The Food and Drug Administration (FDA) periodically conducts meetings on the Prescription Drug User Fee Act (PDUFA) program. The current legislative authority for PDUFA (PDUFA IV), reauthorized in 2007 by the FDA Amendments Act (FDAAA), will expire in September 2012. FDAAA requires that FDA hold public meetings and conduct discussions with both the regulated industry and stakeholder groups in developing recommendations for the next PDUFA program, PDUFA V, which will cover FY2013-2017.
Last month, FDA and industry continued the discussion of FDA’s proposal to introduce a late review cycle meeting between the agency and sponsors for all new molecular entity new drug applications (NME NDAs) and original biologic license applications (BLAs) during PDUFA V. For those applications discussed at an Advisory Committee (AC), the late cycle meeting would be scheduled between a sponsor’s receipt of the agency’s AC background package and the AC meeting.
At the meeting, industry stated its view that there also should be a mechanism to discuss substantive issues for applications that FDA opts not to take before an AC meeting.
FDA noted that the agency shares its reviews in the AC background package because those documents will eventually be part of the public briefing materials for the AC meeting. If an application is not discussed at an AC, FDA noted that sharing that kind of information in the absence of a public process raises disclosure concerns.
Industry stated its expectation that FDA would continue to protect companies’ trade secrets and confidential commercial information, including information about unapproved applications.
As part of future discussions of this proposal, Industry stated its interest in gaining greater clarity in how major amendment extensions will be applied across review divisions and a greater understanding of what constitutes a complete application.
FDA noted that future discussions will also need to ensure that the agency has sufficient capacities across the review disciplines to adequately staff the late cycle meetings.
Data Standards
Industry discussed its draft revision of FDA’s original proposal to require electronic applications in standardized formats during PDUFA V through guidance. FDA noted that, as part of Good Guidance Practices, draft guidance’s are always published for public comment before the guidance is finalized. Industry agreed to revise the draft proposal for discussion at a future meeting.
Benefit-risk / Patient-focused drug development
Industry discussed a draft proposal to develop a structured approach to benefit-risk assessment and communication that would include an opportunity for stakeholder input. Industry stated that the outcome of this proposal over PDUFA V would be broad application of the framework to benefit-risk assessments that would include appropriate guidance and revisions to review templates and other procedural documents associated with human drug review.
FDA and Industry agreed that the objective of FDA’s proposal to more formally engage the patient perspective in benefit-risk assessments could be combined with development of a structured approach to benefit-risk. FDA also agreed to revise the benefit-risk proposal to articulate both concepts.
Risk Evaluation and Mitigation Strategies (REMS)
FDA’s Office of New Drugs Director John Jenkins discussed a draft proposal to standardize and integrate REMS into the healthcare system. This proposal includes developing draft criteria for determining the need for a REMS and a series of public meetings to explore strategies to standardize REMS and better integrate them into the existing and evolving healthcare system. While further discussion of this proposal will take place in an FDA-Industry Working Group, according to the FDA Lawyers Blog, Dr. Jenkins outlined FDA’s vision of “plug-and-play” REMS elements that could be standardized for specific drugs.
According to their coverage of the meeting, Dr. Jenkins explained that “Plug-and-play doesn’t mean that everything’s the same, it means that it’s compatible . . . its interoperable.” The FDA Lawyers Blog noted that based on these reports, Jenkins appears to believe that FDA currently does not have much control over what risk management elements are selected by new drug application (“NDA”) holders, when a product is first approved. Following approval, moreover, FDA can ask a company to impose certain risk management elements but can only withdraw a product from the market, if an NDA holder does not want to comply with FDA’s wishes.
According to the blog, “Jenkins further said that FDA wants to be able to mandate a single, shared risk management program across a class of drugs, such as what FDA has been working towards for the opioid drug class, which is preferable to the other option of about 20-30 different REMS for the current opioid products on the market.” Dr. Jenkins “indicated that there are pharmacy payment computer systems that may be helpful in the REMS standardization effort to facilitate payments and REMS program information for specific products. FDA also plans to reduce the number of Medication Guide-only REMS to reduce some of the REMS workload for pharmacists, who have a spotty record for distributing the mandated information.”
The blog noted that members of industry, such as Robert Clark, Pfizer Vice President of Worldwide Regulatory Strategy, “voiced support for a standardized REMS system at the summit, citing to benefits for not having to design a REMS from scratch. But Jenkins also seemed to acknowledge that while FDA has successfully negotiated some shared systems, it has been difficult to create a shared system for both innovator and generic companies.”
Analyzing Dr. Jenkins comments, the FDA Lawyers Blog noted that in the past, innovator companies, such as Celgene, “have voiced concern that they will be responsible for an increased workload once generics “share” their system, and some risk management program elements may be protected by patents listed in the Orange Book.” On the other hand, they also noted generic companies, such as Dr. Reddy’s Laboratories, Inc. (“Dr. Reddy’s”), who “have asked FDA to prevent innovators from using their REMS as a shield to deny reference listed drug to generic companies, which prevents generic applicants from conducting required bioequivalence studies for filing generic drug applications.”
To date however, the blog states that “both Celgene’s and Dr. Reddy’s petitions remain unanswered by FDA.” The blog predicted that “Even with FDA’s vision for standardized REMS elements, it may prove difficult for FDA to prevent innovator companies from using REMS to block or discourage generic competition.”
Meta-Analysis
FDA discussed a draft proposal to ensure quality in meta-analyses by holding a public meeting to discuss the science, methodological approaches, and best practices in meta-analyses, developing guidance on metaanalysis, and staffing a small review team to conduct and/or review meta-analyses as needed.
Rare diseases
FDA discussed a draft proposal to advance the development of drugs for rare diseases through training for FDA staff and external stakeholders, a public meeting to discuss the complex clinical trial issues in developing these drugs, and a website to serve as a resource and information repository for rare disease drug development.
Non-binding advice
FDA stated that the agency is interested in addressing Industry’s proposal for timely, nonbinding advice – discussed at the November 22 meeting – within its existing systems. This would require that the advice be binding; i.e., vetted by Agency officials with the ability to offer such advice, and documented. FDA also stated that requests for this type of advice would need to be linked to a previous interaction between the sponsor and FDA; e.g., clarification of advice given at a prior meeting such as a pre-IND meeting. If that condition is not met, FDA stated that the request would be considered a new meeting request.
Industry stated that its main interest is in getting timely feedback from the agency. The agency noted that Industry’s request for timely advice implied having additional resources ready to address requests for advice as they are submitted. Industry agreed to revise its proposal for discussion at a future meeting.
PDUFA financial issues
Industry stated that it is interested in evaluating a range of options for calculating the PDUFA inflation adjuster in a working group. FDA stated that it is interested in revisiting the complexity factor component of the PDUFA workload adjuster.
Sentinel Initiative
FDA stated that its proposal to pilot the Sentinel Initiative through proof-of-concept studies is intended to reduce the agency’s reliance on post-marketing requirements (PMRs) and post-marketing commitments (PMCs) where appropriate to evaluate post-market safety signals. Industry noted that it has made significant investments in the Observational Medical Outcomes Partnership (OMOP) that should be reflected in the language of this proposal.
Improving human subject protection and clinical trial oversight
FDA stated that its proposal to improve clinical trial oversight includes a quality systems approach to clinical trials, risk-based and real-time site inspections, and a dedicated inspectorate. Industry stated that preventative approaches that build in rigorous clinical trial oversight should be the target of this proposal.
Biomarkers and pharmacogenomics
FDA stated that its proposal to advance biomarkers and pharmacogenomics contains elements to increase the capacity to both qualify biomarker submissions and review applications that propose to use biomarkers in a development program. Industry noted that biomarkers is a subject that involves more stakeholders than FDA and Industry. The agency noted that biomarker qualification is ultimately a regulatory decision that the biomarker is qualified in a certain context of use. FDA also stated that this work now requires the agency to work with outside consortia developing biomarkers before they are ever submitted to the agency for review and that this work is very resource intensive.
Almost all of the proposals noted above will be discussed at an FDA-Industry Working Group.
FDA should really protect the companies including information about applications. I would want to know about the constitutes of a complete application and how major amendment will be applied?