Celeste Elash, Director, eCOA Sciences

When people with cancer participate in clinical trials, clinicians typically assess and record the treatment side effects that patients experience.  Many key endpoints in oncology trials are not patient-reported outcomes (PROs), but rather pertain to survival, which is essentially a measure of ‘treatment activity’, and do not provide information about how patients feel or function.  In 2016, former FDA Commissioner Dr. Scott Gottlieb argued for a more risk-based approach to regulation. He suggested the FDA should be more open to use of surrogate measures, including those meaningful to patients1.  The 2016 Century Cures Act2, which includes sections devoted to streamlining patient input and using patient experience data in drug development, builds on the FDA's work to incorporate patients’ perspectives into the development of drugs, biological products, and devices and helped focus drug development on patient-focused outcomes. In 2017, Gottlieb stated “Our aim is to facilitate the development and use of patient-focused methods in more parts of our regulatory activities as well as develop and elevate common standards for how to integrate the patient voice, as a matter of science, into product development. Among some of the long-term goals of these new efforts is the creation of consistent approaches to how the FDA develops clinical outcomes assessment tools such as patient-reported outcomes to inform our regulatory decisions.”  With the reissuance of the Prescription Drug User Fee Act (PDUFA)3, patient engagement was elevated to be a core part of the FDA’s regulatory approvals process.  Subsequently, the FDA has been clear that PROs could be the basis of approval of an oncology drug if that drug demonstrates symptom improvement (i.e., the way a patient “feels”), despite having no overall survival benefit.

Despite this promotion of patient-focused outcomes, and although PRO data are currently collected in oncology trials,4 regulatory approval of new therapies based on PRO data has been rare5. In order to accept PRO data for labelling, FDA requires 1) rigorous PRO development and 2) PRO data collected from well controlled, i.e., randomized, double-blind, trials. Further, the FDA recommends focusing on the 3 key areas of disease; symptoms, physical function (i.e., impact of toxicity) and symptomatic AEs (i.e., bothersomeness)6.

While taking into consideration these recommendations, trial sponsors must evaluate their approach to PRO data collection and proactively minimize risks to both data integrity and patient experience during trial design and execution.  In 2012, Ethan Basch and colleagues7 published the Center for Medical Technology Policy effectiveness guidance document to provide recommendations for the appropriate inclusion of PRO measures in the design and implementation of clinical research in adult oncology.  The review includes specific recommendations for measure selection and data analysis and reporting, but of interest here are some of the practical recommendations for PRO implementation.

Our natural interest as scientists is to explore as many research questions as possible. The result of this curiosity has led to oncology trials with numerous endpoints, many of which are collected, not as primary or secondary endpoints, but rather to answer exploratory questions.  As we all know, in oncology trials, patients may be over-taxed with the most fundamentally necessary procedures and the addition of completing multiple lengthy questionnaires at multiple timepoints is an unreasonable burden.  For these reasons, it’s recommended to resist the temptation to include too many endpoints and collect only those data to answer the most important research questions.  This includes limiting endpoints to the most critical, collecting data at only those necessary endpoints, and limiting the time required for data collection at any given timepoint.

Basch also recommends collecting PRO data electronically when possible.  As noted in Howry, Elash, Crescioni et al 20188, the advantages of electronic data collection over paper are numerous and well documented in the literature.9-11 Electronic modes enhance protocol compliance and data quality while reducing administrative burden and trial cost.  Electronic data collection systems allow for more accurate and complete data, improved protocol compliance, avoidance of secondary data entry errors, easier implementation of skip patterns, reduced sample size requirements and potential cost savings12.  Further, despite common misconception that some populations (e.g., older adults or the technology-naïve) are resistant to new technology and may struggle with electronic data collection, data indicate these groups generally prefer electronic data collection to paper after using it13.

A third recommendation involves creative approaches to PRO data collection in oncology trials.  eCOA vendors and sponsors can work together to design studies that minimize the patient burden as well as lost or missing data simply by thinking “out of the box”. To accommodate circumstances in which the patient may be unable to answer questions, the electronic data collection system can permit proxy data recording by an observer or caregiver.  The solution can be designed to log the data as having been recorded by someone other than the patient and can be taken into consideration in the analyses. Some studies may use interviews to collect PRO data when patients are unable to complete the PROs themselves, or when they are unable to visit the site to complete site-based questionnaires. Home-based studies are designed to minimize or eliminate the need for patients to travel to participate in trials.  Keep in mind, however, that, as noted at the recent Clinical Trials Transformation Initiative (CTTI) and FDA Public Workshop on Patient Engagement in Clinical Trials14 that not all patients want to participate in a home-based study.  Multiple workshop participants noted that some patients would rather travel than have others in their homes for simple reasons such as not wanting to have to clean.  Thus, the home-based study is recommended as an option, but not a requirement for trial participation.  Another option to consider is the provision of an alternate mode of data collection to use as a “back-up” when patients are unable to attend a site visit.  The Critical Path Institute’s ePRO Consortium has recently advised against using paper backup for electronic COA data capture8.  They acknowledge, however, that sponsors may want to take a proactive approach and develop a backup solution concurrent with the development of the main mode of data collection.  eDiary vendors are developing creative backup solutions such as a web-based emulator of the actual diary software that patients can use to report their PRO data in the field in the slim chance their diary is lost or malfunctions. This type of solution can be applied in studies, at the sponsors request, when missed site visits are anticipated, or expected, due to patients being too ill to travel.  In lieu of patients traveling to the site to complete their patient-reported outcome measures (PROMs) on a tablet, they may be able to access those same PROMs via a secure internet portal.  In this case, what the patient would see is an emulator, or a replica, of the tablet screen format.  The patient records the data and it is logged as having been recorded via the web instead of on the tablet at the site, but it lands in the same database as the tablet data.  Note, however, when mixing modes of data collection, it is important to consider whether PRO data collected via two or more modes of administration are psychometrically equivalent and provide the relevant support of that equivalence to the regulators - -particularly if the endpoints are primary or secondary15.

As a career COA scientist, I’m encouraged by the proliferation of efforts and advances in patient-focused drug development, albeit in small steps. These initiatives reinforce the importance of the patient’s voice, acknowledge the limitations of traditional approaches and build on the lessons that emerge from each new study. There are still many unknowns but acknowledgement of the need for flexibility, practicality and creativity will advance the science of outcomes research and promote adoption of drug development that meaningfully captures patients' experiences, perspectives, needs, and priorities. For now, the most important thing we can do is collaborate openly and share data among the research community to advance our common goal – the development of safer and more efficacious treatments for patients.

References

1.Gottlieb, S. American Enterprise Institute. “Yes: It prods bureaucratic FDA into taking actions that will save countless American lives.” http://www.aei.org/publication/yes-it-prods-bureaucratic-fda-into-taking-actions-that-will-save-countless-american-lives/

2. 21st Century Cures Act. https://www.congress.gov/bill/114th-congress/house-bill/34/related-bills

3. “PDUFA VI: Fiscal Years 2018 - 2022.” http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm446608.htm

4. Vodika, E., Kim, K., Devine, E., et al. Inclusion of patient-reported outcome measures in registered clinical trials: evidence from ClinicalTrials.gov (2007–2013). Contemp Clin Trials. 2015; 43: 1-9

5. Gnanasakthy A, DeMuro C, Clark M, et al. patient-reported outcomes labeling for products approved by the Office of Hematology and Oncology Products of the US Food and Drug Administration (2010-2014). J Clin Oncol. 2016;34:1928-34.

6. Kluetz, P., Slagle, A., Papadopoulos, E., et al., Focusing on core patient-reported outcomes in cancer clinical trials: symptomatic adverse events, physical function, and disease-related symptoms. Clin Cancer Res. 2016; 22: 1553-1558

7. Basch, E, Abernaty, A., Mullins, D., et al., Recommendations for Incorporating Patient-Reported Outcomes Into Clinical Comparative Effectiveness Research in Adult Oncology. Journal of Clinical Oncology, 2012; 30:34, 4249-4255

8. Howry, C, Elash, CA, Crescioni, et al., Best Practices for Avoiding Paper Backup When Implementing Electronic Approaches to Patient-Reported Outcome Data Collection in Clinical Trials. Ther Innov Regul Sci. 2018,Sep 24:2168479018785160. doi: 10.1177/2168479018785160. [Epub ahead of print

9. Stone AA, Shiffman S, Schwartz JE, et al., Patient non-compliance with paper diaries. BMJ, 2002;324(7347):1193-1194.

10. Shields AL, Shiffman S, Stone A. Patient compliance in an ePRO environment: methods for consistent compliance management, measurement and reporting. In: Byrom B, Tiplady B, eds. ePRO: Electronic Solutions for Patient-Reported Data. Surrey, England: Gower; 2010:127–142.

11. Ganser AL, Raymond SA, Pearson JD. Data Quality and Power in Clinical Trials: A Comparison of ePRO and paper in a randomized clinical trial. In: Byrom B, Tiplady B, eds. ePRO: Electronic Solutions for Patient-Reported Data. Surrey, England: Gower; 2010:49.

12. Coons SJ, Eremenco S, Lundy JJ, et al. Capturing patient-reported outcome (PRO) data electronically: the past, present, and promise of ePRO measurement in clinical trials. Patient, 2015;8(4):301-309.

13. Tiplady B. Electronic Patient Diaries and Questionnaires-ePRO Now Delivering on the Promise? Patient, 2010; 3(3):179.

14. Clinical Trials Transformation Initiative (CTTI) and FDA. Enhancing the Incorporation of Patient Perspectives in Clinical Trials, Public Workshop. Mar 17, 2019. https://www.ctti-clinicaltrials.org/news/recording-now-available-ctti-and-fda-hold-workshop-incorporating-patient-perspectives-clinical

15. Eremenco S, Coons SJ, Paty J, et al. PRO data collection in clinical trials using mixed modes: report of the ISPOR PRO mixed modes good research practices task force. Value Health, 2014;17(5): 501-516.