SCIENTIFIC & ETHICAL STANDARDS FOR
CONDUCTING & REPORTING RESEARCH
RESULTS: AN AGENDA FOR KAZAKHSTAN
INTERNATIONAL CONFERENCE “INTERNATIONAL STANDARDS OF
FUNDAMENTAL AND APPLIED RESEARCH”
SEMEY MEDICAL ACADEMY, SEMIPALATINSK, KAZAKHSTAN, 23-27 SEPT. 2007
IRINA CAMPBELL, PhD, MPH
US DEPT. OF STATE FULBRIGHT SCHOLAR IN
GLOBAL HEALTH
ivm1@columbia.edu
www.CampbellHealthAssociates.com
SUMMARY OF PRESENTATION
• SIGNIFICANCE OF ESTABLISHING & IMPLEMENTING STANDARDS IN
CONDUCTING FUNDAMENTAL & CLINICAL RESEARCH
• ESTABLISHING & IMPLEMENTING STANDARDS FOR REPORTING
RESEARCH RESULTS
• ESTABLISHING & IMPLEMENTING STANDARDS FOR COMMUNICATING
RESULTS AS MAIN METHOD FOR TRANSMITTING INFORMATION TO THE
GLOBAL SCIENTIFIC COMMUNITY
• PEER REVIEW METHOD OF RESEARCH INFORMATION AS MEANS OF
ENSURING TRANSPARENCY IN THE PULIC ARENA FOR RESEARCH
INFORMATION TO BECOME PART OF THE EVIDENCE BASE FOR THE ART &
SCIENCE OF MEDICINE, BIOMEDICAL INDUSTRY, AND OBJECTS OF
INTERNATIONAL TRADE
• SIGNIFICANCE OF STANDARD SETTING ORGANIZATIONS
• SIGNIFICANCE OF STANDARD SETTING AGREEMENTS
KAZAKHSTAN AGREEMENTS
NOT YET ACTIVELY PARTICIPATING IN:
•
IMPLEMENTING TRANSPARENT SCIENTIFIC INT’L STANDARDS IN HEALTH SECTOR
(proposing start in 2009)
•
INSTITUTIONAL REVIEW BOARDS (IRB) AT EACH ACADEMIC RESEARCH CENTER &
HEALTH DELIVERY CENTERS
•
PEER REVIEW OF MEDICAL RESEARCH
•
DETAILED AND SPECIFIC INFORMED PATIENT CONSENT FOR HOSPITAL
TREATMENTS OR VOLUNTARILY PARTICIPATION IN CLINICAL TRIALS
•
CONFIDENTIALITY & PRIVACY OF PATIENT HEALTH INFORMATION
•
PARIS 21 AID EFFECTIVENESS ANALYSIS
•
WHO HEALTH METRICS NETWORK
•
CLINICAL TRIAL REGISTRY
•
WORLD TRADE ORGANIZATION (current ongoing discussions for 2008 admission)
KAZAKHSTAN PROPOSING HARMONISATION
STANDARDS IN HEALTH CODEX OF 2009 BUT
LAGGING IN IMPLEMENTING INT’L EVIDENCEBASED STANDARDS OF MONITORING &
EVALUATION, ESP. IN DELIVERY OF HEALTH
CARE
• KAZAKHSTAN IS CURRENTLY REVISING HEALTH
CODEX, SCHEDULED FOR 2009 – ONE CLAUSE
SPECIFIES THAT INT’L STANDARDS ARE TO PERTAIN
IF THERE IS A CONFLICT BETWEEN NATIONAL AND
INT’L STDS IN HEALTH CARE
• CONSONANT WITH THE WORLD TRADE
ORGANIZATION (WTO) TECHNICAL BARRIERS TO
TRADE (TBT) AGREEMENT
KAZAKHSTAN HEALTH CODEX, 2009
Кодекс Республики Казахстан
«О здоровье народа и системе здравоохранения»
Раздел 1. Общая часть
Статья 1. Отношения, регулируемые настоящим Кодексом
Статья 3. Законодательство Республики Казахстан в области
здравоохранения
1. Законодательство Республики Казахстан в области здравоохранения
основывается на Конституции Республики Казахстан и состоит из
настоящего Кодекса и иных нормативных правовых актов
Республики Казахстан.
2. Если международным договором, ратифицированным Республикой
Казахстан, установлены иные правила, чем те, которые содержатся в
настоящем Кодексе, то применяются правила международного
договора.
Досье на проект Кодекса Республики Казахстан «О здоровье народа и
системе здравоохранения» (август 2007 года)
Проект кодекса, разработанный Институтом законодательства Республики
Казахстан Настоящий Кодекс вступает в силу с 1 января 2009 года.
KAZAKHSTAN HEALTH CODEX, 2009
Codex of the Republic of Kazakhstan
“On the health of the people and system of public health”
Section 1. General Part
Article 3. Legislation of the Republic of Kazakhstan in the sphere
of public health
1. Legislation of the Republic of Kazakhstan in the sphere of
public health is based on the Constitution of the Republic
Kazakhstan and consists of this Codex and other normative
legal acts of the Republic of Kazakhstan.
2. If an international agreement, ratified by the Republic of
Kazakhstan, establishes other laws than those in this Codex,
then the conditions of the international agreement obtains.
citation: Dossier on the project of the Codex of the Republic of Kazakhstan “On the
health of the people and public health” (August, 2007);Project on the Codex,
developed by the Republic of Kazakhstan Institute of Law, this Codex will become law
on 1 January 2009.
INTERNATIONAL
RESEARCH STANDARDS
DECLARATIONS
Physician's Oath: The World Medical Association
Declaration of Geneva (1948)
Adopted by General Assembly of World Medical Association (WMA),
-Geneva, Switzerland, September 1948
-amended by 22nd WMA Assembly, Sydney, Australia, August 1968
• WMA - an association of national medical associations
• Physician Oath - a response to atrocities committed by MDs in Nazi
Germany
• Oath - requires MDs to "not use … medical knowledge contrary to the
laws of humanity."
• adopted by WMA 3 months before United Nations General Assembly
adopted the Universal Declaration of Human Rights (1948) which
protects the security of individual persons
DECLARATION OF HELSINKI 1964
World Medical Association Declaration of Helsinki
• Recommendations for MDs conducting biomedical
research involving Human Subjects
• Adopted, 18th World Medical Assembly, Helsinki,
Finland, 1964
• revised, World Medical Assembly, Tokyo, Japan 1975
• revised, Venice, Italy 1983
• revised, Hong Kong 1989
RECOMMENDATIONS FOR CONDUCTING CLINICAL
RESEARCH
• Declaration of Geneva of the WMA - “The health of my patient will be
my first consideration”
• International Code of Medical Ethics - “Any act or advice which could weaken
physical or mental resistance of a human being may be used only in his interest”
• lab experiments, applied to human beings, further scientific knowledge, but may
harm subjects if PLACEBO and not best available treatment provided during
clinical trial
• MDs not relieved from criminal, civil and ethical responsibilities under the laws of
their own countries
• fundamental distinction exists between clinical research, which aims
at providing essential therapeutics for patients
• and clinical research, which aims at producing purely scientific
knowledge, without direct therapeutic value to the individual
subjected to the clinical research trial
HELSINKI DECLARATION: I. BASIC PRINCIPLES
1. Clinical research must conform to the moral and scientific principles that justify
medical research and should be based on laboratory and animal experiments or
other scientifically established facts.
2. Clinical research should be conducted only by scientifically qualified persons and
under the supervision of a qualified medical person.
3. Clinical research can not legitimately be carried out unless the importance of the
objective is in proportion to the inherent risk to the subject.
4. Every clinical research project should be preceded by careful assessment of
inherent risks in comparison to foreseeable benefits to the subject or to others.
5. Special caution should be exercised by the doctor in performing clinical research in
which the personality of the subject is liable to be altered by drugs or experimental
procedure.
II. CLINICAL RESEARCH COMBINED WITH
PROFESSIONAL CARE
1. In the treatment of the sick persons, the doctor must be free to use a
new therapeutic measure, if in the doctor’s judgment it offers hope of
saving life, reestablishing health, or alleviating suffering.
If at all possible, consistent with patient psychology, the doctor should
obtain the patient’s freely given consent after the patient has been
given a full explanation. In case of legal incapacity, consent should
also be procured from the legal guardian; in case of physical
incapacity the permission of the legal guardian replaces that of the
patient.
2. The doctor can combine clinical research with professional care, the
objective being the acquisition of new medical knowledge, only to the
extent that clinical research is justified by its therapeutic value for the
patient .
III. NONTHERAPEUTIC CLINICAL RESEARCH
1. In the purely scientific application of clinical research carried out on a human being, it is the duty
of the doctor to remain the protector of the life and health of that person on whom clinical
research is being carried out.
2. The nature, the purpose and the risk of clinical research must be explained to the subject by the
doctor.
3a. Clinical research on a human being can not be undertaken without that person’s consent after
being informed; if the person is legally incompetent the consent of the legal guardian should be
procured.
3b. The object of clinical research should be in such a mental, physical and legal state as to be able
to exercise fully the power of choice.
3c. Consent should, as a rule, be obtained in writing. However, the responsibility for clinical
research always remains with the research worker; it never falls on the subject even after
consent is obtained.
4a. The investigator must respect the right of each individual to safeguard his/her personal integrity,
especially if the subject is in a dependent relationship to the investigator.
4b. At any time during the course of clinical research the subject or the subject’s guardian should
be free to withdraw permission for research to be continued.
The investigator or the investigation team should discontinue the research if in their judgment, it
may, if continued be harmful to the individual.
STANDARD OF CARE DEBATE: HELSINKI
DECLARATION vs. INTERNATIONAL
CONSENSUS OPINION
• World Medical Association revision of Helsinki Declaration stated that
all trial participants in every country should receive a universal best
standard of care and permits placebo under certain conditions
• International Consensus has rejected this requirement of WMA/
Helsinki Declaration
• National & international committees, examining this issue, reached
consensus view that it is ethically permissible, under specific
conditions (i.e.,if participants are not subject to serious or irreversible
harm), to provide less than the worldwide best care to research
participants
RK Lie, E Emanuel, C Grady, D Wendler J Med Ethics 2004; 30:190-193
“Equipoise and the ethics of clinical research”
B. Freedman. NEJM v.317, n.3:141-145,
16July1987
Abstract
The ethics of clinical research requires equipoise--a state of genuine uncertainty on
the part of the clinical investigator regarding the comparative therapeutic merits of
each arm in a trial.
Should the investigator discover that one treatment is of superior therapeutic merit, he
or she is ethically obliged to offer that treatment.
The current understanding of this requirement, which entails that the investigator have
no "treatment preference" throughout the course of the trial, presents nearly
insuperable obstacles to the ethical commencement or completion of a controlled
trial and may also contribute to the termination of trials because of the failure to
enroll enough patients.
I suggest an alternative concept of equipoise, which would be based on present or
imminent controversy in the clinical community over the preferred treatment.
According to this concept of "clinical equipoise," the requirement is satisfied if there
is genuine uncertainty within the expert medical community--not necessarily on the
part of the individual investigator--about the preferred treatment.
EQUIPOISE OR UNCERTAINTY PRINCIPLE
• Clinical Equipoise or Principle of Equipoise specifies the ethical criteria for
randomly assigning patients to different treatments in clinical experiments – there
must be disagreement in the collective scientific community about treatment
effectiveness which can only be resolved with a randomized clinical trial
• Uncertainty Principle addresses whether MD can be ethical by recruiting patients
for clinical trials based on individual uncertainty about treatment effectiveness,
considering that the best available treatment may not be provided in the clinical trial
• Helsinki Declaration currently does not permit MD to apply “Uncertainty Principle”
• Clinical Equipoise raises questions about ethical methods of producing scientific
knowledge:
– randomised controlled trials should be designed to produce negative as well as positive
results
– clinical trials should be stopped early if adverse results are found in the interim
– what minimal sample size is adequate with volunteer subjects agreeing to participate
BMJ 2000;321(7263):756 (23 September), doi:10.1136/bmj.321.7263.756; J Med Ethics 2004;30:190-193
PLACEBO (NO) TREATMENT VS. BEST
AVAILABLE TREATMENT
European Agency for Evaluation of Medicinal Products (EMEA) / Committee for
Proprietary Medicinal Products (CPMP) Position Statement on the “Use of Placebo
in Clinical Trials With Regard to the Revised Declaration of Helsinki” issued in
London, Document EMEA/17424/01 on 28 June 2001 (Annex 6 to Document
CPMP/2020/01, 26June2001)
http://www.emea.europa.eu/pdfs/human/press/pr/202001en.pdf
issued statement that “although the efficacy of some new medicinal products can be
satisfactorily demonstrated without the use of a placebo, a placebo remains
essential to demonstrate their value.”
enumerated “a number of conditions that govern and restrict the use of placebos in
order to avoid unethical use.”
concluded that “provided that the conditions that ensure the ethical nature of placebocontrolled trials are clearly understood and implemented, it is the position of the
CPMP and the EMEA that continued availability of placebo-controlled trials is
necessary to satisfy public health needs.”
INTERNATIONAL CONSENSUS OPINION
• under certain conditions, it is ethically justifiable to conduct clinical
trials in developing countries where participants are provided medical
interventions that are less than worldwide best standard of care
• three conditions for ethically acceptable exceptions to providing
research participants the worldwide best standard of care:
– Valid science: there must be a valid scientific reason for using a lower standard
of care than that available elsewhere;
– Social benefits: the research must provide a sufficient level of benefit for the
host community, and
– Favourable individual risk:benefit ratio: there must be an acceptable balance of
risks and potential benefits for the individual participants in the trial.
• with exception of Declaration of Helsinki, 3 conditions have been
accepted international community as a consensus on permitting
exceptions to the general rule requiring that all research participants
receive the best standard of care
RK Lie, E Emanuel, C Grady, D Wendler J Med Ethics 2004; 30:190-193
3 EXCEPTIONS TO HELSINKI DECLARATION OF
RESEARCH ETHICS
1.
2.
3.
Valid science
Social benefits to host country
Favourable individual risk:benefit ratio
•
Declaration of Helsinki makes unconditional declarations on research ethics
•
“Equipoise” and “Uncertainty Principle” provide specific criteria for what
constitutes ethical research given what is accepted knowledge in scientific
community – the evidence base of the research question
•
3 conditions on permitted exceptions to Helsinki Declaration were derived from
“International Consensus” - provide that lower standards of patient care in
clinical trials can be used only when research has potential to improve medical
care
•
ethical guidelines are not unconditional absolutes of behavior but depend on the
position of the scientific community (which individual MDs should follow), thus
are relative to the degree of knowledge available and standards for obtaining
scientific knowledge
NEJM Volume 337:847-849 September 18, 1997 Number 12
TREATY OF NICE 2003
Nice, France – 28 March 2003
European standardization policy revised due to adoption
of new guidelines between
European Commission (EC),
European Free Trade Association (EFTA), and
3 official European Standards Organizations (ESOs)
1.) EU Committee for Standardization (CEN) 1984
2.) EU Committee for Electrotechnical Standards (CENELEC) 1984
3.) EU Telecommunications Standards Institute (ETSI) 1998
revised 2003 guidelines replaced previous version of Nov. 1984,
which specified common political understanding of the
conditions under which the EC and then two ESOs would cooperate.
2007 EU AGREEMENTS
• COMMISSION OF THE EUROPEAN COMMUNITIES
Brussels, 21.3.2007 SEC(2007) 350
• COMMISSION STAFF WORKING ON DOCUMENTATION
FOR AN INFORMATION SOCIETY
• REPORT FROM THE COMMISSION TO
– THE COUNCIL OR EUROPE
– EUROPEAN PARLIAMENT
– EUROPEAN ECONOMIC AND SOCIAL COMMITTEE
2007- SHIFT FROM VOLUNTARY ETHICS TO
LEGAL OBLIGATION IN BIOMEDICAL
RESEARCH
• ICH-GCP Guideline and the EC directive
(which cover only clinical drug trials)
• 3 EU documents deal with (bio)medical research
involving human subjects, incl. those incompetent to
give consent
• proposed Council for International Organizations of
Medical Sciences (CIOMS) guidelines included (in
Art.14 and 15) similar safeguards as the Helsinki
Declaration
(see notes below)
IMPLICATIONS FOR KAZAKHSTAN
• Soviet research tradition separate research from
education
• loss of brainpower, need to re-establish scientific
research community within educational sector
• loss of revenues, resources, technology,
telecommunications industry
• lack of international standards in telecommunication
computer access among scientists, educators, general
public, or medical sector
• any clinical and fundamental research presupposes
and requires a well developed computer accessible
information system, especially management and
analysis of clinical information systems (clinical trials)
WORLD STANDARDS DAY 17 OCT 2007
• World Standards Day in October 2007....
• World Standards Day 2007: “Standards and the
citizen- contributing to society”, Brussels, 17th Oct
2007
• Conference organised by the Enterprise and Industry
Directorate-General of European Commission
The event will focus on how standards benefit society as
a whole, i.e. by supporting consumer protection and
accessibility to information for all
CLINICAL VS. FUNDAMENTAL RESEARCH
• Clinical research is derived from a hierarchy of
fundamental natural sciences, concerning itself with
health outcomes, treatment protocols, quality of life
• Domains for clinical and fundamental research differ in
crucial aspect –
• use of humans in experimental clinical trials
• applicability of rigorous experimental standards for
acquiring scientific knowledge (i.e., in a laboratory setting)
CLINICAL VS. FUNDAMENTAL RESEARCH
DOMAINS
• Both domains require a set of standards
• Both domains need specific systems which
organize the information, as well as
process the information (informatics)
STANDARDS NEEDED IN:
PATIENT SAFETY
HARM REDUCTION
MEDICAL ERROR REDUCTION/
RISK MANGEMENT
BIOMEDICAL INDUSTRY
CLINICAL INFORMATION MANAGEMENT SYSTEMS
CLINIC & HOSPITAL INFRASTRUCTURE
MEDICAL INSTRUMENTS & SUPPLIES
PHARMACEUTICALS
STANDARDS NEEDED FOR:
• INTERNATIONAL TRADE
• COMMUNICATING INFORMATION
• QUALITY MANAGEMENT OF INFORMATION
• CLINICAL INFORMATION SYSTEMS
• REGULATION OF STANDARDS
TWO SIDES OF THE STANDARDS ISSUE
 ETHICAL STANDARDS FOR ACQUIRING KNOWLEDGE & CONDUCTING
RESEARCH
 TECHNICAL SCIENTIFIC STANDARDS FOR ACQUIRING KNOWLEDGE &
CONDUCTING RESEARCH
– TRADITIONALLY THESE 2 ISSUES HAVE BEEN KEPT SEPARATE BUT
NOT EQUAL
– SCIENTIFIC RELIABILITY/ VALIDITY CONCERNS TEND TO HAVE
PRECEDENCE
– CURRENT DEVELOPMENTS IN INTERNATIONAL STANDARDS FOR
CLINICAL RESEARCH HAVE EMPHASIZED INTERACTION BETWEEN
ETHICS & SCIENTIFIC RIGOUR
ETHICS STANDARDS OR SCIENCE
STANDARDS
• A CLINICAL TRIAL THEORY/ CONCEPT/ DESIGN
THAT IS NOT SCIENTIFICALLY RELEVANT OR VALID,
• IS NOT ETHICAL,
• REGARDLESS WHETHER OTHER SCIENTIFIC
CRITERIA FOR CONDUCTING CLINICAL TRIALS ARE
FOLLOWED (FROM ASSERT STANDARD)
BAD RESEARCH IS UNETHICAL RESEARCH
OVERLAP OF ETHICAL & SCIENTIFIC
STANDARDS IN CLINICAL RESEARCH
ASSERT STANDARD REVIEWS CLINICAL TRIAL PROPOSALS –
SPECIFIES 5 CRITERIA OUT OF A DOMAIN OF UNIVERSALLY
ACCEPTED STANDARDS IN NAT’L & INT’L REGULATIONS OF
CONDUCTING ETHICAL & SCIENTIFIC CLINICAL RESEARCH
SOCIAL & SCIENTIFIC VALUE
SCIENTIFIC VALIDITY
UNBIASED SUBJECT SELECTION
FAVORABLE RISK-BENEFIT RATIO
INDEPENDENT PEER REVIEW
INFORMED CONSENT
RESPECT FOR RESEARCH SUBJECTS
DO NO HARM
FORMULATING AND FOLLOWING
STANDARDS ARE DETERMINED BY
SEVERAL STRUCTURAL FACTORS
DEVELOPING COUNTRIES ARE MORE
CONCERNED WITH CLINICAL
APPLICATIONS TO HEALTH
OUTCOMES
GOLDEN STANDARDS FOR QUALITY OF
RESEARCH INFORMATION
• PYRAMID OF VALIDITY/ RELIABILITY
• RANDOMIZED DOUBLE BLIND CLINICAL TRIALS AS
THE MOST RIGOROUS EXPERIMENTAL METHOD
INVOLVING HUMAN SUBJECTS WITH/OUT PLACEBO
– RANDOMISED & NONRANDOMISED
• STANDARDS OF PUBLISHING & REPORTING
RESULTS FROM CLINICAL TRIALS CONTRIBUTES TO
THE GLOBAL GROWTH OF THE EVIDENCE BASE FOR
MEDICAL SCIENCES
THE EVIDENCE PYRAMID
INFORMATION & INFORMATICS RESEARCH
STANDARDS
INFORMATICS IS PROCESSING & COMMUNICATING
INFORMATION GLOBALLY & ACROSS DOMAINS
TECHNICAL STANDARDS
GENERAL STANDARDS
SPECIFIC STANDARDS
CONTENT STANDARDS
CLINICAL CODES STANDARDS
A NUMBER OF INTERNATIONAL
AGREEMENTS HAVE BEEN MADE BY
A NUMBER OF INTERNATIONAL
RESEARCH STANDARDS SETTING
ORGANIZATIONS
INTERNATIONAL STANDARDS
ORGANIZATIONS
AGREE ON CORE ELEMENTS FOR ACCEPTING
RESEARCH STANDARDS
TO BE A VOLUNTARY
CONSENSUAL
& TRANSPARENT PROCESS
INTERNATIONAL STANDARDS SETTING
ORGANIZATIONS
•
•
•
•
•
•
•
•
•
•
•
•
•
WHO HEALTH METRICS
WORLD MEDICAL ASSOCIATION
PARIS 21
PRISM
WORLD TRADE ORGANIZATION (WTO)
OECD
UK NATIONAL CLINICAL DECISION SUPPORT SERVICE BOARD
WORLD MEDICAL ASSOCIATION
CIOMS-COUNCIL FOR INTERNATIONAL ORGANIZATIONS OF MEDICAL
SCIENCES
US FDA
ISO - INT'L STANDARDS ORGANIZATION
CEN-TC251 COMITE EUROPEEN DE NARMALISATION, TECHNICAL
COMMITTEE 251
EN EUROPEAN STANDARD (ISO STANDARDS)
ENV EUROPEAN
PRESTANDARD (ISO TECH REPORTS)
EU POLICY FOR INT’L STANDARDISATION
SECTION (2001) 1296 -ARDS
Europe has an interest in international standardisation because of its potential
to eliminate technical barriers to trade (WTO-TBT) and to increase market
access for all member nations, as well as to promote and disseminate
technologies.
The PROCESS FOR DEVELOPING STANDARDS should respect: openness,
transparency, consensus and participation of all interested parties.
If regulatory authorities USE international standards, they SHOULD use
standards from standards bodies which can be held accountable for
establishing consensus between national positions and interested parties.
International, European and National Standardisation complement each other:
national stakeholders represent national positions independently within the
international context.
INT'L & NAT'L INFORMATION REGULATORY
ORGANIZATIONS
• The WTO Agreement on Technical Barriers to Trade
(WTO TBT Agreement) obligates WTO members to use
existing international standards as a basis for their
technical regulations,
• except when such international standards would be an
ineffective or inappropriate means for the fullfilment of
legitimate national objectives.
WTO TECHNICAL BARRIERS TO
TRADE (TBT) AGREEMENT
• regional or national standards should be aligned
to the greatest possible extent to meet
international standards
• national and regional standards are precursors
to international standardisation
• nations need to explain national deviations from
international standards as foreseen under the
WTO TBT Agreement
WORLD MEDICAL ASSOCIATION (WMA)
Helsinki Declaration (2004) section #29
The control group or placebo problem
• WMA Helsinki Declaration (2004) #29: The benefits,
risks, burdens and effectiveness of a new method
should be tested against those of the best current
prophylactic, diagnostic, and therapeutic methods.
• This does not exclude the use of placebo, or no
treatment, in studies where no proven prophylactic,
diagnostic or therapeutic method exists.
(See http://biomedicum.ut.ee/~andress )
Council for International Organizations of
Medical Sciences Guidelines (CIOMS), 2002
CIOMS Guideline 11: Choice of control in clinical trials
& guidelines for ethical review of epidemiological studies
Research subjects in the control group of a trial of a diagnostic, therapeutic, or
preventive intervention should receive an established effective
intervention
It may be ethically acceptable to use an alternative means for comparing
interventions, such as placebo or "no treatment"
Placebo may be used:
• when there is no accepted effective intervention
• when withholding effective intervention would expose subjects to any
temporary discomfort or delay in receiving relief of symptoms
• when use of effective intervention as comparison would not produce
scientifically reliable results
• when use of placebo would not add any risk of serious or irreversible harm to
the subjects
INTERNATIONAL STANDARDS FOR
CLINICAL RESEARCH
• International, explicit, rules-based methods
exist for all aspects of clinical trial
implementation & reporting
STANDARDS include:
hypothesis formulation
literature searching, literature review
ethical review
trial planning, trial conduct
trial reporting
systematic review
meta-analysis
INTERNATIONAL STANDARDS FOR
CLINICAL RESEARCH
AGREE STATEMENT
www.agreecollaboration.org/
Clinical practice guidelines assessment
ASSERT STATEMENT
www.assert-statement.org/
Ethical review of clinical trial proposals and monitoring Randomized
controlled trial conduct and reporting
COCHRANE COLLABORATION
www.cochrane.org
Systematic reviews of randomized controlled clinical trials
NICE STATEMENT
www.nice.org.uk
Technology appraisal of clinical guidelines National Institute for Clinical
Excellence
QUOROM – CONSORT STATEMENT www.consort-statement.org/QUOROM.pdf
Meta analysis of randomized controlled trials conduct and reporting
INTERNATIONAL STANDARDS FOR
CLINICAL RESEARCH
CDISC
http://www.cdisc.org
CLINICAL DATA INTERCHANGE STANDARDS CONSORTIUM
DUET STATEMENT
www.duets.nhs.uk
The Database of Uncertainties about the Effects of Treatments
MOOSE – CONSORT STATEMENT
www.consort-statement.org/MOOSE.pdf
Meta analysis of observational trials conduct and reporting
INTERNATIONAL STANDARDS FOR
CLINICAL RESEARCH
SDTM: STANDARDS-BASED CLINICAL TRIAL DATA MANAGEMENT (based on
CDISC)
STARD - CONSORT STATEMENT
www.consort-statement.org/stardstatement.htm
DIAGNOSTIC TRIALS CONDUCT & REPORTING
STROBE STATEMENT http://www.strobe-statement.org/
STrengthening the Reporting of OBservational studies in
Epidemiology
TREND STATEMENT http://www.trend-statement.org/
Transparent Reporting of Evaluations with Nonrandomized Designs
improves the reporting standards of nonrandomized evaluations of
behavioral and public health interventions
AGREE STANDARD - APPRAISAL OF
GUIDELINES FOR RESEARCH &
EVALUATION STATEMENT
• USED EXTENSIVELY IN KAZAKHSTAN
• The AGREE Collaboration
Appraisal of Guidelines for Research & Evaluation
Instrument.
www.agreecollaboration.org
• developed for the evaluation of the quality of clinical
recommendations
ASSERT STANDARD - ETHICAL REVIEW OF
RANDOMIZED CLINICAL TRIAL
PROPOSALS & MONITORING
http://www.assert-statement.org
• ethical conduct of research involving human subjects
• ASSERT STANDARD is a checklist of items which need to be
followed by investigators applying for IRB approval to conduct a
clinical trial.
• ASSERT checklist of items encompass universally applicable
requirements for the ethical conduct of research:
•
•
•
•
•
•
social and scientific value
scientific validity
fair subject selection
favorable risk-benefit ratio
respect for potential and enrolled subjects
public dissemination of research results
ASSERT modeled on CONSOLIDATED
STANDARDS OF REPORTING TRIALS
(CONSORT)
• ASSERT checklist includes items from CONSORT
checklist that are relevant to an assessment of social
and scientific value and scientific validity.
• Investigators, who follow the ASSERT checklist or
comply with CONSORT requirements when submitting
a trial report, more likely to be accepted for
publication.
• Adoption of ASSERT by research ethics committees
promotes the ethical conduct of clinical research.
CONSORT STANDARD IN REPORTING
CLINICAL TRIALS
• Publication of clinical trial results is primary means for public dissemination of
scientific knowledge
• Public dissemination is measure of scientific and social value
• CONSORT statement, adopted by most medical journals, ensures standards
for disseminating clinical trial results
• CONSORT checklist specifies those items which must be included in
manuscript submitted for publication
• CONSORT flow diagram details the flow of research subjects in RCT
• CONSORT statement is based on a Working Group that continuously
evaluates the checklist applicability, revising as necessary
CONSORT STANDARD REVISION 2001
Original 2001 and Revised 2005 CONSORT Flow Chart
JAMA 2001;285:1996-1999
Copyright restrictions may apply.
CLINICAL DATA INTERCHANGE
STANDARDS CONSORTIUM (CDISC)
CDISC - open, multidisciplinary, non-profit organization
• established worldwide industry standards for
electronic acquisition, exchange, submission,
archiving of clinical trials data and metadata for
medical and biopharmaceutical product development
CDISC develops global, platform-independent data
standards
• enables information system interoperability to improve
medical research and healthcare industry (interfaces
with research information & informatics).
CDISC: CLINICAL DATA INTERCHANGE STANDARDS
CONSORTIUM
SDTM: STANDARDS BASED CLINICAL TRIAL DATA
MANAGEMENT
• CDISC – WHO – CLINICAL TRIAL REGISTRY PLATFORM
• Pharmaceutical, biotechnology and medical device companies are
confronted with new CDISC SDTM standards for clinical trial data.
• It is > efficient to use e-submission data standards, submit clinical trials data
electronically to regulatory authorities, having access to single-trial and
pooled data for reviews of clinical and safety data.
• CDISC based review tools create pooled datasets which permit safety
screening of clinical data immediately online.
• CDISC SDTM implement e-submission standards for clinical trial
data, furthering analytics and safety.
COCHRANE COLLABORATION
Cochrane Collaboration focuses
• systematic review of randomised controlled trials (RCTs)
• RCT more likely to provide reliable information than other
sources of evidence on differential effects of alternative
forms of health interventions.
• Cochrane Reviewers' Handbook focuses on how to
conduct systematic reviews of RCTs.
• Basic principles of reviewing research apply to all types of
evidence reviewed.
• Structure of Cochrane guidelines are reflected in the
structure of the Handbook.
DATABASE OF UNCERTAINTIES ABOUT
EFFECTS OF TREATMENTS (DUETs)
Database of Uncertainties about the Effects of Treatments (DUETs)
• established in UK to publish up-to-date systematic reviews of
existing research evidence to address those scientific questions
about health interventions with uncertain outcomes
DUETs have three main sources to identify uncertainties about
effects of treatments:
• patients', caretakers’, clinicians' questions of treatment effects
• research recommendations in
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systematic reviews and clinical guidelines
ongoing research
systematic reviews in preparation
new 'primary' studies
DUETs developed in UK to help prioritise research questions in UK
• take into account information needs of patients, caretakers, clinicians in UK
ENHANCING THE QUALITY OF TRIALS AND
OTHER RESEARCH (EQUATOR)
•
EQUATOR aims to increase potential impact of reporting the quality of research. UK
initiative
•
Concerned with deficiencies in published health research
•
EQUATOR acts as an 'umbrella' organisation
•
provides forum for developers of reporting guidelines, medical journal editors and
peer reviewers, research funding bodies, and all those interested in 'improving the
quality of research publications and of research itself’
•
Collaborates with a number of standards which have been developed for reporting
health research.
•
Collaborates with other organizations to specify the minimum information necessary
for reliable/ valid reporting of research methodology and findings:
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QUOROM, recently renamed PRISMA (systematic reviews of randomised trials),
STARD, diagnostic accuracy studies
STROBE (observational studies), and
REMARK (tumour marker prognostic studies).
STANDARDS FOR IMPROVING REPORTING METAANALYSES OF OBSERVATIONAL DATA (MOOSE)
A Proposed Reporting Checklist for Authors, Editors, and
Reviewers of Meta-analyses of Observational Studies
Reporting of study background should include:
Problem definition
Hypothesis statement
Description of study outcome(s)
Type of exposure or intervention used
Type of study designs used
Study population
Reporting of search strategy should include:
Qualifications of searchers (eg, librarians and investigators)
Search strategy, including time period included in the synthesis and keywords
Databases and registries searched
Search software used, name and version, including special features used (eg, explosion)
Use of hand searching (eg, reference lists of obtained articles)
List of citations located and those excluded, including justification
Method of addressing articles published in languages other than English
Method of handling abstracts and unpublished studies
MOOSE - PROPOSED REPORTING CHECKLIST FOR AUTHORS,
EDITORS, & REVIEWERS OF META-ANALYSES OF OBSERVATION
STUDIES
Reporting of methods should include
Description of relevance of hypothesis tested
Rationale for selecting and coding data
Documentation of how data were classified, coded (i.e., multiple raters, blinding,
and interrater reliability)
Assessing confounding (i.e., comparability of cases and controls in studies)
Assessing study quality, including blinding of quality assessors; stratification or
regression on possible predictors of study results
Assessing sample heterogeneity
Describing statistical methods sufficiently clearly for replication (i.e., complete
description of fixed or random effects models, justification of chosen models account
for predictors of study results, dose-response models, or cumulative meta-analysis)
Providing appropriate tables and graphics
Reporting of results should include
Graphic summarizing individual study estimates and overall estimate
Tables giving descriptive information for each study
Results of sensitivity testing (eg, subgroup analysis)
Indication of statistical uncertainty of findings
MOOSE - PROPOSED REPORTING CHECKLIST FOR
AUTHORS, EDITORS, & REVIEWERS OF METAANALYSES OF OBSERVATION STUDIES
Reporting of discussion should include
Quantitative assessment of bias (i.e., publication bias)
Justification for study exclusion (i.e., exclusion of non–Englishlanguage research)
Assessment of quality of included studies
Reporting of conclusions should include
Proposing alternative explanations for observed results
Generalization of conclusions (ie, appropriate for the data
presented and within the domain of the literature review)
Guidelines for future research
Disclosure of funding source
REPORTING META-ANALYSES OF OBSERVATIONAL STUDIES 2010 JAMA, April 19, 2000—Vol 283, No. 15
NATIONAL INSTITUTE FOR HEALTH AND
CLINICAL EXCELLENCE (NICE)
• NICE - independent organisation responsible for providing
national guidance on health promotion and disease prevention
• treating morbidity with tools - cost templates, audit criteria, slide sets with
best available evidence of treatment effectiveness and cost effectiveness
• key objective - to ensure quality of health promotion information
disseminated to end user
• information technology means guidance recommendations reach NHS,
professionals, patients, public, policy makers, through range of external
applications – i.e., clinical decision support systems - by clicking through at
appropriate points on the care pathway
• NICE’s electronic guidance access project (EGAP) is to investigate
how guidance can be produced in an electronic format, appropriate to the
end user, which can easily be displayed on the NICE website or Trust
intranets and that can be easily integrated into information systems such as
the National Library for Health, clinical decision support systems or the Map
of Medicine.
THE QUALITY OF REPORTING OF META –
ANALYSES (QUOROM)
QUOROM conference convened to address standards for improving quality of
reporting meta-analyses of clinical randomised controlled trials (RCTs).
QUOROM group consisted of 30 clinical epidemiologists, clinicians,
statisticians, editors, and researchers asked to identify items which should
be included in a checklist of standards
Checklist items based on research evidence demonstrating that not following
proposed items could lead to biased results
QUOROM statement - checklist and flow diagram
• checklist describes preferred way to present the abstract, introduction,
methods, results, and discussion sections of a report of a meta-analysis.
• organised into 21 headings and subheadings regarding searches, selection,
validity assessment, data abstraction, study characteristics, and quantitative
data synthesis, and in the results with “trial flow”, study characteristics, and
quantitative data synthesis; research documentation was identified for eight
of the 18 items
• flow diagram provides information about both the numbers of RCTs
identified, included, and excluded and the reasons for exclusion of trials
QUORUM STAGES OF A META-ANALYSIS FOR RCTs
STANDARDS REPORTING OF DIAGNOSTIC
ACCURACY (STARD)
• http://www.stard-statement.org/website%20stard/
• STARD objective - improve accuracy and completeness of
reporting studies of diagnostic accuracy
• assess potential for bias in research study (internal validity)
• evaluate generalisability of research study (external validity)
• STARD checklist has 25 items
• recommends flow diagram which describes design of research
study and flow of patients
STARD FLOWCHART
STRENGTHENING THE REPORTING OF
OBSERVATIONAL STUDIES IN
EPIDEMIOLOGY (STROBE)
STROBE - international, collaborative initiative of epidemiologists,
methodologists, statisticians, researchers, editors interested in
the conduct and dissemination of epi observational studies
STrengthening the Reporting of OBservational studies in
Epidemiology
STROBE promotes research guidelines which reduces “a serious
risk that some epidemiological studies reach the wrong
conclusion”.
RATIONALE OF STROBE IS PREVENTION
• Incomplete and inadequate reporting of research in
epidemiological literature
• inaccurate practice of evidence-based health care and
prevention
• assessment of study quality is crucial for valid systematic
reviews and meta-analyses of interventions and observational
studies
• if “basic data” is poorly designed, collected, analyzed, the
conclusions are flawed GARBAGE IN & GARBAGE OUT
• STROBE – provides standards for three epidemiological study
designs: cohort, case-control, and cross-sectional studies
• standards developed for nested case-control studies or topic
areas, i.e. genetic and molecular epidemiology
TRANSPARENT REPORTING OF
EVALUATIONS WITH NONRANDOMIZED
DESIGNS (TREND)
• evidence-based public health decisions are based on evaluations of
intervention studies with randomized and nonrandomized designs
• Transparent reporting is crucial for assessing validity and efficacy of
intervention studies, facilitating synthesis of research results for evidencebased recommendations
• TREND - 22-item checklist for standardized reporting of nonrandomized
controlled trials of behavioral and public health interventions
• TREND – complements CONsolidated Standards Of Reporting Trials
(CONSORT) statement developed for randomized controlled trials
• promoting transparent reporting ensures better research, promotes
evidence-based clinical and management practices and policies
STANDARDS IN CLINICAL TRIAL
INFORMATION REPORTING
INTERNATIONAL COMMITTEE OF MEDICAL
JOURNAL EDITORS (ICMJE)
• Uniform Requirements for Manuscripts
Submitted to Biomedical Journals
• formulated by International Committee of Medical
Journal Editors (Vancouver Group)
• recently amended to include a statement on
publication ethics related to Sponsorship, Authorship
and Accountability
INTERNATIONAL COMMITTEE OF MEDICAL
JOURNAL EDITORS (ICMJE)
2005 POLICY- CLINICAL TRIAL REGISTRATION
• REQUIRES DEPOSIT OF INFO ON CLINICAL TRIAL CONCEPT &
DESIGN TO CENTRAL INTERNATIONAL TRIAL REGISTRY
BEFORE RECRUITING PATIENTS
• PUBLICATION OF RESEARCH RESULTS IS NOT POSSIBLE
WITHOUT PRIOR TRIAL REGISTRATION
•
POLICY AIMS TO MAKE INFO PUBLICLY ACCESSIBLE ABOUT
ONGOING & PLANNED CLINICAL TRIALS, SUPPORTS GROWTH
OF EVIDENCE-BASED MEDICINE
ICMJE CONSIDER CLINICAL TRIAL FOR PUBLICATION
ONLY IF REGISTERED BEFORE ENROLLMENT OF FIRST
PATIENT ON OR AFTER JULY 1, 2005
• September, 2004, members of International Committee of Medical Journal
Editors (ICMJE) published a joint editorial promoting registration of all
clinical trials
• promote transparent, comprehensive, publicly available database of clinical
trials
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complete registry of trials safeguards research volunteer participants
need access to information about the volunteering experience
need to make research study decision-making part of the public record to be available
for guiding decisions about further clinical trials and patient care
• need to know what authors report, what journal editors decide to publish
• WHO promotes single worldwide information standard trial authors disclose
• Governments beginning to legislate mandatory disclosure of all trials
• US Congress, where the proposed Fair Access to Clinical Trials (FACT) Act
would expand the current mandate for registration of clinical trials
APRIL 2007 REGISTRY HAD >40,000
ONGOING CLINICAL TRIALS WITH
>200 NEW TRIAL REGISTRATIONS WEEKLY
• before ICMJE 2005 policy, ClinicalTrials.gov was the
largest trial registry
• ClinicalTrials.gov had 13,153 registered trials, 2005
• number of registered clinical trials increased to >
22,714 one month after ICMJE TRIAL REGISTRATION
policy went into effect
PUBLICATION STANDARDS IN SCIENTIFIC
JOURNALS
COUNCIL OF SCIENCE EDITORS (CSE)
(CSE BOARD OF DIRECTORS APPROVED COPE on Sept.13, 2006)
1997 THE COMMITTEE ON PUBLICATION ETHICS (COPE)-a
consensus statement on misconduct in biomedical research,
and taxonomy of research misconduct in publication practice.
COPE flowcharts - step-by-step guides for journal editors to
resolve most common breaches of publication ethics repeated
in scientific and biomedical journals before and after
publication.
14 COPE flowcharts - based on hundreds of global cases COPE
advised: ethics violations from duplicate/ redundant publication
to copying other researchers’ work and plagiarism to fraud.
STANDARDS IN CLINICAL TRIALS
REGISTRATION
INTERNATIONAL STANDARD RANDOMISED
CONTROLLED TRIAL NUMBER (ISRCTN)
• “CURRENT CONTROLLED TRIALS” REGISTRATION
ORGANIZATION
• provides searachable meta-register of controlled trials, allows
users to search, register and share information about
randomised controlled trials
• searches are free of charge
• registration of clinical trials is made by paying a charge to
Current Controlled Trials
• Controlled Trials can be uniquely identified by ISRCTN
WHO INTERNATIONAL CLINICAL TRIALS
REGISTRY PLATFORM (ICTRP)
• The registration of all interventional trials is a scientific, ethical and moral
responsibility
What is a clinical trial?
• “A clinical trial is any research study that prospectively assigns human
participants or groups to one or more health-related interventions to evaluate
effects on health outcomes.
• Interventions include pharmaceuticals, cells and other biological products,
surgical procedures, radiologic procedures, devices, behavioural treatments,
process-of-care changes, preventive care, etc.
• WHO Network of Collaborating Clinical Trial Registers (The
Register Network) provides a forum for registration organizations to
exchange information and establish best practice for clinical trial registration
WHO - ICTRP LIST OF REGISTERS
Primary Registers adhere to ICMJE
• The following registers meet the requirements of a
Primary Register and contribute data to WHO Search
Portal
• Australian Clinical Trials Registry
• Chinese Clinical Trial Register (ChiCTR)
This register was launched on the 25th of July 2007
and the website is in the final stages of development.
• Clinical Trials Registry – India
This register was launched on the 20th of July 2007
and the first trial has yet to be registered.
WHO PARTNER INTERNATIONAL TRIAL
REGISTERS
• following registers applied to the ICTRP secretariat to
become collaborating registers.
• each register meets requirements of a Partner Register
ArQule, Inc (registering trials on ClinicalTrials.gov)
Dutch Trial Register (registering trials on ISRCTN)
Eli Lilly (registering trials on ClinicalTrials.gov)
Mitsubishi Pharma Corporation (registering trials on
ClinicalTrials.gov)
Physician Data Query (registering trials on ClinicalTrials.gov)
POTENTIAL CONTRIBUTING REGISTERS
• The following registers do not currently contribute data to the
WHO Search Portal. The Registry Platform Secretariat are in the
process of ascertaining whether or not each register meets the
requirements necessary to be a Contributing Register.
• Centre for Clinical Trials, Chinese University of Hong Kong
Clinical Trial Database of the University Hospital Freiburg
German Somatic Gene Transfer Clinical Trial Database
HIV/AIDS, Tuberculosis and Malaria Clinical Trial Registry (ATM
Registry)
HKClinicalTrials.com
Latin American Clinical Trials Register (LatinRec)
National Swedish Competence Centre for Musculoskeletal Disorders
(in development: not yet open to trial registrants)
South African National Clinical Trial Register (SANCTR)
Sri Lanka Clinical Trials Registry
University Hospital Medical Information Network (UMIN)
WHO REGISTRY
UNIVERSAL TRIAL REFERENCE NUMBER
(UTRN)
• Clinical trials – golden standard of scientific evidence
• Access to information about ongoing, completed, published
clinical trials is essential for informed research and decisionmaking
• Researchers, grant funders, policy-makers, medical
practitioners, patients, general public need clinical trial
information to help guide research, make treatment decisions
• Transparency, increasing public trust in conduct of clinical
research, can be promoted with registration of clinical trials
before subject recruitment starts, all details of how clinical trial
was conducted and all negative/ positive results must be made
public
UNIVERSAL TRIAL REFERENCE
NUMBER (UTRN)
• provides unique identification of clinical trials submitted to WHO
Search Portal
• UTRN - number obtained by clinical trial Sponsor before trial
• UTRN - number part of trial's identity
• UTRN – number used to communicate and identify all
information about the trial
• registered trials, require full transparency and accountability,
including all results made available to public in a timely manner
• no formal consensus on international norms and standards for
results reporting exist currently
• The Registry Platform has established Study Group on
“Reporting of Findings of Clinical Trials” to advise WHO
Registry Platform on reporting findings from clinical trials
YOU NEED STANDARDS IF
1. Do you do protocol-based clinical research?
2. Do you do annotate, acquire, aggregate, analyze, archive?
3. Do you want high quality data?
4. Do you want to save time?
5. Do you have limited resources?
6. Do you have limited time to complete your clinical programs?
7. Do you ever have to go back and look at old data for knowledge extraction?
8. Do you need patients and investigators?
9. Do you want to get information from EHRs?
10. Do you track and report safety data?
11. Do you submit to FDA?
12. Do you intend or have you acquired another company?
13. Do you need to be transparent and compliant?
14. Do you use partners (CROs, tech vendors, development partners, labs)?
If you responded ‘yes’ to any of 1-7, you need standards.
If you responded ‘yes’ to any of 8-14, you need industry standards.
For Implementation Decision Trees and Recommendations, see the complete