key: cord-0845719-v802tuuy
authors: Jicha, Gregory A.; Abner, Erin L.
title: COVID-19 and the neurological disease therapeutic pipeline
date: 2020-12-18
journal: Nat Rev Neurol
DOI: 10.1038/s41582-020-00445-w
sha: 27699c6a43cba4b9dc66e090e70740605d1709b6
doc_id: 845719
cord_uid: v802tuuy

From the interruption of clinical trials by shelter-in-place orders to the challenges involved in safely collecting biofluid samples, drug development for neurological disease was hit hard by the COVID-19 pandemic this year. However, the field has responded with innovative solutions, and 2021 could see the therapeutic pipeline flowing again.

Severe acute respiratory syndrome corona virus 2 (SARSCoV2), which emerged in late 2019 and rapidly spread across the globe, led to an almost complete worldwide shutdown of research targeting neurological diseases by midMarch [1] [2] [3] [4] [5] [6] [7] . Thus, the therapeutic pipeline for neurological diseases -which had pre viously been rapidly expanding -came to a grinding halt. Public health measures nec essary to control the spread of coronavirus disease 2019 (COVID19), including social distancing and shelterinplace orders, have impacted every stage of therapeutic develop ment, from basic science discovery to the man ufacturing and distribution of both approved and experimental neurological therapeutics. However, the impact of COVID19 has been most profound in the area of active clinical trial conduct, where both the medical research workforce and clinical trial participants were substantially limited in their ability to meet the rigorous demands and tight time schedules inherent in human clinical trial activities 1,2 .

Many experimental therapeutics require dosing via onsite administration, as well as carefully timed outcome measure assess ments; thus, the interruption of clinical tri als by the COVID19 pandemic has severely damaged the implementation of the precise protocols required to obtain proof of safety and efficacy 1,2 . For example, an article by Joseph Broderick and colleagues 1 published in June described the impact of COVID19 on the NIH StrokeNet, a network of centres performing clinical trials in stroke. An ini tial complete shutdown of all trials across all centres was coordinated centrally and was followed by a phased research restart plan clarifying the treatment estimand of interest with respect to the occurrence of the pan demic, establishing what data are missing for the selected estimator, performing primary analysis under the most plausible missing data assumptions and performing sensitivity analy sis under alternative plausible assump tions. Such an approach begins to define a strategy for interpreting the results of trials interrupted by the pandemic.

Performing clinical trials in the COVID19 era requires consideration of the risks of COVID19 exposure during research engage ment and biomarker collection. In June, Suzanne Schindler and colleagues published a set of recommendations 4 for the collection and analysis of biofluids in Alzheimer disease research during the COVID19 pandemic. These recommendations include adherence to universal precautions and biosafety level1 protocols for most laboratory procedures that do not generate aerosols; use of addi tional safety measures if procedures have the potential to generate aerosols; clear identifica tion of biosamples collected from individuals with known SARSCoV2 infection, as well as provision of this information to anyone receiving such samples; and handling all sam ples collected during the pandemic as if they contain SARSCoV2, given the high rate of asymptomatic infection.

The COVID19 pandemic has also had a downstream effect on the funding that allows the therapeutic pipeline to remain solvent. that took into account local situations and regulatory oversight. This approach was suc cessful in reengaging research activities to at least some degree within 55 days in all but one of the ongoing studies. However, the suc cess of the restart activities and the longterm effects of the shutdown are not yet known.

The interruption of essential components of clinical trial conduct that are necessary for advancement to the next stage of therapeutic development (and/or eventual approval of the experimental therapeutics) has created challenges for both sponsors and regulatory agencies, who have been left uncertain as to how to handle these unprecedented, wide spread disruptions 2,3 . Nevertheless, solutions have been proposed and have started being implemented. Remote assessments to allow distanced trial conduct are under rapid development and include the use of telephone evaluations, video conferenceassisted evalu ations and other remote digital strategies 1,6 . Indeed, Broderick et al. 1 recommended that trial sites incorporate remote assessments as needed, as well as simplifying and limiting participant visits.

A change in assessment modality during a trial or missing data resulting from COVID19 related interruptions can complicate stati stical analyses and might bias the results. The interpretation of adverse events is also complicated by the pandemic as neurologi cal and cognitive outcome measures can be affected by COVID19associated signs and symptoms 1, 2, 4 . In another key publication from this year, Suzie Cro and colleagues proposed a fourstep statistical approach for handling missing outcome data 3 . Their approach entails Maintaining a workforce skilled in clinical trial conduct has been a challenge with wide spread furloughs, layoffs and economic col lapse threatening not only current but also future clinical trial conduct 2 . In addition, the need for additional personal protective equipment, COVID19 testing of research participants and staff, implementation of new equipment and training to facilitate bio marker collection, and the introduction of remote assessments have all contributed to an increase in the financial costs involved in run ning clinical trials. In an article 2 published in September this year, we made several recom mendations for overcoming sitespecific barriers to clinical trial conduct during the COVID19 era, including the allocation of funds to standing site support with the aim of maintaining a researchready infrastructure for future trials. Most importantly, COVID19 has, under standably, negatively affected the interest and willingness of many people to engage in experimental clinical trials 2,5,7 (Fig. 1) . In another key publication from 2020, Daniel Lackland and colleagues 5 highlighted the potential for the COVID19 pandemic to further limit the participation of historically underre presented groups in clinical trials and recom mended that the field increases efforts to recruit participants from these groups. Managing safety concerns and overcoming a growing reluctance to engage in research at this time will require innovative solu tions, and implementing these solutions will require widespread efforts to educate poten tial research volunteers on risk reduction measures. Potential volunteers will also need to be educated on the importance of continu ing to move therapeutic research forward in order to advance the development of new medicines for the treatment of neurological diseases. Without such efforts, the impact of the COVID19 pandemic on the therapeu tic pipeline for neurological diseases could extend indefinitely.

It remains uncertain as to whether effective solutions to the problems induced by the pan demic can be developed, or whether the many affected trials will be left with inconclusive results, necessitating repeat studies that would cost additional years and millions of US dollars (Fig. 1) . In addition, studies scheduled to start this year have been delayed, closing the valve on our previously robust pipeline of new experimental therapeutics even more tightly. Clearly, the impact of COVID19 on research sites responsible for the conduct of human clinical trials has been profound 1,2 . Nevertheless, the innovation spurred by this crisis will move the field forward in new ways, ensuring that 2021 will be a year that allows the therapeutic pipeline to resume its prepandemic vigorous flow. Researchers and clinicians have formed alliances to address barriers to research advancement, allow ing new research into statistical techniques to handle the current disruptions to clinical trial conduct 3 , enabling the production of guidelines for enhanced safety of research conduct 1, 4 , and spurring on the development and validation of novel remote assessment techniques 1,6 . the innovation spurred by this crisis will move the field forward in new ways www.nature.com/nrneurol

National Institutes of Health StrokeNet during the time of COVID-19 and beyond

COVID-19 and geriatric clinical trials research

A four-step strategy for handling missing outcome data in randomised trials affected by a pandemic

Maximizing safety in the conduct of alzheimer's disease fluid biomarker research in the era of COVID-19

Impact of COVID-19 on clinical research and inclusion of diverse populations

Amyotrophic lateral sclerosis care and research in the United States during the COVID-19 pandemic: Challenges and opportunities

Will "social distancing" lead to future "research distancing": A reflection on COVID-19 impacts on Alzheimer's disease research

G.A.J. has received contract research funding from AbbVie, Biohaven, Eisai, Lilly, Neurovision, Novartis and Suven. E.L.A. declares no competing interests.