international research and subjects protections richard carpentier, national council on ethics in...

International Research and Subjects ProtectionsInternational Research

and Subjects Protections

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

AgendaAgenda

1.Increase in International Research1.Increase in International Research

2. Ethical Breaches 2. Ethical Breaches

3.Sustaining Trust 3.Sustaining Trust

5. About International Standards 5. About International Standards

4.Capacity-building4.Capacity-building

6. A Word about FOCUS6. A Word about FOCUS

Why is Research Subjects Protections in International Research So Important Now?

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

Increase in International Research Activities

Increase in International Research Activities

Analysis of National Institutes of Health Awards to Analysis of National Institutes of Health Awards to International OrganizationsInternational Organizations

Distribution of Funded Grants to International Organizations for Human Distribution of Funded Grants to International Organizations for Human Subjects Research in FY 2003 Includes Funding of R&D ContractsSubjects Research in FY 2003 Includes Funding of R&D Contracts

$0

$5

$10

$15

$20

$25

$30Dollars in B

illion

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

Fiscal Year

NIH Budget History

Growth of International Federal Wide AssuranceGrowth of International Federal Wide Assurance

0

200

400

600

800

1000

1200

1400

1600

FY 2001 FY 2002 FY 2003 FY 2004

New FWAs

Total FWAs

Number of Overseas Human Clinical Trials for New DrugsNumber of Overseas Human Clinical Trials for New Drugs

0

1000

2000

3000

4000

5000

6000

7000

8000

'91 '92 '93 '94 '95 '96 '97 '98 '99 '00

Developed CountriesLess Developed Countries

Sources: FDA Biomonitoring Research database; Parexel’s Pharmaceutical R&D Statistical Sources: FDA Biomonitoring Research database; Parexel’s Pharmaceutical R&D Statistical Sourcebook 1999; Aculaunch; Washington Post ResearchSourcebook 1999; Aculaunch; Washington Post Research

Human Subjects in Clinical TrialsHuman Subjects in Clinical Trials

0

20000

40000

60000

80000

100000

120000

2000 2001 2002 2003

US

International

US decrease 40%

International increase 82%

Foreign Clinical TrialsForeign 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

U.S. Department of Health and Human Services

The Globalization of Clinical Trials: A Growing Challenge in Protecting

Human Subjects

U.S. Department of Health and Human Services

The Globalization of Clinical Trials: A Growing Challenge in Protecting

Human Subjects

Janet Rehnquist Inspector General, September 2001

The Globalization of Clinical TrialsThe 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 FDA’s

capacity to assure human subject

protections in these 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 FDA’s determination of the safety and efficacy of new drugs.


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


•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


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


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

Department of Health & Human Services Office of Inspector General

The Orange Book 2005

Department of Health & Human Services Office of Inspector General

The Orange Book 2005

Daniel R. Levinson, Inspector General

The Orange Book 2005: Obtain Data on IRBsThe 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.

The Orange Book 2005The 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.

Ethical BreachesEthical Breaches

Illegal Trials in IndiaIllegal 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.

Improper Research by Johns Hopkins Researcher in India 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.

Use of placebos in AIDS vaccine research in BankokUse 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.

VanTx Research, Basel, SwitzerlandVanTx 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

VanTx Research, Basel, SwitzerlandVanTx 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

Has Canada Let Her Down?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 I’ve made

such a big name all over the world [for

the project], but I’m still in this

business. I need something to lift me

out of Majengo.’

The Globe and Mail, January 7, 2006

Lack of Ethics ReviewLack 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

Sustaining TrustSustaining Trust

Erosion of Public TrustErosion 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

2004 International Will & Why Survey2004 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. "


• 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


There is a fear that only lip service paid to ethics

Ethics Committees are instruments which should help maintaining trust

Ethics Committees are instruments which should help maintaining trust

Need for capacity-building

Capacity-building for Ethics CommitteesCapacity-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


• 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


• 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

About International StandardsAbout International Standards

International StandardsInternational 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

International StandardsInternational Standards

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

US FWAUS 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

US FWAUS 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

US FWAUS 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

FOCUS : the Canada-US Forum

FOCUS : the Canada-US Forum

About FOCUSAbout 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;

About FOCUSAbout 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.

Annual Conferences and PublicationsAnnual 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

Thank you!

www.ncehr-cnerh.org

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