Alison Golla, Clinical Project Manager
The Value of PROs
In this long overdue era when data from the patient perspective are being used to assess the safety, effectiveness, and value of medical products, the acceptance and use of Patient-Reported Outcomes (PROs) in clinical trials continues to increase. The impetus is largely due to an overall shift from a system based solely on patient risk to a benefit-risk strategy informed, in part, by patient input.
The growing trend towards patient engagement throughout all stages of product development stems not only from the pleas of patient advocacy groups, but from professional societies, regulatory bodies and third-party payers alike. From the year 2000 through 2015, the Center for Devices and Radiologic Health (CDRH) observed over a 500% increase of pre-market submissions including PRO measures (PROMs)1. In 2017, in alignment with CDRH strategic priorities, more than 75% of approved, pivotal original and new study IDEs included PROs in support of the submission2. FDA’s first guidance on PROs, in 20093, interprets what is meant by “well-defined and reliable” for PRO measures intended to provide evidence of treatment benefit. Since this time, several guidance documents have been published from various organizations on different aspects of PRO use such as PROM development,4-6 PRO-specific protocol guidance7 and collection and reporting.8-10
The integration of PROs with traditional endpoints in clinical trials provides a comprehensive evaluation of the intervention under study. Data derived from PROs can provide valuable evidence for benefit-risk assessments that can be used to communicate the effect of a treatment on patient symptoms, functioning and quality of life on medical device labels and are subsequently useful for market adoption and consideration as part of value-based framework assessments.3
Selecting the Right Tool
The value PROs add to clinical trial data is well accepted; the challenge is in developing or selecting the right instrument for your trial to produce clinically meaningful data in order to meet regulatory requirements for labeling. Your endpoints or measurement goals should drive your instrument selection such as what areas (domains) would be expected to change with the study intervention (e.g., pain, functional status, anxiety).
Initial steps in selecting a PRO appropriate for your study include conducting a thorough literature search in the therapeutic area to truly understand your patient population and determine if a properly validated disease-specific instrument already exists. Consulting with clinicians, key opinion leaders, investigators, professional societies, and patient advocacy groups in the therapeutic area can also be a tremendous resource.
PROM selection considerations:
– Determine what the PRO-related research questions are early in the study design
– Identify the particular domains affected by the condition and those expected to change with the intervention within the timeframe of the study
– Select a PRO that is proximal to the disease or treatment (i.e., symptoms/treatment side effects)11
– Review the PROM description to assess what domains of function it measures and the appropriate developmental age for administration
– Determine whether the individual PRO questions are relevant to the study population and study question of interest
– Evaluate the psychometric properties of the PRO measure including content and construct validity, reliability (particularly test-retest), and ability (sensitivity) to detect change
– Assess practical factors such as the recall period, respondent burden, mode of administration, and the need for validated language translation11
To assist sponsors and investigators in awareness of the utility of PROs in a particular device or therapeutic area, CDRH issued a report on the Value and Use of PROs in Assessing Effects of Medical Devices1, which included detailed case studies of PRO use in submitted medical device studies (Appendix I) and an CDRH PRO Compendium (Appendix II). While not an exhaustive list, the compendium provides examples of PRO used in various therapeutic areas.
The PROMIS suite, originally sponsored by the NIH, provides over 300 interchangeable measures or item banks that measure health-related PRO domains. These measures have been standardized to provide metrics across a wide range of conditions and diseases, and many are available in several languages. The PROMIS measures have been rigorously tested and validated and are available in most instances at no charge at healthmeasures.net. Also provided is information to help users select, administer, score, and interpret the measures.
Tying it all Together
Including PROs in a clinical trial can be useful for labeling, marketing claims and market adoption, but selecting an appropriate PROM requires careful thought regarding the specific research questions to be addressed and the needs of all stakeholders, including patients, sponsors, clinicians, and regulatory authorities. Device manufacturers must ensure trial design, study endpoints, and selected PRO measures generate meaningful patient data that can be beneficial throughout the device lifecycle.
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- Food and Drug Administration. Value and Use if Patient-Reported Outcomes (PROs) in Assessing Effects of Medical Devices CDRH Strategic Priorities 2016-2017. https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHVisionandMission/UCM588576.pdf.
- Food and Drug Administration. Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Silver Spring, MD: US Food and Drug Administration; 2009.
- Wilson H, Dashiell-Aje E, Anatchkova M, Coyne K, Hareendran A, Leidy NK, McHorney CA, Wyrwich K. Beyond study participants: a framework for engaging patients in the selection or development of clinical outcome assessments for evaluating the benefits of treatment in medical product development.Qual Life Res. 2018 Jan;27(1):5-16. doi: 10.1007/s11136-017-1577-6.
- Patrick DL, Burke LB, Gwaltney CJ, Leidy NK, Martin ML, Molsen E, Ring L. Content validity–establishing and reporting the evidence in newly developed patient-reported outcomes (PRO) instruments for medical product evaluation: ISPOR PRO good research practices task force report: part 1–eliciting concepts for a new PRO instrument.Value Health. 2011 Dec;14(8):967-77. doi: 10.1016/j.jval.2011.06.014.
- Patrick DL, Burke LB, Gwaltney CJ, Leidy NK, Martin ML, Molsen E, Ring L. Content validity–establishing and reporting the evidence in newly developed patient-reported outcomes (PRO) instruments for medical product evaluation: ISPOR PRO Good Research Practices Task Force report: part 2–assessing respondent understanding.Value Health. 2011 Dec;14(8):978-88. doi: 10.1016/j.jval.2011.06.013.
- Calvert M, Kyte D, Mercieca-Bebber R, et al. Guidelines for Inclusion of Patient-Reported Outcomes in Clinical Trial Protocols: The SPIRIT-PRO Extension. 2018;319(5):483–494. https://jamanetwork.com/journals/jama/fullarticle/2671472
- Calvert M, Blazeby J, Altman DG, Revicki DA, Moher D, Brundage MD; CONSORT PRO Group. Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. 2013 Feb 27;309(8):814-22. doi: 10.1001/jama.2013.879.
- Reeve BB, Wyrwich KW, Wu AW, Velikova G, Terwee CB, Snyder CF, Schwartz C, Revicki DA, Moinpour CM, McLeod LD, et al. ISOQOL recommends minimum standards for patient-reported outcome measures used in patient-centered outcomes and comparative effectiveness research.Qual Life Res. 2013 Oct;22(8):1889-905. doi: 10.1007/s11136-012-0344-y.
- Mercieca-Bebber R, Palmer MJ, Brundage M, Calvert M, Stockler MR, King MT. Design, implementation and reporting strategies to reduce the instance and impact of missing patient-reported outcome (PRO) data: a systematic review.BMJ Open. 2016 Jun 15;6(6). doi: 10.1136/bmjopen-2015-010938.
- Luckett T, King MT. Choosing patient-reported outcome measures for cancer clinical research–practical principles and an algorithm to assist non-specialist researchers.Eur J Cancer. 2010 Dec;46(18):3149-57. doi: 10.1016/j.ejca.2010.08.002.