Applied Clinical Trials
Outlining the five critical hurdles faced by clinical teams conducting studies in these nations amid quarantine and other restrictions.
COVID-19 has dramatically impacted clinical trials in high-income countries because of site closures, stay-at-home orders, supply chain issues, and participant reluctance to visit doctors’ offices and hospitals, among other barriers. Many of these difficulties have been exacerbated-and accompanied by new ones-in low- and middle-income countries (LMICs). COVID-19 also is amplifying some of the difficulties that are always present in clinical trials in LMICs.
While the substantial majority of clinical trials still take place in countries classified by the World Bank as high income, a review of clinical trial registrations on the World Health Organization (WHO) International Clinical Trials Registry Platform and clinicaltrials.gov shows that a significant and growing number are being conducted in LMICs, with major centers in Eastern Europe, the Middle East, Brazil, China, India, and South Africa. Even very low-income LMICs without large numbers of investigators and sites trained in International Conference on Harmonization (ICH) good clinical practice (GCP) have dozens or hundreds of trials.
Five critical challenges faced by researchers conducting clinical trials in LMICs are examined ahead.
Several LMICs, including India, South Africa, Kenya, Brazil, Mexico, and Peru,1-6 have issued guidance or directives pertaining to clinical research during the pandemic. These guidance documents often mirror the content of similar documents from the FDA, the European Medicines Agency (EMA), and the U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA). Typically, these agencies urge those conducting trials to take steps to protect participants; allow flexible amendments to protocols for participant safety, remote study visits, and monitoring; and in some cases, such as in Colombia, explicitly prioritize COVID-19 trials. Argentinian regulators are recommending postponement of any recruitment of healthy participants except in COVID-19 studies, for example.
The vast majority of LMICs, however, have not issued specific COVID-19 guidance for clinical trials, which creates uncertainty around study protocol changes that may be needed in light of the pandemic (such as whether telemedicine, electronic acceptance of informed consent documents, or shipping investigational product to a patient are acceptable). This uncertainty is in addition to the normal delays often associated with regulatory approvals in LMICs.
Quarantines and internal travel restrictions will impact the ability of clinical trial participants and research staff to go to investigative sites. Both the International Monetary Fund7 and Oxford University8 are monitoring government responses in each country. Oxford’s heat map9 provides a good visualization of how restrictive a national government’s restrictions are (keeping in mind that many countries also have state, provincial, or local restrictions as well).
In addition, law enforcement and military in LMICs have been more likely than high-income countries to enforce quarantines with violent acts, as has happened in Kenya, Paraguay, and India, among other places. Fear of police action or illness may reduce participants’ willingness to travel to trial sites even if they are not legally prevented from getting there. Participants are also likely to be lost to follow-up as migrant workers throughout South Asia, India, and the Middle East return home; in India, for example, out-of-work laborers are leaving cities in large numbers and returning to rural villages to live with family members.
While remote trial monitoring is an important way to continue research during the pandemic, as the FDA has noted, there are often components of an on-site monitoring visit that cannot be completed remotely. External travel restrictions, which are in place almost everywhere as of this writing, are limiting in-person monitoring of studies that have monitors from outside the country. Some countries, such as Vietnam, are requiring “immunity passports” for foreigners entering the country, or are requiring long quarantines of international arrivals.10
These requirements make in-person monitoring impractical even if contract research organizations (CROs) and other key vendors believe it safe for their monitoring personnel to travel. Medical professionals in several countries, including Mexico, Colombia, 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 West Africa, China, and Ethiopia, which may impact foreign monitoring and any foreign staff operating at a clinical trial site or central lab. Even in-person monitoring by in-country monitors may be prevented by trial site policy or safety.
The availability of necessary supplies and disruptions to supply chains as a result of the pandemic will, in general, impact LMICs more than high-income countries. COVID-19 will likely have a long-lasting effect on global supply chains.11 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.12 Internationally, the World Trade Organization and the World Customs Organization issued a joint statement noting the disruptive impact of the virus on global supply chains and pledged to cooperate to facilitate trade in essential goods.13
LMICs are struggling to obtain limited hospital supplies in the global market in competition with the U.S., the European Union, Japan, and similar high-income buyers, as recent reporting about the COVID-19 outbreak in Nigeria shows.14 Clinical trial sites in LMICs that cannot obtain needed supplies in-country could obtain them from a study sponsor, assuming the products can be legally imported and shipments to that country are not cost-prohibitive in light of global freight and logistic disruptions.
Protocol changes and other circumstances that may impact the risks and benefits of a clinical trial have implications for the participants’ ongoing informed consent and the ethics oversight of the trial. In-person study visits may be riskier in some LMICs than in high-income countries during the pandemic as a result of personal protective equipment (PPE) and eventually vaccine, antibody, or other preventative availability.
Virtual/remote visits could be riskier, where they are allowed, because living arrangements may not facilitate privacy, and internet cost and speed will often prevent video conferencing. Participation in general may be riskier in LMICs because of the capability of the health system to treat COVID-19 or study injuries during the pandemic and because of the privacy concerns government anti-COVID-19 measures may create, such as China’s QR health code system15 and India’s Aarogya Setu app16, both of which are generally mandatory.
In addition, the Declaration of Helsinki, FDA regulations, ICH GCP E6, and influential U.S.17 and U.K.18 ethical reports on research in developing countries all recognize the special considerations that are involved in researching these populations.
The populations in LMICs are more likely to be vulnerable already because of poverty, lack of education, underlying disease (e.g., malaria, HIV/AIDS, and tuberculosis), and in some areas, heightened familial coercion. The United Nations has also produced a working paper containing estimates of the impact of COVID-19 on global poverty as of April.19
Many will not have access to clean drinking water or running water in their homes to wash their hands to prevent COVID-19. Many also will be food insecure; the Famine Early Warning System is an excellent way to determine whether there are food security issues in a country or region.20 Most will have come under some additional stress as a result of losing loved ones or jobs.
The U.S. National Institute of Mental Health has issued “Ethical Issues to Consider in Developing, Evaluating, and Conducting Research Post-Disaster,”21 which will be useful for researchers confronting these issues.
In addition, it would be prudent for drug researchers to plan to address cases of participants facing domestic violence22 or child abuse,23 even if that is not explicitly the subject of the research, by determining what resources might be available for them in their communities.
As clinical trial sponsors work with their CROs and sites to address the challenges posed by COVID-19 in their LMIC-based studies, they should be sure to follow any regulatory guidance available in the countries where the sites are located, either specific to clinical trials or those that generally pertain to the healthcare sector. For those LMICs without regulatory guidance, following the general principles articulated in FDA’s guidance is advisable
to the extent possible. Participant safety must be the priority, so when trials are started or ongoing during the pandemic, decreased in-person study visits and monitoring should be implemented wherever possible. Every protocol deviation and missing data element should be documented.
Finally, informed consent forms and study institutional review board (IRB) and independent ethics committee (IEC) approvals may need to be revisited in light of local conditions.
Clint D. Hermes is an attorney at Bass, Berry & Sims. He can be reached at email@example.com