Investigational new drug application (IND) sponsors communicating with the US Food and Drug Administration (FDA) during the various drug development phases now will have a new set of best practices to consult with prior to their meetings thanks to draft guidance released by FDA on Friday.
The communications between FDA and industry are often opportunities to share cirtical 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’s important that agency-industry interactions “be conducted efficiently and consistently, with clear, concise, and timely communication,” FDA says in announcing the guidance.
Milestone meetings include pre-IND, end-of-Phase 1, end-of-Phase 2, and pre-NDA/BLA (new drug application/biologics license application) 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,” the agency says.
In select circumstances, a face-to-face meeting or teleconference pre-IND meeting may be granted, FDA says. Pre-submission 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 more major issues, such as identifying studies intended to establish the drug’s safety and effectiveness, discussing the status of pediatric studies and discussing appropriate statistical analysis methods or results of analyses.
FDA 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.”
Both FDA and sponsors have different views of what constitutes the IND-phase of development. From FDA’s perspective, the agency says the IND phase spans the time from the first IND-related submission (including a pre-IND meeting request) to the submission of a marketing application.
From the sponsor’s perspective, FDA says, drug development is not limited to the IND phase because it also includes drug discovery and preclinical compound work before an IND submission, including clinical trials conducted in other countries outside the IND.
Each year, sponsors and FDA engage in thousands of formal and informal communications, including meetings and teleconferences, during the IND phase.
At the sponsor’s request, FDA will, if possible, provide advice on specific matters.
“Examples include giving advice on the adequacy of technical data to support an investigational plan, the design of a clinical trial, and whether proposed investigations are likely to produce the data and information needed to meet requirements for a marketing application. Because the complexity and importance of material submitted to an IND will vary by therapeutic indication and development stage, the review divisions retain the flexibility to determine the extent of review and feedback provided for each submission,” FDA says
For drugs developed under expedited programs, such as breakthrough therapy and fast track programs, sponsors receive “more intensive guidance on an efficient drug development program with increased interactions and communications with FDA, including meetings.”
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.
During drug development there are circumstances under which it is appropriate for sponsors to directly contact FDA project managers other than the review division RPM in FDA’s Center for Drug Evaluations and Research (CDER). These 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.
CDER and FDA’s Center for Biologics Evaluation and Research (CBER) also say they “are aware that at times sponsors wish to communicate directly with reviewers assigned to their IND” but such “communications are strongly discouraged and sponsors should not directly contact FDA reviewers. It is critical that sponsor inquiries be directed to the review division RPM to ensure that requests are appropriately communicated to and considered by the review team members, including supervisors as appropriate,” FDA says.
Types of advice that drug sponsors can seek out during the life cycle of drug development can vary according to the experience of the sponsor and include topics such as:
- 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.
Shift in Work
The guidance will be welcomed by investigational new drug application (IND) sponsors, though 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.
And as for 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.”
When sponsors encounter such delays in obtaining FDA response, FDA advises the sponsor to contact (sequentially):
- 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.
Use of secure email can allow for transparent communications between FDA and sponsors, although the agency notes that “it is not a substitute for formal submissions (e.g., new INDs and amendments); formal submissions should be submitted to the respective center’s document room (paper submissions) or via the electronic gateway, as applicable.”
FDA communication via unsecure email also cannot include commercial confidential information, particularly in regard to trade secrets, manufacturing, or patient information so sponsors should establish secure email with FDA to allow for informal communications that may include commercial confidential information.
Sponsors should contact the Office of Information Management (OIM) to request secure email. OIM provides requestors with general industry standard practices and instructions on how to obtain FDA digital certificates but does not otherwise provide outside support.
FDA Draft Guidance on Best Practices for Communication Between IND Sponsors and FDA During Drug Development Guidance for Industry and Review Staff