Evolution of Clinical Trial Agreement
To regulate the conduct, relationships, responsibilities, and obligations of the parties involved in the clinical trial, the Clinical Trial Agreement (CTA) must be in place. The parties in a CTA are not usually limited to sponsors or contract research organizations (CROs), but also include institutions and principal investigators. The Malaysian Guideline for Good Clinical Practice, has defined the CTA as“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.”(1)
The above definition widens the scope of CTAs, where apart from obligation of parties, the clinical trial budget must also be enumerated clearly in the Agreement.
Halsbury Laws of England has also defined the meaning of agreement in general: “A contract or an agreement is usually reached by the process of offer and acceptance and the law requires an offer on ascertainable terms which receives an unqualified acceptance from the person to whom it is made”(2)
In Malaysia, clinical trials are developing rapidly, which has allowed Malaysia to become a preferred site for clinical trials sponsored by multinational sponsors or CROs.(3) With that, Clinical Research Malaysia (CRM) is established as a one stop shop to assist the principal investigators and the industry in matters related to clinical trials. The CRM Legal and Regulatory Affairs’ role is important in providing CTA Review. The experienced CRM Legal and Regulatory Affairs department is equipped with detailed and current legal knowledge that results in a thorough and prudent review of the CTA by respecting all the applicable laws and regulations.
It is most important for the CTA to be drafted in a language that is understandable to all parties. It needs to be written clearly, limiting and defining any legal terms used. Sponsors and CROs share the same interests in relation to clinical trials, which are:
- collecting accurate data to support their application for marketing approval of their investigational product
- protecting confidential information and intellectual property
- complying with the applicable laws and regulations
On the other hand, from clinical trial site perspectives, their interest lies among compliance with the protocol and regulations, which includes:
- to be fairly compensated for their work
- indemnity (subject illness, injury, or death due to participation in the study or as a result of the investigational product) and sufficient insurance coverage protection to the site, principal investigator, and principal investigator’s team
- the ability to publish study results
- payment for subject in relation to the study(4)
When working towards a contract agreement between sponsors/CROs and clinical trial sites, there needs to be two-way communication and negotiation. Without having a clear and straight forward language, it is difficult to finalize the CTA in a short time. Therefore, it is essential to prepare when negotiating a contract with sponsors and CROs for items and changes that are requested. Apart from that, with the presence of experienced, proactive, and efficient CRM Legal and Regulatory Affairs Departments in reviewing CTA, the review and negotiations of CTA are done in a short period of time.
In ensuring a short timeline of CTA Review, a fixed 14-day calendar timeframe is introduced so that the site initiation visit can follow through as planned under the protocol. All CRM’s legal personnel shall maintain a timeline tracker to make sure the 14-day calendar timeframe is achieved for any one CTA review. However, it is still subject to the budget negotiation between all parties, as the clinical trial budget is incorporated as part of the CTA.
The total number of CTAs that have been reviewed by CRM between 2012 and 2017 was compiled and will be illustrated in Schedule 1. This is based on the retrospective data collection by CRM.
|Year||CTA reviewed by CRM|
From 2012 to 2017, a total of 457 CTAs have been reviewed by CRM.
The number of CTA review days is crucial to start a clinical trial at the site because it will affect the activities of the trial. The study cannot commence without execution of the CTA. The data on review days from 2012 to 2017 are illustrated in Schedule 2 below.
|Year||CTA reviewed timeline by CRM (average time by days)|
From 2012 to 2015, CRM took a longer time to review the CTAs—it took 59 days on average to review the CTA until endorsement. The CTA review days decrease from 2016 and were reported as 13 days in 2017.
The substantial improvement is mainly because:
- All CRM Legal and Regulatory Affairs personnel have their own Key Performance Index to review the CTAs within 14 days.
- In 2015, CRM Legal and Regulatory Affairs Department developed an online CTA Review System expediting the CTA review days from 59 to 13. The online review system was launched in March 2016. The online system is our own purchased internal system, where all the CTAs for Malaysian Ministry of Health sites, specifically for industry sponsored research, will be submitted in the system by the clinical research assistant from sponsors and CROs for CRM Legal and Regulatory Affairs Department’s review.
- The CRM Legal and Regulatory Affairs Department had also organized the CTA online review system workshop for sponsors and CROs on how the system works and their role as the external end user of the system. The system was fully utilized in 2017 and has shortened the timeline for CTA review.
- CRM expanded the Legal and Regulatory Affairs Department manpower from 1 in 2012 to 3 in 2017 which contributed to expedite CTAs review.
The four actions described above have reduced the CTA review days. Reduction time in review days improves the study start-up time from the CTA review point of view. This evolution enticed more sponsor and CROs to bring more clinical trials to Malaysia.5The unnecessary delays in finalizing the CTA should be avoided. As a result, the nation benefits with faster and more clinical trials for doctors and patients to include in their treatment options.
- National Pharmaceutical Regulatory Agency (NPRA) Ministry of Health Malaysia. Malaysian Guideline for Good Clinical Practice (Fourth Edition). Glossary 1.21. pg 10. 2018.
- Halsbury Laws of England; 4thedition, Reissue 1998, para 632. 1998.
- Jenny Maganram Goh, 31 October 2016, Moving medical research forward: Malaysia aims for 1,000 clinical trials by 2020 (https://today.mims.com/moving-medical-research–forward–malaysia-aims-for-1-000-clinical-trials-by-2020)
- Pfeiffer, J. and Windschiegl, M. (2016) Managing Clinical Trial Budgets and Contracts. LAD Publishers. Georgia.
- A.J.A. Ooi, K.F. Khalid, MD, January 26, 2017, Malaysia’s Clinical Research Ecosystem (http://www.appliedclinicaltrialsonline.com/malaysia-s-clinical-research-…)
Nurul Atiqah Abd Rahman, Norafizaa Yusop, Clinical Research Malaysia