Dr. Bhaswat S. ChakrabortySenior Vice President and Chairman,

R&D Core Committee, Cadila Pharmaceuticals Ltd.

Vaccines Summit 2012, Hyderabad, India30-31 August, 2012

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ContentsDetermining the financial and decisional risks associated

with the early phase trialsUnderstanding the best study designs and selection of

controls to eliminate candidatesUnderstanding the end point selection for Cancer clinical

trialsComparing progress free and overall survival in Intend To

Treat (ITT) and per protocol (PP) populationsCritically analysing the decision to proceed to Phase III or

to terminate the trialCase study: Discussing the best practice strategies on

‘Phase II clinical trials of vaccines – to go or not to go to Phase III

Concluding remarks2

Success of a [Phase II] Clinical Trial

Right Scientific Questions

Generalizable Results

Right conduct of the trial

Adequate scope, time & budget

Proceed to higher phases

PoC of Efficacy, Safety, Dose & Frequency

Does this drug increase survivability in …cancer?

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Operational Challenges under Resource ConstraintsResource constraints

FiscalOrganizaionalTechnicalRegulatory

Operational challenges under these constraintsOperational planning scheduling under uncertaintyMeeting design objectives, timelines & scopeSupply chain managementQuality and monitoringCompletion within variable? budget

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Resource Constraints – some characteristicsFiscal

Very common in developing countries – low and unrealistic budgets given the scope & conduct of the study

Difficulty in payments even commitment issuesGaining approval for out-of-pocket expenses is difficult

OrganizationalTeam building, team performance and team achievement are often new

concepts in some culturesTechnical

Often drugs are developed one by one rather than a portfolio of a group of drugs which increases success probability

RegulatoryOften a big challenge within the firm & national body– starting from

getting a trial license, not well developed review system, no defined performance standard in timelines up to limited expertise and overreaction to SAEs 5

Design & Control Issues in Phase II Cancer Trials

One of the major issues is the use of controlsOne study* finds that only ~20% Phase II Cancer Trials use active or

historical control or placebo (notwithstanding a higher reporting of Onco trials)

Remember the primary objective of a phase II cancer clinical trials is to determine whether to proceed for a further Phase II or a Phase III study

This requires basically a demonstration of substantial efficacy of a new regimen

However, oncology Phase II has been limited by high rates of failure (lack of efficacy) in subsequent phase III testing

This is in part because of use of single arm studies which can easily discard a study with an apparent low efficacy that due to factors other than the drug itself

*Michaelis et al. (2007). Clin Cancer Res,13, 2400–56

Design & Control Issues in Phase II Cancer Trials

One of the major issues is the use of controlsOne study* finds that only ~20% Phase II Cancer Trials use active or

historical control or placebo (notwithstanding a higher reporting of Onco trials)

Remember the primary objective of a phase II cancer clinical trials is to determine whether to proceed for a further Phase II or a Phase III stdy

This requires basically a demonstration of substantial efficacy of a new regimen

However, oncology Phase II has been limited by high rates of failure (lack of efficacy) in subsequent phase III testing

This is in part because of use of single arm studies which can easily discard a study with an apparent low efficacy that due to factors other than the drug itself

*Michaelis et al. (2007). Clin Cancer Res,13, 2400–57

Design & Control Issues in Phase II Cancer Trials..

The “go or no go” decision at the end of phase II is perhaps the most difficult one to make in the drug development cycledata are limited future investment required for a phase III trial is vast success of the company may depend on the drug in questionan informative phase II trial is crucialafter phase II, the decision makers need to understand toxicity and

pharmacokinetics, should have strong indications of activity in a specific kind of cancer, and should have a clear sense of an approval strategy

There are often gaps in this knowledge, and the decision is guided by both fact and intuition.

The decision becomes easier when the case is unmet medical needsChabner B. (2007). Clin Cancer Res,13, 2307

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Design & Control Issues in Phase II Cancer Trials...

Herceptin, Erbitux, and Avastin may have only modest activity as single agents and produce few clinical responses

Their effect requires more subtle trial designse.g., delay time to progression or recurrence or enhance response rates

to standard cytotoxic agents. single arm phase II trial, with response as the end point, may lead to the

abandonment of a valuable drug

Larger trials, and more complex phase II designs with TTP end points, may be required to show effectiveness of the new agenthere, concurrent controls, treated with standard agents or or other

strategies might show valuable aspects of the toxicity and effectiveness of the new agent

e.g sorafenib, [U of Chicago Researchers] randomized stable patients to continued therapy vs. drug discontinuation, with positive for patients continuing with experimental drug

Chabner B. (2007). Clin Cancer Res,13, 23079

Design & Control Issues in Phase II Cancer Trials...

The best design for phase II will depend on the nature of the agent, activity in phase I, the disease setting, the degree of certainty about best dose and schedule coming out of phase I trials, and the competition faced by the new drug.

A randomization involving two different doses of drug might show a dose-response relationship e.g., imatinib, it is unclear whether escalation beyond the recommended 400

mg/d dose might have long-term benefit for certain patients.

New molecular technologies offer remarkable insights gene expression profiling and molecular studies have illuminated distinct

subpopulations within pathologic categories of cancer role of epidermal growth factor receptor mutations in predicting response to

gefitinib and erlotinib development of biomarkers

phase II setting is the setting for appropriate patient

Chabner B. (2007). Clin Cancer Res,13, 230710

Endpoints in Oncology Trials

Must show either direct evidence of clinical benefit or improvement in an established surrogate for clinical benefit

Clinical benefit: survival improvement Overall survival (OS)Progress-free survival (PFS) (usually Ph III)

Improvement in a patient’s quality of life (QOL) (usually Ph III)Other endpoints on which approval has been given are:

Objective response rate (ORR) by RECIST or any radiological tests or physical examinations

Improvement in survival, improvement in a QOL, improved physical functioning, or improved tumor-related symptoms do not always be predicted by, or correlate with, ORR

Source: US FDA Guidance11

Relative Merits

Endpoint Evidence Assessment Some Advantages Some Disadvantages

Survival Clinical benefit • RCT needed

• Blinding not essential

• Direct measure of benefit• Easily measured• Precisely measured

• Requires larger and longer studies• Potentially affected by crossover therapy• Does not capture symptom benefit• Includes noncancer deaths

Disease-Free Survival (DFS)

Surrogate for accelerated approval or regular approval*

• RCT needed • Blinding preferred

• Considered to be clinical benefit by some• Needs fewer patients and shorter studies than survival

• Not a validated survival surrogate in most settings• Subject to assessment bias• Various definitions exist

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Relative Merits..Endpoint Evidence Assessment Some Advantages Some Disadvantages

Objective Response Rate (ORR)

Surrogate for accelerated approval or regular approval*

• Single-arm or randomized studies can be used • Blinding preferred in comparative studies

• Can be assessed in single-arm studies

• Not a direct measure of benefit• Usually reflects drug activity in a minority of patients • Data are moderately complex compared to survival

Complete Response (CR)

Surrogate for accelerated approval or regular approval*

• Single-arm or randomized studies can be used• Blinding preferred in comparative studies

• Durable CRs represent obvious benefit in some settings (see text)• Can be assessed in single-arm studies

• Few drugs produce high rates of CR • Data are moderately complex compared to survival

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Overall Survival (OS)OS: The time from randomization until death from any cause

Measured usually in the intent-to-treat (ITT) population

Most reliable cancer endpoint, and when studies can be conducted to adequately assess survival, it is usually the preferred endpoint

Precise and easy to measure – no influence of technicality of measurement

Bias is not a factor in endpoint measurement

Survival improvement should be analyzed as a risk-benefit analysis to assess clinical benefit

OS should be evaluated in RCTs

Historical trials are seldom reliable for time-dependent endpoints (e.g., OS, PFS).

The OS in control arm has to be compatible

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Rosell et al. (2008), Annals of Oncology, 19, 362–36915

Endpoints Based on Tumor AssessmentsDisease-free survival (DFS)Objective response rate (ORR)Time to tumor progression (TTP)Progress-free survival (PFS)Time-to-treatment failure (TTF)They are all time-dependent endpointsCollection and analysis of these endpoints are based on indirect

assessments, calculations, and estimates (e.g., tumor measurements)Two critical judgments:

1. whether the endpoint will support either accelerated approval or regular approval

2. endpoint should be evaluated for the potential of bias or uncertainty in tumor endpoint assessments

Drug applications using studies that rely on tumor measurement-based endpoints as sole evidence of efficacy may need confirmatory evidence from a second trial

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Rosell et al. (2008), Annals of Oncology, 19, 362–36917

Cautions in Tumor AssessmentsAccuracy in measuring tumors can differ among tumor settingsImprecision can happen in locations where there is a lack of

demarcated margins (e.g., malignant mesothelioma, pancreatic cancer, brain tumors).

When the primary study endpoint is based on tumor measurements (e.g., PFS or ORR), tumor endpoint assessments generally should be verified by central reviewers blinded to study treatments This measure is especially important when the study is not blinded It may be appropriate for the FDA to audit a sample of the scans to

verify the central review process

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Quality of Life (QoL) EndpointsGlobal health-related quality of life (HRQL) have not served

as primary efficacy endpoints in oncology drug approvals

They are usually patient reported outcome measures For example, the FACT-L is a 44-item self-report instrument which measures

multidimensional quality of life in Phase II and III lung cancer clinical trials

Reliability and validity of such multi-item instruments must be thoroughly examined

For QOL to be used as primary endpoints to support cancer drug approval, the FDA should be able to distinguish between improvement in tumor symptoms and lack of drug toxicity

An apparent effectiveness advantage based on a global QoL instrument can simply indicate less toxicity rather than effectiveness

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BiomarkersUsually not a good idea for cancer drug approvalOther than paraprotein levels measured in blood and urine for

myeloma, biomarkers assayed from blood or body fluids have not served as primary endpoints

Not considered good predictors of clinical benefit The FDA has sometimes accepted tumor markers as elements of a

composite endpointe,g., clinical events such as significant decrease in performance status,

or bowel obstruction in conjunction with marked increases in CA-125 was considered progression in ovarian cancer patients

Biomarkers, however, can be useful in identifying prognostic factors and in selection of patients and stratification factors to be

considered in study designs

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Specific Symptom EndpointsTime to progression of cancer symptoms, an endpoint similar to TTP, is a

direct measure of clinical benefit rather than a potential surrogateProblems in measuring progression (e.g., missing assessments) also exist in

evaluating time to symptomatic progressionBecause few cancer trials are blinded, assessments can be biased

delay between tumor progression and the onset of cancer symptoms can occur alternative treatments are initiated before achieving the symptom endpoint,

confounding this analysis patients may have minimal cancer symptoms also, tumor symptoms can be difficult to differentiate from drug toxicity

Important composite symptom endpoint should have components of similar clinical

importance and the results should not be exclusively attributed to one component

missing data & infrequent treatment are also confounding factors

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Intent-to-Treat PrincipleAll randomized patientsExclusions on prespecified baseline criteria permissible

also known as Modified Intent-to-TreatConfusion regarding intent-to-treat population: define and agree upon in

advance based upon desired indicationAdvantages:

Comparison protected by randomization Guards against bias when dropping out is related to outcome

Can be interpreted as comparison of two strategiesFailure to take drug is informativeReflects the way treatments will perform in populationMore suitable for superiority trials

Concerns:“Difference detecting ability”

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Per Protocol Analyses

Focuses on the outcome dataAddresses what happens to patients who remain on

therapyTypically excludes patients with missing or problematic

dataMore suitable for non-inferiority trialsStatistical concerns:

Selection biasBias difficult to assess

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Intent to Treat & Per Protocol AnalysesBoth types of analyses are important for approval

Results should be logically consistent

Design protocol and monitor trial to minimize

exclusionsSubstantial missing data and poor drug compliance

weaken trial’s ability to demonstrate efficacy

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ITT

PP

Sandler et al. 2006. N Engl J Med, 355, 2542-50.OS & PFS – ITT vs PP 25

Belani et al. (2011), ASCO Annual Meeting26

Decision to Proceed to Phase III or Terminate

This is a consideration for IA Stopping rules for significant efficacy Stopping rules for futility Measures taken to minimize bias A procedure/method for preparation of data for analysis Data has to be centrally pooled, cleaned and locked Data analysis - blinded or unblinded? Interim results must be submitted to IDMC What is the scope of recommendations from IA results? What

should be made known to the Sponsor? Safety? Efficacy? Both? Futility? Sample size readjustment for

borderline results?

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Decision to Proceed to Phase III or Terminate..

Single arm studies Futility is better predicted in IA than success

However, when success/failure response is used Summarize success as the proportion of number of totally included

patients

To proceed for Phase III, it is important to know the norm (activity of current standard) and that the new treatment is expected to exceed this

Example The standard treatment for AML is fludarabine + ara-C (50% success) Addition of GCSF would be beneficial if Phase II shows ~70%

success

Thall & Simon (1994). Biometrics, 50, 337-34928

Concluding RemarksClinical testing of new Oncology products is very sophisticated and

complexCancer clinical data is very complex (censored, skewed, often fraught

with missing data point), therefore, proper hypothesization and statistical treatment of data are required

Resource challenges can affect operations and even the study designThere are many endpoints that are scientifically valid but OS as primary

end point is often preferred by regulatory agenciesPFS & Tumor assessment trials may need another confirmatory CTEndpoints must be demonstrative (directly or indirectly) of clinical

benefitMissing data, infrequent treatment, increased type I error and other

confounding factors must be addressedConsistent ITT & PP facilitate approvalCarefully establish “go or no-go” rules and critically examine IA data;

single arm should exceed the “norm” of standard successDespite good knowledge in endpoints & trial design, meet & consult

FDA before initiating a pivotal trial. 29

Thank you Very Much

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