Case Studies and Practice
Assessing Clinical Research Capacity in Vietnam: A Framework for Strengthening Capability for Clinical Trials in Developing Countries Jonathan Kagan, PhDa Dao Duc Giang, MPHb Michael F. Iademarco, MD, MPHc,d Van TT Phung, MSd Chuen-Yen Lau, MD, MPHe Nguyen Ngo Quang, PhDf
ABSTRACT Although improving health systems promises important benefits, most developing nations lack the resources to support nationally driven clinical research. Strengthened clinical research capacity can advance national health goals by supporting greater autonomy in aligning research with national priorities. From March through June 2010, we assessed six elements of clinical research capacity in Vietnam: research agenda; clinical investigators and biostatisticians; donors and sponsors; community involvement; scientific, ethical, safety, and quality oversight; and clinical research institutions. Assessments were drawn from interviews with investigators, Ministry of Health staff members, nongovernment organizations, and U.S. Mission staff members, and document review. Observations and recommendations were shared with collaborators. Reassessment in 2015 found growth in the number of clinical trials, improved regulation in human subjects protection and community engagement, and modest advances in research agenda setting. Training and investment in institutions remain challenging. A framework for assessing clinical research capacity can affirm strengths and weaknesses and guide the coordination of capacity-building efforts.
National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Clinical Research, Bethesda, MD
a
FH1 360, Clinical Research and Laboratory Science, Hanoi, Vietnam
b
Centers for Disease Control and Prevention, Office of Public Health Scientific Services, Center for Surveillance, Epidemiology and Laboratory Services, Atlanta, GA
c
Health Affairs Attaché Office, U.S. Mission, Hanoi, Vietnam
d
National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Clinical Research, Collaborative Clinical Research Branch, Bethesda, MD
e
Vietnam Ministry of Health, Administration of Science Technology and Training, Hanoi, Vietnam
f
Address correspondence to: Jonathan Kagan, PhD, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Clinical Research, 5601 Fishers Ln., Room 4B40, Rockville, MD 20892-9820; tel. 240-669-5221; fax 301-451-5526; e-mail .
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Investing in health is a priority articulated in the United Nations Millennium Development Goals and is broadly supported by the world’s political leaders for saving lives, stimulating economic development, reducing poverty, and promoting global health security.1 Although the lowest-income nations generally have the poorest health, shorter life expectancies and increased infant mortality also exist among poor people in higher-income countries.2 Even as chronic and degenerative diseases become more prevalent in low-income nations, communicable diseases remain important health risks. Vietnam is an example of a nation that recently passed the middle-income threshold. During the past 30 years, Vietnam made remarkable progress toward reducing poverty and improving basic health indicators. Using World Health Organization (WHO)–recommended public health interventions3 and relatively minimal investment, Vietnam dramatically reduced the incidence of childhood diseases and malaria, stabilized the prevalence of human immunodeficiency virus (HIV) infection, and prevented a generalized HIV epidemic.4–6 Yet Vietnam today has a high burden of historically prevalent infectious diseases and struggles with emerging chronic diseases, health systems strains, and the health challenges of modernization, such as food safety. Although continued improvement of health systems overall promises important benefits, efforts targeted toward strengthening clinical (patient-oriented) research capability could advance national health goals by helping to assure that national health priorities, regulations, ethical principles, cultural considerations, and other factors are given appropriate weight in selecting, designing, and conducting research studies in Vietnam. Vietnam’s capacity for clinical research is low but grew rapidly from 2010 to 2015. In 2010, 25 clinical trials were being conducted in Vietnam, whereas in 2015, 72 active trials were being conducted, half of which were sponsored by industry and the rest supported by nongovernment organizations (NGOs). Most trials (about 70%) were drug studies, another 20% evaluated vaccines, and 10% examined traditional medicines. Among drug trials, infectious disease studies ranked first, followed by cancer and cardiology trials.7 PURPOSE In 2010, based on the strength of 25 years of cooperation between the United States and Vietnamese governments on health issues,8 we broadly assessed clinical research capacity in Vietnam to identify strengths and weaknesses and help prioritize, guide, and coordinate
clinical research capacity-building efforts. In 2015, we reassessed clinical research capacity to determine progress. This report (1) summarizes our initial (2010) and most recent (2015) findings and recommendations and (2) describes our approach, which other developing nations might find useful. METHODS Our initial assessment was conducted from March through June 2010 under the auspices of the U.S. Embassy in Hanoi, and a follow-up assessment took place in 2015. The goal was to help inform and guide the U.S. Mission Vietnam Health Team in working with the Vietnamese government and other partners (e.g., academic, government, nongovernment, pharmaceutical/biotechnology industry) to advance their shared interests in clinical research to improve public health. The assessment was guided by an evaluation framework for the National Institute of Allergy and Infectious Diseases’ HIV/AIDS Clinical Trials Networks9 and integrated diverse viewpoints of researchers, community members, managers, and regulators on what constitutes success in clinical research. The assessment included six capacity areas: (1) research agenda; (2) clinical investigators and biostatisticians; (3) donors and sponsors; (4) community involvement; (5) scientific, ethical, safety, and quality oversight; and (6) clinical research institutions. Sources of information included (1) semiformal and informal guided interviews conducted by the first author in his capacity as a U.S. Embassy Fellow, assisted by a bilingual public health specialist with the Health Affairs Attaché Office of the U.S. Mission, Hanoi; (2) documents (e.g., regulatory guidelines, policies, procedures) and a literature review; (3) ClinicalTrials. gov; and (4) U.S. National Institutes of Health (NIH) Fogarty International Center databases. Interviews involved various numbers of interviewees—from one-on-one interviews to focus groups with as many as 10 people—depending on interest and availability. A precise definition of progress was not formulated for any of the six areas of clinical research capacity assessed. Rather, progress was gauged according to evidence of improved alignment with international standards or models (where available). For example, we assessed progress in regulatory and ethical oversight by using the guidelines of the International Conference on Harmonisation of Good Clinical Practice (ICH-GCP) as a standard for assurance that the rights, safety, and well-being of clinical trial participants are protected and that clinical trial data are credible.10 Data on barriers to progress, though of interest and sometimes articulated, were not systematically collected
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because of insufficient time and resources. Sixty-eight individuals who were variously affiliated with government agencies (Vietnam, United States), research institutes (Vietnam, France, Laos, United Kingdom, Thailand), academia (Vietnam, United States), hospitals (Vietnam), NGOs (Vietnam, United States), and the pharmaceutical industry (Vietnam) contributed information to this project. OUTCOMES Clinical research agenda. A research agenda linked to national health priorities is important for strategic planning and coordination.11–14 A national health research survey in 200715 reported that research had a minor role in Vietnam’s health system. The Five-Year Health Sector Development Plan for 2011–2015 gave priority to promoting research and supported strengthening research capacity, especially for the application of medicines (Unpublished data, Ministry of Health, 4th draft, Five-Year Health Sector Development Plan, 2011–2015, October 2010). Beginning in 2011, Vietnam’s Ministry of Health (MOH) has issued an annual priority list and, following on recommendations from the combined assessment, beginning in 2015, required that clinical trials in Vietnam be registered in ClinicalTrials.gov. The influence of frank, multilateral health diplomacy was an important driver of transparency and prioritization. Continued evolution of a research agenda, including input from national, regional, and international health experts, patient communities, and health-care providers, is vital to assure that research aligns with health priorities. Clinical investigators and biostatisticians. Physicians trained in human subjects research, in partnership with biostatisticians who are experts in study design, are essential for nationally driven clinical research. Without in-country expertise, the priorities of external sponsors might dominate.16–18 Whereas the number of trials with a Vietnamese researcher as the principal investigator increased from five in 2010 to 11 in 2015, the percentage of Vietnamese principal investigators was essentially unchanged because Vietnamese researchers still function principally as site investigators. Vietnamese medical and public health students have little exposure to research or opportunities to learn research methods. Although the Hanoi School of Public Health (HSPH) and the University of Medicine and Pharmacy in Ho Chi Minh City (HCMC), for example, have biostatistics faculties, graduates are not taking leadership roles in clinical research. When surveyed, nearly half of HSPH students graduating with a master’s degree in public health indicated that training in data analysis
was insufficient.19 To strengthen in-country clinical research expertise, Vietnam could (1) better utilize international clinical research training resources20,21 to learn advanced research principles and practices, (2) strengthen training in biostatistics, (3) set aside funding for young physician researchers and provide training and support for grant writing, (4) set and enforce standards for research productivity in Vietnamese medical schools and research institutions, and (5) create opportunities for young medical researchers to compete for faculty positions. Donors and sponsors. Per-participant costs for clinical research are often in the thousands of U.S. dollars and continue to rise.22 Not unlike many developing nations, Vietnam does not have sufficient government (public) resources to support a robust clinical research agenda to address its priority public health issues. In 2010, three ministries of the Vietnam government sponsored competitive grant research programs, but none offered awards greater than approximately U.S. $50,000. According to a 2007 analysis by the Council on Health Research Development, nearly 70% of Vietnam’s health research budget comes from foreign organizations.15 As such, the nation is, and will remain for the foreseeable future, dependent on donations and sponsor-based funding for clinical research. Therefore, it is vital that Vietnam form lasting collaborations with donors that respect its sovereignty and health priorities, especially given that public health concepts are not yet fully embodied in Vietnamese medical culture. Vietnamese health leaders are encouraged to engage partners for durable clinical research support, particularly in underfunded areas such as cardiovascular disease and cancer. Flexible funding mechanisms, including greater ease in forming public–private partnerships, could catalyze these collaborations. Equally important is reducing barriers to collaboration; barriers could be reduced by, for example, streamlining the processes of research review, determination of an NGO’s suitability to sponsor clinical research, and drug importation. Community involvement. Clinical research in Vietnam can be strengthened by establishing a trusting dialogue between scientists and the public. Globally, community involvement in planning clinical research is resulting in improved study enrollment and increased acceptance of study results. Failure to address community concerns can delay or halt clinical research and have longlasting negative consequences, as reported recently in other nations, including neighboring Cambodia.23 Despite highly effective social organizations (e.g., the Women’s Union, the Farmer’s Union), consumers of health research have largely been excluded from
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the priority-setting process.21 Concepts of community engagement in research and mechanisms for obtaining community input are not yet well established in Vietnam, but there is evidence of progress, supported by strengthened partnerships fostered through direct health diplomacy. Following on recommendations from the initial assessment, regulations in 2012 called for the inclusion of non-scientists on the MOH Board of Ethical Assessment (BEA) and local ethics committees.24 Another new regulation,25 introduced in 2013, requires support by a local People’s Committee (equivalent to a jurisdiction’s governing body) for MOH approval of a clinical trial. Vietnam health leadership was encouraged to expand engagement of communities in research. NGOs may be well suited to helping build awareness of clinical research in communities and capacity for community–researcher engagement. Guiding principles and best practices are available to help establish communities as partners in biomedical research.26,27 Scientific, ethical, safety, and quality oversight. At least as early as 2002, the MOH developed requirements for ethical review of all biomedical research to help assure rigor in science, safety, and ethics, and established its BEA. In 2006–2007, with assistance from international regulatory experts, the MOH began strengthening systems to promulgate and support good clinical practices and more closely follow ICH-GCP guidelines. Since 2008, the MOH has required that all clinical trials in Vietnam be conducted in accordance with ICH-GCP. During our initial assessment in 2010, the BEA was chaired by the Vice Minister of Health, and seven of its nine members were MOH employees, raising concerns about its independence. Since 2010, following recommendations from this assessment, membership was increased to 11 members, a non-MOH employee was appointed chairperson of the BEA, MOH membership was proportionally decreased, all human subjects research came under BEA review, and board responsibilities were better aligned with ICH-GCP standards. The BEA has authority to suspend research to limit risks to participants’ safety. Current policy is to receive reports of all serious adverse events. Limiting reporting to only unanticipated problems could ease the burden on the BEA and improve its effectiveness in safety oversight. Similarly, for quality assurance, the BEA has responsibility for monitoring, auditing, and inspecting trial sites. That these responsibilities are assigned to the BEA (instead of a quality assurance unit of the MOH) can detract from the BEA’s primary responsibilities and pose potential conflicts of interest for its members. Guidance issued by the MOH in 2014 on the roles and responsibilities of contract
research and site management organizations in quality assurance will likely help with safety and oversight.28 Whereas in 2010 the relationship between the BEA and local institutional ethics committees was not specified, in 2013, the MOH issued its first regulation on local ethics committees. As the capacity for human subjects, ethics, and research review grows in principal locales conducting clinical research, decentralizing the ethical review of local institutional studies could strengthen capacity across Vietnam and reduce the burden on the BEA, allowing it to focus on multicenter national and international studies. Training and support for local ethics committees is a responsibility shared by the MOH and sponsors. Improvements in Vietnam’s clinical trial regulation and oversight from 2010 to 2015 are summarized (Table 1). Clinical research institutions. Clinical research requires institutions with facilities (e.g., hospitals, clinics, laboratories), infrastructure (e.g., records management, financial management), and trained research professionals (e.g., physicians, biostatisticians, research nurses, laboratory technicians, data managers) capable of executing their roles in compliance with applicable regulations. Few Vietnamese institutions have the requisite human or financial resources. Of approximately 1,180 hospitals nationwide, about 60 are authorized by the MOH to do clinical research. Of these, 20 hospitals have the capacity to conduct clinical research, and 12 hospitals are involved in clinical trials. Hospitals with long-term funding, including Hanoi Medical University, the University of Medicine and Pharmacy in HCMC, the Hospital for Tropical Diseases in HCMC, and the National Institute of Infectious & Tropical Diseases in Hanoi, are among the most experienced, best staffed, and best equipped. Long-term funders include the U.S. Department of Health and Human Services, including the Centers for Disease Control and Prevention and the NIH, Wellcome Trust, Institut Pasteur, and the Japan International Cooperation Agency. Greater long-term investment in the development of clinical research– capable institutions is vital to build national capacity. The MOH’s concept to form a government- sponsored clinical research network in Vietnam is forward looking. However, challenges and barriers to achieving this forward-looking concept include (1) challenges in the formation of a scientific agenda and priorities on which researchers and public health authorities can form consensus; (2) the need for a substantial, sustainable funding commitment to support the human capital required and to build and maintain the physical infrastructure (facilities) required; (3) a paucity of researchers with the requisite management experience to oversee a complex, inter-institutional/
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Table 1. Strengthening Vietnam’s clinical research, regulatory, and ethical oversight, 2010–2014 Clinical research capacity domain • Regulatory authority
New regulation or guidance: 2010 through 2014 • Decree #63120121ND-CP: Defining the Functions, Tasks, Powers and Organizational Structure of the Ministry of Health. August 2012 (http://faolex.fao .org/docs/pdf/vie119157.pdf) • Decision #4059/QD-BYT: Stipulating Functions, Duties, Powers and Organizational Structure of the Department of Science, Technology and Education Under the Ministry of Health. October 2012 (https://clinregs.niaid.nih.gov/documents/vietnam /DecisionNo4059-QD-BYT.pdf)
• Ethical review • Informed consent
• Decision #460/QD-BYT: Regulations on Organization and Operation of Ethical Evaluation Committee in Biomedical Research of Ministry of Health, Period 2012–2017. January 2013 (https://clinregs.niaid.nih.gov/documents/vietnam /DecisionNo460-QD-BYT.pdf)
Capability strengthened Vietnam’s Ministry of Health (MOH) as the authority responsible for clinical trial approvals, oversight, and inspections, including promulgating legal documents, policies, standards, requirements for data and safety monitoring boards, and the national-level ethics committee
National-level and institutional-level ethics committee role and responsibilities for balancing central and provincial authority in the review and approval of clinical trials
• Decision #111/QD-BYT: Promulgation of Regulation on Organization and Operation of Council of Ethics in Biomedical Research at Grass-Root Level. January 2013 (https://clinregs.niaid.nih.gov /documents/vietnam/DecisionNo111-QD-BYT.pdf) • Requirements of sponsors • Safety monitoring • Investigational products • Drug registration • Requirements of clinical trials to support organizations
• Circular 03/2012/TT-BYT: Guidelines for Clinical Trials on Drugs. February 2012 (https://clinregs .niaid.nih.gov/documents/vietnam/C-ClinDrugTrial .pdf) • Decision #44/2014/ TT-BYT: Drug Registration Rules. November 2014 (https://luatminhkhue .vn/en/circular/circular-no-44-2014-tt-byt-dated november-25--2014-of-the-ministry-of-health-on drug-registration.aspx) • Circular 08/2014TT-BYT: Regulated Research Support Activities Clinical Trials in Vietnam. February 2014 (https://clinregs.niaid.nih.gov /documents/vietnam/C-ClinTrialOps_English.pdf)
• Biological specimens
• Decision #43/2011/TT-BYT: Management of Infectious Specimens. December 2011 (https:// clinregs.niaid.nih.gov/documents/vietnam /C-MgmtInfectiousSpecs.pdf)
interagency effort; and (4) the need for greater numbers of well-trained clinical research support staff members to help conduct the research. For the best science and translational research, independent peer review is an essential factor in the selection of network institutions and investigators. Network institutions would also be well suited to create training programs to develop and maintain the skilled workforce needed to support clinical research.
Responsibility of sponsors and investigators for participant safety and safety reporting; defines products requiring clinical trials; specifies product quality standards and requirements for Good Manufacturing Practices certificates; describes requirements for drug import, and safety and efficacy requirements for registration; defines responsibilities of clinical research support organizations; and requires registration with the MOH
The MOH General Department of Preventive Medicine as authority responsible for infectious specimens; defines specimens and sets requirements for specimen import and export
CASE STUDY A case study from the South East Asia Infectious Disease Clinical Research Network (SEAICRN) provides a real-world example of the gains being made in clinical research thinking, strengthening of regulatory and ethical oversight, and durability of research infrastructure. The SEAICRN is a collaborative partnership of research institutions in Vietnam, Thailand, and Indonesia; the U.S. National Institute of Allergy and Infectious Diseases; the Oxford University Centre for Tropical Medicine; the Wellcome Trust; and WHO.29 The SEAICRN Sepsis Study (Trial Registration NCT02157259),30 which
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began in December 2013, was designed to determine the causes of community-acquired sepsis and severe sepsis in adults and children in Vietnam, Thailand, and Indonesia. Across the study lifecycle, including conceptualization, protocol development, study conduct, and analysis, challenges arose that highlighted the importance of several capacity areas described in this article (Table 2). The SEAICRN Sepsis Study (1) aligned with national health priorities for study selection and development; (2) provided support for and training of local investigators to enhance in-country clinical research capability; (3) coordinated sponsor support to secure stable funding, infrastructure, and capacity enhancement; and (4) aligned with three national regulatory frameworks to support the study in accordance with international safety and ethical standards.
Lessons learned The past 15–20 years has seen unprecedented growth in partnerships to strengthen national health systems for improved global health.31 The Organisation for Economic Co-operation and Development’s (OECD’s) best practice principles for global health partnerships articulate fundamental elements for success; these elements highlight the need to harmonize partner efforts and include performance assessment frameworks for national systems.32 Our effort addresses these OECD principles and is directed toward strengthening national capacity for clinical (patient-oriented) research, with the goal of promoting greater autonomy in aligning such research with national health priorities. By providing a guide for establishing a baseline for clinical research capacity, sharing our observations and findings with collaborators, and monitoring changes over time, our intent is to facilitate cooperation and coordination by health systems partners (government, nongovernment, academic, pharmaceutical/biotech
Table 2. The South East Asia Infectious Disease Clinical Research Network (SEAICRN) Sepsis Study:a clinical research capacity, challenges, and solutions, December 2013–present Clinical research capacity domain
Challenge
SEAICRN solution
Research agenda
Need to determine which clinical research concepts proposed from Vietnam, Thailand, and Indonesia would be developed by the network
Extensive discussion occurred between country leaders and sponsors to select topics most relevant to the region in alignment with national priorities. Embracing guidance of Ministry of Health representatives and local investigators, the SEAICRN Sepsis Study was conceptualized to align with regional health priorities. Broad cross-country support was obtained for determining the etiologies of sepsis to generate hypotheses for additional studies that can improve public health.
Investigators
Selection of study principal investigator to guide the research, local investigators to lead in-country study sites, and ways to build investigator capacity for future research
The study principal investigator is from Thailand; several Vietnamese investigators serve as associate investigators. To prepare Vietnamese researchers to serve as principal investigators for future studies, workshops on research methods, proposal writing, and manuscript writing were conducted for promising early career investigators. Protocol development support is provided to local investigators whose proposals are endorsed by the SEAIRCN. Training and supporting local principal investigators is enhancing in-country clinical research expertise and improving sustainability of the research program.
Donors and sponsors
Coordination of study funding across diverse partners in a manner that is commensurate with and makes the best use of their resources, and preserves equity among partners
Partner support for the study varied and included funding, scientific expertise, and in-kind resources for network activities. An in-country contract research organization was provided to support site infrastructure, laboratory capacity, and human resource management. Investigators are provided with information and training in developing proposals for research funding, building capacity to pursue more diverse funding opportunities that can lead to additional partnerships, and attracting additional sponsors.
Scientific, ethical, safety, and quality oversight
Compliance with international ethical and safety standards across multiple sites in Vietnam, Thailand, and Indonesia
To complement existing institutional capacity, an in-country contract research organization provided training for site staff, including ongoing guidance and support for submissions to each institution’s ethics committee. Coordination through a single organization ensured harmonization of the protocol across sites. This experience also highlighted the need for a centralized review process or ethics committee reliance agreements for future multisite studies.
a National Institutes of Health (US). An observational study of the causes, management, and outcomes of community-acquired sepsis and severe sepsis in Southeast Asia (SEA050). 2015 [cited 2016 Feb 12]. Available from: https://clinicaltrials.gov/ct2/show/NCT02157259?term=NCT021572 59&rank=1
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industry, philanthropic) to advance their shared interests in strengthening clinical research capacity. A unique aspect of our framework is its integration of diverse viewpoints of researchers, community members, managers, and regulators. From our case study in Vietnam, we learned the following: 1. Peer-to-peer relationships between research and regulatory agencies of partner nations and public–private partnerships are vital for building national capacity in developing countries. 2. A framework for assessing clinical research capacity can affirm strengths and weaknesses and guide the prioritization, coordination, and monitoring of capacity-building efforts. 3. Clinical research capacity building is essential to the development of a research agenda driven by national health priorities, assuring human subjects protection, and adherence to ethical standards. At the same time, room for improvement exists. Not all topics of potential relevance are included in this framework; expansion of the framework to include other capacities (e.g., pharmaceutical and diagnostic product manufacturing and importation, pharmacovigilance, laboratory quality assurance) could add value. Additionally, our own Vietnam assessments could have been enriched had we the resources needed to gather more in-depth input from larger communities. We anticipate that greater experience with the framework will lead to its continuous enhancement as well as the development of facilitating tools (e.g., data collection instruments, reference standards) to support its effective implementation and utilization. The assessment was conducted as a programmatic evaluation at the request of the U.S. Mission Vietnam and was not deemed to be human subjects research under regulations of the U.S. Department of Health and Human Services (HHS) or Vietnam. The authors acknowledge the following for their contributions to, and support for, this work: Peggy Coyle (FHI360), Stephen Mills (FHI360), Do Gia Canh (deceased) (National Institute of Hygiene and Epidemiology, Hanoi, Vietnam), Paul Brey (Institut Pasteur, Laos), Kripa Raghavan (U.S. National Institutes of Health [NIH]), Bruce Struminger (U.S. Indian Health Service/Navajo Service Area), Andrew Herrup (U.S. Embassy, Kuala Lumpur), Roger Detels (University of California, Los Angeles), Phuong L. Tran (U.S. Mission, Hanoi), Michelle McConnell (U.S. Centers for Disease Control and Prevention), Stuart Nightingale (NIH consultant/contractor), the South East Asia Infectious Disease Clinical Research Network, and Eileen Kane (U.S. Department of State). When this work was initiated in 2010, authors MFI and VTTP were with the Office of Global Health Affairs, HHS, in Hanoi. JK was a U.S. Embassy Science Fellow in Hanoi in March–June 2010. This work was supported by the HHS Office of Global Health
Affairs; the National Institute of Allergy and Infectious Diseases, NIH, HHS; and the Embassy Science Fellows Program, Office of Science and Technology Cooperation, Bureau of Oceans, Environment and Science, U.S. Department of State. This work is dedicated to the memory of R. Palmer Beasley—physician, public health educator, and infectious disease epidemiologist—who, in addition to saving millions of lives from hepatitis B and liver cancer, mentored a new generation of researchers in Vietnam.
REFERENCES 1. United Nations. Millennium development goals and beyond 2015 [cited 2015 Aug 4]. Available from: http://www.un.org /millenniumgoals 2. Murray CJ, Kulkarni SC, Michaud C, Tomijima N, Bulzacchelli MT, Iandiorio TJ, et al. Eight Americas: investigating mortality disparities across races, counties, and race-counties in the United States. PLoS Med 2006;3:e260. 3. United Nations in Vietnam. Details for the One Plan 2012–2016 between the government of the Socialist Republic of Viet Nam and the United Nations in Viet Nam [cited 2016 Feb 12]. Available from: http://www.un.org.vn/en/publications/one-un-documents /doc_details/278-the-one-plan-2012-2016-between-the-governmentof-the-socialist-republic-of-viet-nam-and-the-united-nations-inviet-nam.html 4. General Statistics Office of the Ministry of Planning and Investment of the Socialist Republic of Vietnam. The 2009 Vietnam population and housing census fertility and mortality in Vietnam: patterns, trends and differentials, 2011 [cited 2016 Feb 12]. Available from: http://www.mpi.gov.vn/en/Pages/tinbai.aspx?idTin=1951 5. World Health Organization. World Malaria Report 2015 [cited 2016 Feb 12]. Available from: http://www.who.int/malaria/publications /country-profiles/profile_vnm_en.pdf?ua=1 6. Vietnam Authority HIV/AIDS Control. An annual update on the HIV epidemic in Viet Nam. 2014 [cited 2016 Feb 12]. Available from: http://niheold.nihe.org.vn/uploads/An%20annual%20update%20 on%20the%20HIV%20epidemic%20in%20Viet%20Nam.pdf 7. National Institutes of Health (US). ClinicalTrials.gov [cited 2015 Aug 4]. Available from: https://clinicaltrials.gov/ct2/home 8. Brown MD, Mackey TK, Shapiro CN, Koker J, Novotny TE. Bridging public health and foreign affairs: the tradecraft of global health diplomacy and the role of health attachés. Science & Diplomacy 2014;3:3. 9. Kagan JM, Kane M, Quinlan KM, Rosas S, Trochim WMK. Developing a conceptual framework for an evaluation system for the NIAID HIV/AIDS Clinical Trials Networks. Health Res Policy Syst 2009;7:12. 10. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline: guideline for good clinical practice E6(R1). 1996 [cited 2016 Feb 12]. Available from: http://www .ich.org/fileadmin/public_web_site/ICH_products/guidelines /efficacy/E6/E6_R1_guideline.pdf 11. Pacheco Santos LM, Moura EC, Barradas Barata RC, Serruya SJ, da Motta ML, Silva Elias FT, et al. Fulfillment of the Brazilian agenda of priorities in health research. Health Res Policy Syst 2011;9:35. 12. Kasonde JM, Campbell S. Creating a knowledge translation platform: nine lessons from the Zambia Forum for Health Research. Health Res Policy Syst 2012;10:31. 13. Schluger N, Karunakara U, Lienhardt C, Nyirenda T, Chaisson R. Building clinical trials capacity for tuberculosis drugs in high-burden countries. PLoS Med 2007;4:e302. 14. McKee M, Stuckler D, Basu S. Where there is no health research: what can be done to fill the global gaps in health research? PLoS Med 2012;9:e1001209. 15. Anh LTK. Assessing Vietnam’s health research system. Hanoi (Vietnam): Hanoi School of Public Health, Council on Health Research for Development and National Health Research Assessment Team; 2007. Also available from: http://www.cohred.org/perspectives /assessing-viet-nam-s-health-research-syste [cited 2015 Aug 4]. 16. MacMahon S, Perkovic V, Patel A. Industry-sponsored clinical trials
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17.
18.
19. 20.
21. 22. 23. 24.
25.
in emerging markets: time to review the terms of engagement. JAMA 2013;310:907-8. Gezmu M, DeGruttola V, Dixon D, Essex M, Halloran E, Hogan J, et al. Strengthening biostatistics resources in sub-Saharan Africa: research collaborations through U.S. partnerships. Stat Med 2011;30:695-708. Sexton P, Hui K, Hanrahan D, Barnes M, Sugarman J, London AJ, et al. Reviewing HIV-related research in emerging economies: the role of government reviewing agencies. Dev World Bioeth 2014 [epub ahead of print]. Le LC, Bui QT, Nguyen HT, Rotem A. Alumni survey of masters of public health (MPH) training at the Hanoi School of Public Health. Hum Resour Health 2007;5:24. Goto A, Vinh NQ, Van NTT, Phuc TH, Minh PN, Yasumura S, et al. Developing a public health training and research partnership between Japan and Vietnam. Int Electron J Health Educ 2007;10:19-26. National Institutes of Health (US). Global health resources [cited 2015 Aug 4]. Available from: http://www.fic.nih.gov/global/pages /default.aspx Cutting Edge Information. Per-patient clinical trial costs rise 70% in three years [cited 2015 Aug 4]. Available from: http://www .cuttingedgeinfo.com/2011/per-patient-clinical-trial-costs Singh JA, Mills EJ. The abandoned trials of pre-exposure prophylaxis for HIV: what went wrong? PLoS Med 2005;2:e234. Ministry of Health (Socialist Republic of Vietnam). Decision on the promulgation of regulations on organization and operation of ethical evaluation committee in biomedical research of Ministry of Health, period 2012–2017. 2012 [cited 2016 Feb 12]. Available from: https://clinregs.niaid.nih.gov/documents/vietnam /DecisionNo460-QD-BYT.pdf Ministry of Health (Socialist Republic of Vietnam). Decision on promulgation of regulation on organization and operation of
26.
27.
28.
29.
30.
31. 32.
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council of ethics in biomedical research at grass-root level. 2013 [cited 2016 Feb 12]. Available from: https://clinregs.niaid.nih.gov /documents/vietnam/DecisionNo111-QD-BYT.pdf Community Recommendations Working Group of Community Partners. Recommendations for community involvement in National Institute of Allergy and Infectious Diseases HIV/AIDS clinical trials research. 2009 [cited 2015 Aug 4]. Available from: http://www .niaid.nih.gov/about/organization/daids/networks/documents /cabrecommendations.pdf Joint United Nations Programme on HIV/AIDs (UNAIDS). Good participatory practice: guidelines for biomedical HIV prevention trials, 2011 [cited 2015 Aug 4]. Available from: http://www.unaids.org /sites/default/files/en/media/unaids/contentassets/documents /unaidspublication/2011/JC1853_GPP_guidelines_2011_en.pdf Ministry of Health (Socialist Republic of Vietnam). Circular regulating on research support activities for clinical trials in Vietnam. 2014 [cited 2016 Feb 12]. Available from: https://clinregs.niaid .nih.gov/documents/vietnam/C-ClinTrialOps_English.pdf Higgs ES, Hayden FG, Chotpitayasunondh T, Whitworth J, Farrar J. The Southeast Asian Influenza Clinical Research Network: development and challenges for a new multilateral research endeavor. Antiviral Res 2008;78:64-8. National Institutes of Health (US). An observational study of the causes, management, and outcomes of community-acquired sepsis and severe sepsis in Southeast Asia (SEA050). 2015 [cited 2016 Feb 12]. Available from: https://clinicaltrials.gov/ct2/show/NCT0215 7259?term=NCT02157259&rank=1 Frenk J, Chen L. Overcoming gaps to advance global health equity: a symposium on new directions for research. Health Res Policy Syst 2011;9:11. Manning R. Development co-operation report 2007. OECD J Dev 2008;9:1-214.
Assessing Clinical Research Capacity in Vietnam: A Framework for Strengthening Capability for Clinical Trials in Developing Countries Jonathan Kagan, PhDa Dao Duc Giang, MPHb Michael F. Iademarco, MD, MPHc,d Van TT Phung, MSd Chuen-Yen Lau, MD, MPHe Nguyen Ngo Quang, PhDf
ABSTRACT Although improving health systems promises important benefits, most developing nations lack the resources to support nationally driven clinical research. Strengthened clinical research capacity can advance national health goals by supporting greater autonomy in aligning research with national priorities. From March through June 2010, we assessed six elements of clinical research capacity in Vietnam: research agenda; clinical investigators and biostatisticians; donors and sponsors; community involvement; scientific, ethical, safety, and quality oversight; and clinical research institutions. Assessments were drawn from interviews with investigators, Ministry of Health staff members, nongovernment organizations, and U.S. Mission staff members, and document review. Observations and recommendations were shared with collaborators. Reassessment in 2015 found growth in the number of clinical trials, improved regulation in human subjects protection and community engagement, and modest advances in research agenda setting. Training and investment in institutions remain challenging. A framework for assessing clinical research capacity can affirm strengths and weaknesses and guide the coordination of capacity-building efforts.
National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Clinical Research, Bethesda, MD
a
FH1 360, Clinical Research and Laboratory Science, Hanoi, Vietnam
b
Centers for Disease Control and Prevention, Office of Public Health Scientific Services, Center for Surveillance, Epidemiology and Laboratory Services, Atlanta, GA
c
Health Affairs Attaché Office, U.S. Mission, Hanoi, Vietnam
d
National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Clinical Research, Collaborative Clinical Research Branch, Bethesda, MD
e
Vietnam Ministry of Health, Administration of Science Technology and Training, Hanoi, Vietnam
f
Address correspondence to: Jonathan Kagan, PhD, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Clinical Research, 5601 Fishers Ln., Room 4B40, Rockville, MD 20892-9820; tel. 240-669-5221; fax 301-451-5526; e-mail .
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Investing in health is a priority articulated in the United Nations Millennium Development Goals and is broadly supported by the world’s political leaders for saving lives, stimulating economic development, reducing poverty, and promoting global health security.1 Although the lowest-income nations generally have the poorest health, shorter life expectancies and increased infant mortality also exist among poor people in higher-income countries.2 Even as chronic and degenerative diseases become more prevalent in low-income nations, communicable diseases remain important health risks. Vietnam is an example of a nation that recently passed the middle-income threshold. During the past 30 years, Vietnam made remarkable progress toward reducing poverty and improving basic health indicators. Using World Health Organization (WHO)–recommended public health interventions3 and relatively minimal investment, Vietnam dramatically reduced the incidence of childhood diseases and malaria, stabilized the prevalence of human immunodeficiency virus (HIV) infection, and prevented a generalized HIV epidemic.4–6 Yet Vietnam today has a high burden of historically prevalent infectious diseases and struggles with emerging chronic diseases, health systems strains, and the health challenges of modernization, such as food safety. Although continued improvement of health systems overall promises important benefits, efforts targeted toward strengthening clinical (patient-oriented) research capability could advance national health goals by helping to assure that national health priorities, regulations, ethical principles, cultural considerations, and other factors are given appropriate weight in selecting, designing, and conducting research studies in Vietnam. Vietnam’s capacity for clinical research is low but grew rapidly from 2010 to 2015. In 2010, 25 clinical trials were being conducted in Vietnam, whereas in 2015, 72 active trials were being conducted, half of which were sponsored by industry and the rest supported by nongovernment organizations (NGOs). Most trials (about 70%) were drug studies, another 20% evaluated vaccines, and 10% examined traditional medicines. Among drug trials, infectious disease studies ranked first, followed by cancer and cardiology trials.7 PURPOSE In 2010, based on the strength of 25 years of cooperation between the United States and Vietnamese governments on health issues,8 we broadly assessed clinical research capacity in Vietnam to identify strengths and weaknesses and help prioritize, guide, and coordinate
clinical research capacity-building efforts. In 2015, we reassessed clinical research capacity to determine progress. This report (1) summarizes our initial (2010) and most recent (2015) findings and recommendations and (2) describes our approach, which other developing nations might find useful. METHODS Our initial assessment was conducted from March through June 2010 under the auspices of the U.S. Embassy in Hanoi, and a follow-up assessment took place in 2015. The goal was to help inform and guide the U.S. Mission Vietnam Health Team in working with the Vietnamese government and other partners (e.g., academic, government, nongovernment, pharmaceutical/biotechnology industry) to advance their shared interests in clinical research to improve public health. The assessment was guided by an evaluation framework for the National Institute of Allergy and Infectious Diseases’ HIV/AIDS Clinical Trials Networks9 and integrated diverse viewpoints of researchers, community members, managers, and regulators on what constitutes success in clinical research. The assessment included six capacity areas: (1) research agenda; (2) clinical investigators and biostatisticians; (3) donors and sponsors; (4) community involvement; (5) scientific, ethical, safety, and quality oversight; and (6) clinical research institutions. Sources of information included (1) semiformal and informal guided interviews conducted by the first author in his capacity as a U.S. Embassy Fellow, assisted by a bilingual public health specialist with the Health Affairs Attaché Office of the U.S. Mission, Hanoi; (2) documents (e.g., regulatory guidelines, policies, procedures) and a literature review; (3) ClinicalTrials. gov; and (4) U.S. National Institutes of Health (NIH) Fogarty International Center databases. Interviews involved various numbers of interviewees—from one-on-one interviews to focus groups with as many as 10 people—depending on interest and availability. A precise definition of progress was not formulated for any of the six areas of clinical research capacity assessed. Rather, progress was gauged according to evidence of improved alignment with international standards or models (where available). For example, we assessed progress in regulatory and ethical oversight by using the guidelines of the International Conference on Harmonisation of Good Clinical Practice (ICH-GCP) as a standard for assurance that the rights, safety, and well-being of clinical trial participants are protected and that clinical trial data are credible.10 Data on barriers to progress, though of interest and sometimes articulated, were not systematically collected
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because of insufficient time and resources. Sixty-eight individuals who were variously affiliated with government agencies (Vietnam, United States), research institutes (Vietnam, France, Laos, United Kingdom, Thailand), academia (Vietnam, United States), hospitals (Vietnam), NGOs (Vietnam, United States), and the pharmaceutical industry (Vietnam) contributed information to this project. OUTCOMES Clinical research agenda. A research agenda linked to national health priorities is important for strategic planning and coordination.11–14 A national health research survey in 200715 reported that research had a minor role in Vietnam’s health system. The Five-Year Health Sector Development Plan for 2011–2015 gave priority to promoting research and supported strengthening research capacity, especially for the application of medicines (Unpublished data, Ministry of Health, 4th draft, Five-Year Health Sector Development Plan, 2011–2015, October 2010). Beginning in 2011, Vietnam’s Ministry of Health (MOH) has issued an annual priority list and, following on recommendations from the combined assessment, beginning in 2015, required that clinical trials in Vietnam be registered in ClinicalTrials.gov. The influence of frank, multilateral health diplomacy was an important driver of transparency and prioritization. Continued evolution of a research agenda, including input from national, regional, and international health experts, patient communities, and health-care providers, is vital to assure that research aligns with health priorities. Clinical investigators and biostatisticians. Physicians trained in human subjects research, in partnership with biostatisticians who are experts in study design, are essential for nationally driven clinical research. Without in-country expertise, the priorities of external sponsors might dominate.16–18 Whereas the number of trials with a Vietnamese researcher as the principal investigator increased from five in 2010 to 11 in 2015, the percentage of Vietnamese principal investigators was essentially unchanged because Vietnamese researchers still function principally as site investigators. Vietnamese medical and public health students have little exposure to research or opportunities to learn research methods. Although the Hanoi School of Public Health (HSPH) and the University of Medicine and Pharmacy in Ho Chi Minh City (HCMC), for example, have biostatistics faculties, graduates are not taking leadership roles in clinical research. When surveyed, nearly half of HSPH students graduating with a master’s degree in public health indicated that training in data analysis
was insufficient.19 To strengthen in-country clinical research expertise, Vietnam could (1) better utilize international clinical research training resources20,21 to learn advanced research principles and practices, (2) strengthen training in biostatistics, (3) set aside funding for young physician researchers and provide training and support for grant writing, (4) set and enforce standards for research productivity in Vietnamese medical schools and research institutions, and (5) create opportunities for young medical researchers to compete for faculty positions. Donors and sponsors. Per-participant costs for clinical research are often in the thousands of U.S. dollars and continue to rise.22 Not unlike many developing nations, Vietnam does not have sufficient government (public) resources to support a robust clinical research agenda to address its priority public health issues. In 2010, three ministries of the Vietnam government sponsored competitive grant research programs, but none offered awards greater than approximately U.S. $50,000. According to a 2007 analysis by the Council on Health Research Development, nearly 70% of Vietnam’s health research budget comes from foreign organizations.15 As such, the nation is, and will remain for the foreseeable future, dependent on donations and sponsor-based funding for clinical research. Therefore, it is vital that Vietnam form lasting collaborations with donors that respect its sovereignty and health priorities, especially given that public health concepts are not yet fully embodied in Vietnamese medical culture. Vietnamese health leaders are encouraged to engage partners for durable clinical research support, particularly in underfunded areas such as cardiovascular disease and cancer. Flexible funding mechanisms, including greater ease in forming public–private partnerships, could catalyze these collaborations. Equally important is reducing barriers to collaboration; barriers could be reduced by, for example, streamlining the processes of research review, determination of an NGO’s suitability to sponsor clinical research, and drug importation. Community involvement. Clinical research in Vietnam can be strengthened by establishing a trusting dialogue between scientists and the public. Globally, community involvement in planning clinical research is resulting in improved study enrollment and increased acceptance of study results. Failure to address community concerns can delay or halt clinical research and have longlasting negative consequences, as reported recently in other nations, including neighboring Cambodia.23 Despite highly effective social organizations (e.g., the Women’s Union, the Farmer’s Union), consumers of health research have largely been excluded from
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the priority-setting process.21 Concepts of community engagement in research and mechanisms for obtaining community input are not yet well established in Vietnam, but there is evidence of progress, supported by strengthened partnerships fostered through direct health diplomacy. Following on recommendations from the initial assessment, regulations in 2012 called for the inclusion of non-scientists on the MOH Board of Ethical Assessment (BEA) and local ethics committees.24 Another new regulation,25 introduced in 2013, requires support by a local People’s Committee (equivalent to a jurisdiction’s governing body) for MOH approval of a clinical trial. Vietnam health leadership was encouraged to expand engagement of communities in research. NGOs may be well suited to helping build awareness of clinical research in communities and capacity for community–researcher engagement. Guiding principles and best practices are available to help establish communities as partners in biomedical research.26,27 Scientific, ethical, safety, and quality oversight. At least as early as 2002, the MOH developed requirements for ethical review of all biomedical research to help assure rigor in science, safety, and ethics, and established its BEA. In 2006–2007, with assistance from international regulatory experts, the MOH began strengthening systems to promulgate and support good clinical practices and more closely follow ICH-GCP guidelines. Since 2008, the MOH has required that all clinical trials in Vietnam be conducted in accordance with ICH-GCP. During our initial assessment in 2010, the BEA was chaired by the Vice Minister of Health, and seven of its nine members were MOH employees, raising concerns about its independence. Since 2010, following recommendations from this assessment, membership was increased to 11 members, a non-MOH employee was appointed chairperson of the BEA, MOH membership was proportionally decreased, all human subjects research came under BEA review, and board responsibilities were better aligned with ICH-GCP standards. The BEA has authority to suspend research to limit risks to participants’ safety. Current policy is to receive reports of all serious adverse events. Limiting reporting to only unanticipated problems could ease the burden on the BEA and improve its effectiveness in safety oversight. Similarly, for quality assurance, the BEA has responsibility for monitoring, auditing, and inspecting trial sites. That these responsibilities are assigned to the BEA (instead of a quality assurance unit of the MOH) can detract from the BEA’s primary responsibilities and pose potential conflicts of interest for its members. Guidance issued by the MOH in 2014 on the roles and responsibilities of contract
research and site management organizations in quality assurance will likely help with safety and oversight.28 Whereas in 2010 the relationship between the BEA and local institutional ethics committees was not specified, in 2013, the MOH issued its first regulation on local ethics committees. As the capacity for human subjects, ethics, and research review grows in principal locales conducting clinical research, decentralizing the ethical review of local institutional studies could strengthen capacity across Vietnam and reduce the burden on the BEA, allowing it to focus on multicenter national and international studies. Training and support for local ethics committees is a responsibility shared by the MOH and sponsors. Improvements in Vietnam’s clinical trial regulation and oversight from 2010 to 2015 are summarized (Table 1). Clinical research institutions. Clinical research requires institutions with facilities (e.g., hospitals, clinics, laboratories), infrastructure (e.g., records management, financial management), and trained research professionals (e.g., physicians, biostatisticians, research nurses, laboratory technicians, data managers) capable of executing their roles in compliance with applicable regulations. Few Vietnamese institutions have the requisite human or financial resources. Of approximately 1,180 hospitals nationwide, about 60 are authorized by the MOH to do clinical research. Of these, 20 hospitals have the capacity to conduct clinical research, and 12 hospitals are involved in clinical trials. Hospitals with long-term funding, including Hanoi Medical University, the University of Medicine and Pharmacy in HCMC, the Hospital for Tropical Diseases in HCMC, and the National Institute of Infectious & Tropical Diseases in Hanoi, are among the most experienced, best staffed, and best equipped. Long-term funders include the U.S. Department of Health and Human Services, including the Centers for Disease Control and Prevention and the NIH, Wellcome Trust, Institut Pasteur, and the Japan International Cooperation Agency. Greater long-term investment in the development of clinical research– capable institutions is vital to build national capacity. The MOH’s concept to form a government- sponsored clinical research network in Vietnam is forward looking. However, challenges and barriers to achieving this forward-looking concept include (1) challenges in the formation of a scientific agenda and priorities on which researchers and public health authorities can form consensus; (2) the need for a substantial, sustainable funding commitment to support the human capital required and to build and maintain the physical infrastructure (facilities) required; (3) a paucity of researchers with the requisite management experience to oversee a complex, inter-institutional/
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Table 1. Strengthening Vietnam’s clinical research, regulatory, and ethical oversight, 2010–2014 Clinical research capacity domain • Regulatory authority
New regulation or guidance: 2010 through 2014 • Decree #63120121ND-CP: Defining the Functions, Tasks, Powers and Organizational Structure of the Ministry of Health. August 2012 (http://faolex.fao .org/docs/pdf/vie119157.pdf) • Decision #4059/QD-BYT: Stipulating Functions, Duties, Powers and Organizational Structure of the Department of Science, Technology and Education Under the Ministry of Health. October 2012 (https://clinregs.niaid.nih.gov/documents/vietnam /DecisionNo4059-QD-BYT.pdf)
• Ethical review • Informed consent
• Decision #460/QD-BYT: Regulations on Organization and Operation of Ethical Evaluation Committee in Biomedical Research of Ministry of Health, Period 2012–2017. January 2013 (https://clinregs.niaid.nih.gov/documents/vietnam /DecisionNo460-QD-BYT.pdf)
Capability strengthened Vietnam’s Ministry of Health (MOH) as the authority responsible for clinical trial approvals, oversight, and inspections, including promulgating legal documents, policies, standards, requirements for data and safety monitoring boards, and the national-level ethics committee
National-level and institutional-level ethics committee role and responsibilities for balancing central and provincial authority in the review and approval of clinical trials
• Decision #111/QD-BYT: Promulgation of Regulation on Organization and Operation of Council of Ethics in Biomedical Research at Grass-Root Level. January 2013 (https://clinregs.niaid.nih.gov /documents/vietnam/DecisionNo111-QD-BYT.pdf) • Requirements of sponsors • Safety monitoring • Investigational products • Drug registration • Requirements of clinical trials to support organizations
• Circular 03/2012/TT-BYT: Guidelines for Clinical Trials on Drugs. February 2012 (https://clinregs .niaid.nih.gov/documents/vietnam/C-ClinDrugTrial .pdf) • Decision #44/2014/ TT-BYT: Drug Registration Rules. November 2014 (https://luatminhkhue .vn/en/circular/circular-no-44-2014-tt-byt-dated november-25--2014-of-the-ministry-of-health-on drug-registration.aspx) • Circular 08/2014TT-BYT: Regulated Research Support Activities Clinical Trials in Vietnam. February 2014 (https://clinregs.niaid.nih.gov /documents/vietnam/C-ClinTrialOps_English.pdf)
• Biological specimens
• Decision #43/2011/TT-BYT: Management of Infectious Specimens. December 2011 (https:// clinregs.niaid.nih.gov/documents/vietnam /C-MgmtInfectiousSpecs.pdf)
interagency effort; and (4) the need for greater numbers of well-trained clinical research support staff members to help conduct the research. For the best science and translational research, independent peer review is an essential factor in the selection of network institutions and investigators. Network institutions would also be well suited to create training programs to develop and maintain the skilled workforce needed to support clinical research.
Responsibility of sponsors and investigators for participant safety and safety reporting; defines products requiring clinical trials; specifies product quality standards and requirements for Good Manufacturing Practices certificates; describes requirements for drug import, and safety and efficacy requirements for registration; defines responsibilities of clinical research support organizations; and requires registration with the MOH
The MOH General Department of Preventive Medicine as authority responsible for infectious specimens; defines specimens and sets requirements for specimen import and export
CASE STUDY A case study from the South East Asia Infectious Disease Clinical Research Network (SEAICRN) provides a real-world example of the gains being made in clinical research thinking, strengthening of regulatory and ethical oversight, and durability of research infrastructure. The SEAICRN is a collaborative partnership of research institutions in Vietnam, Thailand, and Indonesia; the U.S. National Institute of Allergy and Infectious Diseases; the Oxford University Centre for Tropical Medicine; the Wellcome Trust; and WHO.29 The SEAICRN Sepsis Study (Trial Registration NCT02157259),30 which
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began in December 2013, was designed to determine the causes of community-acquired sepsis and severe sepsis in adults and children in Vietnam, Thailand, and Indonesia. Across the study lifecycle, including conceptualization, protocol development, study conduct, and analysis, challenges arose that highlighted the importance of several capacity areas described in this article (Table 2). The SEAICRN Sepsis Study (1) aligned with national health priorities for study selection and development; (2) provided support for and training of local investigators to enhance in-country clinical research capability; (3) coordinated sponsor support to secure stable funding, infrastructure, and capacity enhancement; and (4) aligned with three national regulatory frameworks to support the study in accordance with international safety and ethical standards.
Lessons learned The past 15–20 years has seen unprecedented growth in partnerships to strengthen national health systems for improved global health.31 The Organisation for Economic Co-operation and Development’s (OECD’s) best practice principles for global health partnerships articulate fundamental elements for success; these elements highlight the need to harmonize partner efforts and include performance assessment frameworks for national systems.32 Our effort addresses these OECD principles and is directed toward strengthening national capacity for clinical (patient-oriented) research, with the goal of promoting greater autonomy in aligning such research with national health priorities. By providing a guide for establishing a baseline for clinical research capacity, sharing our observations and findings with collaborators, and monitoring changes over time, our intent is to facilitate cooperation and coordination by health systems partners (government, nongovernment, academic, pharmaceutical/biotech
Table 2. The South East Asia Infectious Disease Clinical Research Network (SEAICRN) Sepsis Study:a clinical research capacity, challenges, and solutions, December 2013–present Clinical research capacity domain
Challenge
SEAICRN solution
Research agenda
Need to determine which clinical research concepts proposed from Vietnam, Thailand, and Indonesia would be developed by the network
Extensive discussion occurred between country leaders and sponsors to select topics most relevant to the region in alignment with national priorities. Embracing guidance of Ministry of Health representatives and local investigators, the SEAICRN Sepsis Study was conceptualized to align with regional health priorities. Broad cross-country support was obtained for determining the etiologies of sepsis to generate hypotheses for additional studies that can improve public health.
Investigators
Selection of study principal investigator to guide the research, local investigators to lead in-country study sites, and ways to build investigator capacity for future research
The study principal investigator is from Thailand; several Vietnamese investigators serve as associate investigators. To prepare Vietnamese researchers to serve as principal investigators for future studies, workshops on research methods, proposal writing, and manuscript writing were conducted for promising early career investigators. Protocol development support is provided to local investigators whose proposals are endorsed by the SEAIRCN. Training and supporting local principal investigators is enhancing in-country clinical research expertise and improving sustainability of the research program.
Donors and sponsors
Coordination of study funding across diverse partners in a manner that is commensurate with and makes the best use of their resources, and preserves equity among partners
Partner support for the study varied and included funding, scientific expertise, and in-kind resources for network activities. An in-country contract research organization was provided to support site infrastructure, laboratory capacity, and human resource management. Investigators are provided with information and training in developing proposals for research funding, building capacity to pursue more diverse funding opportunities that can lead to additional partnerships, and attracting additional sponsors.
Scientific, ethical, safety, and quality oversight
Compliance with international ethical and safety standards across multiple sites in Vietnam, Thailand, and Indonesia
To complement existing institutional capacity, an in-country contract research organization provided training for site staff, including ongoing guidance and support for submissions to each institution’s ethics committee. Coordination through a single organization ensured harmonization of the protocol across sites. This experience also highlighted the need for a centralized review process or ethics committee reliance agreements for future multisite studies.
a National Institutes of Health (US). An observational study of the causes, management, and outcomes of community-acquired sepsis and severe sepsis in Southeast Asia (SEA050). 2015 [cited 2016 Feb 12]. Available from: https://clinicaltrials.gov/ct2/show/NCT02157259?term=NCT021572 59&rank=1
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industry, philanthropic) to advance their shared interests in strengthening clinical research capacity. A unique aspect of our framework is its integration of diverse viewpoints of researchers, community members, managers, and regulators. From our case study in Vietnam, we learned the following: 1. Peer-to-peer relationships between research and regulatory agencies of partner nations and public–private partnerships are vital for building national capacity in developing countries. 2. A framework for assessing clinical research capacity can affirm strengths and weaknesses and guide the prioritization, coordination, and monitoring of capacity-building efforts. 3. Clinical research capacity building is essential to the development of a research agenda driven by national health priorities, assuring human subjects protection, and adherence to ethical standards. At the same time, room for improvement exists. Not all topics of potential relevance are included in this framework; expansion of the framework to include other capacities (e.g., pharmaceutical and diagnostic product manufacturing and importation, pharmacovigilance, laboratory quality assurance) could add value. Additionally, our own Vietnam assessments could have been enriched had we the resources needed to gather more in-depth input from larger communities. We anticipate that greater experience with the framework will lead to its continuous enhancement as well as the development of facilitating tools (e.g., data collection instruments, reference standards) to support its effective implementation and utilization. The assessment was conducted as a programmatic evaluation at the request of the U.S. Mission Vietnam and was not deemed to be human subjects research under regulations of the U.S. Department of Health and Human Services (HHS) or Vietnam. The authors acknowledge the following for their contributions to, and support for, this work: Peggy Coyle (FHI360), Stephen Mills (FHI360), Do Gia Canh (deceased) (National Institute of Hygiene and Epidemiology, Hanoi, Vietnam), Paul Brey (Institut Pasteur, Laos), Kripa Raghavan (U.S. National Institutes of Health [NIH]), Bruce Struminger (U.S. Indian Health Service/Navajo Service Area), Andrew Herrup (U.S. Embassy, Kuala Lumpur), Roger Detels (University of California, Los Angeles), Phuong L. Tran (U.S. Mission, Hanoi), Michelle McConnell (U.S. Centers for Disease Control and Prevention), Stuart Nightingale (NIH consultant/contractor), the South East Asia Infectious Disease Clinical Research Network, and Eileen Kane (U.S. Department of State). When this work was initiated in 2010, authors MFI and VTTP were with the Office of Global Health Affairs, HHS, in Hanoi. JK was a U.S. Embassy Science Fellow in Hanoi in March–June 2010. This work was supported by the HHS Office of Global Health
Affairs; the National Institute of Allergy and Infectious Diseases, NIH, HHS; and the Embassy Science Fellows Program, Office of Science and Technology Cooperation, Bureau of Oceans, Environment and Science, U.S. Department of State. This work is dedicated to the memory of R. Palmer Beasley—physician, public health educator, and infectious disease epidemiologist—who, in addition to saving millions of lives from hepatitis B and liver cancer, mentored a new generation of researchers in Vietnam.
REFERENCES 1. United Nations. Millennium development goals and beyond 2015 [cited 2015 Aug 4]. Available from: http://www.un.org /millenniumgoals 2. Murray CJ, Kulkarni SC, Michaud C, Tomijima N, Bulzacchelli MT, Iandiorio TJ, et al. Eight Americas: investigating mortality disparities across races, counties, and race-counties in the United States. PLoS Med 2006;3:e260. 3. United Nations in Vietnam. Details for the One Plan 2012–2016 between the government of the Socialist Republic of Viet Nam and the United Nations in Viet Nam [cited 2016 Feb 12]. Available from: http://www.un.org.vn/en/publications/one-un-documents /doc_details/278-the-one-plan-2012-2016-between-the-governmentof-the-socialist-republic-of-viet-nam-and-the-united-nations-inviet-nam.html 4. General Statistics Office of the Ministry of Planning and Investment of the Socialist Republic of Vietnam. The 2009 Vietnam population and housing census fertility and mortality in Vietnam: patterns, trends and differentials, 2011 [cited 2016 Feb 12]. Available from: http://www.mpi.gov.vn/en/Pages/tinbai.aspx?idTin=1951 5. World Health Organization. World Malaria Report 2015 [cited 2016 Feb 12]. Available from: http://www.who.int/malaria/publications /country-profiles/profile_vnm_en.pdf?ua=1 6. Vietnam Authority HIV/AIDS Control. An annual update on the HIV epidemic in Viet Nam. 2014 [cited 2016 Feb 12]. Available from: http://niheold.nihe.org.vn/uploads/An%20annual%20update%20 on%20the%20HIV%20epidemic%20in%20Viet%20Nam.pdf 7. National Institutes of Health (US). ClinicalTrials.gov [cited 2015 Aug 4]. Available from: https://clinicaltrials.gov/ct2/home 8. Brown MD, Mackey TK, Shapiro CN, Koker J, Novotny TE. Bridging public health and foreign affairs: the tradecraft of global health diplomacy and the role of health attachés. Science & Diplomacy 2014;3:3. 9. Kagan JM, Kane M, Quinlan KM, Rosas S, Trochim WMK. Developing a conceptual framework for an evaluation system for the NIAID HIV/AIDS Clinical Trials Networks. Health Res Policy Syst 2009;7:12. 10. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline: guideline for good clinical practice E6(R1). 1996 [cited 2016 Feb 12]. Available from: http://www .ich.org/fileadmin/public_web_site/ICH_products/guidelines /efficacy/E6/E6_R1_guideline.pdf 11. Pacheco Santos LM, Moura EC, Barradas Barata RC, Serruya SJ, da Motta ML, Silva Elias FT, et al. Fulfillment of the Brazilian agenda of priorities in health research. Health Res Policy Syst 2011;9:35. 12. Kasonde JM, Campbell S. Creating a knowledge translation platform: nine lessons from the Zambia Forum for Health Research. Health Res Policy Syst 2012;10:31. 13. Schluger N, Karunakara U, Lienhardt C, Nyirenda T, Chaisson R. Building clinical trials capacity for tuberculosis drugs in high-burden countries. PLoS Med 2007;4:e302. 14. McKee M, Stuckler D, Basu S. Where there is no health research: what can be done to fill the global gaps in health research? PLoS Med 2012;9:e1001209. 15. Anh LTK. Assessing Vietnam’s health research system. Hanoi (Vietnam): Hanoi School of Public Health, Council on Health Research for Development and National Health Research Assessment Team; 2007. Also available from: http://www.cohred.org/perspectives /assessing-viet-nam-s-health-research-syste [cited 2015 Aug 4]. 16. MacMahon S, Perkovic V, Patel A. Industry-sponsored clinical trials
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17.
18.
19. 20.
21. 22. 23. 24.
25.
in emerging markets: time to review the terms of engagement. JAMA 2013;310:907-8. Gezmu M, DeGruttola V, Dixon D, Essex M, Halloran E, Hogan J, et al. Strengthening biostatistics resources in sub-Saharan Africa: research collaborations through U.S. partnerships. Stat Med 2011;30:695-708. Sexton P, Hui K, Hanrahan D, Barnes M, Sugarman J, London AJ, et al. Reviewing HIV-related research in emerging economies: the role of government reviewing agencies. Dev World Bioeth 2014 [epub ahead of print]. Le LC, Bui QT, Nguyen HT, Rotem A. Alumni survey of masters of public health (MPH) training at the Hanoi School of Public Health. Hum Resour Health 2007;5:24. Goto A, Vinh NQ, Van NTT, Phuc TH, Minh PN, Yasumura S, et al. Developing a public health training and research partnership between Japan and Vietnam. Int Electron J Health Educ 2007;10:19-26. National Institutes of Health (US). Global health resources [cited 2015 Aug 4]. Available from: http://www.fic.nih.gov/global/pages /default.aspx Cutting Edge Information. Per-patient clinical trial costs rise 70% in three years [cited 2015 Aug 4]. Available from: http://www .cuttingedgeinfo.com/2011/per-patient-clinical-trial-costs Singh JA, Mills EJ. The abandoned trials of pre-exposure prophylaxis for HIV: what went wrong? PLoS Med 2005;2:e234. Ministry of Health (Socialist Republic of Vietnam). Decision on the promulgation of regulations on organization and operation of ethical evaluation committee in biomedical research of Ministry of Health, period 2012–2017. 2012 [cited 2016 Feb 12]. Available from: https://clinregs.niaid.nih.gov/documents/vietnam /DecisionNo460-QD-BYT.pdf Ministry of Health (Socialist Republic of Vietnam). Decision on promulgation of regulation on organization and operation of
26.
27.
28.
29.
30.
31. 32.
Public Health Reports / May–June 2016 / Volume 131
council of ethics in biomedical research at grass-root level. 2013 [cited 2016 Feb 12]. Available from: https://clinregs.niaid.nih.gov /documents/vietnam/DecisionNo111-QD-BYT.pdf Community Recommendations Working Group of Community Partners. Recommendations for community involvement in National Institute of Allergy and Infectious Diseases HIV/AIDS clinical trials research. 2009 [cited 2015 Aug 4]. Available from: http://www .niaid.nih.gov/about/organization/daids/networks/documents /cabrecommendations.pdf Joint United Nations Programme on HIV/AIDs (UNAIDS). Good participatory practice: guidelines for biomedical HIV prevention trials, 2011 [cited 2015 Aug 4]. Available from: http://www.unaids.org /sites/default/files/en/media/unaids/contentassets/documents /unaidspublication/2011/JC1853_GPP_guidelines_2011_en.pdf Ministry of Health (Socialist Republic of Vietnam). Circular regulating on research support activities for clinical trials in Vietnam. 2014 [cited 2016 Feb 12]. Available from: https://clinregs.niaid .nih.gov/documents/vietnam/C-ClinTrialOps_English.pdf Higgs ES, Hayden FG, Chotpitayasunondh T, Whitworth J, Farrar J. The Southeast Asian Influenza Clinical Research Network: development and challenges for a new multilateral research endeavor. Antiviral Res 2008;78:64-8. National Institutes of Health (US). An observational study of the causes, management, and outcomes of community-acquired sepsis and severe sepsis in Southeast Asia (SEA050). 2015 [cited 2016 Feb 12]. Available from: https://clinicaltrials.gov/ct2/show/NCT0215 7259?term=NCT02157259&rank=1 Frenk J, Chen L. Overcoming gaps to advance global health equity: a symposium on new directions for research. Health Res Policy Syst 2011;9:11. Manning R. Development co-operation report 2007. OECD J Dev 2008;9:1-214.
