Dr. Bhaswat S. Chakraborty Senior Vice President and Chairman, R&D Core Committee, Cadila Pharmaceuticals Ltd. Vaccines Summit 2012, Hyderabad, India 30-31 August, 2012 1
Jul 01, 2015
Dr. Bhaswat S. ChakrabortySenior Vice President and Chairman,
R&D Core Committee, Cadila Pharmaceuticals Ltd.
Vaccines Summit 2012, Hyderabad, India30-31 August, 2012
1
ContentsDetermining the financial and decisional risks associated
with the early phase trialsUnderstanding the best study designs and selection of
controls to eliminate candidatesUnderstanding the end point selection for Cancer clinical
trialsComparing progress free and overall survival in Intend To
Treat (ITT) and per protocol (PP) populationsCritically analysing the decision to proceed to Phase III or
to terminate the trialCase study: Discussing the best practice strategies on
‘Phase II clinical trials of vaccines – to go or not to go to Phase III
Concluding remarks2
Success of a [Phase II] Clinical Trial
Right Scientific Questions
Generalizable Results
Right conduct of the trial
Adequate scope, time & budget
Proceed to higher phases
PoC of Efficacy, Safety, Dose & Frequency
Does this drug increase survivability in …cancer?
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Operational Challenges under Resource ConstraintsResource constraints
FiscalOrganizaionalTechnicalRegulatory
Operational challenges under these constraintsOperational planning scheduling under uncertaintyMeeting design objectives, timelines & scopeSupply chain managementQuality and monitoringCompletion within variable? budget
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Resource Constraints – some characteristicsFiscal
Very common in developing countries – low and unrealistic budgets given the scope & conduct of the study
Difficulty in payments even commitment issuesGaining approval for out-of-pocket expenses is difficult
OrganizationalTeam building, team performance and team achievement are often new
concepts in some culturesTechnical
Often drugs are developed one by one rather than a portfolio of a group of drugs which increases success probability
RegulatoryOften a big challenge within the firm & national body– starting from
getting a trial license, not well developed review system, no defined performance standard in timelines up to limited expertise and overreaction to SAEs 5
Design & Control Issues in Phase II Cancer Trials
One of the major issues is the use of controlsOne study* finds that only ~20% Phase II Cancer Trials use active or
historical control or placebo (notwithstanding a higher reporting of Onco trials)
Remember the primary objective of a phase II cancer clinical trials is to determine whether to proceed for a further Phase II or a Phase III study
This requires basically a demonstration of substantial efficacy of a new regimen
However, oncology Phase II has been limited by high rates of failure (lack of efficacy) in subsequent phase III testing
This is in part because of use of single arm studies which can easily discard a study with an apparent low efficacy that due to factors other than the drug itself
*Michaelis et al. (2007). Clin Cancer Res,13, 2400–56
Design & Control Issues in Phase II Cancer Trials
One of the major issues is the use of controlsOne study* finds that only ~20% Phase II Cancer Trials use active or
historical control or placebo (notwithstanding a higher reporting of Onco trials)
Remember the primary objective of a phase II cancer clinical trials is to determine whether to proceed for a further Phase II or a Phase III stdy
This requires basically a demonstration of substantial efficacy of a new regimen
However, oncology Phase II has been limited by high rates of failure (lack of efficacy) in subsequent phase III testing
This is in part because of use of single arm studies which can easily discard a study with an apparent low efficacy that due to factors other than the drug itself
*Michaelis et al. (2007). Clin Cancer Res,13, 2400–57
Design & Control Issues in Phase II Cancer Trials..
The “go or no go” decision at the end of phase II is perhaps the most difficult one to make in the drug development cycledata are limited future investment required for a phase III trial is vast success of the company may depend on the drug in questionan informative phase II trial is crucialafter phase II, the decision makers need to understand toxicity and
pharmacokinetics, should have strong indications of activity in a specific kind of cancer, and should have a clear sense of an approval strategy
There are often gaps in this knowledge, and the decision is guided by both fact and intuition.
The decision becomes easier when the case is unmet medical needsChabner B. (2007). Clin Cancer Res,13, 2307
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Design & Control Issues in Phase II Cancer Trials...
Herceptin, Erbitux, and Avastin may have only modest activity as single agents and produce few clinical responses
Their effect requires more subtle trial designse.g., delay time to progression or recurrence or enhance response rates
to standard cytotoxic agents. single arm phase II trial, with response as the end point, may lead to the
abandonment of a valuable drug
Larger trials, and more complex phase II designs with TTP end points, may be required to show effectiveness of the new agenthere, concurrent controls, treated with standard agents or or other
strategies might show valuable aspects of the toxicity and effectiveness of the new agent
e.g sorafenib, [U of Chicago Researchers] randomized stable patients to continued therapy vs. drug discontinuation, with positive for patients continuing with experimental drug
Chabner B. (2007). Clin Cancer Res,13, 23079
Design & Control Issues in Phase II Cancer Trials...
The best design for phase II will depend on the nature of the agent, activity in phase I, the disease setting, the degree of certainty about best dose and schedule coming out of phase I trials, and the competition faced by the new drug.
A randomization involving two different doses of drug might show a dose-response relationship e.g., imatinib, it is unclear whether escalation beyond the recommended 400
mg/d dose might have long-term benefit for certain patients.
New molecular technologies offer remarkable insights gene expression profiling and molecular studies have illuminated distinct
subpopulations within pathologic categories of cancer role of epidermal growth factor receptor mutations in predicting response to
gefitinib and erlotinib development of biomarkers
phase II setting is the setting for appropriate patient
Chabner B. (2007). Clin Cancer Res,13, 230710
Endpoints in Oncology Trials
Must show either direct evidence of clinical benefit or improvement in an established surrogate for clinical benefit
Clinical benefit: survival improvement Overall survival (OS)Progress-free survival (PFS) (usually Ph III)
Improvement in a patient’s quality of life (QOL) (usually Ph III)Other endpoints on which approval has been given are:
Objective response rate (ORR) by RECIST or any radiological tests or physical examinations
Improvement in survival, improvement in a QOL, improved physical functioning, or improved tumor-related symptoms do not always be predicted by, or correlate with, ORR
Source: US FDA Guidance11
Relative Merits
Endpoint Evidence Assessment Some Advantages Some Disadvantages
Survival Clinical benefit • RCT needed
• Blinding not essential
• Direct measure of benefit• Easily measured• Precisely measured
• Requires larger and longer studies• Potentially affected by crossover therapy• Does not capture symptom benefit• Includes noncancer deaths
Disease-Free Survival (DFS)
Surrogate for accelerated approval or regular approval*
• RCT needed • Blinding preferred
• Considered to be clinical benefit by some• Needs fewer patients and shorter studies than survival
• Not a validated survival surrogate in most settings• Subject to assessment bias• Various definitions exist
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Relative Merits..Endpoint Evidence Assessment Some Advantages Some Disadvantages
Objective Response Rate (ORR)
Surrogate for accelerated approval or regular approval*
• Single-arm or randomized studies can be used • Blinding preferred in comparative studies
• Can be assessed in single-arm studies
• Not a direct measure of benefit• Usually reflects drug activity in a minority of patients • Data are moderately complex compared to survival
Complete Response (CR)
Surrogate for accelerated approval or regular approval*
• Single-arm or randomized studies can be used• Blinding preferred in comparative studies
• Durable CRs represent obvious benefit in some settings (see text)• Can be assessed in single-arm studies
• Few drugs produce high rates of CR • Data are moderately complex compared to survival
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Overall Survival (OS)OS: The time from randomization until death from any cause
Measured usually in the intent-to-treat (ITT) population
Most reliable cancer endpoint, and when studies can be conducted to adequately assess survival, it is usually the preferred endpoint
Precise and easy to measure – no influence of technicality of measurement
Bias is not a factor in endpoint measurement
Survival improvement should be analyzed as a risk-benefit analysis to assess clinical benefit
OS should be evaluated in RCTs
Historical trials are seldom reliable for time-dependent endpoints (e.g., OS, PFS).
The OS in control arm has to be compatible
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Rosell et al. (2008), Annals of Oncology, 19, 362–36915
Endpoints Based on Tumor AssessmentsDisease-free survival (DFS)Objective response rate (ORR)Time to tumor progression (TTP)Progress-free survival (PFS)Time-to-treatment failure (TTF)They are all time-dependent endpointsCollection and analysis of these endpoints are based on indirect
assessments, calculations, and estimates (e.g., tumor measurements)Two critical judgments:
1. whether the endpoint will support either accelerated approval or regular approval
2. endpoint should be evaluated for the potential of bias or uncertainty in tumor endpoint assessments
Drug applications using studies that rely on tumor measurement-based endpoints as sole evidence of efficacy may need confirmatory evidence from a second trial
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Rosell et al. (2008), Annals of Oncology, 19, 362–36917
Cautions in Tumor AssessmentsAccuracy in measuring tumors can differ among tumor settingsImprecision can happen in locations where there is a lack of
demarcated margins (e.g., malignant mesothelioma, pancreatic cancer, brain tumors).
When the primary study endpoint is based on tumor measurements (e.g., PFS or ORR), tumor endpoint assessments generally should be verified by central reviewers blinded to study treatments This measure is especially important when the study is not blinded It may be appropriate for the FDA to audit a sample of the scans to
verify the central review process
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Quality of Life (QoL) EndpointsGlobal health-related quality of life (HRQL) have not served
as primary efficacy endpoints in oncology drug approvals
They are usually patient reported outcome measures For example, the FACT-L is a 44-item self-report instrument which measures
multidimensional quality of life in Phase II and III lung cancer clinical trials
Reliability and validity of such multi-item instruments must be thoroughly examined
For QOL to be used as primary endpoints to support cancer drug approval, the FDA should be able to distinguish between improvement in tumor symptoms and lack of drug toxicity
An apparent effectiveness advantage based on a global QoL instrument can simply indicate less toxicity rather than effectiveness
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BiomarkersUsually not a good idea for cancer drug approvalOther than paraprotein levels measured in blood and urine for
myeloma, biomarkers assayed from blood or body fluids have not served as primary endpoints
Not considered good predictors of clinical benefit The FDA has sometimes accepted tumor markers as elements of a
composite endpointe,g., clinical events such as significant decrease in performance status,
or bowel obstruction in conjunction with marked increases in CA-125 was considered progression in ovarian cancer patients
Biomarkers, however, can be useful in identifying prognostic factors and in selection of patients and stratification factors to be
considered in study designs
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Specific Symptom EndpointsTime to progression of cancer symptoms, an endpoint similar to TTP, is a
direct measure of clinical benefit rather than a potential surrogateProblems in measuring progression (e.g., missing assessments) also exist in
evaluating time to symptomatic progressionBecause few cancer trials are blinded, assessments can be biased
delay between tumor progression and the onset of cancer symptoms can occur alternative treatments are initiated before achieving the symptom endpoint,
confounding this analysis patients may have minimal cancer symptoms also, tumor symptoms can be difficult to differentiate from drug toxicity
Important composite symptom endpoint should have components of similar clinical
importance and the results should not be exclusively attributed to one component
missing data & infrequent treatment are also confounding factors
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Intent-to-Treat PrincipleAll randomized patientsExclusions on prespecified baseline criteria permissible
also known as Modified Intent-to-TreatConfusion regarding intent-to-treat population: define and agree upon in
advance based upon desired indicationAdvantages:
Comparison protected by randomization Guards against bias when dropping out is related to outcome
Can be interpreted as comparison of two strategiesFailure to take drug is informativeReflects the way treatments will perform in populationMore suitable for superiority trials
Concerns:“Difference detecting ability”
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Per Protocol Analyses
Focuses on the outcome dataAddresses what happens to patients who remain on
therapyTypically excludes patients with missing or problematic
dataMore suitable for non-inferiority trialsStatistical concerns:
Selection biasBias difficult to assess
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Intent to Treat & Per Protocol AnalysesBoth types of analyses are important for approval
Results should be logically consistent
Design protocol and monitor trial to minimize
exclusionsSubstantial missing data and poor drug compliance
weaken trial’s ability to demonstrate efficacy
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ITT
PP
Sandler et al. 2006. N Engl J Med, 355, 2542-50.OS & PFS – ITT vs PP 25
Belani et al. (2011), ASCO Annual Meeting26
Decision to Proceed to Phase III or Terminate
This is a consideration for IA Stopping rules for significant efficacy Stopping rules for futility Measures taken to minimize bias A procedure/method for preparation of data for analysis Data has to be centrally pooled, cleaned and locked Data analysis - blinded or unblinded? Interim results must be submitted to IDMC What is the scope of recommendations from IA results? What
should be made known to the Sponsor? Safety? Efficacy? Both? Futility? Sample size readjustment for
borderline results?
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Decision to Proceed to Phase III or Terminate..
Single arm studies Futility is better predicted in IA than success
However, when success/failure response is used Summarize success as the proportion of number of totally included
patients
To proceed for Phase III, it is important to know the norm (activity of current standard) and that the new treatment is expected to exceed this
Example The standard treatment for AML is fludarabine + ara-C (50% success) Addition of GCSF would be beneficial if Phase II shows ~70%
success
Thall & Simon (1994). Biometrics, 50, 337-34928
Concluding RemarksClinical testing of new Oncology products is very sophisticated and
complexCancer clinical data is very complex (censored, skewed, often fraught
with missing data point), therefore, proper hypothesization and statistical treatment of data are required
Resource challenges can affect operations and even the study designThere are many endpoints that are scientifically valid but OS as primary
end point is often preferred by regulatory agenciesPFS & Tumor assessment trials may need another confirmatory CTEndpoints must be demonstrative (directly or indirectly) of clinical
benefitMissing data, infrequent treatment, increased type I error and other
confounding factors must be addressedConsistent ITT & PP facilitate approvalCarefully establish “go or no-go” rules and critically examine IA data;
single arm should exceed the “norm” of standard successDespite good knowledge in endpoints & trial design, meet & consult
FDA before initiating a pivotal trial. 29
Thank you Very Much
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