In this installment of this quarterly column, we’ll discuss some key issues that tie into strategic planning for regulatory meetings, with a focus on the FDA Pre-Investigational New Drug (pre-IND) meeting for drugs and biologics. The pre-IND meeting, or PIND, with FDA is a critical milestone for development companies prior to filing the IND, the approval of which allows the conducting of your first clinical trial. Here, we’ll focus on how the meeting feeds into business planning, development strategy, fundraising process and key elements we’ve found useful to keep in mind after years of supporting clients and partners through this process.
We are fortunate in ophthalmology to have ophthalmologists as clinical reviewers at FDA, and a review team that has been very open to meeting with sponsors at any stage to provide guidance and recommendations. The Division of Ophthalmology is part of the Center for Drug Evaluation and Research (CDER), which reviews trial programs involving small molecules, peptides, antibodies, fusion proteins and the like as active pharmaceutical ingredients (APIs). Gene therapies, cell-based therapies, tissue-based therapies and the like are reviewed by the Center for Biologics Evaluation and Research (CBER). Furthermore, over-the-counter products are reviewed by a separate division within CDER—the Office of Nonprescription Drugs. Generic products are reviewed in the Office of Generic Drugs. Despite the different divisions, the clinical review team from CDER’s Division of Ophthalmology is generally consulted for PIND meetings and reviews across the other CDER and CBER divisions to ensure consistency on approach for clinical requirements, treatment endpoints, data review, etc.
Our discussion will look at the “When, What, Why and How” of this process. The key question we often receive from new entrepreneurs and start-ups is “When should we meet with the FDA?” The answer to this depends on what you want to ask the FDA and accomplish with the meeting. In addition, the follow-up question that actually helps you address the “How” of the process is, “When will you be ready for the meeting?”
When to Meet with the FDA
Let’s start by answering the question of why you want to see the FDA and/or what you want to accomplish by meeting with the agency. The reason will usually fall into one or more of the following categories:
• for increased clarity before moving ahead in the near term with certain IND-enabling activities (such as toxicology, PK or formulation/manufacturing);
• to clarify development plans and budgets for preparing financing through the IND and your planned clinical trial(s);
• to de-risk development pathways and confirm development plans and budgets for a follow-on future round, such as a Series B to cover clinical studies;
• to help in discussions with investors or answer questions from your board prior to funding the next stages (or for later programs, questions that you will receive from strategic partners, and especially end-of-Phase-II meetings to plan for Phase III); or
• questions with answers that have strategic value, or will help with overall conceptualization of the future program.
What Are You Going to Ask the FDA?
Here are some general examples of the types of questions entrepreneurs typically have. Hopefully this sparks some thoughts on what you may want to ask. (This isn’t an exhaustive list.)
• Questions related to Chemistry, Manufacturing and Controls (CMC):
— are the planned specifications for the proposed product appropriate?
— adequacy of the starting material for the API (the active drug ingredient);
— manufacturing process for first-in-human POC/Phase I, compared with later stages of development;
— approach to sterility, discussion on container closure system for the first trial; and
— qualification and support for a new ingredient in the formulation, or new component to the product.
• Toxicology-related questions. A final determination on the toxicology requirements will come down to formulation, nature of the excipients, how much drug is being released (e.g., in cases involving drug delivery), how you plan to correlate data on the drug pharmacokinetics and ocular and systemic levels of the drug, with known preclinical and clinical safety data (i.e., the safety margins), etc. Thus, the more information you have to provide in your meeting briefing package, the more specific the confirmation can be on various requirements for your program.
Here are some common topics for questions:
— The need for a single or two different species. Two species are typically required for local ocular toxicology. For those new to ophthalmology development, rats and mice aren’t acceptable species for GLP ocular toxicology because their ocular anatomy isn’t sufficiently similar to a human’s (although they still can be used for systemic toxicology with systemic administration). We get this question often from new start-ups. Species selection is also based on cross-reactivity of biological products. For example, humanized antibodies may only be cross-reactive in primates.
— If your product is being repurposed from a currently available drug, it’s possible that a single species may be appropriate to suggest. But this is situational and a good question for the pre-IND meeting.
— Changes in formulations of existing ophthalmic products may also impact the need for new toxicology studies. The key is if the change in formulation is expected to impact the drug absorption or pharmacokinetics and thus the safety profile of the product.
— Dosing plan for the first clinical trial(s) which will be supported by the toxicology testing.
— For a sustained-release product, the length of toxicology required to support the intended release period of the delivery system in the planned first clinical trial, and relation to the animal PK data. Also, the appropriate dosing frequency required in the toxicology to support the intended dosing regimen in the clinical trial(s).
— General planning for subsequent development, including Phase III studies, based on assumptions from your early toxicology and clinical trials.
— Strategies for incorporating the interim sacrifice of animals and interim reports from your toxicology studies to support an earlier filing of your IND and the start of clinical trial dosing while the full toxicology study is being completed.
• Clinical-related questions:
— questions about endpoints, patient selection, sub-groups, and duration of follow-up;
— requirements for the safety database which may be different from the treatment and follow-up needed for efficacy; (in some situations, the FDA will ask to see follow-up data after dosing cessation);
— confirmation of statistical analysis plans;
— If this a new indication with no currently approved drug and thus no precedent for what has been previously required for safety or efficacy, are you ready to discuss approvable endpoints at the PIND meeting? Sometimes this may be best done in more detail at the end of a Phase II (EOP2) meeting to plan for Phase III, once you have clinical data in hand. But at least you can use the PIND meeting to get insights into the FDA’s thinking and approach. Keep in mind, the agency follows the “So what?” test—i.e., what impact does your product have on visual function and daily living? You can review your validation plan for novel endpoints.
— the best approach to powering non-inferiority, clinical equivalence or bioequivalence studies. It’s wise to review your approach to the statistics, related confidence intervals and the potential need for vehicle control arms early on in your planning, as this will drive the number of patients required, and ultimately the budget needs, for your trials.
— the best approach to first-in-human studies. Is there a need for a traditional Phase I safety study (and appropriate dose escalation), or can you go straight into Phase II in target patients with efficacy assessments? You could review possible approaches to a first clinical trial that’s a combined Phase I/II with two parts: Part I being safety and Part II being dose expansion into a randomized study.
The follow-up question you need to then ask is, “Do we have enough information to ask the question we want to ask?” and “When will we have that information?” That will then drive the “When” for submitting a request for a meeting. There’s no magic answer about when to meet; some companies go in very early while others choose to go post-funding with a lot of data and a package that almost resembles a full IND. When you choose to meet is just a matter of what your objective is and what’s most appropriate for your program.
Typical Steps for Pre-IND Meetings
The meeting request will have initial draft questions, so the FDA can ensure that the appropriate reviewers attend (you’ll submit your final questions in your briefing package). It’s key to keep in mind that once the meeting date is scheduled, the full briefing document is to be submitted one month prior to the meeting; it needs to have sufficient information to support the questions and level of specificity you want from the FDA. Often, we see companies who initially want to rush to request a meeting so they can say to investors that they have a meeting on the books. This isn’t always advisable. Before doing something like that, make sure you have a list of the questions to ask, and that the information for your briefing package will be ready in time for the deadline to get it to the agency.
In conclusion, we hope this summary helps you structure the thought process involved with the pre-IND meeting process and provides a few pearls to consider. The answer to, “When do we meet with the FDA?” is based on your specific program, and available information and data to support your intended agency queries. The best advice: “Don’t request a meeting with the FDA too early, and don’t meet with the agency too late.” REVIEW
Mr. Chapin is a senior vice president of corporate development at Ora, which offers drug, biologic, and device consulting, clinical research, and development strategy and support to catalyze new client and partner initiatives. The author welcomes your comments or questions regarding product development. Please send correspondence to firstname.lastname@example.org or visit www.oraclinical.com.
Review and comments on this column were supported by Aron Shapiro, a senior vice president in the corporate development group at Ora.