NIH Investigator Manual for Human Subjects Research

• Created by Swan, Jeremy (NIH/NICHD) [C], last modified by Pauly, Kelly (NIH/OD) [E] on Mar 20, 2024

Chapter 15 - International Research

---

Overview

Key Points

• Investigators should be aware of additional ethical and cultural considerations when conducting international research.
  
  
• International research involving NIH investigators should be conducted under US federal laws and regulations (45 CFR 46 and, as applicable, 21 CFR) and any local laws and regulations.
  
  
• In-country approval by the local IRB (often referred to as the in-country Ethics Committee (EC)) is required before a protocol will be granted approval by the NIH IRB. (When the NIH IRB is the Reviewing IRB, and when there is no in-country IRB/EC, the NIH IRB will require a written assessment of the research for its consistency with foreign country laws and regulations, or local customs and culture, by an individual with appropriate expertise in the foreign country’s culture, who is independent of the research team.)
  
  
• The level of NIH IRB review of a study is determined by the engagement of the NIH Investigators.

What ethical considerations may exist when human subjects research is conducted internationally?

• Some countries have detailed national/regional human subjects research requirements much like the U.S. (e.g., Europe, India, and Japan), while others have no clearly defined human subject protections.
  
  
• When there are no clearly defined protections, the ethical principles that guide human subject research (e.g., Nuremberg Code, Declaration of Helsinki, Belmont Report) still hold true. This includes allowing subjects to participate in the research voluntarily and with informed consent, minimizing risks to subjects, and appropriately selecting research subjects, etc.

What is cultural competence and what cultural considerations exist when human subjects research is conducted internationally?

• Cultural competence means having a thorough understanding that a site's social habits, language, political and religious views, attitudes, values, and infrastructure are key to the success of the research. Demonstrating awareness of these cultural components should begin early in the planning phase, as the research is being designed and then continue throughout the life of the project. Failing to do so will negatively impact a research team's ability to foster a relationship with the community, communicate and enroll subjects, carry out research procedures and protect the rights, safety and welfare of subjects.
  
  
• Potential communication barriers need to be considered.
  • Consistent with the Belmont Report, communications with potential and enrolled research subjects should be informative (e.g., include adequate information) and comprehensible (e.g., investigators should employ methods to ensure study subjects are understanding the content).
  • Investigators should seek input from individuals with local knowledge to participate in the planning phase of the research and in the development of recruitment methods and materials, informed consent processes and all measures to be used with subjects.
  • Research teams should educate themselves about the site's literacy rates and cultural practices, and incorporate the use of illustrations, videos, demonstrations and/or community advisors.
  • All written materials provided to research subjects must be translated to the site's native language by a fluent individual (translation software is not sufficient) and submitted to the IRB for review and approval with a corresponding Certificate of Translation.
    
    
• Community engagement is very important when conducting international human subjects research.
  • When conducting international research, it is vital to foster community partnerships and to protect and nurture those relationships throughout the life of the project (and potentially beyond the project). Similar to understanding a community's culture, a research team must understand what the community's expectations are concerning the research and then honor those expectations or provide new feedback to the community as to what they can expect as the situation changes.
  • The research team might decide to share the results of the research or provide training, resources or equipment to the community.

What are the regulatory requirements for international research, and where can I find information on these regulations?

• Human subjects research conducted by NIH investigators is subject to federal law, regulation and NIH policy, regardless of whether the research is conducted domestically or internationally. Research may not be conducted by NIH investigators in any foreign country that is contrary to any U.S. Government prohibitions or restrictions on conducting research in that country.
  
  
• When conducting non-exempt human subjects research in a foreign country, NIH investigators must comply with all applicable in-country laws and regulations.
  
  
• If U.S. law, regulation, or policy (including NIH policy) differs from the foreign requirements, the most restrictive approach should be used - so long as it is not contrary to U.S. law or policy.
  
  
• For additional information, please refer to Policy 700, International Research. You can also refer to the OHSRP document, Guideline for International Research-Protocol Document, and the OHSRP Guideline for International Research-Consent Document both of which can be found in the series 700 section of the Policy and Guidelines webpage.
  
  
• The DHHS Office for Human Research Protections publishes the International Compilation of Human Research Standards annually which can be used to aid research teams in identifying applicable international regulations and guidelines.
  
  
• ClinRegs is a website maintained by NIAID that is an online database of country-specific, clinical research regulatory information. ClinRegs serves as a central resource and time-saver for investigators involved in planning and implementing international clinical research.
  
  
• Research teams are also encouraged to collaborate closely with local experts to ensure local requirements are adequately addressed.

When NIH is conducting international research, are the in-country review committees (Ethics Committees) subject to any specific regulations?

• Non-exempt human subjects research conducted or supported by the NIH IRP in a foreign country must be consistent with NIH's Department of Health and Human Services (HHS) Federalwide Assurance (FWA).
  
  
• This means that non-exempt human subjects research conducted in a foreign country with a foreign institution must be with an institution that holds an active FWA and the research must be reviewed by an IRB/Ethics Committee (EC) registered with the HHS Office for Human Research Protections (OHRP) and that, in its review, the local IRB/EC must apply US regulations for the protection of human subjects at 45 CFR 46. Any exception to this policy statement requires a compelling justification and must be approved in advance by the NIH Institutional Official (IO).  
  
  
• You can look up the FWA and status of a local IRB or Ethic Committee in the Office for Human Research Protections Database for Registered IORGs & IRBs and Approved FWAs.

What if the NIH IRB is the Reviewing IRB?

• When the NIH IRB is the Reviewing IRB, its review will be limited to determining if the proposed research meets the requirements of U.S. federal law, regulation and policy. The NIH IRB will not make determinations whether the research is compliant with the laws or regulations of any foreign nation, which will be determined by the in-country IRB/EC, unless there is no in-country IRB/EC.
  
  
• The NIH IRB has no oversight authority over the local investigators, nor their conduct of the research at the international site.
  
  
• When the NIH IRB is the Reviewing IRB, and when there is no in-country IRB/EC, the NIH IRB will require a written assessment of the research for its consistency with foreign country laws and regulations, or local customs and culture, by an individual with appropriate expertise in the foreign country's culture, who is independent of the research team.

What if the study is being completely conducted and overseen locally and I am only collaborating in the data analysis?

• When the NIH IRB is reviewing research conducted collaboratively with foreign investigators and/or institutions, its oversight responsibilities extend only to the activities of those investigators covered by the NIH FWA as specified in NIH Policy 100, NIH Intramural Research Program's Human Research Protection Program.

What if I am supporting international research but I am not actually engaged in human subjects research myself?

• If the NIH is not otherwise engaged in the human subjects research, then review by the NIH IRB is not required; however, in-country IRB/EC review is still required. That IRB/EC must be registered with OHRP and conduct its review compliant with 45 CFR 46 or have equivalent procedures consistent with 45 CFR 46.101(h).

What approvals need to occur before NIH investigators engage in international research?

• Protocol under NIH IRB Review: Non-exempt human subjects research conducted by NIH investigators in a foreign country must be approved by an in-country IRB/EC prior to receiving final approval by the NIH IRB. Note that the NIH IRB will not approve a study that has been disapproved by the in-country IRB/EC.
  
  
• Protocol under other U.S.-based IRB Review: Research may not be initiated in a foreign country until both U.S.-based Reviewing IRB approval and in-country IRB/EC approval has been obtained.
  
  
• Protocol only under local IRB/EC review: If the use of a U.S.-based IRB is not required, then only the required in-country IRB/EC needs to approve the study. That IRB/EC must be registered with OHRP and conduct its review compliant with 45 CFR 46 or have equivalent procedures consistent with 45 CFR 46.101(h).

What information must be included a protocol and consent being submitted to the NIH IRB if any research will be conducted in another country?

Please refer to the OHSRP documents, Guideline for International Research-Protocol Document, and the OHSRP Guideline for International Research-Consent Document.

What are the requirements for shipping test articles and biospecimens internationally?

• When international research will involve the study of test articles (e.g., drugs, biologics, nutritional products or devices) in a foreign country and the test articles will be shipped from the United States to the foreign site, the NIH Principal Investigator (PI) will comply with all below requirements:
  • Comply with FDA regulations for shipping test articles internationally
  • Comply with applicable NIH requirements (e.g., Pharmacy, CC Office of Research Support and Compliance (ORSC))
  • Comply with in-country regulatory requirements, approvals for test articles, and any necessary import requirements
  • Provide written documentation from the foreign site indicating all necessary approvals for use of a test article under the local laws have been obtained to the NIH IRB
    
    
• Note that some countries will not allow international shipping of certain biospecimens so this should be investigated before proceeding. It is recommended that you or someone on your team take the Biological Materials Shipper Training Course at NIH which will help you understand potential limitations such as available local delivery providers. This class is required for any members of your team who are involved in the shipment of specimens and includes the International Air Transport Association Dangerous Goods Regulations (IATA DGR).