Optimising patient centred drug development to realise impact.

Introduction

Patient-reported outcomes (PROs) collected within drug development programmes can provide valuable evidence to inform shared decision making, labelling claims, clinical guidelines, and health policy.

Regulatory agencies, such as the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have released guidance to enhance the incorporation of the patient’s voice in medical product development and regulatory decision making, whilst international societies and consortia have released methodological guidelines and resources to improve study design, reporting and implementation of findings. Here we summarise evidence on the value of PROs throughout the drug development pipeline and provide a summary of guidance documents to support the optimal PRO assessment in drug development (Fig. 1 ).

Impact of PROs on drug development

Although traditionally collected in later phase clinical trials to assess the efficacy of treatments, PROs are increasingly being used in early phase clinical trials. PRO data has been used to confirm the tolerability of the recommended phase 2 dose (RP2D) and to guide dose escalation based on whether the maximum tolerated dose (MTD) was acceptable from a health-related quality-of-life (HRQOL) perspective 1 .

PRO data can demonstrate the efficacy of drugs and support other clinical data. In later phase trials, as primary endpoints, PROs have been used to measure concepts such as palliation of symptoms, which are best assessed by patients 2 , 3 . A randomized trial in patients with symptomatic hormone-resistant prostate cancer compared prednisone with or without mitoxantrone using a PRO as primary outcome. Data collected using the McGill–Melzack Pain Questionnaire showed that mitoxantrone was associated with a sustained improvement in pain 3 .

As secondary endpoints, PROs can support the findings of a clinical primary endpoint. For instance, in the phase 3, double-blind TOURMALINE-MM3 trial in post-transplant multiple myeloma patients, PRO data showed that, compared with placebo, ixazomib did not have an adverse impact on HRQOL, in addition to improving progression-free survival (PFS). Secondary PRO endpoints can also offer contrasting findings to the primary outcome 4 . For example, the Gynecologic Cancer Intergroup International Collaboration on Ovarian Neoplasms 7 (ICON7) trial , which evaluated adding bevacizumab to standard first-line chemotherapy, found that although the drug marginally improved the trial primary endpoint of PFS, it was associated with a clinically relevant negative impact on HRQOL compared with standard treatment at 54 weeks. In another trial, EORTC QLQ-C30 data was collected from women with advanced breast cancer on doxorubicin with or without vinorelbine. The PRO data showed improvements in patients’ cancer pain and dyspnea suggesting palliative benefits 2 .

The field is also increasingly focused on tolerability, a concept well-suited for PRO assessment. The COMPARZ (Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma) trial showed pazopanib to be noninferior to sunitinib for PFS and overall survival. However, the PRO data showed that pazopanib was better tolerated than sunitinib. The PRO data provided a more nuanced picture of treatment effects on fatigue and mouth-hand-foot symptoms than the summative toxicity data 4 .

PRO data can inform regulatory drug approvals, labelling claims and reimbursement decisions. The tolerability data captured using PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE) for a noncontrolled trial of belantamab mafodotin-blmf were discussed during a FDA Oncologic Drugs Advisory Committee. It was noted in the FDA’s accelerated approval letter that PROs should be collected in the confirmatory randomised controlled trial RCT 5 . The FDA also considered a PRO assessment of overall side effect impact from the FACT-GP5 data in a trial of adults and adolescents with advanced or metastatic RET-mutant medullary thyroid cancer. The FACT-GP5 data were supported by a lower incidence of treatment discontinuation due to adverse reactions for RETEVMO (selpercatinib) (4.7%) compared to cabozantinib or vandetanib (27%) in patients who received at least one dose of study treatment.

PRO data also informed FDA approval of ibrutinib for chronic graft vs host disease. The PRO data demonstrated efficacy, supporting the primary clinician-reported outcome, and was used in the FDA’s benefit-risk assessment and included in the product labelling 5 . Other oncology drugs with PRO labelling granted by the FDA include abiraterone (for the treatment of prostate cancer), crizotinib (for the treatment of non-small cell lung cancer [NSCLC]), and ruxolitinib (for the treatment of myelofibrosis). A review by Gnanasakthy et al reported that between 2012 and 2016, there were 21 indications with PRO-related language in SmPCs (EMA PRO labelling), amounting to roughly one-third of all 64 indications reviewed by the EMA. PRO data from trials has been shown to directly inform national and international clinical guidelines and reimbursement decisions by Health Technology Assessment Agencies. For instance, the PRO data from the COMFORT-II trial provided evidence of symptom control that informed National Institute for Health and Care Excellence approval of ruxolitinib for myelofibrosis despite no statistically significant survival advantage.

Whilst evidence of the impact of PROs for real world/post-marketing studies is presently limited, there is a steady increase in the utilisation of PROs in phase IV trials. Of 27,976 phase IV clinical trials posted on Clinicaltrials.gov between 1999 and July 2021 , 21% and 4% used PROs and composite measures, respectively. Similarly, a review of EU post-authorization safety studies conducted between 2012 and 2015 showed that PROs were collected in 14% of Post-Authorization Safety Study (PASS) protocols and included assessments of symptoms, burden of disease and quality of life.

Regulatory and international guidance to facilitate the inclusion of PROs in drug development

Maximising PRO result impact requires attention to unique considerations associated with measure selection, trial design, respondent burden, missing data, PRO score alerts, data capture and analysis, interpretation and presentation of results 4 . A range of international guidance and resources have been developed to support researchers and other key stakeholders throughout the drug development pipeline.

Guidance to support the optimal collection, analysis and reporting of PROs has been available for several decades, particularly in oncology where PROs offer valuable insights on the impact of cancer treatments to complement survival outcomes (overall, PFS).

A seminal moment was the publication of the 2009 FDA PRO guidance . Since then, there have been a series of PRO-related publications from the FDA, including the cancer core set , clinical outcome assessment ( COA) compendium and the Patient-Focused Drug Development Guidance Series . The European Medicines Agency (EMA), have also published work in this area ( EMA Appendix 2 to the guideline on the evaluation of anticancer medicinal products in man The use of patient-reported outcome (PRO) measures in oncology studies ) and a more recent Patient experience data (PED) reflection paper . Alongside this, personnel from the FDA and EMA, the MHRA and Health Canada and NICE are also active contributors to many global initiatives to improve PRO data collection, analysis, reporting and implementation including SISAQOL, SPIRIT, and CONSORT. A limited number of these guidance documents are curated by the PROTEUS Consortium ( P atient- R eported O utcomes T ools: E ngaging U sers and S takeholders), which also offers educational videos, checklists and a handbook to support use. These international guidance and resources are summarised here so that trialists, researchers and other stakeholders can access relevant resources depending on their needs and the stage of the research (Table 1 ).

Study design

Most of the available guidance relates to study design. International guidelines have been developed on PRO-specific content to include in RCT protocols ( SPIRIT-PRO ), including resources for patient partners involved in co-design . Ethical considerations for the inclusion of PROs in clinical research have been provided, including a checklist to support submissions to ethics committees and more detailed recommendations to reduce respondent burden , manage PRO alerts , anonymise PRO data collected in clinical care for secondary use in research and address health equity considerations. Finally, tools are available to support inclusion of PROs in grant applications .

PRO measure selection is a key design consideration, and a recent review by members of the PROTEUS Consortium of International guidance on the selection of patient-reported outcome measures in clinical trials found general consistency across the recommendations. This work includes COSMIN guidance which has recently been updated . The ePROVIDE PROQOLID™ database is a comprehensive online database designed to assist academic researchers, physicians, students, pharmaceutical companies, health authorities, and international organizations search for and evaluate COAs, including PROs. Recommendations on the use of item libraries and tolerability measures, such as the PRO-CTCAE have also been provided. Given the increased use of electronic PROs (ePROs), several guidance documents address ePROs, including usability testing and system validation , measurement equivalence , data structure and standardization requirements to support drug development and training. Further considerations have been provided on the use of PROs in multi-site or multinational trials including the use of ePROs and translations and multi-site pragmatic trials using the electronic health record.

Analysing data

International standards for the analysis of quality-of-life and PRO endpoints in cancer RCTs have been developed by the SISAQOL Consortium and further developed by the SISAQOL-IMI Consortium . SISAQOL-IMI provides guidance on implementing PROs in RCTs and single arm trials, including PRO score interpretation thresholds, PRO data visualisation and terminology. Although developed for oncology, these resources may also be useful for other clinical areas.

Study reporting

CONSORT-PRO aims to promote transparent reporting of trials in which PROs are primary or important secondary outcomes. Guidance on the graphical presentation of findings has also been developed. Specific reporting guidelines are also available for the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale credit and HealthMeasures’ PROs (ASCQ-Me, Neuro-QoL, NIH Toolbox, PROMIS ).

Applying findings

Once reported, PRO data can inform shared decision making, clinical guideline development, labelling claims and health policy. A checklist has been developed to support the use of PROs by clinicians , and a review of PRO considerations in Oncologic Drugs Advisory Committee Meetings provides insights on the use of PRO data in regulatory decision making.

Context-specific guidance

Further context-specific guidance has been developed including use of PROs in early phase trials , for real-world evidence generation and in children and adolescents .

Implementation of results and maximising impact

Several barriers associated with the implementation of PROs in clinical trials may hamper the impact of the data. Adherence to the guidelines recommended in this Comment and multi-stakeholder collaboration are essential to maximise the use of PRO trial data, facilitate impact and minimise research waste.

While it is difficult to isolate the direct impact of international guidelines on the number of trials using PROs and the quality of trial design and reporting, there is evidence to suggest that citing CONSORT-PRO is associated with higher quality reporting 6 . There is also an increasing trend in use of clinical outcomes assessments, including PROs in FDA labels and health technology assessment submissions, in total and across most therapeutic areas, indicating a shift toward more patient centricity 7 .

Supplementary information

Transparent Peer Review file

Acknowledgements

M.J.C. receives funding from the NIHR Birmingham Biomedical Research Centre, NIHR Surgical Reconstruction and Microbiology Research Centre, NIHR Blood and Transplant Research Unit (BTRU) in Precision Transplant and Cellular Therapeutics, and NIHR ARC West Midlands at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, LifeArc, Health Data Research UK, Innovate UK (part of UK Research and Innovation), Macmillan Cancer Support, European Regional Development Fund – Demand Hub, SPINE UK, UKRI, UCB Pharma, GSK, Anthony Nolan, and Gilead Sciences.C.S. currently receives unrestricted education grants through her institution from Pfizer as PI of the PROTEUS Consortium. The funder had no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript.O.L.A. receives funding from the NIHR Birmingham Biomedical Research Centre (BRC), NIHR Applied Research Collaboration (ARC), West Midlands, NIHR Blood and Transplant Research Unit (BTRU) in Precision Transplant and Cellular Therapeutics at the University of Birmingham and University Hospitals Birmingham NHS Foundation, LifeArc, Innovate UK (part of UK Research and Innovation), The Health Foundation, Gilead Sciences Ltd, Merck, Anthony Nolan, GSK, and Sarcoma UK.This work is funded by Merck Healthcare.

Author contributions

M.J.C., P.K., and O.L.A. conceptualised the review. M.J.C., C.Y., and O.L.A. wrote and edited the manuscript. M.J.C., P.K., O.L.A,. C.Y., C.S., and R.W. reviewed the manuscript. M.J.C., P.K., O.L.A., C.Y., C.S., and R.W. approved the final version.

Peer review

Peer review information

Communications Medicine thanks Guro Lindviksmoen Astrup and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Data availability

The full list of screened sources and the data extraction framework used for this scoping review are available from the corresponding author upon reasonable request.

Competing interests

MJC received personal fees from Astellas, Boehringer Ingelheim, Aparito Ltd, CIS Oncology, Gilead, Halfloop, Takeda, Merck, Daiichi Sankyo, Glaukos, GSK, Pfizer, Vertex, Shionogi, and the Patient-Centered Outcomes Research Institute (PCORI) outside the submitted work. In addition, a family member owns shares in GSK. C.Y. report personal fees from Faron Pharmaceuticals, Bayer, Trogenix and Merck, outside the submitted work. C.S. currently receives personal consulting fees from Movember and Pfizer and previously received personal consulting fees from Shionogi. Dr. Snyder has received travel costs for meeting presentations from Shionogi and Executive Insight Healthcare Consultants. She also receives research funding from Johnson & Johnson through her institution. O.L.A. declares personal fees from Gilead Sciences, Merck, Boehringer Ingelheim, Innovate UK, and GSK. All other authors declare no competing interests.

Footnotes

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Supplementary information

The online version contains supplementary material available at 10.1038/s43856-026-01634-2.

References

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7. Krol, M. et al. The increasing use of clinical outcome assessments in US Food and Drug Administration Labels and the German Gemeinsamer Bundesausschuss, National Institute for Health and Care Excellence, and the French Haute Autorité de Santé Assessments From 2012 to 2022. Value Health 28 , 1195–1203 (2025).

Associated Data

Supplementary Materials

Transparent Peer Review file

Data Availability Statement

The full list of screened sources and the data extraction framework used for this scoping review are available from the corresponding author upon reasonable request.