Gordon MacFarlane, PhD, RAC, Sandra D. White, MS, RAC, and Cynthia Nolte, PhD, RAC

This year has been highly productive for FDA. Among the agency’s many achievements are several guidance documents that have substantial, positive implications on portfolio productivity and strategy. The following six guidance documents issued in 2015 merit careful consideration by every device manufacturer.

Adaptive Designs for Medical Device Clinical Studies (Draft Guidance)

What FDA Says: FDA has identified when and when not to utilize an adaptive design, useful types of designs, challenges, and regulatory considerations. This document provides an excellent basis for manufacturers to clearly understand FDA’s view on adaptive designs.

Implications: Device manufacturers should take note of FDA’s recognition and endorsement of the use of adaptive designs where appropriate. In our experience, adaptive designs have strengthened decision making, increased the quality of collected clinical evidence, and improved time-to-market and product valuations (particularly when applied across a portfolio).

The Path Forward: Device makers cannot simply borrow protocols from adaptive designs utilized in pharmaceutical trials. Also, teams inexperienced in adaptive designs may introduce bias to a trial that can complicate characterization of the true effect of the investigational device; poor designs can also confound the interpretation of study results when a pre-planned adaptation causes data collected before the adaptation to be insufficiently similar to those after the adaptation.

Manufacturers should determine whether adaptive designs are appropriate for trials in their portfolios. Manufacturers will need expertise and technology infrastructure, either through hiring internal staff or an experienced contract research organization, to simulate, design, and execute these studies with medical device-specific standard operating procedures.

Acceptance of Medical Device Clinical Data from Studies Conducted Outside the United States (Draft Guidance)

What FDA Says: Clinical trials are conducted across a widening range of geographies. FDA has confirmed its acceptance of data from clinical investigations conducted outside of the United States, including the European Union, provided the applicant demonstrates that the conducted trial met United States standards and requirements (21 CFR 50, 56, 812, 814).

Implications: Compliance with good clinical practice, informed consent, and local clinical trial regulations should produce data that is procedurally acceptable for U.S. marketing submissions. The guidance provides concrete examples.

The Path Forward: Sponsors must be aware of differences in clinical conditions, standards of care, study populations, and local regulatory requirements, as these factors also influence acceptability of data.

The Pre-Submission process is highly recommended to assess the acceptability of the outside of U.S. data, as is early engagement with FDA to define requirements prior to enrollment.

Expedited Access for Premarket Approval and De Novo Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions (Final Guidance)

What FDA Says: FDA has established processes for the Expedited Access PMA (EAP) program, which can accelerate the evaluation of devices that fulfill unmet medical needs for life-threatening or irreversibly debilitating conditions.

Implications: Sponsors can negotiate what data will be collected before and after clearance/approval.

The Path Forward: The EAP program does not change the total amount of data or information to be collected, just the timing of data collection. Early engagement with FDA is critical to define expectations.

Manufacturing Site Change Supplements: Content and Submission (Draft Guidance)

What FDA Says: The draft guidance defines a manufacturing site change, when to submit a PMA supplement for a site change, what documents to submit, and the factors FDA intends to consider when determining whether to conduct an establishment inspection prior to approval of a site change supplement.

Implications: This guidance provides excellent detail on the documentation needed to support approval and the inspection process, including examples for a site change supplement versus 30-day notice. The submission content is helpful and provides insights as to when inspections will likely be conducted.

The Path Forward: As this is a draft guidance, uncertainty remains. To mitigate surprises, ensure your quality assurance department is aligned with the guidance, is involved in the site change from the beginning of the project, and signs off on the contents in the application to FDA.

Refuse to Accept Policy for 510(k)s (Final Guidance)

What FDA Says:FDA added elements to the Refuse to Accept checklist, including useful examples and page numbers where relevant information is to be found.

Implications: The expectations are more clearly defined and should lead to a greater percentage of accepted submissions.

The Path Forward: Sponsors must be more explicit and complete in applications than before. Testing must be completed prior to submission of an application; it is no longer a viable strategy to submit and then complete testing during the review cycle.

Follow the checklist closely, providing all information requested. Use the comments sections to expand or explain aspects that may vary from expectations.

Information to Support a Claim of Electromagnetic Compatibility (EMC) of Electrically-Powered Medical Devices (Draft Guidance)

What FDA Says: FDA recognizes that multiple national and international standards may apply to medical devices; this guidance consolidates requirements in one place.

Implications: The guidance has clear and consistent information for demonstrating electromagnetic compatibility.

The Path Forward: Sponsors will still need to refer to individual recognized standards for specific details of the requirements. This guidance is intended to be used in conjunction with other guidance documents to define specific requirements.

Gordon MacFarlane, PhD, RAC, is senior manager of Regulatory Affairs at ICON plc.

Sandra D. White, MS, RAC, is?director of Regulatory Affairs at ICON plc.

Cynthia Nolte, PhD, RAC, is director of Regulatory Affairs at ICON plc.

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