This content was originally published on April 15, 2020. It was last updated as of Friday, May 29, 2020 at 12:40 p.m. CST.
American universities, hospitals, and other institutions currently have a wide variety of healthcare, research, education, and humanitarian projects underway all over the world, with some individual universities conducting projects in over 100 countries and individual hospitals and health systems conducting projects in several dozen countries. Pharmaceutical, device, and vaccine manufacturers are also conducting an increasing volume of research globally, and a review of clinical trial registrations on ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform shows that a significant and growing number are being conducted in countries classified by the World Bank as low- and middle-income countries (LMICs). Even without the COVID-19 pandemic, there can be a complex interplay of U.S. law; foreign law; grant term compliance; and various operational, political, and ethical considerations when conducting those projects, particularly when they involve human subjects research (HSR) in LMICs.
Many of these HSR projects have been modified or put on hold as a result of the pandemic because of participant safety, personnel or supply availability, medical resource conservation, mandatory quarantines, travel restrictions, or other considerations. Other HSR projects have not yet been put on hold due to local considerations, and still others cannot safely be put on hold. The Food and Drug Administration (FDA), the Office for Human Research Protections (OHRP), and other regulators of medical research around the world (including in India, South Africa, Kenya, Brazil, and Peru) have issued guidelines for what clinical research sponsors should consider when pausing or modifying studies, but such guidelines will not be available in many LMICs.
Restarting paused HSR projects in LMICs will present challenges unique to the LMIC environment. COVID-19 statistics in many LMICs can be unreliable or censored, and testing capacity with existing technologies will not match that of high-income countries (HICs), so it may be difficult to have situational awareness of the local outbreak. In addition, vaccines and treatments are likely to become widely available in HICs first, and some may never become widely available outside of HICs, so there may be a period of time when citizens of a particular country are at significantly higher overall risk than HIC staff working on-site alongside them.
There will also, of course, be projects that are started during the pandemic, including on COVID-19 vaccines, treatments, in vitro diagnostics, social and behavioral interventions, and epidemiology, or research on an emergency itself (e.g., research on the impact of cash transfers on women’s risk of violence during a health crisis). While much of the early phase safety work for vaccine candidates and investigational drugs is likely to be carried out in HICs and China, the bulk of this work will take place globally, and some will be conducted in LMICs exclusively. As of the middle of May, well over a thousand COVID-19 clinical trials were listed in the World Health Organization’s International Clinical Trials Registry Platform that were not also listed on ClinicalTrials.gov.
We provide here a resource for institutions conducting or participating in HSR in LMICs as they evaluate whether to modify or suspend HSR projects in LMICs and when and how to start or restart them. This content is based on the firm’s extensive on-the-ground work throughout the developing world on behalf of universities and hospitals, including on vaccine clinical trials and biological sample collection projects, as well as the firm’s work with a global organization dedicated to the development of vaccines against emerging infectious diseases, including COVID-19. Because of the complex and context-specific considerations involved in these projects, this resource is far from exhaustive, but we hope that it provides a good starting point for many of the relevant issues.
If you have any questions about conducting research or public health projects abroad during the COVID-19 pandemic, please contact the authors of this resource.
COVID-19 Considerations for Projects in LMICs
Sponsored projects are subject to rules imposed by the funding entity, and U.S. government funding, in particular, is subject to complex pre- and post-award rules pertaining to cost principles, administrative requirements, and audit standards. The Office of Management and Budget (OMB) has issued several memoranda addressing relief measures to federal awardees. Those OMB measures are further explained by guidance from numerous federal awarding agencies, some of which are described below.
Non-governmental foundations also support a significant number of overseas projects, and several of the major foundations have similarly issued guidance to awardees.
National Institutes of Health
The National Institutes of Health (NIH) issued a guidance notice and frequently asked questions website for recipients of federal financial assistance affected by COVID-19 providing flexibilities related to pre-award costs; extensions of post-award financial and other required reporting, including closeout reporting; prior approval requirement waivers; and extension of single audit submissions. The NIH also addressed funding considerations related to salaries and stipends and noted that many researchers may be unable to work as a result of COVID-19, so if a recipient organization’s policy allows for the charging of salaries and benefits during periods when no work is performed due to COVID-19, then charges to NIH grant awards will be permissible. Regarding the federal government’s heightened scrutiny of foreign influence at U.S. academic institutions, NIH had initially stated that if a post-doc on an active NIH grant must return home to a foreign country as a result of COVID-19 and work remotely this must be reported to NIH as a foreign component of the award; while NIH has apparently changed its mind on this, the answer may be different if more senior project personnel were working remotely in a foreign country. The NIH has stated in a YouTube video that the FAQs will be updated often, so we encourage awardees to check them regularly.
The NIH also issued guidance specifically for NIH-funded clinical trials and HSR projects affected by COVID-19, directing grant recipients to take all steps necessary to ensure the safety of all participants and research staff and encouraging recipients to consult with their Institutional Review Boards (IRBs) and institutions regarding protective measures. In addition, the NIH acknowledged that recipients may incur unanticipated costs during this time, such as costs to arrange for participants to receive care locally or virtually, rather than the study site; supply chain disruptions; personnel shortages; additional lab testing for COVID-19; and increased transportation costs. Recipients may request administrative supplements from the funding institute or center, which will be addressed on a case-by-case basis.
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention (CDC) has published a frequently asked questions website for grantees addressing the effects of COVID-19 and directs grant recipients to the memoranda published by the OMB dated March 9, 2020, March 19, 2020, April 9, 2020, and April 10, 2020. These memoranda provide flexibility for awarding agencies with regard to application deadlines, no-cost extensions on expiring awards, charging salaries to the grant when personnel are not able to work due to COVID-19, permissibility of costs not normally chargeable to awards, prior approval requirement waivers, and extension of reporting and single audit submission requirements. The agency also addresses the reassignment of personnel. Grant recipients should maintain records and documentation related to grant flexibilities and assess the impact on programmatic activities as originally funded once normal activities resume, as there is no guarantee of additional funding. Guidance on repurposing existing awards to support the emergency response to COVID-19 as well as implementation guidance for supplemental funding is also provided
United States Agency for International Development
The United States Agency for International Development (USAID) issued a memorandum authorizing COVID-19 flexibilities but emphasizes that in no circumstances can costs exceed the amount obligated in the award and clarifying that the agency will not reimburse any overspend. USAID notes that recipients must ensure all costs associated with repatriation, termination, and close-out are within budget and available within the amount of the award. The USAID memorandum discusses, among other things, no-cost extensions on expiring awards at the request of the recipient as well as extensions on reporting requirements, abbreviated non-competitive continuation requests, and the permissibility of charging salaries and other project activities in light of COVID-19 effects. Before incurring related costs, grant recipients must notify the applicable USAID Agreement Officer or Agreement Officer’s Representative. Similar to other funding agencies, USAID has issued FAQs that should be checked regularly. USAID has created a webpage specifically for guidance on COVID-19 funding requests and unsolicited proposals.
NIAID Division of AIDS
The Department of Health and Human Services (HHS) issued guidance on the potential impact of COVID-19 on the NIAID Division of AIDS (DAIDS) sponsored clinical research studies. DAIDS noted that it will expedite the review of clarification memoranda, letters of amendment, and amendments to address the effects of COVID-19 related to the implementation of protocols. DAIDS also provided guidelines for network leadership, protocol teams, site staff, and the management of clinical trials. DAIDS suspended all on-site monitoring visits through April 17, 2020. The organization also issued a memorandum addressing the use of alternative and remote informed consent processes. DAIDS has also provided a memorandum containing guidance for clinical research sites on resuming operations during the pandemic. Inquiries should be directed to DAIDS representatives in the Scientific Research Programs.
National Science Foundation
The National Science Foundation (NSF) has published answers to frequently asked questions and encourages grant recipients and proposers to monitor the NSF’s website for updates. The NSF has also encouraged international collaboration, as several countries are providing funds to support international collaborative research in partnership with U.S. research communities.
Private foundations have also issued guidance for grantees on navigating uncertainties surrounding COVID-19 and its effects. Generally, established project budgets are not being expanded, but a reallocation of funds may be permissible. Harvard University has created a resource page to collect funding information and resources for private foundations.
For example, the Gates Foundation has a specific page on COVID-19 updates and new grant opportunities. The Global Fund is enabling countries to use up to 5% of currently approved grant funding to help protect and treat vulnerable communities related to COVID-19. Under the guidelines, the Global Fund is encouraging countries to redeploy underutilized assets; repurpose grant savings; and, in exceptional cases, reprogram funding from existing grants. Activities under the new COVID-19 guidelines include, but are not limited to, epidemic preparedness assessment, laboratory testing, sample transportation, use of surveillance infrastructure, infection control in health facilities, and information campaigns. The Global Fund also issued a question and answer document on supporting grants during the COVID-19 pandemic.
The Wellcome Trust’s COVID-19 response page for grant holders notes that it may pay for certain costs if recipients are called to work on the coronavirus response for one month or more (e.g., carrying out clinical duties), among other things. Also, if grantees have paid costs for events or travel that have been canceled and are non-refundable, then grantees may be able to claim these against their grants.
Travel Considerations and Quarantines
Travel restrictions, social distancing guidance, lockdown measures, contact tracing, and isolation/quarantines will have an impact on international projects that are difficult to overstate. On March 9, 2020, the CDC advised all institutions of higher education to consider postponing or canceling all upcoming student study abroad programs and also consider bringing back to the United States all students who were participating in study abroad programs at that time. On March 31, 2020, the U.S. Department of State advised U.S. citizens to avoid all international travel due to the global effect of the pandemic and further instructed U.S. citizens who live abroad to arrange for “immediate return” to the United States unless they are prepared to remain abroad for an indefinite period. Many U.S. personnel based or temporarily working overseas have returned to the country as a result of this State Department advice, and their ability to return to the locations of their projects will be impacted by both the U.S. State Department (whose guidance is heavily relied upon by U.S. institutions) and restrictions imposed by their host countries. The U.S. State Department is also maintaining a list of COVID-19 country-specific information and related resources. The World Health Organization (WHO) has noted that if countries lift travel restrictions too quickly, there could be a resurgence of the virus, and the NIH has discouraged travel for large meetings that are not mission-critical and is encouraging the use of tele/videoconferencing services where possible. In addition, institutions also may have private travel risk information available. Many large pharmaceutical and device companies and U.S. institutions have contracts with private services that provide additional, and often more detailed, travel risk information than is available from the U.S. State Department.
Internationally, there have been varying responses to COVID-19 and the degree to which government officials have placed restrictions on public gatherings and travel. Foreign travel restrictions, lockdowns, and quarantines will limit movement into or within a country, inhibiting the work of U.S. or host country personnel currently on the ground and travel of U.S. personnel to study sites. Some government officials have been extremely proactive in implementing social distancing measures, while others have been slower to respond. For example, in India, officials instituted a total lockdown, which drastically curtailed non-hospital based research projects in the country; however officials have begun gradually reopening business and commercial activities. Other countries, including Sierra Leone, Uganda, and Uzbekistan have imposed restrictions that could affect overseas projects. Nicaragua and Brazil, on the other hand, have taken relatively few actions in response. The Partnership for Evidence-Based Response to COVID-19 has published a report on the overall COVID-19 government responses in Africa. Some countries, including Chile and Vietnam, are requiring “immunity passports” or back to work permits to allow individuals who have recovered from COVID-19 entry into the country or to resume normal activity within the country. However, WHO has cautioned against using coronavirus antibody tests as the basis for issuing immunity passports, as there are concerns over false positive results and further research is needed into whether individuals testing positive are immune from secondary infections. Researchers have noted that immunity passports could be catalysts for corruption and implicit bias and impose an artificial restriction on which individuals can participate in civic and economic activities.
These are just a few examples, and we expect most LMICs to impose some form of COVID-19 internal restrictions. Both Oxford University and the International Monetary Fund are tracking government policy responses and travel restrictions related to COVID-19 for most countries, but of course, local partners and any remaining in-country U.S. State Department and USAID personnel will have the most accurate and up-to-date information.
There have been many articles addressing various U.S. labor and employment topics that have arisen from COVID-19 and interpreting recently passed legislation, particularly the Families First Coronavirus Response Act. Topics addressed include employer frequently asked questions on COVID-19, workforce reduction options during the pandemic, HIPAA compliance for employers that are covered entities, and discussion on the CARES Act legislation. U.S. citizens working abroad are covered by some U.S. federal labor laws (e.g., ADEA, Title VII and ADA), except to the extent that an employer’s adherence to those laws would cause the employer to violate the laws of the country where the workplace is located. See 29 USC § 623(f)(1), 42 U.S.C. § 2000e-1(b), and 42 U.S.C. § 12112(c)(1). Likewise, for covered entities, HIPAA is still applicable to employees located outside of the country and to the handling of protected health information of individuals located outside of the United States.
Foreign labor law presents unique challenges for U.S. institutions. Most foreign countries’ labor laws are more pro-employee than U.S. laws are, and it is often difficult to ascertain what the relevant laws require. The Rwandan labor code, for example, is issued in several official languages, and there are conflicts between the French, English, and Kinyarwandan versions. For this reason, U.S. institutions navigating a foreign country’s labor laws should consult local counsel. Organizations should take into consideration any applicable foreign rules or protocols around collective bargaining agreements, leaves of absence, workforce reduction processes, furlough policies, and employee data privacy. Additionally, COVID-19- specific policies, such as whether an employer may lawfully conduct temperature checks or require an employee to see a health care provider, will need to conform with applicable foreign law. The International Labour Organization is monitoring policy responses by country for measures that governments, employers, and worker organizations have implemented to address the effects of COVID-19.
Other Practical Considerations
There is a host of other issues institutions and companies will need to consider as they navigate COVID-19 challenges of conducting projects in LMICs, such as safety and security of staff and participants, the extent to which provisions in memoranda of understanding (MOUs) with host governments will still be honored, availability of supplies and subcontractors, and the terms of institutional insurance.
The Nuffield Counsel on Bioethics published a report titled Research in Global Health Emergencies in January 2020 (Nuffield Report), which includes a discussion of practical issues faced by front-line workers that will need to be handled, such as fair treatment of employees and other ethical concerns. Some of these concerns institutions may need to address include challenges in meeting supply needs, staff being a source of danger for study participants, responding to violence or physical threats, and providing support for the emotional impact of public emergencies on staff.
The safety and security of employees, and employees of key partners and subcontractors, is understandably a top concern for institutions and companies. In addition to concerns over researchers and staff contracting or transmitting COVID-19, particularly in LMICs already experiencing strain on healthcare systems, resulting in social and political upheavals will need to be continuously monitored for risks to the safety of researchers and other staff. For example, there have been protests and police violence in many countries as government officials seek to contain the spread of COVID-19. Medical professionals in several countries, including Mexico, Columbia, Brazil and the Philippines, have been attacked by individuals concerned about contracting COVID-19. In addition, there has been a documented increase in anti-foreigner sentiment worldwide, including in Cameroon, China, and Ethiopia.
Many research projects benefit from exemptions or privileges available through MOUs with host governments. Institutions must confirm whether these MOUs will still be honored in light of COVID-19 challenges and whether MOUs have been impacted by changes in laws or other emergency measures in the host country as a result of the pandemic. In addition to confirming that MOUs are still in effect with regard to the host country signatory, institutions should also determine whether their MOUs present conflicts with the directives of any local or provincial health authorities, which can sometimes be inconsistent with national ministerial guidance.
The availability of necessary supplies and disruptions to supply chains, particularly in LMICs, as a result of the pandemic will also need to be addressed. COVID-19 will likely have a long-lasting effect on global supply chains. The U.S. and more than 50 other countries are restricting or considering restrictions on, exports of supplies that are needed to mitigate the effects of COVID-19 locally. Internationally, the World Trade Organization and the World Customs Organization issued a joint statement noting the disruptive impact of COVID-19 on global supply chains and pledged to cooperate to facilitate trade in essential goods. The Global Fund is monitoring and assessing global health product supply chains on an ongoing basis. The Center for Infectious Disease Research and Policy of the University of Minnesota is monitoring ongoing supply chain issues. WHO, the Global Fund, Wellcome Trust, and the Coalition for Epidemic Preparedness Innovations, among others, have created Access to COVID-19 Tools (ACT) Accelerator, a global collaboration to increase access worldwide to health technologies and related coronavirus response resources.
Companies and institutions will also need to evaluate the terms of their institutional insurance policies to determine whether COVID-19 may have an impact on coverage for medical, travel, or liability claims that may arise. For example, many institutional medical and security evacuation policies do not cover activities in countries designated as a Level 4 risk by the U.S. State Department. Prior to the pandemic, only a few countries (e.g., Somalia, Yemen, Afghanistan, Syria, and the Central African Republic) were in this category. Currently, however, there is a U.S. State Department Level 4 Do Not Travel advisory globally. Likewise, other policies should be considered for language that may be implicated by COVID-19 and its effects on project coverage.
In these times of increased global uncertainty, companies and institutions may also consider reminding employees and researchers that the organization’s compliance with the U.S. Foreign Corrupt Practices Act (FCPA) remains in full effect. The FCPA penalizes bribing or offering, authorizing, or promising to bribe foreign officials, and good motivations are not a defense to a violation. Many enforcement actions involve bribes paid for transactions that are beneficial both to the payor and the country in which the bribe was paid. Amid a global pandemic, the risk for corruption may be heightened because individuals may feel traditional rules preventing such behavior have been suspended, both in the United States and abroad.
While the first half of this resource addresses some COVID-19 considerations for projects in LMICs generally, the remainder of this resource will be specific to HSR projects specifically. While companies and institutions conducting HSR abroad are already familiar with the regulatory definitions of “human subject” and “research,” OHRP’s COVID-19 guidance regarding public health surveillance activities, including collection and testing of information or biospecimens, conducted, supported, requested, ordered, required, or authorized by a public health authority (to the extent not involving an investigational drug or device) should be reviewed in light of the proposed project. OHRP has also stated that it believes the FDA’s more detailed guidance on clinical trials, which is a valuable tool for organizations involved in clinical trials in LMICs, particularly where the host country’s regulator has not issued similar guidance.
Most non-exempt HSR projects involving a U.S. institution will be reviewed by an IRB following the Common Rule (which has been adopted by both HHS at 45 CFR Part 46 and USAID at 22 CFR Part 225) or a sponsor following the similar (but not identical) FDA regulations at 21 CFR Parts 50 and 56. The Common Rule does not supersede foreign laws with respect to HSR conducted abroad but will stand alongside any foreign laws and approval requirements imposed on HSR. OHRP has compiled a list of foreign laws in various countries that impose standards for human research.
The Common Rule and FDA equivalent require an IRB to be sufficiently qualified to promote respect for its advice and counsel in safeguarding the rights and welfare of human subjects and to ascertain the acceptability of proposed research in accordance with institutional commitments, applicable laws or regulations, and professional standards. Organizations conducting a significant volume of projects overseas often have a dedicated global affairs office and legal counsel to assist with this and often have policies pertaining to local context knowledge for HSR conducted abroad. Studies (particularly those involving more than minimal risk) conducted abroad often also involve a research ethics committee or community advisory board (or both) in the host country, whether or not required by local law.
These two regulatory regimes also explicitly acknowledge that the IRB may “invite individuals with competence in special areas to assist in the review of complex issues which require expertise beyond or in addition to that available on the IRB.” These issues might include issues specific to the host country, vulnerable populations (discussed in greater detail below), or expertise specific to COVID-19 research (e.g., infectious disease, intensive care, epidemiology, or virology).
While there are some differences in approval categories and approval criteria for research approved under the pre-2018 Common Rule amendments, in general, the IRB approval criteria for non-exempt HSR include the following:
- The risks to the subjects must be minimized.
- The risk to benefit ratio must be reasonable.
- The selection of subjects must be equitable.
- Informed consent must be obtained from each subject in a language the subject understands.
- Informed consent must be appropriately documented.
- There must be an appropriate data monitoring plan.
- Privacy and confidentiality must be maintained.
- There must be additional safeguards to protect subjects that are vulnerable to coercion or undue influence.
Research not being reviewed pursuant to these precise standards – for example, research in which a U.S. institution is involved but not “engaged” or research in which the primary funding recipient obtains approval under USAID’s equivalence policy – will likely follow similar standards because Common Rule is based on the same basic ethical principles followed by most countries and international organizations. For example, while the three core Belmont Report principles are respect for persons, beneficence, and justice, the Nuffield Report’s ethical compass is oriented around the similar principles of equal respect, helping reduce suffering, and fairness. Moreover, the Declaration of Helsinki and the Council for International Organizations of Medical Sciences are the two major sets of international guidelines on biomedical research, and they adhere to the same values articulated in the Belmont Report and Nuffield Report. As a result, while we have structured the remainder of this resource to follow the Common Rule/FDA approval criteria most likely to be relevant to LMICs or affected by the pandemic, we anticipate that these considerations will be relevant for institutions or ethics committees following different regulatory regimes or the WHO’s ethical standards for research during public health emergencies.
COVID-19 Considerations for HSR Projects
Risks and Benefits
The Common Rule and FDA regulations require the IRB to determine that risks to subjects are minimized and are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. Weighing the risks and benefits of research in LMICs presents ethical issues unique to the project and country, and COVID-19 and its aftermath may in some cases dramatically shift that calculus.
The potential benefits of behavioral and health interventions in LMICs and the importance of the knowledge to be gained during a pandemic can be significant and even life-saving, either in the context of the COVID-19 pandemic or a future pandemic or humanitarian crisis. That safety and efficacy studies of mRNA vaccine candidates in animals will run concurrently with the Phase I clinical trial in humans, and that the World Health Organization and several bioethicists have expressed support for human challenge trials, are evidence of the great extent to which the scientific community has valued the time-sensitive knowledge that will result from these studies. Risks, too, may increase because of devastated economies and health systems; disrupted communities; surges in malnutrition and misinformation about COVID-19; distrust of vaccines in communities such as the Philippines, Gabon, and Haiti; and communities turning to traditional healers to treat COVID-19 in places like Venezuela and Zimbabwe.
Data and Samples
HSR projects that involve the collection of identifiable data or biological samples, and particularly their transfer outside the country of collection, need to account not only for local laws that may impact their activities (some of which, like Argentina’s, can be quite stringent), but also for issues of informed consent, community trust, and certain unique issues pertaining to samples.
Many LMICs do not have laws specifically governing data protection, although, in the context of the COVID-19 pandemic, in particular, China’s Regulations for the Administration of Medical Records constitutes an important exception. A recent United Nations report highlighted, for example, that most African nations do not possess such laws, although we note the adoption of Economic Community of West African States Supplementary Act A/SA.1/01/10 and its enactment into law in at least seven West African nations, as well as the cautionary case of South Africa.
In addition to reviewing the ORHP compilation referenced earlier for country-specific laws, be sure to check whether the government has taken any actions in light of the pandemic to suspend certain laws, including those relating to data privacy, as many LMICs, in particular, are doing so as a means to combat the spread of COVID-19. A U.K. organization is tracking government suspensions of privacy requirements, such as telecommunications tracking, here. China’s QR health code system and India’s Aarogya Setu app, both of which are generally mandatory, will create unique privacy issues for some research subjects. Also, many LMICs are imposing restrictions on reporting about the spread of the disease and banning people and organizations who do, which could affect access to, or export or publication of, research project data. The Committee to Protect Journalists is tracking that issue here.
Informed Consent, Including for Future Uses
For HSR that will remain underway or begin during the pandemic, it is important to be as clear as possible in any consent process how data will be shared with relevant public health authorities, even if OHRP has recently stated that legally-required COVID-19 reporting will not be impeded by consent form wording. Note that the WHO’s International Health Regulations 2005 (agreed to by almost every country in the world, although unenforceable) require each signatory state to share with the WHO “timely, accurate and sufficiently detailed public health information” of events like the COVID-19 pandemic.
While broad consent to future research uses of data and biospecimens is now permitted (if not widely used) in the United States under the revised Common Rule, some countries’ regulations pertaining to HSR only permit specific informed consent for future uses of data and biospecimens or allow broad consent for future uses outside the country for data only. Assuming broad consent is allowed (or not addressed as a matter of law) in a particular country, we advise institutions to be cognizant of empirical research on the use of broad consent in LMICs and to consult the excellent discussion of this topic starting at Section 9.9 of the Nuffield Report. The African Academy of Sciences has also started work on the continent’s first cross-disciplinary guidelines on how to collect, store, and share research data and specimens in ways that protect study participants from exploitation and benefit African citizens; some individual communities, such as the San people, have issued guidelines about this.
Note that while the emergency or post-emergency context may make it more challenging to institute the level of community consultation or engagement necessary to implement best practices in this area, particularly when samples will be removed from the host country, references to ““biopiracy” of samples taken from Liberia and Guinea to Western countries should give companies and institutions pause.
Unique Issues for Samples
Aside from the cultural and religious issues that pertain to the use of samples, the following two legal issues pertain uniquely to samples:
The Nagoya Protocol: The U.N. Convention on Biological Diversity (CBD) is an international treaty, and the Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilization (Nagoya Protocol) is a supplementary agreement to the CBD. The United States is not a party to the CBD, but every other U.N. member state has ratified the treaty, so researchers outside the United States must be mindful of it. A fewer number of countries, but many LMICs, are also parties to the Nagoya Protocol.
The CBD recognizes “the sovereign rights of States over their national resources” and provides that where a signatory country carries out research using another country’s resources, they should endeavor to do so with the full participation of the source country, and where possible in that country. It is our experience that this can present material difficulties in completing research collaborations in some countries. The Nagoya Protocol implements certain provisions of the CBD and pertains to, among other things, the research on the genetic composition of a country’s “genetic resources” (which would likely include SARS-CoV-2 itself and biospecimens related to the outbreak). HSR projects involving a Nagoya Protocol signatory in particular need to take into account whether the host country has adopted implementing legislation and, if not, how the relevant authorities and local institutions intend to approach this issue. There are differing interpretations as to whether the Nagoya Protocol applies to the sharing of the nucleic acid sequence of a virus as opposed to the pathogen itself and concerns about impediments to work during disease outbreaks.
Export Controls and Select Agents: Export control issues are not new to organizations that conduct work overseas. While SARS-CoV-2 is currently covered under Export Control Classification Number EAR99, it is important for organizations to monitor any developments here. SARS-CoV (the virus that causes SARS) is controlled under 1C351, and vaccines for SARS are controlled by 1C991. If the Commerce Department’s Bureau of Industry & Security changes its determination based on subsequent information about SARS-CoV-2, while the fundamental research exception at 15 CFR § 734.8 still protects technology or data that is the result of or arises during ““fundamental research,”” it does not provide a blanket exception for sharing non-public sensitive technical data with a foreign national during the research project itself.
The Federal Select Agent Program (comprised jointly of the CDC’s Division of Select Agents and Toxins and the Animal and Plant Health Inspection Service at the Department of Agriculture) oversees the possession, use, and transfer of biological select agents and toxins, which have the potential to pose a severe threat to the public, animal, or plant health or to animal or plant products. Currently, while SARS-CoV is listed as a select agent, SARS-CoV-2 is not. As above, though, this should be actively monitored, as the Federal Select Agent Program has stated that as it “gains more information about the SARS-CoV-2, we will reassess the select agent status as needed.” Any changes in the select agent status of SARS-CoV-2 would be published in the Federal Register.
The Common Rule requires that IRBs be “particularly cognizant” of the special problems in subject selection that will include a category of subjects who are vulnerable to coercion or undue influence. It also requires that IRBs determine, as a condition to approving research, that “additional safeguards have been included in the study to protect the rights and welfare of these subjects.” Although the Common Rule only recommends that IRB membership include a person knowledgeable about vulnerable populations if the IRB “regularly reviews” research involving those populations, IRBs working with vulnerable populations overseas should strongly consider a consultation with an expert in the relevant population if the expertise is not available on the IRB roster or from a reliable local partner.
While the Common Rule lists as examples of vulnerable populations children and prisoners (research involving who is subject to additional regulations in the United States), individuals with impaired decision-making capacity, and economically or educationally disadvantaged persons (which already include many people in LMICs), there are additional categories of vulnerability in the context of research in LMICs, particularly in the context of a pandemic.
Several guidelines on ethical principles for research in disaster settings, both from U.S. working groups and from working groups abroad (including one from the WHO on ethical issues during disease outbreaks), have been proposed to guide researchers, institutions, and IRBs in navigating research in vulnerable populations. A good review of those guidelines is here. This guide, from the United Nation’s Inter-Agency Standing Committee, provides useful information about how to include marginalized and vulnerable people in risk communication and community engagement.
Refugees, Internally Displaced Persons, and Politically Marginalized Peoples
Refugees, internally displaced persons, and politically marginalized people – for example from Syria, Venezuela, Afghanistan, Libya, South Sudan, Myanmar, and on the U.S. border with Mexico – are particularly at risk for exploitation or harm. Moreover, COVID-19 is likely to both exacerbate the dire situations these refugees face in LMICs and also to create new refugee and internally displaced populations, particularly with migrant workers throughout South Asia, India, and the Middle East being uprooted by the pandemic. COVID-19 also has the potential to create new groups of politically marginalized people as the pandemic results in national security challenges in many LMICs. The United Nations, media, and private organizations are monitoring this situation and should be checked for updates.
Poverty, Lack of Education, and Familial Coercion
These issues are not unique to a pandemic but are heightened in LMICs and will almost certainly be a heightened problem as a result of the pandemic. Although in-country partners are likely to have the most up-to-date information on these topics in light of COVID-19, the World Economic Forum is also tracking these issues and is a good starting point for information. The United Nations has also produced a working paper containing estimates of the impact of COVID-19 on global poverty as of April 2020.
Medical Vulnerability and Physical Security, Food, and Shelter
It is often ethically difficult to ask people to participate in research if their basic security, food, and shelter needs are not being met. While the U.S. State Department usually has reliable and up-to-date information on the security situation in a particular country, the COVID-19 pandemic has resulted in many U.S. Embassy personnel globally to be withdrawn, so this information may not be as accurate during the pandemic. Universities, hospitals, and companies also often subscribe to private information services that provide more detailed assessments than what is available from the U.S. State Department.
The Famine Early Warning System is an excellent way to determine whether there are food security issues in a country or region. It is updated very regularly, and they are closely tracking the effects of COVID-19 on food security.
Unfortunately, we are unaware of a good, up-to-date global source of information on homelessness, particularly in LMICs, where many housing situations are informal in any event and not well tracked by the LMIC governments. In-country partners will be best suited to provide information about this and any local or population-specific security and food concerns.
Ethical issues in COVID-19 vaccine studies and treatment in LMICs are covered in “Informed Consent,” below. But aside from those issues, COVID-19 may increase the risk that populations are more vulnerable to coercion because of scarce medical resources or those already-vulnerable populations in LMICs – such as women or those with underlying disease states such as malaria, HIV/AIDS, and tuberculosis – become even more at risk of harm or exploitation. The World Economic Forum resource mentioned above, Al Jazeera, and the WHO are all likely to track this issue in the LMIC context in the coming months.
We know from our own experiences in the United States in the aftermath of natural disasters that people who have been through disasters are psychologically stressed and may have impaired decision-making capabilities, and this will be especially true for research subjects who have lost loved ones. Cases of domestic abuse have risen worldwide as a result of quarantines. The U.S. National Institute of Mental Health has issued Ethical Issues to Consider in Developing, Evaluating, and Conducting Research Post-Disaster, which will be useful for researchers confronting these issues. In addition, it would be prudent for researchers to plan to address cases of participants facing domestic violence or child abuse, even if that is not explicitly the subject of the research, by determining what resources might be available for them in their communities.
Informed consent for HSR is a challenge everywhere, including in the United States. The special challenges associated with getting truly informed consent from research participants or their legally authorized representatives in LMICs (or assent from children and parental permission) are well known and have been extensively documented by the U.S. National Bioethics Advisory Commission and the Nuffield Council. A few issues among many include language, literacy, therapeutic misconception, and cultural challenges around who gives consent.
In the setting of a pandemic, these challenges are likely to be exacerbated by family and economic disruption, the strain on health systems, and fear. The Common Rule/FDA requirement that information be given to the subject in language understandable to them may pose new difficulties with the migration that a pandemic or its aftermath may cause regionally. The CIA World Factbook has a listing of which languages are spoken in each country, but researchers and local partners on the ground are likely to have the most up-to-date information about a specific population in a fast-evolving environment.
Some tools and recommendations that may be used to address these challenges include:
- Emphasizing to potential subjects that the decision about whether to participate in the study will have no bearing on their medical treatment or access to humanitarian aid. We understand, of course, that in LMICs and particularly during a pandemic, subjects may, in reality, have few avenues to access any meaningful medical care outside the context of a research study, which further complicates this issue.
- Providing information in novel ways, including pictures, participatory drama, traditional games, or simply reading relevant information aloud.
- Wearing apparel, badges, or anything else that will visually distinguish researchers from health authorities or first responders.
- Taking culturally appropriate steps to reduce perceived power imbalances between researchers and potential subjects. For example, in many Middle Eastern countries, seating around a table is arranged hierarchically, and researchers would ideally allow the potential subject to sit at the head of the table, with researchers sitting to the right of and a few seats away from the potential subject.
- For vaccine research, emphasizing that experimental vaccines may not provide any protection from COVID-19 (and usually there will be a placebo control as well), so subjects should not alter their preventive behaviors.
- For COVID-19 treatment studies, recognizing that subjects are already sick and thus vulnerable and may feel they have no alternative but to participate. In some cases, research studies may in fact offer improved standard-of-care controls or related care compared to what may available outside the study.
Community engagement (discussed below), where possible, will significantly inform which combination of measures will overcome the particular consent challenges that may be present in a given community in the context of the proposed study. In addition, we understand that while it is not yet available, WHO is planning to issue a guidance document on informed consent for research during the COVID-19 pandemic, which will likely be available here.
Finally, we note that the Common Rule and FDA diverge somewhat in their informed consent requirements insofar as waivers of documentation of consent and life-threatening situations necessitating the use of an investigational product. We also note that both the FDA regulations and the Common Rule (through a waiver by the HHS Secretary pursuant to 45 CFR § 46.101(i)) somewhat controversially allow planned HSR in emergency circumstances without informed consent, a category of research not contemplated by the laws in most LMICs. These issues (and their likely interplay with host country laws) are not discussed here, except to note that either may arise during an HSR project, depending on the nature of the study and the regulations governing it. In particular, we note that because waivers of documentation are sought in advance, they may be appropriate pursuant to 45 CFR § 46.117(c)(1)(i) in the context of the pandemic where the study may produce results that challenge the host country government’s reporting of COVID-19 cases or deaths.
The Common Rule requires that to approve HSR, an IRB must find that there are additional safeguards to protect subjects that are vulnerable to coercion or undue influence. Beyond that, the Common Rule itself does not provide suggestions or examples; rather, what is required will vary by the locality and context in which the research takes place. OHRP provides some limited guidance with respect to research involving certain categories of vulnerable populations, such as children, prisoners, and those involved in HIV/AIDS research. For vulnerable populations outside of those categories, and for LMIC populations generally, the following are just a few examples that institutions and research sponsors might consider in the context of COVID-19:
- More Frequent Reviews of Research and Independent Verification: The Common Rule and FDA regulations require a continuing review of ongoing full-board research at least annually, but an IRB must determine “which projects require review more often than annually and which projects need verification from sources other than the investigators that no material changes have occurred since previous IRB review.” A study within a rapidly evolving context, such as a pandemic, may well warrant continuing review (or a periodic report from the investigator) more frequently or verification from sources other than the investigator.
- Independent Ethical Review: Using a local research ethics committee has been briefly mentioned above. The Nuffield Report suggests the use of an independent ethical review committee in the country where the research takes place as an added safeguard for research subjects, even where this is not required by law. Local expertise provides a better understanding of the research risks, as well as the wider risks to the people or community in the context of a global pandemic or another emergency. Local ethics review committees are often more likely to raise certain issues than their counterparts in the United States due to their familiarity with the local community and whether certain treatments would actually provide a benefit to the community. Research Ethics Web is one potential resource to consult when looking for local ethics review committees or IRBs for research conducted in Africa. The WHO and the African Coalition for Epidemic Research, Response and Training teamed up to prepare a list of considerations for ethics reviews and preparedness specific to pandemics, which will be particularly useful for those conducting or continuing research during the COVID-19 outbreak.
- Community Engagement: One of the potential challenges in conducting research in LMICs can be building trust with the community from which subjects are drawn. One way to do that is by engaging directly with the community, often through a community advisory board. The nature of a global pandemic makes this more challenging but not impossible. For example, people in LMICs in particular often use large WhatsApp groups to obtain information. But direct interactions and community outreach activities must be thoughtful and varied in approach to ensure a diverse audience is reached, especially keeping in mind vulnerable populations like women, children, refugees, and those with disabilities. As the Inter-Agency Standing Committee (IASC) notes, marginalized people become more vulnerable in emergencies. The IASC published a guide that includes specific tips for ensuring these groups, who are even more at risk due to the COVID-19 pandemic, are accounted for in community engagement activities.
- Standard of Care: There is a significant debate about the standard of care that should be available in the context of a research study (e.g., to subjects enrolled in a control arm of a clinical trial). While a discussion of this debate is beyond the scope of this resource, improving this standard of care available to research subjects may be a feasible additional safeguard in some contexts.
- Care for Injuries during Clinical Trials and Post-Trial Benefits: Ensuring treatment or other coverage for injuries sustained as a result of the clinical trial’s therapy is an additional safeguard that can be provided to vulnerable populations, particularly in LMICs where the health systems are underdeveloped and access to care may be a problem for injured subjects. This is especially important for clinical trials involving new drugs or vaccines in host countries with limited access to quality care. The Joint United Nations Program on HIV/AIDS (UNAIDS) issued a guidance document that, while specific to HIV preventative vaccine studies, can be applied more generally to vaccine studies: for example, these guidelines recommend that, before initiating a study, sponsors address post-study vaccine availability issues in the host country as well as arranging for compensation for adverse vaccine reactions or other injuries related to the study.
- Personal Protective Equipment: Conducting research during a pandemic poses issues for LMICs whose healthcare providers and the general population may lack the basic protective equipment that those in high-income countries have access to, such as masks, gloves, hand sanitizer, or even clean running water and soap. Additional safeguards may include the provision of supplies like soap or hand sanitizer, where feasible, or educating the community about whatever hygienic practices may be possible locally. Furthermore, great care must be taken to avoid spreading COVID-19 to research subjects or others in the community, and the risk of doing so must be assessed as part of the overall risk-benefit determination by the IRB. To the extent that the research team is operating in a location with limited protective equipment, the WHO has issued guidance with considerations for the use of protective equipment when such equipment is scarce.