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 Biomarkers and Surrogate Endpoints in Drug
Development Technical and Regulatory
Considerations 

• Gracie Lieberman,
• Genentech
• 2006 FDA/Industry Workshop

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Content

• Changing landscape
• Efficacy surrogate endpoints used for approval
  case studies
• Herceptin
• Iressa
• Surrogate endpoints in proof of concept trials
• Selecting sub-population
• Selecting dose
• Role of mechanism-based biomarkers
• PET studies in cancer

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Changing landscape

• In the past 15-20 years
• Better molecular understanding of diseases
• Earlier, more precise diagnosis
• New targeted, improved therapies
• Impact on clinical trials
• Assessment of improvements in clinically
  meaningful endpoints require enrolling many
  patients and then following them for a long
  time. 
• Emerging need
• Develop strategies for reducing the time and cost
  of drug development. 
• Use of surrogate endpoints either in
  proof-of-concept or label-enabling trials.
• Defined in clinical practice and used by
  clinicians to monitor and treat patients
• New mechanism-driven biomarkers

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Endpoint considerations

• Study defined endpoints supporting product
  labeling
• Demonstrate clinically meaningful benefit
• Relevant to a specific indication and study
  population
• Reliable and reproducible
• Study defined endpoints supporting early
  decisions
• Correlated with clinically meaningful outcomes
• Relevant to a specific indication and study
  population
• Sensitive to small sample sizes
• Pharmacodynamic markers
• Surrogate endpoints

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Case Studies

• Herceptin PFS as an endpoint
• Iressa Risks of accelerated approval

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Herceptin in MBC

• Herceptin a is recombinant DNA-derived humanized
  monoclonal antibody that targets HER2, the
  protein product of c-erbB-2.
• In September 1998 Herceptin was approved for
• First line treatment in combination with
  paclitaxel in MBC patients whose tumors
  overexpress HER2.
• The primary endpoint used was not overall
  survival (OS) but progression free survival
  (PFS).

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PFS as a primary endpoint

• How to assure objectivity and minimize bias
• Randomized, placebo control study
• Weekly placebo infusions for months
• Impact on enrollment
• Strict schedule of efficacy assessment
• Independent review of radiographic images
• Process for collecting images
• Assessment of skin lesions required distribution
  of cameras to sites
• Strictly define rules for missing data
• Independent review of images not available

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PFS as a primary endpoint

• The challenge continues
• 21 enrolled in the first year
• Protocol amendment to remove placebo
• Impact on primary endpoint (PFS)
• Invoke real time independent review of
  radiographic images
• Primary endpoint had to be confirmed by the
  review committee
• Patients and investigators compliance
• Turn-around review time was critical
• Offer cross-over to control patients

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PFS as a primary endpoint

• Conclusions
• In September 1998 Herceptin was approved based
  PFS
• Survival as a secondary endpoint was
  statistically significant
• 65 of control patients crosses-over to receive
  Herceptin
• Two years later the survival benefit continued to
  be present
• Sub-group analysis impacted by crossover

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Case Studies

• Herceptin PFS as an endpoint
• Iressa Risks of accelerated approval

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Iressa in NSCLC

• Iressa a quinazoline-based small molecule, an
  EGFR TK inhibitor
• In phase I objective responses observed in NSCLC
• Two phase II monotherapy trials
• Response rate (RR) as primary endpoint
• Two dose groups
• May 2003 - Accelerate approval for 3rd line
  monotherapy use based on RR

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Accelerated approval - risks

• Need to conduct large, confirmatory trials
• What if negative?
• Despite meaningful responses in recurrent NSCLC
  patients, Phase III trials failed to show any
  significant clinical benefit
• Approval was revoked in June 2005
• The medicine should be used only in cancer
  patients who have already taken the medicine and
  whose doctor believes it is helping them. New
  patients should not be given Iressa because in a
  large study Iressa did not make people live
  longer.
• What went wrong?
• Patient selection ?
• Dose/schedule ?

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Can this be avoided?

• Demonstrating clinical benefit with
  molecular-targeted agents is more complex than
  with conventional cytotoxic agents
• Selection of sub-population who is most likely
  to benefit
• Identification of optimal biological dose
• Answers before phase III is this achievable
• Proof-of-concept trials
• Is PFS a sufficient endpoint

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Sub-population selection

• Complex process
• Tissue samples required
• Blood/serum feasible
• Tumor samples are challenging
• Missing data
• Archival samples not always relevant
• Randomized, controlled studies required
• Stratification by biomarker for sub-population
  selection
• At randomization or during analysis
• Not possible to distinguish between a prognostic
  and predictive biomarker without a proper control

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Biomarker based population selectionPFS with no
control arm
pHER2 tumors trend toward longer PFS Treatment
effect or natural course of disease?
Gordon et al. J Clin Oncol. 20052316S (abstract
5051). Gordon et al. J Clin Oncol. In press.
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Dose/schedule selection

• Complex process
• May be indication specific
• May be regimen specific
• Typical trial
• Randomized
• 3 arms
• Control/lower dose/higher dose
• 30-40 subjects per arm
• PFS as primary endpoint
• How is dose selected
• Better efficacy compared to control - winner

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Time to event endpointsOptimal vs. sub-optimal
dose
Probability that the observed HR ? 0.75 Probability that the observed HR ? 0.75 Probability that the observed HR ? 0.75 Probability that the observed HR ? 0.75 Probability that the observed HR ? 0.75 Probability that the observed HR ? 0.75
True HR Number of events Number of events Number of events Number of events Number of events
True HR 40 60 80 100 200
0.67 0.64 0.67 0.70 0.72 0.80
0.80 0.42 0.40 0.39 0.37 0.33
0.90 0.28 0.24 0.21 0.18 0.02
We need to do better
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Mechanism-based biomarkers

• Demonstrating clinical benefit with
  molecular-targeted agents is more complex than
  with conventional cytotoxic agents
• Escalating clinical trials costs and large
  numbers of patients required for currently used
  clinical endpoints mandate becoming more
  efficient in determining how well new agents can
  address unmet medical needs.
• That efficiency can be achieved by validating
  correlations between specific biological
  mechanisms of disease and clinical outcomes.
• Easier said than done!

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Mechanism-based biomarkers

• Technological advances provide great opportunity
  for the development of biomarkers
• Molecular and cellular techniques
• Tissue samples
• Tumor/blood/surrogate
• Imaging technologies
• Current pre-clinical models still have limit
  ability to predict clinical effects
• Biomarkers need to be co-developed with the novel
  agent
• In early phases no clinical data
• This will benefit second generation of the new
  agents or new indications
• Systematic way of analyzing and interpreting data

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Mechanism-based biomarkers

• PET imaging
• Use of surrogate endpoints in cancer prevention

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PET studies

• Speed development
• Provide information about the activity of
  molecular pathways
• Determine if new agents are hitting the target
• Measure treatment effect
• Tissue samples are not required

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FDG PET in NSCLC
Wolfgang Weber et al. J Clin Oncol. 2003212651
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FDG PET in Lymphoma
L. Kostakoglu, J Nuc Med 431018 2002
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Challenges

• How to define metabolic response
• Change in standard uptake values (SUV) that based
  on re-tests can be reliably detected
• Arbitrary cut-off
• Optimized thresholds correlated with outcomes
• Based on analysis
• What adjustments made for minimum p-values
• Not applicable to other treatments or indications
• Use of core labs in multi-center trials
• Not ready as a surrogate efficacy outcome for
  combination trials
• Not all lesions are PET avid

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Cancer Prevention

• Preventing heart diseases
• Lowering cholesterol / blood pressure
• Surrogate biomarker endpoints for cancer
  prevention trials
• Establishment of long term safety and efficacy
  for preventive drugs is critical
• Process for accelerated approval based on
  biomarkers will be needed
• Colorectal adenomas
• Current development of mechanism-driven
  biomarkers is critical for future cancer
  prevention trials.

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Questions?Thank you!