1. Gracie Lieberman, Genentech 2006 FDA/Industry Workshop
  Biomarkers and Surrogate Endpoints in Drug Development Technical and Regulatory Considerations  
Gracie Lieberman,
Genentech
2006 FDA/Industry Workshop

2. 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

3. Changing landscape In the past 15-20 years: Impact on clinical trials
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

4. 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
Sensitive to small sample sizes
Pharmacodynamic markers
Surrogate endpoints

5. Case Studies Herceptin – PFS as an endpoint
Iressa – Risks of accelerated approval

6. 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).

7. 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

8. 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

9. 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

10. Case Studies Herceptin – PFS as an endpoint
Iressa – Risks of accelerated approval

11. 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 Accelerate approval for 3rd line monotherapy use based on RR

12. 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 ?

13. 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

14. 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

15. Biomarker based population selection PFS with no control arm
Time (days)
Proportion progression-free
0.2
0.4
0.6
0.8
1.0
100
200
300
400
Median PFS
pHER2 positive n= weeks
pHER2 negative n= weeks
pHER2 unknown n= weeks
All subjects n= weeks
All patients treated with pertuzumab
pHER2+ tumors trend toward longer PFS Treatment effect or natural course of disease?
Gordon et al. J Clin Oncol. 2005;23:16S (abstract 5051).
Gordon et al. J Clin Oncol. In press.

16. 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

17. Time to event endpoints Optimal vs. sub-optimal dose
Probability that the observed HR  0.75
True HR
Number of events 40 60 80
100
200
0.67
0.64
0.70
0.72
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

18. 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!

19. 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

20. Mechanism-based biomarkers
PET imaging
Use of surrogate endpoints in cancer prevention

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

22. FDG PET in NSCLC
Wolfgang Weber et al. J Clin Oncol. 2003;21:2651

23. FDG PET in Lymphoma
L. Kostakoglu, J Nuc Med 43:

24. 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

25. 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.

26. Questions? Thank you!