Submitted: 16 September 2019; Revised: 16 October 2019; Accepted: 17 October 2019; Published online first: 30 October 2019

Around the world, especially in low-and middle-income countries (LMICs), resource-constrained national regulatory authorities (NRAs) responsible for reviewing applications to market medical products have been under increased pressure due to increasing numbers of applications received, complexity of submissions and numbers of categories of medical products [1]. As a result, backlogs of applications to register, i.e. obtain approval to market, medicines have accumulated, leading to long delays in the introduction of generics and biosimilars as well as new chemical entities. For example, the World Health Organization (WHO) notes delays of two to three years in countries with limited regulatory resources, even for WHO-prequalified products or products approved by stringent regulatory authorities [2]. In South Africa, median approval times for marketing authorization applications approved in 2015, 2016 and 2017 were 1,218, 921 and 609 calendar days, respectively for ‘fast track’ applications; and 1,161, 1,678 and 1,422 calendar days for new chemical entities (NCEs), far in excess of target timelines for registration [3]. By February 2018, when the South African Health Products Regulatory Authority (SAHPRA) replaced the Medicines Control Council (MCC) as South Africa’s NRA, the accumulated backlog had reached almost 8,000 new registration applications [4].

The applications stuck in registration backlogs vary in their importance for public health. Applications for NCEs and new formulations of existing medicines may represent major breakthroughs or minor enhancements of existing medicines. For generics and biosimilars, backlogs can delay the robust price competition needed to make medicines affordable long after originators no longer exclude competitors by asserting patents [5]; on the other hand, registering more than seven or eight generic versions of a given medicine generally does little to drive prices lower [6].

The existence of a large backlog requires NRAs to adjust their procedures for reviewing applications for registration. In addition to performing their core functions of evaluating efficacy, safety, quality (and, in the case of generics and biosimilars, bioequivalence or biosimilarity), NRAs facing a large backlog need to identify and prioritize applications that would have the greatest positive impact on public health. For this purpose, broad directives by national departments of health to NRAs to accelerate approval for certain categories of medicines are inadequate and even counter-productive. This is illustrated by the fact that a major contributor to the backlog in South Africa was, ironically, the introduction in 2003 of broad pro-generic policies, including a mandate that the MCC ‘fast-track’ applications to register generics, which led to a jump in generics applications without a commensurate increase in capacity to review them [6]. This problem was aggravated by the MCC inefficiently devoting scarce resources to registering many more generics of some medicines than required to achieve significant incremental price reductions, which delayed registration of other, more urgently needed medicines, including generics and biosimilars of originators’ medicines that faced little or no price competition [6].

Recognizing the need for a more refined approach to prioritizing applications, SAHPRA has, consistent with a proposal by Leng et al. identified prioritizing applications according to ‘public health need’ as a pillar of its strategy to deal with the backlog [5, 6]. Though the strategy has had some success, almost 5,000 applications remain in the backlog and SAHPRA, which struggles to attract and train new talent, can currently finalize only about 2,550 of the approximately 4,700 applications it receives each year [5]. There is thus an ongoing need to identify and prioritize registrations that would have the greatest positive impact.

Based on their active relationships with patients and clinicians, non-governmental organizations (NGOs) play an important role in flagging the areas of greatest public need and pressuring NRAs to take action. In South Africa, NGOs have been key participants in improving access to medicines ever since they mobilized to demand action on the crisis of HIV-AIDS. As South Africa’s registration backlog has grown, the role of the NGOs has evolved to include pushing for action on high-priority generic medicines trapped in the backlog. In 2014, for example, when a fast-track application to register generic linezolid – a medicine used to treat drug-resistant tuberculosis, which has a high incidence in South Africa – was still awaiting approval after 16 months, NGOs brought considerable pressure to bear on the MCC, resulting in registration of the first generic drug two months later [7, 8].

Rising costs of medicines have pushed NRAs around the world, which traditionally were not concerned with pricing, to develop policies to mitigate the budgetary impact of newly authorized products [9]. The confluence of rising costs and registration backlogs puts particularly intense pressure on NRAs in LMICs and suggests an added role for healthcare NGOs, as the example of cancer biosimilars in South Africa illustrates.

In LMICs such as South Africa, the burden of cancer has been increasing [10]. At the same time, expensive biologicals are becoming the standard of care for treatment for many diseases including cancers [11]. Access to and affordability of cancer medicines – increasingly, biologicals – is therefore a growing public health issue, to which the South African Cancer Alliance has responded with a series of access to medicine campaigns [12]. The problem is aggravated by South Africa’s registration backlog, which currently includes about 500 oncology medicine applications [4]. To date, only two biosimilars have been registered [13, 14], leaving even applications for biosimilars of many older ‘first-generation’ biological medicines, such as insulin and (until recently) the supportive oncology medicine filgrastim stuck in the backlog [7, 8, 13, 14]. Cancer medicines and biologicals, including biosimilars, require particularly careful cost-benefit consideration. Cancer medicines vary so greatly in the incremental survival and other benefits they deliver that their use is not necessarily cost justified at current prices, even in high-income countries [15, 16]. Biologicals are more expensive to produce than small molecule medicines and public health authorities are still developing policies to drive price competition among biosimilars, which has, to date, not been as robust as it is among small molecule generics [11]. Given these considerations, NRAs in LMICs cannot simply prioritize medicines that appear in WHO Essential Medicines Lists (EMLs) – indeed, the WHO placed trastuzumab, discussed below, and other cancer medicines on its ‘complementary’ EML due to their high cost [10, 17]. For biosimilar cancer medicines, case-by-case analysis is therefore required to assess whether registration will drive prices low enough to satisfy cost-effectiveness thresholds appropriate to developing countries.

To evaluate whether to prioritize registration of cancer biosimilars, multiple data inputs must be gathered and analysed, for example:

• The incidence of the disease
• The current cost and extent of health insurance coverage and treatment in the private and public sectors
• The incremental health benefit of treatment over available alternatives, as measured by metrics, such as overall survival or quality-adjusted life years
• The prices of biosimilars of the type in question in countries where biosimilar competition already exists
• The number of biosimilar applicants for registration
• An incremental cost-effectiveness ratio or other metric that is an appropriate threshold for deciding whether to use the medicine

For an appropriate decision to be made, the information and decision criteria used must be as specific to the country in question as possible.

Given their limited resources and the fact that historically they have not evaluated cost-effectiveness, NRAs in LMICs may be unable to perform from scratch the analyses needed to decide which applications to prioritize, especially if they also have a significant backlog. In such situations, NGOs can, building on their traditional advocacy role, help to meet the need by preparing and including the required analysis in submissions to NRAs.

An example of such an NGO submission is the Motivation for prompt registration of trastuzumab biosimilars in South Africa that the Cancer Alliance recently submitted to SAHPRA [18]. Submission of this document is the latest phase of a campaign that the Cancer Alliance began in 2016 to make trastuzumab (brand name, Herceptin), a critical biological medicine for treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, affordable and available to all who need it [19]. Following the launch of this campaign, the South African Department of Health added trastuzumab to its EML in 2017 and issued a public sector tender for trastuzumab in 2018, and SAHPRA registered the first trastuzumab biosimilar in June 2019 [19]. A major purpose of the Cancer Alliance in submitting the motivation document was to demonstrate the urgency of registering additional trastuzumab biosimilars, without which the price reductions necessary to make trastuzumab affordable for all South African patients are unlikely to materialize.

As the problems of registration backlogs and costs of medicines in LMICs become more pressing, the South African case set forth in the motivation document for trastuzumab may – with appropriate accounting for differences in disease burdens, health benefits, costs, and criteria for prioritization – serve as a useful template and source of references for NGOs elsewhere who seek to develop their role in helping to make medicines affordable.

Competing interests: The author of this manuscript and the trastuzumab motivation document [16] have no conflict of interest to declare.

Provenance and peer review: Not commissioned; internally peer reviewed.

References
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