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).

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

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

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

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

20. Difference in Clinical Efficacy (Є)
Non-Inferiority
Superiority
+δ
0
Equivalence
-δ
Inferiority
Non-Superiority
Equality δ = Meaningful Difference

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.

26. Thank you Very Much