Review of the Food and Drug Administration's Center for Drug Evaluation and Research Program for New Molecular Entities: Trends and Regulatory Requirements in Mid-Cycle Communications.

The United States Food and Drug Administration (FDA) implemented "the Program" in 2012 to promote greater transparency and increased communication between the FDA and applicants of New Molecular Entity (NME) New Drug Applications (NDA) and original Biologics License Applications (BLA). We examined 128 publicly available NME NDA and original BLA approval packages reviewed and approved under the Program with the goal to educate regulatory professionals about the content and timing of communications from FDA to the Sponsor. This research found that the timing of communications between FDA and the Sponsor through the Mid-Cycle Communication (MCC) was consistent with the 21st-century Desk Reference Guide (DRG); 90% of internal FDA Mid-Cycle Meetings, MCCs with the applicant, and corresponding issuance of MCC minutes were within the target date. The content and format of the MCC were also consistent with the DRG and across disciplines. Almost all MCCs reviewed included a discussion on significant review issues, including major safety concerns. FDA's preliminary opinion on the necessity of a Risk Evaluation and Mitigation Strategy (REMS), which was predictive of REMS requirement at approval. The FDA's MCC comment on advisory committee meeting plans was highly predictive; if the MCC indicated an AC was planned, an AC meeting was held 91% of the time. With respect to the MCC, this research found the DRG and relevant FDA Manual of Policies and Procedures to be reliable resources to predict the FDA's planned actions associated with the review of a NME NDA or original BLA.

The Patient Voice: Exploring Treatment Preferences in Participants with Mild Cognitive Concerns to Inform Regulatory Decision Making.

OBJECTIVE: We aimed to assess the feasibility of developing a discrete-choice experiment survey to elicit preferences for a treatment to delay cognitive decline among people with a clinical syndrome consistent with early Alzheimer's disease, including the development of self-reported screening criteria to recruit the sample. METHODS: Using input from qualitative interviews, we developed a discrete-choice experiment survey containing a multifaceted beneficial treatment attribute related to slowing cognitive decline for respondents with self-reported cognitive concerns. In two rounds of in-person pretest interviews, we tested and revised the survey text and discrete-choice experiment questions, including examples, language, and levels associated with the Alzheimer's Disease Assessment Scale-Cognitive Subscale, along with a set of de novo self-reported questions for identifying respondents who had neither too mild nor too advanced cognitive decline. Self-reported memory and thinking problems were compared with symptoms from studies of patients with early Alzheimer's disease (e.g., mild cognitive impairment, mild Alzheimer's disease) to determine whether those studies' recruited patients were similar to our anticipated target population. Round 1 pretest interviews resulted in significant simplifications in the survey instrument, revisions to the inclusion and exclusion criteria, and revisions to the screening process. In round 2 of the pretest interviews, the ability of participants to provide consistent responses to the self-reported screening questions was further assessed. In addition, to evaluate participants' ability to understand and independently complete the discrete-choice experiment survey, two interviewers independently evaluated each participant's ability to make trade-offs in the discrete-choice experiment questions and to understand the content of the survey. RESULTS: Round 1 (15 pretest interviews) identified challenges with the survey instrument related to the complexity of the choice questions. The screening process did not screen out seven respondents with more advanced cognitive decline, as determined qualitatively by the interviewers and by these participants' inability to complete the survey. The survey instrument and screening criteria were revised, and an initial online screener was added to the screening process before round 2 pretests. In round 2 pretests, 12 participants reported cognitive problems similar to the target population for the survey but were judged able to understand and independently complete the discrete-choice experiment survey. CONCLUSIONS: We developed self-reported screening criteria that identified a sample of individuals with memory and thinking concerns who were similar to individuals with clinical symptoms of early Alzheimer's disease and who were able to independently complete a simplified discrete-choice experiment survey. Quantitative patient preference studies provide important information on patients' willingness to trade off treatment benefits/risks. Adapting the technique for patients with cognitive decline requires careful testing and adjustments to survey instruments. This work suggests it is the severity of cognitive impairment, rather than its presence, that determines the ability to complete a simplified discrete-choice experiment survey.

Review of the Food and Drug Administration's Center for Drug Evaluation and Research Program for New Molecular Entities: Trends and Regulatory Requirements in Acknowledgment Letters and Filing Communications.

The United States Food and Drug Administration (FDA) implemented the PDUFA V New Molecular Entity (NME) Program (the Program) in 2012 to promote greater transparency and increased communication between the FDA review team and applicants of NME New Drug Applications (NDA) and original Biologics License Applications (BLA). We reviewed 128 publicly available NME NDA and original BLA approval packages, submitted after October 2012 and approved by July 2018. Our research had a goal to educate regulatory professionals about the content and timing of communications from FDA to the Sponsor for approved drugs reviewed under the Program. This research found that communications issued within the first 74 days were consistent with the 21st Century Desk Reference Guide (DRG) targets; forecasted dates of other projected interactions included in the Filing Communication (FC) letter were often within 4 weeks of target. The content and format of the FC letter became more consistent with time, often including templated text. Approximately half the FC letters contained at least 1 filing review issue; however, not all appeared to be substantive. The FDA's preliminary comment on advisory committee meeting plans were predictive; 95% correlated with the need (or lack thereof) for an advisory committee meeting. Approximately 62% of FC letters contained actionable labeling comments, with nearly all related to editorial changes. With respect to the FC letter, this research found the DRG and relevant FDA Manual of Policies and Procedures to be reliable resources to predict the FDA's planned actions associated with the filing and review of a NME NDA or original BLA.