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Recent legislation and PDUFA initiatives aim to streamline oversight and testing requirements.
FDA regulation of drug-biologic-device combination products has been a tricky business, with manufacturers struggling to contend with unfamiliar rules and development strategies for these complex therapies. The rise of personalized medicine and technological advances have led to new types of drug-eluting stents, prefilled syringes, autoinjectors, nasal sprays, inhalation devices, and transdermal patches, along with calls for more risk-based and harmonized review, manufacturing, and inspection procedures.
A main challenge for biopharmaceutical manufacturers is to incorporate engineering and design controls for medical devices into quality-based design strategies for a drug or biologic. Policy makers have responded with legislation that streamlines FDA oversight of combination products, while the pending FDA-industry agreement on drug user fees supports efforts to clarify requirements and expand staff involved with reviewing drug-based combination products (1).
These developments reflect increased focus on risk-based manufacturing approaches that adjust testing and oversight to the complexity and function of a therapy. Sponsors may request FDA’s Office of Combination Products (OCP) decide a product’s Primary Mode of Action (PMOA), which determines whether primary jurisdiction for product development, testing, and approval goes to the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), or the Center for Devices and Radiological Health (CDRH) (2).
Manufacturer concerns about too-slow FDA evaluation and approval of certain combination products prompted legislators to address these issues in the 21st Century Cures legislation. It clarifies the PMOA designation process, addressing device maker concerns that too many combination products are designated drugs largely based on evidence of chemical action in the patient. The legislation explains how sponsors may request meetings with FDA to discuss testing strategies and post-approval studies, and clarifies how exclusivity applies to combination products with a generic-drug component.
Medical device makers have proposed to further streamline FDA oversight of combination products through a “third track” process for more coordinated combination product review, but FDA officials first want to see how well the Cures legislation improves combination product evaluation, said CDRH director Jeffrey Shuren at a hearing in March 2017 before the Senate Health, Education, Labor and Pensions (HELP) committee on renewing FDA user fees. Shuren commented that FDA has improved combination product review and oversight and that the new initiatives should accelerate timeframes for bringing innovative therapies to market.
The Senate hearing, and similar sessions before House committees, aims to move forward legislation to reauthorize the Prescription Drug User Fee Act (PDUFA), which needs to be finalized by Sept. 30, 2017 to avoid massive FDA layoffs. One provision in the PDUFA VI performance goals negotiated by FDA and industry aims to advance development of combination products. The plan is to tap fee revenues to expand staff across FDA centers and in OCP to provide more expertise for reviewing manufacturing practices, engineering aspects, protocols for human factors testing, bridging studies, and instructions-for-use labeling.
FDA will start by mapping a “lean process” for combination product review and for tracking timelines for cross-center consultations. The agency also will establish a process by late 2018 for resolving scientific and regulatory issues, and to set standard operating procedures for quality assessments, coordinated inspections of different product components, and labeling requirements for combination products (1).
A main goal is to clarify procedures for testing combo performance and safety. FDA will issue guidance on bridging studies for combination products with different device components for the same drug, or the same device component across different drugs and biologics. And it will confirm a process for review and evaluation of protocols for human factors studies, with the aim of clarifying how sponsors can assess the adequacy of study designs in terms of patient groups studied, critical tasks evaluated, and proposed endpoints. There will be additional staff training on combination product reviews to ensure consistent approaches in all centers, and an independent third party will identify areas that need better inter-center coordination.
These initiatives build on ongoing FDA efforts to improve combination product oversight and policies. A new Pre-Request for Designation option was announced in 2016 that offers manufacturers preliminary, non-binding feedback from OCP on likely classification of a new combination product. FDA issued draft guidance in January 2017 that seeks industry comments on preparing requests for such early advice (3).
Manufacturing standards have been a thorny issue for products with device and drug components. An FDA final guidance issued in January 2017 clarifies where to apply drug GMPs or device design controls and how a lead center should handle manufacturing compliance considerations (4). The guidance addresses industry concerns about cross-labeling requirements, design controls for investigational products, and how to present GMP information in marketing applications.
FDA also published an important final rule in December 2016 on postmarket safety reporting for combination products (5). The regulation seeks more consistency in reporting adverse events based on whether a combination product is regulated primarily as a drug, generic drug, biologic, or medical device, and whether serious safety issues are involved. Adverse event reporting can vary notably, with five-day or 15-day reports required for different events involving different products. Beginning in July 2017, manufacturers will need to comply with reporting requirements for the constituent parts of their products, pending FDA clarification through additional guidance.
FDA officials and industry leaders are examining these issues at numerous industry conferences on drug quality and manufacturing innovation. At the PQRI/FDA conference on product quality in March 2017, Douglass Mead, senior director for regulatory affairs at Janssen Research & Development, explained how new GMP rules and design controls based on critical quality attributes of the drug should help devise a broader control strategy for the combination product. Ramesh Raghavachari, branch chief in CDER’s Office of Life Cycle Drug Products, discussed manufacturing processes and quality issues that impact transdermal patches, pulmonary delivery devices, and autoinjectors, all combination products where CDER is the lead regulator. He noted that the device housing for a drug over a long period can impact stability, and that human factors testing is important for ensuring that patients can use inhalers and autoinjectors correctly, particularly in emergency situations.
A January FDA guidance document describing human factors studies for combination products with generic-drug components (6) advises manufacturers to focus on whether differences in the user interface design for a generic or brand drug could impact clinical safety or effectiveness, explained Irene Chan, deputy director of CDER’s division of medication error prevention and analysis, at the PQRI conference. While the device component does not have to be identical in design to that used in the reference product, human factors studies may be needed to ensure acceptable error rates for generic products, and manufacturers should seek to minimize design differences as much as possible. At the same time, the drug component of a generic combination product can demonstrate therapeutic equivalency following usual testing standards.
Drug-device human factors studies were examined further at the April CMC workshop organized by the Drug Information Association. A Parenteral Drug Association interest group meeting on combination products in May 2017 is discussing a range of hot topics related to quality systems and regulatory expectations for these products.
1. FDA, PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2018 Through 2022, p. 23.
2. FDA, Combination Products, FDA.gov.
3. FDA, How to Prepare a Pre-Request for Designation (Pre-RFD), Draft Guidance for Industry(OCP, January 2017).
4. FDA, Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products, Final Guidance(OCP, January 2017).
5. FDA, Federal Register 81 (244), Dec. 20, 2016.
6. FDA, Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development, Draft Guidance for Industry and FDA Staff (FDA, February 2016).
Volume 30, Number 5
When referring to this article, please cite it as J. Wechsler, "Combination Products Raise New Manufacturing Challenges," BioPharm International 30 (5) 2017.