On September 14, 2012, Friends of Cancer Research and Alexandria Real Estate Equities, Inc, held a half-day forum that brought together researchers, sponsors, advocates and regulators to discuss the opportunities and challenges associated with co-development of drugs and the diagnostic tests used to determine which patients should receive a new treatment
Co-development of a targeted therapy and its companion diagnostic test present unique challenges to sponsors and regulatory agencies. To begin to address these challenges,
FDA issued a guidance in July 2011, entitled “In Vitro Companion Diagnostic Devices,” to provide information about preferred approaches to effective co-development of a drug and diagnostic. Also in 2011, two anti-cancer drugs and their simultaneously developed diagnostics were approved, confirming that the approach can effectively and efficiently be used. However, many questions remained about the best way to co-develop companion diagnostics. Therefore, this forum was organized to identify and address some of the most important questions sponsors and regulators face during the companion diagnostic development process, as well as discuss overarching questions that may affect companion diagnostics in the future.
Prior to the forum, panelists wrote a detailed consensus document, “A Blueprint for Future Drug/Diagnostic Co-development,” that was distributed to attendees prior to the forum. The Blueprint proposed potential approaches for sponsors in dealing with those identified challenges in the companion diagnostic co-development process and provides strategies to help guide future co-development. It focused on three specific areas:
1.) A developmental strategy for diagnostically selected populations.
2.) Approaches to defining a diagnostically selected population.
3.) Strategies for multi-marker diagnostic development.
Panel 1: A Blueprint for Future Drug/Diagnostic Co-development
- Howard Scher, Chief, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center
- Rich Buller, Vice President, Translational Oncology, Pfizer Inc
- Jane Fridlyand, Senior Statistical Scientist, Genentech, Inc.
- Rich Simon, Chief, Biometric Research Branch, National Cancer Institute (NCI)
- Nancy Roach, Chair & Founder, Fight Colorectal Cancer
- Rick Pazdur, Director, Office of Hematology and Oncology Products, Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration
- Liz Mansfield, Director, Personalized Medicine, Center for Devices and Radiological Health, U.S. Food and Drug Administration
The first panel presented the Blueprint and addressed some of the specific issues, mentioned above, that sponsors and regulators felt were not dealt with sufficiently in the FDA guidance. While the forum focused on the common factors that sponsors may need to address throughout the co-Dx development pathway, Dr. Howard Scher stressed in his introduction that sponsors will face different challenges dependent on drug, biomarker and type of assay, and stressed the importance of interacting with the FDA early and often throughout the process. Dr. Richard Buller described the factors, which include understanding of the patient population and biomarker behavior and the nature of the assay, involved in determining when studies should be restricted to diagnostically selected patients. Dr. Buller also suggested how to make these decisions in order to provide the greatest benefit to all patients while minimizing negative reactions, but stressed the importance of not ignoring the marker-negative population. Dr. Jane Fridlyand then discussed issues that arise when using non-binary biomarkers without clear thresholds. She proposed potential approaches towards re-adjusting pre-specified thresholds using pre-specified algorithms, as well as the importance of planning prospective-retrospective analyses for unknown biomarkers. Dr. Rich Simon addressed multi-marker assays, explaining that while single biomarkers are the ideal, the complicated nature of tumors will sometimes require the summary measurement of several biomarkers in determining appropriate treatment. Dr. Simon described how to define, clinically validate, and reassess thresholds for summary measures in multi-marker assays. Nancy Roach highlighted the impact that companion diagnostics can have on patients, but stressed the importance of testing in marker-negative populations so as not to miss unexpected therapeutic response, and emphasized the willingness of even marker-negative patients to receive new and potentially exciting drugs.
Dr. Rick Pazdur from the Center for Drug Evaluation and Research(CDER) and Dr. Liz Mansfield from the Center for Devices and Radiological Health(CDRH) then gave the FDA response to the suggested proposals. Dr. Pazdur emphasized that the diagnostic test must be well-defined and essential to be considered a companion diagnostic, and also stressed that drug efficacy trumps all other considerations. Dr. Mansfield spoke of the importance of appropriate trial design in co-development of companion diagnostics, but also stressed that trial design is only important if the biomarker assay is accurate and valid.
Panel 2: Creating an Environment for Personalized Medicine
- Keith Flaherty, Director of Developmental Therapeutics, Cancer Center, Massachusetts General Hospital
- Pat Mahaffy, President, CEO and Co-Founder, Clovis Oncology, Inc.
- Vince Miller, Senior Vice President, Clinical Development, Foundation Medicine
- Debra Rasmussen, Senior Director, Global Regulatory Affairs, Janssen Diagnostics, Inc.
- Jeff Roche, Medical Officer, Centers for Medicare and Medicaid Services (CMS)
- Jeff Shuren, Director, Center for Devices and Radiological Health, U.S. Food and Drug Administration
- Janet Woodcock, Director, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
The second panel, moderated by Dr. Keith Flaherty, discussed their responses to the companion diagnostic blueprint, with a focus on those issues that will affect targeted therapies and the use of companion diagnostics in the future, including Laboratory Developed Tests (LDTs), insurance reimbursement for diagnostic tests, new technologies including next generation sequencing, and the use of platform technologies.
Specifically, Dr. Janet Woodcock mentioned that companion diagnostics are used in many disease areas, and also expressed her hope that ideally the paradigm of clinical trials will change, due in part to targeted therapies and diagnostic tests. Dr. Jeff Shuren discussed that as technological changes result in testing changes, bridging will be necessary for analytical and clinical validation. He also discussed current FDA policy on LDTs, and how they are still determining what their future approach will be. Dr. Jeff Roche described the collaborative efforts of FDA and CMS in determining reimbursement for diagnostic tests. In the discussion, Dr. Mansfield mentioned that CDRH considers regulatory approval of a multi-marker test “imminently doable,” but they need a sponsor to bring such a test forward.