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Challenges and Dilemmas of Operationalizing COVID-19 Clinical Research in India
Pooja Sharma
Medanta Institute of Education & Research
Anirban Roy Chowdhury
Bharat Serums and Vaccines Limited
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his article reviews several barriers to implementation of clinical studies involving COVID-19 patients in India and attempts to address possible solutions for rapid clinical trial deployment and implementation in line with Good Clinical Practice (GCP) guidelines and regulatory requirements.

When an unknown disease looms as a fatal threat to humanity, it is imperative that the medical research community responds with clinical studies either to understand the nature of the disease or to evaluate the efficacy of new vaccines and therapeutic agents. Conducting clinical studies during pandemics of an infectious nature presents various and complex challenges such as selecting investigational products and participants, study design, identifying efficacy and safety parameters, and aspects of implementation such as ethics review, informed consent, concomitant medications, etc.

Introduction

January 1, 2020, launched the new year at the World Health Organization (WHO) with an IMST (Incident Management Support Team) created across the three levels of the organization to deal with the emergence of an outbreak cluster of pneumonia cases in Wuhan, Hubei, China. Its rapid progress led to the WHO declaration of a COVID-19 pandemic on March 11, 2020.

Advisories for Conducting Clinical Trials During COVID-19

On June 29, the search keyword COVID-19 returned 2,361 studies on the ClinicalTrials.gov registry; 1,322 were interventional studies, 660 were recruiting participants worldwide, and 1,002 were sponsored by groups other than the government or pharmaceutical industry. A search in the Clinical Trial Registry of India (CTRI) with the COVID-19 keyword on that same day returned 272 registered studies.

On March 30, 2020, the Central Drugs Standard Control Organization (CDSCO) issued a notice with advisories on the conduct of clinical trials during outbreak of COVID-19. The advisories assigned to the sponsor the responsibility to make appropriate decisions regarding trial management in consultation with investigators and ethics committees to ensure the rights, safety, and well-being of patients in clinical trials, as well as the integrity of the clinical trial data. The advisory also suggests using electronic media to facilitate communications between stakeholders. While this notice does not provide specifics about how to operationalize and conduct trials during this pandemic, it is probably safe to infer that sponsors can adopt non-traditional modalities for trial conduct if these maintain the rights, safety, and well-being of patients and data integrity.

On the other hand, other regulatory agencies like US FDA, EMEA, and MHRA have subsequently published detailed guidelines on operationalizing trials in the present scenario. It will be pragmatic to try to adapt the guidelines issued by various regulatory authorities in the Indian context wherever applicable to ensure that COVID-19 clinical trials are conducted in a meticulous way, protecting not only the safety of patients in the trial but also the safety of the clinical trial team.

Defining the Protocol: Innovative Clinical Research Design and Delivery

Rapid initiation of clinical studies during a pandemic requires innovations in research design, approval, and delivery. Pragmatic and novel adaptive study designs such as group-sequential designs, mid-course sample size re-estimation or adaptive randomization, and multi-arm multi-stage (MAMS) designs as used in the SOLIDARITY trial may help by incorporating flexibility and can improve trials across all phases of clinical development. Seamless designs allow for more rapid transition between study phases.

The Ministry of Health and Family Welfare (MOHFW), Government of India (GOI), and the WHO have helped define research protocols by providing standard definitions of the severity of the disease and the standard of care for its management. The clinical guidance documents by the MOHFW on appropriate management of suspected and confirmed COVID-19 cases released on March 17 and April 7, and subsequent documents released by MOHFW on May 10 will, in principle, help compare different studies for efficacy against the same control, under the same testing conditions, thus standardizing inclusion/exclusion criteria, concomitant standards of care, and evaluation of outcomes.

The rapidly changing pandemic situation, many amendments to the case definitions, and ever-changing definitions of standard of care create an immense challenge in real word experience. Additionally, various states in India have been following their own treatment protocols. For example, use of convalescent plasma is standard of care in some states but would be a compassionate use protocol only in other states. Evaluation of outcomes that may be attributable to an investigational product is also difficult due to use of several concomitant medications or alternative or rescue treatments, making it difficult to attribute success in meeting trial outcomes and to define relatedness of adverse events. These are further compounded by the complex symptomatology of the disease – upper respiratory symptoms in some patients and gastrointestinal symptoms in others.

It is important to recognize these issues and to optimize our likelihood of figuring out the best treatment options; coordination, cooperation, and collaboration between sites to standardize and minimize these parameters, as in the large RECOVERY trial, will go a long way. Teams who are unable to coalesce on protocols can participate in large-scale data collection independent of any trials; several efforts toward this end are being made in India such as the Covbase registry of the Government of India.

Sample Size and Other Statistical Considerations

Clinical trials during an epidemic must be undertaken rapidly and, since almost no pre-existing information is available, with very little of the information needed to calculate sample size. In the SOLIDARITY trial, for example, no specific sample size was specified, and interim results will be kept under review by an independent Global Data and Safety Monitoring Committee who will decide how often to conduct interim analyses. The larger the number of patients entering the trial, the more accurate the results will be. Large numbers can also generate more conclusive results because response to certain treatments may substantially differ between different populations or sub-populations (e.g., patients with certain prior conditions, older adults, or patients in different countries).

On the other hand, the LOTUS China Trial planned enrolment of 160 patients, but organizers realized upon reaching this number that the trial was underpowered and decided to continue enrolment. Researchers are therefore looking strongly at adaptive sample size calculations. The FDA Guidance for Industry: Statistical Considerations for Clinical Trials during the COVID-19 Public Health Emergency published in June 2020 emphasized the need to proactively plan to address the impact of COVID-19 on the ability to meet the trial objectives. FDA has also asked sponsors to avoid any trial modifications that may introduce bias as well as analyses using histograms and Kaplan–Meier plots that may suggest treatment effect information.

Care must also be taken to minimize missing data, treatment interruptions, treatment discontinuations, participant withdrawals, and missed endpoint assessments. Any modification to the trial, including the original planned analyses, should not be based on data that reveal information on the treatment effect. Sponsors should consider how to approach analysis of data from participants with missing endpoint assessments, or cases where the investigational product supply was interrupted because of COVID-19.

COVID-19 Clinical Research Ethics Committee Review

The CDSCO quickly endorsed using electronic media for communication, per their March 30 notice. Ethics committees very promptly initiated careful online reviews, but these reviews were limited by unclear benefit-risk ratios, because most of the interventions were drugs belonging primarily to two categories: repurposed antivirals and immune modulators and anti-inflammatory drugs. National Guidelines for Ethics Committees reviewing Biomedical and Health Research During COVID-19 Pandemic, issued by the Indian Council of Medical Research in April 2020, helped ethics committees respond rapidly and establish an updated standard review process.

COVID-19 Clinical Research Informed Consent in India

Indian regulations require that the informed consent of a trial participant (in this case a patient in a hospital or in home isolation) be documented on a written consent document that has been approved by the ethics committee and signed and dated by the patient and/or their legally authorized representative at the time of consent. Indian regulations also require audio- visual recording of the consent process for clinical trials of new chemical entities in vulnerable populations. The traditional method of obtaining and documenting informed consent using a signed paper copy of the consent form may be used when feasible.

Taking a cue from the guidance issued by the US FDA, the informed consent document can be sent to the patient electronically when traditional paper methods cannot be employed, and the patient can sign and return the consent form electronically. However, when using this nontraditional method, a detailed standard operating procedure for making the paper documents and other source notes available to the monitors for source data verification (and for eventual archiving) should be established. This is critical in the COVID-19 pandemic: Hospitals are keeping hard copy documents of patients from infection wards for the two- to three-week quarantine period even after the patient is discharged instead of immediately sending them to the medical records department. It is the research team’s responsibility to keep track of these documents and ensure they are appropriately collected, sanitized, and archived.

Acquiring informed consent through video conferencing with the patient or the patient’s legal representative (and, if applicable, an independent witness) is another possible solution. But this has also caused substantial debate among ethics committees as, despite all researchers’ efforts, many patients believe that COVID-19 is a stigmatizing disease. In any case, detailed consent source notes that capture all discussions is critical.

It is best to consider all these scenarios and processes, to account for them in in the protocol, and to get approval for the process from the appropriate regulatory bodies, in advance.

COVID-19 Clinical Research Monitoring

Indian regulations and GCP guidelines do not specify how sponsors must conduct study monitoring. Section 3.1.13 of the Indian GCP Guidelines states: “The determination of the extent and the nature of monitoring should be based on considerations such as objective, purpose, design, complexity, blinding, size and endpoints of the study.” The guidelines thus acknowledge that there may be a range of approaches to monitoring that may vary depending on multiple factors; therefore, certain aspects of site monitoring visits may be done remotely if technically feasible. During the pandemic, traditional onsite monitoring might be difficult for logistical and safety reasons. Sponsors should consider using a risk-based approach to prioritize sites for remote monitoring, which should focus on review of critical study site documentation and source data, including informed consent documents and medical records. Remote monitoring should focus on trial activities that are essential to the safety of patients and reliability of data.

FDA suggests that sponsors may wish to consider one or more of the following options to facilitate remote monitoring access to clinical site records:

  • If the site can provide appropriate resources and technical capabilities, consider establishing a secure remote viewing portal that would permit site staff to provide access to the site’s study documentation and/or trial participants’ source documents for the study monitor’s review.
  • Sites could upload certified copies of source records to a sponsor-controlled electronic system or another cloud-based repository that contains appropriate security controls. The monitor could access the documents remotely for the purpose of source data verification.

Several solutions that provide secure cloud space for document sharing while conducting clinical trials involving COVID-19 patients are already available in India. However, this approach would require an onsite team dedicated to scanning and uploading documents to the cloud. Such scanning will happen in the COVID ward, and the team there must have personal protective equipment (PPE). Given that trial sites in India are not always appropriately staffed, site management organizations (SMOs) may potentially play a critical role in addressing this issue. Remote monitoring activities, including remote review of source documents, should be documented in detail and, if possible, be included in the protocol or monitoring plan.

Human Resource Requirements for Conducting and Monitoring Clinical Study

COVID-19 clinical trials are facing the understandable challenge of limited manpower support. Additionally, research staff and healthcare workers are sometimes contract COVID-19 in the line of duty, and the resultant illness and absence often leads to disruption in study conduct. While SMOs can play a critical role in addressing site resource issues, each site’s Principal Investigators must establish a strong site personnel safety protocol that includes:
 

  • Mandatory use of PPE at the trial site.
  • Create multiple sub-teams who can be deployed on a roster so that members of one team do not interact with members of another team (even after office hours). This reduces the risk of infecting the entire team in case of potential exposure.
  • Twin team technique: Teams working inside the COVID wards and involved in direct patient management should not interact with teams working outside the COVID ward, who take care of the trial’s administrative and documentation aspects.
  • The study team should preferably avoid including members of high-risk populations (e.g., older than 65 years, with comorbidities, etc.).
  • All site staff should coordinate with their backups other departments via email or telephone and avoid meeting in person as much as possible.
  • When exchanging physical documents cannot be avoided, establish and follow a safety protocol to avoid spreading the disease through the documents.

Conclusion

The enabling response of global regulatory authorities to this pandemic has allowed ethics committees to rise up and meet many research challenges. However, detailed guidance from the CDSCO or the Indian Council of Medical Research on aspects like remote monitoring and/or electronic consent would help standardize clinical research operations in today’s unprecedented scenario. It is also important for sponsors, investigators, clinical research institutions, and site management organizations to be proactive, vigilant, and furiously collaborative in finding solutions to these challenges, and to operationalize the protocols that may indeed hold the key to save humanity from this pandemic.
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