Preparing for and Holding Meetings with Regulatory Agencies
Presenting science to the FDA is an art.
–Jerry Halperin, former Food and Drug Administration executive and Food and Drug Law Institute President.
Shallow men believe in luck. Strong men believe in cause and effect.
–Ralph Waldo Emerson, US poet and philosopher.
This chapter focuses on regulatory meetings during development and prior to submission of the marketing application [e.g., Biologic License Application, Premarket Application, New Drug Application (NDA)], although almost all comments apply equally well to other types of meetings with regulators. Food and Drug Administration (FDA) Advisory Committee meetings are a major exception to this rule, and they are discussed in the next chapter. Some of the important differences between the two types of meetings are that FDA Advisory Committee meetings are open to the public rather than being closed and confidential meetings. Moreover, they involve both qualitative and quantitative differences from other regulatory meetings in both the amount of preparation and the nature of the company’s (and the FDA‘s) presentation.
PRIOR TO THE MEETING
Types of Meetings during the Investigational Period
Although the FDA is used as an example in much of this chapter, the types of meetings listed below apply in general to other regulatory agencies as well. Meetings are almost always either face to face or via a teleconference. Video conferences are not common.
Type A meetings are those with a stalled development plan such as a safety problem in an ongoing clinical trial or issues about a trial’s implementation, and are also for a resolution of disputes (e.g., a clinical hold issue). The FDA is required to respond to a company and to hold the meeting within 30 days of receipt of a written request.
Type B meetings are those the company is entitled to expect based on precedent if not actual regulations or guidances. In the United States, these include pre-Investigational New Drug Application (IND), end of Phase 1, end of Phase 2, and pre-NDA meetings. These types of meetings are to be held within 60 days of the FDA‘s receipt of a written request.
Type C meetings include all other meetings that are requested. These meetings are held within 75 days of the FDA‘s receipt of a written request.
Creating a Theme and Core Messages
While some companies understand the purpose and goal(s) of every type of regulatory meeting, they may fail to establish an overall theme or key message to convey to the regulatory agency at the time of their meeting, and in the briefing book sent to the agency prior to the meeting.
It is clear that for some meetings, the company is seeking guidance or concurrence from the regulators in the form of answers to their questions and there may not be an overriding theme or message the sponsor wishes or needs to convey. However, even in those cases, the sponsor must have two or three specific messages to deliver. The sponsor’s goal for any regulatory meeting is not merely to identify the focus of the meeting (e.g., toxicology, statistics, clinical, or manufacturing), but to determine which issues in those areas are of primary importance to the company. An example of a core message (which must be supported with evidence) might be that there has been so much clinical exposure to a specific drug that there is no need for any additional toxicology studies.
The key messages should be worked into relevant questions posed in the briefing book. Questions are usually ordered by function in a briefing book [e.g., preclinical questions; clinical questions; chemistry, manufacturing, and controls (CMC) questions].
Presenting the Public Health Message in the Executive Summary of Regulatory Documents
In all executive summaries, it is common that the first key message will address the “medical need” for a new product that has certain characteristics, i.e., the Public Health message. This may be phrased in terms of numbers of patients who are inadequately treated because of safety or efficacy limitations of current therapy. Even though these facts (e.g., one million patients with disease X have no adequate treatment for their condition because of Y), may be transparent to most or almost all readers of the briefing book, it is, nonetheless, a logical place to begin most meetings with regulatory agencies; and, to include at the start of executive summaries in most documents, including white papers, briefing books, and other summary documents about the drug. Even if your product has only marginal benefits to offer, in addressing the medical need, it is still important to stress the overall Public Health message. Some regulatory staff at the meeting may not be fully cognizant of the nature of the medical need for the product and the degree of urgency that should be accorded to evaluating the product. Even after the medical need for a new product is known to be understood and accepted, this is still an extremely important message to be repeated at most, if not all, meetings (albeit briefly) and in appropriate places in regulatory submissions. This is particularly important in the executive summaries, as those are sometimes the only documents that senior FDA staff has the time to read and consider. These are the people who generally will be leading the meeting and directing the discussion in a more positive, negative, or neutral direction.
Describing the Medical Value of How the Drug Addresses the Medical Need
After the medical need is fully reviewed and understood, the concept of the product’s “medical value” has to be presented (i.e., how well does the specific product address and satisfy the medical need). Then, the specific evidence has to be presented that supports this claim. It is not essential to cover this message in detail at any one, or every, meeting, except for those later in the NDA process, or in one where the medical value is an underlying issue or even the focus of the discussion.
Examples of Core Messages
A few examples of core messages to present may be that the drug offers:
Enhanced safety (and/or efficacy) compared to current therapy
A significant improvement compared with other therapies in convenience for patients
A new therapy that acts via a different mechanism for patients who have failed other therapies
It is extremely important to establish the medical value of a product in the minds of regulators because the standards for approval agreed to by the agency and sponsor often depend to a great degree on both the medical need for a new therapy and the medical value of the product in addressing that medical need. The greater the medical need and medical value, the faster the agency, practicing physicians, and patients will want to have the product introduced onto the market. The weaker these arguments, the less pressure and sense of urgency the regulators will have to progress the product through their system.
Having core messages and themes allows the company to better focus its presentations, responses, and questions, as well as to be able to negotiate better outcomes at each meeting it attends.
A great deal of discussion is needed within a sponsoring company to ensure that a well-thought-through regulatory strategy is developed that optimizes the probability that the relatively few meetings that a sponsor has with a regulatory agency will be productive and facilitate their drug’s development. The time from a pre-IND meeting to the end of a Phase 1 or 2 meeting
may be quite substantial and involve a great deal of effort and resources, which focuses attention on reaching agreement at the first meeting on a development plan that is both realistic and appropriate for the product.
may be quite substantial and involve a great deal of effort and resources, which focuses attention on reaching agreement at the first meeting on a development plan that is both realistic and appropriate for the product.
Presentation of Negative Findings and Problems with the Drug
It is well received by regulatory agencies when a sponsor discusses a negative finding or problem with their product, since these are often ignored or minimized in importance by companies. Being up-front about these issues and stating clearly what was observed, while not trying to hide, ignore, or explain away the findings, is an important way of working collaboratively with a regulatory agency by seeking to develop a mutually acceptable approach to evaluate the issue in greater depth. When approached properly, especially when close to NDA submission, negative findings or gaps in knowledge may be addressed in terms of a post-approval “risk management program,” precluding prolonged delays in review and approval. Too many companies are disingenuous about such data, rather than being open and up front, which invariably is a better tack to take with an agency.
For complex issues or problems, it is usually best to divide them into several parts or components, and deal with each separately. Then pull the individual conclusions or actions to be taken together at the end. Lumping approaches to dealing with a complex issue into one discussion often is difficult to follow and digest if the professionals are not intimately familiar with the problem or have not spent sufficient time to consider it and discuss it with their peers. In other words, keeping the approach to the issues simple has many advantages as long as everything is adequately discussed.
Anticipating Regulatory Reactions to New Development Issues or Problems Presented in the Briefing Book
Anticipation of regulatory reactions to new data, issues, or problems on a drug is an important part of planning for a regulatory meeting as any newly observed drug issues may affect the overall program and lead to major changes in a drug’s development, and require more clinical trials, preclinical studies, or CMC work.
In preparing for a regulatory meeting, a company must consider in what ways it may be asked to modify its development program based on anticipated regulatory reactions to new data, issues or problems presented in the briefing book. Ideally, the company’s reactions and suggested approaches should be identical to those of the agency, if both are reacting based on sound science and medicine. However, there are often major differences in how the company and agency react to the same information.
The spectrum of how companies deal with this issue varies widely. Some companies are unwilling to state in the briefing book how they intend to modify their development program based on a scientific reaction to the new data and also what a regulatory agency might ask or require. Those companies intend to address any comments from the regulators as they arise at the meeting, and in response to any regulatory letters received. A more thoughtful approach is to anticipate regulatory reactions to new data, and to state in the briefing book how the company intends to modify its program, such as conducting additional clinical trials. A third approach is to be prepared to address this issue at the meeting itself and to have several negotiating points and proposals prepared, in case the agency raises this issue.
Even when new issues or problems have not arisen, a few companies have the reputation of conducting some clinical trials that are just “nice to have,” rather than definitely needed. Their intention is simply to provide a strong defense of an NDA and preclude major regulatory questions from arising, even if the agency had not suggested that the new data were needed. This approach is far more expensive and is likely to prolong the time to prepare an NDA if some of the trials cannot be conducted simultaneously with the rest of the program. Moreover, those trials might raise false positive questions or issues to address that should not and need not have been raised.
In conclusion, anticipating regulatory reactions to all problems encountered with a drug must be considered and a company position agreed upon prior to informing regulatory agencies that the data do not support the original profile that was anticipated. Companies that decide not to modify their development program should still be aware of possible studies or new analyses that could be requested and be prepared to either argue against them, or to initiate them rapidly if the situation requires.
PREPARING DOCUMENTS IN ADVANCE OF A MEETING
This section focuses on two issues to address in preparing documents sent to a regulatory agency prior to a formal meeting: (a) tone of the document and (b) posing questions.
Tone of the Document
Some attachments or documents submitted to an agency are likely to be independent documents that were carefully written and reviewed by the sponsor, such as final reports of toxicology, pharmacokinetics, clinical, or other studies. A number of additional reports and commentaries will be prepared for the upcoming regulatory meeting and will be included in the briefing package. Those documents, in particular, must have a balanced tone that is the same as if the document were prepared for a major publication, such as the New England Journal of Medicine. The data, analyses, and interpretations must be presented objectively and in a balanced scientific manner. Opinions and defensive explanations of either loose ends (i.e., issues about the data), or actual problems with the data are to be avoided. If the people preparing the document are too close to the material to view it objectively, then knowledgeable and objective professionals inside the company (or objective and straightforward consultants) could be asked to either prepare a report, or to review reports and documents prior to their submission. All reviewers should be instructed to focus on the many content issues (e.g., is a sufficient amount of data presented and is the interpretation adequate and reflective of the results, are the data presented well and do they accurately reflect the experiment or trial). But in addition, they should be asked to ensure the tone of each report and, in fact, the entire submission as neither defensive nor apologetic or anything other than scientifically balanced and appropriate.
How to Pose Questions of Regulators in a Briefing Book or in Other Documents
Regulatory affairs personnel in a company understand that one does not ask direct questions that seek advice from a regulatory agency. A few examples of direct questions that seek advice from regulators are as follows:
What endpoint should we use in this trial?
What advice do you have for us regarding X?
How should we deal with the following issue (or problem)?
We are unsure about doing a or b, which would you suggest?
Can you help us design the next clinical trial?
If a direct question is posed as if the company is seeking advice or an answer to a question, the company may not like the answer it receives and it will have to deal with this answer for a considerable period of time. An answer that provides a high standard of scientific and medical work to be done, or an inappropriate answer could easily commit the company to a program of work that is far more extensive and time-consuming, than would otherwise be agreed to. The answer could also force the program to take an entirely different direction or tangent (e.g., toward more sick patients or toward a different indication or end point) than the company intended.
The above paragraph is not meant to imply that one does not ask questions of regulatory agencies, but to suggest that how one asks the question is critically important. The major purpose of many, if not most, regulatory meetings is to ask, and hopefully discuss, one or more questions, and provide the material in a briefing book (in advance of the meeting) that the agency will need to answer them.
In reading many briefing books from various companies, it seems that even large companies sometimes forget the first rule, and simply ask one or more direct questions they need guidance on. In fact, some expert regulatory affairs professionals disagree with the rule the author has previously stated and advocate asking direct questions that seek guidance from regulatory agencies in all cases. They argue that the direct question forces a regulatory agency professional to focus on the question and minimizes misinterpretation. They are then less able, it is claimed, to change a vague interpretation at a later date. Some also feel that bad news is better to receive earlier in a project’s life than later in development when more resources and effort have been expended on a project. Obviously, the author disagrees with this approach and will present an alternative method of asking questions.
An easy approach to adopt in posing a question that provides the company with important “wiggle room” to negotiate a win-win conclusion with an agency (see Chapter 86) is to do the following:
Present the category of “Questions for the Agency to Address” as a separate section of the briefing book, and also list it separately on the agenda for the meeting. This is required by the FDA.
Organize the questions by function, such as preclinical, toxicology, pharmacokinetics, clinical, CMC, or others. That way, one does not bounce around from a toxicology question to a clinical one and back to another toxicology one.
Only ask important questions, and try to keep the number to the minimum needed, but spend sufficient time to ensure that all important and relevant questions have been added to the list. Do not ask questions prematurely, such as asking questions at an end of Phase 1 meeting that are appropriate for a pre-NDA meeting.
For each of the questions listed, there should be four parts. First is a statement of the issue. Second is the company’s position. Third is a statement of what the company proposes to do to address the issue. The company should refer to the section(s) of the briefing book that contains the data and evidence to support the company’s position (the data must be presented in the briefing book) and its proposed answer to each question (i.e., parts two and three).
The last part of the question is where the company requests the agency’s concurrence with the company’s perspective and plan. This may be stated, for example, by asking the question, “Does the agency concur with this approach to the question?” If the agency concurs, then, fine. If they do not, it is likely that they will express their viewpoint at the meeting (or in a written response the company will receive shortly before the meeting) and also indicate what approach and/or evidence they believe the company needs to undertake to address the question.
The critical difference between asking a direct question seeking advice and following the above approach is that the above approach is used to make it easier for a company to offer a counter-proposal to the agency’s response. The counter-proposal should show that the sponsor has moved closer to the agency’s position, and seeks a mutually satisfactory (i.e., win-win) agreement through a compromised agreement. While far from guaranteeing success, this approach has been used successfully many times in reaching medically and scientifically sound agreements that both groups found acceptable.
BRIEFING BOOKS SUBMITTED TO A REGULATORY AGENCY IN ADVANCE OF A MEETING
What Goes Into a Briefing Book?
Starting to prepare a briefing book is somewhat analogous to starting a clinical protocol. The first question for both is where to begin. Fortunately, the answer is easy and the same with both documents. It is to begin with the objectives. Once one has determined the overall purpose of the briefing book itself, then one can decide on the strategy for organizing and preparing the briefing book. While there are general topics listed on the FDA‘s website that are expected to be included in most of them (i.e., a proposed agenda, list of attendees, questions to be posed, current status of the project, any new or specific problems or issues that have arisen, plans for the future, plus supporting documentation) there are multiple ways to present each of these and other aspects. The table of contents offers a logical order by which to present the material, but is rarely the best place to begin one’s efforts.
Pre-Investigational New Drug Application Briefing Book
The primary objective of a pre-IND meeting and the briefing book sent to the agency in advance of the meeting is generally to obtain feedback from a regulatory agency on one or more of the following types of issues:
The type, number, extent, and other aspects of preclinical experiments, reports, and documents required for submission of an IND
The design or other questions relating to an initial (or first two) clinical trials
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