Best Practices for FDA Communication with IND Sponsors, Part 2

Last month, FDA published a draft guidance entitled, “Best Practices for Communication Between IND Sponsors and FDA During Drug Development.” The guidance was published with the intention of promoting timely, transparent, and effective communication between IND sponsors and the Agency.

In addition to best practices, a number of FDA recommendations for IND-related communications are provided in the draft guidance.

Additional details on the best practices for FDA communication with FDA sponsors are available in our recent FDA News article, here.

Roles & Responsibilities

The document states that, in ideal situations, the FDA will work collaboratively with sponsors throughout the entire drug development process. In addition, both parties have “distinct roles and primary areas of responsibility,” which are defined as follows:

• Sponsors: “Managing the overall development of their drug (i.e., supporting well-designed and well-conducted nonclinical and clinical trials for approval while ensuring patient safety), determining the nature and timing of regulatory submissions to the IND, soliciting input and guidance from FDA during the course of their development program, and providing well-organized and complete IND submissions (including amendments and supplementary information) to FDA for review.”
• FDA: “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. FDA also has the important responsibility of enforcing requirements related to good clinical practice (GCP) and human subject protections (HSP). FDA reviews IND submissions and takes regulatory actions (e.g., clinical hold) as appropriate. FDA review staff also play an active role during drug development by providing advice and feedback to sponsors on specific trials and overall development programs based on their review of IND submissions and in meetings conducted between sponsors and FDA. Finally, FDA promotes the advancement of regulatory science by authoring FDA and international guidances, conducting and participating in public workshops and public/private consortia, collaborating with academia, publishing in medical and trade journals, and presenting scientific and regulatory topics at professional conferences.”

Scope of Interactions

CDER review division's regulatory project managers (RPM) have comprehensive knowledge of his or her applicable drugs and its regulatory history. Therefore, the document designates the RPM as the primary point of contact for IND sponsors to communicate with the FDA during the drug development process. In addition, “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 guidance also says the Agency understands that, at certain times during drug development it may be appropriate for sponsors to contact other FDA project managers. These include:

• CDER’s Office of Pharmaceutical Quality regulatory business project managers 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.
• 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.

Types of Advice

Throughout drug development, sponsors request regulatory and scientific feedback from the FDA on a regular basis. The FDA provides sponsors with recommendations regarding the types of advice that are appropriate for sponsors to ask for, including:

• “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)”

FDA reminds sponsors that the Agency’s resources are limited. As such, it advises sponsors to seek answers to their questions through the various resources available prior to contacting the FDA. (More information on the available resources in section VII.I., Resources for Sponsors, of the draft guidance, here).

Expectations for Timing

The FDA offers details on the timeline of communication, providing the following information concerning the Agency’s response to the questions incorporated in meeting packages and submissions:

• Communications that involve sharing results and information at critical milestones during drug development or are necessary for a stalled development program to proceed are best addressed in formal meetings between FDA and sponsors (e.g., face-to-face meeting, teleconference, or written response only (WRO)). Timelines for FDA sending feedback to sponsors via the formal meeting process are described in Prescription Drug User Fee Act (PDUFA) and Biosimilar User Fee Act (BsUFA) agreements and in FDA’s formal meetings guidances. This FDA feedback includes: preliminary comments, final meeting minutes, and responses to questions posed in WRO requests.
• Hundreds of supporting documents might be submitted to an IND during its life cycle that require varying degrees of review and for which communication with the sponsor may be needed. Some submissions have regulatory-mandated timelines for reviewing and providing feedback to the sponsor that are described by statute or regulation (e.g., some safety-related submissions, complete response to clinical hold) while other submissions have FDA-established goals for review and feedback (e.g., in a MAPP). These latter submission types include some safety-related submissions, drug development submissions without regulatory timelines where communication to the sponsor is often critical and recommended (e.g., a new protocol or protocol amendment), and other submissions where communication with the sponsor may be needed.

The draft guidance also says, “all other sponsor inquiries, received via telephone, email, or in a submission (i.e., a submission without a review timeline described in a MAPP), that include specific questions for which sponsors are seeking FDA feedback, FDA project managers will strive to acknowledge such communications via telephone or email within three business days of receipt by the FDA project manager. FDA’s acknowledgment will:

1. Include the response itself, if available within the acknowledgment time frame;
2. Include an estimated time frame for division response to question(s);
3. Inform the sponsor that its question(s) involve consultation with other FDA parties (e.g., policy questions where legal input is necessary, questions about combination products where other centers are involved) and therefore an estimated response time frame will be forthcoming;
4. Recommend that the sponsor submit a formal meeting request (e.g., face to face, teleconference, or WRO); or
5. Recommend that the sponsor contact another specialized functional area in FDA (e.g., Import/Export, orphan products or rare diseases, pediatric therapeutics).”

The Agency states that, although it strives to adhere to all established/estimated timelines, it is not always possible. If sponsors experience delays in obtaining the FDA’s responses, the document provides a recommended approach, which should be taken sequentially.

For additional details on FDA recommendations for IND-related communication, view the draft guidance here.

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