Recipe For Doubling Innovative Medicines Includes New Approval Pathway, FDA Management Changes
Executive Summary
Presidential advisory panel makes eight recommendations to improve innovation in drug discovery, development and evaluation; calls for broad partnership of stakeholders to accelerate therapeutics, $40 million annual appropriations for FDA’s Sentinel System.
A presidential advisory panel recommends that FDA test out adaptive drug approvals – in which an initial approval is based on a favorable benefit-risk balance in a defined group of patients – as a way to accelerate the availability of innovative drugs.
The President’s Council of Advisors on Science and Technology (PCAST) set a goal of doubling the output of innovative, new medicines for patients with unmet medical needs, while increasing drug efficacy and safety, over the next 10-15 years. The panel’s Sept. 25 report presents eight recommendations to achieve this goal, some of which are included in the recently enacted FDA Safety and Innovation Act (FDASIA).
Three of the recommendations focus on improving drug evaluation. They call for developing a new pathway for initial approval of “special medical use” drugs, expanding the use of accelerated approvals and testing adaptive drug approvals. Others call for more government funding for basic biomedical research; $40 million annual appropriations for FDA’s Sentinel System for post-marketing surveillance; improvements in FDA management; and the creation of a partnership involving industry, academia, the federal government and other stakeholders which would develop plans for clinical trials networks, among other things.
FDA Commissioner Margaret Hamburg praised the publication at its Sept. 25 release. “This is a very impressive report, which reflects more than a year of intensive work by the PCAST team with broad engagement by stakeholders from across the drug development ecosystem, patients, physicians, biomedical scientists, academic leaders, industry leaders, venture capitalists, payers and of course FDA and NIH,” she stated.
Hamburg noted the connection between the PCAST report and FDASIA, which reauthorized the Prescription Drug User Fee Act. “There was striking overlap, or perhaps I should say synergy, in both the topics and the people who were part of the FDASIA process and the work of this PCAST study,” she said. “There was a lot of shared discussion and brain-storming. In fact, many of the recommendations and issues raised in this PCAST report are mirrored in the FDASIA legislation, which, among other things, will help ensure attention and action.”
Government Funding, Post-Market Surveillance Are Key Issues
The panel’s “Report To The President On Propelling Innovation In Drug Discovery, Development and Evaluation” was drafted by an expert committee of PCAST members with input from more than 30 invited experts, including Pfizer Inc. President Worldwide Research and Development Mikael Dolsten, Eli Lilly & Co. Chairman and CEO John Lechleiter; GlaxoSmithKline PLC Chairman of Research and Development Moncef Slaoui, and Sanofi President of Global R&D Elias Zerhouni. The committee also received input from FDA Center for Drug Evaluation and Research Director Janet Woodcock and CDER Office of New Drugs Deputy Director Sandra Kweder.
One of the invited experts, Jerry Avorn, professor of medicine at Harvard Medical School, said one of the most important recommendations was the call for additional funding to the National Institutes of Health and other sources to support research in the academic setting. He said he was also pleased to see the recommendation for increased post-marketing surveillance and the discussion in the report about the need to validate surrogate endpoints to assure they represent meaningful clinical benefit for patients.
While many reports on the drug approval process have been issued over the years, this one is distinct for its timing and some of its proposals.
Avorn said the report looks more directly at the way FDA operates and the recommendations directed at the agency “should be the most actionable.”
“Another way it is different is that it comes post-FDA Amendments Act, post-Vioxx and post-Avandia,” he said, referring to blockbuster drugs that were found to increase the risk of heart attack. “These experiences helped shape the content.”
Prevision Policy analysts said the direct impact of the report is minimal. “But as a statement of aspirations from the current Administration’s council of scientific advisors it should provide reassurance that FDA will not drop the pro-innovation theme once campaign season is over,” they said in a note.
PCAST’s Eight Recommendations To Double Innovative Medicines
Federal government should support funding for basic biomedical research, NIH’s National Center for Advancing Translational Sciences and the Reagan-Udall Foundation
Stakeholders should create a Partnership to Accelerate Therapeutics
FDA should expand its use of accelerated approvals
FDA should create a new pathway for initial approval of drugs shown to be safe and effective in a specific subgroup of patients
FDA should run pilot projects to explore approaches for adaptive approval
FDA should improve its tools for post-marketing surveillance and Congress should authorize line-item appropriations of $40 million per year to expand FDA’s Sentinel System
FDA should institute management and communication reforms, including designating pre-market review leaders to oversee each drug candidate application, and overhauling its IT systems
HHS Secretary should commission a study of economic incentives to promote innovation in drug development
Speeding Up The Drug Approval Process
On the approval side of the equation, the report proposes three ways FDA could improve the drug evaluation process. It suggests that FDA explore adaptive approval of drugs by running pilot projects to explore mechanisms to generate evidence across the life cycle of a drug. However, the panel advises against legislation to create a formal adaptive pathway for approval.
“For adaptive approval to be a viable approach, it would be necessary to have mechanisms to ensure that
- Drugs are prescribed largely to patients for which they have been approved at the time;
- Evidence about drugs’ risks and benefits is generated on an ongoing basis, including through randomized controlled studies, pharmaco-epidemiological data, and robust monitoring after initial approval; and
- Drugs for which follow-up studies and monitoring are not completed or demonstrate an unfavorable risk-benefit balance can be readily removed from the market.”
The panel makes a distinction between this approach and recent proposals to implement “progressive” approval through legislation. The Biotechnology Industry Organization had advocated this model, under which FDA could approve drugs after Phase II in exceptional circumstances, but subsequently revised its position to instead favor an expansion and clarification of accelerated approval (Also see "BIO Wants Expanded Accelerated Approval In PDUFA Instead Of Progressive Approval" - Pink Sheet, 23 Jan, 2012.).
PCAST does propose creation of a new pathway for initial approval of drugs shown to be safe and effective in a specific subgroup of patients, such as drugs to treat morbid obesity and bacteria resistant to current antibiotics.
“Such drugs would be approved under a designation of Special Medical Use, signaling strongly to payers and prescribers the limited population that should be prescribed a drug,” the report states.
FDA has voiced support for the “special medical use” category for drugs. At a press briefing in March, Hamburg and Woodcock said antibiotics for drug-resistant bacteria would be the initial focus of such a program (Also see "FDA Exploring Limited-Use Approvals For Antibiotics Based On Small Development Programs" - Pink Sheet, 7 Mar, 2012.). The Infectious Diseases Society of America had initially proposed this mechanism, which it dubbed the Limited Population Antibacterial Drug approval pathway (Also see "Antibiotic Incentives: FDA’s Woodcock Says LPAD Could Be Better Than Exclusivity, But Questions Remain" - Pink Sheet, 18 Apr, 2012.).
In commenting on the PCAST report, Hamburg reiterated that this special category of drugs could apply to chronic conditions like obesity or to infectious disease concerns such as drug-resistant infection.
“But under current paradigms, FDA can’t be assured that use of a product will be limited to the indicated use, and drug development plans often must evaluate the risks in a broader population, resulting in larger, lengthier trials, and ultimately less tolerance for risk in all likelihood,” she said.
“To adopt such a strategy, FDA would need a mechanism to designate on a temporary or permanent basis, a drug as ‘special limited use’ for use in the well-defined population for whom the benefits of the drug have been shown to outweigh the risks or when there is a public health need to limit use to specific populations (i.e., treatments for resistant pathogens).”
“This is a straightforward idea, but it does raise a number of complex legal and regulatory issues on top of the science,” Hamburg added.
PCAST also recommends that FDA expand the use of its existing authorities for accelerated approval. The report says that in practice, this pathway has been largely limited to HIV/AIDS and cancer drugs and that FDA could expand its use to address more types of serious diseases. It says FDA should issue clear guidance concerning the types of new drug applications that would be eligible for accelerated approval, engage with the biomedical community in the development and evaluation of specific predictors, and provide guidance about the acceptability of specific surrogate and intermediate endpoints.
FDASIA also directs FDA to increase the use of the accelerated approval and fast-track pathways, requiring FDA to establish a program to encourage the development of surrogate and clinical endpoints. The legislation also created a new designation for “breakthrough” drugs which would allow candidates showing results much better than existing treatments to move more quickly through the clinical trial process (Also see "PDUFA V: Accelerated Approval Expansion May Outshine Rare Disease Improvements" - Pink Sheet, 17 Sep, 2012.).
Bolstering FDA Management, Post-Marketing Surveillance
The report also directs FDA to undertake several reforms, including the designation of a senior staff member to serve as a “pre-market review leader” for each drug candidate.
“This individual would be a ‘quarterback’ for the drug development project, with responsibility for providing sponsors with substantive, informal, clear, and timely advice, and for coordinating and leading FDA responses across diverse areas, including toxicology, trial design, manufacturing and clinical use, and for ensuring that timely decisions are made to resolve outstanding FDA review issues,” the report states.
In addition, the report says FDA should overhaul its outdated information technology systems and establish a program for piloting management reforms and initiatives.
The panel also calls on FDA to strengthen its post-marketing surveillance capabilities and for Congress to provide an initial line-item appropriation of $40 million per year to expand FDA’s Sentinel System. The report says funding for this surveillance system currently comes from FDA’s internal allocation of resources and has varied from about $12 million to $26 million.
FDA launched a pilot for Sentinel, the Mini-Sentinel, in 2009. The report notes that this initiative currently involves insurance claims data from about 125 million patients and electronic health records for about 10 million patients.
Clinical Trial Network As A Joint Venture
With regard to drug discovery and development, the report calls for additional government funding for basic biomedical research, as well as continued support for the National Institutes of Health’s National Center for Advancing Translational Sciences, which was established in December 2011, and the Reagan-Udall Foundation, a nonprofit organization created by Congress in 2007 to support FDA by advancing regulatory science and research.
In addition, the report advocates the creation of a broad-based partnership of stakeholders to accelerate development of therapeutics. The partnership would include members of industry, academia, physician societies and pharmacists, patient-focused research foundations, advocacy groups, health care providers, insurers, and the federal government. The report says this entity would facilitate the development of projects, including new kinds of clinical trials networks. It suggests that biopharmaceutical companies might form a joint venture to create a clinical trials network.
Industry has begun to move in this direction. Ten drug companies recently launched a nonprofit, TransCelerate Biopharma Inc., to jointly identify and solve common drug development challenges and improve clinical trial quality (Also see "Major Pharmas To Collaborate In Non-Profit Initiative To Resolve Clinical Development Hurdles" - Pink Sheet, 19 Sep, 2012.).
Hamburg expressed support for PCAST’s proposed partnership model as well as other public/private partnerships.
“There can be no doubt that modernizing and streamlining the science of how products are developed and evaluated is a complex challenge requiring teamwork and collaboration,” she stated. “We need to support new models and approaches that stress cross-sector and cross-disciplinary research, focused on what it takes to do 21st Century drug discovery, development and evaluation.”