Dr. Bhaswat S. ChakrabortySenior Vice President and Chairman,

R&D Science Core Committee, Cadila Pharmaceuticals Ltd.

National Conference on Innovation in Pharmaceutical Industry

L.J. Institute of Pharmacy 28th January 2012

Contents Clinical Development of a New Drug

Endpoint considerations

Merits and demerits

Overall survival

Tumor assessment based endpoints

QoL, biomarkers and symptom trial

Trial designs

Concluding comments

Clinical Development of New DrugsDevelopment Plan

Define target disease population

Dose range and schedule at which the drug can be shown to be simultaneously safe and effective, to the extent that the risk-benefit relationship is acceptable

Satisfying these broad aims usually requires an ordered program of clinical trials, each with its own specific objectives (ICH E8).

A marketing application should clearly describe the main content of such plans, and the contribution made by each trial.

A statistical summary, overview, or meta-analysis may be informative when medical questions are addressed in more than one trial.

Other major statistical issues (if any) that are expected to affect a number of trials in a common plan should be addressed in that plan

Cancer Research TodayResearch is conducted mainly on

New DrugsNew CombinationsRadiotherapySurgery

In the West, research is usually done by large co-operative groups, in addition to those mentioned for India

In IndiaLarge PharmaceuticalsCo-operative Groups, e.g., ICON (Indian Co-operative Oncology Network)

Regional Cancer Centres & Govt. sponsored studiesAcademia

What does FDA Look for in a Ca RCT?

FDA approves a drug application based onSubstantial evidence of efficacy & safety from “adequate

and well-controlled investigations”  A valid comparison to a controlQuantitative assessment of the drug’s effect

(21 CFR 314.126.) 

The design of cancer trials intended to support drug approval is very important

Oncology based NDAs are usually reviewed on fast track

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)

Improvement in a patient’s quality of life (QOL)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

So, the Endpoint Metrics are:Time to event end points

SurvivalDisease free survivalProgress -free survival

Objective response ratesCompletePartialStable diseaseProgressive disease

Symptom end pointsPalliationQoL

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

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

Overall Survival (OS)OS: The time from randomization until death from any causeMeasured usually in the intent-to-treat (ITT) populationMost reliable cancer endpoint, and when studies can be

conducted to adequately assess survival, it is usually the preferred endpoint

Precise and easy to measureBias is not a factor in endpoint measurementSurvival improvement should be analyzed as a risk-benefit

analysis to assess clinical benefitOS should be evaluated in RCTs

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

Rosell et al., Annals of Oncology 19: 362–369, 2008

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

Rosell et al., Annals of Oncology 19: 362–369, 2008

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

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

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

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

Trial DesignsRandomized Clinical Trials (RCTs)Gold standard in Phase IIISingle centre CT

Primary and secondary indicationsSafety profile in patientsPharmacological / toxicological characteristics

Multi-centre CTConfirmation of the aboveEffect sizeSite, care and demographic differencesEpidemiological determinationComplexityFar superior to meta-analyzed determination of effect

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Non-Inferiority

Equivalence

Inferiority

Superiority

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Non-Superiority

Equality

Other Trial Designs..Single arm studies

no available therapy and where major tumor regressions can be presumed to be attributed to the tested drug

ORR and response duration measurements

Non-inferiority (NI) trials should demonstrate that the new drug is not less effective than a standard

regimen (the active control) by a prespecified amount (noninferiority margin) NI margin is some fraction of (e.g., 50 percent) of the control drug effect (assay

sensitivity) the control should have a well-characterized survival benefit If the new drug is inferior to the active control by more than the NI margin, it

will be presumed to be ineffective

Other approaches No Treatment or Placebo Control Studies Isolating Drug Effect in Combinations Studies for Radio- and Chemotherapy Protectants

Study Design: ApproachesRandomised Controlled Trials (RCT) most preferred

approachDemonstrating superiority of the new therapy

Other approachesSingle arm studies (e.g., Phase II)

e.g., when many complete responses were observed or when toxicity was minimal or modest

Equivalence TrialsNo Treatment or Placebo Control StudiesIsolating Drug Effect in Combinations Studies for Radio- and Chemotherapy Protectants

Placebo Control Equality TrialsNo anticancer drug treatment in the control arm is

unethicalSometimes acceptable

E.g., in early stage cancer when standard practice is to give no treatment

Add-on design (also for adjuvants) all patients receive standard treatment plus either no additional

treatment or the experimental drug

Placebos preferred to no-treatment controls because they permit blinding

Unless very low toxicity, blinding may not be feasible because of a relatively high rate of recognizable toxicities

Drug or Therapy CombinationsUse the add-on design

Standard + PlaceboStandard + Drug X

Effects seen in early phases of development Establish the contribution of a drug to a standard regimenParticularly if the combination is more effective than any of

the individual components

Concluding Remarks Clinical testing of new Oncology products is very sophisticated and complex

Cancer clinical data is very complex (censored, skewed, often fraught with missing data point), therefore, proper hypothesization and statistical treatment of data are required

There are many endpoints that are scientifically valid but OS as primary end point is often preferred by regulatory agencies

Tumor assessment trials may need another confirmatory CT

Endpoints must be demonstrative (directly or indirectly) of clinical benefit

Missing data, infrequent treatment, increased type I error and other confounding factors must be addressed

Prospective RCTs are usually the preferred approach for evaluation of new therapies

Despite good knowledge in endpoints & trial design, meet & consult FDA before initiating a pivotal trial.

Thank you Very Much