As delays in getting clinical trials up and running have financial implications, pharmaceutical companies and contract research organisations (CROs) are looking at ways to accelerate the study start-up process. Challenges in processes such as feasibility assessment, site selection, compilation of essential documents, submission to ethics committee, and application for investigational product import license can affect study milestones and timelines.1,2
In Malaysia, the Ministry of Health established a corporate entity, CRM, that functions as a one-stop centre to facilitate industry-sponsored research in the country to ensure an efficient start-up process. The organisation offers services such as feasibility assessment, budget negotiation, clinical trial agreement review and placement of study coordinators. This article describes CRM’s timeline in feasibility assessment, budget negotiation and clinical trial agreement review, besides the regulatory and ethics approval timeline in Malaysia.
Centralised Feasibility and Site Selection Services
The company has a centralised feasibility team that handles feasibility queries from CROs, pharmaceutical, medical device, and biotechnology companies. The feasibility team maps the sites according to disease specialities and workload, saving the time it takes to identify the right investigators and sites with interest in a particular clinical trial. It also assists interested potential investigators to address the queries and submits the completed feasibility questionnaire to the CRO or sponsor (Figure 1). Having a centralised service is far more efficient as the individual databases of the CROs and sponsors may not always be updated and sufficiently comprehensive.3 As the single point of contact, the standardised processes lead to streamlined communications which reduce delay and confusion on the ground. As a result, the turnaround time is shorter than if a sponsor or CRO were to approach individually. With CRM’s central database and feedback from the sites and investigators, a completed feasibility questionnaire can be sent back to the enquiring company within 5–10 working days (Table 1).
Prompt Review and Negotiations of Clinical Trial Contracts
The top cause of delays in clinical trial start-up time is related to contract and budget negotiations.1,4 Lack of effective communication, unclear processes, bureaucracy, and difficult to understand contracts can lengthen the time it takes to finalise the clinical trial agreements (CTAs).4,5 To address these challenges, an experienced legal and regulatory affairs department reviews and endorses CTAs (on behalf of principal investigators) for all clinical trials conducted at public hospitals in Malaysia within 14 calendar days, from the last feedback received from the party involved in the study budget negotiation (Table 1). In addition to an experienced legal team, CRM has implemented an online system for submission and internal review of CTAs to shorten the timeline for review. Prior to this, the average time to review a CTA was 59 days.
Parallel Ethics and Regulatory Approval Processes
Clinical trials that are conducted in the Ministry of Health (MOH) facilities will require ethics approval from the MREC (Medical Research and Ethics Committee), which is the sole ethics committee for Malaysia’s MOH facilities. MREC also acts as an independent ethics committee for facilities outside the MOH who do not have their own ethics committees. Malaysia’s regulatory authority for pharmaceutical trials is the National Pharmaceutical Regulatory Agency (NPRA). The NPRA is responsible for approving applications for clinical trial import licence (CTIL) and clinical trial exemption (CTX). Ethical approval is needed before the CTIL or CTX is released (Figure 1).
For medical device trials, the Medical Device Authority (MDA) oversees the issuance of the letter of no restrictions for notification of medical devices for clinical use and research supportive use. This would take 14 working days. On the other hand, notification of medical devices for clinical investigational use will go through a review by the Technical Committee of Medical Device Clinical Evaluation (TCMDCE). The issuance of a letter of no restrictions would take seven working days after evaluation by the committee. In 2019, an online system was introduced to facilitate the process.
Applications and tracking of progress are done through a local online registration of clinical studies, the National Medical Research Register (NMRR). With the NMRR being linked to the MREC, ethics approval processes are fast and convenient. An NMRR registration is also needed for CTIL/CTX application.
In Malaysia, regulatory and ethical submissions are done in parallel.6 Regulatory approval takes approximately 30 business days while MREC ethics approval takes about 50 business days7,8 (Table 1). Ethical review and approval can be as short as one month from the time of application if there are no issues/queries.8,9 On average, it takes about four months to obtain regulatory and ethics approval.10
Consistent timelines, reliability and efficient processes are important criteria for sponsors and CROs in deciding where to conduct its clinical trials. With CRM’s involvement at the feasibility and startup phase, as well as a standardised process for regulatory and ethics approval, sponsors will have better understanding and assurance on the timeline, processes and reliability of conducting clinical trials in Malaysia.
Audrey Ooi (Acting Head Business of Development) and Noorzaihan Mat Radi (Senior Feasibility Specialist) are from Clinical Research Malaysia.
- Clinical Researcher. Accelerating Study Start-Up: The Key to Avoiding Trial Delays (February 1, 2017). Available at https://acrpnet.org/2017/02/01/accelerating-study-start-up-the-key-to-avoiding-trialdelays/, visited on 1 November 2019.
- Lamberti, M.J. Clinical Trials Take A Long Time to Get Started. Here’s How to Speed It Up (March 28, 2018). Available at https://www.statnews. com/2018/03/28/clinical-trials-startup-speed/, visited on 1 November 2019.
- Ooi, A.J.A & Khairul, F.K. A Unique Model to Accelerate Industry-Sponsored Research in Malaysia. Journal for Clinical Studies. 11(1), 24–27(2019).
- Applied Clinical Trials Editors. Clinical Trial Agreement Negotiations (June 1, 2012). Available at http://www.appliedclinicaltrialsonline.com/clinical-trial-agreement-negotiations, visited on 1 November 2019.
- Abdul Rahman, N.A. & Yusop, N. Evolution of Clinical Trial Agreement Review in Malaysia Through Clinical Research Malaysia. (September 21,2018). Available at http://www.appliedclinicaltrialsonline.com/evolutionclinical-trial-agreement-review-malaysia-through-clinical-researchmalaysia, visited on 1 November 2019.
- Malaysian Investment Development Authority. Guide on Pharmaceutical Industry in Malaysia. June 2017.
- Ali, S., Egunsola, O., Din Babar, Z.U. & Hasan, S.S. Challenges of Conducting Clinical Trials in Asia. Int J Clin Trials. 5(4), 194–199 (2018).
- Society of Clinical Research Professionals Malaysia. A Guide to Conducting Clinical Trials in Malaysia (1st edition) 2016.
- Burton, P. Malaysia: A Clinical Trials Hub For Southeast Asia? (November 20, 2018). Available at https://pharmaboardroom.com/articles/malaysiaa-clinical-trials-hub-for-southeast-asia/, visited on 1 November 2019.
- Frost & Sullivan (2016) Asia: preferred destination for clinical trials. https://novotech-cro.com/sites/default/files/170217_FrostSullivan_Asia%20white%20paper_full.pdf
The principles of developing, conducting, analysing and subsequently reporting clinical research are widely known.1- 3 However, the success of a clinical trial goes beyond these principles. It also requires a structured, viable and businesslike management of the whole process, without which trials may fail.4 A critical part of managing clinical trials is a solid, well thought out clinical trial budget.5 A successful budget to ensure a good quality clinical trial should not only entail careful detailing of costs that are in line with the trial protocol, but should also include a financial management system that executes this budget in an efficient, timely and transparent manner.
Some issues and challenges in formulating clinical trial budgets could be applicable when managing the finances during conduct of the trials. Examples include how to maintain audit trails and being abreast of billing processes, ensuring all costs have been encountered for, and management of residual monies. Though ultimately the responsibility of the principal investigators, the detailed construction of a clinical trial budget and its management places a huge burden on physicians (or researchers) who have to juggle clinical practice while overseeing the running of multiple clinical trials.
Reducing the Burden of Principal Investigators
Established in 2012, the main objectives of Clinical Research Malaysia (CRM) are to effectively increase the speed, reliability and quality in delivery of outcomes of clinical trials conducted within the country. This is in line with the Malaysian government’s vision to enhance the country’s placing among other clinical trial hubs as a preferred global destination for clinical research.6 CRM, therefore, is also equipped to manage the financial aspects of clinical trials and is currently used extensively by principal investigators, investigators, contract research organisations (CRO) and sponsors conducting clinical trials in Ministry of Health facilities.
CRM’s financial management services extend throughout the trial process, i.e. from prior to study initiation to its close. Legal services are also included during the initial process to support the management of clinical trial agreements (CTAs), parallel with negotiations and refining of the trial budget. CRM reviews and endorses the study budget for the CTA within seven working days (from the last feedback date received from the relevant party involved in the budget negotiation). CRM takes on full financial and administrative duties that include initial budget negotiation with sponsors/CROs and investigators, keeping track of the trial progress, budget and invoicing, receipt of funds from sponsors/ CROs and payments to various stakeholders involved. CRM also prepares statements of account for the principal investigators on a monthly basis to facilitate better planning of clinical trial activities.
Facilitating Initiation of Clinical Trials
Involvement of the finance team starts just prior to initiation of the clinical trial in collaboration with the legal department, principal investigators, CROs and sponsors. This is crucial, as CROs, sponsors and investigators each bring expertise required for the conduct of specific types of trials, whilst the finance team contributes with their experience working on the financial aspect of clinical trials across the board. The legal team facilitates the process by ensuring that the CTA meets local requirements. The finance team also supports CROs, sponsors and investigators when negotiating and finalising the trial budget with approval from these parties. The timeframe for this process is expedited by a dedicated team handling the details of the negotiations and preparation of the approved final budget for submission, though it is still dependent on response time from CROs, sponsors and investigators.
Financial Management During Trial Conduct
CRM’s involvement in the management of the clinical trial budget is to reduce payment time through a standardised financial process by prompt issuing of invoices and providing efficient disbursements of payments. This ensures that the financial management of clinical trials conducted by investigators at their respective clinical trial sites has a proper audit trail and is executed in an efficient and transparent manner.
Prior to the establishment of CRM, all financial transactions to and from government linked facilities were routed via established local medical societies or the clinical research arm of the Ministry of Health (Clinical Research Centre). Between 2012 and March 2015, payments to investigators had to go through a trust account under the purview of the Director of Kuala Lumpur Hospital. Due to red-tape processes, payments could take at least a month.
However, from April 2015, CRM’s role expanded to making payments out directly to investigators and study team members (specifically government-employed staff affiliated with Ministry of Health facilities) and similarly reduced the timelines to within two weeks. With the advancement of online banking facilities in Malaysia, these timelines have further reduced. In 2018, the total value of trial budget managed by CRM was RM 39.5 million, compared to 2015 which was only about RM8.3 million, translating to more than four times in the growth of the budget management.
In addition, CRM’s responsibilities encompass ensuring there are enough funds available for the smooth running of a clinical trial by keeping track of the budget and communicating with sponsors so that payments are as scheduled in the trial budget and CTA. If, for any undue reasons, receipt of funds from sponsors is delayed, CRM steps in to guarantee timely payments to vendors and study subjects, ensuring that trials are on track. All receipts and disbursements of funds are carefully tracked, and monthly statements of account are sent to the principal investigators for review. All financial processes performed by CRM are also audited by internal and external auditors, which include the National Audit Department and the Ministry of Health. During the close of a trial, CRM provides an added service of negotiating the best price for archiving trial-related documents from third-party vendors. This enables cost savings in a clinical trial budget as well as more efficient conduct during clinical trial study closure.
CRM in essence acts as an account manager with in-house expertise in clinical trial budget management. Its focus is to streamline the processes for all clinical trials conducted in Ministry of Health facilities and involving Ministry of Health staff. CRM facilitates the clinical trial process from the budget negotiation stage, receipt and disbursement of study funds and lastly, archiving services upon study closure.
Audrey Ooi (Acting Head Business of Development) and Yau Yit Huan (Head of Finance & IT) are from Clinical Research Malaysia.
1. European Medicines Agency. ICH Topic E8: General considerations for clinical trials – Step 5 (CPMP/ICH/291/95). March 1998.
2. National Pharmaceutical Regulatory Agency, Ministry of Health Malaysia. Malaysian guideline for good clinical practice. Fourth edition. 2018.
3. Chew BH. Planning and conducting clinical research: the whole process. Cureus 2019;n(2): e4n2. DOI: 10.7759/cureus.4n2.
4. Farrell B, Kenyon S, Shalmr H. Managing clinical trials. Trials 2010;11:78. Available at http://www.trialsjournal.com/content/n/1/78. Accessed October 2019.
5. Hatfield E, Dicks E, Parfrey P. Budgeting, funding and managing clinical research projects. In: P. Parfrey and B. Barrett, editors. Methods of Molecular Biology, Clinical Epidemiology, vol. 473. Totowa, New Jersey: Humana Press, 2009; 299-3n.
6. Ooi AJA, Khalid KF. Malaysia’ clinical research ecosystem. Applied Clinical Trials 2017. Available at http://www.appliedclinicaltrialsonline.com/malaysia-s-clinical-research-ecosystem. Accessed October 2019.
Source : Journal for Clinical Studies
The Act was announced by Natural Resources and Environment Ministry to be implemented in Malaysia in 2017. It was aimed to regulate the use of biological resources, addresses issues of biopiracy and ensures that result benefits from the access of biological resources are shared equitably. Its content is mainly to conserve and reserve the biodiversity ecosystem in Malaysia for instance, conservation of natural resources like plants, animals but also included the access to human genetic resources. Access to human genetic resources will surely impacted the Clinical Trial Industry in Malaysia. As Clinical Research Malaysia is a company owned by the Ministry of Health Malaysia where we act as a one stop center for Clinical Trial Industry (“the Industry”) in Malaysia we opined that the implementation of the Act will have several negative impacts in the Industry as such our intention in writing this article is to inform the industry and also the relevant parties as to why similar Act should not be implemented to Clinical Trial Industry be it in Malaysia or other countries and how this is actually has been curbed through the initiative taken by Clinical Research Malaysia.
Obtaining Permit under this Act
Under the Act, any local or foreign individual or corporation who intends to access Biological Resources or Traditional Knowledge associated with Biological Resources for commercial, or potentially commercial or non-commercial purpose must obtain a permit, violation of this application of permit may cause the relevant party to be penalized. However, a permit may not be required for any research and development activity that is under a public higher education institution, research institution or Government agency within Malaysia, the exchange of Biological Resources between persons within a public higher education, institution, public research institution or Government agency within Malaysia or the access is by any person outside Malaysia or in a private institution within Malaysia from a permit holder who possesses a valid permit to access for the purpose of carrying out or continuing any research for non-commercial purpose. Under the Act, in order to have access to biological resources and to obtain a permit to access biological resources, the accompanying documents required to be submitted along with an application for a permit is the Prior Informed Consent which has to be obtained from Indigenous local community, organization, resource provider or their representative and Benefit Sharing Agreement that has to be entered into with the resource provider who gave access to the Biological Resources or Traditional Knowledge. A Benefit Sharing Agreement under the Act is described as a legally binding contract entered between the person who intends to access the resources or traditional knowledge relating thereto with the resource provider and shall be based upon mutual agreed terms and provide a fair and equitable benefit sharing .
Benefits in Protecting Our Natural Resources!!
In our humble opinion, we do agree that the implementation of this Act may bring a lot of benefit in protecting our natural resources but not when it comes to conducting Clinical Trial which is a solution to provide a better healthcare and medicine to Malaysian citizen. The contention on our stand to oppose the application of the Act to the Industry is substantiate on few comprehensive measures currently exist in Malaysia to regulate and control Malaysian Clinical Trial Industry. First, conducting Clinical Trial in Malaysia already have their own guidelines that spells out the procedures in conducting Clinical Trial or Study such as the Good Clinical Practice guidelines. Second, to regulate and oversee the Clinical Trial or Study conduct as well as to approve the application of import license or exemption of the investigational product/drug, the regulatory body/authority like the National Pharmaceutical Regulatory Agency (NPRA) plays a significant role. Third, the presence of Medical Research and Ethics Committee (MREC) that approves the trial, are sufficient enough as all the protocol, procedures of the Clinical Trial have been examined carefully and thoroughly by the said authority/regulatory body to ensure that it is safe, ethical and further comply with all the requirements and guidelines in conducting Clinical Trial . Fourth, as patients’ consent is the utmost consideration before enrolling them as Clinical Trials subjects, their rights are protected and respected where prior to Clinical Trial is being conducted, informed consent must be obtained from the patients. Legally speaking, the law on contract has evolved as a framework to regulate voluntary exchange transaction. Informed Consent is a voluntary agreement to participate in research. It is not merely a form that is signed but is a process, in which the subject understands the research and its risks. Informed consent is essential before enrolling a participant and ongoing once enrolled. Informed Consent obtained from the patients prior to enrol them as the participating subjects in the Clinical Trial is sufficed to reflect the voluntariness of patients. In Malaysia, the Clinical Trial Informed Consent Form (ICF) shall be reviewed by the ethics committee where the committee itself is comprises of medical background members and lay members. This is crucial as the ICF need to be worded in a layman term so that the patients will not be misled or participating out of undue influence.
The Clinical Trial Agreement (CTA) and its Impact
Fifth, before conducting the Clinical Trial, the relevant party also must have entered into a legally binding agreement known as Clinical Trial Agreement (CTA) which manages the relationship between the Sponsor that may be providing the device or study drug, the financial support and /or proprietary information; the Institution that may be providing data facilities, and/or results; the Principal Investigator and the Study Team that are responsible to conduct the Clinical Trial. The CTA also would describe and acknowledge responsibilities of the relevant party, terms of collaboration, requirements for payment and reimbursement, publication and intellectual property terms, guidelines for dispute resolution, and also terms to ensure the patients’ rights and rights of all the parties who involved in the Study are protected such as indemnification, insurance, subject injury /adverse event clauses. As such the Benefit Sharing Agreement proposed by the Act is certainly not relevant to the Industry.
Sixth, implementing the Act in Clinical Trial Industry, will reduce the number of Clinical Trial or Study and also may further delay any Clinical Trial or Study to be conducted in Malaysia as the Industry/ Sponsor must now obtain permit from the relevant authority and enter into benefit sharing agreement with a resource provider and further adhere to additional requirements and procedures which double up the existing procedure and requirements of Clinical Trial in Malaysia (i.e. Informed Consent Form, Clinical Trial Agreement, existing approval from regulatory bodies).Besides that, it may also decrease the innovation in medical industry in providing and improvise the procedure, techniques, medicine and device to be utilised by the patient in Malaysia to provide a better solution to cure their diseases and providing better healthcare. In other words, the patient would be jeopardised from getting alternative treatment/medicine that could prolong their lives. In fact, the implementation of the Act could also reduce the intangible value of research in sharing technology with other countries , recognition from the world for conducting a quality , reliable trial and expanding resources in order to introduce a better treatment, medicine, therapies, procedure and devices to the patient in Malaysia. It is worth to note that any benefits resulting from the Clinical Trial and its applications should be shared with society as a whole and with the global community. The benefits may take in various forms which includes but not limited to giving special and sustainable assistance to and acknowledgement to those that have taken part in the Clinical Trial or Study, public access to quality health care, access to scientific and technological knowledge, building up facilities for research purpose and any other forms of benefit consistent to the above.
Clinical Research Malaysia (CRM) Views
Clinical Research Malaysia (CRM) viewed that, it is best for every Clinical Trial that is to be conducted in Malaysia and other countries to be exempt from the implementation of this Act or any similar Act considering the benefits of it to the country and the people and further due to the adherence of this industry to the fundamental principles, requirement and regulatory compliance and relevant authority in conducting the Clinical Trial or Study in Malaysia. Further, CRM also actively involved in discussing with the relevant authorities in Malaysia on the negative effects of the implementation of the Act to the Clinical Trial Industry. It is a good action that the enforcement body and authorities in Malaysia now support the rights of the people to participate in Clinical Trial and to receive a better healthcare service and medicine by finally giving exemption to the Clinical Trial from the implementation of the Act commencing 2019 .
Nurul Atiqah Abd Rahman (Senior Legal Executive), Siti Nuralis Abd Muis & Siti Nur Hafizah Adnan (Legal Executives) are from Clinical Research Malaysia’s Legal Department
 Section 5 of the Access to Biological Resources and Benefit Sharing Act 2017(Act 795)
 Australian Government National Health and Medical Research Council, Department of Innovation, Industry and Science. (2015, April 8). Retrieved from Australian Clinical Trial: https://www.australianclinicaltrials.gov.au/what-clinical-trial (2019, June 11)
 Health Topics, Clinical Trials. Retrieved from World Health Organization: https://www.who.int/topics/clinical_trials/en (2019, June 11).
 Section 18 of the Access to Biological Resources and Benefit Sharing Act 2017(Act 795)
 Section 22 of the Access to Biological Resources and Benefit Sharing Act 2017(Act 795)
 A Guide to Conducting Clinical Trials in Malaysia. (2016). Society of Clinical Research Professionals Malaysia
 Malaysian Guideline for Good Clinical Practice. (2018). National Committee for Clinical Research (NCCR), National Pharmaceutical Regulatory Agency (NPRA).
 Centre for Clinical and Translational Science. Retrieved from https://ccts.osu.edu/content/clinical-trial-agreement (2019, 11 12)
Source: InfoMed Magazine
A feasibility study is a crucial part of the clinical trial planning process. It enables sponsors and contract research organizations (CROs) to identify relevant clinicians who may be interested in a particular study.1-4 It also provides information on a site’s infrastructure, human resources and pool of eligible patients.1-4 Such information would help these companies strategize to meet timeliness, sample size requirements and regulatory and ethical conditions, as well as plan for potential challenges.
As clinical research involves multiple stakeholders, the presence of a single point of contact can improve communication, simplify processes, and reduce delays.5,6 This centralized approach is particularly useful for feasibility and site selection processes.6 In Malaysia, Clinical Research Malaysia (CRM), a not-for-profit government-owned organization established in 2012 to nurture an ecosystem that supports industry sponsored research in the country, offers sponsors and CROs a one-stop contact point for feasibility requests, access to the public hospital network of investigators, and other services.
This review will present the role of CRM’s centralized feasibility service in attracting sponsors and CROs to Malaysia.
The importance of rigorous feasibility studies
Pre-feasibility is information that is collected for preliminary, higher level assessments which allows sponsors and CROs to make decisions at a national and global level. Such enquiries include general questions on standard of care, drug registration status, epidemiology, and estimated patient pool of a particular therapeutic indication. A full feasibility study is a complete documentation of individual sites which may include a confidential disclosure agreement, protocol synopsis and site assessment questionnaire.
About 35% of delays in clinical trials are attributed to patient recruitment with one in five investigators unable to recruit a single patient.4 As non-active or under-performing trial sites can increase the cost of conducting a clinical trial by 20% or more,7 rigorous feasibility studies conducted in multiple centres are recommended.8 But conducting thorough feasibility assessments and selecting appropriate sites may be time consuming, and delay in these preliminary processes will jeopardise study milestones.7 Therefore, if feasibility processes in individual countries can be centralized with a single point of contact for sponsors and CROs, delays and redundancies may be avoided.5,6
Leveraging the strength of a nationwide access to public hospitals
One of the challenges in conducting feasibility studies is maintaining an updated database of principal investigators. The bulk of studies in Malaysia are conducted in government hospitals where doctors are transferred periodically. Therefore, data built on individual company databases can be outdated, thus misguiding and delaying feasibility approaches.
In Malaysia, CRM is the common link for various stakeholders which include sponsors, CROs, private and public doctors from universities, health clinics and hospitals, as well as the regulatory agencies and ethics committees. It is a centralized government-owned body that manages and overlooks Malaysia’s entire clinical research ecosystem.9 The detailed objectives of CRM are discussed in a prior article.10
As a single point of contact for sponsors and CROs and with presence in 33 clinical research centres within public hospitals throughout the country, CRM is vital in streamlining and accelerating feasibility studies in Malaysia.
Evolving to offer complimentary, centralized feasibility management
As CRM receives a variety of enquiries (Table 1) including pre-feasibility and full feasibility requests across all clinical therapeutic areas from both sponsors (pharma, medical device, biotech) and CROs worldwide, the Ministry of Health, Malaysia through CRM, established a centralized feasibility service. This service which is offered complimentary to sponsors and CROs, capitalizes on a comprehensive updated internal database of investigators, and enables outreach to a wider range of investigators and sites.
Previously, the sponsors and CROs conducted their own feasibility assessments and contacted individual sites on their own.11 Separate databases based on a company’s own experience, may not always be updated, and information such as transfer of clinician, changes in site personnel, and regulatory changes may be missed.11
A centralized process leads to centralized knowledge of the research environment which benefits CROs and sponsors engaging the service. A central database which incorporates data on a site’s performance and experience in recruitment and compliance provides more insight into how the site may perform in future trials.1,7 And as a single point of contact, the standardized processes lead to streamlined communications which reduces delay and confusion on the ground. As a result, the turnaround time is shorter than if a sponsor or CRO were to approach individually.
As CRM has a strong network, good rapport with investigators, and is familiar with ground level capacities of sites, poor site selection is less likely. Sites are mapped according to disease to enable the right sites to be approached for a specific patient pool in future. The sites are also mapped to track investigators who were overwhelmed, conducting competing trials, or transferred to ensure that only available investigators are contacted for upcoming trials. Such data would help narrow down the investigators who will give positive responses, thus reducing the time needed for feasibility studies.
When the feasibility team at CRM receives a feasibility questionnaire, a thorough analysis based on CRM’s central intelligence database is done (Figure 1). The questionnaire is then forwarded to relevant investigators. The process from the time CRM is approached to conduct a full feasibility assessment to the time CRM sends the completed questionnaire back to the company would take 5–10 working days. Pre-feasibility enquiries would take between one and five days depending on the complexity of the questions.
In addition, the feasibility specialists help interested potential investigators to address the queries and submit the completed feasibility questionnaire to the enquiring company. They provide technical consultation and organize meetings between investigators and CROs. Information is also compiled when investigators reject feasibility requests to understand their reasons for doing so.
Centralized service, a key attraction for sponsors and CROs
A centralized feasibility management service is a key attraction for sponsors and CROs,5 as the information from feasibility studies determines the suitability of Malaysia for a particular trial and promotes the capability of the sites to new international companies. The one-stop national feasibility model improves efficiency and timelines, as well as reduces the financial, administrative, and human resource burden of sponsors, CROs and investigators.
Sponsors and CROs are becoming more interested in Malaysia after the introduction of centralized feasibility, with full feasibility requests received by CRM increasing between 2015 and 2018 (Figure 2). There were also a five-fold increase in sponsors and an almost three-fold increase in CROs using CRM’s services in 2018 compared to 2014 (Figure 3). Majority of these companies are international companies (85%).5,11
In addition, feasibility assessments are complimentary, thus contributing to the overall cost-effectiveness of conducting a trial in Malaysia.
Clinical Research Malaysia’s model as a one-stop national center is a primary factor for the expansion in Malaysia’s clinical research industry in the last few years. The growth in sponsors and CROs is made possible through a centralized feasibility team coordinating and overseeing communications with sites. Thus, on a nationwide perspective, a centrally managed feasibility structure is an attractive alternative for sponsors and CROs looking to enhance efficiency and width of a feasibility outreach, avoid redundant processes and promote a more accurate assessment of Malaysia’s capabilities.
Noorzaihan Mat Radi (Senior Feasibility Specialist), Dr. Tan Bee Ying (Feasibility Specialist) and Audrey Ooi (Acting Head of Business Development) are from Clinical Research Malaysia.
- Johnson, O. An Evidence-Based Approach to Conducting Clinical Trial Feasibility Assessments. Clin. Invest. (Lond.). 5(5), 491–499 (2015).
- Orsmond, G.I. & Cohn, E.S. The Distinctive Features of a Feasibility Study: Objectives and Guiding Questions. OTJR. (Thorofare N J). 35(3), 169–77 (2015).
- Arain, M., Campbell, M.J., Cooper, C.L. & Lancaster, G.A. What is a Pilot or Feasibility Study? A Review of Current Practice and Editorial Policy. BMC. Med. Res. Methodol. 10, 67 (2010).
- Rajadhyaksha, V. Conducting Feasibilities in Clinical Trials: An Investment to Ensure a Good Study. Perspect. Clin. Res. 1(3), 106-9 (2010).
- Khairul, F.K., Ooi, A.J.A. & Tay, W.C. How a Centralized Feasibility Service Attracts Sponsors and Contract Research Organizations to Malaysia. Poster presented at the 53rd Drug Information Association Annual Meeting, Chicago US: Jun 18–22, 2017.
- Arenz, D., Siepmann, T. & Cornely, O.A. Centralized Management of Clinical Trial Feasibility Requests: A Single Center Database Analysis from 2008 to 2015. Clin. Invest. (Lond.). 6(1), 867–874 (2016).
- Temkar, P. Accelerating Study Start-Up: The Key to Avoiding Trial Delays. Clinical Researcher, 1 February 2017. Available at https://acrpnet.org/2017/02/01/accelerating-study-start-up-the-key-to-avoiding-trial-delays/, visited on 5 July 2019.
- Turner, C.L., Kolias, A.G. & Hutchinson, P.J. Feasibility Studies, Clinical Trials and Multicentre Collaboration. Acta Neurochir. (Wien). 159(1), 11–12 (2017).
- Society of Clinical Research Professionals Malaysia. A Guide to Conducting Clinical Trials in Malaysia (1st edition) 2016.
- Ooi A.J.A & Khalid K.F. Malaysia’s Clinical Research Ecosystem. Appl. Clin. Trials. 26(4), (2017). Available at http://www.appliedclinicaltrialsonline.com/malaysia-s-clinical-research-ecosystem-0, visited on 5 July 2019.
- Ooi, A.J.A & Khairul, F.K. A Unique Model to Accelerate Industry-Sponsored Research in Malaysia. Journal for Clinical Studies. 11(1), 24–27 (2019).
Source: Journal for Clinical Studies
The International Conference on Harmonization—Good Clinical Practice (ICH-GCP) is an international ethical and scientific quality standard that ensures the rights, safety and well-being of clinical trial subjects are protected and that the clinical trial data generated are credible1.
Malaysia GCP Guideline was developed by National Pharmaceutical Regulatory Agency (NPRA) in 1999. This guideline adopts the basic principles outlined by ICH-GCP with some modifications to adapt to local conditions2. The object of the Malaysia GCP Guideline is to ensure that drug-related trials in Malaysia are conducted in accordance with international ethical and scientific standards2. Although there is currently no legislative requirement for GCP training, mechanisms were in placed to ensure that Investigators are trained on GCP. For example, it is mandatory to submit a copy of Principal Investigator’s GCP certificate when obtaining regulatory approval from NPRA to conduct a clinical trial3. In addition, all investigators must submit their GCP certificates for ethics committee’s approval in Malaysia4. Since the first edition of Malaysian GCP to the current 4th edition, approximately 12,000 clinicians have been GCP certified5.
Since the first workshop in 4 October 2016, CRM has conducted 31 GCP refresher workshops throughout Malaysia to approximately 450 participants at no cost. Majority of the participants are clinicians, nurses, allied health professionals from government hospitals who are involved in clinical trials. Over the course of the conduct of the workshop, modifications have been made based on participants’ feedback to improve the quality and the learning outcome of the workshop. A summary of the changes in the workshop agenda is listed in Table 1.
Table 1: Changes in presented topics from 2016 to present
As shown in Table 1, pre- and post-workshop assessment test was introduced in 16 March 2017 in order to evaluate the effectiveness of the workshop on participants’ knowledge on GCP.
In this paper, we analyzed the pre- and post-workshop assessment scores for workshops conducted since 16 March 2017.
Before the start of the workshop, participants were required to complete 20 multiple-choice GCP-related questions (pre-workshop assessment). The questionnaires were then collected before the start of the workshop. After the workshop, participants are then required to complete the same set of questions (post-workshop assessment). Participants were given 30 minutes to complete the questionnaire.
The average score of the pre- and post-assessment results from participants of the same workshop will then be calculated. This will constitute one set of data point.
The average score of pre- and post-workshop assessment from each workshop conducted since the introduction of the assessment in 16 March 2017 were compiled. Of the 28 workshops conducted since then, 5 workshops’ data could not be retrieved, hence only 23 sets of data points were analyzed.
The compiled average score of pre- and post-workshop were then compared using Microsoft Excel’s t-test assuming unequal variance to evaluate if there is any significant improvement in the average assessment score after the workshop.
Table 2 shows the compiled data from 23 workshops. 420 participants completed the pre-workshop assessment, and 434 participants completed the post-workshop assessment. There is on average, 20% improvement in the assessment score before and after the workshop.
Table 2: Compilation of the average pre- and post-workshop assessment score.
Table 3: Result of T-test assuming unequal variances comparing the pre- and post-workshop average scores.
As shown in Table 3, the p-value is less than 0.05, suggesting that there the improvement in the score is significant after participants attended the GCP Refresher Workshop.
Training of investigators and allied health professions involved in clinical trials on the regulations and standards that govern clinical trials is important to improve the quality of studies and ensure maximum safety for the study subjects. A survey amongst clinical researchers in Saudi Arabia on their ICH-GCP knowledge found that is poor understanding of investigator’s responsibilities on informed consent, and prompt reporting to the ethics committee7. Hence, refreshing investigators’ awareness of their responsibilities could help to improves the performance of investigators in conducting clinical trials particularly in these important ethical aspects.
The GCP refresher workshop conducted by CRM fulfills its objective to provide revision of the principles of GCP to participants, with more an average of 20% improvement in assessment score after the workshop.
Case studies discussion
Case studies were included for “Informed Consent”, “Adverse Event Reporting” and “Protocol Deviations” for discussion. Participants were given real-life scenario case studies and they were required to answer guided questions in groups. Study have shown that case studies are more effective than textbook reading at promoting learning of key concepts and comprehension of the relevance of concepts to real life scenario8.
Several methods were used to make the workshop interactive such as games, quizzes, videos, group activities and group discussion. Active engagement of participants helps in the retain of information9.
Trainers would also actively engage participants by asking questions and encouraging participants to share their experience and practices. Regulations of clinical research can be understood more easily when participants can reflect the principles upon their own experience10.
Feedback from participants
Participants were given evaluation form at the end of the workshop to provide their feedback and opinion of the workshop. Based on their feedback, modifications were made to improve the conduct of the workshop:
- Duration of workshop
The first GCP Refresher Workshop is a half-day (4 hours) workshop. Participants reflected that the workshop felt rushed and suggested to make it a full-day course. Subsequent workshops were then conducted one full day (8 hours) to ensure participants can learn at a better pace, contributing a better learning outcome.
- Content of workshop
One of the earlier feed-back received is to include more activities especially for safety reporting and protocol deviations. Modifications based on this feedback is the shift from a lecture-style workshop to activity-based workshop. Presentation slides were also revised to be more concise to retain attention.
- Provision of GCP booklet
Following a feedback from participants, the current edition of the Malaysian GCP Guideline booklets were provided for participants to refer to during the workshop.
It is important for investigators and allied health professions who are involved in clinical study to be trained on the latest GCP guideline. GCP Refresher Workshop conducted by CRM is effective in refreshing participants’ knowledge on GCP guideline. The success of the workshop could be attributed to providing case studies for discussion, interactive activities as well as taking participants’ feedbacks into consideration. We would recommend other governing bodies to support the conduct of similar interactive workshops in their jurisdiction; and to take participants’ feedback for continuous improvement.
Yoong Kai Shen is the Senior Training Executive, and Joanne Yeoh is the Head of Clinical Operations, both of Clinical Research Malaysia.
- Good Clinical Practice Network, n.d. ICH GCP Good Clinical Practice. Retrieved 05Nov2019 from: https://ichgcp.net/
- National Pharmaceutical Regulatory Agency, 2018. Malaysian Guideline for Good Clinical Practice 4th Edition. Introduction to Malaysian Guidelines For GCP, Page 8.
- National Pharmaceutical Regulatory Agency, 2017. Malaysian Guideline for Application of Clinical Trial Import Licence and Clinical Trial Exemption. Retrieved 05Nov2019 from: http://www.nccr.gov.my/view_file.cfm?fileid=33
- Society Of Clinical Research Professionals Malaysia, 2016. A Guide to Conducting Clinical Trials in Malaysia, First Edition. Retrieved 05Nov2019 from: http://www.clinicalresearch.my/wp-content/uploads/2017/03/A-Guide-to-Conduct-Clinical-Trials-in-Malaysia.pdf
- National Pharmaceutical Regulatory Agency, 2018. Malaysian Guideline for Good Clinical Practice 4th Edition. Forward to the Fourth Edition, Page 4.
- National Institutes of Health, n.d. Good Clinical Practice Training. Retrieved 05Nov2019 from: https://grants.nih.gov/policy/clinical-trials/good-clinical-training.htm
- Al-Nomay NS, 2015. Compliance with ICH-GCP Guidelines among the Saudi Health Care Professionals: Should Saudi Arabia Conduct Widespread ICH-GCP Training? J Public Health Dev Ctries. 2015; 1(2): 75-82. Retrieved 05Nov2019 from: https://pdfs.semanticscholar.org/0112/2b2e7c0fdd762172251e807c273fcb4a399a.pdf?_ga=2.112527492.1640531090.1574928919-1845614418.1571207552
- Bonney KM, 2015. Case study teaching method improves student performance and perceptions of learning gains. J Microbiol Biol Educ. 2015;16(1):21–28. Retrieved 05Nov2019 from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416499/
- Robin L. Bachelor Patrick M. Vaughan Connie M. Wall, 2012. Exploring the Effects of Active Learning on Retaining Essential Concepts in Secondary and Junior High Classrooms. Retrieved 05Nov2019 from: https://files.eric.ed.gov/fulltext/ED531546.pdf
- Halkoaho A, Matveinen M, Leinonen V, Luoto K, Keränen T., 2013. Education of research ethics for clinical investigators with Moodle tool. BMC Med Ethics. 2013;14:53. Published 2013 Dec 12. Retrieved 05Nov2019 from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867673/
Source : Applied Clinical Trails Online
Industry-sponsored research (ISR) has been progressively growing within Asia in the last decade. Early phase trials play a crucial role not only in drug development, but also in expanding the clinical trial ecosystem, bringing in scientific knowledge and novel medical technologies and treatments to individual countries. The benefits of conducting early phase trials also extend towards a “spill-over” effect of boosting locally conducted later phase trials leading to access of novel treatments by a large and relatively naïve patient pool and bringing in investments. With over 20 years experience in conducting late phase clinical trials, the Malaysian government realizes the positive impact of encouraging the growth of early phase clinical trials. The country also has an untapped potential that can be used toward delivering high quality early phase clinical trials such as a naïve and diverse patient pool, established and experienced infrastructure, capabilities and resources, and competitive regulatory timelines compared to its neighbouring countries. In view of this, there is a strong focus on growing the clinical trial ecosystem in the country by optimising the already existing resources while expanding and improving them to further facilitate early phase ISRs in the country. Clinical Research Malaysia (CRM) established for this purpose in 2012 and a Phase 1 Realization Project (P1RP) was launched in 2016. Supported by five pillars ranging from development of guidelines to people and capability development, the goal is to develop Malaysia to cater to early phase studies. This review describes the opportunities for growth of early phase studies in Malaysia and the initiatives taken to build a comprehensive clinical trial ecosystem to attract these trials into the country.
The conduct of industry-sponsored research (ISR) in Asia has been gaining momentum for more than a decade1-9. Frost & Sullivan’s 2017 white paper2 states that the contract research organisation (CRO) market in Asia-Pacific (APAC) is the fastest growing in the world with an expected compound annual growth rate (CAGR) of 20% (from 2016-2021) compared to an increase of 11.4% CAGR globally. This follows from estimates of clinical trial volumes increasing from 5.9% of the total global volume between 2005-2007 to 9.7% in 2011 in the APAC region7 showing a steady influx of clinical studies, as it gains a reputation for being a preferred destination for ISRs.
However, a lack of early phase trials (phase 0 and phase I trials) is evident5,6. Louisa et al.5 studied the number of ISR phase I trials between 2007–2009 found that only 6.8% of phase I trials made their way to this region. The early phase clinical trial market in 2013 was valued at approximately USD 11.9 billion with an expected CAGR of 1.5–2%reaching 4% this year3. Owing to the important roles of early phase trials that range from its scientific benefits4 to capacity building and economic advantages, most Asian countries, including Malaysia have focused initiatives into building adequate infrastructure to attract them.
Early phase trials: Asian benefits
To date (as of 12 July 2018), there are 16,248 interventional ISRs covering all phases globally, 27.2% (4,424) are early phase (phase 0 and phase I) trials10. Figures 1 and 2 show the proportion of early phase trials in Asia and Southeast Asia which are significantly smaller compared to North America and Europe.
Figure 1: Proportion of early phase ISRs in Asia, Southeast Asia, North America and Europe for the year 2018. Search criteria for these and all other values were recruiting, not yet recruiting, active–not recruiting, enrolling by invitation, interventional studies, phase 0, phase I and industry funded. Asia: North Asia, South Asia, East Asia and Southeast Asia; total number of trials in the region will defer from number of trials in an individual country due to inclusion of multicentre trials.
Figure 2: Number of early phase ISRs in Southeast Asia. Total number of ISRs registered in Clinicaltrial.gov as of July 2018 in Asia is 5,126 (of 16,248) and total number of early phase ISRs is 943 (of 4,424). Search criteria for these and all other values were recruiting, not yet recruiting, active –not recruiting, enrolling by invitation, interventional studies, phase 0, phase I and industry funded. Asia: North Asia, South Asia, East Asia and Southeast Asia; total number of trials in the region will defer from number of trials in an individual country due to inclusion of multicentre trials.
There are several benefits in conducting early phase trials in Asia. These are for example, certain diseases which are more prevalent compared to the west wherein epidemiology, health services, social determinants, co-morbidities and genetic components of the population can have an effect on how a treatment may be used, and, differences in genetics and gastrointestinal microbiome effect on the pharmacokinetics and pharmacodynamics of drug molecules4,5. There have also been concerns that racial and ethnic minorities, women and the elderly are often underrepresented in early drug development programmes making Asia an attractive destination for clinical trials1.
Therefore, the conduct of more early phase trials in regions within Asia, like Southeast Asia, plays a pivotal role to ensure that the populations proportional to the potential uses of the product after its registration and approval are conducted from the earliest stages5.
Early phase trials: opportunities for growth in Malaysia
Diverse and accessible subject pool
Malaysia, located in Southeast Asia, is a multi-racial country consisting of Malays, Chinese, Indians and numerous indigenous people who are mostly treatment naïve. This provides the genetic diversity that is important in every clinical trial. The epidemiology of diseases in an individual country is also a crucial consideration when determining the success of a clinical trial as it signifies the availability of study subjects and mitigates the risks of poor accrual rates that can cause trials to fail at huge costs11. Though a strong presence of the disease provides for a rich source of ready patients for later phase clinical trials, it also serves as an important incentive for governments to encourage testing of novel treatments in FIH trials within the country.
Patient pool with cardiovascular risks — diabetes, hypertension and hypercholesterolemia
At a global level, the top 20 indications of industry-sponsored clinical trials, regardless of phase of study include cardiovascular disease, diabetes mellitus, hypertension and hypercholesterolemia7. Conducting early phase trials targeting these conditions would be doubly beneficial to countries like Malaysia that face major public health concerns with them. Early phase trials would allow access to novel treatments and changing standards of care and with a ready pool of relatively naïve patients, sponsors and CROs would have an easy access to subjects for later phase trials. Being part of the drug development process from its early stages allows investigators and clinical trial staff to become familiar with the treatment, thereby allowing continued progress of clinical study phases to occur more smoothly.
In Malaysia, the National Health and Morbidity Survey published in 2015 showed that prevalence of diabetes mellitus among Malaysian adults of 18 years and above was 17.5% (8.3% known and 9.2% undiagnosed)12. The overall prevalence for hypertension and hypercholesterolemia were 30.3% (13.1% known and 17.2% undiagnosed) and 47.7% (9.1% known and 38.6% undiagnosed), respectively. In 2016, disease of the circulatory system was in the top five principal causes of hospital admissions (both private and public hospitals), at 7.44% of total admissions and within the top five principal causes of mortality13. With regards to Type 2 diabetes mellitus, it has more than doubled since 1996 and coupled with a prevalence of 27–31% in overweight and obesity in school children, this disease poses a major public health concern14.
With the high prevalence of cardiovascular risk factors such as diabetes, hypertension and hypercholesterolemia, not only has Malaysia a ready, diverse and relatively naïve patient pool for later phase ISRs that fit into the top 20 clinical trial indications, but it also gives the Malaysian government a strong incentive to encourage early phase trials.
Oncology patient pool
Studies in the field of oncology treatment are currently the top indication for clinical trials. Using the following search criteria, start date 01/01/2013-31/12/2017, recruiting, not yet recruiting, active – not recruiting, enrolling by invitation, early phase I and phases I-III, indication for cancer takes up 54.5% of the total industry sponsored interventional studies . Additionally, projected distributions of available new active substances in the global market by disease type from 1996–2020 show15 a projected growth in oncology biopharmaceutical and pharmaceutical products making up 13% of the total new active substances.Thirty-three percent of novel drug approvals in 2015 by the United States Food and Drug Administration (USFDA) were for oncology related products whilst 27% were approved in 201716-18. In the US alone, there were 836 drugs and vaccines for cancer in various stages of clinical development or awaiting USFDA approvals19.
In Malaysia, cancer is within the top five causes of mortality and in 2016, the total hospital admissions for neoplasms were 4.2% (based on total admissions of > 3 million)13. Breast cancer is the most common of all cancers (17.7%) followed by colorectal (13.2%) and cancer of the trachea, bronchus and lung (10.2%)20.
FIH trials of oncology drugs differ from early phase trials in other therapeutic areas as they are evaluated in patients rather than healthy volunteers. The characteristics of oncology products, mainly its safety profile, do not allow for testing in healthy volunteers. In the absence of alternative effective treatments in oncology, participation in these trials using novel compounds are considered an opportunity to these patients21.
Therefore, with the global pipeline of oncology drugs in clinical development having seen a robust growth over the past two decades22, combined with the strong presence of cancer among Malaysians, not only are sponsors presented an opportunity to tap into the available pool of cancer patients, it is also a considerable push for the Malaysian government to spur the growth of early phase oncology clinical trials within the country.
The cost of developing a new molecular entity can be over USD 1 billion with an average estimate of USD 2.6 billion8. Added to that, the development of a new medicine from identification through approval for marketing can take up to or more than 12 years. In view of the extreme financial investments, Asian countries like Malaysia, which provide treatments and medical procedures at a lower cost than in developed countries1,9, can be seen by sponsors and CROs as an ideal site for conducting clinical trials with lower investments.
The 2017 Frost & Sullivan white paper’s1 costing estimates of conducting clinical research per patient, per visit in all therapeutic areas in all phases shows Malaysia as having the second lowest cost coming before India (USD 350 vs. USD 330) while costs in Singapore was similar to that in the USA (USD 1,210 vs.USD 1,380) and that in South Korea was USD 890.
One of the complexities of performing clinical trials in Asia is the heterogeneous nature of the regulatory processes and timelines among the countries in the region1-3,6.
However, countries in the region have attempted to harmonise these to ensure better data acceptability and reduce trial and drug approval timelines1. Malaysia is part of the ASEAN Free Trade Area (AFTA) that undertook the ASEAN Common Technical Documents (ACTD) and ASEAN Common Technical Requirements (ACTR) initiatives to standardise drug approval processes.
In Malaysia, ethics review and regulatory approvals together with import licensing and contract negotiations occur concurrently allowing for faster processing timelines and is comparable with timelines in South Korea and Singapore (approximately 2-3 months1). In a recent report, regulatory timelines have been improved to within 30 working days23 while the centralized ethics committee under the Ministry of Health has shortened its timelines to 51 calendar days.
Established infrastructure, resources and capabilities
An established and functioning network of clinical trial centres with advanced equipment and technology; knowledgeable physicians and available key opinion leaders in different specialties also play an important role in attracting ISRs1.
Malaysia has a well-developed and equipped healthcare system manned by medical doctors that practice and comply with international clinical practice standards24. ISRs in Malaysia are conducted at government hospitals, teaching institutions, private hospitals and government health clinics. Government hospitals receive and treat the largest number of patients thus presenting a unique opportunity for access to the primary care patient pool.
Developing an ecosystem for early phase clinical research in Malaysia
The Government of Malaysia realizing the potential positive impact of early phase trials for patients, scientific advancements and economic growth is stepping up its existing clinical trial capabilities by building new initiatives to drive early phase clinical research capacity in-country and develop an attractive early phase clinical trial ecosystem.
In lieu of this, the Malaysian government included the creation of a supportive ecosystem with the establishment of Clinical Research Malaysia (CRM) a non-profit company, wholly owned by the Ministry of Health24, to equip the ecosystem of clinical research in the country25. Its goal is to reach at least 1,000 clinical trials by the year 2020. Part of the initiatives stated in this section is to set up more clinical research centres, develop more Good Clinical Practice (GCP) certified investigators and improve existing IRB and EC timelines. The Phase 1 Realization Project (P1RP) initiated by CRM in 2016 was aimed at realizing this aspiration of making sure Malaysia is capable in conducting early phase studies.
The benefits of conducting early phase trials in Malaysia as laid out by the P1RP are the increase of phase II and III trials as a result of a spillover effect from conducting more phase I trials, contribution to the transfer of knowledge and technologies to Malaysians, creation of new jobs in clinical research, spurring local innovation, prevention of investment outflow and moving the country as a whole higher up the clinical research value chain. For patients, it increases the opportunity to receive novel medications or treatment that is not yet available in the market as the majority of ISRs are interventional in nature providing treatment at no cost to patients. It also provides a means for the government to expand its healthcare resources to include more patients and medications especially oncology treatment that are costly.
The P1RP Blueprint
The P1RP stands on 5 pillars, which are the establishment of guidelines for conducting phase I clinical trials in the country, people development, capability development, preparation of sites and risk management. To date, all of the P1RP pillars have been implemented and fulfilled. In the first quarter of 2019, the country’s regulatory authority has indicated that it is ready to review FIH studies by June 2019.
The P1RP strategy is multi-pronged wherein regulatory agencies are equipped with the right knowledge to review phase I clinical trials and conforming to international standards, local experts are trained with the necessary skills to analyze early phase trials through engagement with international consultants, preparation of clinical trial unit at hospitals to conduct phase I studies, and the development of an action plan to manage and mitigate any given crisis that may occur during the clinical trial process.
Development of phase I clinical trial guidelines
The Malaysian Phase I Clinical Trial Guidelines26 was launched in November 2017. Prior to this, the country did not have a specific guideline on phase I clinical trials. The effort saw the coming together of experts and investigators in the field of clinical trials from the Ministry of Health, Ministry of Higher Education, ethics and regulatory bodies as well as industry experts. International key opinion leaders on clinical trials were also invited as subject matter experts. The guidelines were based on The Association of the British Pharmaceutical Industry (ABPI) 2012 version of phase I clinical trial guidelines27 as this document took into account and expanded its content to reflect the latest changes in conducting FIH trials. The Malaysian guidelines in turn considered local regulatory bodies and agencies’ existing procedures, and the local clinical trial environment, adapting relevant areas to facilitate the applicability of the ABPI guidelines in Malaysia.
To gain knowledge and experience in phase I clinical trials so as to implement and impart these to relevant agency officers, three regulatory officers were sent to pursue their postgraduate studies at The Christie, Manchester, as well as King’s College London, under a collaborative scholarship between CRM and the Public Service Department. This will allow them to work within a leading phase I clinical trial unit and gain experience and understanding in the designing and delivering of phase I studies. This attachment is important as these regulatory officers will be the ones responsible in reviewing the dossiers of phase I studies in Malaysia.
The Ministry of Health has also planned to send local investigators to be attached at reputable phase I centres, including the Princess Margaret Cancer Center, to be exposed to the experience in conducting FIH studies.
The government has also started initiatives to bring back Malaysians from overseas. Experts or specialists from higher-income countries coming back would have an edge due to a global mindset. Coupled with an in-depth knowledge of the country, people and the culture, it creates a world-class pool of specialists that can support early phase trials2.
Initiatives to develop and perform centralized professional training for study coordinators to complement the work of investigators have also began. To attract more specialists to participate in clinical trials, the Ministry of Health now allows for 20% of a work-week (or one full day off) for investigators to focus solely on research.
In a 2011 report presentation of the Health Committee at the 49th Parliament sitting in New Zealand28, some of the recommendations put forward to increase New Zealand’s presence in the clinical trial industry were, to establish a strong intra-governmental collaboration between different ministries, ensure a culture that values research within the public health system and requiring the Standing Committee on Therapeutic Trials to carry out all scientific reviews within 30 calendar days.
As part of the capability development pillar of P1RP, a Scientific Review Panel (SRP) for FIH clinical trials was established to support the Medical Research and Ethics Committee (MREC), a centralized ethics committee, in performing scientific evaluations of FIH trials undertaken by and/or conducted in clinical trial sites in Malaysia. The scope of review includes all FIH studies on new chemical, biological and biosimilar drugs not registered in Malaysia.
The intensity of early phase clinical trials is more time-consuming requiring more physical exams, vital signs monitoring, electrocardiogram (ECG) monitoring and pharmacokinetic laboratory tests compared to later phase trials29. The P1RP project and initiatives will harness the available resources and capabilities available within the country’s health system as well as increase its knowledge with international collaborations to ensure that the country is ready to meet with the demands of early phase trials.
Preparation of sites
Sarawak General Hospital located in a major city in East Malaysia is targeted to be fully equipped to handle early phase clinical trials. It also serves as a template for future units to be developed in other hospitals. This hospital is already a major medical centre with a ready access to large patient populations and the clinical trial centre is well-equipped and operated by well-trained scientific and medical staff.
In June 2007, the “Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products” was finalised by the EMA30. The scope of the guidance encompasses both biologics and new chemical entities and, was recently updated in 2016 (EMA/CHMP/SWP/28367/07)31and places the focus on the pharmacological characteristics of a new drug.
The document was created to support the transition from non-clinical to the early phase of clinical development and identifies influencing risk factors of a product, includes consideration of quality aspects, testing strategies, designs for FIH studies and mitigation strategies such as initial dosing calculation and dose escalation30.
Therefore, part of the P1RP initiative is the preparation and training of risk management guidelines and to manage any crisis in relation to early phase clinical trials. These include creation of a standard operation procedure (SOP) to prepare for and manage all types of crises requiring immediate attention during early phase trials (i.e. unexpected side effects from a clinical trial). The SOP is designed to also ensure that all actions are coordinated, timely, accurate, consistent and effective in minimising the potential for confusion, rumor and misinformation. The overall objective of this effort is to offer support to the organisation and processes of early phase trials in difficult situations and to the greatest possible extent, limit potential injury to patients, consumers or the reputation of the institutions.
CRM initiated the ACCELERATE project to move the nation’s focus further upstream to early phase drug discovery and development, utilising readily available resources in the country. The project involves converging expertise and collaborations across agencies, clinical research industries and universities on pre-clinical projects. Through this initiative, CRM has intensified collaborations with various universities and research institutes in ‘bench to bedside’ projects. The conversion of pre-clinical studies into early and late phase trials may spur discovery, local innovation and eventually manufacturing of innovator drugs in Malaysia. Additionally, it can prevent outflow of investments and move the country higher up the clinical research value chain.
Malaysia’s effort through the P1RP and ACCELRATE project underlines the government’s commitment to bring the country into a new phase in the clinical trial industry. In the local context, early phase clinical trials play a key role in enhancing the capability of the country in the development of medical science and treatment of disease as well as placing Malaysia at the cutting edge of research. To this end, the Malaysian government’s goal is to develop the country into becoming the preferred destination for industry-sponsored research.
AJA Ooi is the Business Development Manager; KF Khalid is the Former Head of Business Development, both for Clinical Research Malaysia.
- Frost & Sullivan (2016) Asia: preferred destination for clinical trials. https://novotech-cro.com/sites/default/files/170217_FrostSullivan_Asia%20white%20paper_full.pdf
- Frost & Sullivan (2017) The changing face of global clinical trials: Asia-Pacific as an ideal destination for specialty biopharma. https://www.cmicgroup.com/files/user/en/solution/pdf/Whitepaper_201710.pdf
- Ilancheran M, Pritchard JF (2015) Is South Korea the next emerging early phase destination? Appl Clin Trials Jan 29. http://www.appliedclinicaltrialsonline.com/south-korea-next-emerging-early-phase-destination
- Kapiriri L, Lavery J, Singer P, Mshinda H, Babiuk L, et al (2011) The case of conducting first-in-human (phase 0 and phase I) clinical trials in low and middle income countries. BMC Public Health 11:811. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339411/
- Louisa M, Takeuchi M, Setiabudy R, Nafrialdi, Takeuchi M (2012) Current status of phase I clinical trials in Asia: an academic perspectives. Acta Med Indones 44(1):71-7.https://www.ncbi.nlm.nih.gov/pubmed/?term=Current+status+of+phase+I+clinical+trials+in+Asia%3A+an+academic+perspectives.
- Rahman S, Majumder M (2012) Managing clinical trials in Asia: issues, threats, opportunities and approaches. South East Asia j public health (online) 2(2):80-4. https://www.banglajol.info/index.php/SEAJPH/article/viewFile/15961/11333
- Yathindranath S, Kureishi A, Singh S, Yeow S, Geng G, et al (2014) Evolution of the clinical trial landscape in Asia Pacific. Open access j clin trials 6:75-84. https://www.dovepress.com/evolution-of-the-clinical-trial-landscape-in-asia-pacific-peer-reviewed-fulltext-article-OAJCT
- Mohs R, Greig N (2017) Drug discovery and development: role of basic biological research. Alzheimers Dement (N Y) 3:651-7. https://www.ncbi.nlm.nih.gov/pubmed/29255791
- Murthy S, Mandl K, Bourgeois F (2015) Industry-sponsored clinical research outside high-income countries: an empirical analysis of registered clinical trials from 2006-2013. Health Res Policy Syst 13(28).https://health-policy-systems.biomedcentral.com/articles/10.1186/s12961-015-0019-6
- Clinical trial.gov. https://clinicaltrials.gov/ct2/results/browse?brwse=locn_cat_SE
- Baer A, Bridges K, O’Dwyer M, Ostroff J, Yasko J (2010) Clinical research site infrastructure and efficiency. J Oncol Pract. 6(5):249-52. https://www.ncbi.nlm.nih.gov/pubmed/21197190
- Ministry of Health Malaysia (2015) National Health & Morbidity Survey: Non-communicable disease, risk factors and other health problems.
- Ministry of Health Malaysia (2017) Health facts. http://www.moh.gov.my/images/gallery/publications/HEALTH%20FACTS%202017.pdf
- Tee E, Yap R (2017) Type 2 diabetes mellitus in Malaysia: current trends and risk factors. Eur J Clin Nutr 71(7):844-9. https://www.ncbi.nlm.nih.gov/pubmed/28513624
- Statista.com. Projected distribution of global available new active substances by disease type between 1996 and 2020. https://www.statista.com/statistics/491102/new-active-substance-distribution-projection-by-disease/
- U.S. Food and Drug Administration. Novel drug approvals for 2015. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm430302.htm
- U.S. Food and Drug Administration. Novel drug approvals for 2017. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm537040.htm
- Buffery D (2016) Innovation tops current trends in the 2016 oncology drug piepline. Am Health Drug Benefits 9(4):233-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004820/
- National Cancer Institute, Ministry of Health Malaysia (2016) Malaysian national cancer registry report 2007-2011.https://www.crc.gov.my/wp-content/uploads/documents/report/MNCRRrepor2007-2011.pdf
- Salzberg M (2012) First-in-human phase I studies in oncology: the new challenge for investigative sites. Rambam Maimonides Med J 3(2):e0007. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678815/
- Pharmaceutical Research and Manufacturers of America. Medicines in development 2015 report: medicine in development for cancer. http://phrma-docs.phrma.org/sites/default/files/pdf/oncology-report-2015.pdf
- IQVIA (2017) Lifetime trends in biopharmaceutical innovation: recent evidence and implications. https://www.iqvia.com/institute/reports/lifetime-trends-in-biopharmaceutical-innovation-recent-evidence-and-implications
- Pharmaphorum.com. Regulatory timelines in the Asia-Pacific. http://pharmaphorum.com/views-and-analysis/regulatory-timelines-asia-pacific/
- Ooi AJA, Khalid KF (2017) Malaysia’s clinical research ecosystem. Appl Clin Trials. Jan 26. http://www.appliedclinicaltrialsonline.com/malaysia-s-clinical-research-ecosystem
- National Key Economic Areas (2016) Healthcare NKEA fact sheet. http://etp.pemandu.gov.my/upload/NKEA_Factsheet_Healthcare.pdf
- Clinical Research Malaysia (2017) Malaysian phase I clinical trial guidelines. http://www.clinicalresearch.my/wp-content/uploads/2017/10/Malaysian-Phase-I-Clinical-Trial-Guidelines.pdf
- Association of British Pharmaceutical Industry (2012) Guidelines for phase 1 clinical trials. https://www.abpi.org.uk/media/1627/guidelines_phase1_clinical_trials.pdf
- Health Committee (2011) Inquiry into improving New Zealand’s environment to support innovation through clinical trials. https://www.parliament.nz/en/pb/sc/reports/document/49DBSCH_SCR5154_1/inquiry-into-improving-new-zealands-environment-to-support
- Craft B, Kurzrock R, Lei X, Herbst R, Lippman S, et al (2009) The changing face of phase I cancer clinical trials: new challenges in study requirements. Cancer 115(8):1592-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668727/
- Milton M, Horvath C (2009) The EMEA guideline on first-in-human clinical trials and its impact on pharmaceutical development. Toxicol Pathol 37:363-71. https://www.ncbi.nlm.nih.gov/pubmed/19246571
- European Medicines Agency (2016) Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/07/WC500232186.pdf
Source : Applied Clinical Trails Online
By Soon Wen Xian, a medical graduate from Volgograd State Medical University, a Clinical Research Associate at an international pharmaceutical organization based in Singapore.
There are many stages in a clinical trial, for example: feasibility study, start up, active recruitment stage, maintenance stage and study closure. Each stage of a trial is important, but the recruitment process is undeniably the most important part. Because if there is no patient being recruited, there will be no data to analyse and without data, the trial will not meet any objectives. That is why recruitment process plays a very important role in ensuring a successful clinical trial. Recruitment rate is almost always the main issue in a trial. If we can speed up the recruitment rate, not only would we have the results faster, we would also be able to reduce the cost of the trial. In order to make recruitment process a successful one, both site member and sponsor must know their roles well. For this issue, I would like to share how we can make a trial recruitment process easier, faster, and more effective. Read more
- Miri Hospital is a Secondary Hospital providing services in the north zone of the state of Sarawak.
- The services provided are in terms of patient care to the community.
- Miri Hospital is located about 2.5km from Miri city centre and covers an area of 87.11 acres.
- It began operations on May 6 1995, officially opened by Chief Minister Of Sarawak Tan Sri Pehin Datuk Patinggi (Dr) Haji Abdul Taib Bin Mahmud on 30 August 1996.
Dato’ Dr. Fam Tem Lom was born and raised in a small town in Sarawak called Kampung Beratok. His father is a smallholder planting pepper plants and rubber trees. Dato’ Dr. Fam is the 9thof 15 siblings and they live in a simple house with earthen floor where he shared a room with four of his siblings until he left for university.
In those days, he and his siblings wake up early to help tap rubber and tend to pepper plants and then helps out again after school and completing their homework.
Having graduated from UNIMAS in 2002, Dato’ Dr. Fam went on to serve as a Houseman and then as Medical Officer and Clinical Specialist at Sarawak General Hospital from 2002 until 2010. He obtained the MRCPI in 2007 and FRCPI and FRCP (Glasgow) in 2015. It was in 2010 that he got posted to Miri General Hospital where he stayed until today.
In 2016, Dato’ Dr. Fam was bestowed the DIMP by his Royal Highness SultanHaji Ahmad Shah Al-Musta’in Billah ibni Almarhum Sultan Abu Bakar Ri’ayatuddin Al-Mu’adzam Shahwhich carry the title Dato’. He is married to Datin Dr. Doreen Chan Chu Ching and has three children. Read more
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