PROs in trials - University of Birmingham

The steps to getting PROs right - detailed in Steps 1 to 5 below.

Capturing Patient-Reported Outcomes (PROs) in Clinical Trials.

Patient-reported outcomes (PROs) are increasingly assessed within trials using questionnaires completed by patients. These questionnaires seek to capture the patient's opinion on the impact of their disease and treatment on their life. They are used to inform future patients about the potential symptoms or quality of life they may experience on a particular therapy, thereby helping individual patients and their clinicians to choose the best treatment for them.

PROs are often selected as primary, secondary or exploratory outcomes within clinical trials as they provide the patients' unique perspective on the physical, functional and psychological consequences of treatment and the degree and impact of disease symptoms.

If captured in a scientifically rigorous way, PRO results may aid clinical decision-making, support labelling claims, inform systematic reviews and meta-analyses, clinical guideline development, and influence healthcare policy.

Whilst PRO trial findings can be incredibly impactful, considerable care and planning is required to collect high-quality publishable data. We present five key recommendations aimed at helping researchers to collect and disseminate PRO data according to current international best-practice:

Step 1 - Measure what matters

Choose PROs that matter the most to your target patient population and develop a clear PRO rationale/hypothesis.

Including only the PROs of most importance to the target population will serve to reduce participant burden and enhance the potential impact arising from the research. Establishing a robust PRO rationale and hypothesis will aid selection of the most appropriate outcome measure and methods of analyses.[1] Patient and public involvement (PPI) in this step (and throughout the trial) is integral to the development of patient-focused research questions and objectives/hypotheses, which should ultimately enhance dissemination and implementation of study results.[2]

Helpful resources:

Website

The COMET (Core Outcome Measures in Effectiveness Trials) database allows the user to search for agreed standardised sets of outcomes, known as ‘core outcome sets’ (COS): a minimum recommendation of what should be measured and reported in all trials in a specific area. Any COS should include extensive patient and stakeholder involvement.

Papers

Quality of Life Research Journal Special Edition: Measuring what matters. ISSN: 1573-2649
Documenting the rationale and psychometric characteristics of patient reported outcomes for labelling and promotional claims. PMID: 17268927
Added value of health-related quality of life measurement in cancer clinical trials: the experience of the NCIC CTG. PMID: 20384559
Mapping the impact of patient and public involvement. PMID: 22809132

References

Wilson H, Dashiell-Aje E, Anatchkova M, et al. 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. Quality of Life Research 2018;27(1):5-16.
Brett J, Staniszewska S, Mockford C, et al. Mapping the impact of patient and public involvement on health and social care research: a systematic review. Health Expectations 2014;17(5):637-50.

Step 2 - Select the right tool

Take care to search for the measurement tool that best captures the target outcomes, with the least burden.

It is important to utilise PRO measurement tools that are underpinned by a sound conceptual/measurement model and which possess robust measurement properties – e.g. reliability (reliability, measurement error, internal consistency); validity (content validity, construct validity, criterion validity and, where appropriate, cultural validity); responsiveness and interpretability.[3] Consideration should also be given to PRO-associated patient and investigator burden.

Helpful resources:

Website

The COSMIN (COnsensus-based Standards for the selection of health Measurement Instruments) website includes practical tools to help you find the right measure.

Paper

ISOQOL (International Society for Quality of Life Research) minimum standards for patient-reported outcome measures used in patient-centred outcomes and comparative effectiveness research. PMID: 23288613

References

3. Prinsen CA, Vohra S, Rose MR, et al. How to select outcome measurement instruments for outcomes included in a “Core Outcome Set”–a practical guideline. Trials 2016;17(1):449.

Step 3 - Optimise PRO protocol content

Use the SPIRIT-PRO Extension, SISAQOL and PRO Alert guidelines to guide protocol development.

Clinical trial protocols are a vital blueprint for how a trial is conducted and reported. Contemporary research suggests the inclusion of ‘good-quality’ PRO protocol components facilitates more robust data collection, lower rates of avoidable missing data, and more informative data with which to generate meaningful, publishable, PRO reports.[4]

Helpful resources:

Guidelines/Checklists

The SPIRIT-PRO Extension includes a checklist of PRO-specific components recommended for inclusion in a clinical trial protocol including a PRO as a primary or secondary outcome. PMID: 29411037
The SISAQOL (Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data) consortium have developed recommendations for standardizing the analysis and interpretation of PRO and quality of life data in cancer randomized trials. SISAQOL Website
PRO data may reveal signs of psychological distress or physical symptoms that may require an immediate response, known as ‘PRO alerts’. Having a clear PRO alert management plan in place in the protocol will help reduce the risk of co-intervention bias.[5] See the following paper for guidance: ‘Patient-reported outcome alerts: ethical and logistical considerations in clinical trials.’ PMID: 24065005

References

4. Kyte D, Retzer A, Ahmed K, et al. Systematic evaluation of Patient-Reported Outcome protocol content and reporting in cancer trials. J Natl Cancer Inst. Volume 111, Issue 11, November 2019, Pages 1170–1178, https://doi.org/10.1093/jnci/djz038

5. Sackett DL. Clinician-trialist rounds: 5. Cointervention bias − how to diagnose it in their trial and prevent it in yours. Clinical Trials 2011;8:440-42. doi: DOI: 10.1177/1740774511410995

Step 4 - Minimise missing PRO data

Minimise avoidable missing PRO data.

Missing PRO data undermines randomisation, reduces study power, inflates standard error and increases the risk of type II errors.[6] Data may be missing from those patients with the poorest outcomes, potentially leading to biased estimates if not handled appropriately.[7] Every trial collecting PROs should employ design, implementation and reporting strategies to minimise these risks. Helpful resources:

Papers

Design, implementation and reporting strategies to reduce the instance and impact of missing PRO data. PMID: 27311907

References

6. Mercieca-Bebber R, Palmer MJ, Brundage M, et al. Design, implementation and reporting strategies to reduce the instance and impact of missing patient-reported outcome (PRO) data: a systematic review. BMJ open 2016;6(6):e010938. 7. Fairclough D, Peterson HF, Chang V. Why Are Missing Quality Of Life Data A Problem In Clinical Trials Of Cancer Therapy? Statistics in Medicine 1998;17:667-77.

Step 5 - Publish reader-friendly findings

Publish comprehensive PRO findings in a reader-friendly format.

In a 2019 study evaluating completed cancer clinical trials, non-reporting of PRO trial results was widespread; and where published PRO data were available, there was often considerable delay and standards of reporting were poor.[4] Evidence suggests improved PRO reporting is associated with journal endorsement and author use of the CONSORT-PRO extension.[8] See the resources below for additional guidance on how to optimize presentation of PRO data and facilitate implementation of the findings. Helpful resources:

Guidelines/Checklists

Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. PMID: 23443445
Guidance for Reporting Involvement of Patients and the Public: GRIPP2 reporting checklists. PMID:29062538

Papers

Making a picture worth a thousand numbers: recommendations for graphically displaying patient-reported outcomes data. PMID: 30306533
Clinician's checklist for reading and using an article about patient-reported outcomes. PMID: 24702734
The impact of patient-reported outcome (PRO) data from clinical trials: a systematic review and critical analysis. PMID: 31619266

Additional guidelines

References

8. Mercieca-Bebber R, Rouette J, Calvert M, et al. Preliminary evidence on the uptake, use and benefits of the CONSORT-PRO extension. Quality of Life Research 2017;26(6):1427-37.