Product development can be broken down into a sequence of activities, with the result of the previous step dictating the move forward to the next step.
Complete product redevelopment may be needed if there are fundamental CMC deficiencies at an early stage as a regulatory deficiency in an early stage will carry forward into all later stages.
Opportunities are created during FDA meetings for sponsors to identify gaps in required data, seek out vital agency feedback and come to an agreement on whether the development studies that have been performed are sufficient for FDA review.
Image Credit: DSI, a PLG Company
Once the investigational (IND) or marketing application (NDA/BLA) is submitted, these meetings also give sponsors the chance to educate the FDA about their product so that reviewers have a basis of background and understanding.
This background is especially useful with new compounds that are being developed with innovative mechanisms of action or cutting-edge technology, which may not be familiar to agency officials.
It takes preparation, experience, planning and 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, each corresponding to a different milestone in drug development. Each has a different agenda because each meeting takes place at a different point in the drug development process.
The main aim of each is to gather critical feedback from the FDA, however, so that sponsors are more prepared to move on to the next phase in development.
Pre-IND meetings aim to confirm that the drug formulation, nonclinical studies and chemistry, manufacturing and controls (CMC) are enough to support FDA’s approval to move forward into the clinic.
End–of–Phase–2 meetings give sponsors the chance to update the FDA on Phase 1 and 2 results. They also help to gain clarity regarding issues and questions related to potential Phase 3 pivotal development work.
Pre–NDA/BLA meetings provide sponsors with the chance to supply the FDA a preview of Marketing Application contents and come to an agreement with the agency regarding any challenges which may arise in the drug development process.
These issues could range from the results of pivotal studies and CMC operational updates to how the drug development data is produced and summaries should be formatted.
2. Be sure you have the right individuals at the meeting table
Sponsors should carefully select the representatives from their team who will attend when planning for an FDA meeting. All of the meetings should be attended by the person who has been interacting with the FDA throughout the drug development process, the sponsor’s regulatory lead.
Other sponsor participants will depend on the types of questions asked in the meeting packet and FDA preliminary responses which will be discussed during the meeting. For instance, it is important that your CMC lead is present if you are planning to ask CMC-related questions.
A non-clinical representative and one or two clinical representatives, for example the physicians who are responsible for developing clinical efficacy for studies, should be included for overall program discussions.
Some sponsors make the common mistake of including senior executives in FDA meetings, even when those executives do not possess the appropriate hands-on scientific experience with the compound to discuss the type of highly technical issues that are likely to be discussed.
That mistake can be avoided by only including meeting attendees who are working on the development of the specific drug in question directly. They are the most likely to have the best working knowledge of the product and to be able to answer technical questions effectively.
That said, it is best if meeting attendees also have prior experience meeting with the Agency. This is so that they are comfortable, know what to expect and are able to guide the meeting effectively.
In instances when a meeting participant has limited, or no experience meeting with the FDA, for additional support it is appropriate to send their director, manager or a key consultant with intimate knowledge.
It is a good idea to seek out regulatory authority advice as the regulatory authority could require much more to be done than is currently scheduled. It is also worth considering what impact that would have on the corporate-determined marketing submission date.
Sponsors must understand that it is about involving the regulatory authority as a team player, it is not about a company believing that it knows more about its process and product than the regulatory authority.
It can only be advantageous for a company to ensure that the reviewer clearly understands the science behind the manufacturing process and product, as ultimately, the regulatory authority controls the drug product's fate.
3. Practice and preparation are key and don’t let time get away from you
Advance preparation, planning and punctuality are key to benefit the most from your meeting. Plan to arrive in town at least a full day ahead of time if you are traveling from out of town.
In addition, it is good 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 valuable time with the agency is not lost.
Another helpful practice is scheduling a pre-meeting the day before your FDA meeting. The agency will have supplied you with preliminary written responses to the questions asked. You will have already identified the specific preliminary responses you want to discuss with the FDA, in advance, by the time you get to the in-person meeting.
If some of the FDA’s written responses supply all the direction and clarity required then it is unlikely that you will need to spend valuable meeting time reviewing them. The majority of your meeting time will be focussed on questions or other areas where additional clarity is needed.
Agree in advance on how you want to approach each question and be sure to identify which team members will be responsible for taking the lead with the agency on each question.
The FDA will set a certain amount of time for each meeting and the meeting is usually over promptly when that time is up. That means you need to make the most of every minute.
Be sure to let the agency know in advance which preliminary responses are the most important for you to discuss, and ask that those are discussed in the order of priority.
Make sure one of your team members (preferably someone other than the person leading the meeting) is tasked with checking the time to ensure all responses are discussed within the meeting’s time limit. That person should notify the group to keep the meeting on task if too much time is being spent on one specific response.
4. Make sure you ask the right questions in the right way
Communication is the most important skill to develop and when interacting with the FDA, this is doubly true. Listening is not haphazard, you are likely interested in listening for certain information. This means that you must ask the right question and at the right time in order to communicate well.
The wrong question is almost guaranteed to give the wrong answer. The right question asked while there are pressing distractions, at the wrong time in the wrong context, asked of the wrong person, is equally as useless.
Below 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 dosage forms/formulations used in PK/PD, Tox, Clinical studies conducted to date
- Impurities
- Linkage to toxicology batches
- Batch data
- Qualification of impurities (update in phase 1/phase 2)
- Enantiomers, polymorphs, or other unique physicochemical properties
- Reasons for selection, physicochemical properties of various forms, stability
End of Phase 2 (EoP2)/ Phase 3
- Agreement on starting materials
- Complete information on s.m. such as synthesis scheme, DS data, specifications, fate and removal of s.m. impurities, s.m. impurities,
- Placebo/Comparator Information
- Blinding information (appearance, smell, taste etc)
- Over-encapsulation issues (e.g. dissolution)
- Composition, controls and manufacture
- Stability protocols for Phase 3 and NDA/BLA
- 6 months accelerated, 12 months long term
- Assay/Potency
- ***Fermentation derived products, botanicals, biologics,
- Dissolution
- 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
Phase 3
- General approach to specifications
- Specs are reviewed and finalized during NDA/BLA
- Anticipated manufacturing site changes
- Impact of change (Equipment, product quality, process/parameters etc.)
- 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
- Delivery System or Devices
- Particularly for pen injectors, inhalers, novel forms, transdermals, etc
- May recommend Ph 3 and marketed device be same
Perhaps the most important thing to remember is that FDA reviewers are people and they really do want to help you and your product move forward.
Common courtesies such as being on time, being well prepared and being organized can go a long way in ensuring that each meeting ends with you having all the information needed to develop your drug further.
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.
About DS InPharmatics LLC
DS InPharmatics (DSI) provides regulatory, technical, and project management consulting services to healthcare product companies that manufacture and/or market pharmaceuticals, biopharmaceuticals, and cellular and gene therapy products.
Since 2007 we have provided our clients with innovative strategies and exceptional quality work products intended to enhance product development, approval, and marketing presence. Whether advocating CMC strategy, directing CMC operations or developing CMC submission content that represent the best interests of emerging biotech, we focus on the critical CMC issues and build programs that enhance development.
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