Overview – Establishing a Pathway for the Development of New Drug Combinations
The 2009 Conference included a panel titled: Development of Rational Drug Combinations with Investigational Targeted Agents. The panel developed clinical scenarios for which a large, four-arm phase 3 clinical trial could be modified and proposed development plans that would generate the desired data on the combination as well as the individual agents. Combinations of drugs that target different mechanisms have the potential for greater efficacy in oncology areas as well as other disease settings.
In March of 2010, Friends of Cancer Research submitted a draft guidance to the FDA. This document addressed the unique challenges surrounding development of therapies involving two (or more) new molecular entities (2NMEs).
On December 14, 2010, the FDA released a draft guidance document that mirrors the 2009 panel, subsequent white paper, and submitted draft guidance. This was the product of a great deal of collaborative work between many individuals and organizations, with special acknowledgment to conference supporters the American Association for Cancer Research, the American Society of Clinical Oncology and Susan G. Komen for the Cure.
Panel One – Data Submission Standards and Evidence Requirements
- Richard Schilsky, MD, University of Chicago Medical Center
- Jeffrey Abrams, MD, National Cancer Institute
- Janet Woodcock, MD, Food and Drug Administration
- Gwen Fyfe, MD, Genentech
- Robert Irwin, Marti Nelson Cancer Foundation
Goal: Work to resolve difference in data collection for trials conducted by NCI Cooperative groups vs. industry.
Outcome: A minimum data set for secondary indications was proposed with agreement on 10 of 12 data types (i.e. physical exam data, lab reports, medical history, etc). There was disagreement about the levels of collection for concomitant medication and toxicity. A “decision tree” is needed to identify circumstances in which more/less data collection is appropriate.
Next Steps: A follow-up meeting was held in November between FDA and the NCI Cooperative Group Leaders. In order to help develop a decision tree to outline optimal data standards for different situations, additional clinical trial data for supplemental applications will be analyzed. To date, it has been agreed upon that data sets will be provided and analyzed by Eli Lilly, GlaxoSmithKline, Novartis, and CALGB.
Panel Two – Improved Insights into Effects of Cancer Therapies
- Raymond DuBois, MD, M.D. Anderson Cancer Center
- Donald Berry, PhD, M.D. Anderson Cancer Center
- Jim Doroshow, MD, FACP, National Cancer Institute
- Paolo Paoletti, MD, Glaxo SmithKline
- Richard Pazdur, MD, Food and Drug Administration
- Nancy Roach, C3: Colorectal Cancer Coalition
Goal: Establish a process to evaluate the role of auxiliary endpoints (specifically Progression Free Survival) in evaluating the efficacy of new therapies.
Outcome: Proposed auditing procedures for PFS 3 different scenarios to help build confidence in PFS as an indicator of clinical benefit.
Next Steps: A PFS working group has been established that is being led by GlaxoSmithKline. The working group and NCI will conduct analysis of existing data to develop a model that can be evaluated in real-time clinical trials. Through this process, criteria will be developed to determine a sufficient percentage of radiologic scans that will be required to undergo blinded independent centralized review to confirm study results.
Panel Three – Co-Development of Diagnostics and Therapeutics
- Daniel Hayes, MD, University of Michigan
- Steven Gutman, MD, MBA, Food and Drug Administration
- Richard Frank, MD, PhD, GE Healthcare
- Nancy Roach, C3: Colorectal Cancer Coalition
- Richard Simon, DSc, National Cancer Institute
- Ray Woosley, MD, PhD, Critical Path Institute
Goal: Identify steps that can be taken to resolve differences in the evaluation of diagnostic vs therapeutic components of coupled technologies.
Outcome: An ODAC-like committee should be established to begin work on improving consistency and intra-FDA coordination in tumor marker clearance and approval.
Next Steps: An ODAC meeting was convened last month for experts from both FDA centers (CDER & CDRH) to gather input from advisory committees on best practices for incorporating new information on sub-populations based on retrospective samples. The primary example discussed was evaluation of k-ras mutational status as a predictor of efficacy. Guidance documents on retrospective-prospective studies will likely be developed.
Panel Four – Vision for the Future of FDA
- Bob Young (FCCC)
- Mark McClellan (Brookings)
- Ann Barker (NCI)
- David Kessler (Former FDA)
- David Epstein (Novartis)
- Ellen Sigal (Friends)
Goal: Identify challenges and opportunities for the FDA in the new administration.
Next Steps: A roadmap proposal is being drafted to outline specific steps in the development and regulatory processes for acceleration of targeted cancer drug development. This is being modeled after the current accelerated approval mechanism and “conditional approval” based on FDA’s new post-market authorities.