The COVID-19 pandemic has meant we are all coming to terms with new ways of safely working together. For clinical researchers, new guidance and recommendations from US Food and Drug Administration (FDA) [1], European Medicine Agency (EMA) [2,3], and Independent Review Boards (IRB) [4] provide some structure to the adjustments.

Industry-sponsored clinical trials will require modification in design and conduct. Although patient-centered outcome (PCO) research is not explicitly described in the current recommendations, it’s important we adhere to best practice principles. Here we identify three key areas: qualitative research, mode of administration for patient reported outcome (PRO) questionnaires, and clinical trial systematic missing data.

Hearing the patient voice

One immediate impact on ongoing clinical studies will be the preclusion of in-person face-to-face qualitative interviews or focus groups. In addition, recruitment may be more difficult, as participants may be less willing to be involved in qualitative research, given the uncertainty. Study protocols will need to be amended to conduct interviews by phone or web-based applications. Importantly, to our knowledge, there is no evidence that supports the superiority of face-to-face over telephone interviews in the context of outcomes research in a sample of subjects above 12 years old and not cognitively impaired. This is supported by the research literature [5,6,7]. In addition, transcription and qualitative coding of patient interviews should not be impacted.

Time for technology

Mode of patient reported outcome (PRO) data collection will need to be adapted for clinical trial protocols that specify in-person on-site data collection. Most PRO questionnaires can relatively easily be migrated from hard copy to e-copy [8] using a range of readily accessible tools [9] compliant with the necessary data collection regulations [10]. Study participants who have internet access via a computer, tablet, or smartphone can readily complete questionnaires and immediately submit them online. For those who do not have internet access, it will be necessary to mail them hard copies of the questionnaires with a self-addressed stamped envelope so it can be easily mailed back to the study team.

The recent discussion on FDA PFDD Guidance 4 stated that such mixed mode generated data “may be pooled under very specific and limited conditions[11, page 8] and the EMA Biostatistics Working Party draft “Points to consider on implications of Coronavirus disease (COVID-19) on methodological aspects of ongoing clinical trial” [3] acknowledges that “validation of outcomes that were measured differently” may be a follow-up topic for methodological discussion with the Agency. Therefore, change in mode of administration (e.g., hard copy versus e-copy) should be documented [12]. In addition, psychometric analysis plans should be developed to ensure reliability, validity [13], and equivalence [14].

Mind the gaps

Other types of PCO questionnaires (or rating scales) may not be amenable to change in mode of administration (e.g., for clinician-reported outcomes; ClinROs). This can lead to additional missing data. For risk mitigation strategies to be effective, it will be important that sponsors:

  • capture information in each case-report form that details any information related to COVID-19;
  • document when the COVID-19 pandemic started impacting trial participants and analyze the data in the relevant sub-groups;
  • prior to the database lock, address how protocol deviations related to COVID-19 will be handled for the prespecified statistical analysis plans;
  • discuss potential plans with the regulators (e.g., typically the FDA review division).

Quantifying patient experience in the wake of COVID-19 - the new normal

Ultimately, we need to be cognizant that clinical trial participants will not be engaging in their normal activities, may be concerned about their health, disruptions to their regularly scheduled care visits, and their ability to get medications, and therefore may be experiencing higher levels of stress than usual [15,16]. For all PCO research conducted during this time, it will be important to consider the pandemic’s impact on the way participants respond and react. This needs to be considered and accounted for when collecting, analyzing and interpreting.

While COVID-19 presents unprecedented challenges to researchers, it also offers us the opportunity to respond with flexibility and innovation in terms of how we engage with patients and caregivers. As this situation develops, we’re seeing more willingness to experiment with and adopt patient-centered techniques and approaches such as electronic data collection, customized approaches to site visit requirements, and close collaboration with patients to enable continuing trial participation. We are hopeful that this shift toward patient-centered approaches will continue in the wake of COVID-19, building momentum towards the PFDD paradigm championed by FDA [17] and other international bodies [18]. As the impact of the wake of COVID-19 become clearer, at Modus Outcomes we will continue to review, recommend and support our clients and collaborators as we work together to achieve fit-for-purpose PCO research.


Further reading

[1] United States Food and Drug Administration. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic, March 27, 2020.

[2] European Medicines Agency. Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, March 27, 2020.

[3] European Medicines Agency Biostatistics Working Party. Points to consider on implications of Coronavirus disease (COVID-19) on methodological aspects of ongoing clinical trials (Draft), March 25, 2020.

[4] WIRB Copernicus Group. Clinical Trials in the Era of COVID-19 (weekly webinar series).

[5] Vogl S. Telephone versus Face-to-Face Interviews Mode Effect on Semi-Structured Interviews with Children. Sociological Methodology, 2013, 43, 133-177.

[6] Michel C, Schimmelmann BG, Kupferschmid S, Siegwart M, Schultze-Lutter F. Reliability of telephone assessments of at-risk criteria of psychosis: A comparison to face-to-face interviews. Schizophr Res. 2014;153(1-3):251-3.

[7] Woodyatt CR, Finneran CA, Stephenson R. In-Person Versus Online Focus Group Discussions: A Comparative Analysis of Data Quality. Qualitative Health Res. 2016; 26(6): 741-9.

[8] Dillman D, Smyth J, Christian L. Internet, Phone, Mail, and Mixed-Mode Surveys: The Tailored Design Method Hardcover. Hoboken, New Jersey: John Wiley & Sons, Inc; 2014.

[9] Project REDCap.

[10] United States Health and Human Services Department. Summary of the HIPAA Security Rule.

[11]  United States Food and Drug Administration. PFDD Guidance 4: Incorporating Clinical Outcome Assessments into Endpoints for Regulatory Decision-Making.

[12] Muehlhausen W, Doll H, Quadri N, et al. Equivalence of electronic and paper administration of patient-reported outcome measures: a systematic review and meta-analysis of studies conducted between 2007 and 2013. Health Qual Life Outcomes. 2015;13:167.

[13] Fuzesi S, Cano SJ, Klassen AF, Atisha D, Pusic AL. Validation of the electronic version of the BREAST-Q in the Army of Women Study. Breast. 2017;33:44-49.

[14] Andrich D, Hagquist C. Real and Artificial Differential Item Functioning. Journal of Educational and Behavioral Statistics. 2012;37(3):387-416.

[15] World Health Organization. Mental health and psychological resilience during the COVID-19 pandemic, March,27 2020.

[16] University of Oxford. COVID-19's impact on youth mental health the focus of new research, March, 30, 2020.

[17] Patient-Focused Drug Development.

[18] Patient-Focused Medicines Development.