With steadily increasing drug development costs and significant time spent on clinical trials, outsourcing clinical trials in Asia has rapidly become an appealing option for many firms (Figure 1). As developing a single drug can cost more than $200 million and take at least 10 years, Asia (except Japan) offers a less expensive, less time-consuming process for clinical trials. Simultaneously, increased demand and awareness for various medical drugs and health services (Tables 1 and 2) have encouraged many of these countries to develop their own Contract Research Organizations (CROs), and many U.S. firms have eagerly turned to these options to survive in a growing competitive global market.
|Country||Pharmaceutical Market Size|
|Hong Kong||$1.5 billion|
|Country||Health expenditure per capita||Health expenditure as % of GDP||Physicians per 1,000 people||Hospital beds per 1,000 people|
Source: World Bank, World Development Indicators 2006
Why Go to Asian CROs?
The major incentive for moving clinical trials overseas is cost. Often, the cost of the hospitals, clinical evaluations and data analysis are cheaper in Asia than in the U.S. or Europe. One of the main factors contributing to lower costs with outsourcing clinical trials in Asia is that patient recruitment is generally easier and faster. Recruitment is a time-consuming task, and sometimes accounts for about half of the time required for the clinical trial. In fact, almost 90% of clinical trials experience an unexpected delay of some sort, and problems with recruiting patients are generally the number one reason for these delays.
Other incentives include lower costs due to looser regulations in some of the Asian countries, excluding Japan. For example, governments in some Asian countries may have a less conservative stance on what population segments or parts of the body are permitted for testing. Some countries may also have less complicated regulatory regimes, allowing for faster approval times.
Asia also boasts a genetically diverse population with more than 4 billion people, many of whom have never received medication to treat their conditions. With such large numbers of new candidates, pharmaceutical companies can assess the success of their drug more accurately.
Finally, many of these Asian people may be willing to undergo testing for the access to medication and care they otherwise would not be able to afford. For example, India provides free medication and, in many cases, better medical attention to clinical trial patients than the average Indian hospital would provide.
What to Watch Out For
Despite all of the advantages of outsourcing clinical trials, there are also concerns and potential pitfalls that should be addressed. One concern is the lax enforcement of intellectual property laws or complete lack of intellectual property laws at all. For example, it may be difficult for a foreign pharmaceutical company doing trials in China to ensure that the formula for its new drug will be kept strictly confidential when utilized by a Chinese CRO. Confidentiality agreements, which in theory are binding in the West, may not be so “confidential” in Asia. In addition, enforcement of intellectual property is not uniform throughout the Asian region.
Measures have been taken to address such concerns. Now, with the World Trade Organization’s agreement on Trade Related Aspects of Intellectual Property Rights, member countries are required to establish minimum standards concerning the scope and use of IP rights and the procedures for enforcing them. Contract research organizations (CROs) in Asia are also enforcing stricter IP procedures. At WuXi PharmaTech in Shanghai, China, workers who fail to follow IP protection procedures are fired after two warnings. Of course, by then it may be too late.
Another concern of pharmaceutical companies working with foreign CROs is that the research and clinical trial data will be of low quality. This is certainly a legitimate issue as in some developing countries, the quality of facilities, infrastructure, and data collection may not be as high as one might expect in a typically modern, high-tech hospital in the U.S., Europe, or Japan. However, quality is constantly improving and in places like Singapore and Hong Kong, the facilities and quality control of the trials are comparable to Western standards.
There is also concern about unethical treatment of patients in countries without specific laws protecting participants. Some countries may not get the “informed consent” of the subjects in the trial beforehand. Also, many CROs purport to run facilities that are compliant with the International Committee on Harmonization (ICH) standards of Good Clinical Practice (GCP), but in practice they do not do so.
How to Choose a CRO
Understandably, it can be daunting to find an appropriate, qualified CRO in an Asian (or any foreign) country. The conventional choice is to pick one of the large global CROs that has offices around the world and an excellent reputation. However, this may not always be the best choice for every company. A CRO may have done excellent work in the U.S. or Europe, but its offices in farther-off locales like Asia may not be staffed with the same quality of personnel as its headquarters. A local CRO may be better suited for certain clinical studies because it can devote more attention to smaller projects, and because it may value that client more than a large global CRO would. Local CROs may also have more expertise on the local regulations, as well as closer ties to the local regulatory authorities. In addition, a global CRO may be more concerned about keeping its large pharmaceutical clients, with their large, multi-site studies with hundreds of patients, happy.
Once a CRO is chosen, it may also be a good idea to have a local independent regulatory person or one of your employees move abroad to help oversee the trials. CROs that are monitored locally often times provide their services in a timelier manner and at a higher level of quality.
Aside from differences in cost, one should look at other attributes such as each country’s regulatory and healthcare environment. Ease of regulatory approval can vary significantly depending on each government’s regulations and laws on drugs and clinical research. Some countries may be able to provide large numbers of patients that suffer from a particular disease or illness, while other countries may not have such patient populations. Sometimes you may be willing to do the trials in a foreign language, while in other cases, English is required.
Clinical trial locations in Asia can be divided into three tiers. The first tier is Japan, which has a very high quality, very conservative medical community. Clinical trials in Japan are normally more expensive than comparable trials in the West, and the quality of the clinical research is generally just as high. As more medical companies enter Japan, the need for at least some local clinical trials has increased.
The second tier includes Taiwan, Korea, Singapore, and Hong Kong. These countries provide clinical trial services at a relatively high level of quality and generally at lower cost than in Japan or the West.
The third tier includes India, China, and Southeast Asian countries such as Indonesia, Malaysia, the Philippines, and Thailand. Clinical trials in these countries can be of decent quality and normally offer significantly lower costs than places like Taiwan, Singapore, and Hong Kong. However, issues such as the quality of the trials and intellectual property protection are generally real concerns in these locations. The information below gives some background on most of these Asian countries and outlines how to get started with clinical trials.
Tier One: Japan
Japan’s medical business is very sophisticated and comparable to Western standards. Western companies looking to outsource clinical trials to save money and time should NOT go to Japan. However, in almost all cases, Western companies that wish to sell drugs or more risky medical devices in the Japanese market will need to do at least some clinical trials in Japan in order to get product approval.
In Japan, the Ministry of Health, Labor, and Welfare (MHLW) oversees the regulation and safety of pharmaceuticals, medical devices, cosmetics, and food. It is comparable to the U.S. FDA. The Pharmaceuticals and Medical Devices Agency (PMDA), established in April 2004 under the revised Pharmaceutical Affairs Law (PAL) in 2002, oversees regulatory affairs for drugs and medical devices. Though both have websites in English (http://www.mhlw.go.jp/english/index.html and http://www.pmda.go.jp/), they are not updated as regularly as the Japanese sites.
Currently, there are no base guidelines nor specific laws about what types of foreign clinical data are acceptable for each product. In many cases, the PMDA must work on a case-by-case basis for each medical product with independent Japanese experts to determine specific logistical issues, such as number of participants, what data is required, and how the study should be conducted. However, the PMDA is currently working with experts in specific fields to establish clinical trial guidelines for different product types.
Before making a clinical trial request, an applicant submits a Clinical Trial Notification (CTN) to the PMDA. The notification mainly consists of description and product summary, pre-clinical data, clinical trial protocol, analysis plan, SOPs, contact person, and appropriate research institution. Also, compliance with Good Clinical Practice (GCP) often requires an Institutional Review Board (IRB) to review the clinical trial protocol, written informed consent forms for participants, and adverse event reporting. For those who require further specific guidance on their product, the PMDA also provides more in-depth consultation sessions.
Tier Two: Taiwan, Singapore, Hong Kong, Korea
Taiwan is a country in which CROs are already very active. Quality standards for clinical trials in Taiwan adhere to the accepted international standards of ICH GCP. GCP guidelines were implemented by the Department of Health (DOH; http://www.doh.gov.tw/EN/Webpage/index.aspx) in 1997 and then further revised in 2002 to be consistent with ICH standards. The DOH conducts GCP inspections on nearly all clinical trials to ensure their quality and credibility and is equivalent to the US FDA.
Before a clinical trial in Taiwan can begin, approval of the clinical trial protocol must be obtained from both the IRB and the DOH. The IRB or ethics committee of the individual hospitals will review the protocol for any ethics concerns. Approval takes about 2 to 3 months.
Taiwan also offers the option of joint IRB (JIRB) approval, which allows for multi-center approval as opposed to individual IRB approval from each hospital. More than 40 hospitals have participated in the joint IRB, and JIRB has helped Taiwan attract more multi-center trials.
In addition to IRB approval, the clinical trial protocol must also be reviewed and approved by the Bureau of Pharmaceutical Affairs at the DOH. The Center for Drug Evaluation (CDE), a non-governmental, non-profit organization, assists in reviewing all clinical trial protocols submitted to the DOH. In addition, it also provides regulatory consultation, reviews informed consent documents, and facilitates the drug development process in Taiwan. Regulatory approval to start clinical trials also takes 2 to 3 months.
Singapore is a good location for conducting clinical trials because it boasts the second-best healthcare system in Asia (after Japan). Singapore has 4.3 million people, high-quality facilities, and highly educated doctors, many of whom went to school in the U.S. or Europe (especially England). However, one of the drawbacks of doing clinical trials there is its small population; sometimes trials in Singapore can encounter difficulty recruiting enough patients.
Singapore is also strong in intellectual property (IP) protection, being ranked top Asian country for IP protection for 3 years (2002 – 2004) by the Institute for Management Development (IMD), the World Economic Forum (WEF), and the Political Economic Risk Consultancy (PERC).
The Health Sciences Authority (HSA; http://www.hsa.gov.sg/), established in 2001, is generally responsible for the quality, safety, and efficacy of drugs and devices. The Centre for Drug Administration (CDA), a division of the HSA, regulates and evaluates drugs and medical devices, including clinical trials. All clinical drug trials in Singapore require regulatory approval in the form of a Clinical Trial Certificate (CTC), granted by the CDA before the trial can proceed.
The Medical Clinical Research Committee (MCRC) reviews applications for CTCs, in addition to conducting continuing reviews of the clinical trial and monitoring adverse events. The entire approval process to start clinical trials takes about 2-3 months, including IRB/EC approval. All clinical trials conducted in Singapore must comply with the Singapore Guidelines for Good Clinical Practice (GCP), which were adapted from ICH-GCP standards and implemented in 1998.
This country is an emerging market for clinical trials. The country has advanced medical care, along with developed infrastructure, strong presence of academic institutions, and high-quality investigators. Doctors are highly educated and have studied abroad, particularly in the U.S. and Europe (especially England). The majority of clinical trials conducted in Hong Kong are in Phases II to IV, and clinical trials are regulated by the Department of Health (http://www.dh.gov.hk/eindex.html).
Under Regulation 36B of the Pharmacy and Poisons Regulations, a certificate for Clinical Trial/Medicinal Test (CTC) is required before conducting a clinical trial. Before applying for a CTC, an applicant should first receive approval from the hospital’s Ethics Committee (EC). Obtaining EC approval generally takes 4 to 6 weeks.
The CTC submission will include the protocol, investigator’s brochure, pre-clinical study results, drug samples, the EC approval letter, an informed consent form, and an endorsement letter from the principal investigator. The CTC is granted to the principal investigator, and usually takes an additional 4 to 6 weeks.
The sponsor must also apply for an import license at the Trade and Industry Department for permission to import samples of the drug for the purpose of obtaining the CTC. This will generally be available within a week. A copy of the CTC will be required when the drugs are actually imported for clinical testing. The total approval time will be about 2 to 4 months.
The Korea Food and Drug Administration (KFDA; http://www.kfda.go.kr/), established in 1996, is the main regulatory body for drugs, medical devices, food, and cosmetic products.
To conduct a clinical trial in Korea, the sponsor must obtain both regulatory approval and IRB approval. The KFDA provides optional pre-IND (Investigational New Drug) consultation services, and it is generally recommended that the sponsor engage in these consultations. The sponsor will then submit the clinical trial application dossier with the appropriate supporting documents (such as the protocol, Chemistry, Manufacturing and Control data, etc) to the KFDA. The full clinical trial application must be translated into Korean. All trials must follow KGCP (which was revised in 2001 to harmonize with ICH guidelines) and can only take place at accredited sites.
The KFDA will consult with the Central Pharmaceutical Affairs Committee in making its decision on approving the clinical trial. Regulatory approval takes about 30 days while the IRB approval also takes about 30 days. Both these processes can be done in parallel.
Tier Three: India, China, Southeast Asia
The third tier of clinical research includes countries whose healthcare infrastructures may not be as highly developed as in wealthier Asian countries. However, clinical trial services offered here are often significantly less expensive than in the second-tier countries and can be of decent quality. Even amongst these countries there is some variation. For example, India has a highly educated human resource pool and existing infrastructure for drug production, which has made it easier for Indian companies to transition into clinical research. There are many local CROs that are headquartered in India, along with many satellite offices of global CROs. Recently, China too has become a target location for many clinical trials. In the Southeast Asian countries, however, there are not many local “homegrown” CROs and only a few branch offices of large global or regional CROs. As of today, not many foreign medical companies focus on Southeast Asia (Malaysia, Philippines, Indonesia, and Thailand) when looking to do clinical trials in the region.
For a number of reasons, India’s clinical trial business has grown rapidly throughout the past few years. Perhaps the major factor for such growth is the fact that clinical trials in India are significantly cheaper than in the West. Another factor spurring growth in the Indian market is the large, already-existing presence of pharmaceutical know-how and capacity. Add to that the tremendous diversity of its population, huge geographic expanse, the number of foreign-educated doctors, and the fact that English is a spoken language; it is no surprise, then, that India has become a prime spot for clinical research activity.
India’s recent changes in patent regulations have also encouraged more international business in the past ten years. The Indian Patents Act (1970) did not recognize pharmaceutical product patents as only manufacturing process patents were recognized. However, in 1995, India agreed to uphold the WTO Trade-Related Intellectual Property Rights (TRIPS) where India would recognize and enforce pharmaceutical product patents, in addition to other product patents.
Drug registrations and approvals fall under the responsibility of the Central Drug Standards Control Organization (CDSCO). A key official within this organization is the Drug Controller General India (DCGI), and both work together on regulations for clinical trials. Legislative requirements on clinical trials are guided by specifications of Schedule Y of the Drug & Cosmetics Act, 1940. Schedule Y contains detailed information for each trial Phase, including requirements for Ethics Committees, informed consent, animal pharmacology and other details.
The CDSCO has recently passed new regulations on global clinical trials based on a meeting held in October 2006. For the purpose of granting permission, clinical trials are to be classified into Category A and B. Category A will include those trials whose protocols are approved by the US, UK, Switzerland, Australia, Canada, Germany, South Africa, Japan, and EMEA (European Medicines Agency). Because permission will be granted accepting the approvals of the protocols from these countries, the CDSCO estimates that approval time for clinical trials will take 2-4 weeks. However, all other applicants will fall under Category B which will require protocol verification and take 3-4 months approval time.
The CDSCO (http://cdsco.nic.in/index.html) has also categorized protocol amendments into three groups: those not requiring any notification or permission, those which require notification but no permission, and those requiring prior permission from the CDSCO before implementation of clinical trial protocol amendments.
The State Food and Drug Administration (SFDA; http://www.sfda.gov.cn/eng/) is the Chinese equivalent of the U.S. FDA and is the national authority that approves and reviews clinical research. The regulation of drugs and clinical trials is outlined by the Drug Administration Law of the People’s Republic of China, which went into effect in December 2001, and the Drug Registration Regulation of 2002.
Before a clinical trial can be carried out in China, it must first be approved by the SFDA. The sponsor should prepare and submit the dossier and drug samples to the SFDA, which will consult with the Center for Drug Evaluation before issuing a clinical trial approval letter. Other drug institutes such as the National Institute for the Control of Pharmaceutical and Biological Products will also aide the SFDA in screening applications. The entire process for clinical trial approval takes approximately 7 to 9 months. Fast track review is available for clinical trials of drugs that treat serious or life-threatening illness, or for drugs that are the same kind of drug as one that has already been approved.
Each country has a specific governmental health organization which oversees clinical trials and pharmaceutical regulations. Approval processes can be relatively quick in these countries, taking only 3 to 4 months. The most popular location for clinical trials in Southeast Asia (NOT including Singapore) is Malaysia for its relatively developed hospital infrastructure and advanced regulatory environment for drugs.
Outsourcing clinical trials in Asia provides a way for U.S. and European medical companies to reduce cost and increase productivity and efficiency. Currently, about 25% of U.S. medical companies outsource overseas to some extent. Although IP protection issues still linger, some U.S. companies are now outsourcing all phases of product development, including drug discovery, research and development, clinical trials, and manufacturing. U.S. companies will continue to outsource in Asia as the medical communities in Asian countries continue to become more sophisticated and cost reduction can be more clearly defined.
Ames Gross – President and founder. Mr. Gross is recognized nationally and internationally as a leader in the Asian medical markets. Mr. Gross founded PBM in 1988 and has helped over 200 medical companies with business development and regulatory issues in Asia.
Momoko Hirose – Associate, Pacific Bridge Medical. Ms Hirose works on research, writing, and consulting projects.