NDA 21063

1
NDA 21-063

• Oxaliplatin in combination with 5-FU and
  leucovorin for first line therapy for colorectal
  cancer

2
Regulatory standard for first line therapy of
colorectal cancer is to improve overall
survivalOncologic Drugs Advisory Committee
Recommendation contained inFDA Guidance on
Requirements for Approval of New Drugs for
Treatment of Colon and Rectal Cancers
3
5-FU plus leucovorin has been the standard of
care and will prolong survival compared to 5-FU
monotherapy
4
Survival Results from various 5-FU/LV Regimens
Biweekly Regimen (n2)
Monthly LD LV (n3)
Monthly HD LV (n15)
Mayo Clinic/ NCCTG Regimen (n7)
5
Lack of correlation between response rate and
overall survival in 23 published controlled
studies
6
Lack of correlation between progression free
survival and overall survival in 7 published
controlled studies
7
Regulatory History

• No prior discussions with the FDA with regard to
  trial design
• In 1996, FDA stated Approval of any new product
  in previously untreated advanced colorectal
  cancer would require demonstration of a survival
  advantage when adding oxaliplatin to an
  acceptable US-based 5-FU regimen.
• In 1998, FDA stated that for survival analysis
  the greatest weight will be placed on the logrank
  test.

8
The sponsor submitted information on 33 clinical
studies, and provided datasets for 8 studies of
which 2 were randomized controlled studies
comparing 5-FU/LV to 5-FU/LV plus oxaliplatin in
first line treatment of patients with colorectal
cancer
Contents of NDA 21063
9
Study 2961-Enrolled patients June 1994 - March
1996

• The primary endpoint specified in the protocol
  was response rate.
• Secondary endpoints were progression free
  survival, overall survival, and toxicity.
• Two interim analyses planned
• Primary analysis for survival was log rank test
• Regimen based on chronomodulated schedule

10
Study 2962-Enrolled patients August 1995 - July
1997

• The primary endpoint in the protocol was
  progression free survival.
• Secondary endpoints were response rate,
  tolerance, quality of life and overall survival
• Two interim analyses planned
• Primary analysis for survival was log-rank test
• Regimen based on biweekly infusion schedule

11
Study 2962 Amended Analysis Plan

• An amended analysis plan was appended to the
  protocol in February 1998, 6 months after the
  last patient enrolled and 5 months prior to the
  cut off date for survival.
• The plan once again affirmed the use of the
  log-rank test for overall survival and stated
  that a multivariate analysis would be provided
  using 12 co-variates (defined by terms such as
  renal function and liver function tests) and
  furthermore stated that if other parameters seem
  to be pertinent for this analysis, they will be
  used.

12
Survival Results for Randomized Studies
All calculations confirm the applicants results
except for the hazard ratio, which was not
submitted
13
Kaplan-Meier Survival Curves for Study 2961
14
Kaplan-Meier Survival Curves for Study 2962
15
Clinical Benefit Assessments
The FDA agrees with the sponsor analysis that
there were no statistically significant
differences in performance status, pain scores,
weight change, symptom improvement, or quality of
life between the study arms in study 2962
16
Adverse Event Differences in Study 2961
17
Adverse Event Differences in Study 2962
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Neurotoxicity in Study 2962
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Cumulative Neurotoxicity in Study 2962
20
randomized controlled multicenter studies
Strengths of the Application
21
Weaknesses of the Application

• Results consistent with 5-FU/LV alone
• Reliance on adjusted analysis to demonstrate
  efficacy with
• large number of covariates
• selection of covariates in statistical model
  dependent upon study outcome

22
Weaknesses of Application

• Lack of basis for extrapolation to 5-FU/LV
  regimens used in the United States
• Greater toxicity, particularly neurotoxicity,
  with oxaliplatin containing regimens

23
Substantiation of Results

• A single clinical experimental finding of
  efficacy, unsupported by other independent
  evidence, has not usually been considered
  adequate scientific support for a conclusion of
  effectiveness.
• Independent substantiation of a favorable result
  protects against the possibility that a chance
  occurrence in a single study will lead to an
  erroneous conclusion that a treatment is
  effective.FDA Guidance on Providing Clinical
  Evidence of Effectiveness, 1998

24
Moreover, a single favorable study among several
similar attempts that failed to support a finding
of effectiveness would not constitute persuasive
support for a product use FDA Guidance on
Providing Clinical Evidence of Effectiveness, 1998
Interpreting Results
25
Although an unexplained failure to substantiate
the results of a favorable study in a second
controlled trial is not proof that the favorable
study was in error studies of effective agents
can fail to show efficacy for a variety of
reasons it is often reason not to rely on the
single favorable study.FDA Guidance on
Providing Clinical Evidence of Effectiveness, 1998
Interpreting Results
26
Criteria for submitting a single study

• Findings should be clinically important
• The study should have a statistically very
  persuasive finding.
• ..confirmation of the result in a second trial
  would be practically or ethically impossible.
• FDA Guidance on Providing Clinical Evidence
  of Effectiveness, 1998

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Multivariate Analysis

• Pre-study deliberations should identify those
  covariates
• . When the potential value of an adjustment is
  in doubt, it is often advisable to nominate the
  unadjusted analysis as one for primary attention,
  the adjusted analysis being supportive.
• ICH/FDA Guideline,
• Statistical Principles for Clinical Trials

28
FDA Review Team

• Biopharmaceutics
• Primary Brian Booth, PhD Elena Mishina, PhD,
• Team Leader Atiquar Rahman, PhD,
• Biometrics
• Mark Rothmann, PhD, Team Leader Gang Chen, PhD
• Chemistry
• Chengyi Liang PhD Hari Sarker, PhD Team Leader
  Eric Duffy, PhD
• Clinical
• Steven Hirschfeld, MD PhD, Fumikata Nagamura, MD
• Team Leader John R. Johnson, MD
• Deputy Division Director Robert Justice, MD
• Pharmacology/Toxicology
• Hua Zheng, PhD, Team Leader Paul Andrews, PhD
• Project Management
• Christy Wilson Supervisor Dotti Pease