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Nearing a year into the pandemic, this article describes the legal concerns CRM encountered during the COVID-19 outbreak.
On March 12, 2020, the World Health Organization declared COVID-19 as a pandemic. In Malaysia, the government took several measures to reduce the transmission risk, such as a Movement Control Order and Recovery Movement Control Order. In due course, the worldwide measures led to companies navigating the way they managed their contractual obligations. Clinical Research Malaysia (CRM), established by the Ministry of Health Malaysia (MOH), exists to support and facilitate clinical trials in many therapeutic areas. One of the supports is to review the Conflict-of-Interest Document, Confidentiality Disclosure Agreement (CDA), Clinical Trial Agreement (CTA), including Amendment Agreement, Extramural Agreement (Collaboration Agreement, Memorandum of Understanding etc.,) and other related legal documents to conduct clinical trials through the MOH. This article describes the legal concerns CRM encountered during the COVID-19 outbreak.
As a result of COVID-19, the MOH entered into collaborations or coalitions with other countries to use existing research capabilities to support, promote and accelerate multi-center trials for safety, efficacy, and effectiveness of interventions against COVID-19 in resource-limited settings. As these coalitions were new to MOH, the CRM legal team oversaw reviewing the relevant documents, which included the Conflict-of-Interest form. Generally, a conflict of interest may occur if an interest or activity influences or appears to influence an individual’s/organization’s ability to exercise objectivity or impairs the individual’s/organization’s ability. As such, CRM guided in identifying and handling potential and actual conflicts of interest involving the parties to the collaboration or coalition. It was a crucial role as the coalition participated by MOH involved global stakeholders.
Similar to any study or trial, the first step before any protocol is disclosed, the CDA must be reviewed and signed by the receiving party. At CRM, the legal team reviews the CDA on behalf of the doctors (i.e., investigators) and also for other interested hospitals/institutions. CRM also ensures the response occurs within one day so that the parties can discuss and proceed with the disclosure of the protocol and enroll in active discussion in conducting a clinical trial. In reviewing the CDA, we ensure the parties rights are protected, i.e., the ownership of the confidential information is protected and only disclosed to the parties as specified and agreed by the owner of the information, and the recipient shall abide with the terms and conditions of the agreements and shall be entitled to keep one copy of the confidential information for archival purpose, and as allowed by the law only.
Some examples of COVID-19 related agreements that CRM reviewed include a collaboration agreement for a pre-clinical COVID-19 study, a CTA for Investigator-Initiated Research (IIR), and a CTA for sponsored research.
The pre-clinical collaboration agreement was regarding the in vitro evaluation of antiviral activity using herbal medicine against the acute respiratory system in COVID-19 disease. The investigators, through the IIR, had started to use several drugs as repurpose medicine to prevent or treat COVID-19. And the sponsored research study was to test its marketed drug for another indication to treat COVID-19.
For every CTA, we ensured that there was a clause that the study shall commence when the approval from relevant authority i.e., the Ethics Committee has been obtained, the Informed Consent form has been obtained from the subjects, and the study shall be conducted in compliance with the protocol, ICH-GCP and other relevant laws and regulations. It is also important that all relevant parties, i.e. the sponsor and investigators, understand their role and responsibilities and those are clearly spelled out in the CTA and agreed to by all the parties. For example, suppose there is a Lead Investigator or National Coordinator in the trial. The CTA must define the difference and the specific role of each. In the CTA, we would also highlight that if any of the clauses of the protocol conflict with any clauses of the CTA, that the clauses in CTA shall take precedence concerning all business and financial matters, and the clauses in the protocol shall take precedence with respect to all medical science and/or technical matters.
In general, the important clauses we are describing will be included for every study/trial, not just a COVID-19 study/trial. However, it is important to emphasize clauses in the COVID-19 study/vaccine CTA, as COVID-19 imposed a higher risk not only to the subjects but to the investigators as well, which must be clearly mentioned in the CTA. At CRM, we encountered some CTAs that stated in case of scientific and non-scientific matters, the CTA prevails over protocol; which clearly should not be the case. We, therefore, amended correctly.
In drafting the CTA, we also ensure that all parties rights are protected, and thus we will ensure the clause on the indemnification, termination and insurance covers all the parties. For example, in the termination clause, we ensure that not only sponsor has the right to terminate the trial, but the investigator also has the right to terminate the study, if it can be concluded that termination is in the interests of the health of the study subjects. Apart from that, clinical trial insurance is vital as it protects the subjects in case they are injured in the process. In the MOH Malaysia setting, COVID-19 studies have the added risk where participants must get to the hospital to participate, so their exposure to the virus is greater. As such, the insurance clause was not to be omitted in the CTA. Also, in the CTA, the governing law and jurisdiction must be in accordance with the country or territory in which the investigator practices.
Upon signing the CTA, parties are obligated to abide by all the terms and conditions stipulated in that CTA. The terms and conditions of the CTA can only be amended by an instrument in writing signed by all the parties, and it is also part of CRM’s role to review the said CTA Amendment. Generally, the CTA Amendment is to add, delete, or correct a portion of the CTA without replacing the entire CTA. In the current situation, the CTA Amendment is necessary and relevant to adapt to the changes of the contractual obligations that occurred due to this pandemic. It is to be expected that the study term of the clinical trial will be delayed due to this pandemic and restriction of movement imposed by the government. Eventually, it will cause the terms of the agreement to be extended, the changes of the study budget of the clinical trial, and change in the study’s conduct (i.e., study monitoring). For example, based on the initial CTA, the study trial monitoring typically will be conducted through on-site visits of the monitors to the Study site. However, the restriction of movement imposed by the government has hampered this activity. To mitigate this challenge, the CTA amendment shall be in place to amend the study monitoring clause in the CTA from an on-site visit to the conduct trial monitoring through remote Source Document Verification. Not only that, when the CTA requires the study budget amendment caused by this pandemic, we review and negotiate the legal terms and conditions of the study payment and from financial perspective with the assistance of our finance team.
At CRM, although COVID-19 restricted our movement and activity, we were still able to provide speedy and reliable end-to-end clinical research support. The CRM legal team continued to ensure that all legal documents and agreements were reviewed within our specified dateline and, in some cases, shorten the timeline for a COVID-19 study. The pandemic caused many obstructions in conducting the clinical trials, however, CRM was able to address specific contractual obligation issues in the CTA brought about by COVID-19.
Siti Nuralis Binti Abd Muis is a legal executive; Nurul Atiqah Binti Abd Rahman is a legal executive, and Siti Nur Hafizah Binti Adnan is a senior legal executive; all of Clinical Research Malaysia.