Clinical trial essentials for medical imagers

Sponsoring Organizations: Radiological Society of North America, Oak Brook, ILNational Cancer Institute, NIH, Bethesda, MD

COMPILED AND EDITED BY C. CARL JAFFE, M.D. NCICLICK HERE FOR 2011 FULL PARTICIPATING FACULTY LIST

Concepts addressed in this courseHow does a screening trial differ from a therapeutic trial?How does a randomized control trial (RCT) differ from an observational trial?Must the control arm of a therapeutic RCT always be a placebo?What distinguishes Phase 1, 2, 3 and 4 trials?What are ‘Phase 0’ trials and what role would imaging have in them?What data do you need to determine a statistically valid study size?When does a trial need a Data Safety Monitoring (DSM) board?What functions do interim and futility analyses serve?What are the definitions of type 1 and type 2 errors?How do you constitute an imaging central reading review panel and how does it function?What is the regulatory definition (e.g., FDA) of a “surrogate’ biomarker?How do “prognostic” biomarkers differ from ‘predictive’ markers?What happens if an ‘adverse event’ occurs to a study subject?

Course Guide

TABLE OF CONTENTS

Introduction....................................................................................................................................................3Trials: their types...........................................................................................................................................4Diagnostic Technology Assessment Trials....................................................................................................5Introduction to Therapy Clinical Trials.........................................................................................................6Investigational Drugs and Devices..............................................................................................................14Biases and Their Control.............................................................................................................................15Assessing predictive value of tests...............................................................................................................18Imaging as a Measure of Therapeutic Response.........................................................................................18Ethics Considerations..................................................................................................................................18Monitoring of Clinical Trials: IRB, DSM, CTEP.......................................................................................21Sponsorship and Economics of Imaging Trials...........................................................................................23Informatics Tools for Protocol Development..............................................................................................25Bibliography................................................................................................................................................27Required reading, in advance of the workshop............................................................................................28

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IntroductionWhat are clinical trials? A clinical trial is a carefully designed research process. Studies are done to find out whether promising approaches to disease screening, diagnosis, and treatment are safe and effective <http://www.cancer.gov/clinicaltrials/learning/what-is-a-clinical-trial>.

Information ResourcesThe National Cancer Institute’s (NCI) Web site, cancer.gov, provides access to a wealth of information on clinical cancer care. The site contains information from PDQ®, including the latest information about cancer treatment, screening, prevention, genetics, supportive care, and complementary and alternative medicine, as well as a registry of cancer clinical trials that is coordinated with clinicaltrials.gov. The latter provides a listing of trials that the key medical publishers have agreed must have been pre-specified and announced, without which the trial results will not be published.

At the cancer.gov and the National Library of Medicine (NLM) websites clinical specialists review current literature from the medical journals, evaluate its relevance, and synthesize it into clear summaries, which are reviewed monthly and updated based on new information. Most information summaries appear in two versions: 1) a technical version for the health professional and 2) a non-technical version for patients, their families, and the public. Many of the summaries are also available in Spanish. NCI also maintains a telephone helpdesk for patients seeking cancer care and clinical trials information at 1-800-4-CANCER. The NCI Website also includes approximately 100 fact sheets on various cancer-related topics, information on ordering NCI publications, and educational features and news summaries concerning the latest results from cancer clinical trials.

NCI’s clinical trials registry (PDQ) contains more than 1,800 ongoing clinical trials, including information about studies around the world. The trials listed in the NCI PDQ site are transferred and harmonized weekly with the clinicaltrials.gov website maintained by NLM. The latter site includes trials on a variety of diseases besides cancer. Although no single resource lists every cancer clinical trial being conducted in the United States and abroad, PDQ is the most comprehensive cancer clinical trials registry. It contains information about trials sponsored by NCI, the pharmaceutical industry, and some international groups. Users can narrow their search by multiple parameters, such as stage of disease, phase of trial, treatment modality, and geographic location. PDQ also contains an archival file of more than 11,000 clinical trials that are no longer accepting patients, including contact information for the principal investigators of trials that may not yet be published in the biomedical

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literature. Demographics and incidence of cancer by state and other parameters are accessible from the NCI SEER database.

The American Cancer Society (ACS) has a website that also provides information on cancer prevalence and other information that can be helpful in determining the import and relevance during the planning of a clinical trial.

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Trials: their types Trial types can be classified as:

Treatment Prevention Screening Diagnostic Genetics Quality-of-life

Screening TrialsThe ultimate goal of screening is to reduce the burden of advanced disease. For many types of disease, detection and treatment of the disease at an early stage can result in an improved outcome. Single arm trials can be useful for determining if a new screening test can detect disease earlier, e.g., before it is symptomatic, and for determining the feasibility of screening. Non-invasive ways to detect disease at an early stage include body fluids and imaging. Randomized control trials (RCT) composed of a screened group and a control group is the most reliable method for determining whether earlier detection translates into a reduction in disease morbidity or mortality.

Diagnostic TrialsDiagnostic tests are conducted to determine whether cancer is present, where it is located and its stage. Some diagnostic trials compare two or more techniques to diagnose cancer and determine whether one technique is superior. Genetic tests are being evaluated as diagnostic tools to further classify cancers so as to direct therapies or improve treatments for people with specific genetic changes.

The Clinical Trial ProtocolClinical trials follow strict scientific guidelines. These guidelines clearly state the study’s design and who will be able to participate in the study (patient eligibility). Every trial has principal investigator(s). The principal investigator prepares a plan for the study (a protocol) which describes the clinical trial in complete detail. The protocol explains what the trial will do, how the study will be carried out, and why each part of the study is necessary. It includes information on:

The importance and rationale that justifies the study A statistically justified cohort size (for each arm) Eligibility criteria (requirements may involve type of cancer, general

health, age, prior therapy) The intervention or therapy being tested (e.g. drug dosage, etc.) What tests participants will have and how often (a ‘patient calendar’) What information will be gathered about the participants and how their

privacy will be protected

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The participants options if they choose to withdraw A readable consent form (at an eighth-grade readability level) The endpoints (primary and secondary) and correlative studies Methods of analysis Regulatory requirements and reporting obligations

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Diagnostic Technology Assessment TrialsSome trials are primarily focused on imaging technology endpoints such as sensitivity for disease detection or staging, etc. The trial design and its elements with thus encompass:

Scope of the diagnostic technology assessment process:– Developmental level of technology– Performance of technology, as measured by specific metrics.

Developmental stages of imaging technology Stage I (Discovery): Establishment of technical parameters and

diagnostic criteria. Stage II (Introductory): Early quantification of performance in clinical

cohorts, usually in single institution studies. Stage III (Mature): Comparison to other modalities in large, prospective,

multi-institutional clinical studies (efficacy ). Stage IV (Disseminated): Assessment of performance in the community

at largesetting (effectiveness).

Endpoints for diagnostic test evaluation Diagnostic performance (sensitivity, specificity, measures of accuracy

and predictive value) Intermediate process of care:

– Diagnostic thinking/decision making– Therapeutic thinking/decision making

Patient outcomes: Quality of life, satisfaction, cost, mortality, morbidity

Studies of diagnostic performance are Needed in all phases of diagnostic modality evaluation. Should incorporate the assessment of intra- and inter-reader variability.

Facets of the effect on process of care include: Effects on choice of further diagnostic workup; impact on utilization and

cost. Effects on patient management, such as decision to undergo surgery or

to administration of specific types of therapy. Techniques relatively easy to carry out.

Assessing impact on process of care Has important methodologic limitations:

– Confounding by temporal and institutional factors.– Reproducibility of results?– Generalizability of results?

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– Need to take into account accuracy of diagnosis and appropriateness of care.

Empirical studies of patient outcomes are more feasible for early occurring outcomes.Are subject to confounding by treatment for longer-term outcomes.Magnitude of the effect could be very small, especially for distant outcomes.Randomization is usually needed.However use of randomization leads to inefficient designs for studying accuracy.

Introduction to Therapy Clinical Trials Phases of Clinical TrialsTreatment (therapy) trials are usually classified as one of four phases, each designed to answer different research questions.

Phase1Phase 1

Phase2 Phase3 Phase4Number ofparticipants

15-30 subjects Less than 100 subjects

100 or more Large subject numbers

Purpose • To find a safe dosage• To decide how theagent should begiven• To observe how the agent affects thehuman body

• To determine if the agent or interventionhas an effect on aparticular disease• To see how the agent or interventionaffects the human body

• To compare the newagent or intervention(or new use of atreatment) with thecurrent standard

• To furtherevaluate the long-term safety and effectivenessof a new treatment

Recently, a new special purpose Phase 0 trial structure has been defined: new class of trial has bee defined caPhase 0 trialsNumber of participants: about a dozen

Purpose and Method: Using micro-doses to determine if ‘targeted’ therapeutic agents reach the intended tissue. In early therapeutic development efforts, ‘Phase 0’ human clinical trials often use image-able, nuclear-tagged molecular compounds.

The following outline courtesy of Dr Tony Shields

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Most therapeutic (e.g., drug) trials involve treatment of advanced disease.Are often done with palliative intent, which are the simplest to perform.Trials done with curative intent are generally adjuvant studies after surgery for solid tumors or chemotherapy for leukemia/lymphoma and use regimens proven effective in advanced disease, but require large phase II and III trials.

Prevention trials may include vitamin and hormonal therapies.– Require extremely large patient populations and years to complete.

Clinical Therapeutic Studies Surgery is the backbone of effective treatment for most solid tumors and

is usually done with curative intent. Radiation can be done with curative or palliative intent and these

protocols use radiation with curative intent, either as primary therapy or adjuvant treatment.

Chemotherapy trials generally use new drugs with palliative intent and may include single agents or complex combinations (usually the latter). Successful use of new agents in the advanced setting can lead to use earlier in therapy.

Sources of new protocol ideasArise from: 1) Extension of pre-clinical cellular or animal laboratory work 2) Inspired by a unique patient or series of patients 3) A new imaging instrument is available 4) A new imaging probe is available 5) New software or hardware have improved an older instrument 6) A common problem or disease seen at your institution 7) A device or pharmaceutical company suggests a protocol

Design basics: you must critically evaluate:– Feasibility coordinated with other research programs– Adequate space– Personnel availability/ commitment– Competing protocols for patients or protocol complements other studies– Can include patients enrolled in another protocol– Will include a similar tumor type as an ongoing protocol with different eligibility

Protocol synopsis should address:• Study objectives• A basic description of the study design• The number of subjects to be enrolled• Summary of inclusion and exclusion criteria• The dosage regimen or device utilization plan• Planned study procedures• The planned methodology for statistical analysis

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Design: Objectives• The primary objective is key: it will drive your design, statistics, and accrual goals• Secondary objectives may include related measures of results (e.g. overall vs. progression free survival)• Secondary objectives may look at completely different issues (e.g. cost analysis) • Make sure the main objective is one that is clinically or scientifically meaningful• Correlative studies are often included to expand the base of science knowledge of the disease

Statistical vs. Clinical Significance• A good study will have validity that is both: Statistical – probability that a finding is true; and Clinical – the contribution that the finding makes an impact on medical practice

Design: Endpoints• Should be an identifiable clinical change indicating attainment of the goal• Needed to define data and assess results in a consistent manner• Must be objective and measurable

Design: Study Population• Is the total number of subjects needed for clinical and statistical significance taking into account: 1) Inclusion/ exclusion criteria 2) Demographic criteria 3) Diagnostic methods to determine clinical eligibility

Pitfalls in Protocols: Eligibility• Write eligibility carefully-- or it will come back to bite you• Do not include unnecessary conditions that you will be tempted to ignore, such as limits on:

– acceptable labs– co-morbid conditions– prior malignancies– prior treatments– results from standard imaging techniques (“measurable disease”)

• Conversely, make sure you include limits that would otherwise prevent enrollment of patients who would be endangered by the study or give uninterpretable results

Screening Procedures Prior to Study Entry• Make sure the timing of procedures is appropriate– if screening is done too far in advance of enrollment; lab or imaging may have changed.– if evaluation must be done just prior to the start you may need to repeat lab and imaging.

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– generally, imaging can be done up to 4 weeks before treatment and labs within 7- 14 days.– insurance will often not cover imaging if too frequent– screening that is not part of standard of care may need to be paid for by the study.

Consent procedure:Make sure patient and investigator sign consent before starting protocol or pre-enrollment screening procedures that are not part of standard of care. The consent should be readable at an eighth-grade level. It may contain components for opt-in or opt-out sub-consent signatures involving correlative studies or data-sharing that are not part of the primary endpoint.

Study Structure Determines• In a diagnostic trial how the test will be verified – type of treatment for each group – duration of treatment – if more than one treatment, the order in which treatments will be administered• Phase II Design

– all patients receive same treatment or procedure– compare to historic controls– imaging trials may compare to a “gold standard” of pathology or

clinical follow up• Two Group Studies

– Parallel: each group receives a different treatment or procedure from all other groups

– Crossover: each group receives a different treatment order from all other groups

Data CollectionCreate a table that defines the clinical test sequence in a study calendar• Data collection and management of a clinical trial currently accounts for up to 60% of the overall clinical trial process• Industry is pressured to test, approve, and market new drugs faster than ever so they are now automating the documentation process relevant to the clinical trial and can cut the time of the trial by two-thirdsElectronic Case Report Forms (CRFs) and Remote Data Capture (RDC)• Streamlines the clinical trials process by capturing, authoring, processing and managing the clinical documentation• By standardizing, controlling and securing clinical trials-related content, the companies can now reduce the costs of data acquisition and clean up during trials, and makes data much more accessible• Internet-based Clinical Trials (RDC)

Has been recently introduced to replace paper-based processes. Clinical sites are beginning to embrace this but it often requires them to retrain staff, but

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leads to more rapid data capture from electronic records and data sharing, and has potential privacy implications.

Design: Budget• All protocols cost money, even if it is just your own time but include regulatory and review costs, physicians and nurses recruiting patients, reimbursement of patient expenses and modest compensation, physicians and nurses to follow-up results of treatment or imaging, laboratory tests that are not part of the standard of care, data management costs, imaging costs: machine time, tech support, supplies that are not part of standard of care. Some of these costs may be hidden and not explicitly charged, but they are all real• The protocol is the tool to develop the budget– look at all the tests on the study calendar; is hospitalization needed (just drawing blood can be expensive) cost of data collection, validation, and analysis. It identifies all study - plan related costs: time: staff spends with subjects & on protocol, varies; procedures: cost per subject; overhead: dictated by institutional guidelines; divide costs into up front costs for evaluation and review of the protocol: IRB charges etc., figure per patient costs. You may need to separately charge for procedures if they are expensive (e.g., image guided therapy, extra scans etc.)• Develop potential sponsors

– Internal seed money– Grants from funding institutions, such as NIH program

announcements, unsolicited investigator initiated grants, SBIR grants or Industry such as

pharmaceutical manufacturers, medical device companies, contract research organizations

Pre-study DocumentsLaboratory’s accreditation certificateCurrent laboratory rangesForm FDA1572 completed for all investigators (establishes their registration as investigators)Primary Investigator (PI) and Co-investigator CVsFinancial Conflict of Interest StatementsRadiation Safety ApplicationIND number, if investigational drugIDE number, if investigational deviceIRB Submission FormCancer Center Submission FormHIPAA compliance documentationInformed consentProtocolProtocol Review

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FDA review• Required for investigational device unless it has “no significant risk”• Always required for investigational drug Cancer Center Protocol Review Committee (PRC)Includes: Medical oncologists; Surgeons; Radiation oncologists; Radiologists (not always - but participation is highly recommended); Statisticians; Nurses; Data managersRadiology input in the PRC can be variable, so be prepared to have your protocol reviewed by clinical oncologists.

Protocol Review Protocol Review Committee (PRC) will assess:• Scientific and clinical rationale• Competing protocols and prioritization• Ability to accrue patients• Statistical review• Treatment plan and safety (this group will have the better expertise than the IRB)• Use of Cancer Center resources (funding)

Institutional Review Board (IRB)• Safeguards the rights, safety and well-being of all trial subjects• Reviews protocol, amendments, recruitment procedures, payment & compensation to the subject and PI’s qualifications• IRB or Human Investigation Committee includes: Physicians, scientists, statisticians, lay public but is less likely to include radiologists• Will assess: Safety -- but may have limited expertise for your specific protocol; Consent form -- completeness, readabilityHopefully, your IRB has developed standard wording for common issues such as risks of standard procedures, confidentiality issues, treatment of side effects or problems.

Design: Adequate Accrual• Plan for accrual management; prepare remedies for contingencies• Consider communication of protocol to physicians and practice groups – all communication must be IRB approved• Include talking points showing the merits of research• Consider publicity for potential patients through brochures, posters, newsletters, the web and patient support groups for specific diseases (IRB approved).

Design: Compliance & Discontinuance• Ensure special measures are defined to monitor subject compliance• Include procedures for subjects lost to follow-up• Define criteria for voluntary and involuntary dismissal

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Design: Protocol Revisions• Despite careful planning they occur – certain aspects of the plan may be unworkable in practice – circumstances change (adverse event, shortage of subjects)• Implement when a change will reduce risk to subjects• One time deviations may be allowed, but must be documented as protocol violations

Enrollment Decisions• Initial intake interview• Take the medical history• Alert to medical barriers to participation, conditions listed in the exclusion criteria• Warning signs that the patient may be unable or unwilling to comply with study procedural requirements• Identify uncooperative attitudes or problems that may prevent adherence to study schedules - will reduce instances of poor compliance later in the study

General Considerations• FDA does not formally recognize protocol “deviations or exceptions.” All departures from the protocol are considered “protocol violations” even if sanctioned by the sponsor.• Nothing should be assumed. If it is not documented it theoretically did not happen.Maintain Trial Files• Investigator must set up study-specific files per patient in which all appropriate documentation is filed• Files can be in binders or regular files but they must be coordinated• All study documents must be stored in a safe, secure and confidential environment

Good Clinical Practice (GCP)Source documentation should be able to withstand an audit; this includes data obtained from imaging• First place a clinical observation is recorded• Supports a study’s findings• Legally valid raw data• Establishes an audit trail• Tells the complete story of the subject

Good Trial Files• Treat the files as “gold” and ensure that they do not get lost or destroyed prematurely• Once the study has ended, the PI is required to keep study-related documents until the sponsor tells them it is no longer necessary

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• Documents should be retained at least 2 years after the last approval of a marketing application

Points to Remember• Source documents include medication charts, patient diaries, traces and printouts from automated machines and even appointment diaries• Make sure there is sufficient evidence in a subjects chart to justify patient eligibility• Data must be recorded on study specific CRFs• It must be possible to reconstruct CRFs using data recorded in the patient file

Documentation of Adverse Events• An adverse experience (also called event, AE) is any untoward medical occurrence in a trial subject who has been administered a pharmaceutical product• AE may have no relationship to the treatment• Prompt reporting to the sponsor, the IRB, and the FDA (if required)• If AE is serious the PI must report it immediately; 21 CFR Part 312.64 (b) (called an SAE, e.g. death)• In an imaging study one may limit AE to those that occur for a short time after time after the procedure (e.g. 2 hours)• For therapeutic trials usually report AE for up to 30 days after treatmentSafety Reporting• Laboratory abnormalities may also be classified as AEs• Good documentation needed to summarize medical occurrences of serious adverse event (SAE):results in death; is life threatening; requires in-patient hospitalization; prolongs existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly/birth defectWhen in doubt report it!!!• Regular Schemes for dose modifications are needed for chemotherapy trials when patients experience adverse events.

– Dose modifications schemes can be complex when multiple agents are being used.

– They need to take into account the timing, severity, and recovery from the toxicity.

– They need to indicate which patients should be removed from the study, while keeping those

that may benefit from a lower dose.

Imaging’s roles in clinical trials: Resectable or curable disease imaging may be limited to the detection of recurrence– in some cases recurrence is documented by biopsy– in some cases imaging alone is adequate proof of progression.

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Imaging may be the primary or secondary endpoint. The usual primary endpoints are: • Survival • Response (e.g. partial or complete response rate). (See RECIST and WHO criteria) [Central review may be needed] • Progression-Free Survival (PFS)When measuring response local reviewers, involved in patient care or unblended to the therapeutic arm, have a bias to read scans in the patients favor.

Imaging Response to Treatment• The protocol should define in detail how imaging will be done – include technical details such as use of contrast or tracer, instrument specifications, training of readers, etc.• Be careful to limit specifications to those that are essential or you may:: inadvertently disqualify patients– limit the sites that can participate– interfere with the usual work flow in the Radiology Dept– limit the generalizability of the study to a few “experienced” academic sites• Many therapeutic protocols give no direction on how the imaging should be done or even the type (e.g. “CT or MR measurement is needed”).

Imaging Response to Treatment: Problems• RECIST (Response Evaluation Criteria in Solid Tumors) criteria are difficult to use as part of routine care because: – scans are often done away from academic medical centers due to patient travel distance and/or insurance – readers often don’t measure lesions, especially the 10 allowed by RECIST – measuring irregular and ill defined lesions is arbitrary – the most recent scan is usually compared to the last scan, not the pre-treatment or best-response scan – different readers may read scans differently over time – new targeted therapies may not shrink lesions (e.g. the angiostatins)• We regularly see reports that: describe the tumor are “slightly better or worse”; give measurements that are not consistent with the previous reading; making it hard to tell what lesion or where a lesion was measured• Objectives: give measurements; look at previous measurement; record the slice used to measure the lesions (it is always simpler when there are new lesions, since that is automatic progression)

ConclusionsCareful planning of clinical trials is essential to their successful conduct.Make sure that you have thoughtfully defined:• Eligibility• Pre-study procedures• Study calendar• Treatment• Dose adjustment• Data collection forms

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Investigational Drugs and Devices“Investigational” means any drug or device not currently marketed in the US in the exact form that you are using for the exact indication for which you are using it. For example, updated device software is investigational, as is investigation of an marketed drug for a disease or histology that is not explicitly in the drug labeling.

Investigational New Drugs (INDs)21 CFR 312 (CFR = Code of Federal Regulations)IND is required for all investigational drugs (except for a few radiopharmaceuticals)Drug is not marketed in USDrug is marketed, but this is a new indication or route of administrationDrug is a modification of existing drug (even the solution)IND “Sponsor” can be: Company; Institution (e.g., hospital, NCI); Individual (usually physician)Application must be made to the appropriate FDA Division (CDER, CBER…)Specific data are needed for this application; Pharmacology and toxicology informationChemistry, manufacturing, and controlDosimetry for radiopharmaceuticalsImportant reporting requirements

o Serious adverse eventso Annual report

FDA Guidance on the IND process with multiple links to other documentation -http://www.fda.gov/cder/regulatory/applications/ind_page_1.htmComprehensive FDA Guidance Page–http://www.fda.gov/cder/guidance/index.htmA “how-to” guide from the Biological Development Program at NCI-Frederick with multiple links– http://wwwbdp.ncifcrf.gov/pdf/GuidetoRegSubs.pdf

Investigational Device Exemptions (IDEs)21 CFR 812 appliesIDE is required for investigational devices that pose a significant riskDevice is not marketed in USDevice is marketed, but this is a new indication or modification“Significant risk” as determined by local IRB or by FDAIND “Sponsor” is responsible which can be: Company, Institution (e.g., hospital, NCI), Individual Application must be made to the appropriate FDA Division (CDRH, etc)Important reporting requirements

o Serious adverse events

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o Annual and semi-annual reportInformation resources: FDA Center for Devices and Radiological Health

http://www.fda.gov/cdrh/index.htmlDevice Advice: http://www.fda.gov/cdrh/devadvice/

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Biases and Their Control Contributor: Nancy Obuchowski,

PhD

What is “bias”? bias is any systematic deviation of observation / study result from a true clinical state

Examples of BiasThe (average of readers') sensitivity of MRI for detecting asymptomatic breast lesions is 0.80. But, in a study by XX the estimated sensitivity is 0.96. The following examples will instruct:

How to control/correct for bias:Design study to avoid biasImplement strategies to minimize biasUse statistical methods that adjust for bias

EXAMPLE 1: Risk factors for Cerebral AneurysmsDesign: Retrospective review of patients who underwent head CTSample: 500 patients; 50 with cerebral aneurysmsGoal: Determine if patients with aneurysm and patients without aneurysm differ on symptoms, family history, demographics

- Selection and referral bias: Composition of sample is influenced by external factors. Here, sample is not representative of population of patients with and without aneurysms.Referral bias is a common type of selection bias in radiology studies. Study patients are selected for test (CT) for various (unknown) reasons. Only “referred” patients included in study.

- Other types of selection bias- Centripetal bias: Major medical centers with reputations in specialized areas often are referred problem cases- Popularity bias: Experts preferentially keep track of difficult cases over less challenging cases- Referral filter bias: Tertiary care centers generate cases much different than general population. Correction for referral bias is to prospectively recruit a random sample of headache patients from primary care.

EXAMPLE 2: MRI detection of early rheumatoid arthritisDesign: Prospective study of patients with rheumatoid arthritis (RA). Recruited patients undergo MRI and x-ray.Sample size: 20 RA patientsGoal: Compare sensitivity of MRI and x-ray as a screening tool for early RA

- Generalizability issues and spectrum bias

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Study sample does not include complete spectrum of patient characteristics. Here, study does not include patients with early RA who have not yet been diagnosed. Pathways by which patients entered study and characteristics of patients should be described so readers able to determine if results apply to patients in their practice.

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- Generalizability problemsResults of study have limited value because sample of patients (or readers), techniques used, etc. were atypical. Here, MRIs and x-rays of only RA patients were interpreted - no patients without RA. No measure of specificity!

- CorrectionRedesign study to avoid or reduce bias (e.g. conduct prospective study of people who present with symptoms of early RA)

- Verification BiasPatients with + (or -) test results preferentially referred for gold standard. Bias occurs when accuracy is estimated only on verified patients. Is most common type of bias in radiology studies.

- Corrections for Verification BiasDesign study so test results don’t influence which patients undergo gold standardUse different (but equal) gold standardsStatistical corrections are available

EXAMPLE 3: Digital MammographyDesign: Prospective study of patients with lesions found on mammography with a new digital algorithm applied.Sample: 30 patients. If digital +, then undergo core biopsy; if -, then needle biopsy.Goal: Assess accuracy of digital mammo to distinguish benign vs. malignant lesions.

- Imperfect Gold Standard BiasThe gold standard/reference procedure is not nearly 100% accurate. Needle biopsy is not nearly 100% accurate.

- Work-Up BiasGold standards not equally accurate and one is associated with a particular test result. Core biopsy is much more accurate than needle biopsy. Negative test results will be verified with much less reliability than positive test results.

- Correction for Imperfect Gold StandardIf possible, re-design study to avoid use of imperfect gold standard Statistical methods exist to correct for imperfect gold standard bias

EXAMPLE 4: Multi-reader study of breast cancerDesign: Prospective study of high-risk patients - all patients undergo mammo and MRI. Biopsy and/or clinical follow-up is gold standard. Radiologists interpret all images.

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Sample: 150 patients and 8 readersGoal: Assess and compare accuracy of mammo and MRI

- Biases in studies with subjective test interpretationTest-Review BiasDiagnostic-Review BiasReading-Order Bias

- Test-Review BiasDiagnostic test is performed or results are interpreted without blinding of gold standard results or competing test results Need to ask were did readers blinded to the biopsy results and mammo results when interpreting MR images?

- Diagnostic review BiasGold standard is performed or interpreted without blinding from results of test(s) under study. Need to ask: is clinical FU assessed with blinding of MRI or mammo results? Is clinical FU also used in biopsy patients?

- Reading Order BiasWhen comparing 2 or more tests, readers’ interpretations are affected by memory of results from competing test. Need to ask: did readers interpret 1/2 cases with mammo first and 1/2 with MRI?

- CorrectionsMRI and mammo interpreted without knowledge of biopsy or FU results.Clinical FU assessed without knowledge of MRI and mammo findings. FU also used for biopsy patients.Randomize reading order so 1/2 of cases seen with mammo first and other 1/2 with MRI first.

- Other BiasesIncorporation BiasContext biasPublication bias (meta-analyses)

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Assessing predictive value of tests Imaging as a biomarkerIdentify disease in asymptomatic populations or individualsPredicting disease course with or without therapyBiomarkers for disease onset, presence or course of diseaseQuantify risk assessmentPrognostic – predict disease outcome at time of diagnosis prior to therapyPredictive – predict outcome of a particular therapyMonitoring – measure response to treatment or relapseSurrogate endpoint: substitutes for definitive endpoint to shorten trial or reduce cost

Prognostic markers do not interact with a particular treatment (so they might not be predictive)Predictive markers can be used to make individual or group decisions about specific treatments (but a predictive marker may not be prognostic if it does not predict outcome in untreated patients)

Contributor: Constantine Gatsonis

Imaging as a Measure of Therapeutic Response Learning Objectives

Understand why and how RECIST imaging measurements are made and usedDescribe alternative approaches to quantitative measurement of tumor responseRecognize the role of imaging as a correlative biomarker in drug testingReport the regulatory meaning of imaging as a ‘surrogate’ marker in therapy trials

Ethics Considerations Learning Objectives

• Review key historical events regarding participant protection• Describe how participants are protected through the informed consent process• Explain how review boards and panels protect participants• Demonstrate familiarity with government regulations and agencies• Knowing evolution of participant protection; origins: Nuremberg Code; Tuskegee syphilis study• National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

Belmont Report

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National Research Act• Understanding government oversight of safeguards for participants Office for Human Research Protections (OHRP) – The Common Rule • Understanding FDA regulations• Protecting participants before a trial: Scientific review by sponsoring organization; Institutional Review Board (IRB) approval; Informed consent• Learning how to protect participants during a clinical trial: Institutional Review Boards (IRBs); Data and Safety Monitoring Boards (DSMBs) act to minimize risks, ensure integrity of data and can stop study if necessary

History of patient protection Although we now have strong safeguards for protecting those who

participate in research, these protections resulted from abuses of human rights in the past. The first formal statement of protection for individuals in research emerged from the Nuremberg trials in Germany, where Nazi scientists and physicians who had conducted experiments on World War II concentration camp victims were convicted. The Nuremberg Code outlined broad concepts for the protection of human subjects and forms the basis of today’s international code of ethics for the conduct of research.

In the United States, several controversial research studies highlighted the critical need for protection for those participating in clinical trials. None of these studies sought to inform the participants about the research or gain their consent. From 1932 to 1972, the Tuskegee syphilis study followed low-income African American men with syphilis but did not treat them. During the study, the men were offered free medical care and were told that they would be treated for ”bad blood.”

In the 1960s, two other research studies received major public attention. The first was a series of experiments with mentally retarded children; another involved debilitated elderly participants.

In response to these tragedies, regulations and policies were developed to ensure that people are told about the benefits, risks, and purpose of research for which they volunteer. In 1976, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research developed three basic principles governing research involving human subjects that were published in the Belmont Report. These principles, which today form the basis for human subject protection regulations in the United States are:

• Respect for persons—recognition of personal dignity and autonomy of individuals, and special protection of persons with diminished autonomy• Beneficence—obligation to protect persons from harm by maximizing unanticipated benefits and minimizing possible risk of harm• Justice—fairness in the distribution of research benefits and burdens

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The Informed Consent ProcessInformed consent is a critical part of ensuring participant safety in research. Informed consent is an ongoing process during which potential participants learn important information about a clinical trial. This information helps them decide whether to participate. The research team first explains the trial to potential participants in understandable language. This explanation entails the trial’s:

• Purpose• Procedures• Risks and benefits• Participant rights, including the rights to:

– Make an independent decision about participating– Leave the study at any time without jeopardizing future treatment

Before agreeing to take part in a trial, people have the right to:• Learn about all their treatment options• Learn all that is involved in the trial—including all details about treatment, tests, and possible risks and benefits• Discuss the trial with the principal investigator and other members of the research team• Learn if the investigators have any vested interest in the outcome of the study

The participant should hear and read the information in language they can understand.

Informed Consent FormAfter discussing all aspects of the study with a potential participant, the team gives the person an informed consent form to read. The form includes written details about the information that was discussed and also describes the confidentiality of the participant’s records. If a person agrees to take part in the study, he or she signs the form. Although informed consent documents can vary in their length and complexity, they should all contain information on:*• The clinical trial’s nature, purpose, and duration; the procedures to be followed; and which procedures are experimental• Reasonable, foreseeable risks and discomforts• Benefits to the participants and to others• Alternative procedures or treatments• Confidentiality of records• Procedures if the trial involves more than minimal risk (e.g., compensation, availability of medical treatment)• Contact for questions• Voluntary participation—that there will be no loss of benefits on withdrawal and that participants may stop participating at any time All Government-funded trials must contain this information by law.

– * These informed consent requirements are listed in Title 45 CFR Part 46, Sub part A.

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Consent Forms: Make them easy to understand. The informed consent process can be effective only if potential participants understand the information given to them. In recent years, both participants and investigators have voiced concerns that informed consent documents for clinical trials were becoming too long, complicated, and difficult to understand. NCI has issued recommendations designed to help research institutions and clinical centers write user-friendly informed consent documents. Sample templates can be found online in both English and Spanish in the clinical trials section of www.cancer.gov.

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Monitoring of Clinical Trials: IRB, DSM, CTEP Review CommitteesMost clinical trials are subject to different types of review that are designed to protect all participants. Clinical trials that are sponsored by NCI—whether funded by a grant, run by a Cooperative Group, or run through a Cancer Center—are reviewed through different types of panels, including experts who review the scientific and technical merit of the proposed research. Many other clinical trial sponsors, such as pharmaceutical companies, also seek expert advice on the scientific and technical merit of their trial protocols. In addition, all federally-funded clinical trials and all trials with investigational drugs or devices must be reviewed by groups called Institutional Review Boards (IRBs). All trials with investigational drugs or some investigational devices must be reviewed by the appropriate FDA division, except for highly limited radiopharmaceutical trials that are reviewed by Radioactive Drugs Research Committees (RDRC), which are under FDA oversight. Note that a marketed drug or device can be investigational and require IND or IDE.

Institutional Review Boards (IRBs)IRBs are made up of people who are qualified to evaluate new and ongoing clinical trials on the basis of scientific, legal, and ethical merit. The board members determine whether the risks involved in a trial are reasonable with respect to the potential benefits. IRBs also monitor the ongoing progress of trials from beginning to end. Federal regulations require that each IRB be made up of at least five people; one member must be from outside the institution conducting the trial. IRBs are usually made up of a mix of medical specialists and lay members of the community, and many include members from diverse occupations and backgrounds. In most cases, IRBs are located where the trial is to take place. Many institutions that carry out clinical trials have their own IRBs. Federal law requires IRB approval for clinical trials that are: 1) Federally funded 2) Evaluating a investigational drug, agent, or medical device or a new indication or method of administration of a marketed drug or device, or 3) subject to FDA regulationA number of institutions require that all clinical trials, regardless of funding, be reviewed and approved by local IRBs. Potential participants considering a clinical trial should ask if it has been approved by an IRB.

During the Trial: IRB MonitoringIf the IRB grants approval for a trial, it also must decide how frequently the trial should be reviewed once it is underway. Frequency is usually determined according to the degree of risk the trial involves. At least once a year, the IRB must review a progress report provided by the clinical researcher in charge of the trial. The report features information about how many people are enrolled and how many have withdrawn, a description of participants’ experiences, including benefits and adverse effects, and the progress to date. Based on this

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information, the IRB decides whether the trial should continue as described in the original research plan, and, if not, what changes need to be made. An IRB can decide to stop a clinical trial at any time if the researcher is not following requirements or if the trial appears to be causing unexpected harm to participants.

Data and Safety Monitoring Boards, DSMBs For phase 3 trials, DSMBs are appointed to help ensure participants’ safety. A DSMB may also be appropriate and necessary for certain phase 1 and 2 clinical trials. The DSMB is an independent committee made up of statisticians, physicians, and other expert scientists. The data and safety monitoring board must: • Ensure that any risks associated with participation are minimized to the extent practical and possible• Avoid exposing participants to excessive risk• Ensure the integrity of data• Stop a trial if safety concerns arise or as soon as its objectives have been metDSMBs also monitor all trial results. If early results show clear advantages of a new drug, the sponsor of the study may choose to end the trial early and establish a protocol allowing wider use of the drug before final approval for marketing. If a drug is shown to have a strongly negative effect, the trial is stopped immediately. For example, in 1995, a trial of the drug tamoxifen (tamoxifen citrate) showed that the drug dramatically reduced the short-term risk of breast cancer. The DSMB and the researchers assessed the data and halted the trial so that the results could be made widely available and all women in the trial could have the opportunity to take the drug. Researchers submitted a new application to FDA, which expedited its review status. The new application was the basis for FDA approval of tamoxifen for reducing breast cancer risk.

Office of Human Research Protection OHRP RegulationsOffice of Human Research Protection protects those participating in research and provides leadership for all Federal agencies that carry out research involving people. The OHRP enforces important regulations for participant protection in clinical trials called the Common Rule.4 These regulations set standards regarding the:• Informed consent process• Formation and function of IRBs• Involvement of prisoners, children, and other vulnerable groups in research

FDA RegulationsFDA enforces another set of regulations on participant protection in clinical trials.5 It concerns any clinical trial that involves an FDA-regulated drug or device, regardless of whether the trial receives Federal funding. FDA

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periodically inspects IRB records and operations to certify the adequacy of approvals, participant safeguards, and conduct of business.

Can a person be put in a clinical trial without his or her knowledge?No ! The researchers running the trial are required by law to present and explain the study as part of the informed consent process. This process includes:• Signing an informed consent document (so that people know they are entering a study)• Discussing with the research team what the trial entails• Understanding the potential risks and benefits of participatingAlthough reputable researchers do not fool people or sign them up against their will, sometimes people have difficulty understanding the information they need to know about a trial before agreeing to join. For many people, it is important to ask a friend or family member to come with them to be sure that all important questions are raised. Taking notes or using a tape recorder can also help.

If someone is in a phase 3 trial and it is found that there is a clear advantage for the participants in the other group, what happens?The DSMB would report the information to the study sponsor. If early results show that there is a clear advantage for one of the groups, the sponsor may choose to end the trial early and establish a protocol allowing wider use of the drug before final approval for marketing.

What happens if someone wants to stop participating in a trial?Under the informed consent process, a person has the right to discontinue their participation in a trial at any time. A participant’s decision to leave a clinical trial does not jeopardize future treatment, and the participant will have the chance to discuss other treatments, or care with a doctor from the trial.

Sponsorship and Economics of Imaging Trials NCI-Sponsored Clinical Trial Programs• Clinical Trials Cooperative Group Program• Clinical Trials Support Unit (CTSU)• Community Clinical Oncology Program (CCOP)• Minority-Based Community Clinical Oncology Program• Cancer Centers Program• Clinical Grants Program

Organizations That Sponsor Clinical TrialsNCI, pharmaceutical companies, medical institutions, and other organizations sponsor clinical trials. NCI often partners with pharmaceutical companies to develop new agents. Regardless of sponsor, clinical trials take place at universities, large medical centers, small hospitals, and doctors’ offices.

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Individual physicians at cancer centers and other medical institutions can also sponsor clinical trials themselves.

NCI-Sponsored Clinical TrialsNCI sponsors many clinical trials that are conducted through four different programs:1. Clinical Trials Cooperative Group Program2. Community Clinical Oncology Program (CCOP) and the Minority-Based Community Clinical Oncology Program (MBCCOP)3. Cancer Centers Program4. Clinical Grants ProgramAll NCI-sponsored trials must meet all FDA and Office for Human Research Protections (OHRP) regulations for participant protection in clinical trials.

Clinical Trials Cooperative Group ProgramClinical trials are often conducted through NCI cooperative clinical trial groups, which are networks of institutions that jointly carry out large clinical trials following the same protocols.Members of these groups include: University hospitals, Cancer centers, Community physicians and community hospitalsCooperative groups develop and conduct new clinical trials that follow national priorities for cancer research. They conduct phase 3 trials as well as phase 2 trials. Some of the groups are categorized by type of cancer, others by type of treatment or other reasons, such as:

American College of Surgeons Oncology Group (ACOSOG) Cancer and Acute Leukemia Group B (CALGB) Children’s Oncology Group (COG) Eastern Cooperative Oncology Group (ECOG) Gynecologic Oncology Group (GOG) National Surgical Adjuvant Breast and Bowel Project (NSABP) National Wilms Tumor Study Group (NWTSG) North Central Cancer Treatment Group (NCCTG) Radiation Therapy Oncology Group (RTOG) Southwest Oncology Group (SWOG) American College of Radiology Imaging Network (ACRIN)

For more information about the Cooperative Group program, seehttp://ctep.info.nih.gov.

Community Clinical Oncology Programs (CCOPs) and Minority-Based CCOPs (MBCCOPs)These programs allow community physicians to work with scientists conducting NCI-supported clinical trials. Participation in the CCOP benefits lay people and health professionals in the community as well as scientists in research centers. The MBCCOP provides members of ethnic and racial

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minorities with access to state-of-the-art cancer treatment, prevention, and control technology.

Cancer Centers ProgramNCI cancer centers conduct clinical trials under an NCI-approved protocol review and surveillance mechanism. The Cancer Centers Program consists of more than 50 NCI-designated cancer centers involved in many different cancer research efforts. Cancer centers also participate in at least one cooperative group. List of Cancer Centers

Clinical Grants ProgramMany clinical trial protocols are carried out under the direct support of an NCI peer-reviewed grant (often labeled R21 grants)

Industry-Sponsored TrialsPharmaceutical and biotech companies conduct their own trials, both locally nationally and internationally. These partners may be universities, hospitals, NCI, or local doctors. These trials are subject to the companies’ own review panels and to an IRB, which may be local or national in scope.

Referrals to Clinical TrialsOnce someone is diagnosed with cancer, the health care provider may suggest several possible treatment options, one of which may be a clinical trial. Similarly, health care providers may offer people at high risk for cancer several options for prevention, including a clinical trial. If a person finds that his or her physician does not participate in clinical trials, the person can request a referral to a physician who does.

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Informatics Tools for Protocol DevelopmentValuable Information

Tie all your efforts together on your local PC: By using and mastering a combined approach through integrated plug-ins: Word, Acrobat, PowerPoint, Endnote, PubMed, you will increase your information access by copying and pasting – and make trial protocol development faster and easier

Learning Objectives:

Identify network resources that provide clinical-trial relevant templatesUse common desktop applications to speed trial document developmentReach time-saving resources that avoid duplicated effortsFind regulatory guidance and funding sourcesUnderstand how to use internet to interact with colleagues efficiently

There is value in learning in greater depth: PubMed http://www.ncbi.nlm.nih.gov/entrez/ My NCBI is a central place to customize NCBI Web services. To use it, you must first register, and your browser must accept cookies. You can use My NCBI to: Save searches; Set up e-mail alerts for new content; Display links to Web resources (LinkOut); Choose filters that group search results

What you can do with: Quosa – http://www.quosa.com/ Connects automatically to PubMed and extracts full article PDFs if you have an institutional license

Powerful document management and reusable material in: Acrobat (Reader and Professional) – extract text (Select Tool) and images (Advanced ->export all images); track changes (Comments & Markup). You can also publish a smaller, unchangeable PPT as a PDF. You can drag-and-drop text from Acrobat to MSWord.

Learn it Word – Convert to Adobe PDF using an Acrobat plug-in; Track changes (ctrl+shift+E); email document as a draft for comment; add images; has hierarchical outline view. Since the patient consent form must be readable at an eighth grade level, did you know that when you use Spelling & Grammar check from the Tools menu in MS Word it will provide a readability statistics score? Do you also know that invaluable plug-ins are available for integrating simultaneous document citation management available from such programs as EndNote and RefManager?

Comprehensive reference management with Word and PubMed

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Endnote – links to Word; does its’ own PubMed searching, constructs a complete bibliography. and dynamically formats your references while you write

Selling your idea PowerPoint (PPT) – you can incorporate and edit web pages and images for presentations

Templates are readily available – use them! Find and use Clinical Trial Templates and protocols from NCI: http://ctep.cancer.gov/guidelines/index.html

Clinical trials nation-wide are listed indetail in: All government sponsored Cancer Clinical Trials and some privately sponsored trials are listed in detail in http://www.cancer.gov/clinicaltrials/search and http://www.clinicaltrials.gov/

Regulatory approval of trial results Find FDA Guidance about clinical trials (remember ClinTrials are mostly about therapies – not imaging) http://www.fda.gov/oc/gcp/default.htm

Regulatory requirements for Investigational drugs or devices FDA Guidance on the IND process with multiple links to other documentation: http://www.fda.gov/cder/regulatory/applications/ind_page_1.htmFDA Center for Devices and Radiological Health http://www.fda.gov/cdrh/index.htmlFDA Device Advice: http://www.fda.gov/cdrh/devadvice/Comprehensive FDA Drug Guidance Page–http://www.fda.gov/cder/guidance/index.htm•

A “how-to” guide from the Biological Development Program at NCI-Frederick with multiple links–http://wwwbdp.ncifcrf.gov/pdf/GuidetoRegSubs.pdf

Regulatory guidance for Imaging drugs: --Part 1: Conducting Safety Assessments:http://www.fda.gov/cder/guidance/5742prt1.pdf –Part 2: Clinical Indications http://www.fda.gov/cder/guidance/5742prt2.pdf –Part 3: Design, Analysis, and Interpretation of clinical studies http://www.fda.gov/cder/guidance/5742prt3.pdf

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BibliographyNotes:

a. This bibliography corresponds roughly to the topics of the didactic portion of the workshop. The list of references included here is meant to provide broad coverage of each topic. It is not a required reading list for the workshop. The references in each section are listed in reverse chronological order of publication

b. A small set of papers is highlighted as “required reading” (see below). Students are urged to familiarize themselves with this material in advance of the workshop.

c. But in addition all students are urged to refresh their command of biostatistics concepts before coming to the course.. The bibliography lists two handy sources for such material:

The text by Dawson and Trapp (see D1 below): Chapters 4-6 present basic material you need to know. It will also be useful to have some familiarity with concepts from correlation and regression analysis (Ch 8) and survival analysis (Ch 9).

The series of articles : Fundamentals of Clinical Research for Radiologists Am J Roentgenol. 2001-2006 The hyperlinks below will give you the PDF files by just performing a CTL-click to access the link

Introduction to Probability Theory and Sampling Distributions Joseph 2003 AJR. 180:917

Clinical Evaluation of Diagnostic Tests Weinstein 2005 Am. J. Roentgenol. 184:14

Data Collection in Radiology Research Crewson 2001 Am. J. Roentgenol. 177:755

Meta-Analysis of Diagnostic and Screening Test Accuracy Evaluations: Gatsonis 2006 AJR. 187:271

Statistical Inference for Proportions Joseph 2005 Am. J. Roentgenol. 184:1057

Randomized Controlled Trials Stolberg 2004 Am. J. Roentgenol. 183:1539

Statistical Inference for Continuous Variables Joseph 2005 Am. J. Roentgenol. 184:1047

Population and Sample Kazerooni 2001 Am. J. Roentgenol. 177:993 Statistically Engineering the Study for Success Beam 2002 Am. J.

Roentgenol. 179:47 Observational Studies in Radiology Blackmore 2004 Am. J.

Roentgenol. 183:1203 Visualizing Radiologic Data Karlik 2003 Am. J. Roentgenol. 180:607 Reader Agreement Studies Crewson 2005 Am. J. Roentgenol.

184:1391 Radiology Cost and Outcomes Studies: Hollingworth 2005 AJR.

185:833

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ROC Analysis Obuchowski 2005 Am. J. Roentgenol. 184:364 Survival Analysis Stolberg 2005 Am. J. Roentgenol. 185:19 Multivariate Statistical Methods Obuchowski 2005 Am. J. Roentgenol.

185:299 Correlation and Regression Dendukuri 2005 Am. J. Roentgenol. 185:3 Screening for Pre clinical Disease Herman 2002 Am. J. Roentgenol.

179:825

Required reading, in advance of the workshop1. Bossuyt P, Reitsma J, Bruns D, Gatsonis C, Glasziou P, Irwig L, Lijmer

J, Moher D, Rennie D, de Vet HC. Standards for Reporting of Diagnostic Accuracy steering group. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. Academic Radiology, 2003;10:664-669.

2. Gatsonis C, McNeil B. Collaborative evaluation of diagnostic tests: Experience of the Radiologic Diagnostic Oncology Group. Radiology, 1990;175:571-575.

3. Weinstein S, Obuchowski NA, Lieber ML. Clinical evaluation of diagnostic tests. Am J Roentgenol. 2005 Jan;184(1):14-9

4. Obuchowski, N. ROC analysis. Am J Roentgenol. 2005 ;184:364-72 .

5. Black WC, Welch HG. Screening for disease. AJR, 1997;168(1):3-11.

6. Emanuel EJ, Wendler D, Grady C. (2000). What makes clinical research ethical? JAMA. 283(20): 2701-11.

A. Diagnostic imaging evaluation: General

1. The Evidence Base of Clinical Diagnosis. JA Knottnerus (Ed.) London: BMJ Books, 2002.

2. Houn F, Bright RA, Bushar HF, Croft BY, Finder CA, Gohagan JK, Jennings RF, Keegan P, Kessler LG, Kramer BS, Martynec LO, Robinowitz M, Sacks WM, Schultz DG, Wagner RF. Study design issues in the evaluation of breast cancer imaging technologies. Academic Radiology, 2000, Sep; 7(9):684-692.

3. Gatsonis C. Design of evaluations of imaging technologies: Development of a paradigm. Academic Radiology, 2000;7:681-683.

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4. Thornbury JR. Clinical efficacy of diagnostic imaging:. AJR 1994;162:1-8.

B. Introduction to Clinical Trials

1. Piantadosi S. Clinical Trials: A Methodologic Perspective, 2nd Ed, New York: Wiley, 2005.

2. Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials. 3 ed. St. Louis: Mosby, 1998.

3. Johnson, J. Williams G, Pazdur R. End Points and United States Food and Drug Administration Approval of Oncology Drugs. J Clin Oncol 2005; 21:1404-1411.

4. Perrone F, Di Maio M, DeMaio E, Maione P, Ottaiano A, Pensabene M, Di Lorenzo G, Lombardi AV, Sinoriello G, Gallo C. Statistical design in phase II clinical trials and its application in breast cancer. Lancet Oncol, 2003;4:305-311.

5. Eisenhauer EA, O’Dwyer PJ, Christian M, Humphrey JS. Phase I clinical trial design in cancer drug development. J Clin Oncol, 2000; 18:684-692.

C. Introduction to Biostatistics

1. Dawson B, Trapp RG. Basic & Clinical Biostatistics. 4th ed. Lange Medical Books-McGraw-Hill, 2004

2. Pagano M, Gavreau K . Principles of Biostatistics 2nd Ed, Duxbury Press, 2000.

D. Statistical methods for diagnostic test evaluation: General Textbooks, Chapters, Tutorials

1. Articles in the series: Fundamentals of Clinical Research for Radiologists Am J Roentgenol. 2001-2006 (see hyperlinked PDFs above)

2. Toledano AY. Cancer diagnostics: Statistical methods. In Biostatistical Applications in Cancer Research. Beam C (Ed.) Kluwer Norwell: Academic Publishers, 2002, 183-218.

3. Pepe M. The Statistical Evaluation of Medical Tests for Classification and Prediction. New York: Oxford Press, 2003.

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4. Zhou X-H, Obuchowski N, McClish D. Statistical Methods in Diagnostic Medicine. New York: Wiley, 2002.

E. Statistical methods for diagnostic test evaluation: Special topics

Biases and Their Control

1. Reid MC, Lachs MS, Feinstein AR. Use of methodologic standards in diagnostic test research: Getting better but still not good. JAMA, 1995;274:645-651.

2. Black WC. How to evaluate the radiology literature. AJR, 1990;154:17-22

3. Begg CB, McNeil BJ. Assessment of radiologic tests, control of bias, and other design considerations. Radiology, 1988;167:565-569.

4. Ransohoff DJ, Feinstein AR. Problems of spectrum and bias in evaluating the efficacy of diagnostic tests. NEJM, 1978;299:926-930.

Predictive Value of Tests

1. Sargent D., Conley B., Allegra C., Collette L. Clinical Trial Designs for Predictive Marker Validation in Cancer Treatment Trials .JCO Mar 20 2005: 2020-2027.

2. McShane L, Altman DG, Sauerbrei W, et al. Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Canc Inst, 2005;97:1180-1184.

3. Heagerty P, Zheng Y. Survival model predictive accuracy and ROC curves. Biometrics, 2005;61:92-105.

4. Fleming, T.R. Surrogate Endpoints and FDA’s Accelerated Approval Process: The challenges are greater than they seem. Health Affairs 2005 ;24:67-78.

Meta analysis of diagnostic accuracy studies

1. Gatsonis C, Paliwal P. Meta-analysis of diagnostic and screening test accuracy evaluations: A methodologic primer. AJR 2006; 187:271-281

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2. Irwig L, Macaskill P, Glasziou P, Fahey M. Meta-analytic methods for diagnostic test accuracy. J Clin Epi, 1995;48:119-130.

3. Irwig L, Tosteson AN, Gatsonis CA, Lau J, Colditz G, Chalmers TC, Mosteller F. Guidelines for meta-analyses evaluating diagnostic tests. Ann Int Med, 1994;120:667-676.

F. Quality of Life, Patient Satisfaction, Health Care Utilization Outcomes

1. Brazier J, Deverill M, Green C. A review of the use of health status measures in economic evaluation. J Health Serv Res Policy, 1999;4:174-184.

2. Spilker B (Ed.). Quality of Life and Pharmacoeconomics in Clinical Trials. New York: Raven Press, 1996.

3. Torrance G, Furlong W, Feeny D, Boyle M. Multi-attribute preference functions: Health Utilities Index. Pharmacoeconomics, 1995;7:503-520.

4. Ware JE Jr, Shelbourne CD. The MOS 36-item short-form health survey (SF-36): I. Conceptual framework and item selection. Medical Care, 1992;30:473-483.

G. Imaging as a Measure of Therapeutic Response

1. Therasse P, Eisenhauer EA, Verweij J.RECIST revisited: a review of validation studies on tumour assessment. Eur J Cancer. 2006 ;42:1031-9

2. Hallet W Quantification in clinical fluorodeoxyglucose positron emission tomography. Nucl Med Commun. 2004 ;25:647-50.

3. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000; 92:205-16 .

4. Website for Q&A RECIST problem solving.

H. Imaging as a Predictor of Therapeutic Response

1. Sasaki R, Komaki R, Macapinlac H, Erasmus J, Allen P, Forster K, Putnam JB, Herbst RS, Moran CA, Podoloff DA, Roth JA, Cox JD.

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[18F]flurodeoxyglucose uptake by positron emission tomography predicts outcome of non-small-cell lung cancer. J Clin Oncol, 2005;23:1136-1143.

2. Fernandez FG, Drebin JA, Linehan DC, Dehdashti F, Siegel BA, Strasberg SM. Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 flurodeoxyglucose (FDG-PET). Ann Surg, 2004;240:438-447.

3. Weber WA, Petersen V, Schmidt B, Tyndale-Hines L, Link T, Preschel C, Schwaiger M. Positron emission tomography in non-small-cell lung cancer: Prediction of response to chemotherapy by quantitative assessment of glucose use. J Clin Oncol, 2003;2651-2657.

4. Kostakoglu L, Coleman M, Leonard JP, Kuji I, Zoe H, Goldsmith SJ. PET predicts prognosis after one cycle of chemotherapy in aggressive lymphoma and Hodgkin’s disease. J Nucl Med, 2002;43:1018-1027.

I. Imaging in clinical studies

1. Schnall M, Rosen M. Primer on imaging technologies for cancer. J Clin Oncol. 2006;24(20):3225-33. Review.

2. Barkhof F, Filippi M, Miller DH, Tofts P, Kappos L, Thompson AJ. Strategies for optimizing MRI techniques aimed at monitoring disease activity in multiple sclerosis treatment trials. J Neurol. 1997;244(2):76-84

J. Screening Studies: Methods

1. Hillman BJ, Black WC, Hauser B, Smith R. The appropriateness of employing imaging screening technologies: Report of the methods committee of the ACR task force on screening technologies. JACR, 2004;1(11):861-864.

2. Obuchowski NA, Graham RJ, Baker ME, Powell KA. Ten criteria for effective screening: Their application to multislice CT screening for pulmonary and colorectal cancers. AJR, 2001;176(6)1357-1362.

3. Black WC. Overdiagnosis: An underrecognized cause of confusion and harm in cancer screening. J Natl Cancer Inst, 2000;92(16)1280-1282.

4. Morrison AS. The natural history of disease in relation to measures of disease frequency. In Screening in Chronic Disease, 2nd Ed. New York: Oxford University Press, 1992, 21-42.

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K. Modeling for the Assessment of Screening Modalities

1. Claxton K, Cohen JT, Neumann PJ. When is evidence sufficient? Health Affairs, 2005:24(1);93-101.

2. Ramsey S, McIntosh M, Etzioni R, Urban N. Simulation modeling of outcomes and cost effectiveness [Review]. Hematol Oncol Clin North Am, 2000;14(4):925-938.

3. Russell LB, Gold MB, Siegel JE, Daniels N, Weinstein MC. The role of cost-effectiveness analysis in health and medicine. JAMA, 1996; 276(14)1172-1177.

L. Medical Ethics

1. Hellman S and Hellman D. (1991). Of mice but not men: problems of the randomized clinical trial. NEJM 324:1585-9.

2. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1979). The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington, D.C.: Dept. of Health, Education, and Welfare

M. Investigational drugs and devices

FDA Guidance on the IND process with multiple links to other documentation:–http://www.fda.gov/cder/regulatory/applications/ind_page_1.htm

Comprehensive FDA Guidance Page–http://www.fda.gov/cder/guidance/index.htm

A “how-to” guide from the Biological Development Program at NCI-Frederick with multiple links– http://wwwbdp.ncifcrf.gov/pdf/GuidetoRegSubs.pdf

Regulatory guidance for Imaging drugs:Part 1: Conducting Safety Assessments www.fda.gov/cder/guidance/5742prt1.pdfPart 2: Clinical Indications www.fda.gov/cder/guidance/5742prt2.pdfPart 3: Design, Analysis, and Interpretation of Clinical studies www.fda.gov/cder/guidance/5742prt3.pdf

FDA Center for Devices and Radiological Health http://www.fda.gov/cdrh/index.html

Device Advice: http://www.fda.gov/cdrh/devadvice/N. Resources Available on the Web

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1. http://www.fda.gov/cder/cancer/docs/overview.html

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