by Robert E. Litman, MD; Peter Sorantin, PhD; and Elia E. Acevedo-Diaz, MD
Drs. Litman is with CBH Health, Georgetown University Medical School in Washington, DC. Dr. Sorantin is with Sorantin Outcomes, LLC, in Mountain Lakes, New Jersey. Dr. Acevedo-Diaz is with CBH Health and the National Institute of Mental Health (NIMH) in Bethesda, Maryland.
FUNDING: No funding was provided for this study.
DISCLOSURES: Dr. Litman is a member of the Speaker’s Bureau for Janssen, AbbVie, and Allergan Pharmaceuticals. The other authors have no conflicts of interest relevant to the content of this article.
ABSTRACT: Objective. The goal was to review the impact of the COVID-19 pandemic on psychiatric drug development and clinical trials.
Main Points of Discussion. Disruption of pharmaceutical industry- sponsored clinical trials for psychiatric disorders by the COVID-19 pandemic, prompted by concerns regarding the safety of trial participants and the feasibility of trial conduct, has adversely impacted psychiatric drug development. In response, psychiatry trial sites have modified clinical trials and adapted trial conduct, through the use of social distancing, personal protective equipment, laboratory testing, and remote assessments, to reduce the risks of COVID-19. We review the implications of these modifications for participant safety, safe trial conduct, and data integrity.
Conclusion. Given these implications, ongoing communication and consultation are needed between trials sites, sponsors, and all other stakeholders to ensure continued progress in psychiatric drug development during the pandemic.
Keywords: Clinical Trials, psychiatry, COVID-19
Innov Clin Neurosci. 2021;18(1–3):
The COVID-19 pandemic has significantly disrupted clinical trials worldwide for most medical specialties, including those pharmaceutical industry-sponsored for psychiatric illnesses.1–3 Ongoing trials for mental illness have been paused, and important drug development programs for promising compounds in depression, bipolar disorder, and schizophrenia have been postponed.4 Some of the slowdown is due to the diversion of resources by industry and academia to COVID-19 vaccine development. However, pharmaceutical sponsors and scientists also fear that clinical trials might be operationally difficult to conduct during the pandemic because of stay-at-home orders, social distancing, quarantine requirements, shortages of personal protective equipment (PPE), and scarce laboratory testing, all of which are needed to ensure safety and combat the pandemic. More importantly, sponsors fear increased risks and liability for COVID-19 infection and associated morbidity and mortality for trial participants. Indeed, safety risks are likely increased for mentally ill patients, a population felt to be more vulnerable to the pandemic’s ill effects.5–7
Of equal concern, however, is the interruption in drug development programs when there is a great unmet need for better treatments for psychiatric illnesses, especially now, when there is significant progress toward developing efficacious medications for psychiatric disorders.8–12 Moreover, the pandemic’s serious mental health implications, not only for the seriously mentally ill but also for society as a whole, further highlight the need to ensure continued progress in drug development and other treatment options for mental illness.5–7
Response to COVID-19 by Psychiatry Clinical Trial Sites
In March 2020, the United States (US) Food and Drug Administration (FDA) rapidly issued guidance to investigators and sponsors regarding clinical trial conduct during the COVID-19 public health emergency; recommendations included modifications to study protocols that might maximize participant safety while maintaining study data integrity.13 This guidance paved the way for psychiatry clinical sites to adapt and innovate clinical trial practices to increase safety and mitigate the risk to participants from COVID-19 infection.
Adapting COVID-19 Safety Recommendations from the CDC to Clinical Trials
In keeping with their status as essential services, psychiatry clinical trial sites have implemented the public health safety measures issued by the US Centers for Disease Control and Prevention (CDC).14,15 Mental health research sites are providing CDC-recommended screening for COVID-19 symptoms (e.g. fever/chills, cough, shortness of breath, fatigue, muscle/body aches, headache, congestion, new loss of taste or smell) and risk factors (e.g., exposure history, recent travel, high community infection rates) for patients throughout trial participation.
Mentally ill patients suspected of infection or exposure are educated regarding quarantine and referred as indicated to physicians, emergency rooms or urgent care, primary care clinics, and public health-conducted laboratory testing and contact tracing.
Patients are given PPE to use while at the facility and in the community. Study participants are educated regarding the importance of social distancing, handwashing, face masking, and of refraining from shaking hands and touching the face during clinical research. Quarantine capacity is made available for study participants being evaluated for infection, especially during inpatient studies.
Growing evidence points to the efficacy of PPE and social distancing in decreasing SARS-CoV-2 transmission and infection rate.16 However, when it comes to implementing these measures, our experience suggests that seriously mentally ill research participants need much more in the way of psychoeducation and emotional support, especially when psychological stresses of the pandemic exacerbate mood symptoms, cognitive deficits, and thought disorder.5 In fact, mental health clinical trial sites have become even more “point-of-care” facilities for mentally ill research participants who, due to clinical acuity, functional impairment or poor resources, might not be able to obtain or properly use PPE, maintain social distance, or report and seek help for symptoms. By supporting and monitoring safe behavior and, if symptoms arise, acting as a point-of-care facility, clinical trial sites may mitigate the increased risk to safety from the pandemic for trial participants.
Certainly, for these measures to work, research staff also must be diligent in their compliance with PPE and social distancing. Trial site staff and leadership must vocally endorse and visibly comply with CDC-recommended measures to emphasize the importance of safety to psychiatric patients wishing to participate in clinical trials during the pandemic.
Using Laboratory Testing for SARS-CoV-2 in Psychiatry Clinical Trials
Accurate, reliable, and readily available laboratory testing for SARS-CoV-2 is crucial for safely reopening society and the economy, and that is particularly true for clinical trials. Clinical trial sites are already experienced with screening for viral infections: CNS clinical trials generally exclude patients with viral illnesses, such as humanimmunodeficiency virus (HIV) or hepatitis C. Testing for SARS- CoV-2 at clinical trial sites will enable the screening out of research volunteers who are actively infected, thus, upholding safe conduct of trials and data integrity. Testing will also enhance a site’s ability to identify and refer for care patients with COVID-19 while protecting noninfected individuals.17
Currently, two types of tests are most widely available:
The RT-PCR (or Reverse- Transcriptase Polymerase Chain Reaction) test, which detects SARS-CoV-2 viral ribonucleic acid (RNA) in an infected individual through nasopharyngeal sampling
Antibody (IgM and IgG immunoglobulin) testing, which measures antibody production during viral infection in blood.
RT-PCR is best suited for diagnosing infection since it directly measures viral RNA. Also, since it detects virus in almost all phases of infection (for symptomatic and asymptomatic individuals), it is the most reliable test for screening research participants in clinical trials.
Nasopharyngeal samples must be sent to a clinical pathology laboratory for analysis, so quarantine and/or self-isolation might be required of patients while the sites are waiting for results. Testing of inpatients may be repeated at intervals during trial participation if symptoms appear or exposure is suspected. Testing also may be repeated frequently for outpatient treatment trials, where social distancing and the use of PPE are more difficult to monitor.18,19
While antibody testing is far more convenient and provides a faster response, detection of antibodies is less meaningful regarding acute infection and, therefore, not as reliable for diagnosing or ruling out active disease in suspected COVID-19 infection. In fact, antibody testing has been found to have false negative rates as high as 70 percent in the first week postinfection due to the delay in both IgM and IgG production.20 However, between Days 22 and 35 postinfection, false negative rates can be as low as four percent.20 Also, false positives arise from cross-reactivity with other coronavirus antibodies. Moreover, it is currently unclear whether antibody production provides immunity to re-infection. Thus, it is inadvisable to use antibody testing alone to make decisions regarding immunity in the absence of more clinical correlative data.
The role of antibody testing is likely better suited to epidemiologic surveillance of virus exposure in larger populations.18,19
There is still a need to develop and widely deploy accurate, reliable, rapid-turnaround, FDA-approved, point-of-care testing. For now, most clinical sites must still rely on in-house hospital or outside contract laboratories. There are also unresolved issues regarding the clinical significance of a positive PCR test at various phases of illness as well as the transmissibility of SARS-CoV-2 that might make test interpretation difficult.18 For these reasons, it will be important for sites to have access to infectious disease and clinical pathology experts who can provide up-to-date guidance regarding advances in and utility of SARS-CoV-2 testing.
Using Telemedicine to Conduct Clinical Trials
Other opportunities to mitigate risk from COVID-19 in psychiatry clinical trials might come from innovative techniques already developed for telemedicine. Internet and phone-based live-streaming and recording technologies, which are already used to remotely monitor data quality, can be used to collect trial data while maintaining the safe social distance necessary to combat spread of the virus. Just as in telemedicine, remote video and/or audio sessions with research participants can enable researchers to assess clinical status, perform symptoms ratings, inquire about adverse events, perform certain neuropsychological tests and investigate compliance with study medication and other trial requirements.21–24
Adapting remote telemedical assessment is especially appropriate for use in psychiatry clinical trials, which depend greatly on clinical outcomes that are based on clinicians (raters) assessing subject symptoms in a live session for deriving efficacy data. Advantages, in addition to improving safety and infection prevention, could include greater efficiency in overall trial cost, number of raters, and reduced visits and increased retention of participants in trial.
The use of remote trial technologies has some limitations. Some biomarker data still must be collected onsite or via home visit, such as phlebotomy for pharmacokinetic levels, safety measures (laboratory tests, physical/neurological exams), lumbar punctures for cerebrospinal fluid, as well as electrocardiography and electroencephalography. In general, the use of technology to collect trial data must take into account that psychiatric patients with chronic, debilitating mental illness are often without the resources to access technology hardware or connectivity.
Ideas for using technology often do not incorporate formidable logistical issues concerning availability and scheduling of assessments off site, especially when patients reside in institutional settings (e.g., group homes). Furthermore, when incorporating newer technologies, sites must ensure the protection of personal health information and the confidentiality and authentication of participants who use the internet. For these reasons, many clinical trial sites have developed their own tablet and/or phone audio–video systems to remotely collect data within the site (“intra-site” remote assessment) to ensure both research staff and participants stay safe during a site visit.
Given these considerations, the use of telemedical technology to perform psychiatric ratings and assessments remotely might improve ratings accuracy, provide instantaneous monitoring of trial data, increase convenience for trial participants, and possibly increase recruitment and retention for clinical trials. The promise of greater safety has only heightened the already growing interest in technological innovations that might decentralize and virtualize clinical trials.
Implications of the COVID-19 Pandemic for Psychiatric Clinical Trials
As psychiatry clinical trial sites modify trial conduct to keep research participants safe during the COVID-19 pandemic, it is important to understand the impact of these modifications on trial data. Implementing changes for current studies requires site investigators, sponsor scientists, and regulatory agency leaders to communicate and collaborate more fully and to consider their effects on data integrity, and the analysis and interpretation of trial results. For example, will using omitted visits or remote assessments done to conform with social distancine and stay-at-home orders inevitably lead to missing data and differences in the quality of pre- and postpandemic protocol data? If investigators alter the quantity or types of visits, can they adequately guarantee study drug adherence? Regarding efficacy data, is there absolute certainty that ratings done with remote technology exactly replicate data and can be mixed with data obtained from traditional face-to-face ratings? How does one account for the emotional effects of the pandemic on psychiatrically ill individuals in study results?6 Similarly, is complete safety data from a trial assured if physical examinations, vital signs, or biomarker assessments cannot be performed to evaluate adverse events associated with investigational compounds? Given the Promethean effects of SARS-CoV-2 on central nervous system (CNS) involvement and neuropsychiatric symptoms, laboratory testing should be incorporated into CNS clinical trial designs for subject selection and to rule out changes in mental status due to COVID-19.25 Appropriate amendments to protocol documents of a priori changes to the statistical plan and analysis of data before and after the pandemic onset are advisable. Ultimately, balancing how to ensure study drug adherence, completeness of data, and patient retention while protecting study participants will determine the integrity of study results, the statistical analysis of data, and its clinical generalizability.26
The future is unknown, but existing data on coronaviruses indicate social distancing might be necessary for at least two more years, and SARS-COV-2 might see a resurgence in 2024.27 Therefore, clinical investigators, sponsors and other important stakeholders, such as contract research organizations, data experts, technology experts, Institutional Review Boards, patient representatives, and the FDA must transparently discuss whether drug development can be conducted safely in pandemic conditions and, if so, how to balance this with preserving the integrity of clinical trials. Agencies and bodies with the power to convene, including the FDA, National Institutes of Health (NIH), and academic conferences, should set up forums to discuss what changes in methodologies and practice can be made to mitigate the risks associated with COVID-19 as related to continued clinical trial activity, data integrity, and drug development. This is especially relevant to applications of new technologies, which, while holding great potential for moving the field forward in the pandemic, still must be objectively evaluated from logistical, scientific, regulatory, and ethical standpoints.
Finally, prospective design of clinical trial programs should facilitate necessary adaptation in the face of a possible resurgence of SARS-CoV-2 or other unforeseen circumstances, including built-in modifications to protocol design, visit schedule, laboratory testing, remote assessment, and priorities for data collection. Taken together, these considerations will not only maximize protection for our patients from COVID-19, but also insure our continued best efforts to develop safe and effective medications for the treatment of their psychiatric illness.
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