Product development is mainly a sequence of activities. Moving forward to the next step depends upon the result of the previous step. Fundamental CMC deficiencies at an early stage may require complete subsequent product redevelopment. A regulatory deficiency in an early stage will therefore carry forward into all later stages.
The FDA meeting provides opportunities for sponsors to seek out critical agency feedback, identify gaps in required data, and come to an agreement on whether the development studies that have been conducted are sufficient for FDA review. These meetings also provide sponsors the opportunity to educate the FDA about their product so that reviewers have a basis of background and understanding once the investigational (IND) or marketing application (NDA/BLA) is submitted. This background is particularly helpful with new compounds that are being developed with cutting-edge technology or innovative mechanisms of action, which may not be familiar to agency officials.
That said, it takes experience, preparation, planning as well as an understanding in both directions to ensure sponsors get the ultimate benefit from each meeting.
1. Understand the purpose of the three main types of FDA milestone meetings.
There are three types of FDA meetings – and each corresponds with a different milestone in drug development. Because each meeting takes place at a different point in the drug development process, each has a different agenda. However, the main purpose of all three is to gain critical feedback from the FDA, so sponsors are more prepared to move on to the next phase in development.
- Pre-IND meetings aim to confirm that the nonclinical studies, drug formulation, and chemistry, manufacturing and controls (CMC) are sufficient to support FDA’s approval to move forward into the clinic.
- End–of–Phase–2 meetings provide sponsors the opportunity to update the FDA on Phase 1 and 2 results, and gain clarity related to questions and issues related to potential Phase 3 pivotal development work.
- Pre–NDA/BLA meetings offer sponsors the opportunity to provide the FDA a preview of Marketing Application contents and come to an agreement with the agency regarding any issues that may arise in the drug development process – ranging from the results of pivotal studies and CMC operational updates to how the drug development data generated and summaries should be formatted.
2. Be sure you have the right individuals at the meeting table
When planning for an FDA meeting, sponsors should carefully select the representatives from their team who will attend. All meetings should be attended by the sponsor’s regulatory lead – the person who has been interacting with the FDA throughout the drug development process. Other sponsor participants will depend on the types of questions asked in the meeting packet and FDA preliminary responses that will be discussed during the meeting. For example, if you are planning to ask CMC-related questions, it’s important that your CMC lead is present. For overall program discussions, you’ll also want to include a non-clinical representative and one or two clinical representatives, such as the physicians who are responsible for developing clinical efficacy for studies.
Some sponsors make the common mistake of including senior executives in FDA meetings, even when those executives don’t have the appropriate hands-on scientific experience with the compound to discuss the type of highly technical issues that are likely to be discussed. Avoid that mistake by only including meeting attendees who are directly working on the development of the specific drug in question. They are the most likely to have the best working knowledge of the product and to be able to effectively answer technical questions.
That said, it is best if meeting attendees also have prior experience meeting with the Agency — so they’re comfortable, know what to expect, and can guide the meeting effectively. In cases when a meeting participant has no or limited experience meeting with the FDA, it’s appropriate to send his or her manager or director or a key consultant with intimate knowledge for additional support.
Seek out regulatory authority advice. What if the regulatory authority wants much more to be done than is currently scheduled? What impact would that have on the corporate-determined marketing submission date? Sponsors must understand that it is not about a company believing that it knows more about its process and product than the regulatory authority; it is about involving the regulatory authority as a team player. Since the regulatory authority ultimately controls the drug product's fate, it can only be an advantage for a company to ensure that the reviewer dearly understands the science behind the manufacturing process and product.
3. Practice and preparation are key and don’t let time get away from you
In order to get the most benefit from your meeting, advance preparation, planning, and punctuality are essential. If traveling from out of town, plan to arrive in town at least a full day ahead of time. You’ll also want to arrive at the meeting location at least 45 minutes ahead of time to allow time for check-in. These common-sense preparatory tactics can help ensure you don’t lose any valuable time with the agency.
Scheduling a pre-meeting the day before your FDA meeting is also a helpful practice. The agency will have provided you with preliminary written responses to the questions asked. By the time you get to the in-person meeting, you will already have identified the specific preliminary responses you want to discuss with FDA, in advance. If some of the FDA’s written responses provide all the direction and clarity you need – you likely don’t need to spend valuable meeting time reviewing them. You’ll want to focus the majority of your meeting time on questions or other areas where you need additional clarity. Be sure to identify which of your team’s participants will be responsible for taking the lead with the agency on each question and agree in advance on how you want to approach each question.
The FDA will allot a specific amount of time for each meeting – and when that time is up, the meeting is usually over, promptly. That means you need to make the most of every minute. First, be sure to let the agency know in advance which preliminary responses are the most important for you to discuss, and request that those be discussed in the order of priority. Also, make sure one of your team members (preferably someone other than the person who’s leading the meeting) is tasked with watching the clock to ensure all responses be discussed within the meeting’s time limit. If too much time is being spent on one specific response, that person should notify the group to keep the meeting on task.
4. Make sure you ask the right questions in the right way
There is an old adage that says one should seek to understand before seeking to be understood. I say, we have two ears and only one mouth for a reason because we need to listen twice as much as we speak. Communication is the most important skill to develop and this is doubly true when interacting with the FDA. But listening isn’t haphazard. You are likely interested in listening for specific information. This means that in order to communicate well, you need to ask the right question and ask it at the right time. The wrong question is almost guaranteed to generate the wrong answer. The right question asked at the wrong time in the wrong context, while there are pressing distractions, asked of the wrong person is equally useless.
Here is a framework for asking the right “CMC” questions at the right time to create clarity and agreement around issues and to gain binding agreement;
Pre-IND/ Phase 1
- Link formulations/dosage forms used in Tox, PK/PD, Clinical studies conducted to date
- Polymorphs, enantiomers, or other unique physicochemical properties
- Reasons for selection, stability, physicochemical properties of various forms
- Batch data
- Linkage to toxicology batches
- Qualification of impurities (update in phase 1/phase 2)
End of Phase 2 (EoP2)/ Phase 3
- Agreement on starting materials
- Complete information on s.m. such as synthesis scheme, specifications, s.m. impurities, fate and removal of s.m. impurities, DS data
- ***Fermentation derived products, biologics, botanicals
- Placebo/Comparator Information
- Over-encapsulation issues (e.g. dissolution)
- Blinding information (appearance, taste, smell,….)
- Composition, manufacture and controls
- Stability protocols for Phase 3 and NDA/BLA
- 12 months long term, 6 months accelerated
- Discuss dissolution method development at EOP2, if not earlier. Earlier the better
- Approach for setting specification
- Gather complete profile data from bio batches (PK & clinical) and registration/stability batches
- Specifics vary for Immediate, Extended, Controlled Release and Enteric-Coated products
- Extended Release (ER)
- If ER claim appropriate
- General approach to specifications
- Specs are reviewed and finalized during NDA/BLA
- Anticipated manufacturing site changes
- Impact of change (Equipment, process/parameters, product quality,..)
- pre NDA stage often too late for discussion of Ph 3, registration stability, and commercial site changes
- Issues related to sterility and sterilization process validation
- Devices or Delivery System
- Particularly for inhalers, pen injectors, transdermals, novel forms, etc
- May recommend Ph 3 and marketed device be same
Perhaps most importantly, remember that FDA reviewers are people, just like you. And they really do want to help you and your product move forward. Extending the common courtesies of being on time, well prepared, and organized can go a long way in ensuring that you leave each meeting with all the information you need to further develop your drug. And tapping regulatory experts – with proven experience in communicating with the FDA – to lead and help you plan for meetings with the agency can also give you the peace of mind of knowing that your time together will be well spent.