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Jill Wechsler is BioPharm International's Washington Editor, firstname.lastname@example.org.
Efforts to accelerate drug development will alter fee structure and require ready production sites.
FDA officials and industry leaders have agreed on a set of recommendations for revising and updating the Prescription Drug User Fee Act (PDUFA) and are looking for broad support from patients and the medical community to spur Congressional approval of PDUFA VI. The legislators need to reauthorize FDA fees for drugs and biologics, along with similar programs for biosimilars, medical devices, and generic drugs, before the fees expire on Sept. 30, 2017. The pressure is on because a change in administration in January 2017 will delay Congressional consideration of new programs and policies for several months.
For PDUFA VI, the agreed-on commitment letter maps out strategies to make the program less burdensome and complex, while also providing more flexibility for expediting the assessment of certain innovative products (1). An emphasis on hearing the patient voice will support development of breakthrough therapies and treatments for rare diseases and encourage innovative clinical trial designs. FDA will hold public workshops and develop a series of guidance documents for collecting patient input on disease burden, treatment impact, and clinical outcomes assessment, with an eye to enhancing reviewer understanding of the benefits of a test therapy to patients, in addition to risks.
Related initiatives are to further incorporate real-world evidence and benefit-risk assessment into drug development so that these approaches can help evaluate efficacy, in addition to tracking safety issues postapproval. FDA also plans to expand the Sentinel System to enhance drug safety monitoring and promises timely, advance communication to manufacturers on emerging safety signals.
More streamlined oversight of combination products is another priority of PDUFA VI, and FDA plans to expand staff and promote more coordination between at the Office of Combination Products and review centers for drugs, biologics, and medical devices. PDUFA will fund an increase in reviewers for these complex products, development of guidance on bridging studies and labeling, goals for timely review of protocols for human factors studies, and an independent evaluation of the combination program.
These and other initiatives will be supported by a significantly revised PDUFA fee structure. A new “program” fee will replace current levies on manufacturing facilities and on products, and will be calculated to yield 80% of the anticipated $1.2 billion collected by PDUFA in 2018. Application fees will add up to only 20% of program cost, thus reducing FDA’s reliance on revenues that can vary from year to year.
A related change is to drop user fees altogether for efficacy and manufacturing supplements. FDA has found this aspect of PDUFA difficult to administer, and supplement fees have not been a major source of revenue for the program. The change also aims to encourage manufacturers to update labeling on a more-timely basis and to pursue improvements in production systems to ensure quality operations.
The new program fee will be based on the number of approved drugs and biotech therapies marketed by a firm. This move away from facility fees reflects industry’s expanded use of contract manufacturers for drug production, which often makes it difficult to assess the portion of a facility allotted to each pharmaceutical client. FDA and manufacturers have found it hard to administer the billing process for facility fees due to frequent changes in the drugs a contractor produces and the clients involved.
Levying a larger fee for each marketed product, however, could encourage manufacturers to halt production of older drugs that are only marginally profitable. Another risk is that high product fees might discourage development of personalized therapies that may have 5, 10, or more different formulations of the same product. To prevent that outcome, the negotiators agreed to set program fees on a maximum of five versions of the same therapy; additional formulations would not pay another fee. Despite some uncertainty about how fee changes may influence production decisions, manufacturers and FDA are optimistic that the new fee structure will be more predictable for all parties and that the PDUFA program will be more sustainable and manageable.
At the same time, PDUFA VI puts more pressure on manufacturers to fully prepare and identify production sites before submitting a new drug application (NDA), biologics license application (BLA), or supplement so that all relevant facilities can be listed in the filing. The user fee program sets increasingly short timeframes for the Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) to take action on applications, especially those for more innovative therapies. FDA may delay product approval if an application lacks certain important data, and now that specifically applies to information on manufacturing facilities.
The aim is to provide FDA with sufficient time to inspect and evaluate all planned production sites. PDUFA VI gives FDA authority to extend an approval goal date by two or three months if a sponsor fails to identify a facility in its initial list, a serious shortcoming according to Kay Holcombe, senior vice-president of the Biotechnology Innovation Organization (BIO). She commented at the August 2016 PDUFA public meeting that industry is obligated to submit complete and high-quality applications to FDA, and that failing to mention where the firm plans to make a drug or biologic is “shocking.” But evidently, agency staffers have run into enough incomplete facility listings to single this issue out for specific attention.
FDA also plans to tap user fees to improve certain internal operations and programs. There will be added resources to make the agency’s electronic submissions process faster, more transparent, and more predictable. And PDUFA will support strategies to keep FDA staffers from drowning in meetings. While agency officials encourage sponsors to meet early and often with staff to discuss and gain agreement on product development plans and strategies, this approach has overwhelmed CDER and CBER with some 3000 meeting requests in 2015, which also involve pre-review of thousands of pages of background data. Agency officials seek to improve the process by resolving some issues in writing, instead of in-person meetings, and to provide staff with more time to examine meeting documents.
A main goal for FDA in negotiating PDUFA VI was to gain stakeholder support for a more concerted effort to improve the agency’s hiring process. FDA wants to bring more scientists and experts into the agency, but has difficulty competing for talented professionals due to low salaries, strict conflict-of-interest (COI) policies, and a long and convoluted hiring process. While the low-pay and COI issues reflect broader federal employment standards that FDA cannot easily change, this latest PDUFA plan sets clear goals and timeframes for filling vacancies more expeditiously. New procedures would clarify and simplify job announcements and bring in head hunters to identify prime candidates.
A new high-level office will oversee recruitment and retention of qualified scientific and medical personnel, reflecting a commitment by top FDA officials to improving its staffing situation. The current shortfall of 200 employees in CDER’s Office of New Drugs is not just an FDA issue, commented Holcombe of BIO, but “a public health problem.” Without added expertise, stakeholders believe that FDA cannot meet the many goals and challenges of the PDUFA program.
1. FDA, PDUFA Reauthorization Performance Goals And Procedures Fiscal Years 2018 Through 2022, FDA.gov, www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM511438.pdf
Vol. 29, No. 10
When referring to this article, please cite it as J. Wechsler, “Manufacturers Face Major Changes under PDUFA VI," BioPharm International 29 (10) 2016.