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Meeting Agenda. Presentations on endpoints Regulatory issues Scientific issues Pros and cons of end points Classical end points Non-classical end points End points and trial designs according to lung cancer stage. Presentations . Regulatory background General regulatory requirements

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meeting agenda
Meeting Agenda
  • Presentations on endpoints
    • Regulatory issues
    • Scientific issues
  • Pros and cons of end points
    • Classical end points
    • Non-classical end points
  • End points and trial designs according to lung cancer stage
presentations
Presentations
  • Regulatory background
    • General regulatory requirements
    • US lung cancer approvals
    • International lung cancer approvals
  • Classical lung cancer end points
  • Non-classical lung cancer end points
outline of presentation
Outline of Presentation
  • FDA requirements for new drug approval
  • Regular approval of cancer drugs: end points used
  • Accelerated approval
  • Endpoints and issues
requirements for drug approval
Requirements for Drug Approval
  • Safety (FDAC, 1933)
  • Efficacy demonstrated in adequate and well controlled studies (1962)
  • Basis for efficacy:
    • Regular approval
      • Clinical benefit, or
      • Established surrogate for clinical benefit
    • Accelerated approval
      • Surrogate (reasonably likely to predict CB)
how many trials
How many trials?
  • 505(d) of the Act:

Substantial evidence: “Adequate and well-controlled investigations”

  • Single trial1:

“generally only in cases in which a single multicenter study of excellent design provided highly reliable and statistically strong evidence of an important clinical benefit… and a confirmatory study would have been difficult to conduct on ethical grounds.”

    • 1Efficacy Guidance, May 1998
oncology efficacy supplements
Oncology Efficacy Supplements

Only one additional trial may be needed for closely related indications:

  • Advanced cancer and earlier cancer
  • Different dosing regimens
  • New combinations of drugs

1Draft Guidance on New Cancer Treatment Uses, 1997.

clinical benefit endpoints supporting oncology drug approval
Clinical Benefit Endpoints Supporting Oncology Drug Approval
  • Survival
  • Improvement in tumor-related symptoms
  • Disease-free survival (selected settings)
established surrogates supporting approval
Established Surrogates Supporting Approval
  • Complete response rates in some settings (e.g., acute leukemia)
  • Partial response rate in some settings (e.g., hormonal treatment of breast cancer)
dodp endpoints for approval 1 1 90 11 1 02
DODP: Endpoints for Approval (1/1/90 - 11/1/02)

Approvals not based on Survival:

  • 73% (48/66) of all approvals
  • 67% (37/55) excluding accelerated approvals
examples of endpoints in oncology
Examples of endpoints in oncology
  • Idarubicin -Prolonged remission in leukemia
  • Zinecard -Protection from cardiac toxicity
  • Photofrin -Dysphagia scale
  • Aredia -Skeletal morbidity scale
  • Daunozome -Visible lesions of KS
  • Novantrone -Pain
accelerated approval
Accelerated approval
  • Serious or life-threatening disease
  • Drug must provide benefit over available therapy
  • Surrogate endpoint may be used
  • Surrogate endpoint must be reasonably likely to predict clinical benefit
  • Post marketing studies must verify clinical benefit
slide14

New Drug Approval Efficacy Requirement

  • Regular approval: clinical benefit or established surrogate
  • Accelerated approval (AA): surrogate endpoint reasonably likely to predict clinical benefit.
    • AA used only when new treatment represents benefit over available therapy
    • Sponsor must do phase 4 trial showing clinical benefit
evidence for accelerated approval
Evidence for Accelerated Approval
  • Substantial evidence from well controlled clinical trials regarding a surrogate endpoint
  • NOT: Borderline evidence regarding a clinical benefit endpoint
odac meeting on accelerated approvals march 2003
ODAC Meeting on: Accelerated Approvals(March 2003)
  • 19 NDAs or BLAs for new treatment indications (involving 16 drugs)
odac meeting on accelerated approvals march 200318
ODAC Meeting on: Accelerated Approvals(March 2003)
  • Confirmatory studies should be part of drug development plan
  • Early discussion of confirmatory studies with Agency
  • ODAC wanted to be consulted on confirmatory study plans
single arm trials sat and accelerated approval aa
Single Arm Trials (SAT) and Accelerated approval (AA)
  • SAT require few patients
  • SAT for AA limit study to refractory disease
  • SAT have limited ability to evaluate valuable endpoints such as TTP, QOL, and Survival
randomized trials rt and accelerated approval aa
Randomized Trials (RT) and Accelerated approval (AA)
  • More patients and time
  • Allows AA at any disease stage

(surrogate beats available therapy)

  • Allows “add-on” design

(A vs A + B)

  • Allows a variety of endpoints
    • Time to event (TTP, survival)
    • Endpoints requiring blinding (symptoms, QOL)
  • Defines individual drug contribution
    • (oxaliplatin vs 5FU/LCV versus oxaliplatin + 5FU/LCV)
survival
Survival
  • Gold standard
  • Superiority design: beat anything
  • The crossover problem
  • Non-inferiority design: problematic with current regimens
tumor response rate
Tumor Response Rate
  • Can be assessed in single-arm study
  • Documents activity in a subset of patients
  • When can it be considered an established surrogate?
    • Suggested as such by ODAC for topotecan treatment of refractory small cell lung cancer
  • When can it be considered a “reasonably likely surrogate”?
    • ODAC, lung cancer discussion 2002
slide25

TTP: Critical Regulatory Questions

  • Does it measure clinical benefit?
  • Is it reliable?
slide26

TTP: Advantages

  • Measured in all patients
  • Measures cytostatic activity
  • Progression is often the basis for change in therapy
  • Assessed before crossover
  • Requires smaller studies
  • ?Face validity
slide27

TTP: Problems

  • Indirect measure of patient benefit.
  • Unclear clinical meaning of small TTP difference
  • Expensive to measure carefully
  • Reliability in unblinded setting?
  • Unknown reliability of small TTP difference with usual trial monitoring
slide28

Determining Event Dates

Survival Analysis

Survival Event Date

Randomization

Visit 1

Visit 2

TTP Analysis

TTP Event Date

Randomization

Visit 1

Visit 2

= Date of Death or actual tumor progression

tumor related symptoms
Tumor-Related Symptoms
  • Evaluation of patient morbidity has supported many NDA approvals
  • Major impediments
    • Lack of blinding
    • Missing data
  • Time to symptomatic progression
    • Frequently discussed, not yet successful
review of presentation
Review of Presentation
  • FDA requirements for new drug approval
  • Regular approval of cancer drugs: end points used
  • Accelerated approval
  • Endpoints and issues
endpoints discussion
Endpoints Discussion
  • Classical end points

(pros and cons)

  • Non-classical end points

(pros and cons)

  • Discussion according to stage

(End points and trial designs)

1 what are the pros and cons of each end point
1. What are the Pros and Cons of each end point:
  • As a regular approval endpoint?

(A measure of clinical benefit or a reliable surrogate)

  • As an accelerated approval endpoint?

(A surrogate reasonably likely to predict clinical benefit)

  • As a secondary end point for labeling?
classical endpoints
Classical Endpoints
  • Survival
  • Response Rate
  • Time to progression
  • Disease-free Survival
non classical endpoints
Non-classical endpoints
  • Specific quality of life instruments
  • Assessment of tumor-specific symptoms
treatment settings
Treatment settings
  • Neoadjuvant
  • Adjuvant
  • First-line therapy
  • Second-line and subsequent therapy
trial designs
Trial designs
  • Superiority design

(A beats B)

  • Add-on design

(A+B beats A)

  • Non-inferiority design

(e.g., A + B is non-inferior to A + C)