FDA Draft Guidance: Best Practices for Communication with FDA during Drug Development – Safety
FDA issued a draft guidance to industry in December 2015 entitled “Best Practices for Communications Between IND Sponsors and FDA During Drug Development.” This document is some 30 pages long and covers details on all aspects of meetings, emails, phone calls, faxes and other communications with FDA during drug development.
Anyone who plays a role in drug development, particularly those communicating with FDA, should read this document even though it is still only a guidance. In fact, anyone dealing with FDA should read this document.
The goals of the guidance are to convey FDA’s “philosophy” on communication with IND sponsors, the scope, type of advice appropriate to seek from FDA, expectations and best practices in order to have effective, timely and transparent dealings. As FDA is now a sort of “partner” in drug development, communication with FDA is necessary for successful drug development. I will highlight some of the comments made about drug safety during such communications.
Both for the sponsor and FDA, the first responsibility listed in this section is safety. The sponsor has many responsibilities amongst which are “ensuring patient safety” in clinical trials. The FDA’s responsibility during all phases of development are to “ensure the safety and rights of subjects” again the first responsibility mentioned for FDA.
FDA notes that sponsors should not directly contact FDA reviewers; rather they should contact the division regulatory project manager (RPM).
Comment: As always, safety is “a”, if not “the” primary concern in drug development.
Types of advice that are appropriate for sponsors to seek
In regard to safety, FDA has a specific list: “safety issues identified in nonclinical studies and early clinical trials, size of the overall safety database, concerns related to particular populations, postapproval pharmacovigilance plans, risk evaluation and mitigation strategies, plans for human factors studies, issues related to evaluation of abuse potential)”.
Comment: This is pretty much everything about drug (and trial) safety. FDA recommends using other available resources to answer questions before actually communicating with the agency. Such resources include FDA SOPs, MAPPs, guidances etc. and are discussed in detail at the end of the document. FDA would prefer direct communications to deal with “the more complex and challenging drug development issues.”
Timing, Priorities and Expectations
FDA notes that they will try to be timely and effective in dealings with sponsors balancing promptness with “public health priorities and workload.” However, FDA will give a higher priority to safety-related inquiries.
In a long paragraph, FDA notes that responses to what seem to the sponsor to be quick, simple questions may require complex and time-consuming work by FDA to answer. Complex questions and issues should be addressed in formal submissions or meetings rather than quick communications.
FDA notes that some submissions have mandated timelines for their review and response (such as some safety-related submissions, clinical holds) whereas others have less rigid timing goals for response. FDA will try to answer more routine matters sent by phone, email or in a submission within 3 to 4 days. If a full response cannot be given then, FDA will try to estimate when it can, whether FDA has to consult with other governmental parties, whether a more formal consultation or meeting is needed, etc. There is a long section on how to go about handling such back and forth matters. See the document for details.
Interestingly, FDA notes that, in terms of language, when they respond using the words “shall, must, required, requirement,” this reflects statutory or regulatory requirements. That is, you have to do it. When they use words like: “advisable, critical, important, may be appropriate, should, consider, discourage, encourage, prefer, recommend, suggest, or urge,” this represents advice rather than obligation.
Comment: Nice to see this clearly written down. Advice does not always need to be followed but… if you reject FDA’s advice, you should have a rather good and defensible reason to do so.
There are multiple meetings possible during a drug’s development including pre-IND, End of phase 1 and 2 (EOP 1 and EOP 2 respectively) and pre-NDA/BLA meetings. In regard to safety, FDA notes that the EOP 2 meeting can be useful in determining the safety brefore proceeding to phase 3, the adequacy of current studies and pediatric safety studies. The Pre-NDA/BLA meeting is most important in regard to acquainting FDA with the format and content of the application including labeling and risk management activities as well as helping to prevent clinical hold issues from arising. They can also be used to “uncover major issues, identify studies intended to establish the drug’s safety” amongst other things.
Submissions from Sponsors
FDA discusses the mechanics and contents of submissions from sponsors for all of these types of meetings. Stating the obvious, FDA notes that “Sponsors must adhere to required timelines for their submissions (e.g., IND safety reports, annual reports)” as noted in 21CFR312. Secure email can be used for communication between FDA and sponsors though it is not a substitute for “formal submissions” through the center’s document room for paper submissions or the electronic gateway for e-submissions. Secure email mechanisms can be worked out with the Office of Information Management at FDA.
Phone calls are useful for administrative matters. When calls are done for complex, regulatory or technical issues, the caller should follow up with a written communication. Faxes may be used if secure email has not been established but not for a formal submission. All proprietary/secret information must be done via secure mechanisms.
FDA refers to:
See the guidance for other documents including FDA Basics for Industry, FDA Interactive Media, FDA Presentations, labeling and approvals, rules and regulations, and the Code of Federal Regulations, Import and export, rare diseases, the office of Special Medical Programs, Advisory Committees, Orphan Products, the Office of Pediatric Therapeutics, Combination Products, the Office of GCP (Good Clinical Practice) for issues touching GCP in trials including informed consent, IRBs etc.
Other resources for special topics that may relate to safety are also noted in the document including sources for controlled substances, the Division of Drug Information, the Division of Pediatric and Maternal Health and special situations (The Enhanced Communications Team in the Office of New Drugs).
This is a detailed document, of which the key elements are what meetings can, should and must occur and how they should be set up. The mechanics and operational details are noted. The reference sections give the high-level URLs after which one must search for the documents that (might) answer your question. That is often not easy.
In regard to safety, there are several areas that we can summarize here:
- Routine safety submissions: IND safety reports, annual safety reports, DSURs etc. Obviously, these must be done correctly and on time.
- Routine safety matters should be discussed at scheduled EOP 1 and 2 and pre-IND/BLA meetings.
- Special issues: This is where it gets tricky. Matters here include a newly discovered risk posing (possible) danger to the subjects, safety matters brought up by IRBs, investigators, data monitoring committees, data safety boards, adjudication committees, actions by other health authorities etc. These special situations fall out of the “routine” scope. In practice, a new and critical issue which must be acted upon rapidly should be communicated to FDA quickly using phone, fax or possibly email though when you phone, you know you’ve gotten through. This must then be followed up with written communications. Additional phone calls, emails etc. will almost certainly occur leading to sponsor or FDA action such as clinical holds, an emergency meeting (phone or face-to-face) etc.So the general rules noted in this document may not always apply to special situations, particularly if there is an imminent danger that must be addressed. These communications to FDA must be fully and carefully discussed internally by the sponsor and a clear and precise formulation of the information conveyed to FDA by whatever method must be prepared. The sponsor representative doing this should be at a fairly senior level and fully briefed on what he or she can and cannot say and, importantly, what he or she can and cannot commit the sponsor to do. This may require full mobilization at the sponsor on multiple fronts if the issues involve stopping studies, informing investigators, patients and IRBs etc.
Finally, keep in mind what information must be made public under FDA, SEC and other US requirements; what other health agencies must be informed both of the issue at hand and of FDA actions and, perhaps the hardest of all, what might go viral on the internet.
And, as always, keep in mind the usual admonition that our job in drug safety and pharmacovigilance is protecting the public health.
Tags: drug safety, FDA, Pharmacovigilance