Patient-Reported Outcomes (PROs) are one of the Clinical Outcome Assessment (COA) tools – along with Observer-Reported, Clinician-Reported and Performance Outcomes. PROs, in particular, capture patient’s own evaluation of the impact of a disease and/or treatment on their quality of life, daily function, or symptoms. They are key measures for the inclusion of the patient's voice in the drug discovery and approval process in a way that is scientifically sound and acceptable.
Health Authorities have developed various guidelines and qualification programs over the years on the appropriate use of COAs and PROs in the design and conduct of clinical trials. Previous reports show high drug approval and labeling convergence between the EMA and FDA (Kashoki M. et al., Clin Pharmacol Ther. 2020). However, more substantial differences have been identified in the role of Patient-Reported Outcomes and Health-Related Quality of Life data in labeling claims granted by the two regulatory bodies (DeMuro C. et al., Value Health. 2013, Marquis P. et al., Pharmaceutical Medicine, 2011), significantly in oncology (Kashoki M. et al., Clin Pharmacol Ther. 2020).
Understanding the differences in approaches between FDA and EMA is critical for sponsors to develop PRO strategies that appropriately use PRO data for drug labeling claims.
Method: COAs and PROs recommendations from guidelines and as endpoints in oncology drug label claims
The ePROVIDETM platform and its three interlinked databases containing COA descriptive information, COA label claims and authorities’ guidelines are designed to provide a comprehensive COA knowledge landscape and support the development of successful endpoint strategies.
To understand the differences in approaches between FDA and EMA, we have analyzed the number of drugs with a PRO claim, PRO endpoint positioning, and the underlying concepts and instruments from the following databases:
- PROLABELSTM database: COAs and PROs mentioned in label claims approved by EMA or FDA with a focus on oncology. We tabulated the data by decade (≤2009, 2010-2015, 2016-2022) to examine the trends in use of COAs in claims.
- PROQOLIDTM database: COA description and psychometric information for the instruments mentioned in the labels retrieved above. We further focused on identifying the concepts of interests that have been measured.
- PROINSIGHTTM database: regulatory guidelines for the use of COAs in oncology from FDA versus EMA over the same period of time.
FDA vs EMA: Differences of COA mentions in labeling claims (numbers and endpoint positioning)
EMA and FDA both granted PROs in drug labels over the past two decades. During 2015-2022, 60% of EMA-approved drugs (47% of oncology drugs) included PROs in claims. For the FDA, these rates were 47% and 27%, respectively (Figure 1).
Analysis of distribution of COA types in oncology claims confirmed that PROs were included in majority of EMA-approved drugs which is not the case for drugs labels approved by the FDA-approved drugs (Figure 2). This observation was made regardless of endpoint positionings.
Then, we observed that for both EMA and FDA oncology-approved drugs, PROs were preferably used as secondary endpoints. They were rarely used as primary endpoints in EMA-approved drugs (7% only), in comparison with FDA-approved drugs for which PROs were more often used as primary endpoints (29%).
FDA vs EMA: Differences of PRO-related concepts of interest in drug labels
Among the drugs approved for all therapeutic indications, for PROs claim granted by EMA, Quality of Life (QOL) was the primary concept of interest followed by symptoms (including pain) and physical functioning. For the FDA claim, however, PROs were mainly measuring symptoms (including pain).
To demonstrate the differences in more details, we focused on breast and prostate cancer. Among the EMA-approved drugs, the main concept measured was QOL with the following PROs:
- EORTC QLQ-C30 - EORTC Quality of Life Questionnaire - Core Questionnaire,
- EQ-5D-5L - EuroQoL 5-Dimension 5-Level,
- FACT-B - Functional Assessment of Cancer Therapy - Breast Cancer,
- FACT-P - Functional Assessment of Cancer Therapy - Prostate Cancer
Among the FDA-approved drugs in breast and prostate cancer, symptoms and pain were mainly assessed with the following PROs:
- BPI-SF - Brief Pain Inventory - Short form
- BPI - Brief Pain Inventory
- SDS - Symptom Distress Scale
FDA vs EMA: Differences in COAs and PROs recommendations in oncology trials
For the neoplasms therapeutic area, there were six guidelines released by the FDA compared to three from the EMA.
EMA provides general recommendations on symptoms and QOL measures in “Appendix 2 to the guideline on the evaluation of anticancer medicinal products in man”, released in 2016: “Oncology clinical studies to support regulatory submissions may include PRO measures as secondary or exploratory outcomes and rarely as primary outcomes. […] It is important to include patient-reported symptoms that are appropriate to the study population, intervention, objectives and setting (Basch et al., 2012). If symptom PRO measures are used to evaluate the impact on specific symptoms it should be ensured that a benefit in respect to these symptoms is not accompanied by a negative effect on other symptoms. One way of doing this could be to include a sensitive multidimensional HRQL instrument. […] As with all PROs, the inclusion of HRQL assessment in clinical trials should have a strong scientific rationale and researchers should utilize existing validated instruments where available” (EMA, 2016).
In “Core Patient-Reported Outcomes in Cancer Clinical Trials Guidance for Industry” released in June 2021, FDA specifically recommends assessing symptomatic adverse events, side effect impact, role function, pain with PROs in oncology trials and “additional PROs that are important to patients, outside of these core concepts, could be prospectively specified and collected in clinical studies based on the context of a given clinical trial” but they “should be carefully considered to minimize patient burden and improve the quality of data collected by focusing on the most meaningful and measurable outcomes”. Finally, in the guidance document “Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments” released in June 2022, FDA provides a detailed roadmap to develop or select fit-for-purpose COAs (Figure 3).
As final remarks, it should be noted that for successful COA strategies, the selection of the appropriate COA or the development of a dedicated COA should be considered in the early phases of clinical studies. Preparation of dossiers for new drug approval requires expert input in regulatory and COA science.
Watch our recent webinar to learn more about the FDA and EMA perspective on PROs as endpoints in oncology trials and marketing claims.Watch the webinar