Regulatory Systems Strengthening: Substandard or Falsified Medicine

Summary

Developing and delivering diagnostics, therapeutics, and vaccines for patients in low- and middle-income countries (LMICs) will be less effective in helping implement strategies to treat and eliminate diseases than we hope as long as those patients continue receiving large quantities of substandard or falsified (SF) medicines.

Substandard medicines are those that do not meet product quality standards due to manufacturing and/or storage issues. Substandard medicines may be made using cheaper ingredients, by less-qualified workers, by using inferior manufacturing processes, or in rundown facilities. Many manufacturers of drugs engage in what is known as tiered manufacturing, which means that they make a quality version of a product for high-income country markets where regulation is stringent and consequences for SF medicines are significant - and a nonor unknown quality and lower-cost version for African or other LMIC markets where there is not the same level of regulatory oversight, where return on investment is marginal for manufacturers, and where there are major downward pressures put on pricing (e.g., by national procurers). Falsified medicines are deliberately made so, potentially using diluted or even no active ingredients, or sometimes, toxic materials. Both substandard and falsified medicines are circulating in both the informal market and public health systems in many LMICs.

Some of the worst cases, such as the death of 70 children in the Gambia from tainted cough syrup, generate headlines. But the problem is widespread and takes a massive toll on public health across our target geographies. Although good data can be hard to come by, according to the WHO, 1 in 10 medicines in LMICs failed quality control tests in 2017. In Africa, that number is difficult to know but many estimates peg it at closer to 20% SF and some commodities like oxytocin as high as 50% SF depending on where it is being sampled. The UN's Office on Drugs and Crime (UNODC) reported in 2023 that more than 400,000 deaths per year in sub-Saharan Africa are linked to SF antibiotics and antimalarials.

Beginning in 2023, the Gates Foundation invested in African National Regulatory Agencies (NRAs) and other key stakeholders like the African Union Development Agency (AUDA) and the World Health Organization to help them find and implement policies to help eliminate SF medicines.

Impact on Ecosystem

The key elements of a functioning regulatory system to try to keep a market clear of SF products are laid out in the WHO Global Benchmarking Tool (see the Maturity Level/GBT case study for more information). They include:

• The capacity to conduct risk-based sampling of the full range of medical products across the country, including laboratory capacity to analyze the samples collected from the marketplace.
• Digital reporting systems so that suspected SF reports are routinely sent to the regulator by patients, pharmacists, and health care practitioners, and so that this data is captured and analyzed to facilitate regulator decision-making.
• Authority given to NRAs and law enforcement to take effective action to stop the proliferation of SF products.

One key challenge of developing successful plans is the need for a whole-of-government approach, since NRAs must work with customs officials, law enforcement, national security officials, and the transportation ministry, among others, to intervene effectively. The grantee countries started the planning process by convening and getting alignment among the full range of stakeholders.

In line with newly published WHO guidance in 2023, Burkina Faso, Ethiopia, the Gambia, Guinea, Kenya, Nigeria, South Africa, and Togo have developed national multisectoral SF plans, with their focuses now shifting to implementation.

In 2024, the foundation supported Nigeria to use increased market sampling and product testing to identify and take regulatory action on SF maternal, neonatal, and child health-related products. That project showed that anywhere from 24-40% of commodities such as oxytocin, antimalarials, amoxicillin, and azithromycin are SF on the Nigerian market, and the Nigerian regulator NAFDAC has taken over 50 regulatory actions such as recalling products, destroying illegal products, and arresting perpetrators of SF products. Since the start of the project, the number of recalls has doubled. NAFDAC plans to set up ~120 sentinel sites across the country to increase sampling, detection, and reporting on priority products.

The African Medicines Agency (AMA) is working toward the development of a continental plan, with the standing up of a new SF technical committee of experts from across the continent and world. Key priorities include national plans, addressing tiered manufacturing, working on the regulatory/procurement interface, and establishing a continental "watchlist" of repeat manufacturer violators of regulatory standards so that regulators and procurers can exercise more caution/diligence around their products.

Additional Results and Next Steps

The national SF plans and increasing maturity levels of national regulators are translating into results on the ground. For example, Nigeria recently launched a campaign to disrupt informal markets, including an operation in conjunction with the minister of national security to seize 130 truckloads of products like IV oxytocin stored at room temperature. The country has now put about 10,000 vendors through a registration process as part of its strategy to create coordinated wholesale centers.

There are two additional areas the foundation is focusing on:

Addressing the problem of tiered manufacturing: The tiered manufacturing problem poses a challenge to reliance-based regulatory pathways that can improve access to lifesaving medical products. NRAs may approve a product based on reliance but actually receive a different, unknown quality product that is much cheaper for the manufacturer to produce. More rigor in dossier reviews and more transparency regarding versions of products, in addition to more sampling and stronger enforcement systems, can help address this problem.

The regulatory-procurement interface: Naturally, there is an incentive for the procurers of medical products to get the best prices they can. Since quality products cost more than substandard or unknown-quality products, there is a point at which financial incentives function in perverse ways to get substandard or unknown-quality products into public health systems and jeopardize public health. One solution involves incentivizing quality as the primary criterion of procurement selection - for example, by instituting a transparency requirement that countries publish what they purchase. The WHO is in the process of developing global guidance around this issue of making quality rather than cost the first requirement of any procurement tender.