Current Dilemma in Drug Development Increasing Failure Rate of Investigational Drugs in Phase 3 Clin

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Current Dilemma in Drug Development Increasing
Failure Rate of Investigational Drugs in Phase 3
Clinical Trials
Food Drug Administration in the
U.S. Copenhagen, Denmark November 5, 2008 Martin
M. Kaplan, MD, JD Drug Regulatory Affairs
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Failure Rates of Investigational Drugs in
Clinical Trials

• Historical algorithm for planning investigational
  drug development
• 9 of 10 drugs entering Phase 1 clinical trials
  will fail
• Historical timing of drug development failures
• 10 discontinuation in Phase 1
• 50-60 discontinuation in Phase 2
• 20-35 discontinuation in Phase 3

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Failure Rates of Investigational Drugs in Phase 3
Clinical Trials (cont.)

• Failure rates of drugs in Phase 3 trials have
  increased from 30 to 50
• Lack of efficacy vs. placebo (50)
• Safety concerns (30)
• Inability to differentiate either superior
  efficacy or superior safety against relevant
  comparators (20)

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Causes of Drug Failure in Phase 3 Clinical Trials

• Extrapolating results from an enriched Phase 2
  clinical trial to a broader study population in
  pivotal Phase 3 trials
• Overestimating drug effect or underestimating
  variance

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Enriched Study Designs

• Encouraged by FDA for many years
• Potential to increase size of drug effect, to
  increase number of observed study events, and to
  decrease heterogeneity of patient responses
• Critical issue raised by FDA is
  generalizability of results from an enriched
  clinical trial
• Phase 3 study design must balance outcome of
  restricted indication in product labeling vs.
  risk of failure in broader study population

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Examples of Enriched Study Designs

• Elimination of placebo-responders in study
  lead-in phase
• Elimination of patients with advanced disease
  that might not survive until study completion
• Restriction of enrollment to pre-screened drug
  responders
• Inclusion of patients with established biomarkers
  (e.g., Her2 breast tumors)

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Causes of Drug Failure in Phase 3 Clinical Trials
(cont.)

• Selecting a previously untested drug dose for
  Phase 3 after failure to identify a safe and
  effective dose in Phase 2 trial
• Too low dosing leading to failure to
  demonstrate drug efficacy due to fear of
  observing serious drug-related toxicity
• Too high dosing leading to failure to
  demonstrate an acceptable benefit/risk profile

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Causes of Drug Failure in Phase 3 Clinical Trials
(cont.)

• Basing Phase 3 development on a Phase 2 per
  protocol set or study completers analysis
• Per Protocol Set Analysis
• Definition the set of data generated by the
  subset of patients who complied with the protocol
  sufficiently to ensure that these data would be
  likely to exhibit the effect of treatment,
  according to the underlying scientific model

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Causes of Drug Failure in Phase 3 Clinical
Trials (cont.)

• Per Protocol Set Criteria completion of certain
  pre-specified minimal exposure to the treatment
  regimen availability of measurements of the
  primary variable(s) absence of major protocol
  violations
• Critical issue FDA requires full analysis set
  statistical analysis of data (consistent with
  intent-to-treat principles) from pivotal Phase 3
  trials in NDA submissions
• Most common problem elimination of early
  patient dropouts due to adverse events

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Causes of Drug Failure in Phase 3 Clinical Trials
(cont.)

• Misuse of a retrospective subgroup analysis of
  Phase 2 study results
• Extrapolating results for a subgroup of
  responsive patients that were not prospectively
  defined for special evaluation in the Phase 2
  clinical trial protocol to serve as the target
  study population in pivotal Phase 3 trials

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Examples of Late-Stage Drug Development Failures

• Oncology drugs make up the highest proportion of
  late-stage development failures due to inability
  to demonstrate clinical benefit in controlled
  Phase 3 trials over standard of care (after
  modest tumor response rates observed in
  open-label Phase 2 trials)
• Drugs developed for therapeutic indications such
  as ischemic stroke and septic shock in which
  Phase 3 studies are conducted in absence of
  proof of concept in Phase 2 trials

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Examples of Late-Stage Drug Development Failures

• Drugs that were continued into Phase 3 despite
  early warning signals of drug toxicity (e.g.,
  ximelagatran)
• Drugs with unanticipated safety risks first
  observed in Phase 3 trials (e.g., torcetrapib)

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Examples of Late-Stage Drug Development Failures

• The remarkable saga of the U.S. development of
  vesnarinone, a positive inotropic drug for
  symptomatic congestive heart failure
• Reduction in morbidity and mortality demonstrated
  in initial Phase 3 trial (p 0.003)
• FDA agrees to halting of second pivotal trial for
  ethical considerations based on highly positive
  first trial findings
• FDA Cardio-Renal Drugs Advisory Committee meeting
  recommends against approval, citing need for
  confirmatory trial
• Replication of results of first trial not
  achieved

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Conclusions

• Clinical drug development of new chemical
  entities with novel mechanisms of action entails
  high risks and costs
• Critical Go or No Go decisions to conduct Phase
  3 clinical trials must be based on a rigorous
  evaluation of available preclinical and clinical
  data, including an understanding of limitations
  of certain statistical analytic methods
• Risk of failure in Phase 3 trials may be reduced
  by maintaining use of enriched study designs in
  clinical trial protocols

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