International Research and Subjects Protections

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International Research and Subjects Protections

• Richard Carpentier, National Council on Ethics in
  Human Research and FOCUS Secretariat, CANADA

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Agenda
1.Increase in International Research
2. Ethical Breaches
3.Sustaining Trust
4.Capacity-building
5. About International Standards
6. A Word about FOCUS
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Why is Research Subjects Protections in
International Research So Important Now?
Because research activities are increasing
Because research is moving in countries with less
experience and infrastructures
Because research is less and less in control of
academic/public institutions and more in control
of for-profit corporations
Because we have multiple experiences of ethical
breaches
BECAUSE WE NEED TO SUSTAIN TRUST
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Increase in International Research Activities
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Analysis of National Institutes of Health Awards
to International Organizations Distribution of
Funded Grants to International Organizations for
Human Subjects Research in FY 2003 Includes
Funding of RD Contracts
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NIH Budget History
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Growth of International Federal Wide Assurance
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Number of Overseas Human Clinical Trials for New
Drugs
Sources FDA Biomonitoring Research database
Parexels Pharmaceutical RD Statistical
Sourcebook 1999 Aculaunch Washington Post
Research
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Human Subjects in Clinical Trials
US decrease 40 International increase 82
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Foreign Clinical Trials

• Percentage of NDA submissions using foreign data
• 1995 --- 9
• 1999 --- 27
• Numbers of foreign human subjects participating
  in NDA clinical trials
• 1995 --- 4,000
• 1999 --- 400,000

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U.S. Department of Health and Human ServicesThe
Globalization of Clinical Trials A Growing
Challenge in Protecting Human Subjects

• Janet Rehnquist Inspector General, September 2001

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The Globalization of Clinical Trials

• Purpose of the Report
• To document the growth of non-U.S. clinical drug
  trials contributing data to New Drug Applications
  for Food and Drug Administration (FDA) approval,
  and to assess FDAs capacity to assure human
  subject protections in these trials.

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The Globalization of Clinical Trials

• Background
• In our June 2000 report, Recruiting Human
  Subjects Pressures in Industry-Sponsored
  Clinical Research (OEI-01-97-00195), we drew
  attention to the fact that clinical drug trials
  conducted outside the U.S. can be an important
  source of data in FDAs determination of the
  safety and efficacy of new drugs.

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The Globalization of Clinical Trials

• We recommend that FDA
• Obtain more information about the performance of
  foreign institutional review boards
• Help foreign review boards build capacity to
  conduct effective human subject reviews

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The Globalization of Clinical Trials

• Encourage sponsors to obtain attestations from
  foreign investigators that they will adhere to
  ethically sound principles of research
• Encourage greater sponsor monitoring
• Develop a database to track the growth and
  location of foreign research

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The Globalization of Clinical Trials

• We recommend that the Office for Human Research
  Protections
• Exert leadership by developing strategies to
  ensure that adequate human subject protections
  are afforded for non-U.S. clinical trials that
  are funded by the Federal government and/or that
  contribute data in support of a New Drug
  Application

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The Globalization of Clinical Trials

• Encourage accreditation of institutional review
  boards in a voluntary accreditation system as one
  way to improve the capacity to conduct
  appropriate reviews of human subject protections
  in proposed research.
• The Office for Human Research Protections,
  working with FDA, NIH, and others, can help
  develop such a system internationally

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Department of Health Human Services Office of
Inspector General The Orange Book 2005

• Daniel R. Levinson, Inspector General

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The Orange Book 2005 Obtain Data on IRBs

• We recommended that FDA examine ways to obtain
  more information about the performance of non-US
  IRBs and help those inexperienced IRBs build
  their capacities encourage all non-US
  investigators participating in research to sign
  attestations upholding human subject protections
  and develop a database to track the growth and
  location of foreign research.

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The Orange Book 2005

• We recommended that OHRP exert leadership in
  developing strategies to ensure adequate human
  subject protections for non-US clinical trials
  funded by the Federal Government and those that
  contribute data to new drug applications.

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Ethical Breaches
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Illegal Trials in India
OVER 430 unsuspecting young women have been used
as guinea pigs by self-styled researchers in
India to test if an anti-cancer drug, Letrozole,
can be used to induce ovulation. The clinical
trials have been conducted illegally,
predominantly at private clinics not recognised
as research centres. At least one
investigator with just a diploma in
gynaecology could hardly claim to be qualified or
competent enough to try untested drugs.
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Improper Research by Johns Hopkins Researcher in
India

• A Johns Hopkins University scientist, Dr Ru Chih
  C. Huang, tested experimental cancer drugs on
  patients in India without required federal
  approval, nor university research ethics
  approvals and without adequate preliminary tests
  in animals.

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Use of placebos in AIDS vaccine research in Bankok
A Thai nurse prepares a syringe with an
experimental AIDS vaccine to inoculate a
"volunteer" at the Bangsue Narcotics Clinic in
Bangkok. Some participants in the drug study are
given placebos, not real medicine.
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VanTx Research, Basel, Switzerland

• In 1998-1999, VanTx, a CRO, was recruiting
  Estonian and Polish students, proposing
  vacations in Switzerland, with high salary. It
  was working for major pharmas.
• Reports say subjects were sequestrated with
  passports confiscated

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VanTx Research, Basel, Switzerland

• Use of non-recognized ethics committee
• Consent form signed after minimal information, in
  a foreign language (German)
• Participants coerced to remain enrolled in trials
• The firm falsified test results
• Absence of medical follow-up after study

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Has Canada Let Her Down?
After more than 20 years of having her remarkable
resistance to HIV studied by Canadian and Kenyan
scientists, she is grateful for the free medical
service she receives in return but pines to
escape her life of prostitution. I feel they
take advantage of me, she says of the
researchers, because Ive made such a big name
all over the world for the project, but Im
still in this business. I need something to lift
me out of Majengo. The Globe and Mail, January
7, 2006
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Lack of Ethics Review

• A survey of more than 200 developing-country
  health researchers has found that a quarter of
  clinical trials carried out in developing
  countries do not undergo any kind of ethical
  review in the host nation.
• Re Journal of Medical Ethics, February 2004

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Sustaining Trust
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Erosion of Public Trust

• There is a public perception that subjects of
  clinical trials are equivalent to guinea pigs
• Trust is an essential ingredient in the success
  of clinical trials as necessary to recruit
  subjects
• Need to be very honest with subjects about the
  nature of research (this is not treatment) the
  risks and benefits, and avoid conflicts of
  interest

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2004 International Will Why Survey

• "Of the Polish respondents who would not
  participate in a clinical trial, 45 percent
  responded because of the health risks in clinical
  trials and 28 percent responded because of the
  "guinea pig" perception associated with clinical
  trials. "

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Erosion of Public Trust

• People are not aware that over and above the
  confidence they have in their doctors, there are
  protections in place
• International research should not create double
  standards in terms of experimental treatment
• Need to publicize ethical protections, make
  policies available

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Erosion of Public Trust

• There is a fear that only lip service paid to
  ethics

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Ethics Committees are instruments which should
help maintaining trust

• Need for capacity-building

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Capacity-building for Ethics Committees

• Local research ethics committees are essential
  as they provide the knowledge of the local
  research context
• Vulnerability of research participants
• Specific conditions of research and of health
  system
• Cultural variability in the application of norms
  and policies
• Assessing risks and benefits, appropriate
  language

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Capacity-building for Ethics Committees

• National education strategy aimed at
  researchers, institutions and Research Ethics
  Committees
• Applicable law, regulations and policies
• How to review a protocol
• Rules for informed consent
• Inventory of RECs

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Capacity-building for Ethics Committees

• Development of national criteria and standards
  based on cultural background and needs
• Friendly educational visits to help at the
  application of criteria and standards to
  develop eventually into accreditation

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About International Standards
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International Standards

• Most standards are principle-based
• Most standards are voluntary, for example
  Helsinki and CIOMS
• International declarations agreed upon by states
  need to be embedded in enforceable instruments
• However there is little verification in terms of
  quality of implementation

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International Standards

• The implementation of other standards subject to
  better monitoring
• Good clinical practice
• US Regulations (FDA, OHRP)

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US FWA

• One of the most powerful instrument is perhaps
  the FWA required from all institutions receiving
  funds from HHS
• Many institutions seem to adopt a naïve attitude
  and not to read the fine prints but signatory
  institutions commit themselves to doing many
  things

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US FWA

• All research in the institution must be guided by
  a statement of ethical principle
• Need written procedures for
• Reporting to the EC and appropriate officials
• Unanticipated problems creating risks to subjects
• Serious or continuous non-compliance
• Suspension or termination of research
• Conducting initial and continuing review
• Determining which projects need more than annual
  review

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US FWA

• Ensuring prompt reporting to EC of proposed
  changes to research activities and ensuring they
  are not implemented without EC approval, unless I
  would eliminate risks to subjects
• AND THERE IS MORE TO READ
• Inspections may be conducted on the basis of FWA
  and use of research funds suspended if not
  satisfactory

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FOCUS the Canada-US Forum
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About FOCUS

• FOCUS strives to achieve its objective through
  the following activities
• Providing a forum for regular meeting and
  discussion of research ethics issues common to
  Canada and the United States and to facilitate
  dialogue, co-operation and exchange of experience
  between individuals and organization in order to
  enhance the protection of human participants in
  research
• Fostering communication and partnerships between
  Canada and the United States, between governments
  and other organizations that share common values
  and goals

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About FOCUS

• Improving communication among IRBs/REBs
• Promoting the development and implementation of
  actions designed to improve the quality of ethics
  review (e.g., accreditation)
• Promoting education about the ethics of research
  in humans across all disciplines.

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Annual Conferences and Publications

• 2003 Canadian and American Perspectives on
  Quality Improvement and Performance Evaluation in
  Systems of Human Research Protection
• 2004 International Conference on Conflicts of
  Interest
• 2005 Ethical Issues in Behavioral and Social
  Sciences Research
• 2006 Research Ethics Education for Investigators
• 2007 Maintaining Public Trust in Clinical Research

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Thank you! www.ncehr-cnerh.org