Registering New Drugs for Low-Income Countries: The African Challenge
Authors: Mary Moran, Nathalie Strub-Wourgaft, Javier Guzman, Pascale Boulet, Lindsey Wu, Bernard Pecoul
Journal: PLoS Medicine (2011)

What is the best strategy to approve novel drugs for disease such as sleeping sickness that predominantly affect patients in Africa? How can African regulators best be supported to evaluate these drugs for their own populations? For many years, African medicines regulatory authorities (MRAs) have relied on stringent regulators in developed countries to assess novel pharmaceutical products such as drugs and vaccines for use in African populations. However, a recent shift in the drug product environment for Africa has put this approach under strain. A score of new products are now being, or have been, developed specifically for diseases of the developing world (Table 1), creating new challenges for regulators in Africa and elsewhere.



Table 1

Sample of novel neglected disease products presented to regulators since 2005 [8],[11],[12],[20]–[23].



However, it is not at all certain that African regulatory authorities currently have the capacity to meet these new demands. A study conducted by the World Health Organization (WHO) in 2010 concluded that 90% of MRAs in sub-Saharan Africa “were in a situation which did not allow them to adequately carry out regulatory functions,” and thus could not guarantee the safety and efficacy of medicines to be used in their country [1]–[3]. While undoubtedly improving, growth in African regulatory capacity is not keeping up with these new challenges.

The growing demand to assess novel neglected disease (ND) products for African use has generated a range of responses from policymakers and product developers, as outlined below. While each approach offers unique benefits, none is ideally suited as a primary vehicle for drug registration for Africa. There is also no guidance to product developers in choosing between approaches, and little or no integration between approval mechanisms (see Figure 1). It is now critical to review how novel ND drugs are assessed and approved for African use. This article is based on research conducted for a report titled “Registering New Drugs: The African Context” [4], commissioned by the Drugs for Neglected Diseases initiative (DNDi), and builds upon this work with additional research and analysis.



Figure 1

Neglected disease drug registration timeline [7],[9],[11]–[19].




Western Regulatory Approval Routes
Historically, the majority of new ND drugs have been first submitted to well-established Western regulatory authorities (e.g., United States Food and Drug Administration [FDA], European Medicines Agency [EMA], SwissMedic), either for routine regulatory review or under specific pathways such as Orphan Drug legislation (ODL) or expedited approval mechanisms. Multinational pharmaceutical companies and some Product Development Partnerships (PDPs) have typically used this approach because it offers clear protocols and rules, liability management and, in the case of ODL, tax breaks, free scientific advice, and market exclusivities. Firms also welcome the access Western regulatory approval provides to early commercial returns on products with overlapping rich and poor markets.

While bringing decades of regulatory experience to the table, use of Western authorities to review ND drugs also has drawbacks. It delays access for African patients since African MRAs often wait for the Western MRA decision before commencing action, and it puts ND product decisions in the hands of regulators who have less experience in tropical disease products, presentations, and epidemiology, and who are not accountable for the needs and safety of target African patients.

For instance, Western regulations may omit data requirements vital for safe large-scale use in Africa (e.g., trials assessing the safe interaction of HIV and malaria drugs). Rifapentine, a novel tuberculosis (TB) drug registered under US Orphan Drug provisions, ultimately could not be used in African TB patients despite being approved by the FDA because the trial design excluded HIV-positive patients. While HIV is less commonly associated with TB in the US, it represents up to 70% of TB patients in some sub-Saharan Africa countries, making the efficacy data submitted to the FDA inadequate for use in African populations [5]. Furthermore, the relative risk-benefit of ND drugs can be dramatically different in Africa and the West, where analysis against the same criteria can lead to completely different conclusions. For example, the first rotavirus vaccine, RotaShield, developed by Wyeth-Ayerst and licensed by the FDA in August 1998, was withdrawn from the US market in October 1999 due to a one in 10,000 risk of intussusception in children. This precluded its subsequent introduction in the developing world. While this risk-benefit analysis may have been valid for the US, where rotavirus causes less than 60 deaths per year, the vaccine was likely to have a much more favorable risk-benefit ratio in Africa, where rotavirus is responsible for approximately 5% of deaths in children under the age of five (a mortality rate of 183/100,000). Many of these problems are heightened in the case of regulatory pathways such as Orphan Drug approval and FDA Accelerated Review, which allow clinical trials to be abridged or downsized in order to expedite registration of treatments for diseases that are rare and life-threatening in the Western context (such as malaria), but affect millions of patients in the developing world.