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3 TIPS: Writing Effective Requests for Feedback

“The definition of insanity is doing the same thing over and over again and expecting different results.”

While your organization may not actually be considered “insane,” ask yourself at what point is your organization leaning towards “submission insanity” if you continue to utilize procedures or methods that consistently produce the same insufficient documentation per regulatory body guidance and recommendations.

If you are one of the many organizations that struggle with crafting regulatory body responses, there are ways to improve your maneuvering through the intimidating regulatory submission process. The FDA (Food and Drug Administration) strives to provide plenty of pathways for sponsors to receive feedback, guidance, and assistance in order to maximize a sponsor’s chances to be successful. Representatives from the organization regularly participate in conferences such as the International Symposium on Human Factors in Health Care, provides content on the FDA Learning Portal, publishes numerous guidance documents to their website, and has established opportunities to have direct engagement with FDA staff via written responses, teleconferences and in person meetings.

Suttons Creek’s combination product specialists track all of these resources, and we have curated a clear-cut path to getting what you need to improve your regulatory submission processes.

 STOP #1: Review Published FDA Recommendations

To be successful with regulatory authorities such as the FDA, it is critical to integrate the current FDA thinking into your workflow, procedures, and strategies. The FDA provides some insight into their current thinking through their published draft and final guidances. These documents outline the recommendations for the manufacturing process including, but not limited to design controls and human factors. The guidance documents provided by the FDA are generally helpful, but they often lack the clarity needed for your specific situation or may not exist for a topic with which your organization is struggling. While these limitations may exist, the documents are published regularly and provide both a wide range of topics focused on the most common challenges both the FDA and companies face and should be a first stop for developing your regulatory strategies.

STOP #2: Set Up FDA Meetings

Is there no clear guidance on a specific challenge in your development project? Does your organization lack the experience with technical elements that may impact your ability to gain approval of your product? If so, there is no better way to gain understanding than directly from those who will be conducting the review of your product. Not only can they provide the clarity you need, but they may also be able to share information on changes related to new FDA findings, changes to FDA personnel, and new data related to your specific device type that may impact your pathway. Sponsors have the opportunity to request several different types of meetings with the FDA, the results of which are non-binding but can be very informative.

The results are non-binding.

It is important to remember that the results of these meeting are non-binding. Changes related to new FDA findings, changes to FDA personnel, and new data related to your specific device type may all impact the FDA provided feedback. Therefore, it is critical that you get the most out of these meetings and much of that will be contingent upon the quality of your questions and supporting documentation.

If the submission is primarily for a drug/biologic, then the sponsor can request a meeting with the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). Depending on the development stage, sponsors may request Type A, B, or C meetings. Type A meetings assist in moving stalled product development programs forward. Type B meetings allow for the scope and design of clinical testing to be discussed. If there is other information that needs to be discussed that is not discussed in either a Type A or B meetings, a Type C meeting with CBER or CDER can be requested.

When the combination product is device-led, a sponsor may request a meeting with Center for Devices and Radiological Health (CDRH) and request to add representatives from the appropriate drug center. Furthermore, the FDA also has recommendations for their Q-Submission (Q-Sub) program. The Q-Sub program recommendations provides guidance for several submissions including but not limited to Pre-Submissions (Pre-Subs), Submission Issue Requests (SIRs), and Study Risk Determinations. A Q-Sub meeting is requested primarily when a sponsor is focusing on the device instead of a drug/biologic.

 Come prepared.

It is critical to come prepared with quality questions and supporting documentation and to ensure the correct reviewers at the FDA attend these meetings. Most often the meeting request will go to the center that has primary jurisdiction over your product based on the primary mode of action. However, it is not uncommon or unreasonable to request other subject matter experts from other centers attend to address questions related to that center. For instance, a biologic filled autoinjector may have CDER as the primary reviewing center, however, if questions related to break loose and extrusion forces are to be discussed, a sponsor could request CDRH attendance as well. The requested attendees from the FDA should be clearly stated in your meeting request.

The reality is that if you don’t know the structure of the FDA, you should be engaging an expert to help ensure the right attendees. The FDA usually grants the request unless they feel it is unnecessary or redundant.

STOP #3: Write An Effective Request For FDA Feedback

It is possible to request an in-person or teleconference meeting or written feedback from the FDA. However, it is important to keep in mind that it may not always be necessary to schedule a meeting with the FDA and, therefore, it would not be an efficient use of your organizations time and resources. When a Type A, B, or C meeting is not appropriate, it may be appropriate to request written feedback when seeking clarity for your program. No matter if you are receiving written feedback from the FDA or requesting a meeting, the inputs should be clear regardless as suggested by the 4 tips for writing effective FDA Requests for Feedback provided below.

Gather All Relevant Inputs

When a movie receives acclaim or rejection, it is generally the director that basks in the glory or the shame. However, film production includes more than the director – producers, actors and actresses, screenwriters, costume designers, special effects technicians, cameramen, composers, etc. When these teams work together as a seamless unit, film magic comes to life. We also see this in medical device manufacturing. There are also a lot of people and teams that influence product success – company executives, department managers, designers, engineers, regulatory affairs specialists, quality systems specialists, and human factors experts. All of these parties play a role in the collection and dissemination of information that drives the manufacturing process and ultimately crafts the history of the product’s manufacturing lifecycle. Therefore, a medical device manufacturer must rely on inputs from many teams when making a submission to a notified or regulatory body such as the FDA.

Develop Well Thought Out Questions

As we noted previously, the feedback provided by the FDA is non-binding. To ensure you receive the best answer from the FDA, we recommend that you do not ask for approval for your plan, rather ask for agreement. To many this may sound like the same thing, but when it comes to semantics, a slight change in language can be the difference. Additionally, do not leave open ended questions. You want the FDA to agree with your proposed strategy. Open ended questions may lead the FDA to implement their own most desired strategy, which may be far more burdensome than you had hoped.

 Bad Example: We are conducting a usability study for a home-use autoinjector. How many participants are needed to complete the study?

 Good Example: We are conducting a human factors summative usability study on an autoinjector for treating allergic reaction. The summative protocol has been provided in Appendix A. This autoinjector will be used for thigh injections and is intended for home use. Per current FDA guidance, we expected to enroll 15 participants in each of three arms of the study for a total of 45 participants. Does the FDA agree that use of the current guidance would be sufficient for the provided summative study?

Provide The Appropriate Supporting Data

Sticking with our movie-making analogy, the key to writing successful documents for the FDA is to author a fully developed storyline for your product. The storyline provides the context, data, and justifications to support your position or to lead the FDA reviewer down the desired path. The FDA is inundated with requests and submissions and will not have time to conduct its own fact-finding mission. It is up to the sponsor to provide the FDA with the necessary information. And, the more information the FDA receives about the product and the procedure, the more informed feedback they are going to be able to provide. Providing the appropriate data also builds trust and transparency with the Agency.  Asking the FDA questions without providing any details of your product or plan is similar to asking your doctor for advice on how to improve your health without providing any information on symptoms, diet, fitness routine, etc.

To provide the most accurate feedback, the FDA needs as much information as possible. If the FDA does not have enough information about your project to answer’s a sponsor’s questions, the agency will likely take the most conservative approach. It is the responsibility of the sponsor to make a compelling case for your strategy, and for the FDA, that means providing strong scientific logic supported by compelling data.

 Bad Example: We plan on conducting stability testing on the unpackaged prefilled autoinjectors at time points X, Y, and Z. Does the agency find this acceptable?

 Good Example: We have performed validation studies on the packaging process and have assessed the packaging materials.  … [Make sure to summarize your results here] … Using this data, and following our risk management process, we have determined that the packaging and labeling of the autoinjectors does not significantly impact on the long-term stability of the drug product (see Appendix A – Packaging Process Validation Report) relative to our previously collected data. The validation data supports the use of unpackaged autoinjectors for ongoing stability studies. As a result, we plan to conduct ongoing stability studies at time points X, Y, and Z per current FDA guidance with devices that are not packaged in the final carton configuration. Does the agency find this strategy acceptable?

Do Not Leave An Opportunity For The FDA To Ignore The Actual Question

The purpose of requesting feedback from the FDA is to receive guidance or clarification for your project. If you ask more than one question at the same time, the FDA may get confused about what you are asking and may not answer all of your questions. The FDA has limited resources and may not have time in the meeting to answer many multifaceted questions. Prioritize your most critical questions and make those concise in scope to ensure the FDA provides a response that adds value to your program.

 Bad Example: We plan to terminally sterilize the product utilizing Ethylene Oxide (EtO) sterilization.  Is the sample size noted in Report A appropriate? We have sourced an alternative biological indicator (BI) not used in our initial sterilization validation. Does the FDA agree that the justification provided for the BI in Report A is appropriate? The sterilization process parameters have been slightly modified from the original filing.  We are current in the process of revalidating the process (see protocol in Appendix B). If the results are positive, will the FDA agree to modification of the process parameters without an additional notification?

 Good Example: Due to a supply issue, we have selected an alternative biological indicator (BI) for use in the revalidation of our sterilization cycle with modified sterilization parameters. The BI has been qualified and the results are provided in Appendix A. Does the FDA agree that method and results of the qualification of the BI are acceptable for use in the validation of the new sterilization cycle?

As previously mentioned…

The FDA provides guidance related to the many aspects of product and process development, but it is the responsibility of the sponsor to integrate the necessary procedures needed to successfully gain product clearance or approval.

The key to a successful submission to the FDA is having an informed and experienced team on your side. If your organization needs any support with your FDA interactions, Suttons Creek’s quality and regulatory experts have the knowledge and experience to help.

Co-Author: Rob Schulz, Consultant – Rob has over 18 years of multifunctional FDA regulatory experience with 16 years of Management experience and 12 years of Global Quality and Regulatory Affairs experience. Rob has hands on experience in Quality and Regulatory compliance for Class I, II, and III, devices including combination, IVD/companion Diagnostics, sterile, software, and implantable products for both design and manufacturing. As a thought leader, Rob has leveraged his vast project management, leadership and combination product experience to build effective teams, drive and deliver projects on time and trouble shoot challenges to execute projects. LinkedIn: Rob Schulz

Co-Author: Matthew Nare, Consultant – Matthew Nare is a junior consultant on the human factors team for Suttons Creek, Inc. His previous work as a physical therapy aide provided an opportunity to gain clinical experience in inpatient and outpatient rehabilitative care settings. He came to Suttons Creek, Inc. following an internship completing clinical observational research with MedStar Health’s National Center for Human Factors in Healthcare. Additionally, he spent over a year completing accessibility evaluations at Cal State Long Beach’s Center for Usability in Design and Accessibility. This combination of work experience and his educational background provides him with a unique perspective on how the medical devices and their users function. LinkedIn: Matthew Nare