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How To Respond to Health Authority Questions

Your biotech company has just submitted the marketing application for your first drug product. It’s a moment of celebration after years of hard work! But you know that the reviewers’ questions could arrive within weeks. Now what? 

Replying to Health Authorities’ questions can be your greatest challenge in the drug approval process. The Applicant must prepare appropriate responses to each question, usually within a limited time. In the case of simultaneous submissions in worldwide markets, these responses to multiple Agencies must occur in parallel. This process can be daunting for any pharmaceutical company and requires effective planning before receiving any questions. 

The questions posed can be similar across countries and regions. However, when regulators issue questions after dossier submission as well as the response timeframe can differ (see Table 1). These regional differences are important when planning responses to Health Authority questions. 

Table 1. Regional Differences in Timings for Responding to Health Authority Questions During Dossier Review 

Timing EMA (EU)FDA (US)
Receipt of Questions from Healthy Authority On Day 120 and Day 180 after the dossier submissionAny time after dossier submission up to the end of the review period 
Provision of Responses by Applicant 3 months for Day 120;  
1 month for Day 180 
Days or weeks depending on the complexity of the question(s) 

The Response Team 

Submission of your marketing application is the end of a long and arduous process. But it’s just the beginning of the regulatory response process. Even before submission, many companies initiate planning and preparation for responding to Health Authority questions. 

The first step in planning is to form the Response team. It is also important to make sure that enough resources are available. The team should have clearly defined roles and responsibilities.  

Ideally, the same team that prepared the application should be members of the Response team to answer questions from the Health Authorities about the dossier. Often submission teams are exhausted from developing the marketing application documents and their attention quickly turns to other projects. Don’t disband the submission team after they submit the application! Prioritize the response work for key individuals from each function. Holding regular meetings will help to keep the Response team focused on the postsubmission activities. Starting these meetings before the application submission but after the peak of the application submission activities, works well. 

Response Timelines 

The team needs to agree on timelines for drafting and finalizing the Responses. However, planning timelines for responding can be challenging. This is particularly true for applications to the FDA. These reviewers can pose questions any time from shortly after submission until the end of the 6- to 10-month review (see Figure 1).  

The timeline for responding also varies, depending on the complexity of the question. It can range from days to weeks. The team therefore needs to be very reactive in answering the questions, and available at extremely short notice. Within 24 hours of receiving a question, the Regulatory team should review and share it with the rest of the Response team.  

Identify back-ups for all functions for any possible schedule conflicts. Don’t forget to consider team members’ planned vacations, holidays, and professional society meetings.  

The timing of questions after the submission of the dossier is more predictable for applications to the EMA (see Figure 2). It’s typically three months for questions received on Day 120 and one month for questions received on Day 180. However, planning should consider situations like receiving FDA questions during the peak development stage of EMA responses. 

Regulatory Response Tracker 

When preparing the application dossier, document any gaps or perceived weaknesses that may trigger questions from the assessors. A tracking spreadsheet, organized by topic area (e.g., Nonclinical, Quality, Clinical Efficacy, Clinical Safety) is a useful tool for capturing potential questions. 

When formal questions do start to arrive, add them to the tracker. Use this tracker to monitor the status of each question from receipt through to drafting, completion, and publishing. Tracking the progress of each question is important. The medical writers will likely draft numerous responses in parallel in a short time frame.  

This tracker will also become a critical reference for any future submissions to other countries. You’ll also use it for continued interactions with the initial health authorities (e.g., EMA and FDA). So, maintain the tracker and keep it available. 

Response Strategy 

In my experience, preparing answers for expected questions is not very useful. Even small changes in the questions can make your preparation pointless. Instead, spend this time ensuring all the sources you might need to access from the submission are readily available.  

Identify and assemble existing relevant response information that can be re-purposed, such as Regulatory responses in other regions. The team should brainstorm on the strategy for answering any anticipated responses and record bulleted notes. Any of the potential questions that would require additional analyses should be identified at this stage  

For EMA submissions, the initial assessment report (received on Day 80) will suggest the questions that can be expected on Day 120. The joint assessment report received on Day 157 is a preview of the likely outstanding issues adopted by the CHMP on Day 180.  

In the US, the FDA’s Day 74 letter also provides foresight into the types of questions to expect. This enables your team to focus their response strategy on the most likely questions. This letter also helps teams estimate the potential workload required for responses. 

Figure 1. Overview of FDA (NDA/BLA) Review Timeline 

Figure 2. Overview of EMA (MAA) Review Timeline 

Response Logistics 

Before you receive Questions, prepare a template for the format of the Responses. For applications in the EU, this must be consistent with the specific EMA template. The FDA does not have a formal template. Thus, I recommend matching the format of the drug application dossier.  

Notably, multiple regions may accept some of the same response content. So, writers can author individual responses once and then compile them into responses to different Health Authorities. Follow the Regulatory Documents Style Guide and Lexicon used for the application. Use the same naming conventions for cross-referencing to a source.  

Establish document management systems for the response writing before the questions land. All necessary team members should have access to file authoring and storage areas. Using the same authoring, review, approval, and publishing processes for the Responses as for the initial application will let the team focus on the Responses and ensure everything runs smoothly. 

Conclusions: Early preparation is key! 

Responding to Health Authorities’ questions during their review of your marketing application can be the greatest challenge in a drug’s approval. Regional differences in issuing questions after submission, and regulators’ expectations for rapid responses only add pressure. With the right planning, your team can deliver high-quality responses on time. 

If you need help responding to health authority questions, our regulatory submissions leadership team can help. To learn about how to develop a submission to the FDA and EMA simultaneously, watch this webinar. 

About the author

Dr. Natalie Brine
By: Dr. Natalie Brine

Dr. Natalie Brine has a research background in pharmacology and over 20 years of experience in the medical/regulatory writing field. During her writing career, she has led a wide range of projects, encompassing submission-level, study-level, and drug safety documents as well as briefing packages and responses to regulatory questions. Dr. Brine has worked in multiple therapeutic areas, including autoimmune disease, allergy, cardiology, cell-based medicinal products, dermatology, endocrinology, gastroenterology, neurology, oncology, respiratory, urology, and wound healing.

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