By Joshua Taylor, Ph.D., R.A.C. (US), Regulatory Scientist The Prescription Drug User Fee Act (PDUFA) reauthorization for fiscal years (FYs) 2018 to 2022, known as PDUFA VI, includes language to facilitate the development and application of exposure-based, biological, and statistical models derived from preclinical and clinical data sources, referred to as model-informed drug development (MIDD) approaches. MIDD approaches, when successfully applied, can improve clinical trial efficiency, increase the probability of regulatory success, and optimize drug dosing/therapeutic individualization in the absence of dedicated trials. PDUFA VI mandates that FDA will:
- develop its regulatory science and review expertise and capacity in MIDD approaches;
- convene a series of workshops to identify best practices for MIDD;
- conduct a pilot program (beginning in FY 2018) for MIDD approaches, during which an initial and a follow-up meeting on the same drug development issues will be held with a sponsor;
- publish draft guidance, or revise relevant existing guidance, on MIDD (by end of FY 2019); and
- develop or revise, as appropriate, relevant Manuals of Policies and Procedures or Standard Operating Policy and Procedures, and/or review templates and training, to incorporate guidelines for the evaluation of MIDD approaches (by end of FY 2021).
The pilot program for meeting with FDA regarding MIDD approaches was posted to the Federal Register on April 16, 2018, and FDA began accepting meeting requests the next day. Successful applicants to the pilot program will be granted two meetings with FDA (initial and follow-up), separated by 120 days. As described by Raj Madabushi, Ph.D., of CDER’s Office of Clinical Pharmacology, “[u]nder the pilot program, an internal FDA group will review programs with limited clinical data, and where non‑traditional sources of evidentiary support may be helpful. The pilot program aims to advance the use of MIDD as part of the regulatory pathway for drugs, helping both FDA and sponsors to work through issues around developing models, establishing their credibility, and determining how they can be used to address regulatory or drug development issues.” In an introduction to the pilot program, FDA explains that any drug or biologic company with an active Investigational New Drug (IND) or pre-IND number for the relevant development program is eligible to participate in the pilot program, as are any interested consortia or software/device developers so long as they come in partnership with a drug development company. The pilot program excludes statistical designs that involve complex adaptations, Bayesian models, or other features requiring complex simulations. Because only two to four paired‑meeting requests will be accepted per quarter during the pilot program, FDA will prioritize applications that are related to:
- Dose selection or estimation (e.g., for dose/dosing regimen selection or refinement)
- Clinical trial simulation (e.g., based on drug-trial-disease models to inform the duration of a trial, select appropriate response measures, or predict outcomes)
- Clinical trial simulation (e.g., based on drug-trial-disease models to inform the duration of a trial, select appropriate response measures, or predict outcomes)
Meeting requests are submitted electronically to the relevant application (i.e., IND or pre-IND), and “MIDD Pilot Program Meeting Request for CDER [or CBER, depending on the application]” must be placed in the subject line. FDA will notify applicants during the first week of each quarter whether the meeting request was accepted or denied. If FDA accepts the meeting request through the pilot program, meeting packages must be submitted to FDA no less than 30 days before each of scheduled meetings (initial and follow-up). The expected content of the meeting request and packages is provided in the aforementioned introduction to the pilot program, and FDA will send a meeting summary to the sponsor within 60 days of each meeting. Importantly, MIDD approaches have the potential to help in all phases of drug development and may allow sponsors to perform smaller or shorter clinical trials or to carry out fewer postmarketing studies. If you think MIDD approaches may help your development program, this new opportunity to work with and get feedback from FDA through the pilot program is well worth your consideration.