Documents:
Panel One – Developing Standards for Breakthrough Therapy Designation
Panel Two – Design of a Disease-Specific Master Protocol
Panel Three – Re-evaluating Criteria for Accelerated Approval
Overview:
Each year, Friends of Cancer Research(Friends)and the Engelberg Center for Health Care Reform at Brookings convene the Conference on ClinicalCancer Research to address critical issues in the development of new drugs. This annual conference brings together leaders from federal health and regulatory agencies, academic research centers, patient advocacy organizations and the private sector to propose consensus solutions and develop a clear path forward on critical issues surrounding the development and regulation of drugs and therapies.
On November 14, 2012, the fifth-annual Conference on Clinical Cancer Research was convened in Washington DC with the support ofSusan G. Komen for the Cure, theAmerican Society of Clinical Oncology (ASCO), and theAmerican Association for Cancer Research (AACR).The 2012 conference focused on new policies and research strategies to improve and expedite drug development. Through a series of Issue Briefs released at the meeting, members of the expert panels proposed ways to implement the newly created Breakthrough Therapies designation and how to optimize the Accelerated Approval pathway. In addition, a proposal for a biomarker-driven, multi-drug registration trial for potential agents to treat lung cancer was also presented as an innovative approach to accelerate drug development.
In her opening remarks,Dr. Ellen Sigal, Chair of Friends, described some of the major accomplishments that have been achieved through this unique collaborative model, including the release of an FDA guidance in 2010 on the co-development of two new molecular entities (2NMEs) for use in combination, and the passage by Congress of The Advancing Breakthrough Therapies for Patients Act earlier this year. Echoing these remarks,Dr. Mark McClellan, Director of the Engelberg Center praised the actionable and practical recommendations that this conference has produced During the breakfast keynote,Dr. Harold Varmus, Director of the National Cancer Institute (NCI)described four approaches that the NCI is taking to bring precision medicine to oncology: The Cancer Genome Atlas; The development of an informatics infrastructure for joint mining of genomics data and clinical outcomes to inform systems biology and predictive modeling; The Provocative Questions Initiative, which seeks to stimulate new ways of thinking about cancer care; and the development of new ways to test novel therapeutics in suitable settings. This encompasses the reorganization of the cooperative groups as well as the Exceptional Cases Initiative, which calls for genomic analysis in all clinical trials and is aimed at understanding the rare responders in otherwise unsuccessful trials, or conversely, those that do not respond to otherwise effective therapies.
Senator Michael Bennet (CO), a member of the Senate HELP Committee (Health, Education, Labor, and Pensions), delivered the afternoon keynote address. Sen. Bennet is a prominent advocate of advancing the scientific rigor of new medical product development and FDA review processes, and was a co-sponsor of the Advancing Breakthrough Therapies for Patients Act. Senator Bennet discussed some of the challenges facing our country today, and emphasized the need for continued investment in biomedical research in the current fiscal climate. He stated that partnership between the public and private sectors will be needed to maintain the United States’ position as a leader in medical innovation. He praised this conference for bringing together such diverse stakeholders for open discussion and collaboration, and emphasized how essential these types of partnerships are for helping patients by finding the treatments of tomorrow.
Dr. Janet Woodcock, the Director of the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration also addressed the conference in the afternoon Keynote session. She highlighted the importance of drug development being patient-focused, utilizing the benefit-risk framework, and incorporating natural disease history, patient experience, patients’ willingness to trade-off side effects for drug benefits into the evaluation and development pathway.
Dr. Woodcock announced that the Breakthrough Therapy Designation has already been given to one drug. She stressed the importance now of focusing on how the designation affects the development process. The FDA is aware that with a faster regulatory pathway, drug manufacturing may be the rate-limiting step in the development process. Dr. Woodcock stressed the importance of having separate, early meetings on manufacturing that discuss the scale up plan for the drug.
Panel One – Developing Standards for Breakthrough Therapy Designation
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Click HERE to read the complete Panel One issue brief
- Charles L. Sawyers, Chair, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center; Investigator, Howard Hughes Medical Institute
- Daniel A. Haber, Director, Cancer Center, Massachusetts General Hospital; Investigator, Howard Hughes Medical Institute
- Sandra J. Horning, Senior Vice President, Global Head, Clinical Development Hematology/Oncology, Genentech
- S. Percy Ivy, Associate Branch Chief, Investigational Drug Branch, CTEP, NCI
- Wendy K.D. Selig, President and CEO, Melanoma Research Alliance
- Robert Temple, Deputy Director for Clinical Science, CDER, FDA
Panel One discussed the implementation of the newly designed FDA Breakthrough Therapy Designation. This designation was created by The Advancing Breakthrough Therapies for Patients Act, which was introduced into legislation following the 2011 Conference on Clinical Cancer Research panel, Development Paths for New Drugs with Large Effects Seen Early. With this pathway, a new drug may be designated as a Breakthrough Therapy if it is intended to treat a serious or life-threatening disease and preliminary clinical evidence suggests that it provides a substantial improvement over existing therapies. Upon designation, the FDA and sponsor would collaborate in a dynamic and cross-disciplinary process to determine how to condense or abbreviate development of the investigational agent without compromising the FDA’s rigorous standards for safety and efficacy. As described by Wendy Selig and Dr. Dan Haber, the Breakthrough Therapies designation could enable highly effective therapies to quickly reach the patients who need them most.
Dr. Percy Ivy described the panel’s proposed qualitative criteria for Breakthrough Therapy designation: 1) the potential Breakthrough Therapy should seek to treat a serious disease with no established standard of care or a standard that yields poor outcomes; 2) Breakthrough designation should be based on compelling early evidence suggesting major clinically meaningful improvement over existing therapies in a defined disease setting; 3) the potential Breakthrough Therapy under consideration will typically have a compelling scientific rationale and promising mechanism of action, such as targeting a molecular driver of a biologically characterized disease. Dr. Sandra Horning called for flexibility in current manufacturing and companion diagnostics requirements for Breakthrough Therapies, and proposed a new category of meetings between a single point of contact at FDA and the sponsor to enable a close working relationship and allow real-time sharing of study findings. Dr. Bob Temple concluded that the Breakthrough Therapy Designation will bring collective wisdom to efforts to expedite truly exceptional new drugs, and encourage the use of innovative trial designs and analyses.
Panel Two – Design of a Disease-Specific Master Protocol
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Click HERE to read the complete Panel Two issue brief
- Roy Herbst, Chief of Medical Oncology, Yale Cancer Center
- Eric Rubin, Vice President, Clinical Research Oncology, Merck
- Lisa LaVange, Director, Office of Biostatistics, CDER, FDA
- Jeffrey Abrams, Associate Director, Cancer Therapy Evaluation Program, NCI
- David Wholley, Director, The Biomarkers Consortium, FNIH
- Karen Arscott, Patient Advocate, Lung Cancer Alliance
- Shakuntala Malik, Medical Officer, FDA
The second panel detailed a potential biomarker-driven, multi-arm, multi-drug registration trial in non-small cell lung cancer (NSCLC) that was designed to address some of the current drug development challenges that result in inefficient, expensive trials. As mentioned by Dr. Shakun Malik, this type of project had been suggested by Dr. Rick Pazdur at the February 2012 thoracic malignancies steering committee and workshop. Other groups are also designing and implementing alternative trial designs that include biomarker screening, such as I-SPY 2 and ALCHEMIST, described by Dr. David Wholley and Dr. Jeff Abrams, respectively. The benefits of this type of trial, described by Dr. Roy Herbst, include reducing the overall screen failure rate of trials for targeted therapies, providing consistency by establishing a trial infrastructure, and resulting in bringing safe, effective drugs to patients faster. NSCLC was chosen as the prototype disease for a master protocol trial as it is a common cancer with multiple mutations and potential therapeutic targets. Dr. Eric Rubin described the master protocol trial design: upon enrollment, patients will receive a fresh core needle biopsy, and the tissue analyzed with appropriate assay(s); patients are then directed to a trial arm based on tumor subtype and randomized between the experimental drug and SoC. The primary endpoint is overall survival, with an interim analysis of either PFS or OS. In order for drugs to be included in the trial, they must already have clinical data demonstrating activity. Over time, new drugs will be able to be added to or removed from the study. Importantly, this trial would be run by a neutral third party, allowing data to be centralized and firewalls to be established, so that active drugs will not be compared to each other. Dr. Lisa LaVange explained that if firewalls were used, control patients could be leveraged between experimental arms, further shortening timelines and reducing costs. Dr. Shakun Malik offered the FDA perspective, and agreed that the master protocol could provide consistency to drug development and improve trial efficiency an, but stressed that FDA approval is dependent on trial integrity, clear clinical results and risk:benefit ratio.
The discussion following Panel Two addressed some of the practical concerns that may arise during this trial. One focus was on the necessity of standardization and streamlining of trial protocols, in order to encourage both patient and doctor participation. Dr. Jeff Abrams mentioned that NCI has created a single database across the US that may be appropriate for this type of screening trial. There was also further discussion on some of the particulars of the trial design, including the best organization to run the trial, how the inclusion of drugs and biomarker would be determined, and how to encourage sponsors to include their drugs in this trial.
Panel Three – Re-evaluating Criteria for Accelerated Approval
Click HERE to download the presentation slides
Click HERE to read the complete Panel Three issue brief
Click HERE for the article “Reevaluating the accelerated approval process for oncology drugs”
- Richard L. Schilsky, Chief, Section of Hematology-Oncology, University of Chicago Medical Center
- David P. Schenkein, CEO, Agios Pharmaceuticals
- Wyndham H. Wilson, Senior Investigator, Chief, Lymphoma Therapeutics Section, NCI
- Cheryl L. Jernigan, Research/Patient Advocate, Susan G. Komen for the Cure
- Janet Woodcock, Director, CDER, FDA
The final panel proposed ways to optimize the accelerated approval pathway and promote the use accelerated approval in earlier disease settings. Currently, the increasing number of available therapies, coupled with the lack of qualified surrogate endpoints and the lack of clarity early in development regarding circumstances in which a new product will qualify for accelerated approval, is pushing developers to pursue accelerated approval in heavily pre-treated patients in order to fulfill an “unmet need”. The panel proposed broadening the definition of “unmet medical need” and narrowing the definition of “available therapy”. Dr. Richard Schilsky stated that despite the availability of new therapies, unmet medical need still exists because the majority of existing therapies are not curative, have major toxicities, and also because there is a need for mechanistic diversity. The panel proposed that any cancer lacking a curative therapy should be regarded as having “unmet medical need”, that a new therapy could be considered eligible for accelerated approval if it demonstrates clear activity on a surrogate endpoint, and that “Available Therapy” should be defined in a biological context for targeted agents- i.e., if an investigational agent targets a specific pathway and will be labeled for use in a selected patient population, the only drugs that should be considered “available therapy” are those that target the same pathway.
The panel also discussed the need for new qualified surrogate endpoints. Dr. Wyndham Wilson described four criteria needed for qualification of a surrogate endpoint:
- A standardized definition;
- A statistically robust correlation between surrogate endpoint and clinically meaningful outcome;
- Large trials designed prospectively to validate the correlation between surrogate endpoint and clinical outcome;
- Prospective studies to determine the context-dependent utility of surrogate endpoint.
Dr. David Schenkein proposed a structured process for designating a product for development through the accelerated approval pathway. In this process, sponsors and FDA would meet early and agree that a drug will be developed by either an “Adaptive Clinical Development Plan” with possibility for accelerated approval if certain results are generated, or through the full approval process.A decision to pursue accelerated approval should include agreement on the patient population being studied, the surrogate endpoint to be assessed, the trial design and magnitude of benefit needed for accelerated approval, and on post-marketing commitments.
In the following discussion, Dr. Richard Pazdur, Director of the Office of Hematology and Oncology Products at FDA, stressed the need for sponsors to complete their confirmatory trials in a timely fashion and said that the FDA could benefit from an easier way to remove drugs from the market that fail to confirm clinical benefit.
