Global Compassionate Use—A New Lens on a Long-standing Inequity

In this issue of JAMA Health Forum, Aliu and colleagues¹ present data from Novartis on the global distribution of requests for compassionate use of the company’s medications, defined as use of unlicensed products outside of clinical trials. The authors identify 3 country-level factors associated with the number of requests for compassionate use. The most important is the national level of economic development, with the vast majority of requests coming from high-income countries, and just 3% from low- and low-middle-income countries, where more than half of the world’s population lives. Also associated with more compassionate use requests are the presence of regulations governing compassionate use and the number of in-country clinical trials registered on ClinicalTrials.gov.

Exploring these 3 factors opens a window to the vast inequities in health that exist between countries. Compassionate use cannot be understood without appreciating the foundation—or lack thereof—on which access to unapproved medication rests. People and organizations devoted to closing these gaps must first recognize and address fundamental inequities in global health systems.

The authors¹ offer several possible explanations for why lower-income countries have so few compassionate use requests despite the fact, as they note, that these countries “display the highest burden of diseases.” The countries may “lack the necessary medical organizational infrastructure and facilities” for investigational use of medications and may struggle to afford the related costs of treatment, even though the company provides the investigational medications for free. The authors also state that the ability to request compassionate use “may be influenced by the overall country’s health care system’s capabilities.”

Indeed, the differences in access to unapproved medications reflect a much bigger picture. More than 2 billion people—the vast majority of whom live in low- and middle-income countries—lack access to essential medications,² which include antibiotics, insulin, pain medications, antidepressants, anti-inflammatories, and other critical therapies. Residents of these countries also face a critical shortage of health care professionals to care for patients with advanced disease. For example, compared with a US ratio of new cancer cases to oncologists of 137:1, in 27 countries, the ratio exceeds 1000:1. In 13 countries on the continent of Africa, the ratio either exceeds 5000:1, or there are no oncologists at all.³ There are also major disparities between countries in access to diagnostic testing, hospital care, and insurance coverage. These deep inequities in access to health care lead to preventable morbidity and mortality on a massive scale. It is not surprising that online requests for access to unlicensed medications lag behind as well.

The report by Aliu and colleagues¹ also shines a bright light on gaps in global regulatory systems. It is plausible, as the analysis suggests, that the absence of a policy on compassionate use leads to fewer requests for unapproved medications. But a more fundamental concern is why so few compassionate use policies exist: substantial weaknesses in regulatory capacity writ large. A 2020 report of the National Academies of Science, Engineering, and Medicine⁴ found that the underfunding of drug regulation in many parts of the world, combined with the complexity and burden of country-by-country regulatory processes, raises major safety concerns and slows the spread of medical innovation. It is true that compassionate use is an option when there are delays in approving medications that are safe, effective, and licensed in other countries. However, a far better approach is for national regulatory agencies to have the capacity and resources to license and monitor these therapies more quickly themselves.

Compassionate use further provides a window into global disparities in clinical trial research. Aliu and colleagues¹ found that countries with fewer researchers have less capacity to seek unapproved drugs for patients. Here again, the gravity of the underlying disparity is the fundamental problem. Many countries lack the capacity to study local diseases in their own populations, a capacity the World Health Organization has described as “fundamental to the improvement of health in all countries.”^5(p4) A 2017 convening by the UK Academy of Medical Sciences found that “strong clinical research requires not only well-trained scientists, clinicians and grant managers but also personnel equipped with key skills such as ethics, statistics, and data management” with “the availability of experts in these areas within clinical research in [low- and middle-income countries]…commonly very limited or missing entirely.”^5(p10)

The responsibility for tackling this difficult set of challenges rests on national leaders, civil society including professional associations, and global funders, as well as on the pharmaceutical industry itself. For some basic medicines, the cost in low- and middle-income countries can be substantially greater than those in wealthy countries.⁶ The United Nations’ Millennium Development Goal 8.E reads, “In cooperation with pharmaceutical companies, provide access to affordable essential drugs in developing countries.”⁷ To do their part to achieve this goal, manufacturers can create lower pricing tiers for low- and middle-income countries, transfer knowledge and support for local production of medications, and license their patents to low-cost generic manufacturers through patent pools and other mechanisms.⁸ Such steps are as urgent as ever today, as access challenges for COVID-19 vaccines threaten millions of lives and livelihoods as well as global control of the pandemic.⁹

With respect to weak regulatory systems, global organizations and national governments can prioritize building capacity at a regional level, sharing patent information, and establishing agreements for regulatory reliance.¹⁰ An investment by the European Union and the Bill & Melinda Gates Foundation in the recently established African Medicines Agency is an important step forward. Clinical trial improvement requires an infusion of funding and a long-term commitment to building and maintaining a scientific workforce.

Novartis should be commended for its global compassionate use program and for sharing the data that are the basis of this study.¹ The company’s transparency has revealed not only the existence of major differences in access to unapproved medications, but also the fact that these gaps are symptoms of a much more fundamental disorder. That disorder is inequity, and the treatment must go far beyond what is compassionate to what is necessary, just, and overdue.

Published: April 15, 2022. doi:10.1001/jamahealthforum.2022.0500

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Eng ML et al. JAMA Health Forum.

Corresponding Author: Joshua M. Sharfstein, MD, Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, W1033, Baltimore, MD 21205 (joshua.sharfstein@jhu.edu).

Conflict of Interest Disclosures: None reported.