How to Better Prepare for Regulatory Requests and Minimize Impact

The pressure to increase efficiency in medical device development has been prevalent across the industry over the past year, especially with the intensified regulatory expectations. Many projects continue to experience delays during the submission process with governing bodies, particularly when responding to requests for additional information.

There is a great deal of time and resources invested with each submission to ensure the device is safe and effective. Still, not all submission packages provide supporting data in the way reviewers are looking for, leading to outstanding questions. Companies that identify trending preferences and consider regulatory expectations in earlier project phases can align their efforts and minimize delays from additional information requests.

Identifying Common Pitfalls
Requests for additional information are unique to each regulatory submission, governing body, and reviewer. Manufacturers should be familiar with the overarching patterns and apply these insights to their development processes. Governing bodies are always refining their review processes, but current expectations and key trends to be aware of include:

Evaluating devices throughout the entire lifecycle. As the EU Medical Device Regulation (MDR) continues to hold the industry’s attention, so does its intent to monitor medical devices more closely throughout the entire product lifecycle. The enhanced formalization of post market surveillance (PMS) guidance further supports this effort to continue device monitoring after regulatory approval. Additionally, some reviewers have recently requested that companies demonstrate biocompatibility at the end of shelf life. Manufacturers should consider any material differences from a chemical standpoint, especially devices produced with polymers and elastomers, that could alter toxicity at the end of the lifecycle and put biocompatibility at risk.

Minimizing in vivo testing. European regulators are also paving the way when it comes to reducing in vivo testing. Any animal testing lacking a clear purpose or justification will raise questions from regulators. Ensure in vivo testing is only in the submission if necessary and, if so, pair in vivo evaluations with proper justifications.

Proving expert qualifications. Credibility is one of the top priorities for regulators. Reviewers will often request CVs of any staff members conducting medical device evaluations to better understand the quality of the testing and submission. The expectation primarily pertains to toxicology experts, but a testing lab’s experience is of growing interest and regulators may require this documentation for other testing areas in the future. Acquiring background materials about staff experience during testing helps minimize requests and reduce information gaps later on if any staff members have entered new positions.

Applying state-of-the-art methods. The ambiguity surrounding what “state-of-the-art” means and how to apply it is a common challenge under the EU MDR. An exact definition is not currently available, but there seems to be a consensus that testing should be up to date with expectations in the latest standards. In some cases, reviewing submissions against state-of-the-art methodologies may reveal a gap that prompts completely new device testing. For instance, most accept ISO 10993-18:2020 as state-of-the-art guidance, requiring additional chemical characterization studies for many devices.

Considering these pitfalls can help manufacturers better anticipate what regulators may ask and take measures to minimize delays that would come from additional information requests. For some, putting this to practice may only take a few small changes, but for others, it may mean shifting perspectives about how they engage with regulators.

Planning Proactively
Instead of using the “wait and see” approach with medical device submissions, bring regulators into the conversation sooner. Pursuing a pre-submission meeting is a proactive way to clarify final submission expectations and refine testing strategies.

To get the most out of these meetings, come prepared with specific questions and a clear evaluation plan. With feedback from regulators, teams can adapt program design or parameters appropriately and take it into consideration when making decisions going forward. Laboratories are not always able to adjust study parameters after testing is complete. If regulatory expectations shift mid-study, a manufacturer may have to retest or face lost data investment. A pre-submission meeting can identify necessary adjustments early on.

Considering the technical background and the priorities of each regulatory body can also help companies anticipate what kind of requests for additional information they might receive. They must ask themselves, what is important to the specific reviewer? What drives their questioning?

Regulatory expectations can vary based on technical background and regulation changes. In some cases, reviewers have greater input on the technical aspects of device evaluation. They can understand findings and translate the meaning of data sets without the same level of explanation other reviewers may need. Still, these reviewers may issue requests that require more in-depth technical knowledge because of their heightened expertise. Alternatively, other reviewers are adjusting to completely new standards, like in the EU, and they prefer more significant background and insight into the strategy for each submission. Such a disparity in questioning may be seen between notified bodies as the EU MDR takes effect.

Testing partners typically understand how each regulatory body will vary in their evaluations, so pulling partners in early for support is a critical step.

Readying Responses
It may not be possible to completely avoid requests for additional information, but improving the responses to them when they do occur can reduce the likelihood of follow-up requests or lengthy delays. To strike the perfect balance for a timely and thorough response, pull in partners, fall back on expert advice, and record learnings for the future. After receiving additional information requests, there is no time to waste.

Giving testing partners enough time to provide a thoughtful response to a request is critical. They typically need to dig deeply into archives to retrieve data, and tight turnarounds are not always possible. Ideally, manufacturers should provide partners a minimum of one week to respond.

When developing responses, testing laboratories take their regulatory expertise and background of the testing plan into consideration. After companies receive drafted responses from laboratory experts, avoid making changes to the provided feedback. If something about the response is unclear, ask for clarification to understand what the expert’s intentions are with what they shared. Often, justifications are defending methodology because the adaptations are not possible.

Finally, document all additional information requests. Regulations and current expectations can be vague and evolve rapidly, but a record can reveal trends specific to a company’s submission pathways.

Taking a Fresh Approach
When looking to minimize requests for additional information, everyone has room to improve their approach and reduce possible delays. By considering common pitfalls, engaging regulators prior to submission and maintaining communication with lab testing partners, manufacturers can set their device up for success and keep the project on track, even when requests for additional information arise. 

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Sandi Schaible is the senior director of analytical chemistry and regulatory toxicology at WuXi AppTec Medical Device Testing, which specializes in extractables and leachables studies. She is a U.S. delegate and international delegate for ISO 10993 part 18 in chemical characterization, and also a U.S. delegate for ISO 10993 part 13 and the particulates committee (TIR42).

Sherry Parker, Ph.D., has more than 20 years of toxicology and medical device experience, and is an expert in analytical, pharmacological, and toxicological evaluations of medical devices and combination products. After receiving her Ph.D. in molecular and cellular pharmacology from the University of Miami, Dr. Parker worked as a toxicologist for the U.S. EPA, RTI International, OrbusNeich Medical, and Fresenius Medical Care. In her current position as senior director of Toxicology, Dr. Parker provides manufacturers with guidance on global regulatory and technical requirements and testing program design. In May 2019, Dr. Parker was appointed to a three-year term as co-chair of the Advancing Safety in Health Technology/Biological Evaluation Committee. In addition, she is currently an internationally recognized ISO expert and a U.S. Delegate for TC 194, the technical committee for ISO 10993, and was former president of the Medical Device and Combination Products Specialty Section of the Society of Toxicology.

Kim Ehman, Ph.D., serves as a Technical and Regulatory director, with a focus on medical device and combination products. Before joining WuXi AppTec, she served as a toxicology consultant and scientific program manager at Toxicology Regulatory Services for more than three years and was a toxicology study director at RTI International for five years. At RTI, she managed preclinical and safety evaluation studies for a broad range of clients in both industry and government under prevailing EPA, FDA, and OECD guidelines. At Toxicology Regulatory Services, Dr. Ehman designed and managed toxicology testing programs in support of company and consortia regulatory requirements. She also prepared risk assessment and weight-of-evidence documents to facilitate decision-making during various phases of product development. Prior to working at RTI and Toxicology Regulatory Services, Dr. Ehman was a postdoctoral associate in the EPA’s Neurotoxicology Division for three years, where her research efforts focused on developmental neurotoxicity. She earned a B.Sc. degree in biology from Seton Hill University and a Ph.D. in parasitology from McGill University.