker Design
• Bayesian Adaptive Design
• Marker Designs
• Combined Phase Trials
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Phase 0
• Slide 69
• Additional Considerations
• Slide 71
• Slide 72
• Data Collection
• Slide 74
• Slide 75
• Privacy
• Consent Form
• Regulatory Burden
• Slide 79
• Slide 80
• DSMB
• Slide 82
• Final thoughts
• Slide 84

Privacybull Large restrictions on data captured due to

privacy

bull Date of birth diagnosis ndash restricted to year

bull Genetic markers

bull Want tissue sample sent to third party for QA review ndash did you specify in the consent

Consent Formbull Legal document describing procedures

goals information needed options for patient

bull Very detailed (I have seen gt30 page consents)

bull Sub-consents for biomarker research

bull Signed by patient personnel (not in position of authority)

Regulatory Burdenbull 296 distinct processes required to activate a phase III trial

bull Dilts DM Sandler AB Cheng S et al (2009) Steps and time to process clinical trials at the Cancer Therapy Evaluation Program J Clin Oncol 271761ndash1766

Area Processing Step Decision Point Loop Stopping Point

Concept (total) 106 21 5 6

emspemspemspemspCRM 76 13 2 4

emspemspemspemspTask force 71 19 4 5

Protocol 88 17 8 4

PMB 10 6 2 1

CDE 20 4 1 0

CIRB 34 9 5 2

Final review 16 3 3 0

Total CRM 244 52 21 11

Total task force 239 58 23 12

Comparison of Works Steps Decision Points Loops and Stopping Points by Major Stage of Development

Dilts D M et al JCO 2009271761-1766

Median of gt600 days from concept to activation

Procedure CostLife-Year Saved

Clinical trials regulations $2700000

Hemodialysis29 $43000-$104000

Statins for heart disease (moderate- to high-risk patients)30 $19000-$25000

Colorectal cancer screening by colonoscopy32 $14000

Adjuvant trastuzumab breast cancer31 $20000

Bevacizumab advanced nonndashsmall-cell lung cancer33 $380000

Paclitaxelcisplatin for advanced ovarian cancer34 $26000

David J Stewart Simon N Whitney Razelle Kurzrock Equipoise Lost Ethics Costs and the Regulation of Cancer Clinical Research JCO 28(17) 2925-2935 2010

Costs per Year of Life Gained by Selected Interventions

DSMBbull Debate about if they are needed

bull Phase I probably not

bull Cancer phase II ndash depends on design (randomized or single-arm of patients)

bull Non-cancer phase II - probably

DSMBbull 1-2 sites investigators know each patient

bull DSMB knows just numbers

bull Steering committee should meet before every stagedose escalation decision etc

bull Larger studiesmore sites may need independent review

Final thoughtsbull Early phase studies often have lsquosimplersquo

designs

bull More complex logistical practical issues than late stage designs

bull These must be incorporated in analysis design interpretation inference

Final thoughtsbull Must as a biostatistician have understanding

of non-statistical aspects and

bull Must be able to communicate effectively with non-statisticians (clinicians nurses CRA ethics regulatory pathologists radiologists lab technicians scientists IT geneticists hellip)

• Early Phase Clinical Trials
• Learning Objectives
• My Background (biases)
• Your Background
• Thought Experiment
• Standard Drug Development Paradigm
• Phase I
• Phase II
• Clinical Trial Phases
• Clinical Trial 1
• TGN1412 for RA
• Dose Levels
• Phase I Cancer (3+3)
• DLTs
• Slide 15
• Phase I Non-cancer
• Slide 17
• Slide 18
• Cancer Phase I Ethics
• Ethics
• Slide 21
• Correct RP2D
• PowerPoint Presentation
• Slide 24
• Modified Designs
• Model-Based Designs
• Example dose-toxicity curve
• Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74
• Others
• Slide 30
• Secondary Outcomes
• Slide 32
• Howeverhellip
• Targeted Agents
• Slide 35
• Slide 36
• Phase II non-cancer
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Phase II Cancer
• Slide 44
• Slide 45
• Slide 46
• Design Issues
• Questions
• Slide 49
• Randomized Phase II designs
• Randomized Phase II Outcomes
• Other designs
• Slide 53
• lsquoNovelrsquo designs
• Slide 55
• RDT Trials
• Crossover
• Slide 58
• Bayesian Response-Toxicity Curve
• Genetic Marker Design
• Bayesian Adaptive Design
• Marker Designs
• Combined Phase Trials
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Phase 0
• Slide 69
• Additional Considerations
• Slide 71
• Slide 72
• Data Collection
• Slide 74
• Slide 75
• Privacy
• Consent Form
• Regulatory Burden
• Slide 79
• Slide 80
• DSMB
• Slide 82
• Final thoughts
• Slide 84

Consent Formbull Legal document describing procedures

goals information needed options for patient

bull Very detailed (I have seen gt30 page consents)

bull Sub-consents for biomarker research

bull Signed by patient personnel (not in position of authority)

Regulatory Burdenbull 296 distinct processes required to activate a phase III trial

bull Dilts DM Sandler AB Cheng S et al (2009) Steps and time to process clinical trials at the Cancer Therapy Evaluation Program J Clin Oncol 271761ndash1766

Area Processing Step Decision Point Loop Stopping Point

Concept (total) 106 21 5 6

emspemspemspemspCRM 76 13 2 4

emspemspemspemspTask force 71 19 4 5

Protocol 88 17 8 4

PMB 10 6 2 1

CDE 20 4 1 0

CIRB 34 9 5 2

Final review 16 3 3 0

Total CRM 244 52 21 11

Total task force 239 58 23 12

Comparison of Works Steps Decision Points Loops and Stopping Points by Major Stage of Development

Dilts D M et al JCO 2009271761-1766

Median of gt600 days from concept to activation

Procedure CostLife-Year Saved

Clinical trials regulations $2700000

Hemodialysis29 $43000-$104000

Statins for heart disease (moderate- to high-risk patients)30 $19000-$25000

Colorectal cancer screening by colonoscopy32 $14000

Adjuvant trastuzumab breast cancer31 $20000

Bevacizumab advanced nonndashsmall-cell lung cancer33 $380000

Paclitaxelcisplatin for advanced ovarian cancer34 $26000

David J Stewart Simon N Whitney Razelle Kurzrock Equipoise Lost Ethics Costs and the Regulation of Cancer Clinical Research JCO 28(17) 2925-2935 2010

Costs per Year of Life Gained by Selected Interventions

DSMBbull Debate about if they are needed

bull Phase I probably not

bull Cancer phase II ndash depends on design (randomized or single-arm of patients)

bull Non-cancer phase II - probably

DSMBbull 1-2 sites investigators know each patient

bull DSMB knows just numbers

bull Steering committee should meet before every stagedose escalation decision etc

bull Larger studiesmore sites may need independent review

Final thoughtsbull Early phase studies often have lsquosimplersquo

designs

bull More complex logistical practical issues than late stage designs

bull These must be incorporated in analysis design interpretation inference

Final thoughtsbull Must as a biostatistician have understanding

of non-statistical aspects and

bull Must be able to communicate effectively with non-statisticians (clinicians nurses CRA ethics regulatory pathologists radiologists lab technicians scientists IT geneticists hellip)

• Early Phase Clinical Trials
• Learning Objectives
• My Background (biases)
• Your Background
• Thought Experiment
• Standard Drug Development Paradigm
• Phase I
• Phase II
• Clinical Trial Phases
• Clinical Trial 1
• TGN1412 for RA
• Dose Levels
• Phase I Cancer (3+3)
• DLTs
• Slide 15
• Phase I Non-cancer
• Slide 17
• Slide 18
• Cancer Phase I Ethics
• Ethics
• Slide 21
• Correct RP2D
• PowerPoint Presentation
• Slide 24
• Modified Designs
• Model-Based Designs
• Example dose-toxicity curve
• Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74
• Others
• Slide 30
• Secondary Outcomes
• Slide 32
• Howeverhellip
• Targeted Agents
• Slide 35
• Slide 36
• Phase II non-cancer
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Phase II Cancer
• Slide 44
• Slide 45
• Slide 46
• Design Issues
• Questions
• Slide 49
• Randomized Phase II designs
• Randomized Phase II Outcomes
• Other designs
• Slide 53
• lsquoNovelrsquo designs
• Slide 55
• RDT Trials
• Crossover
• Slide 58
• Bayesian Response-Toxicity Curve
• Genetic Marker Design
• Bayesian Adaptive Design
• Marker Designs
• Combined Phase Trials
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Phase 0
• Slide 69
• Additional Considerations
• Slide 71
• Slide 72
• Data Collection
• Slide 74
• Slide 75
• Privacy
• Consent Form
• Regulatory Burden
• Slide 79
• Slide 80
• DSMB
• Slide 82
• Final thoughts
• Slide 84

Regulatory Burdenbull 296 distinct processes required to activate a phase III trial

bull Dilts DM Sandler AB Cheng S et al (2009) Steps and time to process clinical trials at the Cancer Therapy Evaluation Program J Clin Oncol 271761ndash1766

Area Processing Step Decision Point Loop Stopping Point

Concept (total) 106 21 5 6

emspemspemspemspCRM 76 13 2 4

emspemspemspemspTask force 71 19 4 5

Protocol 88 17 8 4

PMB 10 6 2 1

CDE 20 4 1 0

CIRB 34 9 5 2

Final review 16 3 3 0

Total CRM 244 52 21 11

Total task force 239 58 23 12

Comparison of Works Steps Decision Points Loops and Stopping Points by Major Stage of Development

Dilts D M et al JCO 2009271761-1766

Median of gt600 days from concept to activation

Procedure CostLife-Year Saved

Clinical trials regulations $2700000

Hemodialysis29 $43000-$104000

Statins for heart disease (moderate- to high-risk patients)30 $19000-$25000

Colorectal cancer screening by colonoscopy32 $14000

Adjuvant trastuzumab breast cancer31 $20000

Bevacizumab advanced nonndashsmall-cell lung cancer33 $380000

Paclitaxelcisplatin for advanced ovarian cancer34 $26000

David J Stewart Simon N Whitney Razelle Kurzrock Equipoise Lost Ethics Costs and the Regulation of Cancer Clinical Research JCO 28(17) 2925-2935 2010

Costs per Year of Life Gained by Selected Interventions

DSMBbull Debate about if they are needed

bull Phase I probably not

bull Cancer phase II ndash depends on design (randomized or single-arm of patients)

bull Non-cancer phase II - probably

DSMBbull 1-2 sites investigators know each patient

bull DSMB knows just numbers

bull Steering committee should meet before every stagedose escalation decision etc

bull Larger studiesmore sites may need independent review

Final thoughtsbull Early phase studies often have lsquosimplersquo

designs

bull More complex logistical practical issues than late stage designs

bull These must be incorporated in analysis design interpretation inference

Final thoughtsbull Must as a biostatistician have understanding

of non-statistical aspects and

bull Must be able to communicate effectively with non-statisticians (clinicians nurses CRA ethics regulatory pathologists radiologists lab technicians scientists IT geneticists hellip)

• Early Phase Clinical Trials
• Learning Objectives
• My Background (biases)
• Your Background
• Thought Experiment
• Standard Drug Development Paradigm
• Phase I
• Phase II
• Clinical Trial Phases
• Clinical Trial 1
• TGN1412 for RA
• Dose Levels
• Phase I Cancer (3+3)
• DLTs
• Slide 15
• Phase I Non-cancer
• Slide 17
• Slide 18
• Cancer Phase I Ethics
• Ethics
• Slide 21
• Correct RP2D
• PowerPoint Presentation
• Slide 24
• Modified Designs
• Model-Based Designs
• Example dose-toxicity curve
• Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74
• Others
• Slide 30
• Secondary Outcomes
• Slide 32
• Howeverhellip
• Targeted Agents
• Slide 35
• Slide 36
• Phase II non-cancer
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Phase II Cancer
• Slide 44
• Slide 45
• Slide 46
• Design Issues
• Questions
• Slide 49
• Randomized Phase II designs
• Randomized Phase II Outcomes
• Other designs
• Slide 53
• lsquoNovelrsquo designs
• Slide 55
• RDT Trials
• Crossover
• Slide 58
• Bayesian Response-Toxicity Curve
• Genetic Marker Design
• Bayesian Adaptive Design
• Marker Designs
• Combined Phase Trials
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Phase 0
• Slide 69
• Additional Considerations
• Slide 71
• Slide 72
• Data Collection
• Slide 74
• Slide 75
• Privacy
• Consent Form
• Regulatory Burden
• Slide 79
• Slide 80
• DSMB
• Slide 82
• Final thoughts
• Slide 84

Dilts D M et al JCO 2009271761-1766

Median of gt600 days from concept to activation

Procedure CostLife-Year Saved

Clinical trials regulations $2700000

Hemodialysis29 $43000-$104000

Statins for heart disease (moderate- to high-risk patients)30 $19000-$25000

Colorectal cancer screening by colonoscopy32 $14000

Adjuvant trastuzumab breast cancer31 $20000

Bevacizumab advanced nonndashsmall-cell lung cancer33 $380000

Paclitaxelcisplatin for advanced ovarian cancer34 $26000

David J Stewart Simon N Whitney Razelle Kurzrock Equipoise Lost Ethics Costs and the Regulation of Cancer Clinical Research JCO 28(17) 2925-2935 2010

Costs per Year of Life Gained by Selected Interventions

DSMBbull Debate about if they are needed

bull Phase I probably not

bull Cancer phase II ndash depends on design (randomized or single-arm of patients)

bull Non-cancer phase II - probably

DSMBbull 1-2 sites investigators know each patient

bull DSMB knows just numbers

bull Steering committee should meet before every stagedose escalation decision etc

bull Larger studiesmore sites may need independent review

Final thoughtsbull Early phase studies often have lsquosimplersquo

designs

bull More complex logistical practical issues than late stage designs

bull These must be incorporated in analysis design interpretation inference

Final thoughtsbull Must as a biostatistician have understanding

of non-statistical aspects and

bull Must be able to communicate effectively with non-statisticians (clinicians nurses CRA ethics regulatory pathologists radiologists lab technicians scientists IT geneticists hellip)

• Early Phase Clinical Trials
• Learning Objectives
• My Background (biases)
• Your Background
• Thought Experiment
• Standard Drug Development Paradigm
• Phase I
• Phase II
• Clinical Trial Phases
• Clinical Trial 1
• TGN1412 for RA
• Dose Levels
• Phase I Cancer (3+3)
• DLTs
• Slide 15
• Phase I Non-cancer
• Slide 17
• Slide 18
• Cancer Phase I Ethics
• Ethics
• Slide 21
• Correct RP2D
• PowerPoint Presentation
• Slide 24
• Modified Designs
• Model-Based Designs
• Example dose-toxicity curve
• Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74
• Others
• Slide 30
• Secondary Outcomes
• Slide 32
• Howeverhellip
• Targeted Agents
• Slide 35
• Slide 36
• Phase II non-cancer
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Phase II Cancer
• Slide 44
• Slide 45
• Slide 46
• Design Issues
• Questions
• Slide 49
• Randomized Phase II designs
• Randomized Phase II Outcomes
• Other designs
• Slide 53
• lsquoNovelrsquo designs
• Slide 55
• RDT Trials
• Crossover
• Slide 58
• Bayesian Response-Toxicity Curve
• Genetic Marker Design
• Bayesian Adaptive Design
• Marker Designs
• Combined Phase Trials
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Phase 0
• Slide 69
• Additional Considerations
• Slide 71
• Slide 72
• Data Collection
• Slide 74
• Slide 75
• Privacy
• Consent Form
• Regulatory Burden
• Slide 79
• Slide 80
• DSMB
• Slide 82
• Final thoughts
• Slide 84

Procedure CostLife-Year Saved

Clinical trials regulations $2700000

Hemodialysis29 $43000-$104000

Statins for heart disease (moderate- to high-risk patients)30 $19000-$25000

Colorectal cancer screening by colonoscopy32 $14000

Adjuvant trastuzumab breast cancer31 $20000

Bevacizumab advanced nonndashsmall-cell lung cancer33 $380000

Paclitaxelcisplatin for advanced ovarian cancer34 $26000

David J Stewart Simon N Whitney Razelle Kurzrock Equipoise Lost Ethics Costs and the Regulation of Cancer Clinical Research JCO 28(17) 2925-2935 2010

Costs per Year of Life Gained by Selected Interventions

DSMBbull Debate about if they are needed

bull Phase I probably not

bull Cancer phase II ndash depends on design (randomized or single-arm of patients)

bull Non-cancer phase II - probably

DSMBbull 1-2 sites investigators know each patient

bull DSMB knows just numbers

bull Steering committee should meet before every stagedose escalation decision etc

bull Larger studiesmore sites may need independent review

Final thoughtsbull Early phase studies often have lsquosimplersquo

designs

bull More complex logistical practical issues than late stage designs

bull These must be incorporated in analysis design interpretation inference

Final thoughtsbull Must as a biostatistician have understanding

of non-statistical aspects and

bull Must be able to communicate effectively with non-statisticians (clinicians nurses CRA ethics regulatory pathologists radiologists lab technicians scientists IT geneticists hellip)

• Early Phase Clinical Trials
• Learning Objectives
• My Background (biases)
• Your Background
• Thought Experiment
• Standard Drug Development Paradigm
• Phase I
• Phase II
• Clinical Trial Phases
• Clinical Trial 1
• TGN1412 for RA
• Dose Levels
• Phase I Cancer (3+3)
• DLTs
• Slide 15
• Phase I Non-cancer
• Slide 17
• Slide 18
• Cancer Phase I Ethics
• Ethics
• Slide 21
• Correct RP2D
• PowerPoint Presentation
• Slide 24
• Modified Designs
• Model-Based Designs
• Example dose-toxicity curve
• Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74
• Others
• Slide 30
• Secondary Outcomes
• Slide 32
• Howeverhellip
• Targeted Agents
• Slide 35
• Slide 36
• Phase II non-cancer
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Phase II Cancer
• Slide 44
• Slide 45
• Slide 46
• Design Issues
• Questions
• Slide 49
• Randomized Phase II designs
• Randomized Phase II Outcomes
• Other designs
• Slide 53
• lsquoNovelrsquo designs
• Slide 55
• RDT Trials
• Crossover
• Slide 58
• Bayesian Response-Toxicity Curve
• Genetic Marker Design
• Bayesian Adaptive Design
• Marker Designs
• Combined Phase Trials
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Phase 0
• Slide 69
• Additional Considerations
• Slide 71
• Slide 72
• Data Collection
• Slide 74
• Slide 75
• Privacy
• Consent Form
• Regulatory Burden
• Slide 79
• Slide 80
• DSMB
• Slide 82
• Final thoughts
• Slide 84

DSMBbull Debate about if they are needed

bull Phase I probably not

bull Cancer phase II ndash depends on design (randomized or single-arm of patients)

bull Non-cancer phase II - probably

DSMBbull 1-2 sites investigators know each patient

bull DSMB knows just numbers

bull Steering committee should meet before every stagedose escalation decision etc

bull Larger studiesmore sites may need independent review

Final thoughtsbull Early phase studies often have lsquosimplersquo

designs

bull More complex logistical practical issues than late stage designs

bull These must be incorporated in analysis design interpretation inference

Final thoughtsbull Must as a biostatistician have understanding

of non-statistical aspects and

bull Must be able to communicate effectively with non-statisticians (clinicians nurses CRA ethics regulatory pathologists radiologists lab technicians scientists IT geneticists hellip)

• Early Phase Clinical Trials
• Learning Objectives
• My Background (biases)
• Your Background
• Thought Experiment
• Standard Drug Development Paradigm
• Phase I
• Phase II
• Clinical Trial Phases
• Clinical Trial 1
• TGN1412 for RA
• Dose Levels
• Phase I Cancer (3+3)
• DLTs
• Slide 15
• Phase I Non-cancer
• Slide 17
• Slide 18
• Cancer Phase I Ethics
• Ethics
• Slide 21
• Correct RP2D
• PowerPoint Presentation
• Slide 24
• Modified Designs
• Model-Based Designs
• Example dose-toxicity curve
• Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74
• Others
• Slide 30
• Secondary Outcomes
• Slide 32
• Howeverhellip
• Targeted Agents
• Slide 35
• Slide 36
• Phase II non-cancer
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Phase II Cancer
• Slide 44
• Slide 45
• Slide 46
• Design Issues
• Questions
• Slide 49
• Randomized Phase II designs
• Randomized Phase II Outcomes
• Other designs
• Slide 53
• lsquoNovelrsquo designs
• Slide 55
• RDT Trials
• Crossover
• Slide 58
• Bayesian Response-Toxicity Curve
• Genetic Marker Design
• Bayesian Adaptive Design
• Marker Designs
• Combined Phase Trials
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Phase 0
• Slide 69
• Additional Considerations
• Slide 71
• Slide 72
• Data Collection
• Slide 74
• Slide 75
• Privacy
• Consent Form
• Regulatory Burden
• Slide 79
• Slide 80
• DSMB
• Slide 82
• Final thoughts
• Slide 84

DSMBbull 1-2 sites investigators know each patient

bull DSMB knows just numbers

bull Steering committee should meet before every stagedose escalation decision etc

bull Larger studiesmore sites may need independent review

Final thoughtsbull Early phase studies often have lsquosimplersquo

designs

bull More complex logistical practical issues than late stage designs

bull These must be incorporated in analysis design interpretation inference

Final thoughtsbull Must as a biostatistician have understanding

of non-statistical aspects and

bull Must be able to communicate effectively with non-statisticians (clinicians nurses CRA ethics regulatory pathologists radiologists lab technicians scientists IT geneticists hellip)

• Early Phase Clinical Trials
• Learning Objectives
• My Background (biases)
• Your Background
• Thought Experiment
• Standard Drug Development Paradigm
• Phase I
• Phase II
• Clinical Trial Phases
• Clinical Trial 1
• TGN1412 for RA
• Dose Levels
• Phase I Cancer (3+3)
• DLTs
• Slide 15
• Phase I Non-cancer
• Slide 17
• Slide 18
• Cancer Phase I Ethics
• Ethics
• Slide 21
• Correct RP2D
• PowerPoint Presentation
• Slide 24
• Modified Designs
• Model-Based Designs
• Example dose-toxicity curve
• Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74
• Others
• Slide 30
• Secondary Outcomes
• Slide 32
• Howeverhellip
• Targeted Agents
• Slide 35
• Slide 36
• Phase II non-cancer
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Phase II Cancer
• Slide 44
• Slide 45
• Slide 46
• Design Issues
• Questions
• Slide 49
• Randomized Phase II designs
• Randomized Phase II Outcomes
• Other designs
• Slide 53
• lsquoNovelrsquo designs
• Slide 55
• RDT Trials
• Crossover
• Slide 58
• Bayesian Response-Toxicity Curve
• Genetic Marker Design
• Bayesian Adaptive Design
• Marker Designs
• Combined Phase Trials
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Phase 0
• Slide 69
• Additional Considerations
• Slide 71
• Slide 72
• Data Collection
• Slide 74
• Slide 75
• Privacy
• Consent Form
• Regulatory Burden
• Slide 79
• Slide 80
• DSMB
• Slide 82
• Final thoughts
• Slide 84

Final thoughtsbull Early phase studies often have lsquosimplersquo

designs

bull More complex logistical practical issues than late stage designs

bull These must be incorporated in analysis design interpretation inference

Final thoughtsbull Must as a biostatistician have understanding

of non-statistical aspects and

bull Must be able to communicate effectively with non-statisticians (clinicians nurses CRA ethics regulatory pathologists radiologists lab technicians scientists IT geneticists hellip)

• Early Phase Clinical Trials
• Learning Objectives
• My Background (biases)
• Your Background
• Thought Experiment
• Standard Drug Development Paradigm
• Phase I
• Phase II
• Clinical Trial Phases
• Clinical Trial 1
• TGN1412 for RA
• Dose Levels
• Phase I Cancer (3+3)
• DLTs
• Slide 15
• Phase I Non-cancer
• Slide 17
• Slide 18
• Cancer Phase I Ethics
• Ethics
• Slide 21
• Correct RP2D
• PowerPoint Presentation
• Slide 24
• Modified Designs
• Model-Based Designs
• Example dose-toxicity curve
• Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74
• Others
• Slide 30
• Secondary Outcomes
• Slide 32
• Howeverhellip
• Targeted Agents
• Slide 35
• Slide 36
• Phase II non-cancer
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Phase II Cancer
• Slide 44
• Slide 45
• Slide 46
• Design Issues
• Questions
• Slide 49
• Randomized Phase II designs
• Randomized Phase II Outcomes
• Other designs
• Slide 53
• lsquoNovelrsquo designs
• Slide 55
• RDT Trials
• Crossover
• Slide 58
• Bayesian Response-Toxicity Curve
• Genetic Marker Design
• Bayesian Adaptive Design
• Marker Designs
• Combined Phase Trials
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Phase 0
• Slide 69
• Additional Considerations
• Slide 71
• Slide 72
• Data Collection
• Slide 74
• Slide 75
• Privacy
• Consent Form
• Regulatory Burden
• Slide 79
• Slide 80
• DSMB
• Slide 82
• Final thoughts
• Slide 84

Final thoughtsbull Must as a biostatistician have understanding

of non-statistical aspects and

bull Must be able to communicate effectively with non-statisticians (clinicians nurses CRA ethics regulatory pathologists radiologists lab technicians scientists IT geneticists hellip)

• Early Phase Clinical Trials
• Learning Objectives
• My Background (biases)
• Your Background
• Thought Experiment
• Standard Drug Development Paradigm
• Phase I
• Phase II
• Clinical Trial Phases
• Clinical Trial 1
• TGN1412 for RA
• Dose Levels
• Phase I Cancer (3+3)
• DLTs
• Slide 15
• Phase I Non-cancer
• Slide 17
• Slide 18
• Cancer Phase I Ethics
• Ethics
• Slide 21
• Correct RP2D
• PowerPoint Presentation
• Slide 24
• Modified Designs
• Model-Based Designs
• Example dose-toxicity curve
• Garrett-Mayer E Understanding the Continual Reassessment Method for Dose Finding Studies An Overview for Non-Statisticians (March 2005) Johns Hopkins University Dept of Biostatistics Working Papers Working Paper 74
• Others
• Slide 30
• Secondary Outcomes
• Slide 32
• Howeverhellip
• Targeted Agents
• Slide 35
• Slide 36
• Phase II non-cancer
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Phase II Cancer
• Slide 44
• Slide 45
• Slide 46
• Design Issues
• Questions
• Slide 49
• Randomized Phase II designs
• Randomized Phase II Outcomes
• Other designs
• Slide 53
• lsquoNovelrsquo designs
• Slide 55
• RDT Trials
• Crossover
• Slide 58
• Bayesian Response-Toxicity Curve
• Genetic Marker Design
• Bayesian Adaptive Design
• Marker Designs
• Combined Phase Trials
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Phase 0
• Slide 69
• Additional Considerations
• Slide 71
• Slide 72
• Data Collection
• Slide 74
• Slide 75
• Privacy
• Consent Form
• Regulatory Burden
• Slide 79
• Slide 80
• DSMB
• Slide 82
• Final thoughts
• Slide 84