Advancing patient-centric care: integrating patient reported outcomes for tolerability assessment in early phase clinical trials - insights from an expert virtual roundtable

Christina Yap¹, Olalekan Lee Aiyegbusi^{2

3

4

5

6}, Emily Alger¹, Ethan Basch^{7

8}, Jill Bell⁹, Vishal Bhatnagar¹⁰, David Cella¹¹, Philip Collis², Amylou C Dueck¹², Alexandra Gilbert¹³, Ari Gnanasakthy¹⁴, Alastair Greystoke¹⁵, Aaron R Hansen^{16

17}, Paul Kamudoni¹⁸, Olga Kholmanskikh¹⁹, Bellinda L King-Kallimanis²⁰, Harlan Krumholz²¹, Anna Minchom²², Daniel O'Connor²³, Joan Petrie²⁴, Claire Piccinin²⁵, Khadija Rerhou Rantell²⁶, Saaeha Rauz^{27

28}, Ameeta Retzer^{29

30}, Steven Rizk³¹, Lynne Wagner³², Maxime Sasseville³³, Lesley K Seymour²⁴, Harald A Weber³⁴, Roger Wilson³⁵, Melanie Calvert^{2

3

4

5

6}, John Devin Peipert¹¹

Affiliations

¹ Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK.
² Centre for Patient-Reported Outcomes Research (CPROR), Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
³ National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre (BRC), University Hospital Birmingham and University of Birmingham, Birmingham, UK.
⁴ NIHR Applied Research Collaboration West Midlands, University of Birmingham, Birmingham, UK.
⁵ NIHR Blood and Transplant Research Unit in Precision Transplant and Cellular Therapeutics, University of Birmingham, Birmingham, UK.
⁶ Birmingham Health Partners Centre for Regulatory Science and Innovation, University of Birmingham, Birmingham, UK.
⁷ Lineberger Comprehensive Cancer Center, Chapel Hill, NC, 27514, USA.
⁸ Division of Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC, 27514, USA.
⁹ AstraZeneca, Oncology Research and Development, Gaithersburg, MD, USA.
¹⁰ Oncology Center of Excellence, US Food and Drug Administration, Silver Spring, MD, USA.
¹¹ Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹² Department of Quantitative Health Sciences, Mayo Clinic, Scottsdale, AZ, USA.
¹³ Leeds Institute for Medical Research, University of Leeds, St James's University Hospital, Leeds, UK.
¹⁴ RTI Health Solutions, Patient Centered Outcomes Research, Research Triangle Park, NC, USA.
¹⁵ NU Cancer, Newcastle University, Newcastle upon Tyne, UK.
¹⁶ Princess Alexandra Hospital, Cancer Services, Brisbane, Queensland, Australia.
¹⁷ University of Queensland, Faculty of Medicine, Australia.
¹⁸ Merck KGaA, Darmstadt, Germany.
¹⁹ Federal Agency for Medicines and Health Products (FAMHP), Brussels, Belgium.
²⁰ LUNGevity Foundation, Bethesda, MD, USA.
²¹ Center for Outcomes Research and Evaluation, Yale New Haven Hospital, New Haven, CT, USA.
²² Drug Development Unit, Royal Marsden/Institute of Cancer Research, Sutton, UK.
²³ The Association of the British Pharmaceutical Industry, UK.
²⁴ Canadian Cancer Trials Group (CCTG), Kingston, Ontario, Canada.
²⁵ Quality of Life Department, European Organisation for Research and Treatment of Cancer, Brussels, Belgium.
²⁶ Medicines and Healthcare Products Regulatory Agency (MHRA), UK.
²⁷ Academic Unit of Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, UK.
²⁸ Birmingham and Midland Eye Centre, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.
²⁹ Centre for Patient Reported Outcomes Research (CPROR), Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
³⁰ National Institute of Health and Care Research (NIHR) Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
³¹ Veloxis Pharmaceuticals, Cary, NC, USA.
³² University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, USA.
³³ Health Canada, Ottawa, Ontario, Canada.
³⁴ Pfizer Oncology, Global Medical Affairs/Early-Stage Development, Zug, Switzerland.
³⁵ Cancer Research Advocates Forum UK, Sarcoma Patient Advocacy Global Network, UK.

PMID: 39386161
PMCID: PMC11462221
DOI: 10.1016/j.eclinm.2024.102838

Review

Advancing patient-centric care: integrating patient reported outcomes for tolerability assessment in early phase clinical trials - insights from an expert virtual roundtable

Christina Yap et al. EClinicalMedicine. 2024.

. 2024 Sep 24:76:102838.

doi: 10.1016/j.eclinm.2024.102838. eCollection 2024 Oct.

Authors

Affiliations

¹ Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK.
² Centre for Patient-Reported Outcomes Research (CPROR), Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
³ National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre (BRC), University Hospital Birmingham and University of Birmingham, Birmingham, UK.
⁴ NIHR Applied Research Collaboration West Midlands, University of Birmingham, Birmingham, UK.
⁵ NIHR Blood and Transplant Research Unit in Precision Transplant and Cellular Therapeutics, University of Birmingham, Birmingham, UK.
⁶ Birmingham Health Partners Centre for Regulatory Science and Innovation, University of Birmingham, Birmingham, UK.
⁷ Lineberger Comprehensive Cancer Center, Chapel Hill, NC, 27514, USA.
⁸ Division of Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC, 27514, USA.
⁹ AstraZeneca, Oncology Research and Development, Gaithersburg, MD, USA.
¹⁰ Oncology Center of Excellence, US Food and Drug Administration, Silver Spring, MD, USA.
¹¹ Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹² Department of Quantitative Health Sciences, Mayo Clinic, Scottsdale, AZ, USA.
¹³ Leeds Institute for Medical Research, University of Leeds, St James's University Hospital, Leeds, UK.
¹⁴ RTI Health Solutions, Patient Centered Outcomes Research, Research Triangle Park, NC, USA.
¹⁵ NU Cancer, Newcastle University, Newcastle upon Tyne, UK.
¹⁶ Princess Alexandra Hospital, Cancer Services, Brisbane, Queensland, Australia.
¹⁷ University of Queensland, Faculty of Medicine, Australia.
¹⁸ Merck KGaA, Darmstadt, Germany.
¹⁹ Federal Agency for Medicines and Health Products (FAMHP), Brussels, Belgium.
²⁰ LUNGevity Foundation, Bethesda, MD, USA.
²¹ Center for Outcomes Research and Evaluation, Yale New Haven Hospital, New Haven, CT, USA.
²² Drug Development Unit, Royal Marsden/Institute of Cancer Research, Sutton, UK.
²³ The Association of the British Pharmaceutical Industry, UK.
²⁴ Canadian Cancer Trials Group (CCTG), Kingston, Ontario, Canada.
²⁵ Quality of Life Department, European Organisation for Research and Treatment of Cancer, Brussels, Belgium.
²⁶ Medicines and Healthcare Products Regulatory Agency (MHRA), UK.
²⁷ Academic Unit of Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, UK.
²⁸ Birmingham and Midland Eye Centre, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.
²⁹ Centre for Patient Reported Outcomes Research (CPROR), Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
³⁰ National Institute of Health and Care Research (NIHR) Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
³¹ Veloxis Pharmaceuticals, Cary, NC, USA.
³² University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, USA.
³³ Health Canada, Ottawa, Ontario, Canada.
³⁴ Pfizer Oncology, Global Medical Affairs/Early-Stage Development, Zug, Switzerland.
³⁵ Cancer Research Advocates Forum UK, Sarcoma Patient Advocacy Global Network, UK.

PMID: 39386161
PMCID: PMC11462221
DOI: 10.1016/j.eclinm.2024.102838

Abstract

Early phase clinical trials provide an initial evaluation of therapies' risks and benefits to patients, including safety and tolerability, which typically relies on reporting outcomes by investigator and laboratory assessments. Use of patient-reported outcomes (PROs) to inform risks (tolerability) and benefits (improvement in disease symptoms) is more common in later than early phase trials. We convened a two-day expert roundtable covering: (1) the necessity and feasibility of a universal PRO core conceptual model for early phase trials; (2) the practical integration of PROs in early phase trials to inform tolerability assessment, guide dose decisions, or as real-time safety alerts to enhance investigator-reported adverse events. Participants (n = 22) included: patient advocates, regulators, clinicians, statisticians, pharmaceutical representatives, and PRO methodologists working across diverse clinical areas. In this manuscript, we report major recommendations resulting from the roundtable discussions corresponding to each theme. Additionally, we highlight priority areas necessitating further investigation.

Keywords: Dose-finding; Early phase trials; Patient-centred clinical development; Patient-reported outcomes; Phase I; Phase II; Quality of life; Tolerability; Trial designs.

PubMed Disclaimer

Conflict of interest statement

C.Y. has received consulting fees from Faron Pharmaceuticals and an honoraria from Bayer. O.L.A. reported receiving grants from the National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research center, NIHR Applied Research Collaboration West Midlands, NIHR Blood Transplant Research Unit (BRTU), UK Research and Innovation (UKRI), Health Foundation, Gilead, Anthony Nolan, GlaxoSmithKline, Merck, and Sarcoma UK. OLA declares personal fees from Gilead Sciences Ltd, Merck, and GlaxoSmithKline, Innovate UK outside the submitted work. E.B. has received payments as a scientific advisor for Navigating Cancer, AstraZeneca, Resilience, N-Power Medicine, and Verily. J.B. is an employee of AstraZeneca, with ownership interest in AstraZeneca and is engaged by Evinova, a separate healthtech business within the AstraZeneca group. A.H. has Research funding (paid to institution): Advancell, BMS, MSD, Macrogenics, Tyra Biosciences, Janssen, Seagen, Aveo, Roche/Genetech; Consulting (paid personally): MSD, Pfizer, Eisai, Astellas, Bayer. P.K. has shares in Merck Healthcare KgaA and is a Full-time employee of Merck Healthcare KgA. B.K.K. has grants paid direct to organisation from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Jazz Pharma, Genentech, Eli Lilly, Janssen, Takeda, Dachii Sankyo, Blueprint, Medicines, Janssen, Amgen, Seagen, Manta Cares and personal consultancy fees from Eli Lilly, BMS, AbbVie, Shionogi. H.M.K. has received grants unrelated to the work from the American Heart Association to Jansson; Agency for Healthcare Research and Quality to Kenvue; National Institutes of Health to Novartis; Centers for Medicare & Medicaid Services to Pfizer and Centers for Disease Control and Prevention. These grants and contracts are unrelated to the work above and are through Yale University or Yale New Haven Hospital. Received consulting fees from Massachusetts Medical Society (to Co-Editor, Journal Watch Cardiology); UpToDate (as Section Editor) and Ensight (unpaid advisor). Payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events would have received occasional travel expenses and/or honoraria to speak at various educational/academic venues. Received travel expenses and/or honoraria to speak at various educational/academic venues. Stocks in Element Science and Identifeye. A.M. has served on advisory boards for Janssen Pharmaceuticals, GSK, Merck Pharmaceuticals, Takeda Pharmaceuticals, MSD Pharmaceuticals, Faron Pharmaceuticals, Pfizer Pharmaceuticals, AZ, Genmab Pharmaceuticals and Immutep Pharmaceuticals. Has received honoraria from Chugai Pharmaceuticals, Faron Pharmaceuticals, Merck Pharmaceuticals, GSK, Seagen, Takeda Pharmaceuticals and Janssen Pharmaceuticals. Has travel support from Amgen Pharmaceuticals and Janssen Pharmaceuticals. Has received research funding from Astex Pharmaceutical, Merck Pharmaceuticals and MSD. J.P. is a Patient representative on CCTG. S.R. Research grants with Medical Research Council, NIH/NEI, NIHR outside permitted work. A.R. reported receiving grants from National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC) paid to University of Birmingham and has funding outside the submitted work from NIHR, Birmingham City Council, ACCELERATE, Office of Health Disparity and Inequality. Support for attending meetings from Outsourcing in Clinical Trials UK/Ireland as invited speaker. Honoraria from Wellcome Sanger Institute Representative Research Strategy Advisory Group and ACCELERATE (Innovations for Children and Adolescents with Cancer) International Patient-Reported Outcomes Working Group—Core Group Member and Work-package Lead (unpaid). S.R. is employed by Veloxis Pharmaceuticals, Inc. Stock in the following companies: Bristol Myers-Squibb, Gilead Sciences, IGM Biosciences, Merck & Co, Pfizer. L.I.W. has received consulting fees from Celgene/Bristol Myers Squibb; Connect Multiple Myeloma registry, member Scientific Steering Committee. L.K.S. reports funding to institution from AZ, Bayer, Roche, GSK, Treadwell, REPARE, Novartis, Janssen, MERCK. Shares: AZ. H.A.W. is employed by Pfizer AG, Switzerland and owns non-voting shares of Roche Ltd. M.J.C. is the Director of Birmingham Health Partners Centre for Regulatory Science and Innovation and Centre for Patient Reported Outcomes Research and a National Institute for Health and Care Research (NIHR) senior investigator; has received funding from Anthony Nolan, European Regional Development Fund-Demand Hub and Health Data Research UK, Gilead, GSK, Janssen, Macmillan Cancer Support, Merck, NIHR, NIHR ARC WM, NIHR Birmingham BRC, NIHR BTRU Precision and Cellular Therapeutics, UCB Pharma, UKRI, and UK SPINE; and has received consultancy fees from Aparito, Astellas, Boehringer Ingelheim, CIS Oncology, Daiichi Sankyo, Gilead, Glaukos, GSK, Halfloop, Merck, Patient-Centered Outcomes Research Institute, Pfizer, Takeda, and Vertex Pharmaceuticals Incorporated, outside of the submitted work. The views and opinions expressed in this publication are those of the individual co-authors and may not be understood or quoted as being made on behalf of or reflecting the position of any organisation, committee, working party or group with which the co-authors are affiliated.

Figures

**Fig. 2**
**Core set of PRO conceptual model adapted from US FDA guidance**.

**Fig. 3**
Poll questions for participants for themes one and two. For illustrative purposes, high level of agreement (≥70% of participants) indicative that consensus is reached are coloured in green, and the rest are coloured in orange (<70% of participants).

See this image and copyright information in PMC

References

1. Cook N., Hansen A.R., Siu L.L., Abdul Razak A.R. Early phase clinical trials to identify optimal dosing and safety. Mol Oncol. 2015;9(5):997–1007. doi: 10.1016/j.molonc.2014.07.025. - DOI - PMC - PubMed
1. Harrington J.A., Hernandez-Guerrero T.C., Basu B. Early phase clinical trial designs – state of play and adapting for the future. Clin Oncol. 2017;29(12):770–777. doi: 10.1016/j.clon.2017.10.005. - DOI - PubMed
1. Yap C., Rekowski J., Ursino M., et al. Enhancing quality and impact of early phase dose-finding clinical trial protocols: SPIRIT Dose-finding Extension (SPIRIT-DEFINE) guidance. BMJ. 2023;383 doi: 10.1136/bmj-2023-076386. - DOI - PubMed
1. The Association of the British Pharmaceutical Industry . 2018. Guidelines for phase I clinical trials.https://www.abpi.org.uk/publications/guidelines-for-phase-i-clinical-tri...
1. Lai-Kwon J., Yin Z., Minchom A., Yap C. Trends in patient-reported outcome use in early phase dose-finding oncology trials – an analysis of ClinicalTrials.gov. Cancer Med. 2021;10(22):7943–7957. doi: 10.1002/cam4.4307. - DOI - PMC - PubMed

Publication types

Actions

LinkOut - more resources

Full Text Sources
- Elsevier Science
- PubMed Central
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Advancing patient-centric care: integrating patient reported outcomes for tolerability assessment in early phase clinical trials - insights from an expert virtual roundtable

Affiliations

Advancing patient-centric care: integrating patient reported outcomes for tolerability assessment in early phase clinical trials - insights from an expert virtual roundtable

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

LinkOut - more resources

Full Text Sources

Miscellaneous