FDA Draft Guidance: Best Practices for Communication Between IND Sponsors and FDA During Drug Development

 

To guide investigational new drug application (IND) sponsors’ communication with the FDA during development phases, a new set of best practices has been outlined in a draft guidance. During this communication, FDA and industry share information on clinical trials, nonclinical study requirements, and other issues. According to the guidance, each year, sponsors and FDA engage in thousands of formal and informal communications, including meetings and teleconferences during the IND phase of drug development. Because these communications are often opportunities to share information and provide critical advice, FDA stressed the importance that interactions be conducted efficiently and consistently, with clear, concise, and timely communication.

FDA and Sponsor Responsibilities

The guidance outlines the primary responsibilities of sponsors, which relates to the management of the overall development of drugs, determining the nature and timing of regulatory submissions to the IND, soliciting input and guidance during the course of the development program, and providing well-organized and complete IND submissions for FDA to review. On the agency side, FDA’s primary responsibilities with respect to INDs are, during all phases of an investigation, to ensure the safety and rights of subjects, and, during phase 2 and phase 3, to help ensure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug’s effectiveness and safety.

Scope of Interaction Between Sponsor and Review Team

FDA clearly states the agency’s review division regulatory project manager (RPM) is the primary point of contact for communications between IND sponsors and FDA during the life cycle of drug development. The RPM has comprehensive knowledge of the drug and its regulatory history. The RPM is also the primary contact for facilitating the timely resolution of technical, scientific, and regulatory questions, conflicts, or communication challenges between the sponsor and the review team.

The RPM is not the only possible contact, however. FDA notes examples of other appropriate contacts, such as: CDER’s Office of Pharmaceutical Quality regulatory business project managers who manage meeting requests, regulatory submissions, and other inquiries that are solely related to chemistry, manufacturing, and controls, including facility and product quality issues; CDER’s Office of Surveillance and Epidemiology safety regulatory project managers manage sponsor requests for proprietary name review; and CDER’s Formal Dispute Resolution Project Manager manages sponsor requests for resolving scientific and/or medical disputes that cannot be resolved at the division level.

However, if a sponsor has challenges getting timely feedback, FDA encourages them to contact the RPM’s supervisor or division/office management officials. FDA recommends that sponsors provide staff with background information on the purpose of the request to assist in determining the proper official to handle the call and also to allow the FDA official to conduct any preparations needed in advance of the call to make most efficient use of the allotted time. To streamline communication, FDA recommends that sponsors and the agency’s project managers establish a mutually agreeable communication strategy. Informal communications can be established around the time of the IND submission and modified if more/less frequent contact is necessary.

Types of Advice Appropriate for Sponsors

During the life cycle of drug development, sponsors routinely solicit feedback from FDA on both scientific and regulatory issues. The breadth and frequency of advice sought can vary according to the experience of the sponsor, as well as the novelty and development stage of the proposed drug. During the IND phase of development, sponsors often solicit advice at critical junctures in their development program. These topics include, but are not limited to the following:

• 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, post approval 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)

When soliciting feedback from FDA, sponsors should keep in mind that FDA policy positions are typically documented and described in FDA guidances, MAPPs, and SOPPs. Complex scientific/technical drug development questions should be directed to the FDA project manager, typically the review division RPM, via either a submission or through the formal meeting request process. General questions that cannot be answered by using existing resources can be directed to an FDA project manager, to the designated enhanced communication staff within each FDA center, or to CDER’s Division of Drug Information. Depending on the nature and complexity of the question(s), FDA will either respond to the question(s) or redirect the sponsor to an alternative pathway for receiving a response (e.g., other FDA subject matter expert, formal meeting request process).

General Expectation for Timing of Communications

FDA recognizes that timely and effective communication with sponsors during the IND phase of drug development provides sponsors with information they seek to inform the design of studies and trials, as well as product quality information, intended to support approval of a future marketing application. As such, FDA staff strive to respond to sponsor questions promptly while balancing FDA public health priorities and their other workload responsibilities, noting that responses to safety-related inquiries will be prioritized higher than other inquiries in alignment with FDA’s previously stated primary responsibilities with respect to INDs.

During the course of these collaborative interactions, sponsors sometimes pose questions to FDA that they perceive as being simple or clarifying questions with the expectation that only minimal time will be needed for an FDA response. However, what appear to the sponsor to be simple or clarifying questions are often more complex and necessitate significant review and communication among review team members, including conducting an internal meeting(s), before an answer can be provided. For example, questions that involve interpretation of regulations and statutes, or application of existing FDA policy to novel circumstances, are often complex and therefore demand additional vetting and response time. Similarly, questions involving combination products usually demand significant time to solicit and consider feedback from multiple FDA centers.

Best Practices and Communication Methods

Effective and timely communication between FDA and sponsors promotes understanding of mutual goals and is invaluable to the drug development process. Central to this is the ability to communicate clearly, both orally and in writing, inside and outside the formal meeting format. It is also important that FDA and sponsors have a common understanding of terms and phrasing used in communications with each other, and that they are used consistently by both parties. In FDA communications related to INDs:

• 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.