By Albert Yehaskel, President and CEO, Refuah Global Pharmaceutical Development
While many may perceive the FDA as a large bureaucratic organization trying to impede the progress of a new drug or to getting an NDA (new drug application), ANDA (abbreviated NDA), or other submission approved, it is not so. When it comes to dealing with and interacting with the FDA, attitude plays an important part in ensuring the agency is on your side. How do you do this? Simple: Be genuinely interested in the personnel at the FDA, particularly the review division that handles your drug. Below are some obvious but overlooked suggestions:
- Be a good listener and don’t interrupt.
- Make the other person feel important, and do it sincerely.
- Don’t criticize, condemn, or complain.
- The only way to get the best of an argument is to avoid it.
- Show respect to the reviewer or personnel at the FDA. Never say “you’re wrong” (even if they are).
- If you are wrong, don’t cover it up. Admit it quickly and emphatically and move on.
- Be friendly.
- Let the other person do most of the talking.
- Ask questions instead of giving orders.
- Try to honestly see things from the agency’s perspective or point of view.
The above suggestions will help provide smooth interactions with the agency, cultivate good relationships, and create a situation in which both the sponsor and the agency win. Remember, interacting with the FDA can be either verbal (face-to-face meetings and/or teleconferences) or written, such as emails, faxes, or letters.
So why does a sponsor interact with the FDA? There are five major reasons:
- To obtain FDA advice and direction
- To clarify procedures
- To clarify expectations
- To resolve issues
- To try and reduce the overall development timeline
One or more of the above will come into play during the development of your drug, and each of them can be dealt with through face-to-face meetings, teleconferences, or written communications (letters, emails, submissions, requests).
Communicating With FDA staff
Most of your interactions with the FDA will be in written form. Make sure these submissions are clear and organized. The easier they are to read and understand, the quicker they will be reviewed and the fewer questions will arise. However, where gaps exist (and oftentimes they do … it’s natural in drug development), acknowledge them and provide the status of each. In all your communications, be sure to provide scientific rationale, including references to literature where appropriate.
As you prepare your documents, bear in mind that FDA staff members are smart, intelligent, and well-versed in a myriad of areas and topics. However, do not assume prior knowledge on the reviewer’s part. You, as the sponsor, should provide background information to put results or information into perspective. You should also educate the reviewer when and where necessary. There are clearly some new breakthrough areas that even agency personnel may not understand or have full knowledge of. In such cases, FDA staffers appreciate being educated by a company that has a thorough knowledge of a specific area.
The reverse is also true. Accept advice from the reviewer openly. Why? They may know something you don’t, and they really do want to help. They are on your side.
Meet Early And Often
When is a good time to start interacting with FDA? In my opinion, you should engage with the agency as early as possible, even before your key pre-IND (investigational new drug) meeting, especially if you have a new drug that is unique, problematic, or otherwise requires open discussion. This may happen as you are conducting your preclinical trials and issues surface that you need to vet with the FDA. Or perhaps you are having issues with the synthetic route, toxic impurities, or other aspects. Communicate with the FDA, explain the project, and tell them that you would like to speak with them even before a pre-IND meeting.
Early agency-sponsored meetings make a difference in developing quality applications that do not require additional information later on, and close communication with the FDA early in a drug’s development reduces the chance that an application will have to go through more than one cycle of review.
There are several key meetings that a sponsor should take advantage of. The first is the pre-IND meeting. Assuming you have had no prior FDA interaction, this meeting will set the tone between you as the sponsor and the FDA review division that will be your contact for many years until the NDA and beyond.
Why is the pre-IND meeting important?
- It is an opportunity to meet the FDA team (the reviewers) you will be working with and allows you to make a good impression.
- It provides a forum to discuss potential issues that can enhance the program.
- It affords an opportunity to discuss a clinical development plan and specific development issues that may arise.
- It supports your CMC (chemistry, manufacturing, and controls) program and can obviate issues.
- It alerts the agency of the nonclinical studies or issues needed to develop the program further.
- It fosters constructive feedback for your development plan and any necessary adjustments.
- It provides an opportunity for you to ask the right questions (nonclinical, clinical, CMC, manufacturing, etc.) to ensure a complete (i.e., no gaps) and high-quality IND.
- It is useful in resolving questions and issues raised during the preparation for an IND (which should have been started, in most instances, prior to the pre-IND meeting).
Preparing For Meetings
Careful and thorough preparation is critical for all your meetings or teleconferences with the FDA. The first order of business is the meeting request letter, which must contain adequate information for the division to determine the utility of the meeting and to identify FDA staff necessary to discuss proposed agenda items. In its draft guidance Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products, the agency provides a very specific 13-item list of what the letter should include:
- Product name and application number (if applicable)
- Chemical name and structure.
- Proposed indication(s)
- The type of meeting being requested (i.e., Type A, Type B, or Type C)
- A brief statement of the purpose of the meeting. This statement could include a discussion of the types of completed or planned studies or data that the sponsor or applicant intends to discuss at the meeting, the general nature of the critical questions to be asked, and where the meeting fits in overall development plans.
- A list of the specific objectives/outcomes expected from the meeting
- A preliminary proposed agenda, including estimated amounts of time needed for each agenda item and designated speaker(s).
- A draft list of specific questions, grouped by discipline
- A list of all individuals (including titles) who will attend the proposed meeting from the sponsor's or applicant's organization and consultants
- Proposed/suggested dates (at least 3) and times (AM or PM) for the meeting
- The approximate date on which supporting documentation (i.e., the briefing package) will be sent to the review division.
The required information includes a list of proposed questions to be covered in the meeting. Those questions are the most important aspect of the entire communication. The questions should be grouped by discipline, e.g., chemistry, CMC microbiology, pharmacology/toxicology, etc.
The questions should be as specific, comprehensive, and precise as possible to identify the critical issues and should be presented in a logical manner to aid in the review of the information.
Once the request letter has been sent to FDA’s review division, the sponsor should hear back within two weeks or less. During this time (and even before as time allows), the preparation of the briefing package (or briefing document) should be well underway. The construction and review of this document may take many weeks to produce and will require careful thought and very thorough review.
The briefing document is, as its name suggests, a brief document containing pertinent data and information needed for the meeting. It identifies very specific questions for the FDA that will assist the sponsor with any IND issues; these questions may be the same as in the request letter, as well as revised and additional new questions.
The contents of briefing documents will vary for different types of meetings and serve different purposes. For example, the questions and content included will be different for a pre-IND meeting than those for an end-of-Phase 2 meeting.
Make Your Briefing Document Count
The quality of the briefing document is paramount, and your time spent on developing a good document will pay dividends. The success of the document will be predicated on FDA’s ability to read and understand its contents. The information in the briefing document should be logical and built on an orderly presentation of history, facts, and data. While the document should be concise, brief, and to the point, it should contain the relevant information to allow the FDA to reach decisions and/or respond to questions.
Specific information to present includes:
- Specific questions organized by discipline. In order to elicit proper responses from the agency, the questions must be clearly thought out and contain the proper quantity of information/summaries to allow the FDA to respond to the questions.
- Product information, including name, chemical name, and structure; proposed indication; dosage form, route of administration, and dosing regimen.
- Data summaries, including preclinical data, clinical data, and CMC.
In addition, the package should be well organized, with a table of contents, consistent pagination, and appropriate labeled tabs.
Once the briefing document has been completed, several copies (oftentimes 15 or more; check with the division) must be mailed to the agency prior to your meeting (four to six weeks before; check with the review division).
After submitting the briefing document, it is time to prepare for the FDA meeting. This will take the guise of reviewing your project and, most importantly, rehearsing for the meeting. I recommend holding several rehearsals (two or three before the meeting and one the day before the meeting).
To ensure a higher success of achieving positive interactions with the FDA, keep the following points in mind in all communications with the agency:
- FDA interactions (verbal or written) are serious and must be taken seriously.
- Interactions are limited in time, so use the available time wisely.
- A specific agenda is required.
- Go in with a focus and a strategy based on key questions to be answered.
- Know the regulations.
- Don’t offer a dog and pony show; it’s not a sales presentation. Instead, communicate the science and the medicine; state the scientific facts.
And above all, remember that maintaining the right frame of mind throughout will go a long way to making the FDA part of your organization’s team.
About The Author
Albert Yehaskel is president and CEO of the consulting firm Refuah Global Pharmaceutical Development. He has been in the pharmaceutical industry for over 40 years, working for companies including Schering-Plough, Lederle Laboratories (part of American Cyanamid, now known as Wyeth), Block Drug, Sanofi, Purdue Pharma, Daiichi-Sankyo, Shionogi USA, and Indigo Pharmaceuticals. Over 25 years of his career has been devoted to regulatory affairs, managing and directing domestic and international regulatory submissions, orchestrating key FDA meetings, and conducting pharmaceutical research and development. He has two master’s degrees — an MBA in economics and finance from Fairleigh Dickinson University and an M.S. in organic chemistry from Queens College, City University of New York — as well as a B.S. in chemistry from the Polytechnic Institute of Brooklyn.