PFDD: Draft guidance seeks to demystify clinical outcomes assessments

Regulatory NewsRegulatory News | 30 June 2022 |  By 

The US Food and Drug Administration (FDA) this week issued a sweeping draft guidance intended to help stakeholders incorporate patient experience data through the use of meaningful clinical outcome assessments (COAs).

On 29 June, the FDA published a draft guidance titled, Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments. It’s the third in a series of four guidances the agency is developing to further field of patient-focused drug development (PFDD); the final guidance will focus on incorporating COAs into endpoints for regulatory decision-making. (RELATED: FDA’s first patient-focused drug development guidance now final, Regulatory Focus 17 June 2020; PFDD: FDA finalizes guidance on identifying what’s important to patients, Regulatory Focus 28 February 2022)

 Broadly speaking, the new draft guidance outlines FDA’s expectations for how stakeholders, including patients, caregivers, researchers and sponsors, should collect, justify, develop and model patient preference data for product development and regulatory decision-making.
“This document provides guidance that is generally applicable to COAs, including patient-reported outcome (PRO), observer-reported outcome (ObsRO), clinician-reported outcome (ClinRO), and performance-based outcome (PerfO) measures,” the agency noted. “[It] is intended to help sponsors use high quality measures of patients’ health in medical product development programs.”
FDA says that ensuring high quality measurement is not just important for understanding what was measured in the clinical trial but also what matters to patients, adding that it is also important for evaluating the effectiveness, tolerability, and safety of treatments and avoiding misleading claims.
Ultimately, the objective is to gather patient preference data that goes beyond standard efficacy data that helps regulators understand how patients may benefit from a treatment.
FDA notes the draft guidance takes into consideration new developments research and applications of COAs to derive clinical trial endpoints since the agency released a 2009 guidance on patient-reported outcomes. That includes the fact that patients and caregivers have increasingly been integrated into the drug development process and better understanding of how COAs can be used in clinical trials.
The guidance goes on to describe four different types of COA measurements including PROs, ObsROs, ClinROs and PerfOs, and it discourages the use of proxy-reported outcome measures as COAs.
“A proxy-reported measure is an assessment in which someone other than the patient reports on patient experiences as if the individual were the patient,” the agency said. “FDA acknowledges that there are instances when it is impossible to collect valid and reliable self-report data from the patient. In these instances, it is recommended that an ObsRO measure be used to assess the patient’s behavior rather than a proxy-reported measure to report on the patient’s experience.”
FDA said that digital health technologies (DHT) such as certain wearables and software applications may be used as part of COA measurements to assess patient preferences. In some cases, the agency also notes that a combination of COA measurements may be used, but composite measures are beyond the scope of the guidance.
Another important aspect of the guidance is clarification from FDA on what COAs regulators consider "fit-for-purpose.” The agency said whether a COA is fit-for-purpose depends on whether the level of validation associated with a medical product development tool is sufficient to support its use within the context of the trial.
“Fit-for-purpose in the regulatory context means the same thing as valid within modern validity theory, i.e., validity is ‘the degree to which evidence and theory support the interpretations of test scores for proposed uses of tests,’” FDA wrote.
Sponsors should also provide reasons for the evidence they collect when supporting the use of a COA over other measurements according to FDA. The agency said it needs to understand the sponsor’s rationale and evidence which they expect will facilitate conversation between the agency, sponsors and measurement developers on the best COA within its context of use.
To help sponsors with that conversation, FDA has listed eight components for considering evidence-based rationale when proposing a COA as fit-for-purpose in an easy-to-read table. It touches on topics such as how the COA measurement captures important aspects of the concept of interest, the method of scoring responses to the COA is appropriate for assessing the concept of interest, scores from the COA correspond to the specific health experience the patient has related to the concept of interest, and the scores are sufficiently sensitive to reflect clinically meaningful changes within patients over time in the concept of interest within the context of use.

“Though scores on the measure might correspond to the real experiences of patients, the assessments might not have enough sensitivity to detect consequential changes within patients over the duration of a clinical trial,” FDA emphasized. “Thus, it is important to show evidence that the scores are sensitive enough to detect such changes.”
In the draft guidance FDA also proposes a “Roadmap to Patient-Focused Outcome Measurement in Clinical Trials” that may help sponsors develop their clinical trial plans to collect COA data.

It starts out with understanding the disease or condition from different perspectives including the patient and caregiver perspective, the natural history of the disease/condition, what subpopulations have been associated with it, and input from other experts on the disease such as health care providers. It then asks sponsors to conceptualize the clinical risk/ benefit profile of potential treatments, before selecting or developing potential COAs, and then narrowing down the fit-for-purpose COAs that are most meaningful for regulators and providing rationales.
FDA notes that the roadmap is just a suggested path and sponsors may present their own plans for developing the right COAs to the agency.
“Sponsors and COA developers are not required to use this approach, and it may not fit every development program, but it has worked well for a number of COA,” the agency said. “FDA recommends sponsors seek FDA input as early as possible and throughout medical product development to ensure COAs are appropriate for the intended context of use.”
Stakeholders can comment on the draft guidance on under docket no. FDA-2018-N-2455 until 28 September.


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