Since the 1980s, patient reported outcomes measures (PROMs) have been incorporated in cancer clinical trials providing invaluable information about symptoms, functioning, and quality of life from the patients’ perspective. In 2009, the US Food and Drug Administration (FDA), issued industry guidance on the use of PROMs in product label claims . The guidance stressed the importance of developing tools with stringent criteria. These may be problematical for legacy PROMs, i.e. those developed prior to the guidance [2-3]. The issue then is, if we need to replace older PROMs to comply with the FDA guidance, are we at risk of abandoning tools with over 20 years’ of post development validation?
The FDA guidance underlined two broad points: 1) the importance of patients’ assessment of the effect of an intervention, and 2) the use of valid and reliable measures to collect PRO data. Crucially the guidance emphasised patient input throughout the development of PROMs. The importance the FDA place on this last point is starkly underlined by the fact that despite oncology products representing the largest proportion of drugs approved between 2006-2010 (16/116; 14%) none included a PRO label claim . A review of the reasons for rejecting PRO label claims across all therapy areas revealed over a third were rejected because the instruments were not fit for purpose. 
PROMs that failed to be granted a label claim include legacy instrument, potentially because many were developed with little or no patient involvement, and therefore fall short of the guidance requirements for content validity.  Yet paradoxically these legacy instruments have also been employed to support successful PRO claims. 
One possible way around the label claims hurdle is to expose legacy instruments to a gap analysis (for example, identified through patient interviews, literature reviews, or quantitative analyses) to assess whether they meet FDA requirements or require further modification . However, it has recently been demonstrated that legacy instruments in oncology cover most, if not all, of the core set of symptoms recommended for assessment in cancer patients . And although legacy oncology instruments have remained mostly unchanged since their development in the 1980s, they have been completed by thousands of patients across hundreds of trials so have been exposed to significant post-development validation.
Another solution, one that is acknowledged by the FDA, is to create new PROMs from scratch. As such, the FDA has funded the Critical Path Institute (C-Path) PRO-Consortium to develop PROMs specifically for the purpose of label claims. To-date the PRO-Consortium has made limited progress in just one cancer type (lung) having identified a symptom inventory that, at least superficially, differs little from domains covered by legacy instruments. That aside any newly developed instruments will require a lengthy validation process and in following this path we are at risk of not only using under-validated instruments, but also losing the ability to compare new therapies with older treatments.
The irony in re-inventing the wheel is that we are at risk of losing vital data if trial sponsors become reluctant to include PROMs in future trials given the cost of investing in a potentially risky and unsuccessful PRO strategy. The consequence of this would be to undermine the FDA’s own principle of capturing the patient voice in trials.
The FDA is right to set standards high in terms of the “quality” of PROMs; however by ignoring ongoing patient validation of legacy instruments and starting from scratch with tool development, are we at risk of throwing out the baby with the bathwater?
Adam B Smith is a project director at York Health Economics Consortium (YHEC) leading the Outcomes Research workstream. He has a longstanding interest in patient-reported outcome measures, particularly in oncology.
Competing interests: None declared.
Contributing authors: Sarah Dickinson, research assistant, York Health Economics Consortium (YHEC) and Alicia Wooding, marketing and training coordinator, York Health Economics Consortium (YHEC).
Disclaimer: The views expressed in this blog are the authors’ own and do not necessarily reflect the views of York Health Economics Consortium (YHEC) Ltd.
1. US Department of Health and Human Services. Guidance for industry: Patient-reported outcome measures: use in medical product development to support labeling claims. December 2009.
2. Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, Silberman M, Yellen SB, Winicour P, Brannon J. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol. 1993 Mar;11(3):570-9.
3. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993; 85: 365-76.
4. Gnanasakthy A, Mordin M, Clark M, DeMuro C, Fehnel S, Copley-Merriman C. A review of patient-reported outcome labels in the United States: 2006 to 2010. Value Health. 2012 May;15(3):437-42.
5. DeMuro C, Clark M, Mordin M, Fehnel S, Copley-Merriman C, Gnanasakthy A. Reasons for rejection of patient-reported outcome label claims: a compilation based on a review of patient-reported outcome use among new molecular entities and biologic license applications, 2006-2010. Value Health. 2012;15:443-8.
6. DeMuro C, Clark M, Doward L, Evans E, Mordin M, Gnanasakthy A. Assessment of PRO label claims granted by the FDA as compared to the EMA (2006-2010). Value Health. 2013;16:1150-5.
7. Rothman M, Burke L, Erickson P, Leidy NK, Patrick DL, Petrie CD. Use of existing patient-reported outcome (PRO) instruments and their modification: the ISPOR Good Research Practices for Evaluating and Documenting Content Validity for the Use of Existing Instruments and Their Modification PRO Task Force Report. Value Health. 2009 Nov-Dec;12(8):1075-83
8. Reeve BB, Mitchell SA, Dueck AC, Basch E, Cella D, Reilly CM, Minasian LM, Denicoff AM, O’Mara AM, Fisch MJ, Chauhan C, Aaronson NK, Coens C, Bruner DW. Recommended patient-reported core set of symptoms to measure in adult cancer treatment trials. J Natl Cancer Inst. 2014;106(7)