A DIALOGUE ON THE CURRENT REGULATIONS OF THE MINISTRY OF HEALTH - IMPLEMENTING CLINICAL RESEARCH IN VIETNAM
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Implementing clinical research in Vietnam:
A dialogue on the
current regulations of
the Ministry of Health
SYMPOSIUM PROCEEDINGS
A two-day workshop organized by
Vietnam Ministry of Health
12-13 July 2007, Hanoi, Vietnam
VIETNAM
MINISTRY OF HEALTHIn July 2011, FHI became FHI 360. FHI 360 is a nonprofit human development organization dedicated to improving lives in lasting ways by advancing integrated, locally driven solutions. Our staff includes experts in health, education, nutrition, environment, economic development, civil society, gender, youth, research and technology – creating a unique mix of capabilities to address today’s interrelated development challenges. FHI 360 serves more than 60 countries, all 50 U.S. states and all U.S. territories. Visit us at www.fhi360.org.
Implementing clinical research in Vietnam:
A dialogue on
the current regulations
of the Ministry of Health
SYMPOSIUM PROCEEDINGS
A two-day workshop organized by Vietnam Ministry of Health
12-13 July 2007, Hanoi, Vietnam
VIETNAM
MINISTRY OF HEALTHTable of contents
Abbreviations and acronyms 3
Preface 4
Approval of protocol, monitoring and evaluation, final review, and 6
dissemination of research
Ethical aspects of biomedical research 9
Good Clinical Practice 12
Guidelines for review and evaluation of protocols 15
Plan for GCP implementation: 2007−2010 18
Procedures for manufacture and import of medicinal drugs for 20
clinical research
Pharmacovigilance and reporting of adverse drug reactions 23
Review and approval of foreign, non-government sponsored 25
projects
Guidelines for financial management of foreign NGO funding 28
Appendix 29
Appendix 1: List of presenters 30
Appendix 2: List of participants 31
Appendix 3: List of regulations and guidelines on clinical research 35
Glossary 36
Implementing Clinical Research in Vietnam - Symposium Proceedings 1Abbreviations and Acronyms
ADR Adverse Drug Reaction
CIOMS Council for International Organization of Medical Sciences
CFR Code of Federal Regulations
CPP Certificate of Pharmaceutical Product
CRA Clinical Research Associate
DAD Drug Administration Department
DPF Department of Planning and Finance
DST Department of Science and Training
EC Ethics Committee
FDA U.S. Food and Drug Administration
FSC Free Sales Certificate
GCP Good Clinical Practice
GMP Good Manufacturing Practice
HCMC Ho Chi Minh City
ICH International Conference on Harmonization
IEC Independent Ethics Committee
INGO International Non-Governmental Organization
IRB Institutional Review Board
M&E Monitoring and Evaluation
MOH Ministry of Health
MPI Ministry of Planning and Investment
NGO Non-Governmental Organization
PACCOM People’s Aid Coordinating Committee
PHS Provincial Health Services
PI Principal Investigator
PM Prime Minister
SOP Standard Operating Procedure
VUFO Vietnam Union for Friendship Organizations
WHO World Health Organization
Implementing Clinical Research in Vietnam - Symposium Proceedings 3Preface
Three departments within Vietnam’s Ministry of Health—the Departments of Science and Training, Finance and
Planning, and Drug Administration—joined together in July 2007 to present a two-day introductory workshop on
Vietnam Government’s Regulations on Clinical Research. Attending the workshop were approximately 60 doctors
and other hospital staff from throughout the country, all of whom are working on international clinical trials at
their hospital sites.
The workshop covered various aspects of clinical research, including the important role of ethics—an area that
clinic site personnel, and physicians in particular, must understand when asking patients to participate in a new
drug study. The workshop also covered guidance for hospitals regarding the process which must be followed to
seek MOH approval for new study protocols; the process of importing drugs and supplies needed to conduct the
study; and the close monitoring of patient safety which is required for all clinical studies in Vietnam.
As it has become evident that there is a need for improved clinical research study oversight in Vietnam as well as
capacity building in research ethics and good clinical practices, the Ministry of Health will soon publish a docu-
ment describing Guidelines for Clinical Research in Vietnam which provides a detailed endorsement of interna-
tionally accepted guidelines on clinical research and research ethics. The MOH is also in the process of developing
inclusive operational guidance to meet the increasing demands in clinical research in Vietnam while ensuring
adherence to strict technical and ethical requirements.
We thank Family Health International (FHI) for their guidance and support for the workshop and look forward to
working with all local and international partners in improving the conduct of clinical research in Vietnam.
Prof. Dr. Truong Viet Dung
Director
Department of Science and Training- Vietnam Ministry of Health
4 Implementing Clinical Research in Vietnam - Symposium ProceedingsIn July 2007 a two-day workshop was held in Hanoi in which representatives from the Ministry of Health pre-
sented government regulations and procedures for conducting clinical research in Vietnam. Attending this work-
shop were approximately 60 medical professionals from institutions in Vietnam who participated as representa-
tives from sites conducting international multi-center clinical research. Since internationally sponsored clinical
trials are relatively new in Vietnam and the appropriate processes have not always been clear to investigators and
medical centers, the purpose of the workshop was to clarify these procedures and open a dialogue between the
Ministry of Health and clinical research sites.
Family Health International (FHI) has worked for over 10 years in Vietnam in the fields of reproductive health, HIV/
AIDS, and clinical research in numerous infectious disease areas. FHI’s clinical research team has expanded within
the past two years and now includes capacity building to clinical site staff on research ethics and Good Clinical
Practice (GCP). Other training has been provided, including protocol implementation, regulatory management
and many other aspects of clinical trials operations.
We would like to acknowledge the Ministry of Health representatives who presented the material and were open
to questions and comments from investigators from research sites throughout the country. We are also grateful
to the clinical study site staff that have been present and shared their experience in conducting clinical research
trials in Vietnam so far.
We see this meeting as an important step in the ongoing development of the practice of clinical research in
Vietnam.
Stephen Mills, MPH., PhD
Country Director
Family Health International/Vietnam
Implementing Clinical Research in Vietnam - Symposium Proceedings 5Approval of protocol, monitoring and
evaluation, final review, and dissemination
of research
Nguyen Ngo Quang, MSc.
Department of Science and Training, Vietnam Ministry of Health
This presentation reviews important issues in mitted for approval and implementation. These laws
the current approval process for clinical research also address evaluation. They are, however, often
protocols in Vietnam fragmented and insufficient. Before January 11, 2007,
there was no law regulating clinical trials. But the
current regulations for conducting clinical trials
Vietnam Ministry of Health (MOH) is engaged in the
in Vietnam
process of developing inclusive operational guidance
to meet increasing demands in clinical research in
There are several legal and regulatory provisions in
Vietnam while ensuring adherence to strict technical
Vietnam describing different aspects of the process
and ethical requirements.
by which a clinical research protocol should be sub-
The current approval process for clinical
research protocols
Preambles to regulations for clinical research
When a protocol has been jointly developed by the
The Pharmaceutical Law, issued in June 2005 principal investigator (PI) and the sponsor of the
Decision No. 186/BYT-QD, issued May1975 on study, it is sent to the MOH’s Department of Science
Guidelines for clinical trials and treatment and Training (DST) for review by the Ethics Committee
Decision No. 371/BYT-QD, March 1996 on and the Science Committee, and eventually approved.
Guidelines for Evaluation of Safety and Efficacy DST coordinates the process of reviewing protocols,
of Traditional Medicines monitoring trial implementation, and evaluating trial
results as well as providing guidance.
Helsinki Declaration 1986
WHO Guidelines for Good Clinical Practice (GCP)
Regulations on clinical research protocols
and ECB
ICH Harmonized Tripartite Guidelines for Good Since the majority of clinical studies are ‘multi-center’
Clinical Practice E6 projects, protocol must follow a standard MOH format,
Protection of Human Subjects and Research clarifying actual procedures and written in either Viet-
efficacy namese or English. It should include the following
topics with additional documents, such as an investi-
Ensuring Good Clinical Practice standards in
gator’s brochure, submitted for reference only.
clinical trials in Vietnam.
6 Implementing Clinical Research in Vietnam - Symposium Proceedings letter of interest (format provided) ceutical Product (CPP), and Certificate of Good
a clinical research contract between the sponsor Manufacturing Practice (GMP).
and the PI (format provided)
MOH must respond within 60 working days of receipt
trial design
of complete protocol documents. Once approved,
curriculum vitae of principal investigator and co- contents of a protocol must not be changed or revised
investigators without prior approval from the MOH-DST. However,
a statement on ethical considerations current wording “revising the MOH-approved proto-
col’s contents is prohibited” can create misunderstand-
a description of product(s)
ing, and is therefore under review in the upcoming
»» summary of findings from non-clinical studies version.
»» summary of findings from pre-clinical studies
»» summary of findings from clinical trials of the Regulations on the qualifications of
previous phases investigators
a report from the committee at the institutional
level on scientific and ethical aspects of the trial The investigating organization should be quali-
fied with the facilities, equipment, and human
samples of trial product(s), provided in the small-
resources necessary to guarantee proper conduct
est possible packaging unit
and to comply with Good Clinical Practice (GCP).
For protocol on clinical trial Phase 4, include Free There should be no financial or organizational
Sales Certificate (FSC) or Certificate of Pharma- relationship between investigators and the
sponsor outside of the study.
Currently, only health institutes at the central
level directly managed by MOH may conduct
Essential points
clinical trials. In Ho Chi Minh City (HCMC), pro-
vincial level hospitals can be investigators given
Health institutes at the district level are not
prior approval from the Provincial Health Service
allowed to implement a clinical trial.
(PHS).
Protocols must follow MOH format and be in
The PI should be a medical doctor with qualifica-
either English or Vietnamese.
tions and clinical experience necessary to under-
Special ethical considerations should be given take the study, and should demonstrate the
to trials on vulnerable groups. ability to work according to GCP guidelines and
MOH responds within 60 working days of receipt other relevant legislation. Participating investi-
of complete protocol documents. gators should have appropriate qualifications
and be trained on current GCP knowledge and
All revisions in the protocol should be approved
research skills.
by MOH prior to implementation. Minor amend-
ments can be approved by DST while decisions
MOH currently allows two approaches for selecting
on major changes should be made by the
the investigating organization: (1) after approving the
review committee.
proposal, MOH suggests at least three eligible, domes-
Review and approval of study results must be tic institutes, or (2) the sponsor directly contacts an
done at two levels, institutional and ministerial. institute and proposes them to MOH. In the latter,
Result should only be disseminated or pub- the Ministry reserves the right to reject the proposed
lished after being approved by the MOH review institute.
committee.
Implementing Clinical Research in Vietnam - Symposium Proceedings 7Protection of study participants Quality Assurance
Study participants should be voluntary, suitable Quality assurance can be performed in three ways
for the study, and competent in civil behaviors. by the monitoring and evaluation working group
Participants or their guardians should give appointed by the MOH through routine and
informed consent. unscheduled visits
An ethics committee must give special consider- by the monitor(s) appointed by the sponsor
ation to protecting the welfare of special partici- by the ethics committee
pants, such as children, pregnant women, people
with mental disabilities, people living with HIV/
AIDS (PLHA), prisoners, detainees, and other Review and approval of results
special populations. The Minister of Health must
approve all trials involving these populations. Research results should be reviewed according to current
regulations for research projects at the ministerial and
institutional levels. For trials conducted by provincial insti-
Budgeting tutions in HCMC, results should be reported to, but not
reviewed by, the PHS.
Budgets for clinical research should be presented
in the contract in the provided format covering
fees for review, approval, management, monitor- The way forward for 2007 to 2010
ing and evaluation.
MOH is in the process of developing guidelines for best
In government-sponsored research projects,
practices in clinical trials and in training investigators
budgets for clinical trials may be included in the
and clinical research associates (CRA). DST is also devel-
original total budget, or provided separately by
oping and piloting GCP standards and establishing a
the organization.
data management system in collaboration with the
Investigating organizations and the PI are respon- MOH’s Drug Administration Department (DAD).
sible for managing their budgets.
8 Implementing Clinical Research in Vietnam - Symposium ProceedingsEthical aspects of biomedical research
Nguyen Ngo Quang, MSc.
Department of Science and Training, Vietnam Ministry of Health
Ethical principles While “ethics” refers to a set of moral principles govern-
ing human character and conduct, traditionally the prin-
Ethics is one of the most ancient concepts in human ciples of medical ethics embrace the principles of auton-
society. Since the time of Hippocrates—or of Hai Thuong omy, beneficence (do good); non- malfeasance (do no
Lan Ong in Vietnam—protection of patients has been a harm), and justice. These principles are as much relevant
chief concern in medicine. Ethical issues in biomedical to biomedical research as they are to healthcare.
and public health research are clearly of great impor-
tance, as any health care team involved in research is International guidelines for research on
ethically bound to respect the patient or human subject. human subjects
Good research requires that researchers respect the
rights of their subjects, listen to and share information 1947: the Nuremberg Code—but does not
with them, and treat them courteously and caringly. mention clinical trials
1964: the World Medical Association Declaration
of Helsinki—underscored 12 basic principles for
Essential points the conduct of human biomedical research
1980, 1983, 1989, 1996 and 2000: the Helsinki
All biomedical research conducted in Vietnam, Guidelines revised
including postgraduate projects, requires ethical
1982: the Council for International Organization
review.
of Medical Sciences (CIOMS) proposed guide-
The Ethics Committee operates at two levels, lines for international research. These were
institutional and ministerial, and represents dif- amended in 1993 and 2002 as the International
ferent areas of expertise. Ethical Guidelines for Biomedical Research Involv-
Investigators submit the protocol proposal ing Human Subjects.
to the DST, who will then send it to the Ethics
Committee for review. Important requirements for ethics in
The Ethics Committee advises the Minister of biomedical research
Health on ethical considerations, and takes
decisions through voting. Evaluating benefits and risks: ensures that
The committee is currently responsible for initial a subject’s rights are respected, benefits are
review only. Its role in continuing review of enhanced and risks are minimized, and par-
ongoing research is still weak. ticipating groups are receiving the benefits and
bearing the risks equally.
Regulation No. 5219/BYT-QD, December 2002,
details the organizational structure and opera- Obtaining informed consent: ensures that par-
tions of the ethics committee. ticipants decide, and then only after being fully
informed on what the research is about, possible
Implementing Clinical Research in Vietnam - Symposium Proceedings 9benefits and risks, confidentiality, and incentives. The monitoring role of the ethics committee in Vietnam
Although consent must be obtained in writing, a has not been a priority in recent years but the govern-
signed consent form alone does not constitute ment has plans to strengthen this. Currently the DST
informed consent. oversees investigators and study protocols.
Ensuring personal confidentiality: participants’
personal information must be respected and kept The ethics committee in Vietnam is appointed by MOH
confidential. and therefore not completely independent of the gov-
ernment. It reviews protocols and advises the Minister
Research involving vulnerable communities
of Health on the ethical aspects. The Minister of Health
carries additional responsibilities: special
has the ultimate say in decisions to approve or reject
considerations must be paid to groups such as
a proposal.
children, pregnant women, prisoners, detainees,
people with mental disabilities, the poor, minori-
Organizational structure and operational guidelines
ties, the illiterate, people living with HIV, men
for the ethics committee at both levels are detailed in
who have sex with men, sex workers, and others.
MOH regulation No. 5129/BYT-QD, issued in 2002. Each
institution or organization will have its own guidelines
Ethical practice in biomedical research in on organizational structure and operation of its own
Vietnam ethics committee, as well as guidance on procedures
for appeal of regulations.
Ethics committees
For ethical review
In Vietnam, the procedure for clinical trials requires
that MOH establish an ethics committee to review and For review, the ethics committee needs
evaluate the ethical aspects of biomedical research. a letter requesting approval
This is to safeguard the rights, safety, and well-being
a copy of the research protocol
of all human subjects in a clinical trial. MOH regulation
No. 5129/BYT-QD requires all biomedical research, curriculum vitae of principle investigator and co-
including epidemiological surveys, to be reviewed by investigator(s)
an ethics committee. the information form to be provided to partici-
pants
The committee can be at two levels, institutional and
written informed consent forms
ministerial. An institutional committee has a term of
four years and provides for seven members. A ministe- a statement of adherence to ethical requirements
rial committee has a term of five years and provides and any agreement with participants set forth in
for nine members. Committee members should have the consent form and information form
different qualifications and experience to represent
many areas of medicine, and must include a lawyer Review procedures
and the chair of the Healthcare Labor Union.
determine the adequacy of the proposed proto-
Currently the ethics committee in Vietnam is primarily col according to ethical concerns and law
responsible for committee members review proposal and, if
organizing and conducting reviews of protocol necessary, non-members with expertise, before
committee’s bi-weekly meetings
notifying the investigator/institution about
research-related decisions and issues where they review meeting including discussion
have concern vote on approval
10 Implementing Clinical Research in Vietnam - Symposium Proceedings notification of the committee’s decision, issues Current practice of the ethics committee: Other
and questions attendees raised questions about whether there is only
continuing review of the ongoing research one ethics committee to review all protocols during
the five-year term or whether a committee is newly
established whenever a new protocol is submitted.
Questions and discussion Dr. Quang responded that the ethics committee must
review all new protocols during its term. But current
Biomedical research under postgraduate courses: practice has been less than the standard following
Attendees at these proceedings raised the question of the deaths of the Chair and the Vice-chair during the
ethical review for biomedical research conducted as 2002−07 term. A new committee will not be estab-
partial fulfillment of a postgraduate degree, particu- lished until the new term starts, and in this transition
larly in non-medical universities. Dr. Quang from the period the Minister of Health will appoint an ethics
DST-MOH responded that theoretically all biomedi- committee for each protocol. MOH has also proposed
cal studies require ethical review regardless of the one new branch of the Ethics Committee in HCMC so
context. In fact, the Ethics Committee is currently only that proposals in southern areas can be reviewed in a
operating at the Hanoi Medical University and HCMC prompt manner.
Medical and Pharmaceutical University, and generally
review applies only to students of these two universi- Participants then asked about voting and evaluation:
ties. At other universities, biomedical research may not The ethics committee makes its decision through
undergo the ethical review process because there may voting. A decision needs a two-thirds majority to pass.
be no ethics committee, because postgraduate theses Decision follows three levels: (1) accepted without
are managed by the Ministry of Education and Train- amendment (2) accepted with minor amendments,
ing (MOET), or due to lack of coordination between and (3) not accepted. If approved it is then presented
MOH and MOET. to the Minister of Health for final approval.
Implementing Clinical Research in Vietnam - Symposium Proceedings 11Good Clinical Practice
Nguyen Ngo Quang, MSc.
Department of Science and Training, Vietnam Ministry of Health
The purpose of this presentation is to provide an over- Why GCP?
view of good clinical practice (GCP). This includes con-
cepts, goals, principles, activities, and phases of clini- The purpose of GCP is to ensure that clinical research
cal trials, as well as World Health Organization (WHO) conducted on human subjects is designed and con-
GCP guidelines and their current use in Vietnam. MOH ducted according to sound scientific and ethical
is also developing a first edition Guidelines for GCP in standards. Compliance assures that the rights, safety,
Vietnam, planned for late 2007. and well-being of subjects are protected, the clini-
cal research data are credible, and quality assurance
What is Good Clinical Practice? systems are functioning well.
Good Clinical Practice (GCP) is an international scien- GCP Principles
tific and ethical quality standard for designing, con-
ducting, recording, and reporting on clinical research GCP Principles reflect the Declaration of Helsinki, the
involving human subjects. The ICH Harmonized Tri- Nuremberg Code, the CIOMS, and WHO Guidelines on
partite Guideline for Good Clinical Practice (E6) is the Good Clinical Practice, as well as other recognized con-
latest such standard approved by the U.S. Food and ventions.
Drug Administration (FDA).
1. Ethical conduct: Clinical research should be con-
ducted in accordance with basic ethical principles,
namely respect for persons, beneficence, and
justice, which permeate all other GCP principles.
Essential points
2. Risk-benefit assessment: A risk-benefit analysis
GCP is an international scientific and ethical of the study should precede the research itself.
standard for designing, conducting, recording, 3. Weighing risk and benefits: A research study
and reporting on clinical research that involves should be initiated and continued only if the
human subjects. anticipated benefits for the individual subject and
Clinical research should comply with basic society justify the risks, especially the risks related
ethical principles in ICH E6. to the safety and well-being of human subjects.
Responsibility for GCP is shared by all parties 4. Compliance with protocol: A research study
involved including sponsors, investigators, CROs, should be conducted in compliance with proto-
ethics committees, authorities, and subjects. col that has received prior approval and receives
ongoing oversight while an active protocol from an
Vietnam GCP is planned for publication in late ethics committee and institutional review board.
2007. Currently, ICH Guidelines provide detailed
guidance on roles, responsibilities, and essential 5. Supporting documents: Review and approval of
documents for the protocol. the clinical research study should be adequately
supported by available non-clinical and clinical
information.
12 Implementing Clinical Research in Vietnam - Symposium Proceedings6. Protocol: Clinical research should be scientifi- to further evaluate toxicity, dosage and also
cally sound and described in a clear and detailed efficacy
protocol. Phase III: involves randomized controlled trials
7. Informed consent: Voluntarily informed consent on large groups, often multi-center, offering
should be obtained from every subject, or guard- a definitive assessment of how effective the
ian in case the subject is not mentally or legally product is; research results provide scientific evi-
capable prior to participation. dence which, together with previous results, is
8. Investigator qualifications: Investigators giving submitted to regulatory bodies for review and
medical care to subjects must be qualified physi- approval for marketing
cians, even if the subject has decided to withdraw Phase IV: follows product approval and market-
from the research. ing, to gather information on effects in various
9. Staff qualifications: Each individual conducting populations and side effects associated with
research should be qualified with proper edu- long-term use.
cation, training, and experience, and should be
licensed, if necessary, to perform required tasks. Currently, MOH does not provide an exact figure for
number of human subjects required for each phase,
10. Records: All clinical data should be recorded,
as this depends on the nature of the product and
handled, and stored in a manner that allows for
protocol.
accurate reporting and interpretation.
11. Confidentiality and privacy: Human subjects’
Main contents of the ICH Guidelines on Good
personal information and study records must be
Clinical Practice
kept confidential. Respect for privacy and confi-
dentiality are integral parts of these regulatory
1. Glossary
requirements and are universal.
2. The Principles of ICH GCP: 13 above-mentioned
12. Good Manufacturing Practice (GMP): Products
principles
developed from or used in research should be
manufactured, handled, and stored in accordance 3. Independent Ethics Committee (IEC): responsi-
with applicable GMP guidelines and should be bilities; composition; function; and operations
used in accordance with the approved protocol. 4. Investigators: qualifications; available resources;
13. Quality systems: Procedures must assure the medical care of research subjects; communication
quality of every aspect of clinical research. with IEC; compliance with protocol; investigation
product(s); randomization procedures and un-
blinding; informed consent from subjects; records
Phases in clinical research and reports; progress reports; safety reporting; ter-
mination or suspension of research; final report
The development of new medical products (i.e., medi-
cine, vaccine, equipment) involves 5. Sponsor: quality assurance and quality control;
contracted research organization; medical exper-
Pre-clinical phase: conducted on animals,
tise; research design; management; data handling
studies biomedical characteristics, toxicity, and
and recordkeeping; selection of investigators; allo-
in some cases dosage
cation of responsibilities; compensation to sub-
Phase I: tests the product in a small group of jects and investigators; financing; notification/sub-
people for the first time to determine safe dosage, mission to regulatory authorities; confirmation of
identifies side effects, and evaluates product review by IRB/IEC; information on investigational
safety product(s); manufacturing, packaging, labeling
Phase II: continues testing on a larger group and coding investigational product(s); access to
Implementing Clinical Research in Vietnam - Symposium Proceedings 13records; safety information; adverse drug reaction ticipation. MOH responded that is not responsible
(ADR) reporting; monitoring; audits; non-compli- for specifying the amount of compensation (this is
ance; premature termination and/or suspension of the role of the Ministry of Finance (MOF) and there is
research; multi-center research currently no guideline. It is the matter of negotiation
6. Clinical research protocol and protocol amend- between investigator(s) and participants and depen-
ments: general information; background informa- dent on the nature of the research. However, the
tion; research objectives and purposes; research compensation, method, and manner, as well as other
design; selection and withdrawal of subjects; treat- benefits for subjects, should be clarified in advance an
ment of subjects; assessment of efficacy; assess- information form.
ment of safety; statistics; direct access to source
data/documents; quality control and quality assur- Overlap in responsibilities of regulatory authori-
ance; ethics; data handling and record keeping; ties: Attendees raised the issue of overlapping respon-
financing and insurance; publication policy; and sibilities between different departments at MOH. Dr.
supplements Quang responded that currently the DST is responsi-
ble for technical and ethical review while the Depart-
7. Investigator’s brochure: introduction; general
ment of Finance is in charge of the financial aspects
considerations; contents of the investigator’s bro-
of the protocol, and funding procedures are reviewed
chure; Appendices 1 and 2
by the Department of Planning. Ministry leadership
8. Essential documents for the conduct of clini- on allocation of tasks, however, is not clear and could
cal research: introduction; period before clinical be interpreted differently by each department. This
phase commences; during the clinical research; creates complicated and overlapping procedures for
after completion or termination of research investigators during the approval process, particularly
for research with international cooperation. It is now
Questions and discussion the role of the MOH to detail and clarify responsibili-
ties and the scope of review for each body.
Compensation for subjects: Attendees asked how
much is enough compensation for research subjects
without affecting the voluntary nature of their par-
14 Implementing Clinical Research in Vietnam - Symposium ProceedingsGuidelines for review and evaluation
of protocols
Nguyen Ngo Quang, MSc.
Department of Science and Training, Vietnam Ministry of Health
This presentation reviews the international guide- Have research teams obtained information on
lines for the ethical and scientific evaluation of clini- subjects and informed consent in writing?
cal research. It is based on close examination of well- Have researchers confirmed confidentiality?
established guidelines, including WHO Operational
Guidelines for Ethics Committees that review bio- What are the main considerations in product
medical research, and the WHO and ICH Guidelines for safety, risk to subjects, product efficacy, monitor-
GCP, as well as the few existing regulations on clinical ing of product effectiveness and tolerance during
research in Vietnam. These guidelines are intended to the study, as well as follow-up after research?
facilitate and support the current review process in
Vietnam, to develop consistent national guidelines for Scientific and medical values
the ethical and scientific review of clinical research.
This process must consider potential for the use of
General requirements results, the previous similar research, recruitment of
study participants, treatment, and follow-up. Check-
Following are the four main elements in the review of lists include
research proposals and their supporting documents. In Is this research necessary (e.g., not repeating a
addition, review committees need to take into account previous study)?
the requirements of applicable laws and regulations.
ethics and safety for research subjects and
researcher(s)
Essential points
scientific relevance and value of the clinical
study International guidelines for review and evalua-
research methodology tion of a clinical study proposal are intended to
facilitate and support the current review process
feasibility of the research itself and quality
in Vietnam.
assurance
Four main elements are recommended for
review of research proposals: ethics and safety;
Ethics and safety
scientific relevance; research methodology; and
research feasibility.
Evaluation of protocol should involve the following
questions: Detailed guidelines for ethical review are avail-
able but scientific review guidelines are still in
Has it been reviewed by an appropriate ethics
development.
committee?
Implementing Clinical Research in Vietnam - Symposium Proceedings 15 Are there inclusion and exclusion criteria? Questions and discussion
Are treatment regimens for subjects appropri-
ate? Impartiality and partiality among EC members:
A participant raised a doubt about the relevance of
Is the follow-up and medical care provided ade-
evaluation from EC members. The ethics commit-
quate?
tee in Vietnam does not always represent a variety of
Will the outcomes (e.g., suitability, feasibility, perspectives, but merely a scientific view. Their com-
international acceptability) be measured and are ments and evaluations are often focused on the tech-
these appropriate? nical rather than the ethical aspects. Dr. Quang from
Are the recording procedures for adverse effects the DST responded that though the guidelines are
appropriate? available, the EC does not always fully understand or
follow them. But MOH has a plan to train and re-train
members on the principles and guidelines for ethical
Research methodology and bias
review of research protocols in the near future.
Are the selected methods (e.g., clinical trial,
Guidelines for scientific review: Attendees also
cohort study, case-control study) suitable to the
asked whether there were as detailed guidelines for
research topics?
scientific review as there are for ethical review. Dr.
Is there an acceptable calculation for required Quang responded that detailed guidelines are being
sample size? Are the prognostic biases caused by prepared by the DST. At the ministry level, two differ-
the withdrawal of research subjects considered? ent protocols have been prepared for two review pro-
Are exclusion criteria accurate, valid, and justi- cesses: scientific and ethical. Thus there is less confu-
fied? sion at this level. However, the two committees at the
institutional level may still need training or re-training,
Are suspension and termination criteria well
which MOH hopes to provide in the near future.
defined and acceptable?
Is the plan for data analysis clearly described? Guidelines for review of pre-clinical research pro-
tocols: Attendees noted the lack of guidelines for
Feasibility reviewing protocols in the pre-clinical phases. The pre-
senter responded that before January 2007, Decision
Investigators should also prove that they are capable No. 371 BYT-QD regulated all pre-clinical and clini-
of carrying out research with sufficient infrastructure cal research processes. And Decision No. 01 replaced
and staff, specifically the previous regulations on all items related to clini-
cal research in January 2007. The pre-clinical research
Is the investigating organization strong in the
process, however, still does not adhere completely
recruitment and provision of care and follow-up
to Decision No. 371 and new regulations are in the
for research participants?
process of development.
Will the products be managed according to the
plan? Attendees also asked whether it is necessary to
Will the outcomes be measurable? conduct pre-clinical trials for drugs that cannot be
Are the experiments technically appropriate? tested on animals. This revealed a misunderstanding,
as pre-clinical trials could be animal or laboratory-
Are the data collection methods and treatment based. Ultimately all clinical trials require study results
procedures appropriate? from the pre-clinical phase.
Will the clinical trial be sufficiently supervised
and monitored?
Will there be sufficient follow up for subjects?
16 Implementing Clinical Research in Vietnam - Symposium ProceedingsGuidance for different categories of clinical medicinal drugs and vaccines, the regulation on clini-
research: The audience further asked whether cal research (Decision No. 01) cannot separate them.
MOH has detailed policy on specific types of clinical Regulations, therefore, are still vague and difficult to
research, as many aspects and procedures are not the implement. But MOH plans to issue detailed guide-
same across trials. Dr. Quang responded that since lines for specific categories of clinical research, which
the law defines the term “medicine” as covering both likely won’t be included in regulatory documents.
Implementing Clinical Research in Vietnam - Symposium Proceedings 17Plan for GCP implementation: 2007−2010
Nguyen Ngo Quang, MSc.
Department of Science and Training, Vietnam Ministry of Health
Biomedical research is becoming increasingly impor- Proposed activities
tant in Vietnam and a more comprehensive, more
stringent regulatory environment for scientific and Objective 1: Increase knowledge and skills of
ethical standards will follow. From 1996 to 2002 MOH investigators, monitors, supervisors, managers, and
developed its first regulations on clinical research, yet members of review committees in GCP and ethics in
there are many more that need to be implemented clinical research.
by 2010. Funding is the major impasse and MOH will
Issue the GCP Guidelines of Vietnam (September
mainly depend on international aid for training of clin-
2007).
ical research personnel. And this training must comply
with MOH guidelines. Establish the ethics committee for the new term
(2007−2012).
Conduct trainings and provide MOH certificates
Objectives of MOH’s GCP plan
on GCP.
To increase knowledge and skills of investigators, Complete a GCP training package comprised of
monitors, supervisors, managers and review com- GCP guidelines and other regulatory documents.
mittees in GCP and ethics in clinical research. Increase collaboration between MOH and inter-
To establish a monitoring and evaluation (M&E) national organizations (NGOs, pharmaceutical
system for clinical research in accordance with companies).
GCP standards.
Objective 2: Establish an M&E system for clinical
To establish a network of investigating organiza-
research in accordance with GCP standards.
tions meeting GCP requirements in conducting
clinical research. Develop M&E tools and protocols.
To develop a data management system for clini- Train monitors at the national and institutional
cal research. levels.
Conduct routine M&E by the ethics committee,
Although these four objectives will be implemented national monitors, sponsors, and managerial
simultaneously over the next three years the first bodies.
remains the most important, as it concerns the person-
nel aspect. Strengthened capacity of people involved Objective 3: Establish a network of investigating
in GCP will result in better implementation, monitor- organizations meeting GCP requirements in conducting
ing, and management. clinical research.
18 Implementing Clinical Research in Vietnam - Symposium Proceedings Develop criteria and tools for reviewing and eval- Objective 4: Develop a data management system for
uating investigating organizations. clinical research.
Disseminate these evaluation criteria and tools Develop protocols for management and storage
so that investigating organizations are well of clinical research.
informed for their preparation. Develop a computer system for data manage-
Review, evaluate, and grant the GCP certificate ment (currently paper-based).
for eligible organizations. Provide training for data management personnel
Support DST and standardized investigating on applying the new system.
organizations with equipment for data manage- Pilot a new management system for clinical
ment and for GCP trainers. research data.
Implementing Clinical Research in Vietnam - Symposium Proceedings 19Procedures for manufacture and import of
medicinal drugs for clinical research
Dr. Do Minh Hung
Drug Administration Department, Vietnam Ministry of Health
Any medicinal product used for clinical research must GMP certificate, it should be evaluated by MOH prior
receive approval from the Drug Administration Depart- to approval of the application. The sponsor, investigat-
ment for production if locally produced or for import ing organization, or an officially-designated organiza-
if donated. The application is due after the clinical tion may submit the application.
research protocol has been reviewed by the science
and ethics committees and approved by MOH.
Pharmaceutical products
In Vietnam, “medicinal drug” is understood as includ-
An applicant must submit the following documents
ing pharmaceuticals and other biomedical products.
to DAD for review. Upon obtaining written permission
Drugs and medical biological products used for clini-
(due in five to seven working days), the organization is
cal research must be manufactured at GMP-qualified
entitled to produce, receive, or import the study phar-
facilities. If a facility (e.g., a hospital) does not have the
maceutical for clinical trials.
Locally-produced drugs: per Decision No. 3121/2001/
Essential points QD-BYT on Drug Registration, the application should
include
DAD must approve import or manufacture of a letter of request for manufacturing
study drug or biological product. product specifications, analytical methods, and
Written approval for research protocol should analysis prepared by the manufacturer (if the
be obtained from the DST prior to the applica- manufacturer is GMP-certified) or the national
tion for manufacturing/import. analytical institution
Application dossiers should comply with regula- manufacturer’s protocol: a list of all components
tions and vary according to product as follows and the quantitative composition of the inves-
»» Pharmaceutical products: locally produced tigational product (active ingredients only), a
or imported/donated description of manufacturing method and pro-
cedure, as well as a list of equipment and facilities
»» Vaccines/biological products
used to produce this product
Packaging, coding, and labeling of products
labeling indicating the quantity for each packag-
should comply with regulations for drugs and
ing unit
vaccines while ensuring the trials remain ‘blind’.
an approval letter from MOH for the clinical
Destruction of products should strictly follow
research protocol (original copy or a photocopy
guidance for specific types of drugs.
certified by the investigating organization)
20 Implementing Clinical Research in Vietnam - Symposium ProceedingsDonated drugs: per Circular No. 06/2006/TT-BYT on vaccines, biomedical products, chemicals, medical
import and export of drugs and cosmetics equipment, antiseptics, and disinfectants for domestic
a letter of request for receiving donated drugs for and medical use
clinical research a letter of request for import
a list of donated drugs (format provided) written approval from MOH for the clinical
an approval letter from MOH for the clinical research protocol (original or notarized copy).
research protocol (original copy or a photocopy
certified by the investigating organization) Packaging, labeling, and coding of
investigational product
Imported drugs: per Circular No. 13/1998/TT-BYT on
receiving, management, and use of donated drugs
Vaccines and medical biological products
a letter of request for import of drugs used for
Products for investigation should be packaged to
clinical research
prevent contamination and deterioration during
completed customs form for import transport and storage.
approval from MOH for the clinical research pro- Labeling should comply with Vietnamese regu-
tocol (original copy or a photocopy certified by lations. In addition, products should be labeled
the investigating organization) and coded in a manner that protects the process
of blinded trials.
Vaccines and medical biological products In blinded trials, the coding system for products
should include a way to identify if the subject is
DAD receives applications to use/import vaccines and receiving study product or placebo (or other treat-
medical biological products. Upon written approval ment) in case of medical emergency, but does
from DAD—due in seven working days for locally- not permit any study investigator or the subject
produced products and 15 working days for imported to discover if the drug given to the patient is an
products after receipt of the dossier—the organiza- active study drug or placebo.
tion is eligible to produce, receive and import vaccines
or biomedical products for clinical trials. The following The product label should include
documents must be included in the application. name of the product
name and address of the manufacturer
Locally-produced vaccines and medical biological
products: per Decision No. 4012/2003/QD-BYT on composition
Vaccine and Medical Biological Registration indications, uses, contra-indications if applicable
a letter of request for production product presentation
specifications and analytical methods packaging form
analysis report batch number, expiry, storage conditions, manu-
description of manufacturing processes, facture date
methods, and quality assurance methods precautions (indications)
labeling printed note: “This product is for clinical trial only.
written approval from MOH for the clinical Use for other purposes is prohibited.”
research protocol (original or certified copy)
Imported vaccines and medical biological prod-
ucts: per Circular No. 08/2006/TT-BYT on import of
Implementing Clinical Research in Vietnam - Symposium Proceedings 21Destruction of products for investigation Questions and discussion
At the conclusion of clinical study, investigated prod- Labeling in blind research: Participants asked how
ucts will either be returned to the sponsor, destroyed, to declare imported products to customs if the label
or recycled after obtaining written permission from is blind and the importing organization cannot iden-
DAD. This must comply with regulatory requirements, tify the active comparator(s) and the placebo. Dr. Hung
particularly for controlled drugs such as toxics, nar- from DAD responded that the importing organization
cotics, and psychotherapeutics. Safety and protec- should be able to declare the quantity of each cate-
tion for humans, animals, and the environment must gory but does not need to indicate which packaging
be ensured. unit is the active product and which is the placebo.
Destruction of investigated products must be carried Different labeling between the protocol and the
out upon written decision from the sponsor and application: One participant asked about the situ-
under witness of a minimum three-person board ation when the import application mentions the
specifically for that purpose. Upon completion this generic name of the drug while the clinical trial uses
panel should complete a report for submission to the the brand name. Dr. Hung suggested the applicant
regulating body. revise the dossier to make it consistent or to provide
written confirmation to explain this difference.
22 Implementing Clinical Research in Vietnam - Symposium ProceedingsPharmacovigilance and reporting
of adverse drug reactions
Nguyen Thu Thuy, MSc.
Drug Administration Department, Vietnam Ministry of Health
Pharmacovigilance is the recording, reporting, and ration with the Uppsala Monitoring Center, of which
analysis of adverse events in relation to the use of Vietnam is a member.
medicines. It has been estimated that such adverse
drug reactions (ADRs) are the fourth largest cause of Among other things, monitoring of ADR helps regu-
mortality in the USA, and this figure could be higher in latory bodies to approve clinical trials and to make
developing countries. The aims of pharmacovigilance prompt decisions on premature termination or sus-
are to enhance patient care and safety and to improve pension of trials.
public health and safety with medicines by providing
reliable information. This includes hospitals and aca-
ADR reporting in Vietnam
demia, health professionals, the pharmaceutical indus-
try, authorities, the media, and patients in detecting
While strongly promoted in developed countries, ADR
and reporting adverse events. Pharmacovigilance is
reporting, especially in clinical trials, has not been
promoted at the country level by the WHO in collabo-
prominent in Vietnam. Since its establishment in 1994,
the Vietnam ADR has only received reports for the
post-marketing phase in trials and not for actual trial
Essential points phases. The National ADR Center operates as an inde-
pendent institute and is totally dependent on foreign
Reporting on adverse events and side effects financial support. This makes it difficult for the center
related to the use of medicines or treatment to be actively involved in processing and making deci-
is crucial to ensure patient safety and public sions about reported ADRs.
health.
Starting in 2006, ADR reporting by pharmaceutical and
There are different types of adverse drug events.
other commercial companies is compulsory but there
ADR reporting in clinical research focuses on
is no requirement for research and treatment facilities,
ADRs that are both serious and unexpected.
such as hospitals. The current approach to ADR report-
Current regulations in Vietnam require compul- ing in clinical research in Vietnam is for encouraging
sory ADR reporting by companies and manu- investigators only, and does not establish any legally
facturing organizations. There is no regulatory enforceable responsibilities. Recommendations focus
requirement for research and treatment. merely on situations when the investigated product
Investigators are encouraged to report ADRs may pose a clinically important or unexpected risk.
during the course of clinical trials, indepen-
dently from ADR reporting by the sponsor. The following may therefore be used as a reference
for investigators in reporting ADRs during the clinical
research.
Implementing Clinical Research in Vietnam - Symposium Proceedings 23Glossary What should investigators report?
An adverse drug reaction (ADR) is a response to a Investigators and sponsors should report all suspected
medicine which is noxious and unintended, and occurs adverse reactions that are considered “likely” associ-
at doses normally used in men. ated with the trial, and those of clinical importance,
with an emphasis on ADRs that are serious and unex-
An unexpected adverse reaction is a reaction, the pected.
nature or severity of which is not consistent with
domestic labeling or market authorization, or with While almost all international sponsors have indepen-
expected characteristics of the drug. dent monitoring committees to oversee compliance
with the approved protocol and adverse events—
A side effect is any unintended effect of a pharmaceu- and while sponsors must report ADRs—investigators
tical product occurring at doses normally used by a submit their own report on reactions that may emerge
patient, related to the pharmacological properties of the during the course of clinical trials in order to avoid mis-
drug. leading data due to conflict of interest.
An adverse event is any untoward medical occurrence
How to report ADRs
that may present during treatment with a medicine
but which does not necessarily have a causal relation-
An ADR Report Form covers four sections on patient
ship with the treatment under investigation.
information, adverse events and product problems,
suspected medications, and reporter information. The
A serious adverse event is any event that is fatal, life-
completed report should be sent to the National ADR
threatening, permanently or significantly disabling,
Center in Hanoi or its office in HCMC, either by post,
requires or prolongs hospitalization, or causes a con-
email, or facsimile. Feedback from the ADR Center is
genital anomaly.
free of charge.
Evaluating ADR- drug/treatment causal Procedures for processing ADR reports
relationship
The National ADR Center classifies reports according
The causal relationship between an ADR and the treat-
to drug category. A consultation group will meet to
ment/drug can be evaluated according to six levels of
review and evaluate cases. They will then give their
possibility:
conclusions to the reporting body and to the Uppsala
1. certain Center. Due to funding shortfalls, this consultation
2. probable/likely group holds review meetings every six months, but
conducts actual reviews within one week, passing on
3. possible
feedback to investigators and regulatory bodies on
4. unlikely ADRs that are both serious and unexpected.
5. conditional/unclassified
6. unassessable/unclassifiable
Identifying the level of causal relationship between an
adverse event and the treatment, the severity of the
event, and the frequency of its presence is critical for
investigators in reporting on the adverse event and for
regulators in making decisions about the continuity of
the treatment or research.
24 Implementing Clinical Research in Vietnam - Symposium ProceedingsReview and approval of foreign,
non-government sponsored projects
Tong Hoai Nam, MPH
Department of Planning and Finance, Vietnam Ministry of Health
Foreign funding in general, and foreign non-govern- Circular No. 04/2001/TT-BKH on implementation
mental (NGO) aid in particular, play an important role of Decision No. 64/2001/QD-TTg
in the development of Vietnam and the health care Direction No. 11/2002/CT-TTg strengthening
sector is no exception. The Government of Vietnam management and use of foreign non–govern-
has issued regulations for reviewing and approving ment aid
foreign NGO-sponsored project proposals and the
Decision No. 1829/2002/QD-BYT by the Ministry
purpose of this presentation is also to provide an over-
of Health on management and use of non–gov-
view of these procedures.
ernment aid in the health sector
Regulations on non-government aid
On approval
Decision No. 64/2001/QD-TTg on the manage- The Prime Minister (PM) is responsible for ratifying
ment and use of foreign non-governmental aids
programs and projects using NGO aid valued at
US$ 500,000 or above
non-project aid valued at US$ 200,000 or more
Essential points
non-project aid involving items that have been in
use (except for goods imported as non-trade)
Clinical NGO research must have approval for
receipt of funds in addition to approval for
The Minister of Health is responsible for approving
research protocol.
programs and projects of US$ 200,000 to
NGO aid requires approval at the governmen-
500,000
tal, ministerial, departmental or provincial level
depending on scale. non-project aid under US$ 200,000, except for
used goods and equipment
Review involves several ministries or MOH
departments. Implementing agencies should
Heads of the ministerial departments will approve
»» prepare proper documents with sufficient
programs and projects under US$ 200,000
information
»» apply for approval and receipt of aid at the Chairs of the provincial People’s Committees will
same time approve
»» All details (drug names, quantities) must be programs and projects under US$ 500,000
consistent across proposal documents. and funded directly for a provincial agency—
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