K M Chang MRCP(UK)FRCP(UK)FRCPA(Haem) Hospital Ampang MREC
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K M Chang
MRCP(UK)FRCP(UK)FRCPA(Haem)
Hospital Ampang
MREC
Note These statistics are based on the number of applications received by National Pharmaceutical Control Bureau for the
clinical trial import license for unregistered products.
Drug-related clinical trials for registered products which do not require clinical trial import license is not controlled by the Drug
Control Authority.
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10
20
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60
70
80
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Year
Number of Clinical Trials Conducted in
Malaysia
(excluding Bioequivalence Studies)
Note These statistics are based on the number of applications received by National Pharmaceutical Control Bureau for the
clinical trial import license for unregistered products.
Drug-related clinical trials for registered products which do not require clinical trial import license is not controlled by the Drug
Control Authority.
0
10
20
30
40
50
60
Year
Phase of Clinical Trials Conducted in Malaysia
(excluding Bioequivalence Studies)
Phase I
Phase II
Phase III
Phase IV
Note: OTHERS : Hormone therapy, perfussion solution, antidote and endotoxin neutralizing agent
These statistics are based on the number of applications received by National Pharmaceutical Control Bureau for the clinical trial import license for unregistered products.
Drug-related clinical trials for registered products which do not require clinical trial import license is not controlled by the Drug Control Authority.
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No. of CTs Conducted by Therapeutic Class
2003 - 2010
MREC_MOH_CReaTE08 5
National Institutes of Health (NIH) Guidelines
for Conducting Research in the Ministry of
Health (MOH) Institutions and Facilities
Update and standardization of MOH policies
and procedures for research
5 September 2007
MREC_MOH_CReaTE08 6
I. 1. All research require prior registration with and approval by the MOH National Medical Research Register (NMRR) Approval
Head of Department
Institutional approval
NIH approval
2.Research involving human subjects require prior review and approval by the Medical Research & Ethics Committee (MREC)
Review and approval via NMRR
3. All research publications must have approval from the DG of Health
Prior review by the NIH
Submit drafts + form to NIH Secretariat
Ethics is about norms, values, right and wrong, good and bad, and what ought and ought not to be done.
(Raphael DD Moral Philosophy OUP 1981)
Bioethics is the philosophical study of ethical issues that arise from advances in biology and medicine
Basic/ preclinical research • Important for expanding knowledge of basic
biological mechanisms
• Can contribute to discovery of new treatments
Clinical research • Clinical laboratory or interventional studies
• To test new procedures, clinical diagnostic tools
or medicinal products/devices
• Involves human subjects
The purpose of
research is to
develop
generalizable
knowledge to
improve health, and
is therefore valuable
to society
Research subjects are
the means to
securing such
knowledge; respect
for their safety,
dignity and
autonomy is
necessary
“The primary ethical struggle in clinical research is that a few individuals are
asked to accept burden or risk as research subjects in order to benefit others and society…... ethical concerns arise because of the potential for exploitation and/or abuse of these human research subjects.”
Christine Grady in “Principles and Practice of Clinical Research ”
Definition by US regulation [4; 45 CFR 46]
A human subject (in the context of research) is “a living individual about whom an investigator obtains either
1. Data through intervention (eg. Trial) or interaction (eg Questionnaire in health survey) with the individual, or
2. Identifiable private information”
To protect:
• research subjects
• the integrity of the research
• the integrity of the researcher
• the integrity of the research
institution
Historically, observing research ethics & protecting
human subjects were left to investigators’ discretion, in
the wisdom that investigators could be counted on to do
the “right” thing
Past research abuses however have confirmed the
potential for exploitation & abuse
Three events were salient and influential in research
ethics Nazi experiments on POW & Nuremberg Trial (1946) ; similar
experiments by Japanese physicians
Beecher’s paper “Ethics & Clinical research” New Engl J Med 1966
Tuskagee Syphilis study
Hypothermia experiments: A prisoner is
submerged in cold tank ; goal of to
determine how long German pilots would
survive after parachuting into the cold
north sea
High altitude experiments: Prisoners put
into low-pressure tanks with little oxygen;
goal to test how long pilots would survive
after being ejected.
• Nuremberg trial 1947: Nazi doctors and
scientists put on trial for the murder of
concentration camp inmates who were
used as research subjects
Voluntary consent absolutely essential
Experiment should yield fruitful results, for the good of society,
unprocurable by other methods
Based on animal experiments and knowledge of natural history
Avoid unnecessary physical and mental suffering and injury
Should not be conducted if there is reason to believe death or
disabling injury will occur except perhaps experimental physicians
also serve as subjects
Risk should never exceed humanitarian importance
Adequate facilities…minimise risks
Conducted only by scientifically qualified persons
Subject at liberty to bring experiment to an end
Scientists must …terminate experiment… if probable cause to
believe…
The Nuremberg Code
became the first
codification of research
guidelines to protect
human subjects;
BUT without the force of
law
Study in Tuskegee, Alabama between 1932 and 1972 by US PHS to
determine
natural history of untreated latent syphilis.
Over 400 black men with syphilis and 200 men without syphilis as the
controls, were the subjects
Tuskegee famed school for uplifting blacks; worst poverty rate
Ethical issues: Non-therapeutic
Aim to document natural history in untreated
black males
Did not inform participants they had syphillis,
only “bad blood”
No informed consent
Witheld critical info on nature of illness and true
purpose of study
Spinal taps without consent
Burial stipends as inducements if they agreed to
autopsies
Handed out pink-coloured aspirin as treatment
No formal protocol
Open time frame
“Helicopter research”
Henry Beecher published 22 examples of abuses in NEJM 1966
Withholding antibiotics from patients with rheumatic fever
Purposely infecting institutionalized children with hepatitis
Injecting live cancer cells into nursing home patients
Etc
Respect for persons Informed consent
Purpose is protection of autonomy and personal dignity
Persons not adequately autonomous be protected by third party consent
Investigators held responsible for ensuring adequate comprehension
Beneficence
Do no harm, balance benefits vs risks, maximise possible benefits and minimise possible harms
Systematic and non arbitrary presentations of benefits and risks
Assessment by IRB
Justice
Fair distribution of burdens and benefits of research
Select persons best prepared to bear burden e.g healthy adults
Persons who are already burdened by disability or institutionalisation should not be asked to accept burden unless other participants cannot be located or are in appropriate
“the most widely accepted guidance worldwide on
medical research involving human subjects.” Christie.
BMJ 2000
World Medical Association (est. 1946), in response to the
Nuremberg Code, develop this guideline for research
ethics; adopted at its 18th General Assembly in Helsinki
in 1964
It is the first set of rules for research formulated by the
international medical community
Has gone thru’ 6 revisions since, latest
October 2008 Seoul
Extend Nuremberg code to include: • Research combined with medical care
• Incompetent subjects and Vulnerable subjects
• Review by an independent review committee
• International research (research in developing
countries)
However…no explanatory notes..lack the
force of law…
Nuremberg Code Declaration of Helsinki
Belmont Report The National Commission for the Protection of Human Subjects of Biomedical
and Behavioral Research, April 18, 1979
Three Basic Ethical Principles:
1. Respect for Persons
Individual autonomy [Cruzan]
Protection of individuals with reduced autonomy 2. Beneficence
Maximize benefits / minimize risks 3. Justice
Equitable distribution of research costs and benefits Common Rule - IRB
International Conference on Harmonisation of
Technical Requirements for Registration of
Pharmaceuticals for Human Use
US, EU and Japan
Objective is to eliminate unnecessary delay in global
development and availability of new medicines and
maintaining safeguards on quality, safety and efficacy,
and regulatory obligations to protect public health
ICH GCP E6 Guideline 1996
ICH GCP 2.1 Clinical trials should be conducted in accordance with
the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the regulatory requirement(s).
WHO GCP All research involving human subjects should be
conducted in accordance with the ethical principles contained in the current version of the Declaration of Helsinki. Three basic ethical principles should be respected..as defined by the the International Ethical Guidelines for Biomedical Research Involving Human Subjects
Collaborative partnership Social value Scientific validity Fair participation selection Favourable risk-benefit ratio Independent review Informed consent Respect for participants
E.Emanuel, D Wendler, C. Grady, Oxford Textbook of Clinical Research Ethics
Social good, enhance health and healthcare Identify representatives Shared responsibility Mutual respect Receive fair benefits from the conduct of the research
and results Fair distribution of tangible and intangible rewards
eg.royalties, publications
Research should generate knowledge that
leads to improvement in health or healthcare
Delineate short- and long-term beneficiaries
Outline the potential value
Develop mechanisms to enhance the social
value
Consider impact on existing health-care
infrastructure
Fundamental ethical requirement
Consider the scientific,method and statistical
design
Results should be useful and interpretable
Research objectives must be realised
Should be feasible in the social,political and
cultural context
Research objective should be primary
determinant for selection
Determine the scientific reason for selection
Select participants that minimises risks
Social value and benefits to participants
Determine if any vulnerability
Important vulnerable (NOT to be unfairly
targeted) or underrepresented (NOT to be
unfairly excluded) groups: Children
Women
Emergency patients
Populations of developing countries
Minority populations
Institutionalized populations (vulnerable only)
Members of a group with a hierarchical structure, eg.
students, employees, subordinates, armed forces,
prisoners ICH GCP 1.61 (vulnerable only)
Fetus and embryo (Vulnerable only)
Favorable net risk-benefit
If potential risks outweigh benefits, social value
must be justified
Delineate risks and minimise
Identify type, probability and magnitude of
benefits
Compare benefits vs risks
More complex evaluation in Phase 1 studies
Minimise concerns regarding researchers conflict of interest
Public accountability Review must be independent and competent Transparent Minimise multiple reivews and reconcile
differences
ICH GCP 1.31 Institutional Review Board (IRB) or Independent Ethics
Committee (IEC)
An independent body constituted of medical, scientific, and non-scientific
members, whose responsibility is to ensure the protection of the rights,
safety and well-being of human subjects involved in a trial by, among
other things, reviewing, approving, and providing continuing review of
trial protocol and amendments and of the methods and material to be
used in obtaining and documenting informed consent of the trial
subjects.
Respect for autonomy
Must be valid
Recruitment procedures and compensation should be consistent
Written and verbal disclosure should be based on local level of understanding and culture
Disclosure should be complete and relevant but not overwhelming
Strategies for individuals unable to consent
“spheres” of consent
Participants free to refuse or withdraw
Formal assessment and monitoring
When seeking informed consent, the physician should
be cautious if potential subject is in a dependent
relationship….consent should be sought by an
appropriately qualified independent individual
Declaration of Helsinki
A process of information exchange between the researcher/investigator and the subject
Informed Consent is obtained before the subject
participates No person should be subjected to coercion or pressure
into deciding whether to participate or continue to participate
Subjects or subject’s legally acceptable representative
should be given ample time and opportunity to inquire about details of the research
PI can request waiver Criteria
No more than minimal risk
“minimal risk” is defined where the probability and magnitude of harm or discomfort anticipated in research are not greater than those encountered in daily life or during routine physical or psychological exams or tests
Medical records or biological specimens taken in course of clinical care with research of minimal risk
Collection of data, documents, records, specimens or diagnostics already available
Public service programmes
Impracticable to obtain consent
Preliminary review
As in expedited review
Individuals must continue to be treated with respect from the time they are enrolled, throughout their participation and even after their participation ends.
Respecting subjects means : 1. Protect subject’s confidentiality & privacy 2. Provide opportunity to withdraw early, without penalty 3. Monitor subject’s well-being. Have procedures to manage:
- Adverse reactions, emergencies, change in clinical status
- Pregnancy, discontinuation, ? Monitor till outcome 4. Inform subject of new information, and re-consent if
necessary 5. Inform subject the study results, in recognition of his
contribution to research 6. Compensate subject for research related injury
Procedures to protect confidentiality Subjects identified only by study number and initial Investigator keep Patient Identification List with complete ID
information on subject. Documents not for submission to sponsor maintained by the
investigator in strict confidence. Monitor/auditor/IEC/Reg. granted direct access to subject
medical records… without violating the confidentiality of the subject.
Electronic data processing identified by patient number Encryption during data transfer
For medical research using identifiable human material
or data, physicians must seek consent for collection,
analysis, storage or reuse. There may be situations
where consent would be impossible or impractical…in
such situations…approval of a research ethics
committee
Declaration of Helsinki
Malaysian Guidelines for Good Clinical Practice 3nd Edition (Updated 2011, NPCB website)
Guidelines for Application of CTIL and CTX in Malaysia 5th Edition (Updated June 2009, NPCB website)
Guidelines for Good Clinical Practice Inspection (1st Edition Oct 2010)
39
EC, MOH 6 – 8 weeks
Universities 4 – 8 weeks
National Heart Institute 3 – 6 weeks
DCA 30 working days*
40
*Note: except for first in man trial, advanced therapy medicinal product (ATMP),
Biotechnology product and Herbal products.
5.19 of M’sian GCP Guidelines
By the local Regulatory Authority
External Regulatory Authorities
e.g: FDA,USA
EMEA,Europe
41
1.55 Regulatory Authorities :- • are bodies having the power to
regulate, • includes the authorities
that review submitted clinical data that conduct inspection
(Competent Authorities) 1.26 Drug Control Authority (DCA)
• An authority established for the purpose of regulating the Control of Drugs and Cosmetics Regulations, 1984
42
To ensure the rights and safety of study
subjects have been protected.
To determine the validity of the data
submitted to the regulatory authority.
To assess adherence to GCP guidelines
and regulations.
To assure the integrity of scientific testing
and study conduct.
43
1. ALTERED DATA
• Generating biased data or changing data is legitimately obtained.
2. OMITTED DATA
• Not reporting data which has an impact on the study outcome
• E.g.
• Removing subjects from study population during analysis
• Not reporting or disguising adverse events
3. MANUFACTURED DATA
• Fabricating information or creating results without performing the work
• E.g.
• Filling in data in the CRF when work is not done
• Photocopying data and using it for multiple subjects
• Creating fictitious subjects
44
Three general types of fraud:
MOH encourage and promote stem cell research in Msia All must be reviewed by IRB…must strictly adhere to National
Guidelines Copy to be submitted to NSCRE subcommittee Research on human adult stem cells allowed Laboratories conform to GLP and for clinical trials GMP
compliant All imported stem cells/tissue products for use in clinical
trial and therapy shall be GMP certified and registered by DCA
Therapeutic outcomes, adverse effects and tissue integration shall be documented or reported to NSCRE
Regulatory oversight
Key requirements for IRBs
Preclinical studies
Phase I, II and III studies
Cell processing and manufacturing
Product registration
Cell characterisation
Investigators
Centre registration
Patient information
Submission of protocol to committee
MREC_MOH_CReaTE08 47
Pharmacogenomics/pharmacogenetics
• KKM tidak ada halangan
• Sampel ke luar negeri
• Relevan pada penyelidikkan
• Informed consent
• Ujian tambahan perlu dimaklumkan kepada JEKK
MREC_MOH_CReaTE08 48
• A web portal through which research are registered & research requiring
approval are submitted and processed (review & decision making) online.
• The registered research constitutes the NMRR, a database of ongoing and
completed medical research projects in Malaysia
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