National Conference on Innovation in Pharmaceutical Industry L.J. Institute of Pharmacy 28th January 2012 Dr. Bhaswat S. Chakraborty Senior Vice President and Chairman, R&D Science Core Committee, Cadila Pharmaceuticals Ltd.
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 Today Research is conducted mainly on New Drugs New Combinations Radiotherapy Surgery In the West, research is usually done by large co-operative groups, in addition to those mentioned for India In India Large Pharmaceuticals Co-operative Groups, e.g., ICON (Indian Co-operative Oncology Network) Regional Cancer Centres & Govt. sponsored studies Academia
What does FDA Look for in a Ca RCT?FDA approves a drug application based on Substantial evidence of efficacy & safety from “adequate and well-controlled investigations” A valid comparison to a control Quantitative assessment of the drug’s effect (21 CFR 314.126.)The design of cancer trials intended to support drug approval is very importantOncology 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 Survival Disease free survival Progress -free survivalObjective response rates Complete Partial Stable disease Progressive diseaseSymptom end pointsPalliationQoL
Relative MeritsEndpoint Evidence Assessment Some Advantages Some DisadvantagesSurvival Clinical benefit • RCT needed • Direct measure of • Requires larger and • Blinding not benefit longer studies essential • Easily • Potentially affected by measured crossover therapy • Precisely • Does not capture measured symptom benefit • Includes noncancer deathsDisease-Free Surrogate for • RCT needed • Considered to • Not a validatedSurvival accelerated • Blinding be clinical benefit survival surrogate in most(DFS) approval or preferred by some settings regular • Needs fewer • Subject to assessment approval* patients and bias shorter studies than • Various definitions survival exist
Relative Merits..Endpoint Evidence Assessment Some Advantages Some DisadvantagesObjective Surrogate for • Single-arm or • Can be assessed • Not a direct measure ofResponse accelerated randomized in single-arm benefitRate (ORR) approval or studies can be studies • Usually reflects drug regular used activity in a minority of approval* • Blinding patients preferred in • Data are moderately comparative complex compared to studies survivalComplete Surrogate for • Single-arm or • Durable CRs • Few drugs produce highResponse accelerated randomized represent obvious rates of CR(CR) approval or studies can be benefit in some • Data are moderately regular used settings (see text) complex compared to approval* • Blinding • Can be assessed survival preferred in in single-arm comparative studies studies
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 endpointPrecise 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 Assessments Disease-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 endpoints Collection 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 approvalsThey 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 examinedFor 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 toxicityAn 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 endpointsNot considered good predictors of clinical benefitThe FDA has sometimes accepted tumor markers as elements of a composite endpoint e,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 patientsBiomarkers, however, can be useful in identifying prognostic factors and in selection of patients and stratification factors to be considered in study designs
Specific Symptom Endpoints Time to progression of cancer symptoms, an endpoint similar to TTP, is a direct measure of clinical benefit rather than a potential surrogate Problems in measuring progression (e.g., missing assessments) also exist in evaluating time to symptomatic progression Because 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 indications Safety profile in patients Pharmacological / toxicological characteristicsMulti-centre CT Confirmation of the above Effect size Site, care and demographic differences Epidemiological determination Complexity Far superior to meta-analyzed determination of effect
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 ineffectiveOther 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 approach Demonstrating superiority of the new therapyOther approaches Single arm studies (e.g., Phase II) e.g., when many complete responses were observed or when toxicity was minimal or modest Equivalence Trials No Treatment or Placebo Control Studies Isolating 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 + Placebo Standard + Drug XEffects seen in early phases of development Establish the contribution of a drug to a standard regimen Particularly 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.