|Year : 2020 | Volume
| Issue : 2 | Page : 81-85
Strategies adopted in conduct of clinical trials amidst coronavirus disease-2019 (COVID-19)
Subramani Poongothai1, Ranjit Mohan Anjana1, Ramasamy Aarthy1, Selvam Kasthuri1, Mohamed Althab Begum1, Kulasegaran Karkuzhali1, Kannikan Viswanathan1, Balasundaram Bhavani Sundari1, Ravi Pavitha1, Boopathi Hemalatha1, Abdul Ali Tameem Nisha1, Mahalakshmi Ravisankar1, Rajkumar Marappan1, Jagannathan Ramesh2
1 Department of Clinical trials, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India
2 Indian Society for Clinical Research, Bengaluru, Karnataka, India
|Date of Submission||12-May-2020|
|Date of Decision||21-May-2020|
|Date of Acceptance||23-May-2020|
|Date of Web Publication||24-Jun-2020|
Dr. Subramani Poongothai
Department of Clinical Trials, Madras Diabetes Research Foundation, 4, Conran Smith Road, Gopalapuram, Chennai 600086, Tamil Nadu.
Source of Support: None, Conflict of Interest: None
The conduct of clinical trials is crucial to all research stakeholders and very challenging to the investigators, study teams, and participants during (coronavirus disease-2019) COVID-19 pandemic. The main challenges include difficulties in maintaining complete adherence to approved protocol, regulatory provisions applicable guidelines, recruitment of subjects, protection of rights, safety and well-being of trial subjects (participants), is of paramount importance. The CDSCO (Central Drugs Standard Control Organization), EMA (European Medicines Agency), and FDA (Food and Drug Administration) have come out with the guidelines on the management of clinical trials during the COVID-19. This article describes the process of conducting clinical trials at Department of Clinical Trials at Madras Diabetes Research Foundation (MDRF), Chennai, during the COVID-19 pandemic. Effective strategies taken at our site include compliance with scheduled visits of subjects, laboratory testing (investigations), administration of investigational product(s), assessment of safety and efficacy parameters, reporting of SAEs (serious adverse event). These strategies could be a useful reference to investigators, doctors, and research staff across hospital sites in India and elsewhere.
Keywords: Challenges, clinical trials, COVID-19
|How to cite this article:|
Poongothai S, Anjana RM, Aarthy R, Kasthuri S, Begum MA, Karkuzhali K, Viswanathan K, Bhavani Sundari B, Pavitha R, Hemalatha B, Nisha AA, Ravisankar M, Marappan R, Ramesh J. Strategies adopted in conduct of clinical trials amidst coronavirus disease-2019 (COVID-19). J Diabetol 2020;11:81-5
|How to cite this URL:|
Poongothai S, Anjana RM, Aarthy R, Kasthuri S, Begum MA, Karkuzhali K, Viswanathan K, Bhavani Sundari B, Pavitha R, Hemalatha B, Nisha AA, Ravisankar M, Marappan R, Ramesh J. Strategies adopted in conduct of clinical trials amidst coronavirus disease-2019 (COVID-19). J Diabetol [serial online] 2020 [cited 2020 Jul 13];11:81-5. Available from: http://www.journalofdiabetology.org/text.asp?2020/11/2/81/287607
| Introduction|| |
A severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) known to cause the coronavirus disease-2019 (COVID-19) was first identified in December 2019 at Wuhan, the capital of China’s Hubei province and spread globally causing a pandemic., The first case in India was reported on January 30, 2020 and has led to many challenges in the conduct of ongoing clinical trials including enrollment and continued involvement of participants in the trial, restrictions of hospital site visit, trial staff availability, and delay in initiation of new trials. This article will discuss some of the challenges due to COVID-19 and strategies adopted to overcome the same.
The conduct of clinical trials is crucial to all research stakeholders and very challenging to the investigators, study teams and participants during COVID-19 pandemic. Some additional challenges include optimal medical care of study participants; dispensing of study medication(s); entering data in the electronic case report form (e-CRF); treatment and follow-up of any adverse events; and overall compliance to trial protocol. Self-isolation also leads to difficulties in management of medical conditions.
Various regulatory bodies—CDSCO (Central Drugs Standard Control Organisation), EMA (European Medicines Agency), and FDA (Food and Drug Administration)—have provided guidance and recommendations for conduct of clinical trials during the COVID-19 pandemic without compromising the participant’s safety, rights and well-being.,, Actions were based on risk–benefit considerations taken nationally and locally by the authorities with priority given to the impact on the health and safety of the trial participants. Such procedures relate to data collection, patient monitoring, adverse-event reporting, staff challenges due to quarantine measures or illnesses, informed consent and more.
For any trial affected by the pandemic, study reports should include notes of all contingency measures put in place to maintain the trial integrity, a list of participants affected by changes related to COVID-19 disruptions and analyses addressing how the changes may impact the trial, especially trial’s safety and efficacy results. Impact on the trial’s integrity should be minimized where possible, but necessary protocol deviations must still be made and documented which is unavoidable.
Trial investigators and the hospital site staff always have an additional burden to conduct the study in midst of crisis. Furthermore, the fear and anxiety faced by the participants and their families need to be addressed and the high responsibility lies with the investigator and his/her team.
This article describes the process of conducting clinical trials at Department of Clinical Trials at Madras Diabetes Research Foundation (MDRF), Chennai, during the COVID-19 pandemic.
It is important to provide optimal medical care to all the trial participants with diabetes, many with other comorbidities, as they are more prone to adverse impact of infections and COVID-19 is not an exception. Furthermore, given the restrictions from authorities on travel, including to hospitals, there are higher chances for inadequate control for participants with diabetes and other metabolic disorders. In this context, clinical trial participants are monitored as per the protocol norms and even more so during this pandemic. This article focuses about how clinical trials are being conducted at our hospital site without significant interruption during COVID-19, which could be a useful reference to investigators, doctors, and research staff across hospital sites in India and elsewhere.
The following strategies were adapted by our investigators and site staff as per the revised guidelines provided by authorities in pandemic situations (CDSCO, EMA, and FDA).
Medical management and adverse events
Although the safety of the participant is of primary importance, the risks of involvement in the trial, in particular the added challenges due to COVID-19, should be weighed against anticipated benefit for the participant and society (ref: principle 2.2 of ICH GCP). Due to restrictions in travel, physical visits of participants were reduced or postponed to later date; however, it is important that the investigator continues collecting adverse events from the participant through alternative means, for example, by telecommunication (phone).
The co-investigators at our site contacted the participants over phone for dose adjustments, identified adverse events and ensured continuous medical care and prevented oversight. Serious adverse events were reported within 24h and have been communicated to the DCGI (Drugs Controller General of India), EC (Ethics Committee), and the trial sponsor. It is important to note that the participants and their family members played a significant role by sending the relevant medical reports through phone messaging and communication such as WhatsApp. This shows the involvement of the participants and their commitment to the study.
Follow-up of participants
In clinical trials, the role of participants is very important and retaining them during the entire study duration becomes vital. Generally, at our site, a good rapport with the participants is built by calling them on a regular basis to know about their well-being, even if not mandated by the trial protocol. During this crisis, we used telephonic conversations to know the health status of the participants and also enquired about any symptoms of COVID-19. The study visits and checking for any adverse events, if any, were also done during the phone call to study participants. After knowing the participant’s willingness, we informed about the clinic visits as required by the protocol to understand whether they would encourage the same. If willing, we offered our staff visit their homes.
The health status of the trial staff/phlebotomist/home service staff was assessed every day. They were allowed to complete the tasks assigned to them only after their temperature was checked on a daily basis. They were also asked to verbally assure that any symptoms such as cold, cough, and fever were absent. All the front-line health care workers wore masks and other hygienic practices were followed strictly by them. The participants were reassured of the hygienic practices adopted by the hospital team. Only after participants confirmed that the hospital staff could visit their house to collect blood and deliver the IP etc., the study team was assigned.
Many home visits were conducted successfully. The study coordinator and the phlebotomist visited the participant’s homes and samples were collected for both local and central lab storage. The stored sample would be run again in the central lab as per the protocol requirement after the lockdown ends. Local laboratory analysis could be used for safety decisions. When the study coordinator was not able to visit the participant’s house, help from the home care staff was sought as they had permission to travel. Some trial sponsors accepted that planned site visits by participants could be changed into telephone visits and in such instances, there were no challenges.
Dispensing investigational medicinal product
One of the primary concerns is the continuation of the Investigational Medicinal Product (IMP) for the participants and ensuring that the participants have enough supplies during the crisis. Study team staff visited the site to ensure this by taking the required study IMP for the participants from the study drug storage room. Thereafter, the IMP was handed over to the home service staff, packed in cool bags in order to maintain the required temperature. The site staff provided the participants’ home address and contact numbers to the home care staff.
Before dispensing and making an IWRS (Interactive Web Response Systems) call, our study team called the participants and checked their availability. We successfully dispensed the IMP and no participants were “off the drug” during this time. Further, we called the participants to check the status of the drugs received by them and also verified if it was intact. This process satisfied the trial participants and hence would serve as an important tool for their participation and retention in the trial.
Documentation and communication with trial sponsors
The conduct of clinical trials during this crisis was documented in the source documents during the clinic visits, and other activities like dispensing medication, temperature monitoring, and phone contacts were documented by mail and shared to the sponsors. Reporting of adverse events was communicated immediately to the respective regulatory authorities, Ethics committee, and the sponsors. The electronic CRFs were entered by the study team and were kept up to date.
| Other Challenges Faced|| |
Safety reporting and EC notification
The sponsors are expected to continue safety reporting in adherence to EU and national legal frameworks (Directive 2001/205; CT-36)., CIOMS (Council for International Organizations of Medical Sciences) safety concerns and other safety mailings were notified through mail to the EC members and the member secretary acknowledged the same by e-signature. The feasibility of starting a new clinical trial or including new trial participants in an ongoing trial remains as a great challenge as audio–video recording of trial participants’ consent, obtaining a written consent, and performing special investigations other than blood tests are very challenging. Initiation of new trial sites is generally not expected in the current situation unless no other solution exists for the trial participant and other research stake holders. Participants should not be included in trials without proper eligibility assessment, including performance of planned tests, and written informed consent according to national laws and regulations. Investigator should inform the IEC and the sponsor when a visit been performed and it should be noted in the study documentation. A modification to the protocol does not need to be submitted until the time of next renewal of protocol.
Revised regulatory guidelines
The CDSCO, EMA, and FDA have published their revised guidelines in conduct of clinical trials during the COVID-19 pandemic. The salient features of those guidelines are described in [Table 1].
|Table 1: Guidance from regulatory authorities regarding conduct of clinical trials during the COVID-19 pandemica,b,,|
Click here to view
| Discussion|| |
The regulatory authority stated that the rights, safety, and well-being of trial participants were of paramount importance during the COVID-19 pandemic. Changes to trial conduct should be agreed with and communicated clearly to investigator sites by the sponsor. To support implementation by sites, it is important that changes and local implications are made clear, including marking of changed documents with track changes. Agreements may be documented as e-mail exchange. In addition, trial participants should be informed by the investigator in time, about changes in the conduct of the clinical trial relevant to participants (e.g., cancellation of visits, change in laboratory testing, delivery of IMP).
Considering this exceptional situation, if, in order to implement urgent measures for the protection of participants involved in a clinical trial, expenses may arise which may be borne initially by the participants, these should typically be compensated subsequently by the sponsor via the investigator. If additional financial compensation is provided to sites/investigators (e.g., to cover the cost of using couriers for IMP delivery), this needs to be documented and performed according to national legislation. Handling of reimbursement of such expenses should follow national legislation and/or guidance.
In line with the reduction of physical site visits, we foresee that there will be a need for delivery of the IMP directly to trial participants during the COVID-19 pandemic. This is to avoid the trial participant’s travel to reach the site with the consequent risk of spreading/acquiring infection. The delivery is generally expected to happen from investigator sites to trial participants.
| Conclusion|| |
Considering all the above guidelines, the Investigator and the study team at hospital sites should conduct the clinical trials during the COVID-19 very effectively and proactively handling the difficulties faced by trial participants. Effective strategies taken at our site discussed earlier helped us to conduct clinical trials well during this pandemic. We can expect further guidance from regulatory and health authorities in the coming months to effectively manage both ongoing and new clinical trials due to unforeseen situations such as COVID-19, which will be important for all stakeholders of clinical trials.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Mayo Clinic. Coronavirus disease 2019 (COVID-19)—Symptoms and causes. Available from: https://www.mayoclinic.org/diseases-conditions/coronavirus/symptoms-causes/syc-20479963. [Last accessed on 2020 Apr 21].
Hui DS, I Azhar E, Madani TA, Ntoumi F, Kock R, Dar O, et al
. The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health: The latest 2019 novel coronavirus outbreak in Wuhan, China. Int J Infect Dis 2020;91:264-6. doi:10.1016/j.ijid.2020.01.009
WHO. Director-General’s opening remarks at the media briefing on COVID-19, March 11, 2020. Available from: https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. [Last accessed on 2020 Apr 21].
Ministry of Health and Family Welfare. COVID-19 India. https://www.mohfw.gov.in/. [Last accessed on 2020 Apr 21].
CDSCO. Announced clinical trials conduct rules during COVID-19 outbreak. Available from: https://cliniexperts.com/cdsco-clinical-trials-conduct-rules-during-covid-19-outbreak/. [Last accessed on 2020 Apr 21].
European Medicines Agency. Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, Version 3, April 28, 2020. Available from: https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdf. [Last accessed on 2020 May 4].
FDA (Food and Drug Administration). FDA guidance on conduct of clinical trials of medical products during COVID-19 public health emergency; guidance for industry, investigators, and institutional review boards. March 2020. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency. [Last accessed on 2020 Apr 21].
Remote monitoring, protocol amendments spike with COVID-19 spread. Available from: https://www.centerwatch.com/articles/24590-remote-monitoring-protocol-amendments-spike-with-covid-19-spread. [Last accessed on 2020 Apr 21].
Medicines: COVID-19 updates. Health Products Regulatory Authority. Available from: http://www.hpra.ie/homepage/medicines/covid-19-updates. Accessed on May 4, 2020.
EudraLex—Volume 10—Clinical trials guidelines. Available from: https://ec.europa.eu/health/documents/eudralex/vol-10_en. [Last accessed on 2020 Apr 21].
US grants EUA approval for remdesivir as a COVID-19 treatment. Available from: https://www.thepharmaletter.com/article/us-grants-eua-approval-for-remdesivir-as-a-covid-19-treatment. [Last accessed on 2020 Apr 21].
European Commission. Available from: https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2010:082:0001:0019:EN:PDF. [Last accessed on 2020 Apr 21].