Vaccines Summit 2012, Hyderabad, India          30-31 August, 2012                          Dr. Bhaswat S. Chakraborty    ...
ContentsDetermining the financial and decisional risks associated with the early phase trialsUnderstanding the best stud...
Success of a [Phase II] Clinical Trial       Right          Right conduct of the trial                                    ...
Operational Challenges under ResourceConstraintsResource constraints    Fiscal    Organizaional    Technical    Regul...
Resource Constraints – somecharacteristicsFiscal   Very common in developing countries – low and unrealistic budgets    ...
Design & Control Issues in Phase II CancerTrials  One of the major issues is the use of controls  One study* finds that ...
Design & Control Issues in Phase II CancerTrials  One of the major issues is the use of controls  One study* finds that ...
Design & Control Issues in Phase II CancerTrials.. The “go or no go” decision at the end of phase II is perhaps the most ...
Design & Control Issues in Phase II CancerTrials... Herceptin, Erbitux, and Avastin may have only modest activity as  sin...
Design & Control Issues in Phase II CancerTrials...  The best design for phase II will depend on the nature of the agent,...
Endpoints in Oncology Trials Must show either direct evidence of clinical       benefit or improvement  in an established...
Relative MeritsEndpoint       Evidence           Assessment       Some Advantages        Some DisadvantagesSurvival       ...
Relative Merits..Endpoint     Evidence        Assessment        Some Advantages       Some DisadvantagesObjective    Surro...
Overall Survival (OS) OS: The time from randomization until death from any cause Measured usually in the intent-to-treat...
Rosell et al. (2008), Annals of Oncology, 19, 362–369                                                 15
Endpoints Based on Tumor Assessments Disease-free survival (DFS) Objective response rate (ORR) Time to tumor progressio...
Rosell et al. (2008), Annals of Oncology, 19, 362–369                                                 17
Cautions in Tumor AssessmentsAccuracy in measuring tumors can differ among tumor settingsImprecision can happen in locat...
Quality of Life (QoL) EndpointsGlobal health-related quality of life (HRQL) have not served as primary efficacy endpoints...
BiomarkersUsually not a good idea for cancer drug approvalOther than paraprotein levels measured in blood and urine for ...
Specific Symptom Endpoints Time to progression of cancer symptoms, an endpoint similar to TTP, is a  direct measure of cl...
Intent-to-Treat Principle All randomized patients Exclusions on prespecified baseline criteria permissible    also know...
Per Protocol AnalysesFocuses on the outcome dataAddresses what happens to patients who remain on therapyTypically exclu...
Intent to Treat & Per ProtocolAnalyses Both types of analyses are important for approval Results should be logically con...
ITT       PPOS & PFS – ITT vs PP                                                25                       Sandler et al. 20...
Belani et al. (2011), ASCO Annual Meeting                                            26
Decision to Proceed to Phase III orTerminate  This is a consideration for IA  Stopping rules for significant efficacy  ...
Decision to Proceed to Phase III orTerminate..  Single arm studies   Futility is better predicted in IA than success  H...
Concluding Remarks Clinical testing of new Oncology products is very sophisticated and  complex Cancer clinical data is ...
Thank you Very Much                      30
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Addressing the unpredictability issues in cancer vaccine trials

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Determining the financial and decisional risks associated with the early phase trials
Understanding the best study designs and selection of controls to eliminate candidates
Understanding the end point selection for Cancer clinical trials
Comparing progress free and overall survival in Intend To Treat (ITT) and per protocol (PP) populations
Critically analysing the decision to proceed to Phase III or to terminate the trial
Case study: Discussing the best practice strategies on ‘Phase II clinical trials of vaccines – to go or not to go to Phase III

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  • The best of these drugs, such as Herceptin (Trastizumab, anti-HER2/neu receptors), Erbitux (Cetixumab, anti-EGFR), and Avastin (Bevacizumab, anti-VEGF-A), may have only modest activity as single agents and produce few clinical responses. Their value may only be obvious in more subtle trial designs, in which they delay time to progression or recurrence or enhance response rates to standard cytotoxic agents (5, 6). The traditional single-agent phase II trial, with response as the end point, may lead to the abandonment of a valuable drug. Larger trials, and more complex phase II designs with time-to-progression end points, may be required to show effectiveness of the new agent. In this sort of trial, concurrent controls, treated with standard agents or randomized either to discontinue the experimental drug or perhaps to begin the drug after a period of placebo treatment, might show valuable aspects of the toxicity and effectiveness of the new agent. Such is the case with sorafenib, in which the University of Chicago group randomized stable patients to continued therapy versus drug discontinuation, with strikingly positive findings for patients who continued to receive the experimental drug (2). In other settings, in which a standard cytotoxic is an alternative to a new targeted drug, the choice of appropriate end points may be complicated. Although time to progression might be most appropriate for the cytostatic agent, partial or complete remission might be a clearer end point for the cytotoxic drug. Sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar ), [1] is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma).
  • The best design for any given agent in phase II will depend on the nature of the agent, the early hints of activity in phase I, the disease setting, the degree of certainty about best dose and schedule coming out of phase I trials, and the competition faced by the new drug. A randomization involving two different doses of drug might show a dose-response relationship and a clear advantage for one and thereby might resolve questions that often persist even after approval. Even for effective drugs, such as imatinib, it is unclear whether escalation beyond the recommended 400 mg/d dose might have long-term benefit for certain patients. Other trial designs might evaluate target inhibition as an end point versus the maximum tolerated dose and thereby answer questions of the benefits and risks of escalating beyond the biologically effective dose (7, 8). New molecular technologies offer remarkable insights that can inform unexpected development pathways. Increasingly, gene expression profiling and molecular studies have illuminated the existence of distinct subpopulations within pathologic categories of cancer and may be helpful in defining effective treatment for distinct subpopulations (9). The role of epidermal growth factor receptor mutations in predicting response to gefitinib and erlotinib offers an outstanding example of the value of a biomarker in defining a development strategy (10). Both the National Cancer Institute and the Food and Drug Administration have declared their intention to support the development of biomarkers to speed and inform drug development. 1 The phase II setting, rather than phase I, may be the appropriate arena for addressing the question of how to identify the appropriate patient subpopulation for drug X (11) because this determination requires responses or other evidence of antitumor activity (such as delayed time to progression) to establish a correlation of activity with a biomarker. Thus, it might be useful to compare the molecular profile of responding patients or patients with stable disease beyond a defined time period, with the profile of nonresponders or those subjects who progress early after initiation of treatment. In the longer run, intensive molecular and immunologic characterization of the responsive subset of the phase II patient pool might provide more valuable information than randomization, with the potential for enrichment of the population for responders (12).
  • The different approaches to phase II trial design which are described in this section will be illustrated by the design of a single-arm phase II trial described by Thall & Simon [2]. The purpose of the trial was to assess treatment with ¯udarabine +ara-C+ granulocyte colony stimulating factor (GCSF) for poor prognosis acute myelogenous leukaemia patients. All patients in the trial receive the new treatment. The clinical endpoint is complete remission (CR) of the leukaemia. For patients achieving such a state, the treatment will be termed successful. The standard treatment is ¯udarabine+ara-C, for which the success rate is 50%. The use of GCSF would be considered bene®cial if it increased the success rate to 70%.
  • Addressing the unpredictability issues in cancer vaccine trials

    1. 1. Vaccines Summit 2012, Hyderabad, India 30-31 August, 2012 Dr. Bhaswat S. Chakraborty Senior Vice President and Chairman, R&D Core Committee, Cadila Pharmaceuticals Ltd. 1
    2. 2. ContentsDetermining the financial and decisional risks associated with the early phase trialsUnderstanding the best study designs and selection of controls to eliminate candidatesUnderstanding the end point selection for Cancer clinical trialsComparing progress free and overall survival in Intend To Treat (ITT) and per protocol (PP) populationsCritically analysing the decision to proceed to Phase III or to terminate the trialCase study: Discussing the best practice strategies on ‘Phase II clinical trials of vaccines – to go or not to go to Phase IIIConcluding remarks 2
    3. 3. Success of a [Phase II] Clinical Trial Right Right conduct of the trial Generalizable Scientific Adequate scope, time & Results Questions budget Does this drug increase PoC of Efficacy, Safety,survivability in …cancer? Dose & Frequency Proceed to higher phases 3
    4. 4. Operational Challenges under ResourceConstraintsResource constraints  Fiscal  Organizaional  Technical  RegulatoryOperational challenges under these constraints  Operational planning scheduling under uncertainty  Meeting design objectives, timelines & scope  Supply chain management  Quality and monitoring  Completion within variable? budget 4
    5. 5. Resource Constraints – somecharacteristicsFiscal  Very common in developing countries – low and unrealistic budgets given the scope & conduct of the study  Difficulty in payments even commitment issues  Gaining approval for out-of-pocket expenses is difficultOrganizational  Team building, team performance and team achievement are often new concepts in some cultures Technical  Often drugs are developed one by one rather than a portfolio of a group of drugs which increases success probabilityRegulatory  Often a big challenge within the firm & national body– starting from getting a trial license, not well developed review system, no defined performance standard in timelines up to limited expertise and overreaction to SAEs 5
    6. 6. Design & Control Issues in Phase II CancerTrials  One of the major issues is the use of controls  One study* finds that only ~20% Phase II Cancer Trials use active or historical control or placebo (notwithstanding a higher reporting of Onco trials)  Remember the primary objective of a phase II cancer clinical trials is to determine whether to proceed for a further Phase II or a Phase III study  This requires basically a demonstration of substantial efficacy of a new regimen  However, oncology Phase II has been limited by high rates of failure (lack of efficacy) in subsequent phase III testing  This is in part because of use of single arm studies which can easily discard a study with an apparent low efficacy that due to factors other than the drug itself *Michaelis et al. (2007). Clin Cancer Res,13, 2400–5 6
    7. 7. Design & Control Issues in Phase II CancerTrials  One of the major issues is the use of controls  One study* finds that only ~20% Phase II Cancer Trials use active or historical control or placebo (notwithstanding a higher reporting of Onco trials)  Remember the primary objective of a phase II cancer clinical trials is to determine whether to proceed for a further Phase II or a Phase III stdy  This requires basically a demonstration of substantial efficacy of a new regimen  However, oncology Phase II has been limited by high rates of failure (lack of efficacy) in subsequent phase III testing  This is in part because of use of single arm studies which can easily discard a study with an apparent low efficacy that due to factors other than the drug itself *Michaelis et al. (2007). Clin Cancer Res,13, 2400–5 7
    8. 8. Design & Control Issues in Phase II CancerTrials.. The “go or no go” decision at the end of phase II is perhaps the most difficult one to make in the drug development cycle  data are limited  future investment required for a phase III trial is vast  success of the company may depend on the drug in question  an informative phase II trial is crucial  after phase II, the decision makers need to understand toxicity and pharmacokinetics, should have strong indications of activity in a specific kind of cancer, and should have a clear sense of an approval strategy There are often gaps in this knowledge, and the decision is guided by both fact and intuition. The decision becomes easier when the case is unmet medical needs Chabner B. (2007). Clin Cancer Res,13, 2307 8
    9. 9. Design & Control Issues in Phase II CancerTrials... Herceptin, Erbitux, and Avastin may have only modest activity as single agents and produce few clinical responses Their effect requires more subtle trial designs  e.g., delay time to progression or recurrence or enhance response rates to standard cytotoxic agents.  single arm phase II trial, with response as the end point, may lead to the abandonment of a valuable drug Larger trials, and more complex phase II designs with TTP end points, may be required to show effectiveness of the new agent  here, concurrent controls, treated with standard agents or or other strategies might show valuable aspects of the toxicity and effectiveness of the new agent  e.g sorafenib, [U of Chicago Researchers] randomized stable patients to continued therapy vs. drug discontinuation, with positive for patients continuing with experimental drug 9 Chabner B. (2007). Clin Cancer Res,13, 2307
    10. 10. Design & Control Issues in Phase II CancerTrials...  The best design for phase II will depend on the nature of the agent, activity in phase I, the disease setting, the degree of certainty about best dose and schedule coming out of phase I trials, and the competition faced by the new drug.  A randomization involving two different doses of drug might show a dose- response relationship  e.g., imatinib, it is unclear whether escalation beyond the recommended 400 mg/d dose might have long-term benefit for certain patients.  New molecular technologies offer remarkable insights  gene expression profiling and molecular studies have illuminated distinct subpopulations within pathologic categories of cancer  role of epidermal growth factor receptor mutations in predicting response to gefitinib and erlotinib  development of biomarkers  phase II setting is the setting for appropriate patient 10 Chabner B. (2007). Clin Cancer Res,13, 2307
    11. 11. Endpoints in Oncology Trials Must show either direct evidence of clinical benefit or improvement in an established surrogate for clinical benefit Clinical benefit: survival improvement  Overall survival (OS)  Progress-free survival (PFS) (usually Ph III) Improvement in a patient’s quality of life (QOL) (usually Ph III) Other endpoints on which approval has been given are:  Objective response rate (ORR)  by RECIST or any radiological tests or physical examinations Improvement in survival, improvement in a QOL, improved physical functioning, or improved tumor-related symptoms do not always be predicted by, or correlate with, ORR Source: US FDA Guidance 11
    12. 12. 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 12
    13. 13. 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 13
    14. 14. Overall Survival (OS) OS: The time from randomization until death from any cause Measured usually in the intent-to-treat (ITT) population Most reliable cancer endpoint, and when studies can be conducted to adequately assess survival, it is usually the preferred endpoint Precise and easy to measure – no influence of technicality of measurement Bias is not a factor in endpoint measurement Survival improvement should be analyzed as a risk-benefit analysis to assess clinical benefit OS should be evaluated in RCTs  Historical trials are seldom reliable for time-dependent endpoints (e.g., OS, PFS).  The OS in control arm has to be compatible 14
    15. 15. Rosell et al. (2008), Annals of Oncology, 19, 362–369 15
    16. 16. 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 16
    17. 17. Rosell et al. (2008), Annals of Oncology, 19, 362–369 17
    18. 18. Cautions in Tumor AssessmentsAccuracy in measuring tumors can differ among tumor settingsImprecision 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 18
    19. 19. Quality of Life (QoL) EndpointsGlobal 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 19
    20. 20. BiomarkersUsually not a good idea for cancer drug approvalOther 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 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 patientsBiomarkers, however, can be useful in identifying prognostic factors  and in selection of patients and stratification factors to be considered in study designs 20
    21. 21. 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 21
    22. 22. Intent-to-Treat Principle All randomized patients Exclusions on prespecified baseline criteria permissible  also known as Modified Intent-to-Treat Confusion regarding intent-to-treat population: define and agree upon in advance based upon desired indication Advantages:  Comparison protected by randomization  Guards against bias when dropping out is related to outcome  Can be interpreted as comparison of two strategies  Failure to take drug is informative  Reflects the way treatments will perform in population  More suitable for superiority trials Concerns:  “Difference detecting ability” 22
    23. 23. Per Protocol AnalysesFocuses on the outcome dataAddresses what happens to patients who remain on therapyTypically excludes patients with missing or problematic dataMore suitable for non-inferiority trialsStatistical concerns:  Selection bias  Bias difficult to assess 23
    24. 24. Intent to Treat & Per ProtocolAnalyses Both types of analyses are important for approval Results should be logically consistent Design protocol and monitor trial to minimize exclusions Substantial missing data and poor drug compliance weaken trial’s ability to demonstrate efficacy 24
    25. 25. ITT PPOS & PFS – ITT vs PP 25 Sandler et al. 2006. N Engl J Med, 355, 2542-50.
    26. 26. Belani et al. (2011), ASCO Annual Meeting 26
    27. 27. Decision to Proceed to Phase III orTerminate  This is a consideration for IA  Stopping rules for significant efficacy  Stopping rules for futility  Measures taken to minimize bias  A procedure/method for preparation of data for analysis  Data has to be centrally pooled, cleaned and locked  Data analysis - blinded or unblinded?  Interim results must be submitted to IDMC  What is the scope of recommendations from IA results? What should be made known to the Sponsor?  Safety? Efficacy? Both? Futility? Sample size readjustment for borderline results? 27
    28. 28. Decision to Proceed to Phase III orTerminate..  Single arm studies  Futility is better predicted in IA than success  However, when success/failure response is used  Summarize success as the proportion of number of totally included patients  To proceed for Phase III, it is important to know the norm (activity of current standard) and that the new treatment is expected to exceed this  Example  The standard treatment for AML is fludarabine + ara-C (50% success)  Addition of GCSF would be beneficial if Phase II shows ~70% success Thall & Simon (1994). Biometrics, 50, 337-349 28
    29. 29. 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 Resource challenges can affect operations and even the study design There are many endpoints that are scientifically valid but OS as primary end point is often preferred by regulatory agencies PFS & 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 Consistent ITT & PP facilitate approval Carefully establish “go or no-go” rules and critically examine IA data; single arm should exceed the “norm” of standard success Despite good knowledge in endpoints & trial design, meet & consult FDA before initiating a pivotal trial. 29
    30. 30. Thank you Very Much 30

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