To assess the impact of the coronavirus disease 2019 (COVID-19) pandemic on clinical trials design and conduct, a Working Group was formed by the Clinical Pharmacology Leadership Group within the International Consortium for Innovation and Quality in Pharmaceutical Development. The Working Group collected and summarized data for IQ member companies' experience on impact of the pandemic on design and conduct of clinical trials, the extent of missed doses and missing pharmacokinetic/pharmacodynamic data, and implementation of mitigation strategies. As of August 30, 2023, there have been over 770 million confirmed cases of coronavirus disease 2019 (COVID-19) and nearly 7 million deaths reported to the World Health Organization.1 The pandemic has led to significant changes in clinical research conducted to evaluate the safety and efficacy of both COVID-19 and non-COVID-19 treatments.2-5 To help assess the impact of the COVID-19 pandemic on clinical trials design and conduct, a Working Group was formed in 2020 by the Clinical Pharmacology Leadership Group within the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium). The IQ COVID-19 Working Group aimed to collect data for IQ member companies' experience on the impact of the pandemic on design and conduct of clinical trials, the extent of missed doses, and missing pharmacokinetic (PK)/pharmacodynamic (PD) data, and implementation of mitigation strategies. Additionally, case studies that refer to the experience of IQ companies were collected and are presented herein. The survey presented here was administered to IQ companies in October 2021 (~ 19 months into the pandemic). Survey questions were designed at trial level and multiple responses per company were collected. Further details are provided in the Supplementary Materials. A total of 47 responses were received across 10 IQ member companies. Summary of key characteristics of the clinical trials included in the survey responses is provided in Figure 1. The clinical trials represented were for small molecules and biologics at different clinical phases of drug development, conducted across different regions and involved different dosing and PK sampling strategies. Responses indicated that the majority of clinical trials (63%) were conducted as planned. Approximately 34% of trials were paused or delayed, and about half of these trials restarted with trial modifications. Overall, ~ 18% of trials had sample size change due to the pandemic, and those were approximately equally divided between increasing and decreasing sample size. Compared with similar trials conducted pre-pandemic, clinical trials conducted during the pandemic had similar number of treatment arms or treatment periods (96% of responses), however, 43% of patient studies had reduced number of visits and 13% of trials allowed a wider sample collection window. The majority (92%) of patient trials (phase Ib, II, or III) allowed subjects to stay in the trial if they contracted COVID-19 and allowed administration of treatments for COVID. For phase I clinical pharmacology studies, the majority (85%) of trials started on time but 70% of the trials took longer to complete compared with similar pre-pandemic studies. Top reasons for delay were the reduced site capacity due to COVID safety protocols (67% of responses), and subjects' reduced willingness to participate (61% of responses). The dropout rate in phase I studies was similar to that pre-pandemic in 80% of responses. The survey assessed the extent of missed or delayed doses and the extent of missed PK and PD samples in trials due to restrictions under the pandemic (Figure 2). Whereas most (83%) of the trials experienced minimal impact (≤ 10%) of missed or delayed doses, three trials (8%) experienced significant delays in dosing (> 10% beyond protocol-defined window). Similarly, most (76%) trials experienced minimal impact (≤ 10%) of missing PK and PD samples, however, 9 trials (25%) experienced > 10% missed PK or PD. Top causes of missingness were that the patient or caregiver decided to skip visits or that the patients could not access the clinic for visits. The most common mitigation strategies that were implemented to minimize the COVID-19 impact on trials included remote visits via telemedicine (24% of responses) and use of local laboratories (24% of responses). Feedback from companies was sought regarding the utilization of patient-centric sampling (PCS) strategies. Several companies (N = 5 trials, 11% of responses) indicated that PCS strategies were implemented. Advantages of PCS, according to survey respondents, were (1) data were collected during the pandemic, (2) less effort for site staff, (3) convenient and local laboratory generally accepted by site and patients, (4) no travel for patients, and (5) minimized dropouts. The disadvantages and biggest hurdles to implementing PCS were reported to be (1) the concern about incorrect sample collection, (2) the need for logistical planning and setup, (3) the possibility of data being missing (e.g., due to not receiving the samples), and (4) the required time, resources, and cost. The companies were also asked questions assessing their views for the future of PCS sampling in clinical trials. Responses indicated that, in the future, PCS approaches would be expected to be used through at-home sampling, patients driving through local laboratories for sample collections, and through utilizing digital devices. It is expected that home samples will be collected by a mobile nurse (~ 60% of responses) more commonly than self-collection by patients (~ 35% of responses). Prose questions were included in the survey, which gathered case studies on mitigation strategies used by companies to support trial conduct during the pandemic. Further details of case studies are provided in the Supplementary Materials. Case Study 1: Reducing enrollment into the organ impairment phase I study by using virtual healthy matched control groups. Phase I organ impairment studies are among those hardest to enroll (~ 1.5–2 years). In the typical study design, organ impairment studies will have control participants enrolled without the underlying organ impairment and similar in age, weight, gender, or any other covariate demonstrated or hypothesized to affect PK. Use of virtual controls, in theory, could facilitate study enrollment and reduce the exposure to healthy participants. The concept of using PK data from healthy participants in other clinical studies as "virtual" matched healthy controls was explored in the renal impairment study with glasdegib.6 Data from 83 subjects treated with a single oral dose of 100 mg glasdegib in 4 previously conducted healthy volunteer studies was used. Virtual healthy controls were matched by age (± 20 years) and body weight (±15 kg) to the renal impairment participants from the glasdegib renal impairment study. The impact of renal impairment on the PKs of the drug was assessed for both scenarios: using "virtual" controls and within study controls with normal renal function (observed). Adjusted geometric mean ratios and 90% confidence intervals for comparisons between renal impairment groups and normal or "virtual" normal renal function groups produced similar results. Case Study 2: Reducing PK assessments in a special population study through early feasibility feedback from investigators and prospective incorporation of modeling. PK assessments in phase II/III trials remain a challenge (especially in hard-to-study populations; i.e., pediatrics). Described here is a safety, efficacy, and PK study of remdesivir in pediatric patients with COVID-19 from birth to < 18 years (CARAVAN). Due to lack of available treatment options, there was an urgent need to complete this study. PK was the primary objective of the study and PK profiles of three different circulating species with different half-lives needed to be characterized. To accomplish this, the study team launched a survey targeting investigators to understand the number and timing of PK samples which would be feasible to collect per patient. Survey responses and modeling were leveraged to design a study that was feasible to execute. Enrollment into this study was completed in ~ 1 year for the adolescent to infant cohorts; 50 out of 53 enrolled participants had PK data available. Case Study 3: Bringing the study to the patient by utilization of home health and tele-health to facilitate enrollment. The pandemic decreased access of patients to the study sites and increased hesitancy regarding travel. This case study describes a phase Ib/IIa study in participants with early stage COVID-19 (NCT04539262). To facilitate the enrollment and ensure patient safety, the following elements were incorporated into the design: > 50% of visits were allowed to be home-care visits, patient-centric sampling was introduced (at home safety/PK sampling done by mobile nurse and conventional venipuncture), and PK sample volume was minimized through additional bioanalytical methods development. The study enrolled faster compared with similar studies prior to pandemic, < 10% of doses/visits were missed, but ~ 26–50% PK samples were missed. The primary obstacle identified was operational complexity of PK sample collection and availability of trained individuals at remote locations. Based on a survey of 47 clinical trials, the pandemic led to longer completion time of phase I studies, and reduced the number of study visits compared with similar studies conducted pre-pandemic. Although most studies had a minimal impact in terms of missed doses and missed PK/PD sample collections, there were a few trials that experienced significant missed or delayed dosing or missing PK/PD samples primarily because patients skipped visits or were not able to access clinics due to the pandemic. Approaches utilized during the COVID-19 pandemic, as presented in the case studies, can be generalized to future clinical trials to support innovation, decrease costs, and shorten the drug development cycle. Virtual matched healthy controls may be a viable option to leverage already available clinical data efficiently, minimize exposure of healthy participants in organ impairment studies, and reduce study duration or cost. Communication and early engagement of investigators to align on the need and feasibility of study assessment is critical for the success of the study. Decentralized trials hold potential to shorten trial duration, increase patient safety, and increase participation in clinical trials but additional logistical challenges remain to be optimized. In summary, the survey results and presented case studies provide insight on the impact of the COVID-19 pandemic on clinical trials conducted for drug development. Additionally, they provide valuable perspective on approaches which can be implemented to facilitate decision making in drug development after the pandemic or during similarly exceptional times. The authors would like to acknowledge the invaluable help provided by the IQ Secretariat Lee Nagao and the IQ CPLG leadership. Medical writing support was provided by Mia DeFino, MS, ELS, CMPP, a freelance medical writer under contract with AbbVie. No funding was received for this work. M.-E.F.M., S.G., R.H., S.N., A.D., A.D.-M., F.G., J.K., S.C., and T.G. are or were employees of their respective affiliations at the time of research conduct and may hold stock or stock options. Data S1 Data S2 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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