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Endpoint considerations in cancer clinical trials
1. 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.
2. 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
3. Clinical Development of New Drugs
Development 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
4. 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
5. 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 important
Oncology based NDAs are usually reviewed on fast track
6. 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
7. So, the Endpoint Metrics are:
Time to event end points
Survival
Disease free survival
Progress -free survival
Objective response rates
Complete
Partial
Stable disease
Progressive disease
Symptom end points
Palliation
QoL
8. Relative Merits
Endpoint Evidence Assessment Some Advantages Some Disadvantages
Survival 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
deaths
Disease-Free Surrogate for • RCT needed • Considered to • Not a validated
Survival 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
9. Relative Merits..
Endpoint Evidence Assessment Some Advantages Some Disadvantages
Objective Surrogate for • Single-arm or • Can be assessed • Not a direct measure of
Response accelerated randomized in single-arm benefit
Rate (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 survival
Complete Surrogate for • Single-arm or • Durable CRs • Few drugs produce high
Response 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
10. 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
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).
13. 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
15. 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
16. 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
17. 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
18. 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
19. Trial Designs
Randomized Clinical Trials (RCTs)
Gold standard in Phase III
Single centre CT
Primary and secondary indications
Safety profile in patients
Pharmacological / toxicological characteristics
Multi-centre CT
Confirmation of the above
Effect size
Site, care and demographic differences
Epidemiological determination
Complexity
Far superior to meta-analyzed determination of effect
21. 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
22. Study Design: Approaches
Randomised Controlled Trials (RCT) most preferred
approach
Demonstrating superiority of the new therapy
Other 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
23. Placebo Control Equality Trials
No anticancer drug treatment in the control arm is
unethical
Sometimes 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
24. Drug or Therapy Combinations
Use the add-on design
Standard + Placebo
Standard + Drug X
Effects 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
25. 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.