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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 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
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 important
Oncology 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 survival
Objective response rates
   Complete
   Partial
   Stable disease
   Progressive disease
Symptom end points
Palliation
QoL
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
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
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).
Endpoint considerations in cancer clinical trials
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 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
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
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
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 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
Difference in Clinical Efficacy (Є)
                                                                           Non-Inferiority
                                               Superiority

                                          +δ

                                          0
                                                                           Equivalence
                                          -δ

                                               Inferiority

                                                                           Non-Superiority


Equality                                       δ = Meaningful Difference
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
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
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
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
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.
Thank you Very Much

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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).
  • 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.