The first column in this series discussed the importance of “beginning with the end in mind” and creating the target product profile early in the development process ( See March 2013, p. 6). This is critical to help define product strategy early and guide preclinical and clinical approaches. This installment will address another key question that early companies or new physician-entrepreneurs commonly ask: “When do I go to meet with FDA?” The regulatory perspective from the Food and Drug Administration is a key input in defining the overall development strategy.

The general guidance is to meet with FDA early, and always transparently. The balance is between going to confirm plans early, or waiting for a later meeting to bring further data in hand. The ophthalmic division at FDA is very open to early discussions in order to help guide the product strategy; it is grounded in clinical science and focused on helping sponsors to be as efficient as possible. The division will raise items that will be very helpful to consider during development. For the clinical study, it is desirable to submit a detailed clinical protocol with full design, inclusion/exclusion criteria, endpoints, visit schedule, details of the clinical scales, and statistical analysis plan for FDA review. This will ensure the most complete feedback from FDA, as opposed to providing them just a brief summary outline.

Here are some brief key considerations to help decide when it may be appropriate for the pre-IND meeting with FDA, which precedes and helps shape the preparation of the IND (Investigational New Drug Application) that must be submitted to FDA prior to initiation of clinical trials. Addressing this question also draws us closer to some key issues encountered during early development, specifically in the areas of toxicology and formulation/CMC (chemistry, manufacturing and controls), and can help avoid costly delays.

Sometimes a specific pharmacology study is put on the critical path for meeting with FDA. However, in shaping the early discussion with FDA, it is important to balance what might just be interesting to include or test in a preclinical efficacy or pharmacokinetic study, with what will impact decision making. Will this change whether we move ahead, or which lead drug to select to move to IND-enabling studies? Will this study definitively help us to chose a formulation, etc.?

Once preclinical proof of concept is obtained, from the perspective of the timing of a regulatory discussion, the key outcome of these studies—dose selection, route of administration and potential pattern for use—feeds into the pre-IND discussion. Beyond that, the focus and need is safety.

Early interaction in the form of a pre-IND meeting can uncover answers that help the design of the toxicology program. For example, how many species are required? Is the proposed dosing sufficient? And how can the studies be streamlined? While generally two species are required with ocular toxicology for a new IND, if the drug is being repurposed from a non-ocular area in which significant systemic data is already available or human data exists, it may be possible to reduce the program to one species and reduce the systemic assessments. In that case, meeting early can save the company from expending resources that can be used elsewhere. If the compound is a reformulation of an existing ophthalmic product, it’s preferable to confirm as early as possible the question of any further GLP ocular toxicology being needed, or whether it is reasonable to reduce the number of animals or treatment arms required. Even a short-term GLP ocular toxicology study of 14 to 28 days in duration of dosing will take several months when considering start-up and reporting by the laboratory. Further, when systemic toxicology is an open question, having at least some information on systemic absorption following ocular dosing will help define the safety margin and ability to use and bridge to existing systemic toxicology, making the discussion with FDA most productive.

It is important for early-stage companies to recognize that you also want to enable the FDA to answer the question as completely as possible. For example, if the intent is to obtain general guidance from FDA on the approach to toxicology, and there are other strategic reasons to go early, one could consider meeting prior to identifying the final clinical formulation or the exact final dose. However, in order to obtain more complete responses from FDA on details of the toxicology requirements, or what aspects can be waived, you should attempt to detail as closely as possible what the final clinical formulation to be used in the initial clinical trial will be, including a list of which excipients (inactive ingredients) the clinical formulation will contain (if not the final formulation), and a target concentration range. An issue arises when the intent is to get FDA to commit to details of a toxicology program too early, before the clinical formulation is defined. For drugs of a novel mechanism, for example, it would be especially prudent to have at least some early toxicology (even non-GLP) studies completed going into the meeting, so that the proper proposal can be included for discussion with FDA.

One issue that comes up frequently is formulation change, as it impacts the decision making on when to go to FDA. Many times we see formulation changes made after the proof of concept is defined in an appropriate animal model, or after the GLP ocular toxicology is completed with an early formulation, or following the initial human study going into Phase II follow-up studies. While formulation changes may be unavoidable and driven by a need to correct issues seen during stability testing, for example, the impact this may have on pharmacokinetics, comfort, dwell time on the surface of the eye, efficacy and toxicology must all be considered. This highlights the importance of an appropriate, formal, formulation-development process, with some accelerated and room-temperature stability data obtained as soon as possible in the intended container closure system. You need to plan for the FDA meeting when key data will be in hand that will allow proper positioning of the intended formulation and container closure in the pre-IND briefing package.

Many times, minor adjustments are not an issue. However if the new formulation may potentially impact penetration or dwell time significantly, or introduces novel excipients, then a bridging GLP toxicology study may be needed. Sometimes there is a desire driven by need for extended patent coverage to combine a drug with a novel formulation technology as a vehicle to enhance the agent’s dwell time or penetration. However, the impact of an enhanced vehicle—for example in the case of dry eye—must be considered in the context of what that will do to the placebo effect and ultimately the ability to show a treatment effect. Further, in that case, inclusion of what is intended to be an excipient, such as a demulcent that is also listed as an active ingredient on the dry-eye monograph (such as HPMC, CMC, glycerin, etc.) will have a regulatory impact and a need to show the contribution of the elements or treatment as a combination product. This is definitely an area that requires a multi-disciplinary approach to the decision-making process, and consideration of when the formulation change and future plans should be discussed with FDA to assure there won’t be surprises when the IND is filed.

Ultimately, the appropriate timing of the pre-IND meeting comes down to the critical questions the sponsor wants to ask FDA. Even when there may not be significant technical issues, it serves as a key milestone for the board, investors or internal team to vet the program. Other times, prior to embarking on the GLP toxicology studies, the goal may be to confirm the designs and requirements for supporting the IND and initial trial, or to confirm that a formulation change does not require repeating certain toxicology work that was conducted with a prior formulation.

Rushing to request the pre-IND meeting can also be a potential pitfall. It takes a of couple months to get a date with FDA, but this is initiated before a full technical assessment is completed and overlaid with detailed time lines of activities and delivery of key data. Then when the deadline comes for submission of the briefing package (which is one month ahead of the scheduled FDA meeting), the anticipated data may not be available or is not as expected, and plans need to be modified. It comes down to identifying what the critical questions are for the pre-IND meeting and what info you want to submit in the package. Then you backtrack to when any actions need to start in order to have that data.

These are just a few of the elements of the decision process on when to meet with the FDA. It is acceptable to go and have early conceptual discussions, and it is acceptable to go later when all elements are completed and the IND is almost ready to file. It is important to remember that for the questions being asked, the responses from FDA will be directly related to the information provided to them for review. The timing and elements for discussion at the pre-IND meeting with FDA will be guided by these questions about technical, regulatory and business considerations. It is these strategic inputs that will allow determination of when is “not too early, and not too late.”   REVIEW

Mr. Chapin is vice president, corporate development at Ora Inc. Ora provides a comprehensive range of product development services in ophthalmology.