1. International Human Subject Research Legal and Ethical Considerations for Investigators Theresa J. Colecchia, Esq. Associate General Counsel May 8, 2006

2. Basic Contracting Issues When subcontracting for human subject research overseas, be aware that liability for research subject harm, intellectual property rights, and legal requirements for approval of human subject research may vary in other countries. When subcontracting for human subject research overseas, be aware that liability for research subject harm, intellectual property rights, and legal requirements for approval of human subject research may vary in other countries. If the University is the sponsor of the research (e.g. the IND holder or the NIH prime), allowance will have to be made for regular site visits at the foreign site. If the University is the sponsor of the research (e.g. the IND holder or the NIH prime), allowance will have to be made for regular site visits at the foreign site.

3. Basic Contracting Issues For all studies, whether or not federal funds are used, investigators should notify the Office of Research at the time of accepting the prime contract that enrollment at foreign sites is planned. For all studies, whether or not federal funds are used, investigators should notify the Office of Research at the time of accepting the prime contract that enrollment at foreign sites is planned. Some sponsors may require prior approval of all foreign sites, or may restrict international locations. Some sponsors may require prior approval of all foreign sites, or may restrict international locations. The University will require foreign sites to produce evidence of adequate insurance to cover any claims of subject harm. The University will require foreign sites to produce evidence of adequate insurance to cover any claims of subject harm.

4. Contracting and Legal Issues For federally funded studies, if the foreign site is “engaged in” the human subject research, the foreign site must file an international Federal Wide Assurance with OHRP. http://www.hhs.gov/ohrp/assurances/ass urances_index.html#international For federally funded studies, if the foreign site is “engaged in” the human subject research, the foreign site must file an international Federal Wide Assurance with OHRP. http://www.hhs.gov/ohrp/assurances/ass urances_index.html#international OHRP has issued guidance on when a site is “engaged in” human subject research:http://www.hhs.gov/ohrp/policy/ index.html#engagement OHRP has issued guidance on when a site is “engaged in” human subject research:http://www.hhs.gov/ohrp/policy/ index.html#engagement

5. Legal Requirements Under the HHS Regulations In addition to the requirement for an international FWA, under the HHS regulations, all human subject research must be reviewed by an IRB with knowledge of the local research context. The University IRB will need to receive a copy of this local IRB’s approval, as well as copies of the informed consent translated into the local language. In addition to the requirement for an international FWA, under the HHS regulations, all human subject research must be reviewed by an IRB with knowledge of the local research context. The University IRB will need to receive a copy of this local IRB’s approval, as well as copies of the informed consent translated into the local language.

6. Legal Requirements Under the HHS Regulations While review by a local, foreign IRB is required, it may not be all that is required. While review by a local, foreign IRB is required, it may not be all that is required. Foreign sites may have different legal requirements for handling biological samples, for registering investigational drugs, or for patient data privacy. Foreign sites may have different legal requirements for handling biological samples, for registering investigational drugs, or for patient data privacy. OHRP maintains a useful compilation of relevant foreign laws and policies on its international research website: OHRP maintains a useful compilation of relevant foreign laws and policies on its international research website:http://www.hhs.gov/ohrp/international/

7. Legal Requirements Under the HHS Regulations Where the foreign site is located in a country where the ethical principles differ from the Common Rule, the funding agency can make a determination that the foreign country’s system is “substantially equivalent” to the Common Rule, and the site may then follow those local rules in lieu of the Common Rule. 45 C.F.R. § 46.101(h). Where the foreign site is located in a country where the ethical principles differ from the Common Rule, the funding agency can make a determination that the foreign country’s system is “substantially equivalent” to the Common Rule, and the site may then follow those local rules in lieu of the Common Rule. 45 C.F.R. § 46.101(h). No funding agency has exercised this authority. No funding agency has exercised this authority.

8. IRB Submission Requirements A full listing of the University IRB submission requirements for protocols that include foreign sites may be found in the IRB Manual in Chapter 7.3, Section 3.4. A full listing of the University IRB submission requirements for protocols that include foreign sites may be found in the IRB Manual in Chapter 7.3, Section 3.4. These submission requirements address all of the HHS regulations. These submission requirements address all of the HHS regulations.

9. Issues for Drug Intervention Studies If the study involves a drug or device that requires an IND or IDE from the FDA, additional rules apply. If the study involves a drug or device that requires an IND or IDE from the FDA, additional rules apply. FDA Guidance on Good Clinical Practice (“GCP Guidance”), which was developed as part of the work of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), provides the standards which should be followed by all sites, including foreign sites. The Guidance is available at: FDA Guidance on Good Clinical Practice (“GCP Guidance”), which was developed as part of the work of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), provides the standards which should be followed by all sites, including foreign sites. The Guidance is available at: http://www.fda.gov/cder/guidance/index.htm#clinical%20 medicine http://www.fda.gov/cder/guidance/index.htm#clinical%20 medicine

10. Issues For Drug Intervention Studies The GCP Guidance provides a consistent set of definitions and requirements for record-keeping, adverse event reporting and all other aspects of conduct of a clinical trial. The GCP Guidance provides a consistent set of definitions and requirements for record-keeping, adverse event reporting and all other aspects of conduct of a clinical trial. The agreement with the foreign site should expressly reference this GCP Guidance, and the University investigator should be comfortable that the foreign site is equipped to meet its standards. The agreement with the foreign site should expressly reference this GCP Guidance, and the University investigator should be comfortable that the foreign site is equipped to meet its standards.

11. Issues For Drug Intervention Studies If drugs or devices produced in the United States will be sent to the foreign site, an export certificate from the FDA should be secured. Guidance on securing these certificates is available at: If drugs or devices produced in the United States will be sent to the foreign site, an export certificate from the FDA should be secured. Guidance on securing these certificates is available at: http://www.fda.gov/cber/gdlns/exprtcert.htm#ii http://www.fda.gov/cber/gdlns/exprtcert.htm#ii http://www.fda.gov/cber/gdlns/exprtcert.htm#ii Other export restrictions may apply, and the University Purchasing Department will assist in obtaining appropriate clearances. Other export restrictions may apply, and the University Purchasing Department will assist in obtaining appropriate clearances.

12. Ethical Considerations in International Studies Protocol design and informed consent documents should reflect the cultural and ethical standards of the host country, provided that those standards are consistent with the basic principles of the Belmont Report and the Declaration of Helsinki. Protocol design and informed consent documents should reflect the cultural and ethical standards of the host country, provided that those standards are consistent with the basic principles of the Belmont Report and the Declaration of Helsinki. The status of women and children may be both legally and culturally different in other countries—which can present an ethical dilemma for a US researcher. The status of women and children may be both legally and culturally different in other countries—which can present an ethical dilemma for a US researcher.

13. Ethical Considerations in International Studies An overview of the ethical issues inherent in intervention trials is presented by the National Bioethics Advisory Commission in an April, 2001 report entitled, “Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries.” An overview of the ethical issues inherent in intervention trials is presented by the National Bioethics Advisory Commission in an April, 2001 report entitled, “Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries.” The FDA perspective is reviewed in the HHS Inspector General Report from September 2001, entitled “Globalization of Clinical Trials: A Growing Challenge in Protecting Human Subjects.” http://oig.hhs.gov/oei/reports/oei-01- 00-00190.pdf. The FDA perspective is reviewed in the HHS Inspector General Report from September 2001, entitled “Globalization of Clinical Trials: A Growing Challenge in Protecting Human Subjects.” http://oig.hhs.gov/oei/reports/oei-01- 00-00190.pdf.http://oig.hhs.gov/oei/reports/oei-01- 00-00190.pdfhttp://oig.hhs.gov/oei/reports/oei-01- 00-00190.pdf

14. Ethical Considerations in International Clinical Trials Of particular concern in international clinical trials is the appropriate justification for the use of placebos in foreign countries. Of particular concern in international clinical trials is the appropriate justification for the use of placebos in foreign countries. An example of these issues involved an NIH- funded research study in Uganda which used nevirapine to protect newborns from transmission of HIV. An example of these issues involved an NIH- funded research study in Uganda which used nevirapine to protect newborns from transmission of HIV. Among the ethical issues considered was whether use of a placebo control arm in this study, where effective treatments for the reduction of transmission of HIV to infants were available, but financially unattainable for many Ugandans, was appropriate. Among the ethical issues considered was whether use of a placebo control arm in this study, where effective treatments for the reduction of transmission of HIV to infants were available, but financially unattainable for many Ugandans, was appropriate.

15. Further Questions For more information on international research, contact the IRB Office at 412-383-1480. For more information on international research, contact the IRB Office at 412-383-1480.