KF Khalid

Industry-sponsored research (ISR) has been progressively growing within Asia in the last decade. Early phase clinical 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 “spillover” 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 neighboring countries.

	In view of this, there is a strong focus on growing the clinical trial ecosystem in the country by optimizing the already existing resources while expanding and improving them to further facilitate early phase ISRs in the Malaysia. 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 enable Malaysia to cater to early phase drug studies.

	The conduct of ISR in Asia has been gaining momentum for more than a decade.

 states that the contract research organization (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 region,

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 I studies) is evident.

 examined the number of ISR Phase I trials between 2007–2009 and found that only 6.8% of them made their way to the APAC region. The early phase clinical trial market in 2013 was valued at approximately $11.9 billion USD with an expected CAGR of 1.5–2%, reaching 4% this year.

 Owing to the important roles of early phase trials that range from their scientific benefits

 to capacity-building and economic advantages, most Asian countries, including Malaysia, have focused initiatives into building adequate infrastructure to attract them.

	As of last summer, there were 16,248 interventional ISRs covering all phases globally; 27.2% (4,424) were in the early phases (Phase 0 and I trials).

 Figures 1 and 2 show the proportion of early phase trials in Asia and Southeast Asia, which are significantly smaller levels compared to North America and Europe.

	There are several benefits in conducting early phase trials in Asia. One is that there are certain diseases that are more prevalent in Asia compared to the West, wherein epidemiology, health services, social determinants, comorbidities, and genetic components of the population can influence how a treatment may be used, as well as differences in genetics and gastrointestinal microbiome effect on the pharmacokinetics and pharmacodynamics of drug molecules.

 There have also been concerns that racial and ethnic minorities, women, and the elderly are often underrepresented in early drug development programs, making Asia an attractive destination for clinical trials.

	The conduct of more early phase trials in regions within Asia, like Southeast Asia, can  play a pivotal role in ensuring that the populations proportional to the potential uses of the product after its registration and approval are performed from the earliest stages.

	Early phase trials: Opportunities for growth in Malaysia

	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 costs.

 Though a strong presence of the disease targeted 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 first-in-human (FIH) trials within the country.

Patient pool with cardiovascular risks-diabetes, hypertension, hypercholesterolemia

	At a global level, the top 20 indications of ISR trials, regardless of phase of study, include cardiovascular disease, diabetes mellitus, hypertension, and hypercholesterolemia.

 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 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 18 years old and above was 17.5% (8.3% known and 9.2% undiagnosed).

 The overall prevalence for hypertension and hypercholesterolemia was 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 among the top five principal causes of hospital admissions (both private and public hospitals), at 7.44% of total admissions, and was among the top five principal causes of mortality.

 With regard to type 2 diabetes mellitus, diagnosis of disease in Malaysia has more than doubled since 1996, and coupled with an overweight and obesity prevalence of 27–31% in school children, the condition poses a major public health concern.

	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.

	Studies in the field of oncology treatment are currently the top indication for clinical trials. Using the following search criteria, start date 01/01/2013-12/31/2017, recruiting, not yet recruiting, active-not recruiting, enrolling by invitation, early Phase I and phases I-III, indications 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 show 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 FDA were for oncology-related products, while 27% were approved in 2017.

 In the U.S. alone, there were 836 drugs and vaccines for cancer in various stages of clinical development or awaiting FDA approvals.

	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).

 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%).

	FIH oncology trials differ from early phase trials in other therapeutic areas-they are evaluated in patients rather than healthy volunteers. The characteristics of oncology products, mainly their safety profiles, do not allow for testing in healthy volunteers. In the absence of alternative effective treatments, participation in these trials using novel compounds are considered an opportunity to these patients.

	Therefore, with the global pipeline of oncology drugs in clinical development having seen robust growth over the past two decades,

 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 $1 billion USD with an average estimate of $2.6 billion USD.

 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 countries,

 can be seen by sponsors and CROs as an ideal site for conducting clinical trials with lower investments.

	The 2017 Frost & Sullivan white paper’s

 costing estimates of conducting clinical research per patient, per visit, in all therapeutic areas and in all phases, shows Malaysia as having the second-lowest cost, ahead of India ($350 vs. $330 USD); while costs in Singapore was similar to that in the U.S. ($1,210 vs. $1,380 USD) and that in South Korea ($890 USD).

	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 region.

	However, countries in the region have attempted to harmonize these to ensure better data acceptability and reduce trial and drug approval timelines.

 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 standardize drug approval processes.

	In Malaysia, ethics review and regulatory approvals, together with import licensing and contract negotiations, occur concurrently, allowing for faster processing timelines. These are comparable with timelines in South Korea and Singapore (approximately 2-3 months).

 In a recent report, regulatory timelines have been improved to within 30 working days,

 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 centers with advanced equipment and technology, knowledgeable physicians, and available key opinion leaders in different specialties also play an important role in attracting ISRs.

	Malaysia has a well-developed and equipped healthcare system manned by medical doctors that practice and comply with international clinical practice standards.

 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 CRM, a non-profit company, wholly owned by the Ministry of Health,

 to equip the ecosystem of clinical research in the country.

 Its goal is to reach at least 1,000 clinical trials by 2020. Part of the initiatives stated in this section is to set up more clinical research centers, develop more good clinical practice (GCP) certified investigators, and improve existing institutional review board (IRB) and ethics committee (EC) timelines. The Phase 1 Realization Project (P1RP) 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 treatments that are 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 stands on five 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 had indicated that it was ready to review FIH studies.

	The P1RP strategy is multi-pronged wherein regulatory agencies are equipped with the right knowledge to review Phase I clinical trials. 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 units 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 Guidelines

 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 guidelines,

 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 for 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 centers, including the Princess Margaret Cancer Center, to be exposed to the experience of conducting FIH studies. The government has also started initiatives to bring back Malaysians from overseas. Experts or specialists from higher-income countries returning home 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 trials.

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 Zealand,

 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 increased amounts of physical exams, vital signs monitoring, electrocardiogram (ECG) monitoring, and pharmacokinetic laboratory tests compared to later phase trials.

 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 Malaysia is ready to meet with the demands of early phase trials.

	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 center with ready access to large patient populations, and the clinical trial center 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 finalized by the European Medicines Agency (EMA).

 The scope of the guidance, which encompasses both biologics and new chemical entities, was recently updated in 2016 (EMA/CHMP/SWP/28367/07),

and 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 escalation.

	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 minimizing the potential for confusion, rumor, and misinformation. The overall objective of this effort is to offer support to the sponsor 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 Malaysia’s focus further upstream to early phase drug discovery and development, utilizing readily available resources in the country. The project involves converging expertise and collaborations across agencies, clinical research industries, and universities on preclinical projects. Through this initiative, CRM has intensified collaborations with various universities and research institutes in “bench to bedside” projects. The conversion of preclinical 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.

		Frost & Sullivan (2016) Asia: preferred destination for clinical trials. 

		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?

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. 

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. 

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. 

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. 

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. 

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. 

 https://health-policy-systems.biomedcentral.com/articles/10.1186/s12961-015-0019-6

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. 

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. 

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/

Articles

Exploring the nation’s opportunities for growth and the initiatives undertaken to build an attractive clinical trials ecosystem for early stage research.

Establishing Early Phase Capabilities in Malaysia

	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 decade

 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 region

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 evident

 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 year

. Owing to the important roles of early phase trials that range from its scientific benefits

 to capacity building and economic advantages, most Asian countries, including Malaysia have focused initiatives into building adequate infrastructure to attract them.

	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) trials

. 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 molecules

. 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 trials

	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 stages

	Early phase trials: opportunities for growth in Malaysia

	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 costs

. 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 hypercholesterolemia

. 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)

. 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 mortality

. 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 concern

	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.

	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 [10]. Additionally, projected distributions of available new active substances in the global market by disease type from 1996–2020 show

 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 2017

. In the US alone, there were 836 drugs and vaccines for cancer in various stages of clinical development or awaiting USFDA approvals

	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)

. 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%)

	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 patients

	Therefore, with the global pipeline of oncology drugs in clinical development having seen a robust growth over the past two decades

, 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 billion

. 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 countries

, can be seen by sponsors and CROs as an ideal site for conducting clinical trials with lower investments.

 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 

USD 330) while costs in Singapore was similar to that in the USA (USD 1,210 

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 region

	However, countries in the region have attempted to harmonise these to ensure better data acceptability and reduce trial and drug approval timelines

. 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 months

). In a recent report, regulatory timelines have been improved to within 30 working 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 ISRs

	Malaysia has a well-developed and equipped healthcare system manned by medical doctors that practice and comply with international clinical practice standards

. 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. 

	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 Health

, to equip the ecosystem of clinical research in the country

. 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 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

 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 guidelines

 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 trials

	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 49

, 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 trials

. 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.

	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 EMA

. The scope of the guidance encompasses both biologics and new chemical entities and, was recently updated in 2016 (EMA/CHMP/SWP/28367/07)

	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 escalation

	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.

is the Former Head of Business Development, both for Clinical Research Malaysia.

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AJA Ooi and KF Khalid, of Clinical Research Malaysia, describe the opportunities for growth of early phase studies in Malaysia and the initiatives taken to attract these trials into the country. 

KF Khalid

Articles

Establishing Early Phase Capabilities in Malaysia

Initiatives to Establish Capabilities in Early Phase Clinical Research in Malaysia