International Consensus Guidance on the Inclusion of Patient-Reported Outcomes (PROs) in Clinical Trial Protocols: The SPIRIT-PRO Extension

Background

Patient reported outcomes (PRO) including; health-related quality of life, symptoms such as pain or fatigue and health utility are often assessed in clinical trials as a measure of effectiveness. Increasingly PRO data may be used to inform clinical care and decision-making, predict long-term outcomes and inform health policy. 

This work has been published in JAMA

The SPIRIT-PRO guidelines provide recommendations for items that should be addressed and included in clinical trial protocols in which PROs are a primary or key secondary outcome. Improved design of clinical trials including PROs could help ensure high-quality data that may inform patient-centered care.  

The use of PRO ensures that the patient perspective is at the heart of health research and clinical decision-making. Therefore, studies with a PRO outcome should strive to maintain the highest standards; in-terms of selection of valid and appropriate PRO measures for the study objectives and population.  This should also include the design of the trial protocol, the in-trial implementation of PRO assessment and during post-trial reporting.  There is extensive guidance available in the literature regarding PRO selection and validation.  A recent development of the CONSORT-PRO extension has also sought to address poor PRO clinical trial reporting.  However, there is limited consensus guidance on specific protocol content regarding PRO use in clinical trials or health related research.

Improving trial protocols has been identified as a priority research area for the enhancement of trial integrity and an evidence-based approach to protocol design is currently being led by the SPIRIT Initiative. The SPIRIT 2013 international consensus guidelines promote the inclusion of important general methodological components in trial protocols; however, it does not provide specific guidance in relation to the use or selection of PRO.

The Centre for Patient Reported Outcomes Research (CPROR) and their international partners have conducted a systematic review to identify existing PRO-specific guidance for trial protocol writers. Following the review, 162 unique PRO-specific recommendations were identified.  Our findings suggest that current guidelines where they exist were inconsistent and challenging for PRO protocol writers to access and implement. 

Our experience suggests that there are three key factors which need addressing:

  1. A lack of accessible internationally recognized and endorsed guidelines for protocol writers, which contain recommendations and guidance on the inclusion of standard PRO-specific protocol items.
  2. Funders and research ethics committees do not currently require or consider, minimum requirements for the PRO content of protocols during their review processes.  Therefore at present there is little incentive for trialists to improve or consider such items in any detail.
  3. A lack of PRO-specific education/training available for trialists involved in production of trial protocols with a PRO component.  

What information should be included in a clinical trial protocol when a patient-reported outcome (PRO) is a primary or secondary outcome?

Aim

To develop international, consensus-based, PRO-specific protocol guidance: an official SPIRIT-PRO extension.

Phases of the study

The SPIRIT-PRO Extension was developed following the Enhancing QUAlity and Transparency Of health Research (EQUATOR) Network’s methodological framework for guideline development. This included:

Phase 1: a systematic review of existing PRO-specific protocol guidance to generate an exhaustive long-list of candidate PRO-specific protocol items;

Phase 2: refinements to the long-list and removal of duplicate items by the International Society for Quality of Life Research (ISOQOL) PROtocol Checklist Taskforce;

Phase 3: an international stakeholder survey;

Phase 4:  an international Delphi survey and consensus meeting

Phase 5: feedback on the final guidance was sought from our Delphi panel and international partners during a three week consultation period.

Next steps

Phase 2 Stakeholder survey and Delphi Panel Exercise

These 56 items form the basis of a stakeholder and Delphi Panel survey, an invitation to complete the survey will be sent to members of stakeholder groups and the Delphi panel members. 

  • Stakeholders and Delphi panel members will include: clinical trialists, academics/researchers, health economists, methodologists, trial personnel, patient user representatives and advocates, PRO experts, psychometricians, funders, industry representatives, journal editors, policy makers, ethicists and researchers.  
  • This will allow us to gain a broad range of opinions on the perceived suitability of each of the remaining 56 items for inclusion in the final SPIRIT-PRO extension guidance and checklist.

The Delphi Exercise

In total 100 international experts will form a Delphi panel tasked with reviewing the 56 items, alongside the results of the online stakeholder survey.  The aim of the Delphi exercise will be to decide which of the 56 items should be taken forward to an international consensus meeting.

The Consensus Meeting

Following the Delphi exercise, approximately 30-35 members of the Delphi panel will meet and agree on the final content of the SPIRIT-PRO extension for publications.

Results

The systematic review identified 162 PRO-specific protocol recommendations from 54 sources. The ISOQOL Taskforce reduced this to 56 items, which were considered by 138 international stakeholders and 99 Delphi panelists. The final wording of the SPIRIT-PRO Extension was agreed by the consensus meeting participants (n=29) and reviewed by external stakeholders during a consultation period. Eleven extensions and five elaborations to the SPIRIT 2013 checklist are recommended for inclusion in clinical trial protocols where PROs are a primary or key secondary outcome.  The final guidance is currently under peer review for publication.   A link to the final guidance will be provided once published.

Delphi results

Systematic Review and Reduction of Items

  • A systematic review of existing PRO-specific guidance for trial and health related research protocol writers identified 162 unique PRO-specific recommendations (Calvert et al., 2014).
  • An International Society for Quality of Life Research (ISOQOL) expert taskforce was convened to review these 162 items.  Redundant items were removed and where possible similar items were merged, as a result the number of recommendations was reduced to 56 (Kyte et al., 2014).  

Stakeholder survey and Delphi Panel Exercise

These 56 items formed the basis of Stakeholder and Delphi Panel surveys, an invitation to complete the survey was sent to members of the Stakeholder groups and the Delphi panel members:

  • Stakeholders and Delphi panel members included: Clinical trialists, Academics, Researchers, Clinicians, Health Economists, Methodologists, Trial personnel, Patient user representatives and advocates, PRO experts, Psychometricians, Funders, Industry Representatives, Journal Editors, Policy Makers, Ethicists and Researchers.  
  • The Stakeholder and Delphi panel surveys allowed us to gain a broad range of opinions on the perceived suitability of each of the remaining 56 items for inclusion in the final SPIRIT-PRO extension guidance and checklist.

The Delphi Exercise

In total 99 international experts were included in the Delphi panel, they reviewed the 56 items and completed their first survey.  They then reviewed the stakeholder survey results completed by 138 stakeholders.  A report was then sent to the Delphi panellists including the results from the stakeholder survey, the first Delphi exercise alongside their own results.  They were then given the opportunity to amend their own survey if they felt it was necessary.  The aim of the Delphi exercise was to decide which of the 56 items should be taken forward to the international consensus meeting.

The Consensus Meeting

Delegates at the International Consensus meeting.

The international consensus meeting took place on the 11th and 12th May at the University of Birmingham.  Following the Delphi exercise, 29 members of the Delphi panel plus the SPIRIT PRO executive were present at the consensus meeting where panellists were given copies of the final results of the Delphi exercise and options on which items should be considered for inclusion.  These were discussed and participants voted anonymously on which of the final items should be included or not into the final SPIRIT-PRO guidelines.

Results of the Consensus Meeting

11 SPIRIT PRO item Extensions and 5 Elaborations were identified for reporting in randomised control trials where PROs are a primary or secondary outcome.  These are currently being written up for publication and we will include links to the publications once they have been accepted.

Next Steps

If you would like to help disseminate the research please contact us: CPROR@contacts.bham.ac.uk