By Andrew Emmett, director of science and regulatory affairs, BIO
This year’s BIO International Convention is occurring at a critical time in our industry. For companies that need to quickly understand and adapt to recent requirements by the FDA, the convention presents an opportunity to come together with other industry leaders for key discussions and idea sharing.
BIO has long supported efforts to enhance the consistency, predictability, and transparency of the process for selecting appropriate postmarketing commitments (PMCs) and postmarketing requirements (PMRs). The FDA recently issued draft guidance on Postmarketing Studies and Clinical Trials — Implementation of Section 505(o) of the Federal Food, Drug, and Cosmetic Act. In light of the new FDA authority to require postmarket studies and trials under the Food and Drug Administration Amendments Act (FDAAA), it is important that the FDA and sponsors have a firm understanding of the statutory requirements and procedural considerations for making decisions on postmarket studies/clinical trials.
The FDA commissioned a study on the PMC/PMR process and issued harmonized staff policies for selecting postmarketing studies. Continued refinement of the processes for selecting PMCs and PMRs will help to ensure that the FDA and sponsors can agree upon medically appropriate, ethical, scientifically sound, and operationally feasible studies that can be completed in the agreed upon time frame and that will serve the interest of the public health. Ultimately, these studies will contribute to the body of knowledge around a product’s benefit and risk profile and help to inform physician prescribing decisions and enhance patient care.
The draft guidance recognizes that under FDAAA, postmarket studies and clinical trials can be required if, based upon appropriate scientific data, a study or trial is warranted to assess a known serious risk related to the use of the drug involved, assess signals of serious risk related to the use of the drug, and identify an unexpected serious risk when available data indicate the potential for a serious risk. It is important that the FDA consider the potential need for a study, if any, and what the potential purpose of a study would be, prior to addressing the type of study or clinical trial that might be warranted. Clearly, Congress did not intend that all drug approvals would warrant a postmarket study or clinical trial, so it is important to first identify what the purpose of a study or trial might be, and whether a study or trial can address that purpose. Further, BIO believes that illustrations or examples of situations that fit the above three purposes would be useful to include in the guidance.
Best practices suggest that interactions between the FDA and sponsors early in the review process and well in advance of the action date will encourage a selection of studies that will result in the most valuable and medically relevant information for patients, physicians, and regulators. Consistent with ongoing implementation of the Good Review Management Principles (GRMPs), the FDA’s commitment to notifying sponsors of target dates for key review milestones as part of the 74-day letter, including discussion of PMRs/PMCs, represents a significant enhancement in the FDA’s review process. However, there are additional considerations to maximize the value of this interaction for the FDA and sponsors.
First, the draft guidance states that the FDA plans to send a list of potential PMRs/PMCs near the target date, giving the sponsor the opportunity to discuss design and timing with the FDA. However, the draft guidance is not specific enough regarding when the applicant can expect to receive feedback from the FDA. Of paramount concern for sponsors is that adequate time is included to have a dialogue with the FDA on these important requirements. Sufficient time must be afforded for PMR discussions to enable adequate design and planning of the study or trial.
The guidance should discuss a process or timeline for this interaction as a standard provision. In addition, there should be at least four to six weeks to permit a dialog between sponsor and OSE/OND prior to issuance of a PMR. And when PMRs are part of a REMS (risk evaluation and mitigation strategy), the dialog should begin earlier (end of phase 2 or preNDA [new drug application]).
Second, the draft guidance should clearly state that prior to the FDA sending a list of potential PMRs and PMCs to the applicant, there should be thorough discussions regarding each of the three conditions for a PMR. Applicants should have adequate insight into the FDA’s process and rationale for determining that a PMR is required or a PMC is warranted so that there is opportunity for the applicant to develop alternate ways to further evaluate signals of serious risk. Transparency of this process is particularly important with regard to PMRs to assess signals of serious risk or unexpected potential risks. Conducting a postmarket clinical trial to identify an unexpected serious risk not discovered during the pivotal trial is challenging because it is built on hypothesis and may require a very large trial. A study designed to identify a potential risk should be limited to a “study” as defined in this draft guidance (e.g. observational, animal, laboratory). As part of the discussion, the FDA’s assessment of the serious risk should take into consideration the patient population and the disease severity, and the FDA should qualify the signal by qualitative and quantitative analyses.
Finally, after a sponsor has submitted the “timetable for completion of the study or clinical trial for the PMRs and a schedule for milestone submissions and final reports for PMCs,” the FDA will decide “whether the proposed timetable will be realistic and provide for timely completion of the study or trial.” However, the draft guidance is silent regarding the time frame for FDA feedback on the proposed timetable. A reasonable time period should be identified to acknowledge agreement with the proposed timetable and minimize the potential for misunderstandings regarding the expected deliverables. The guidance also should include language defining the duration that the FDA would have to comment on a particular protocol. At a minimum, we encourage the FDA to provide an acknowledgement within a reasonable time period that the submitted protocol will satisfy the intent of the PMR, or provide comments, if any.
THE VALUE OF EXAMPLES
In general, the use of examples in the draft guidance provides additional clarity and transparency around the criteria for PMRs and PMCs. However, the examples can be made more useful. First, the examples of categories of studies that would either be PMRs or PMCs are helpful, but there are few examples of PMCs. It would be useful if the lists were better balanced with examples in each category and offered more relevant and realistic examples of the types of studies that could be considered a PMR.
The draft guidance also could provide more illustration of the difference between the types of studies that are considered PMRs versus PMCs. Based on the examples provided, there may be instances in which some of the studies discussed in the draft guidance could be interchanged as PMRs or PMCs, depending on the data from individual product programs. For example, a study conducted by one sponsor as a PMC could be a required study (i.e. PMR) for another program because of its safety profile.
Lastly, the examples should be presented in a manner that clearly distinguishes between studies and clinical trials. A simple notation next to each example such as (Trial) or (Study) would suffice.
The draft guidance states that “an applicant’s failure to comply with the timetable, periodic report submissions, and other requirements will be considered a violation unless the applicant demonstrates good cause for the noncompliance,” and the FDA will determine what constitutes good cause. The FDA could provide additional explanation and examples in the guidance of what the agency considers “good cause” for failure to comply with planned milestones. This may include certain medical, ethical, and practical considerations that may constitute good cause for not completing a planned study or trial.
The draft guidance also states that “In determining the amount of a civil penalty, the FDA will consider the applicant’s efforts to correct the violation.” The draft guidance takes into account a sponsor’s good faith efforts to resolve a violation and the guidance should explicitly note that sponsors will be provided an opportunity to correct the issue before a civil monetary penalty (CMP) is imposed. The guidance further should clarify when CMPs would be imposed. For example, the guidance should be clear that CMPs should be imposed only for egregious violations rather than minor infractions, unless those violations are numerous and repetitive.