Earlier this month FDA (CDER and CBER) issued a new draft guidance, Best Practices for Communication Between IND Sponsors and FDA During Drug Development. Based on Premier Consulting’s frequent communications with the Agency during product development, the guidance does not present any profound or significant changes in how they conduct and or prefer communicating with IND sponsors. Rather, it does a good job of summarizing what most of the review divisions already do, and provides sponsors with useful instructions on how to effectively get the information they need from FDA. And, to the extent that it creates consistent behavior across all reviewing divisions it would provide a good deal of clarity for regulated industry.

The stated purpose of the guidance is:

“… is to describe best practices and procedures for timely, transparent, and effective communications between investigational new drug application (IND) sponsors and FDA at critical junctures in drug development, which may facilitate earlier availability of safe and effective drugs to the American public.”

The guidance was assembled using input on best communication practices from across CDER and CBER as well as input from interested parties who responded to an October 29, 2014 request for comment published in the Federal Register (79 FR 64397). There is a good deal of emphasis on the benefits of effective communication for both FDA and IND sponsors, to achieve more efficient and robust drug development programs. The guidance also discusses timelines a good deal, but provides few if any specifics, pointing instead to the various statutes, regulations, guidances, MAPPS and other FDA documents which do provide the timeline expectations involved for various FDA responses and/or actions. Emphasis is placed on the role of the Regulatory Project Manager (RPM) as the lynchpin for communication between an IND sponsor and the Division. Beyond that, the general policy towards the timing of responses to industry inquires and requests might be best summed up as “We’re interested, we know it’s important to you, we’ll get back to you as soon as we can, but we have resource and priority constraints too, and we may be dealing with lots of things you’re unaware that are currently occupying us.” There are also a number of exhortations for industry to consult FDA websites and guidances for answers to their questions before contacting FDA, in fact a section (VII.I., Resources for Sponsors) is devoted to it. There are seven primary areas which FDA expects will be topics for communication:

Regulatory (e.g., plans for submission of proprietary name requests, plans to defer or waive specific studies, development plans with other FDA centers (e.g., the Center for Devices and Radiological Health) for combination products), applicability of an expedited program

• Clinical/statistical (e.g., planned clinical trials to support effectiveness, validity of outcomes and endpoints, trial size, enrichment designs)
• Safety (e.g., 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)
• Clinical pharmacology and pharmacokinetics (e.g., dose selection, use in specific populations, drug-drug interactions)
• Nonclinical pharmacology, pharmacokinetics, and toxicology (e.g., genetic toxicology, reproductive and developmental toxicology, carcinogenicity, mechanism of action)
• Product quality (e.g., proposed shelf life and stability studies, delivery systems, characterization of drug substance/product, facility compliance with good manufacturing practices, comparability of lots used in clinical trials and commercial lots)
• Pediatrics (e.g., proposed pediatric development plan, dosing)

Regarding the timing of responses to questions and issues, FDA points out that what may seem to be a simple question to the IND sponsor, amenable to a phone call or email, may be from an FDA perspective anything but simple, i.e., a complex question. Here, FDA emphasizes the importance of using Meeting Requests and official submissions to the IND as the appropriate mechanism for getting an answer to a question. Again, as far as specifics go regarding timing, the guidance refers the reader to the other available guidances, and MAPPS regarding meetings and submissions. For those items which do qualify for a less formal process, three days is the default for an FDA acknowledgement. The acknowledgement may include the answer to the question if that works out, but otherwise it will be a high level description of the steps FDA needs to go through to formulate the answer, and an estimated time frame for a response, or a recommendation that the sponsor make a meeting request or request for WRO, or a recommendation that the sponsor contact another specialized functional area in FDA. Also emphasized is the importance of prompt sponsor acknowledgement.

Concerning best practices, FDA wants to make sure it’s communication are clear:

• “As a best practice, FDA staff will use words such as shall, must, required, or requirement to convey a statutory or regulatory requirement.
• As a best practice, FDA staff will use the following words to communicate advice (e.g., on trial design), comments, or current thinking often include the following terminology: advisable, critical, important, may be appropriate, should, consider, discourage, encourage, prefer, recommend, suggest, or urge. Because FDA has the advantage of viewing the spectrum of drug development across sponsors, indications, and drug classes, FDA is able to communicate advice to sponsors with that expertise in mind, while upholding commercial confidentiality.”

Importantly, FDA adds this caveat regarding its responses to sponsors questions and other advisements:

The IND phase of drug development is typically a multiyear process, and FDA staff recognize that new data will become available and that scientific advances and changes in clinical practice may occur during this time. Because sponsors are ultimately responsible for managing the overall development program for their proposed drug, sponsors should closely monitor for advances in the field and/or changes in FDA guidance, and inquire if those changes may necessitate changes in prior FDA recommendations for their development program. Although FDA reviewers consider new information and revise recommendations as needed, they try to support and adhere to their prior critical recommendations where appropriate. Changes in recommendations are expected to be based on new scientific or safety information or advances in clinical practice that make earlier FDA recommendations outdated, inappropriate, or unethical. In such cases, review staff via the project manager should inform sponsors in writing of these changes and the rationale behind the changes.” (Emphasis added)

In other words, you may have it in writing, but that doesn’t mean it’s written in stone. You need to keep current and assure your application will meet standards at the time of submission.

The guidance provides FDA’s viewpoint on 4 types of meetings:

• “Pre-IND meetings are valuable for understanding proof of concept and initiating dialogue for drug development in its early stages. They can prevent clinical hold issues from arising and aid sponsors in developing a complete IND submission. FDA encourages sponsors to request a pre-IND meeting for the following: a drug not previously approved/licensed, a new molecular entity (NME), a planned marketing application intended to be submitted under the 505(b)(2) regulatory pathway, drugs for which it is critical to public health to have an effective and efficient drug development plan (e.g., counter-terrorism), drugs with substantial early development outside the United States, a planned human factors development program, and drugs with adequate and well-controlled trials to support a new indication. However, a sponsor of any IND can request a pre-IND meeting. Because of limitations of FDA resources, it is common for review divisions to use the WRO meeting procedures for pre-IND meetings; however, in selected circumstances a face-to-face meeting or teleconference may be granted.
• EOP1 meetings are useful to review and reach agreement on the design of phase 2 controlled clinical trials and to discuss issues related to the proposed drug development program, including pediatric study plans, as appropriate. Because of limited resources, FDA has traditionally encouraged sponsors to request an EOP1 meeting only for drugs intended to treat life-threating and severely debilitating illnesses, particularly situations where approval based on phase 2 trials or accelerated approval may be appropriate.
• EOP2 meetings are of considerable importance in planning later studies and in determining the safety of proceeding to phase 3. EOP2 meetings evaluate the phase 3 plan and protocols, the adequacy of current studies and plans to assess pediatric safety and effectiveness, the human factors validation plan, and identify any additional information necessary to support a marketing application for the uses under investigation. FDA encourages sponsors to request an EOP2 meeting for NMEs or major new uses of marketed drugs. However, a sponsor of any IND can request an EOP2 meeting.
• Pre-NDA/BLA meetings are helpful in acquainting FDA reviewers with the format and content of the planned application, including labeling and risk management activities (if applicable), presentation and organization of data, dataset structure, acceptability of data for submission, as well as the projected submission date of the application. They are also intended to uncover major issues, identify studies intended to establish the drug’s safety and effectiveness, discuss the status of pediatric studies, and discuss appropriate statistical analysis methods, or results of analyses. FDA encourages sponsors to request pre-NDA/BLA meetings for all planned marketing applications, particularly applications to be reviewed under the PDUFA V Program for Enhanced Review Transparency and Communication for NME NDAs and Original BLAs.”

The guidance provides a fairly useful summary for Meeting Requests, Meeting Packages, Meeting Conduct and Meeting Minutes.

The guidance becomes more specific when discussing the mechanics of written correspondence, submissions from sponsors, acknowledging receipt of communications, email, telephone and fax communications between the FDA and sponsors, even getting down to the use of out-of-office messages.

The guidance concludes with the aforementioned list of resources for sponsors, which is fairly comprehensive, and Section VIII, which lists additional contacts at FDA for special issues, e.g., Controlled substance staff.

Interestingly, scattered throughout the guidance are brief descriptions of the appropriate steps to take if it seems that the appropriate party or parties are unresponsive to a sponsor’s inquires.

All in all the guidance is a good primer for those involved in communicating with FDA during drug development under an IND. Also, as mentioned earlier, it creates at least the possible prospect of greater uniformity across the FDA review Divisions.

Premier Consulting is frequently involved in all of the activities described in the draft guidance. If there are questions beyond what the guidance has to offer, Premier Consulting is available to assist.