Best Practices for FDA Communication with IND Sponsors

On December 9, 2015, the FDA released a draft guidance entitled, “Best Practices for Communication Between IND Sponsors and FDA During Drug Development.” The guidance attempts to promote timely, transparent, and effective communication between IND Sponsors and the FDA.

The draft guidance includes the following best practices for FDA communication with IND Sponsors:

• “FDA's philosophy regarding timely interactive communication with IND Sponsors as a core activity.
• The scope of appropriate interactions between the review team and the Sponsor.
• The types of advice appropriate for Sponsors to seek from FDA in pursuing their drug development program.
• General expectations for the timing of FDA response to IND Sponsor inquiries.
• Best practices and communication methods to facilitate interactions between the FDA review team and the IND Sponsor during drug development.
• Expectations for appropriate methods, including the frequency, of such communications.”

Meeting Types & FDA Best Practices

In the draft guidance, the FDA states that “effective and timely communication between FDA and Sponsors promotes understanding of mutual goals and is invaluable to the drug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.” As such, the Agency will abide by the following best practices when communicating with Sponsors of IND applications:

• “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.”

FDA meetings are essential for both Sponsors and the Agency. They help resolve questions and issues that may come up during drug development and allow Sponsors to confirm that they are on the same page as the FDA. In order for Sponsors to achieve efficient drug development, it is absolutely critical that they learn FDA's views on all applicable requirements prior to submitting an application.

The draft guidance states that these meetings occur at critical points in drug development, and include:

1. “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.
2. EOP1 meetings (end of phase 1) are useful to review and reach agreement on the design of phase 2 controlled clinical trials (to support safety and efficacy) 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. The EOP1 meeting is critical for a successful product development, and may qualify for fast track designation in some cases.
3. EOP2 meetings (end of phase 2) 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. If the Sponsor cannot reach an agreement with the FDA during the EOP2 meeting, the Sponsor must have follow-up discussions to resolve any remaining issues before proceeding to phase 3.
4. 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, data set 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 draft guidance also provides a comprehensive list of best practices for meeting-related communication between Sponsors and the FDA. Click here to see a full list of meeting-related best practices is available.

In addition to meeting-related best practices, the draft guidance provides Sponsors with additional recommendations regarding:

• Written Correspondence from FDA,
• Submissions from Sponsors,
• Acknowledging Receipt of Communication,
• Email Between FDA & Sponsors,
• General Telephone Calls Between FDA & Sponsors,
• Faxes Between FDA & Sponsors,
• Use of Out-of-Office Messages by FDA & Sponsors, and
• Resources for Sponsors.

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).

• 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.

Are you in the process of developing a new drug, preparing for a pre-IND meeting, or developing an IND for submission to the FDA?

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