The Food and Drug Administration’s initiative to ensure patients’ perspectives, needs, and priorities are meaningfully incorporated into medical product development has culminated in the agency’s release of four guidance documents: The Patient-Focused Drug Development Guidance Series.¹ This series provides a framework for the collection of patient experience data using electronic clinical outcomes assessments or eCOA in clinical trials.  

The latest recommendations give a much-needed update to PRO guidance released in 2009. Over the past 14 years, the clinical trials industry has undergone significant changes: technological advancements, a global pandemic, as well as growing emphasis on capturing the patient voice and incorporating methods that reduce patient burden—including electronic patient-reported outcomes (ePROs) capture outside of the clinic.² All of these have accelerated the adoption of decentralized elements.  

So, how has the FDA recognized these industry shifts? This article provides a perspective on whether the new COA guidance aligns with the accelerated pace of progress currently occurring in the industry.
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The Guidance Basics: Data collection for clinical outcome assessmentce Basics

First, let’s review the definition of COA. According to the FDA, it is a measure that reflects or describes how a patient feels, functions, or survives.³ The definition of eCOA is no different, except that the measure is captured electronically.  

This new guidance, which consists of four separate documents—two of which are still in draft—focuses on the importance of, and methods for, capturing outcomes that are meaningful and central to patients. “What is important to patients is important to regulators,” Dr. Laura Lee Johnson, Director of Biometrics Division III at the FDA, said during a podcast about this new guidance.⁴  

Many of the familiar COA principles remain the same: The instruments must be fit-for purpose, measuring the concept of interest within the context of use. One key difference is that this guidance moves beyond a sole focus on PRO to evaluate all four types of COA—PRO, ClinRO, ObsRO and PerfO—acknowledging the role of site clinicians and observers in the collection of patient experiences as well as the assessment of their conditions.

Interestingly, the guidance says very little about a preferred mode of administration, choosing not to favor traditional paper instruments or electronic clinical outcomes assessments (eCOA), which are prominently used in decentralized clinical trials. One can assume the FDA does not consider it appropriate to arbitrate between paper and electronic reporting, preferring to leave the evaluation of how best to deploy COAs to trials sponsors based on their protocols and study populations. Many will find it disappointing that, despite a growing body of evidence,⁵ the agency still broaches a potential impact to comparability in the transition from paper to mobile devices. This is especially puzzling in light of the recent publication from an ISPOR Taskforce on this very topic.⁵

However, the through-line in the guidance shows strong support for digital data capture where relevant. In the words of Florence Mowlem, PhD, Vice President of Science at ObvioHealth: “The guidance may not explicitly say electronic is better, but it does highlight the benefits of technology.”  
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How does the guidance support eCOA in clinical trials?

Let’s look at the ways the guidance underscores the merits of technology for capturing COAs.
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Reducing Patient Burden  

The FDA strongly recommends delivering COAs in a way that is most convenient to patients, stating that minimization of patient fatigue and burden can “maximize the quality and completeness of information collected.”⁶ This section appears to implicitly support eCOA; research⁷ suggests that delivering a COA in an electronic format can reduce burden. For example, a 2020 study among oncology patients showed participants had “a positive attitude toward the use of technology to complete assessments and expressed (unprompted) a preference for electronic over paper completion.”^7(p1197)
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COA Frequency

The agency recommends consideration of “the natural course of the disease” when determining the timing and frequency of assessments, distinguishing between chronic, acute, and episodic diseases.⁶  

For episodic conditions, where an event triggers the need to capture data, the benefit of electronic data capture is self-evident. Rather than explicitly stating so in the guidance, the FDA does use a illustrative example where the use of electronic methods would best serve the collection of data related to an episodic event: The document says, in the case of urinary urgency, the patient could be asked to “record each urination episode and complete a short assessment immediately following the event.”⁶ This data would be difficult to capture on paper in real time, especially when the patient is at work or outside their home. Imagine a participant lugging paper questionnaires everywhere to capture these events as they occur—it’s an unrealistic request to make and would ultimately result in inaccurate data capture.
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Modifying COAs

The guidance also recognizes the benefits of using computer adaptive testing (CAT), which modifies eCOA questionnaires by using fewer questions to generate a sufficiently precise score for each patient. This reduces redundancy in questionnaires, making the assessment more efficient and less burdensome. This type of PRO cannot be done using a paper format, hence an indirect endorsement for ePRO.
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Digital Health Technologies (DHTs)

Perhaps the most explicit reference to the use of technology to capture outcomes occurs in the third guidance document—still in draft format—which includes a section on digital health technologies (DHTs).⁶  

The FDA backs the use of DHTs to capture data, including mobile apps (such as ObvioHealth’s ObvioGo^®) to administer eCOAs in clinical trials. Digital devices can also be used to capture PerfOs, according to the FDA—for example, conducting a “walk-test” using a device to measure how far a person can walk within a specified timeframe (This is referred to as ePerfO.).

Noticeably absent is the idea of passive or continuous data capture from sensors or wearables. Readers are instead referred to the DHT guidance document. Many in the industry were hoping for more clear-cut direction from the FDA on the use of DHTs for continuous data capture. In public comments, pharmaceutical companies—including Genetech and Novartis—asked for more context around the use of DHTs for COA purposes.⁸ In the past, this type of data has been referred to as “DHT-passive monitoring COAs,” but, in this recent guidance, it remained undefined.⁹  

Given the many comments, and the fact that the document remains in draft, it is possible that the FDA will make further updates to the guidance.  

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Conclusion

Despite the FDA’s reticence to express an explicit preference for electronic over paper data capture, they continue to encourage clinical researchers to use technology when appropriate. The FDA commissioner Robert Califf, MD, recently said he encourages “innovative trial designs and health technologies … to truly advance clinical trials and generate meaningful results.¹⁰ Trial sponsors should give serious consideration to the incorporation of the four categories of eCOA into their clinical trials. The benefits of electronic data capture are too compelling for the industry to ignore.

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References:

1. FDA. FDA Patient-Focused Drug Development Guidance Series for Enhancing the Incorporation of the Patient’s Voice in Medical Product Development and Regulatory Decision Making. FDA.gov. April 2023. Accessed October 4, 2023. https://www.fda.gov/drugs/development-approval-process-drugs/fda-patient-focused-drug-development-guidance-series-enhancing-incorporation-patients-voice-medical  

2. CDER. Core Patient-Reported Outcomes in Cancer Clinical Trials: Guidance for Industry. FDA. June 2021. Accessed October 5, 2023. https://www.fda.gov/media/149994/download  

3. FDA. Clinical Outcome Assessment (COA): Frequently Asked Questions. FDA.gov. December 2020. Accessed October 4, 2023. https://www.fda.gov/about-fda/clinical-outcome-assessment-coa-frequently-asked-questions

4. FDA. Guidance Recap Podcast | Selecting, Developing or Modifying Fit-for-Purpose Clinical Outcomes Assessments. FDA.gov. September 2022. Accessed October 5, 2023. https://www.fda.gov/drugs/guidances-drugs/guidance-recap-podcast-selecting-developing-or-modifying-fit-purpose-clinical-outcomes-assessments

5. O’Donohoe P, Reasner DS, Kovacs SM, et al. Updated Recommendations on Evidence Needed to Support Measurement Comparability Among Modes of Data Collection for Patient-Reported Outcome Measures: A Good Practices Report of an ISPOR Task Force. Value Health. 2023;26(5):623-633. doi: 10.1016/j.jval.2023.01.001

6. CDER. Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for Purpose Clinical Outcome Assessments. FDA. June 2022. Accessed October 5, 2023. https://www.fda.gov/media/159500/download  

7. Mowlem FD, Sanderson B, Platko JV, Byrom B. Optimizing electronic capture of patient-reported outcome measures in oncology clinical trials: lessons learned from a qualitative study. J Comp Eff Res. 2020;9(17):1195-1204. doi: 10.2217/cer-2020-0143

8. Craven J. Stakeholders want more clarity on concepts introduced in third PFDD draft guidance. Regulatory Focus. RAPS. October 2023. Accessed October 6, 2023. https://www.raps.org/news-and-articles/news-articles/2022/10/stakeholders-want-more-clarity-on-concepts-introdu  

9. Izmailova ES, Guo C, Coons SJ. Conflicting Terminology in Digital Health Space: A Call for Consensus. Applied Clinical Trials. February 2023;32(1/2). https://www.appliedclinicaltrialsonline.com/view/conflicting-terminology-in-digital-health-space-a-call-for-consensus

10. FDA. FDA Announces Additional Steps to Modernize Clinical Trials. FDA.gov. June 2023. Accessed October 4, 2023. https://www.fda.gov/news-events/press-announcements/fda-announces-additional-steps-modernize-clinical-trials