Legal Executive, Clinical Research Malaysia

Siti Nuralis binti Abd Muis

A Clinical Trial Agreement (CTA) as defined in The Malaysian Guideline for Good Clinical Practice is “a written, dated, and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol may serve as the basis of a contract.”

Review and negotiation of a CTA is an important process as it affects the trial activities conducted at site since the study or trial could not commence without any CTA in place. In 2015, the Clinical Research Malaysia (CRM) Legal & Regulatory Affairs Department developed its Clinical Trial Agreement System (CTA System) to provide a systematic and efficient way to review, as well as speed up the CTA process. This CTA System is an online platform where all the CTA(s) for the Malaysian Ministry of Health sites are submitted by sponsors and CROs.

The CTA System was launched in March 2016 and since then, all the negotiation, review, approval, and endorsement of the CTA are conducted via the CTA System, which features automatic alerts to CRM Legal to review. The total number of CTAs that have been reviewed via CTA System is illustrated below featuring a total of 562. Currently, there are 180 sponsors, 49 CROs who are registered under the CTA system, who are in charge of negotiating the CTA terms and conditions, as well as the study budget with the site.

Sponsors and CROs can keep track of CTA status from the day of study registration until completion. The system offers transparency of the collaboration of work between the sponsor/CROs and CRM’s Legal & Finance department as all the correspondences and communication are held within the system.

The CTA System enables the CRM Legal & Regulatory Affairs department to keep track of studies by accessing ‘New’ & ‘Review’ tabs for the studies which are still in the reviewing process, and the ‘Settled’ tab for the studies which have been endorsed by the reviewer. Registered users can also transfer and handover a specific study from a previously registered clinical research assistant to the new appointed clinical research assistant, which provides a seamless flow of information. This assignment and changes of the study is still subject to the approval of the registered user of the study in the CTA System. Another alert feature prompts a notification via-email when a user has given a comment in the platform, allowing all parties to be aware of changes or a need to act.

Prior to the system’s implementation, from 2012 to 2015, the CRM Legal & Regulatory Affairs department took an average of 59 days to review CTA until endorsement.

 Since the system’s implementation, CTA review has been expedited only 14 days.

When there are any activities that involve data interchange, secure data management should be a top priority. With CTA System authentication and encryption methods, a secure data management protects parties involved in the CTA negotiation from data losses, thefts, and breaches. Strong data security ensures that critical CRM and clinical research assistant data is backed up daily and retrievable in the event that the primary source fails. The CTA system provides a safe, centralized site for data collection and storage, as the clinical research assistant provides some confidential data in the CTA system for the purpose of CTA review, such as the study protocol, study budget, and so on. All data entered into the CTA system is backed up in the backup system, which serves as a risk mitigation measure in the event of a system failure. Apart from the foregoing, the CTA system has a function that allows the study CTA information to be quickly retrieved. The CRA can find any previous CTA submissions by searching the Protocol ID or NMRR ID of the study. The same applies to CRM Legal.

In fact, CRM has gone a step further in terms of CTA review by recognizing the CTA system as a single source of operational truth, allowing all audit processes to run smoothly because all communication and data are saved and stored in proper tabs with specified dates and times. In addition, the essential data in the CTA system can be collected and organized at the corporate level through CRM Legal and Finance as departments to better track CRM's key performance indicator.

To conclude, CRM’s investment into an efficient and well-ordered collaborative Clinical Trial Agreement System serves to encourage sponsors and CROs to do more clinical trials in Malaysia.

 is a Senior Legal Executive of Clinical Research Malaysia

National Pharmaceutical Regulatory Agency (NPRA) Ministry of Health Malaysia. Malaysian Guideline for Good Clinical Practice (Fourth Edition). Glossary 1.21. pg 10. 2018.

https://clinicalresearch.my/evolution-of-clinical-trial-agreement/

Articles

How Clinical Research Malaysia sped up CTA turnaround using a web-based system.

Managing Clinical Trial Agreements 

We all recognize and know that the classic signature is a handwritten representation of a person's name or title. Its legal nature is to verify a person's identity, and it constitutes proof of consent, contractual intention, and endorsement of the information contained in a document. Given the COVID-19 pandemic, digital technology is vital in today’s world, and electronic communication has become necessary. The company and business have strived to advance the technology to cater to the industry's uprising needs, including the Clinical Trial Industry. Electronic signature (“e-signature”) is an electronic means that indicates a person adopts the agreement's contents and signifies their agreement by capturing their signature through third-party platform/software i.e., DocuSign, HelloSign and the likes, signing on a digital device, signing a document, and sending a scanned copy through email or pasting manuscript of digitized image of the signature. It is a legally recognized means of reflecting the signer’s intent to adhere to the terms and conditions of the document signed. Given the circumstances, people must maintain social distance with many workers working from home, and some Principal Investigators (PI) whose signature is required for a Clinical Trial Agreement (CTA) may experience self-isolation at times, it is past time to accept the practise of e-signature, not only during this pandemic outbreak but in the long run term. It is pertinent to note that with travel restrictions, limited access to printers, etc., businesses and individuals will need to adapt and find alternative document signing. Hence, this article will be focusing on the position of law for e-signatures and their benefits and the role of Clinical Research Malaysia (CRM) in educating the Principal Investigator and Hospital Director industry on the practicality of e-signature.

In Malaysia, e-signatures have been legally recognized under the Electronic Commerce Act 2006 (“ECA”) to provide for legal recognition of electronic messages in commercial transactions. The act mentioned that any contract should not be denied legal effect, validity, or enforceability because an electronic message is used in its formation. However, for the e-signatures to be recognized under ECA, an electronic signature must (a) be attached to or logically associated with the electronic message; (b) adequately identify the signer and adequately indicate the signer’s approval of the information to which the signature relates, and (c) be as reliable as is appropriate for the purpose and circumstances in which it is required.

 In other words, the usage of e-signatures in the CTA has legal effect enforceable and admissible in court, provided that the legal requirements stipulated in the ECA must have complied. Based on the Contract Act 1950 and the applicable law, if the legally competent parties reach an agreement, whether they agree verbally, electronically, or in a physical paper document to the agreement, it is considered valid agreement despite written signature is not given.

 A signature or e-signature is simply an evidentiary procedure to formalize the parties’ intention and enter into an Agreement. Therefore, it can be deduced that any contract or agreement in the business or commercial transaction to be specific for a CTA signed by using e-signatures shall be of the same legal effect, validity, or enforceability as a written executed signature. 

Advantages and practicality of electronic signature

There are some advantages of using e-signatures in CTAs. Firstly, using e-signatures in CTA will reduce the time taken for the agreement to be executed. Usually, the parties involved in the CTA will be more than two parties: the sponsor/CRO, PI, and institution. When there are many parties to the CTA, it will take a longer time for the CTA to be couriered from one party to another party for execution. When we can reduce the time taken for the CTA to be executed, it will give another advantage that eventually improves the study start-up timeline to commence a clinical trial. Among the top cause of delays in a clinical trial, is the start-up timeline is due to CTA negotiation and finalization. Implementing e-signatures in the execution of CTA will improve the study start-up timeline in a clinical trial. Besides that, e-signatures also bring the advantage in the business transaction since it is cost -effective. It will reduce the cost of printing and courier delivery service for the execution of CTA. Apart from that, e-signature has a higher level of security, mainly when an e-signature platform is used, as e-signature platforms have encryption software that helps verify the signatory's identity, captured with time stamp, and thus increased the evidential weight to the e-signature process. Less dispute will arise concerning the authenticity of the signatures. Parties may find fewer documents error if an e-signature is implemented, exceptionally when more than two signatories and more than one CTA are executed for one study. Some parties may inadvertently omit to sign some parts of the document, and the same will have to courier back to them to re-sign. Lastly, using e-signatures in CTA can reduce the physical contact between the staff, such as PI and study coordinator associated with wet-ink signatures, especially during this pandemic outbreak. In summary, there are many advantages of using e-signatures in CTA: time and cost saving, improving the study start-up timeline in a clinical trial, higher level of security, less documents error, and reduced physical contact during this pandemic.

Clinical Research Malaysia (CRM) plays a vital role in expediting the negotiation of a CTA and CRM fully supports and encourages the use of e-signature in CTA and other legal documentations considering its benefit, especially during this pandemic era. The company's practice is to allow and utilize e-signatures whenever applicable in CTA, even before this pandemic. In our effort to create awareness on e-signature, CRM has initiated a discussion with the Legal Adviser of the Ministry of Health (“MOH”) to confirm that this arrangement of using e-signature in CTA is in line with the applicable law and regulations. Further, CRM also has created awareness to disseminate the information on e-signature. The information includes the law of using e-signature in CTA and inculcating the benefit of using e-signature in CTA to all the staff, the PI, Hospital Director, Clinical Research Center, and other parties involved in clinical trials via several programs. such as Nurturing New Talent and Investigator Dialogue. By conducting such a program this awareness, CRM hopes that more and more parties are keen to use e-signature in CTA and acknowledged the benefit of utilizing e-signature in CTA.

is a Senior Legal Executive of Clinical Research Malaysia.

Considerations in respect of using Electronic Signatures during MCO

. (2020, April 22). SKRINE. https://www.skrine.com/insights/alerts/april-2020/considerations-in-respect-of-using-electronic-sign

Overview of eSignature Legality in Malaysia

.Hello Sign.https://www.hellosign.com/esignature-legality/Malaysia.

A focus on the position of law for e-signatures, their benefits, and the role of Clinical Research Malaysia in educating the industry on the practicality of e-signature.

A View of Electronic Signature in Clinical Trial Agreements in Malaysia

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.

Clinical trial agreement and extra-mural agreement

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 

 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.

 is a senior legal executive; all of Clinical Research Malaysia.

Nearing a year into the pandemic, this article describes the legal concerns CRM encountered during the COVID-19 outbreak.

Siti Nuralis binti Abd Muis

Articles

Managing Clinical Trial Agreements

A View of Electronic Signature in Clinical Trial Agreements in Malaysia

Legal Perspectives on Conducting Clinical Trials During COVID-19 Outbreak in Malaysia