In December, the FDA issued a guidance describing 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. The guidance applies to communications between IND sponsors and FDA during the IND phase of drug development, including biosimilar biological product development (BPD).
Guidance
Communications between FDA and industry are often opportunities to share information on clinical trials and for the agency to provide advice on trial design, dose selection, nonclinical study requirements, and manufacturing and facility issues. It is important that agency-industry interactions “be conducted efficiently and consistently, with clear, concise, and timely communication,” FDA says in announcing the guidance.
Pre-IND Meetings
Pre-IND meetings, which can prevent clinical hold issues, can be valuable for understanding proof of concept and initiating dialogue with the agency as the company develops 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,” FDA says.
FDA further says it “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.”
Interaction with FDA
The review division regulatory project manager (RPM), who has comprehensive knowledge of the drug and its regulatory history, is the primary point of contact for communications between IND sponsors and FDA during the life cycle of drug development. The RPM is the contact for facilitating the timely resolution of technical, scientific, and regulatory questions, conflicts, or communication challenges between the sponsor and the review team, FDA says.
Other project managers can include:
- CDER’s Office of Pharmaceutical Quality regulatory business project managers, who manage meeting requests, regulatory submissions, and other inquiries related to chemistry, manufacturing, and controls, including facility and product quality issues;
- CDER’s Office of Surveillance and Epidemiology safety regulatory project managers, who manage sponsor requests for proprietary name review; and
- CDER’s Formal Dispute Resolution Project Manager, who manages sponsor requests for resolving scientific and/or medical disputes that cannot be resolved at the division level.
Types of Advice
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 drug development, sponsors often solicit advice at critical junctures in their development programs. 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); and
- 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); and
- The proposed pediatric development plan and dosing.
Complex questions that involve interpretation of regulations and statutes, or the application of existing FDA policy to novel circumstances, can demand additional vetting and response time, FDA says.
More on Communication
FDA notes that the guidance does not apply to communications or inquiries from industry trade organizations, consumer or patient advocacy organizations, other government agencies or other stakeholders not pursuing an IND development program.
Regarding companies that fail to respond, FDA notes that later drug development can be negatively affected by sponsors’ delay or failure to respond to FDA, though the timing of FDA’s response may also be negatively affected if the review team experiences “an unexpected shift in work priorities or team staffing. In these cases, the FDA project manager will try to keep sponsors apprised of changes to the estimated response timeline.”
Regarding delays in obtaining FDA response, FDA advises the sponsor to contact:
- The appropriate FDA project manager, typically the review division RPM, for a status update after the expected amount of time (e.g., the timelines described in a MAPP) for a FDA response that has passed;
- The appropriate FDA project manager, typically the review division RPM, for a status update after the estimated response time has passed (i.e., the estimated FDA-response date communicated to the sponsor previously);
- The appropriate FDA project manager’s next level supervisor for assistance in eliciting a response from the project manager; and
- The appropriate division or office management officials for assistance in eliciting a response from the project manager; or
- CDER’s or CBER’s Ombudsman for assistance in eliciting a response from the project manager.