International Human Subjects Research Edward E. Bartlett, PhD International Human Research Liaison Office for Human Research Protections September 20, 2006

Outline Overview of the Office for Human Subjects Research 2. Trends in international research 3. Coordinating IRB reviews in multi-site research 4. Informed consent 5. Q and A

OHRP Mission Provide leadership and oversight on all matters related to the protection of human subjects participating in research conducted or supported by the DHHS. Provide education, guidance, and enforcement of 45 CFR 46

OHRP Organization Chart Division of Compliance Office of the Director International Activities SACHRP Division of Education and Development Division of Policy and Assurances Division of Compliance Oversight

What Sub-set of Research Does OHRP Regulate? A. All research B. Conducted or Funded by DHHS C. Human subjects research: 1. Living persons, AND 2. Direct intervention or interaction, OR Obtain private identifiable information D. Non-Exempt Research

International Compilation of Human Subject Research Protections A compilation of the laws, regulations, and guidelines for human subjects research around the world. Scope: 73 countries with pertinent laws, regulations, and guidelines Includes information on: Drug research Privacy/data protection Human biological materials Genetic research

Contents of Listings Denmark Laws and URLs Regulations and Guidelines, including year of issue Names and URLs of Key Organizations Denmark Key Organizations Laws Regulations Guidelines General 1. Danish Central Scientific Ethical Committee (CVK): www.cvk.im.dk 2. Danish Council of Ethics (DCE): www.etiskraad.dk/sw293.asp Act on the Biomedical Research Ethics Committee System (2003): www.cvk.im.dk/visArtikel.asp?artikelID=1606 CVK: Ministerial Order of October 12, 2000 Guidelines on Biomedical Experiments (2000)

Outline Overview of the Office for Human Subjects Research 2. Trends in international research 3. Coordinating IRB reviews in multi-site research 4. Informed consent 5. Q and A

NIH International Research Trends FY2004: Direct Foreign Awards: $350,000; FCDA: $350,000

Largest Recipients of NIH Awards: Millions $ in FY2004 Sweden $14.6 U.K. $121.9 Denmark $118.7 NL $13.0 Austria $46.9 Canada $95.7 China $11.7 South Africa $41.3 Australia $46.4

Projected Growth in Drug Clinical Trials, 2004-2011 Europe (esp. Eastern Europe): Annual growth rate 11-14% Japan: Global market share will increase from 4% to 8%. Latin America: Another growth area. India: Market share will increase From 1% - 6%. Source: Visiongain

Outline Overview of the Office for Human Subjects Research 2. Trends in international research 3. Coordinating IRB reviews in multi-site research 4. Informed consent 5. Q and A

Regulatory Requirements For international research, no regulation explicitly requires IRB review in the host country However, the criteria for IRB approval (eg, risks are minimized, risks are reasonable, selection of subjects is equitable, informed consent, privacy and confidentiality, protection of vulnerable subjects) cannot be appropriately assessed without knowledge of local research context. So in most cases, it is desirable to have a local IRB review the protocol.

The Way It’s Usually Been Done: Separate IRB Reviews Example: Study is conducted in the US and 4 other countries. The US and 4 local IRBs independently review the entire protocol. Direct Awardee’s IRB Site #4 – Local IRB Site #1 – Local IRB Site #2 – Local IRB Site #3 – Local IRB

Problems with Multiple IRB Reviews Overlapping effort Communication breakdowns among IRBs Sometimes contradictory requests to investigators Time delays

Coordinating the IRB Review §46.114 Cooperative research. Cooperative research projects are those projects covered by this policy which involve more than one institution. In the conduct of cooperative research projects, each institution is responsible for safeguarding the rights and welfare of human subjects and for complying with this policy. With the approval of the Department or Agency head, an institution participating in a cooperative project may enter into a joint review arrangement, rely upon the review of another qualified IRB, or make similar arrangements for avoiding duplication of effort.

A. “Joint Review Arrangement” The roles and responsibilities of each IRB are delineated in advance: Direct Awardee’s IRB Site #1 – Local IRB Site #2 – Site #3 – Site #4 –

B. “Rely Upon the Review of Another Qualified IRB” Site #2 Site #1 Site #3 Site #4 Direct Awardee - US Institution Central IRB Legend: = IRB = Research institution

C. “Make Similar Arrangements for Avoiding Duplication of Effort” One possibility: Direct Awardee’s IRB Central Site #4 Site #3 Site #2 Site #1 Legend: = IRB = Research institution

Outline Overview of the Office for Human Subjects Research 2. Trends in international research 3. Coordinating IRB reviews in multi-site research 4. Informed consent 5. Q and A

Summary of Common Rule Provisions on Informed Consent PROCESS CONTENT DOCUMEN-TATION Basic Require-ments Sufficient time Understandable language - Minimize coercion 8 required elements 6 additional elements, when appropriate Written consent form, or A short form with summary and witness Alteration or Waiver 4 requirements: Minimum risk Rights not affected Impracticable Subjects provided with additional info 2 provisions for waiver

Key Issues Issues are more cultural and ethical than regulatory Western conception of informed consent is based on individual, autonomous decision-makers In many cultures, decision-making takes place more at the community and family levels How do we reconcile these two perspectives?

“Medical Research and Ethics in Mali” Article by Ogobara Doumbo, director of the Malaria Research and Training Center and member of the Mali National Committee on Ethics Key issue: “the social structures demand that decision-making be done more communally than in the West.” Source: Science, Feb. 4, 2005

1. Study of the Natural History of Malaria in Children Four-step approach to seeking informed consent: Discussion with village elders Discussions with heads of extended families Discussions with parents of potential children-subjects Consent of parents

2. Trial of Three Drugs to Prevent Malaria in Pregnant Women Four-step approach to informed consent: Meeting with village women’s council Meeting with mothers-in-law of pregnant women Meeting with individual pregnant women Meeting with husbands and fathers-in-law (done at the request of the pregnant women)

Ethical Informed Consent “In some developing countries, however, individual and community consent are part of the same process…By approaching individuals first, one is likely to introduce social conflict in the village, and this could be unethical.”

Outline Overview of the Office for Human Subjects Research 2. Trends in international research 3. Coordinating IRB reviews in multi-site research 4. Informed consent 5. Q and A