Synopsis of FDA Colorectal Cancer Endpoints Workshop

1
Synopsis of FDA Colorectal Cancer Endpoints
Workshop

• Michael J. OConnell, MD
• Director, Allegheny Cancer Center
• Associate Chairman, NSABP
• Pittsburgh, PA

2
FDA Colorectal Cancer Workshop (11/12/03)

• Purpose
• Discussion of positive and negative aspects of
  various endpoints for approval of new drugs for
  colorectal cancer
• Identify areas for further research
• Provide information to ODAC for recommendations
  to FDA

3
Colorectal Endpoints Workshop Format

• Regulatory background and summary of previous
  approvals provided by FDA
• Five presentations
• Interactive discussion by speakers and
  multidisciplinary panel
• Discussion of questions posed by FDA

4
Goals of This Presentation

• Capsule summary of presentations and main points
  of discussion
• Focus on possible new endpoints for regulatory
  approval of drugs for colorectal cancer
• Help ODAC advise FDA

5
Biomarkers or QOL in CRC Drug Approvals(Dr.
Charles Blanke)

• Not possible to consistently predict clinical
  benefit based on reduction of CEA
• ASCO guidelines do not recommend other biomarkers
  for CRC

6
Biomarkers or QOL in CRC Drug Approvals(Dr.
Charles Blanke)

• Methodologic issues of paramount importance if
  QOL used as endpoint
• Unknown whether changes in QOL reliably occur
  with effective chemo
• Cannot discriminate between safety and efficacy
• Best use of resources in colon cancer?

7
Biomarkers or QOL in CRC Drug Approvals(Dr.
Charles Blanke)

• Clinical Benefit Response (Pain, performance
  status, weight loss)
• CBR does not adequately encompass symptoms
  experienced by patients
• Methodologic issues in assessment
• Not useful if asymptomatic (colon vs rectum)

8
Endpoints in Neoadjuvant and Adjuvant Rectal
Cancer(Dr. Meg Mooney)

• Locoregional failures are usually symptomatic in
  rectal cancer
• Local tumor control at 3 years is an appropriate
  endpoint for full approval
• Pathologic complete response (pCR) -quality
  control issues
• Colostomy-free survival applies mainly to low
  lying tumors

9
Surrogate Endpoints and Non-Inferiority
Trials(Dr. Thomas Fleming)

• Primary endpoints sensitive, measurable, and
  clinically relevant (eg. Survival decreased
  symptoms)
• Surrogate endpoints
• May reflect biological activity without
  establishing clinical efficacy
• Meta-analyses required to validate
• Validated surrogate endpoints are rare
• FDA has granted approval using surrogate
  endpoints not formally validated

10
Surrogate Endpoints and Non-Inferiority
Trials(Dr. Thomas Fleming)

• Non-inferiority trials
• Insufficient for curves to overlap
• Conservative margins to exclude significant
  decrease in efficacy
• Rigorous study conduct to avoid incorrect
  conclusion of non-inferiority
• Will results move the field forward (eg
  significant decrease in toxicity)?

11
TTP Clinical Benefit Endpoint in 1st Line
MCRC(Dr. Langdon Miller)

• Multiple effective therapies for metastatic
  colorectal cancer have confounded the
  relationship between early tumor control and
  survival
• Evaluation of symptoms problematic as endpoint
  because progression frequently not symptomatic,
  is subjective, and difficult to measure

12
TTP Clinical Benefit Endpoint in 1st Line
MCRC(Dr. Langdon Miller)

• Arguments for TTP as endpoint for full approval
• Directly evaluates changes in disease burden
• Correlates with other outcomes (in particular,
  survival)
• Not confounded by subsequent therapies
• Offers utility as an endpoint in non-inferiority
  trials (more rapid completion)

13
TTP Clinical Benefit Endpoint in 1st Line
MCRC(Dr. Langdon Miller)

• Can be objectively quantified, reviewed, and
  audited
• Offers clear interpretation and straightforward
  analysis
• Conserves patient resources and hastens drug
  development

14
TTP Clinical Benefit Endpoint in 1st Line
MCRC(Dr. Langdon Miller)

• Correlation of TTP and Survival Was Highly
  Significant two examples
• 1000 patients in two phase III trials with
  primary patient data
• Meta-analysis on published summary results of 29
  trials involving 13,000 patients

15
TTP Clinical Benefit Endpoint in 1st Line
MCRC(Questions and Comments)

• Need for objective and reliable methodology for
  assessing TTP
• Does TTP reflect clinical benefit in its own
  right? (Full approval)
• Is TTP reasonably likely to predict clinical
  benefit? (Accelerated approval)
• RR, survival and toxicity also important

16
3-YR DFS as Endpoint in Adjuvant Colon Cancer
(Dr. Dan Sargent)

• Preliminary findings of meta-analysis to
  determine if 3-YR DFS can replace 5-YR OS as
  endpoint for colon cancer adjuvant trials
• 12 clinical trials
• 38 treatment arms
• gt 10,000 patients

17
3-YR DFS as Endpoint in Adjuvant Colon Cancer
(Dr. Dan Sargent)

• Preliminary Conclusions
• 3-YR DFS seems to be an excellent predictor of
  5-YR OS
• Event rates were virtually identical (no impact
  on sample size)
• 3-YR DFS may slightly overestimate differences in
  5-YR OS
• Three studies significant difference in 3-YR
  DFS (borderline p values) but no significant
  difference in 5-YR OS
• Not a formally validated surrogate

18
3-YR DFS as Endpoint in Adjuvant Colon Cancer
(Questions and Comments)

• Work in progress updated analysis today!
• Does improvement in 3-YR DFS represent clinical
  benefit in its own right?
• DFS is used for full approval in breast cancer
  adjuvant therapy

19
Key Questions for ODAC

• Should the following endpoints be recommended to
  FDA for new drugs in colorectal cancer?
• Full or Accelerated approval?
• Setting Endpoint
• Colon adjuvant 3-YR DFS
• 1st line metastatic TTP
• Rectal adjuvant 3-YR local control