Before any Covid-19 vaccines can be made available in South Africa, they must be authorised by the South African Health Products Regulatory Authority. Catherine Tomlinson explores how the regulator is preparing to review and authorise the use of Covid-19 vaccines in the country and the different authorisation approaches they may use.
More than 100 vaccine candidates are under development for Covid-19 globally. Twelve of these are undergoing large-scale phase III clinical trials to assess their safety and efficacy. Vaccines being developed by BioNtech/Pfizer, Moderna and Oxford University/AstraZeneca all appear to be highly effective based on preliminary findings – although not all effective vaccines will necessarily be appropriate for use in South Africa.
As more evidence for competing vaccine candidates becomes available, South Africa’s national essential medicines list committee will need to review available evidence and identify which products are appropriate for use in our public health sector. As it is anticipated that initial vaccine supply will be limited and prices may be prohibitive, South Africa will need to identify priority populations for initial vaccination. The ministerial advisory committee is developing recommendations for the Minister of Health Dr Zweli Mkhize on who should be prioritised for initial vaccination and how vaccines should be delivered to priority populations.
But before any vaccines can be delivered to priority populations – or marketed through the private sector – their use must be authorised by the regulator.
The role of the regulator
Director of affordable medicines at the national department of health, Khadija Jamaloodien, explains that “South Africa has a well-respected Regulatory Authority and that in terms of Section 14 of the Medicines and Related Substances Act, no medicine may be sold in the country unless it is registered by the regulatory authority”.
“This would apply to vaccines as well.”
The regulatory authority, which replaced South Africa’s former medicines regulator (the Medicines Control Council [MCC]) in 2018, ensures that all medicines (including vaccines) that are distributed and marketed in the country are safe, effective and of good quality. Before medicines can be provided in the public sector, or sold through private sector facilities, they must be registered by the regulatory authority. This process is, however, often very slow and—when delayed or inefficient—can limit access to new medicines in South Africa. Under the former medicines regulator, the MCC, the registration of new medicines took on average around four years.
As Covid-19 requires urgent access to safe, effective and quality health technology – and particularly vaccines – the regulatory authority must ensure that regulatory delays do not impede access to vaccines once required evidence for registration is available and dossiers (applications) are submitted. Pharmaceutical companies must also ensure that dossiers for registration of Covid-19 vaccines are timeously submitted in South Africa and other low- and middle-income countries –as sometimes tardiness on the side of pharmaceutical companies is to blame for registration delays.
How the WHO is supporting rapid regulatory review
Recognising the harmful impact of weak regulatory systems and delayed regulatory processes on medicine access and public health, the World Health Organisation (WHO) has created systems and processes to support the strengthening of regulatory bodies in low- and middle-income countries, as well as the rapid registration of essential medicines and critical health technologies. These processes can support rapid and trustworthy regulatory decision-making for Covid-19 vaccines by the regulatory authority and other low- and middle-income countries regulatory authorities.
Over the past two decades, the WHO has established and grown its prequalification procedures, building on earlier efforts to evaluate vaccines and in vitro diagnostics dating back to the 1980s. Through its prequalification processes, the WHO evaluates the safety, efficacy and quality of essential and critical medicines, vaccines, diagnostics, and other health technologies. Products that are “WHO Prequalified” are essentially certified as meeting WHO standards.
National medicine regulatory authorities can then leverage and use the work already done by the WHO when making domestic regulatory assessments.
South Africa is a participating country in the WHO’s Collaborative Procedures for Finished Pharmaceutical Products and, as of this year, began registering products domestically using these collaborative procedures.
In addition to its prequalification and collaborative procedures, the WHO recently committed to work with the International Coalition of Medicines Regulatory Authorities to promote greater transparency and sharing of data between regulatory agencies in response to Covid-19. In announcing their collaboration, they stated, “as in other areas of the pandemic response, multilateral cooperation between regulatory authorities will be critical in ensuring there is a level playing field, that Covid-19 vaccines and medicines are safe, effective and quality-assured, and that all countries may benefit from such products equitably and at the same time”.
The United States’ medicines regulatory authority, the Food and Drug Administration (FDA), further committed (on 17 November) to “publicly post their reviews of the scientific data and information supporting the issuance, revision or revocation of [Emergency Use Authorisations] for all drug and biological products, including vaccines, as part of [its] Covid-19 response”.
Andy Gray, senior pharmacy lecturer at the University of KwaZulu-Natal, explains that “the major national and regional medicines regulators, including the US Food and Drug Administration and European Medicines Agency, and the International Coalition of Medicines Regulatory Authorities have committed to maximising transparency surrounding the approval of Covid-19 vaccines”.
“They will work with one another, and with [the] WHO, to ensure that the data supporting their decisions are in the public domain. Not only will this be critical to public trust in the decisions, but it will also make it easier for regulators like the regulatory authority, which will rely on the global efforts,” says Gray.
How the regulatory authority is preparing to review dossiers for Covid-19 vaccines
The regulatory authority will be under massive public pressure to green light vaccines in the country once regulatory applications have been received. In the face of this pressure, the regulatory authority will need to balance the need to ensure products are rapidly available with the need to ensure that products are properly evaluated and regulated – to prevent the entry of potentially harmful and unsafe products into the market.
Spokesperson for the regulatory authority, Yuven Gounden, explains that “the regulatory authority has in preparation or anticipation of Covid-19 vaccines undertaken a readiness programme that included establishing a specialised working group called the Covid-19 Vaccine registration Working Group consisting of both external and internal experts specialising in areas of vaccinology, manufacturing, clinical trials, epidemiology, vigilance and other specialisations informing quality, safety and efficacy of the products”.
“The working group is mandated to formalise scientific approaches and processes to be followed, as well as look into innovative review mechanisms to ensure prioritisation and expeditious review without compromising on any of the regulatory authority’s pillars of quality, safety and efficacy of medicines,” says Gounden.
Pathways for domestic registration of vaccines
Depending on the availability and strength of quality, safety and efficacy data, as well as the type of applications submitted and technology used in the vaccine, there are different processes and pathways that the regulatory authority may use to authorise the use of Covid-19 vaccines in the country. The type of authorisations used by the regulatory authority will impact who can access Covid-19 vaccines – besides other factors, such as cost, delivery mechanisms, and global supply.
The most common way that new products are introduced into the market is through domestic registration. Although, as noted above, domestic registration is often a slow process.
To reduce decision-making times for domestic registration, the regulatory authority adopted guidelines in 2019 enabling the regulator to “rely” on the work and decisions of other “recognised” regulatory authorities and the WHO in making domestic registration decisions. Recognised regulatory authorities include, among others, the FDA and the European Medicines Agency. The guidelines outline different reliance models that may be used by the regulatory authority to register new products, with each model requiring a different level of domestic review.
While it is anticipated that the regulatory authority will use reliance approaches in evaluating regulatory applications for Covid-19 vaccines– the precise type of approach that will be used by the regulatory authority to evaluate dossiers for Covid-19 remains to be seen.
In response to questions from Spotlight, Gounden clarifies that the regulatory authority’s registration approach “will be informed by the type of applications submitted, the technology used in vaccine development and the available data including reviews from other regulators and organisations such as WHO, to inform its decision-making process”.
“Therefore, consideration will be given to reliance processes.”
Another remaining question is whether the regulatory authority will require additional clinical evidence for the registration of vaccines that have not been trialled in South Africa or other similar populations. Regulatory agencies sometimes require that companies undertake a type of study called a ‘bridging study’ to assess the safety and efficacy of new products in domestic populations, when clinical trials were not undertaken in similar populations or contexts.
In response to queries from Spotlight on whether the regulatory authority anticipated that bridging studies or additional clinical evidence would be required for products not trialled in populations similar to South Africa’s, Gounden notes that “this would depend mostly on the information submitted in support of registration and whether the necessary populations have been adequately accounted for in the trials and if they are proposed to be included/excluded from the indications”.
“This would also depend on the risk benefit evaluation where the proven benefits might outweigh any theoretical risks in the emergency situation.”
Mechanisms to enable vaccine access in the absence of domestic registration
In the absence of domestic registration, the regulatory authority can use Section 21 authorisations to permit the use of unregistered medical products in the country. Section 21 refers to a section of the Medicines and Related Substances Act that empowers the regulatory authority to authorise the importation and use of unregistered medicines into South Africa.
Gounden explains that “Section 21 authorised unregistered medicines are not intended for marketing purposes”.
“They are only intended to satisfy unmet medical needs for a specific individual/patient, or a defined group of individuals/patients, where there are no alternative registered medicines,” he says.
“It is anticipated that as safety, efficacy, and quality data mature in the vaccine development process, applicants, in conjunction with the national department of health sector wide procurement directorate, will apply for Section 21 authorisations to satisfy an unmet emergency public health need for defined target populations. Target population restrictions will be informed by the study populations on which evidence of safety and efficacy was obtained during vaccine development,” notes Gounden.
He adds that “restrictions on types of facilities that would handle the vaccines will be informed by the national department of health determinations on the ability of their facilities to maintain cold-chain specifications and other relevant operational considerations”.
The regulatory authority is also exploring options to provide conditional registration for marketing purposes, as an additional mechanism to enable access to products without domestic registration.
“The possibility also exists for an applicant to apply for a conditional registration (marketing authorisation) for emergency use in a pandemic situation, such as in Covid-19, based on the available safety and efficacy data,” Gounden explains.
“The submitted available data still has to meet minimum regulatory standards of safety and efficacy before a conditional registration can be granted. The conditions of registration in such cases invariably include a risk management plan to manage and monitor emerging risks of a medicine approved on the basis of limited data.”
Gray notes that “while there is no specific provision for conditional registration for emergency use in South Africa’s law, there is broad enablement for this implied in the act”.
This article was produced by Spotlight – health journalism in the public interest.