1. Controversias de Temas de Actualidad: ¿Sería Necesario Modificar el Desarrollo Clínico de los Nuevos Fármacos? a Favor
Manuel Hidalgo, M.D., Ph.D.

2. Agenda Current regulatory legislation.
Why?
Progress in cancer understanding and molecular targets development.
Why I think the system is in crisis.
Alternatives.

3. FDA Mission
The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation.
The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health.

4. Criteria for Drug Approval
The requirement for demonstration of drug safety was introduced in 1938 with passage of the Federal Food, Drug, and Cosmetic Act (FDC).
The requirement for demonstration of effectiveness prior to marketing in the United States was codified in the 1962 Kefauver-Harris Drug Amendments to the FDC.

5. Criteria for Drug Approval
Submission of results from more than one well-controlled and well conducted clinical trial.
Characteristics of a single adequate and well-controlled study that could make it adequate to support an effectiveness claim.
a large multi-center study.
consistency in findings across study subsets.
multiple studies in a single study (such as a factorial design).
persuasive evidence of an effect in multiple endpoints.
statistically very persuasive findings.

6. Criteria for Drug Approval

7. Criteria for Drug Approval

8. Phase III trial BR.21 demonstrated improvement in OS versus placebo
100 75 50 25
Tarceva
Placebo
(n=488)
(n=243)
Median survival (months)
6.7
4.7
HR=0.73 (0.60–0.87), p=0.001*
27% reduction in risk of death with Tarceva
Survival probability (%)
42.5% increase in median survival with Tarceva
Survival time (months)
Shepherd, et al. NEJM 2005 Tarceva Summary of
Product Characteristics
*HR and p (log-rank test) adjusted for stratification factors at randomisation and EGFR status

9. Overall Survival for All Patients
HR = 0.81*
95%CI 0.67 – 0.97
P=0.025
* Adjusted for PS, pain and disease extent at randomization

10. What is changing Better knowledge of cancer biology: New drugs:
New critical targets.
Understanding of the complexity of the tumor.
Heterogeneity.
New drugs:
Less toxic.
More specific.
Work in define molecular subgroups.

11. Simplified Hh Signaling
Hidalgo and Maitra, NEJM 2009

12. Models for Hedgehog Activity in Cancer
Type-1
Type-2
Type-3
Cancers with mutations
in Hh signaling
Cancers with autocrine
requirement for Hh
Cancers with paracrine
requirement for Hh
Rype-1: Single agent
Type-3: Combination
glioblastoma
myeloma
BCC, medullo
pancreatic, colon, ovarian

13. A targeted Hedgehog inhibitor has activity against PTCH-1 mutant tumors
Basal cell carcinoma
Medulloblastoma
Von Hoff et al., N Engl J Med, 2009
Rudin et al., N Engl J Med, 2009

14. The Results for the 41yo With Multiple Advanced Facial BCCs
Baseline
After 5 months
41 yo woman with history of BCC since age 15, possible BCNS but no affected family members. History of >20 prior surgeries. No prior systemic therapy or RT.
Von Hoff et al., N Engl J Med, 2009 14

15. EML4-Alk Translocation in NSCLC
Soda et al., Nature 2007

16. PF-02341066 Fase II Data Inhibitor of EML4-ALK.
Patients selected with EML4-ALK traslocation.
76 patients reported.
64 % RR and 90 % DCR.
Bang et alJ Clin Oncol 28:18s, 2010

17. Pivotal Clinical Trial PF-02341066
Previously treated stage IIIB/IV
EML4-ALK translocation
(n=308)
Docetaxel
Pemetrexed
Primary endpoint: PFS
Clinicaltrials.gov

18. Genomic Alterations in Colon Cancer
Sartore-Bianchi et al. PlosOne 2009

19. Genomic Alterations in Colon Cancer
Sartore-Bianchi et al. PlosOne 2009

20. Flow Chart of Molecular Markers for EGFR inhibitors in in Colon Cancer
Sartore-Bianchi et al. PlosOne 2009

21. Genomic Diversity of Pancreas Cancer
Jones et al, Science 2008.

22. Core Gene Pathways in Pancreas Cancer
Jones et al, Science 2008.

23. Issues The more we know, the smaller the groups.
Feasibility of testing time dependant endpoints.
Drugs manufacture and toxicity is less of an issue.
Small studies suffice for safety assessment.
Greater activity in biologically define groups.
Differences between approval and reimbursement.
Public may just not accept this.

24. Alternative
For targeted agents with phase I clinical data indicating activity in biologically define group:
Approval base on single arm, large, phase II study ~ 100 pts.
This provides enough safety information.
RR or PFS endpoint is appropriate.
Activity needs to be CLEARLY superior to expected ie from 10 % RR to 80 % RR.
We need better historical controls.
Better recording of activity in practice.
Make all data publically available.
Let doctors and patients make choices.