FDA Final Guidances Expand on Patient Advisers, PROs in Device Trials
The FDA is gearing up its efforts for sites and sponsors to increase their use of patient advisers in clinical trials for medical devices.
Two new final guidances issued last week by the FDA offer clarity to sites and sponsors on the agency’s expectations when it comes to using patient engagement — specifically, the consultation of so-called “patient advisers” — and patient-reported outcomes (PROs) in the design and conduct of medical device trials.
The impact of the agency’s recommendations will be two-fold: first, sponsors and sites are being encouraged to increase the use of patient advisers in their device trials to improve the ways they design studies and interact with participants. And second, there is now specific advice on how PROs are to be gathered in device trials and analyzed by sites.
In the 11-page guidance on patient engagement, the agency recommends having a diverse group of patient advisers offering feedback on a device trial, including racially and ethnically diverse advisers.
The guidance stresses that patient advisers — individuals who have experience living with a disease or condition but who are not trial participants, participant caregivers or healthcare professionals — can provide helpful feedback for device trials and goes into greater depth on who exactly may qualify to be a patient adviser in a study.
The FDA also provided sites and sponsors with considerations on interacting with patient advisers, the benefits of using patient advisers to inform trial design/conduct and the engagement activities the agency doesn’t consider subject to its regulations, including institutional review board (IRB) regulations.
“Successful adoption of legally marketed medical devices increasingly depends on patient acceptance of that technology and patients being more engaged in the healthcare process, along with demonstrated public health benefits. The FDA believes effective patient engagement can help mitigate some of the practical challenges to robust clinical studies,” the agency said.
The early planning phases of a device trial are a great time to bring in patient advisers, as getting their input early on gives them the opportunity to inform the study design, the guidance says. This is especially true for innovative areas and new target patient populations. Patient advisers should also be considered after a device trial has concluded to gather their thoughts on improving future trials.
The FDA says that the difference between the draft guidances and the final guidances on patient engagement and PROs in device trials is not major although industry feedback was used to clarify several issues. Specifically, the finalized PRO guidance clears up language on PRO instrument scores, expands upon previous examples and clarifies the applicability of PRO instruments in device trials. The finalized patient engagement guidance clears up terminology, provides more background on the agency’s patient engagement efforts and clarifies how sponsors can gather specific feedback from the agency on their patient engagement plans and patient-centered study designs.
The patient engagement draft guidance was published in September 2019 while the PRO draft guidance came out in August 2020.
The 13-page guidance on PROs emphasizes that the measurements can serve as useful assessments across the product life cycle, such as in early feasibility/feasibility studies, pivotal trials and postmarket trials, as well as in the early design and development stages and in postmarket surveillance efforts.
PROs, the agency says, must be proven “fit for purpose.” For example, patients with late-stage disease may have different symptoms or perspectives than patients in early stage. Because of this, questions, statements or tasks on a PRO developed by a sponsor and implemented by a site for early-stage patients may not be useful or relevant for patients whose diseases have progressed.
The agency is letting sites and sponsors know that it’s important that patients can easily understand the PRO. Use plain language when writing the PRO’s instructions, items, recall period (the span of time patients are asked to consider in their response) and response options so that responses are informed no matter what the patient’s literacy levels are. Also, using appropriate points of reference, activities or symptom wording can assist patients in reporting their health status as accurately as possible. For instance, a PRO assessing visual function may work best using items that assess the difficulties patients have with common daily activities, such as reading books, menus and drug labels.
It’s also critical to be clear, in the protocol and statistical analysis plan, about the PRO’s role in the trial. For instance, the FDA may want to see different validity evidence for a PRO used to measure a secondary effectiveness endpoint compared to one used to descriptively evaluate a safety endpoint, the guidance states. To be crystal clear, provide a statement of what is being measured, how it’s being measured/interpreted and how results will be conveyed in the labeling.
In addition, describe the specific role of the PRO in the development and evaluation process, including defining the endpoint being captured and the estimated amount of clinically meaningful change being measured. For example, a PRO for pain intensity could list reduction in pain intensity as its primary effectiveness outcome and the endpoint as a specified reduction in a pain intensity scale score at three months compared to baseline.
Sponsors and sites should also strongly consider using existing, validated PROs rather than developing new ones, as modifying or adapting existing PROs may require the least amount of work. Modifications to existing PROs should be outlined clearly in submission documentation (the PRO dossier or appendix), according to the guidance. In addition, it’s helpful for the agency when sponsors/sites note existing publications or data that support the use and/or validity of the modified PRO. Sponsors and sites should also note that new validity data may be necessary depending on the extent of the changes. The FDA’s Center for Devices and Radiological Health maintains a noncomprehensive list of PROs that have appeared on device labels based on recent approvals and classifications.
In gathering validity data for PROs, sponsors and sites should think about looking to real-world evidence (RWE) as an alternative source, the guidance recommends. Similarly, professional and patient-driven registries may also help to identify patients who can provide validity evidence. Those sponsors and sites that are proactively developing or modifying a PRO for use in the future may also want to think about using early feasibility, phased clinical trials, pivotal trials, postmarket studies and/or RWE data platforms to gather validity evidence. This may be less costly and more efficient than running a separate PRO validation study.