Demystifying Asia: Best Practices For Conducting Multinational Clinical Trials. Barb Geiger, BSN, RN Chris Wang

Transcription

1 Demystifying Asia: Best Practices For Conducting Multinational Clinical Trials Barb Geiger, BSN, RN Chris Wang

2 Demystifying Asia: Best Practices For Conducting Multinational Clinical Trials Introduction» With increasing need for pharmaceutical and biotechnology companies to bring more products to market faster, there has been growing interest in accessing multinational patient populations to speed enrollment. This paper reviews issues around conducting clinical trials in select Asian countries, starting with general benefits, followed by discussion of country-specific considerations for protocol development, regulatory requirements, and recruitment and concluding with the advantages of partnering with an experienced global contract research organization (CRO). Table 1. Population and Age of Select Countries in Asia Figure 1. Why Go To Asia With Your Clinical Trial? PATIENT POPULATION HARMONIZATION OF STANDARD OF CARE SIMILAR DATA QUALITY IP PROTECTION Why go to Asia with your clinical trial?» When sponsors or CROs consider conducting clinical trials in Asia, the biggest perceived advantage is the availability of patients. Asia, as a whole, represents 60% of the world s population, while select Asian countries (Table 1) have a combined total of 1.7 billion people, representing 25% of the world s population. Based on 2014 estimates by the CIA (CIA factbook) * Countries in which Clinipace Worldwide maintains Asian offices. There is also a growing Asian pharmaceutical and clinical trials market, with growth in Asia continuing at double-digit rates. 1 Furthermore, R&D investment increased more than 20-fold between 2000 and This may reflect the interest in expanding the pharmaceutical market, but also an increased awareness of health issues within these countries. clinipace.com 1

3 Particularly strong growth has been predicted for China, South Korea, Taiwan, and Singapore through Although the proportion of total registered clinical trials in clinicaltrials.gov in the select Asian countries only increased from 11% in 2005 to 13% in 2014 (Figure 1), a shift in emerging countries is evident with China and South Korea representing the largest increases in the number of registered multinational clinical trials. Figure 2. Percentage of Total Clinical Trials Registered in clinicaltrials.gov in Select Asian Countries Not only are there a significant number of patients, but there are also groups of patients that are treatment naïve, particularly for the increasing Western patterns of illness. As a result, there is an increasing disease burden. Although the specific recruitment rates are not known, local experience indicates that patients are willing to enroll in clinical trials, and study timelines can benefit from the rapid enrollment that have been observed in a number of Asian countries. In our experience with one multinational trial, the enrollment in Korea was so successful, we made the decision to stop recruiting there to make sure there was balanced enrollment across all countries. China remains a key emerging market for multinational pharmaceutical companies and is the world s 2nd largest market, with expectations that it will be first by Market size is forecast to exceed $155 billion by In addition to the growth of the Chinese market, South Korea is one of the fastest growing countries for clinical trials in East Asia, 4 in part due to the creation of a specialist agency, the Korean National Enterprise for Clinical Trials, in December 2007 that aims to develop Korea as a preferred clinical trials location. Meanwhile, Taiwan conducts new global studies annually. clinipace.com 2

4 China remains a key emerging market for multinational pharmaceutical companies and is the world s 2nd largest market, with expectations that it will be first by Similar data quality In our experience, the quality of data in many Asian countries, particularly those with previous clinical trial experience, is comparable to that obtained in the US and Europe. Investigators that have been trained in international pharmaceutical countries help ensure that international standards are followed. The sponsor or CRO can also enforce adequate data quality and consistency by employing experienced and reliable project management teams and monitors. Local Clinipace Worldwide employees indicate that this can significantly influence outcomes of a multinational trial. Countries interested in joining the international pharmaceutical market are employing and enforcing these guidelines, as discussed later. Furthermore, as drugs become increasingly available, issues related to comparator drugs may be fewer. Intellectual property protection Sponsors have previously expressed concerns about the protection of intellectual property (IP) in a number of Asian countries. However, robust IP protection is known to exist in countries such as Singapore, China, Taiwan, and Korea, 5 where specific laws have been developed and enforced. In China, a revision to the Chinese patent law was enacted in 2009, 6 while Taiwan supports a patent extension for up to 5 years while a clinical trial is ongoing, and data exclusivity is also available for up to 5 years. 7 In Singapore, IP protection is particularly well enforced, as is regulatory compliance. 5 In other countries, there are continuing development and improvements in legislation for IP rights. 5 Figure 3. Robust IP Protection Harmonization in standard of care The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), which has expanded beyond the original members in the US, Europe, and Japan, promotes similar standards of care in multinational clinical trials. The World Health Organization (WHO) also provides guidance documents for countries with little to no clinical trial experience. clinipace.com 3

5 Important considerations before conducting a clinical trial in Asia» Despite the increasing similarities between the US and European countries, which have been conducting clinical trials for decades, and Asian countries, which have been conducting clinical trials for only the last years, there are still varying levels of experience, particularly in countries like Vietnam where such experience is limited as compared to Korea or Taiwan. However, with experienced CRO partners, such as Clinipace Worldwide, these considerations can be accounted for and incorporated into the early development of the trial protocol, saving considerable time and expense and allowing expansion of clinical trial activities into these high-growth areas. Figure 4. Considerations Before Conducting a Clinical Trial Protocol development Specific regulatory considerations by country Timelines Standard of care Data quality Recruitment Pharmacokinetics/dosing Protocol development Historically, trial protocols were developed in the US and Europe for US and European-based studies, and these protocols were then applied, as is, in Asia. In the interest of accommodating these protocols, a number of Asian countries attempted to follow what had been developed elsewhere (>10 years ago). With the growth of local pharmaceutical and biotech companies in the Asian region during the last 5 years, protocols reflecting regional requirements are now being developed locally, and protocols developed elsewhere without specific Asian considerations are no longer readily accepted. Sponsors in the US and Europe wishing to conduct multinational trials in Asia should incorporate local Asian requirements in the initial protocol development, rather than as an afterthought. Moreover, each autonomous nation should be considered its own entity with regards to regulations, culture, and ethnicity, rather than the whole of Asia as one homogenous unit. This will ultimately save time in the approval process and facilitate proactive solutions to considerations such as local standard practices, comparator availability, and dosing requirements. Specific regulatory considerations by country In China, active management of regulatory affairs is particularly important; the application process involves a number of regulatory bodies at various levels of the central and local governments. Separate Good Clinical Practices (GCP), Good Laboratory Practices (GLP), and Good Manufacturing Practices (GMP) standards must also be accommodated. clinipace.com 4

6 A Clinical Trial Application (CTA) is submitted for a completely new drug, which allows a full clinical development program (Table 2). 8 However, there is no clear, comprehensive guidance for the technical, pre-clinical, or clinical requirements at the CTA stage. Technical support is required to respond to queries and requests for additional data during the CTA review. 8 Drugs previously approved in other countries are considered import drugs, and the majority will require domestic clinical data from China for an Import Drug License (IDA). 8 In these cases, a CTA could save up to several years time in market approval compared to the import drug route. China has strict restrictions regarding the transport of human tissue samples that affects the use of biomarkers. The use of central, local laboratory facilities in China may be necessary. In Hong Kong, a Certificate for Clinical Trial/Medicinal Test is required to conduct a clinical trial on human beings or a medicinal test on animals, including evidence that approval has been received by the ethics committee of the institution. Payment of the certificate fee and collection of the certificate should be done in person at the Drug Office of the Department of Health. Table 2. Regulatory Considerations by Country clinipace.com 5

7 In Malaysia, the Clinical Trial Import License (CTIL)/Clinical Trial Exemption (CTX) must be completed for both new and existing drugs and can be completed by any investigator who is an authorized person from a locally registered pharmaceutical company/cro/sponsor with a permanent address in Malaysia. However a License A holder must submit the CTIL/CTX in the case of a poison, which includes a number of different drug types. A CTIL/CTX will not be issued prior to ethics committee approval; however, a simultaneous review by the ethics committee and the National Pharmaceutical Control Bureau (BPFK) is allowed. South Korea is a preferred location for Phase I studies and has streamlined regulatory processes for Phase II and III studies. The reviews of the ethics application and Korean Food and Drug application can also occur in parallel. 4 The majority of the Investigational New Drug (IND) application must be in Korean, including the application, protocol, consent form, non-clinical study report, and clinical study report. In Taiwan, the collection of local clinical data is a key success factor for the mandatory ethnic sensitivity evaluation (Bridging Package Evaluation). Other specific considerations include GMP requirements, which differ based on country and previous inspection. For manufacturers from Pharmaceutical Inspection Co-operation Scheme (PIC/S) or ICH countries and for manufacturers not from a PIC/S or ICH country that have been inspected by a PIC/S or ICH National Drug Regulatory Authority (NDRA), a valid Certificate of GMP Compliance from the NRDA is required. For manufacturers from an Association of Southeast Asian Nations (ASEAN) country, a valid Certificate of GMP Compliance issued by an NDRA as mutually agreed in the ASEAN Sectoral Mutual Agreement (MRA) for GMP Inspection of Manufacturers of Medicinal Products is required. 9 In addition, a Drug Accountability and Disposal report should be submitted to BPFK within 3 months from the site closure. In Singapore, a Clinical Trial Certificate (CTC) is required before study commencement, and the sponsor/cro submitting the CTC application must be a locally registered company. The PI must also be working in a local hospital or facility. Ethics approval must be obtained prior to the study; however, parallel submissions can be made to the ethics committee of the institution and the Health Sciences Authority (HSA). 10 Rescue Trials Choice Pharma has been involved in a number of rescue trials in which their local knowledge, experience, and relationships have been particularly useful. With a regional trial for breast cancer being conducted in Hong Kong, Taiwan, Korea, and Malaysia and managed by another CRO, recruitment remained slow one year into the trial. Of the 342 patients targeted for enrollment within 2.5 years, only 35 had been recruited at 1 year. Choice Pharma became involved, to rescue this trial. Malaysia was removed from the list of countries, and the target enrollment was increased to 285 patients, who were recruited within the original timeline. Choice Pharma had experience with local hospital practices and PIs and proposed successful strategies for improved recruitment. Choice Pharma recognized that the Taiwanese manufacturer of the drug was not PICS certified or audited, and the Malaysia Ministry of Health did not approve the import of the product. Therefore, patients could not be recruited in Malaysia. clinipace.com 6

8 Multinational pharmaceutical companies typically conduct Phase II or III studies in Taiwan for products that will be made available in Taiwan. The clinical trial application can be submitted in Chinese or English; however, the informed consent form and any questionnaires must be in Chinese. Parallel review of the ethics application and clinical trial application is possible, but must be clearly stated in the clinical trial application. Also of note, upon trial completion, investigational products cannot be destroyed or exported immediately; however, a local depot can be used instead. 11 In Vietnam, all new products that have been available in other countries for less than 5 years must undergo a Vietnam-based clinical trial. 12 For all countries, it would be beneficial to have local legal representation assist with regulatory requirements, particularly when the process is not well defined. This will also assist with country-specific contracting and payment processes. Timelines In the majority of Asian countries, approval timelines are no different from those in the US or Europe (Table 3). The longest review times are experienced in China and can take up to 7-12 months 8, or longer if the trial is evaluating a biological product. In multinational trials, this can result in a 2-6 year lag between the introduction of the product in US/Europe and China. 8 An amendment requires a new application, and the entire review process must begin again. 8 What About Japan? Japan will be discussed separately here owing to its unique characteristics in relation to clinical trials. The regulatory bodies in Japan are the Ministry of Health, Labor and Welfare (MHLW), which is ultimately responsible for drug approval, and the Pharmaceuticals and Medical Devices Agency (PMDA), which reviews the drug application submission and safety report. The clinical trial application must be in Japanese. Per site accrual rate is typically very low, and Japan is considered one of the most expensive places to conduct a clinical trial. Investigator and site fees can be high. In addition, consultations with the PMDA incur a fee, while other countries do not charge consultation fees. Relationships with investigator sites are especially important in Japan; failing to establish trust-based relationships before initiating a trial will more than likely result in an unsuccessful trial. NDAs require data from Japanese subjects who were studied in Japan, including results from a study to determine the recommended dose in Japanese patients. 13 Japanese Phase I data must be available. Phase II can be a global trial. Phase III can also be conducted as a global trial, unless ethnic factors are determined to influence the efficacy; then, Phase III should be conducted as a local clinical trial. Depending on the study/ indication, 10-20% of the patients in the Phase III evaluation must be Japanese. In contrast, quick start-up times are possible in most other Asian countries (Table 3). Ongoing initiatives between Japan, Korea, and China are addressing ways for the countries to accept data from each other, enabling faster reviews. 4 Prior FDA or European Medicines Agency (EMA) approval allows for a fast-track review of the study protocol by the regulatory bodies in China, Taiwan, Korea, Hong Kong, and possibly others. In Taiwan, a fast-track review is also allowed with prior approval of a multinational clinical trials protocol from any of the following countries: United Kingdom, France, Japan, Switzerland, Canada, Australia, Belgium, Sweden, or Germany. In China, a fast-track application based on prior FDA or EMA approval can reduce the time from 13 months to 8 10 months. clinipace.com 7

9 Table 3. Approval Timelines by Country EC, ethics committee; CTA, clinical trial application; IND, investigational new drug; SIV, site initiation visit; NDA, new drug approval; BLA, biologic license application; NCE, new chemical entity; CFDA, Chinese Food and Drug Administration *Taiwan: Expedited review (2-3 weeks) can be conducted for protocols already approved in select countries **China: CTA approval in China is 9 ± 2 months for NCE (chemical) and 18 ± 2 months for biological IND/MRCT ***Korea: including time to reply to additional supplements from MFDS, CTA approval is 30 working days Standard of care Despite similarities in the standard of care for a number of larger Asian cities, there is still considerable heterogeneity between countries, healthcare systems, and research areas. For example, within China, the level of healthcare can vary between urban and rural areas and even between doctors. Moreover, clinical treatment guidelines may differ between and within countries (e.g., by site), although these differences may be somewhat reduced with the increased adoption of internationally recognized and accepted treatment guidelines. Traditional and herbal medicines may be widely prescribed or used clinically in addition to, or in preference to, pharmaceutical options. Furthermore, a comparator in the US and/or Europe may not be available in some Asian countries and must be replaced with a locally available drug. Because comparisons cannot be conducted between two investigational drugs or with a non-licensed drug, the intended comparator cannot be studied at the same time. clinipace.com 8

10 Data quality Of primary importance for data quality and consistency in all countries is the appropriate choice of site and PI. This is particularly true in countries, such as Vietnam, that have less experience and oversight in conducting clinical trials. Overall sponsor-paid clinical trial costs in Asian countries (as elsewhere) are affected by the extent to which health insurance is available. In countries without good coverage (generally in Southern Asia), the trialrelated costs for healthcare delivery may limit the available budget for quality monitoring. In countries with good insurance plans (generally in North Asia), healthcare delivery costs may be covered by insurance, freeing more budget money for monitoring and greater assurance of quality data. Overall sponsor-paid clinical trial costs in Asian countries (as elsewhere) are affected by the extent to which health insurance is available. In China, the CFDA-GCP is almost identical to that of the WHO-GCP, and investigators have had considerable experience in global studies guided by the WHO-GCP, particularly after The majority of these studies were audited by US/European auditors, and no significant deviation was found with trials conducted in China. The US FDA has also established an office in China for trial oversight, assisting with quality assurance for multinational trials conducted in both the US and China. However, despite these recent improvements, multinational sponsors should still spend time to choose study sites carefully, particularly given the potential lack of standardization in levels of care between locations (e.g., urban vs rural). It is important to ensure that investigators and research staff fully understand and comply with not only the CFDA-GCP but also the WHO-GCP/ICH-GCP. Frequent training and site monitoring may be beneficial to ensure consistent quality. The Malaysian Guidelines for GCP are also based on the ICH-GCP and are required for all investigators. However, strict enforcement is lacking, as is a specific system of quality control. In Singapore, the Singapore Guideline for GCP (SG-GCP) is based on the ICH-GCP, and the minimum training for PIs conducting clinical trials includes completing the SG-GCP program workshop. Ethics approval is not provided without proof the PI completed the course, and all investigators are required to complete the Collaborative Institutional Training Initiative (CITI) certification for clinical trials in human subjects. Although the South Korean GCP is the basis of the clinical trials process, the research staff must fully understand and comply with the ICH-GCP as well. Clinical trials can only be conducted at one of the 163 MFDS-accredited clinical institutes (as of March 10, 2014). To be accredited, the institution must have a pool of personnel to support the clinical study, an ethics committee structure and activities, a GCP education program, and infrastructure to manage the study. clinipace.com 9

11 As with most of the other countries, the Taiwan GCP is based on the ICH-GDP. The clinical trial sites have passed inspection by the US FDA, EMA, and Pharmaceuticals and Medical Devices Agency (PMDA). In Vietnam, there is a GCP training program for investigators offered by the Ministry of Science and Technology. In an effort to improve the research environment, a working group was formed in November 2013 to address a variety of topics over the next two years, including improved trial management processes, streamlined processes to improve trial efficiency and quality, and training for investigators and ethics committees. monitoring is implemented. In addition, there may be a significant difference in supportive care, which can affect outcomes. Competition for patients and limited access to treatment naïve patients are issues in countries with smaller populations and excellent research environments (e.g., Singapore). In contrast, fewer competing trials in countries with less clinical trial experience (e.g., Vietnam) increase the availability of patients. Figure 5. Variations That Cause Differences in Dosing It is possible that different dosing will be required for specific or general Asian populations depending on: Confidence in the data quality of studies in these countries is supported by audits conducted by regulatory agencies. Choice Pharma has records of a number of audits that have been conducted by the CFDA, TFDA, FDA, and KFDA for clinical studies of various indications between 2009 and These studies, sponsored by a variety of companies and conducted in different countries, all received satisfactory results, with no critical findings. COUNTRY REGULATIONS SPECIFIC ETHNIC DIFFERENCES FORMULATION THE DRUG ROUTE OF ADMINISTRATION Recruitment Longer recruitment periods are likely when patients already have access to robust and comprehensive health care and insurance (e.g, in Singapore, South Korea), compared to those in countries with limited health coverage (e.g., Vietnam). In the latter countries, trial participation can mean access to health care, and local experience indicates that some patients are willing to travel considerable distances. Late phase trials, in particular, may benefit from this willingness to participate. However, the trade-off may be inconsistent data quality, unless adequate and rigorous Pharmacokinetics/dosing It is possible that different dosing will be required for specific or general Asian populations depending on the drug, formulation, route of administration, specific ethnic differences, and country regulations. For example, Taiwan has specific requirements for evaluation of ethnic sensitivity for the 12 intrinsic and extrinsic factors for a new chemical entity (NCE), according to ICH E6, that must be submitted with the Bridging Package Evaluation. clinipace.com 10

12 The protocol should reflect any dosing differences, and specific pharmacokinetics (PK) studies may be required. The requirements for PK studies may differ from a full clinical trial, and it is best to consult the head authority of the country before writing the protocol. Figure 6. Possible Paths for an NDA in Singapore 19 Marketing applications» As with the initial trial application, considerable heterogeneity exists between countries for the marketing application process. Taking advantage of local expertise for marketing planning during protocol development can reduce later setbacks resulting from inadequate data or inappropriate timing. A full dossier An abridged dossier NDA In China, an NDA is filed for a new drug, while an IDL is filed for an existing drug (Table 4). If filing an NDA, the drug must not have been approved in any other country at the time of application, 8 and safety and efficacy data from China are required. Only drug companies or CROs registered in the People s Republic of China are allowed to apply. Upon completion of the clinical trial, the product must undergo a quality test while applying for the NDA with enough samples for three complete tests, including samples of the investigational drug, drug substance for biological products, and reference standards. 8 There are specific quality requirements that must be followed, and the process can take at least three months. In Hong Kong, a certified copy of the GMP certificate of the manufacturer is required. For products containing a new chemical or biological entity, official evidence of registration approval of the product in two or more of the following countries must be provided: Australia, Austria, Belgium, Bulgaria, Canada, Cyprus, Czech Republic, Denmark, Estonia, Finland, A verification dossier France, Germany, Greece, Holland, Hungary, Ireland, Italy, Japan, Latvia, Lithuania, Luxembourg, Malta, Poland, Portugal, Romania, Slovak Republic, Slovenia, Spain, Sweden, Switzerland, UK, or USA. 17 At least three months stability test data are required. The application for an innovator product is required for a new drug product or a biologic in Malaysia. The application for a generic product is completed for a product that is essentially similar to a currently registered product in Malaysia. 18 The applicant must be registered locally, and the manufacturer must follow GMP guidelines from their local authority. Separate applications are required for different strengths/ dosages. To complete the application process, samples must be submitted to the Centre for Quality Control within 14 days of application payment. clinipace.com 11

13 Table 4. Marketing Application Process By Country In Singapore, the NDA has three possible paths for evaluation: a full dossier (product not approved by any drug regulatory agency at time of submission), abridged dossier (product evaluated and approved by at least one drug regulatory agency), or a verification dossier (product evaluated and approved by at least two of HSA s reference drug regulatory agencies: EMA, US FDA, Health Canada, Australia Federal Goods Administration [TGA], or UK Medicines and Healthcare Products Regulatory Agency [MHRA] and meets other eligibility criteria). 19 The application is submitted in two parts: PRISM (online submission) and registration dossier, which must be submitted within two working days of the PRISM submission. A local agency must complete the application, and proof of GMP compliance is required. In addition, at least six months accelerated stability data and 12 months real time stability data are required. Separate applications are required for different strengths/dosages. *Includes clinical and scientific documentation of safety Certain categories of OTC products and traditional medicines In South Korea, an approval application is required for products requiring a safety and efficacy review, while a notification application can be completed for a product that is already included in the Korean, US, Japanese, British, German, and French Pharmacopeia and has already obtained safety and efficacy approval. clinipace.com 12

14 An NDA in Taiwan requires a complete data package to ensure safety and efficacy. While a rule states that two reference countries must approve a new drug first, this rule may be waived if a multinational clinical trial, regional, or local clinical study is conducted in Taiwan. For NCEs that are available elsewhere, a Bridging Study Evaluation (BSE) can be completed. The TFDA states the purpose of the BSE is to provide clinical data, such as PK/PD, efficacy, safety, dosage, and dose regimen, associated with the population in Taiwan, so that foreign clinical data can be extrapolated to the corresponding population of Taiwan, hence minimizing the duplication of clinical trials. If evaluation of the product has been completed in a population that reflects Taiwan, even in a foreign country, and the product is not sensitive to ethnic variations, no further studies may be required. If sensitivity to ethnicity is detected, then a bridging study is required. However, local experience suggests that local clinical data is a key success factor for this application, and the protocol may need to include plans for locally collected data. In Vietnam, a domestic drug manufacturer must meet the GMP standards of the Health Ministry while foreign drug manufacturers must satisfy GMP standards that are at least equivalent to the WHO-GMP. 20 How can Clinipace Worldwide help with entry to Asia?» Clinipace Worldwide, as a global CRO, has recognized abilities in clinical trial design and experience with over 1,800 global clinical research studies, strategic product development projects, and regulatory engagements. With the recent acquisition of Choice Pharma, a Pan-Asian CRO, Clinipace acquired offices and local knowledge in Taiwan, China, Hong Kong, South Korea, Vietnam, Singapore, and Malaysia that are available to assist companies new to Asia gain entry to those countries. Figure 7. The Benefits of Working With Local Experts These local experts are positioned and available to assist with regulatory requirements, local legal representation for contracts and payment processes, comparator availability, local clinical/treatment guidelines, and availability and suitability of both PIs and sites. Proactive risk mitigation during protocol development saves time and headaches later, while experience with rescue trials can help sponsors save a trial that is not progressing due to unforeseen challenges with local regulatory requirements or recruitment. Trust-based relationships with investigators and sites that have been developed over time by local CROs are of great significance. In some Asian countries, the existence of these relationships prior to protocol development, when investigators and sites are being chosen, can deter-mine the success of the trial. Local CROs can help select a site and PI that will accommodate even a difficult study and will even provide advice for successful study completion. clinipace.com 13

15 We were conducting a clinical trial in China with a big sponsor, and we expected 5-6 PIs to participate in the trial. After completion of the study, the sponsor sent a global auditor to audit the study, and he reported a major finding. He said the recruitment speed was too fast; the investigators must have done something wrong. He hadn t seen recruitment that fast in his 30 years of experience. When we looked into the recruitment, it ended up that over 100 PIs were mobilized in advance of the study to identify and recruit patients. This was despite only paying for 5-6 PIs. We believe this was a reflection of the relationship we built with the site and investigators, and they wanted to help us have a successful trial. Clinipace Worldwide conducts analysis of the sites/pis during protocol development to determine which are the most appropriate to include in the trial. Selection is based on experience and reliability as well as any potentially competing ongoing clinical trials. Such information is available through their local investigator networks. The larger hospitals in a number of these countries are in high demand for clinical trials, and the competition for patients can be high. Other PIs or smaller facilities may be just as or more appropriate for the needs of a clinical trial, and Clinipace Worldwide is positioned to provide advice about other options. The e-clinical, cloud-based software platform, TEMPO, available through Clinipace Worldwide, has the ability to store protocols specific to a country, provides real-time visibility to operational progress, and allows access to start-up data. Transparent access to data, regardless of where it s collected, enables decision-making relating to that data on a real-time basis, thereby saving time and preventing delays. This applies to the recruitment progress, monitoring of adverse events/safety issues, and data trends for the overall trial as well as specific to each site. Upon trial completion, the platform has the ability to easily meet reporting requirements for all countries involved in the trial. The ability to monitor your trial through TEMPO allows decisions to be made regarding the data. For example, we were able to stop recruitment in Korea in our multinational trial because we could monitor the enrollment easily across sites. Figure 8. Cancer: The Leading Cause of Premature Death in Asia Cancer is responsible for: 21% 14% 12% of all the deaths in South Korea of all the deaths in Vietnam of all the deaths in Malaysia Oncology trials Clinical trials in oncology present particular opportunities in Asia. There are large populations of drug- and clinical trial-naïve oncology patients. In 2002, approximately one-third of new cancer cases worldwide were diagnosed in select countries in South, East, and Southeast Asia. 21 In China specifically, cancer is the leading cause of premature death, killing more than 1.9 million people a year. 22 According to WHO mortality data (2010), cancer represented 21% of all deaths in South Korea, 15% of all deaths in Malaysia, and 14% of all deaths in Vietnam. clinipace.com 14

16 There are some cancers that are more prevalent or only present in Asian populations, including lung, hepatocellular carcinoma (HCC), and gastric cancers. There are high rates of smoking, and lung cancer is associated with the highest cancer-related death rate for males in these countries. Of the global HCC diagnoses, the men in these countries account for 3/4 of all diagnoses in men, and the women account for 2/3 of all diagnoses in women. 21 Hepatitis infection, a risk factor for HCC, remains common with inadequate treatment in a number of Asian countries. This region also accounts for more than half of the world s new cases of stomach cancer 21 while 75% of esophageal cancers are diagnosed in Asia, making it the 6th most common cancer in the region. 23 Figure 9. Oncology Clinical Trials Accounting For >10% Each of All Oncology Trials in Each Country These three cancers, in addition to breast cancer, are also the most widely studied (clinicaltrials.gov, Figure 2). Each represented >10% of the total oncology trials conducted in each country, and breast cancer was the only other cancer that also represented that majority. Despite the common occurrence, the standard of care and cancer treatment guidelines can differ by country, site, and doctor. This may represent a particularly important research area where time should be taken to identify the most appropriate site/pi during protocol development to ensure consistent standard of care and data quality. Conclusion» The large and growing populations in Asian countries provide a large and not fully accessed pool of patients for clinical trials. To achieve market growth and appeal to international companies, international guidelines for clinical trials are increasingly being adopted in a number of Asian countries, and the processes are becoming more standardized. In the meantime, international CROs with a strong presence in Asia, such as Clinipace Worldwide, can help navigate the nuances of local regulatory and contracting processes and relationships across countries in multinational trials. Centralized, transparent, and real-time access to data enables monitoring and ensures data quality across all facets of a clinical trial. Oncology trials represent a particular opportunity to take advantage of large patient populations in Asian countries, particularly for exclusively prevalent cancer types. clinipace.com 15

17 Authors» Barb Geiger, BSN, RN Executive Vice President, Oncology and Latin America, Clinipace Worldwide Barb Geiger has been in the clinical research and development industry for over 25 years. She is an executive clinical operations professional with extensive experience in oncology and CNS drug development. References» 1. IMS Institute for Healthcare Informatics. The global use of medicines: outlook through November, Accessed at IMS%20Health%20Institute/Reports/Global_Use_of_Meds_Outlook_2017/IIHI_Global_Use_of_ Meds_Report_2013.pdf 2. Toller C. Clinical studies in Asia-Pacific: a regional perspective. Journal for Clinical Studies 5: Bhuller R, Koul N. The rising dominance of the Asian CRO market. Frost and Sullivan Accessed at 4. Korieth K, Anderson A. New growth and decline in Asia clinical trials. The CenterWatch Monthly, 2013;20: Price Waterhouse Coopers. The changing dynamics of pharma outsourcing in Asia: are you readjusting your sights? Accessed at 6. Patent Law of the People s Republic of China January 25, Accessed at chinaipr.gov.cn/lawsarticle/laws/lawsar/patent/201101/ _1.html 7. Ministry of Economic Affairs, Taiwan. Patent Act Accessed at sp?xitem=479550&ctnode=6817&mp=2 8. Pharmaceutical Product Development, LLC. Optimizing drug registration in China: Category 1 route: whitepaper. April Accessed at CategoryI-Registration-PPD_White%20Paper.pdf 9. ASEAN sectoral mutual recognition arrangement for good manufacturing practice (GMP) inspection of manufacturers of medicinal products. April, Accessed at org/archive/documents/agreement%20on%20mra%20for%20gmp%20pharmaceutical.pdf 10. Health Sciences Authority, Singapore. Guideline on Application for Clinical Trial Certificate. January 8, Accessed at regulation/clinical_trials/guidelines/ctc_application.html 11. Schulz G. Clinical trial in Asia: opportunities and challenges. 2012Accessed at zuelligpharma.com/news/clinical-trial-asia-opportunities-and-challenges bn php lut/view_detail.aspx?itemid=27484 (translated by Google translate) Chris Wang Managing Director, Asian Operations, Clinipace Worldwide Chris Wang serves as Managing Director, Asian Operations, following the company s recent acquisition of Choice Pharma. Chris is responsible for managing the day-to-day operating responsibilities for Clinipace s Asian entities. Chris previously served as Associate Director, North East Asia at Choice Pharma. She is based out of Clinipace s Taipei, Taiwan office. 13. Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare. Basic Principles on Global Clinical Trials (Reference Cases), September 5, Accessed at GCT-jirei_en.pdf 14. Department of Health, Taiwan. Application Guideline for Clinical Trials. gov.tw/chi/flaw/flawdat01.asp?lsid=fl China Food and Drug Administration. Application and approval procedure for clinical trials. Accessed at Health Sciences Authority, Singapore. Target Processing Timelines. January 8, Accessed at timelines.html 17. Drug Office, Department of Health, Government of Hong Kong Special Administrative Region. Guidance Notes on Registration of Pharmaceutical Products. Accessed at gov.hk/eps/do/en/doc/guidelines_forms/guid.pdf 18. National Pharmaceutical Control Bureau, Ministry of Health Malaysia. Drug Registration Guidance Document. October Accessed at updated_oct_2012_edited_ pdf 19. Health Sciences Authority. Guidance on Medicinal Product Registration in Singapore, effective April 1, Updated January, Accessed at medialib/hsa_library/health_products_regulation/western_medicines/files_guidelines.par File.dat/Updates%20for%20Guidance%20on%20Medicinal%20Product%20Registration%20 in%20singapore%202014%20(annotated).pdf 20. The Ministry of Health. Circular on Registration of Drugs. November 24, Accessed at November html 21. Pfizer. The burden of cancer in Asia Accessed at cancer_in_asia.pdf 22. Cheng MH. Cancer research funding in Asia. Molecular Oncology 2007;1: World Cancer Research Fund. Data for cancer frequency by country. Accessed at wcrf.org/cancer_statistics/cancer_frequency.php clinipace.com 16