African Regulatory Harmonization Project Cuts Drug Approval Times And Saves Scarce Resources
Executive Summary
A pilot project of joint assessments in East Africa has shown that regulatory review times for a number of branded medicines were reduced from one or two years to a median of seven months, representing a reduction of 40-60%. The project was part of the African Medicines Regulatory Harmonization initiative, which is intended to strengthen and align regulatory practices in sub-Saharan Africa. Part one of this article looks at the history of the AMRH, the 2016 Model Law that guides national regulators in implementing their own procedures, and the East African pilot that has shown joint reviews to be feasible at the regional level.
The African Medicines Regulatory Harmonization (AMRH) initiative, a project aimed at strengthening and harmonizing drug regulatory systems in Africa, is being expanded after a trial of joint regional assessments and other collaborative review practices showed it was possible to secure timely drug approvals and avoid duplication of effort.
Under a joint assessment pilot carried out with a number of drugs in five East African countries in 2015-16 as part of the AMRH, the median timeline from dossier submission to national marketing authorization fell to seven months, compared with the one to two years that would typically have been the case with separate national applications – a reduction of 40-60%.
The AMRH, whose stakeholders hope it will improve patient access to safe, effective and quality medicines in a continent where they are often in short supply, is now being extended to other African regions. It will also be expanded to cover clinical trial approvals and pharmacovigilance activities as well as marketing authorization (MA).
Coordinated by the African Union’s technical body, the New Partnership for Africa’s Development (NEPAD), the focus of the AMRH is on the countries of sub-Saharan Africa. Partners in the venture include the World Health Organization, the African Union Commission (AUC), the Bill and Melinda Gates Foundation (BMGF), the World Bank, the UK Department for International Development (DFID), the US government, and the Global Alliance for Vaccines and Immunization (GAVI).
Industry is represented by the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), which has set up an African Regulatory Network (ARN) to work with regulatory bodies and other stakeholders.
The conception of the AMRH in 2009 as driven by the need to remove the barriers that hinder patient access to healthcare products, a problem that afflicts many low- and middle-income countries (LMICs) but is particularly pressing in sub-Saharan Africa. Research has shown that the introduction of new vaccines and medicines in poor countries can take four to seven years longer on average in poorer countries than in richer ones.
The reasons for these delays include:
- Different regulatory standards and requirements among countries.
- Limited resources and technical capabilities.
- Lengthy approval times.
- Failure to leverage review work already done by the WHO and better resourced national regulatory authorities (NRAs).
- A lack of clarity over the roles of the various national regulatory authorities and ethics committees in the area of clinical trial authorization.
Trevor Mundel, president of global health at the BMGF, says that in poorer countries different regulatory authorities sometimes conduct the same evaluations and visits to manufacturing sites, “so a process that should only take a few months can stretch into years.” For example, he said, “a drug used to treat HIV received regulatory approval in the US after just six months; seven years later, some countries in sub-Saharan Africa were still waiting for local registration.”
The initial focus of the AMRH was on strengthening and aligning regulatory requirements for marketing authorizations, but now, on the basis of results to date with approvals, it is being extended to cover clinical trial approvals and pharmacovigilance activities.
The Concept
As Vincent Ahonkhai, senior regulatory officer for global health delivery at the BMGF, explains, the seeds of the initiative were sown some eight years ago. “We convened a meeting of all regulators in Africa, from the regional economic communities [RECs], in 2009, and the consensus was that yes this was a problem, and it was agreed that it was well worth tackling through a partnership,” Ahonkhai told the Pink Sheet. “High-level standards were to be applied so that we can have good quality products, and this meant we also had to find the resources and use them in a smarter way.”
This was to be done by encouraging NRAs in Africa to rely more on work performed by other major regulators (including the European Medicines Agency and the US Food and Drug Administration) and the WHO in order to reduce duplication and allow local regulators to focus on value-added activities, and harmonizing regulatory standards and requirements among NRAs within the same REC.
Specific actions included the development of harmonized technical guidelines and procedures for marketing authorizations, clinical trials and pharmacovigilance, and their implementation through joint reviews and other resource-sharing activities coordinated at regional level.
Harmonization on such a vast scale might seem like an impossible task in a continent where regulatory systems are often fragmented and rudimentary. It was therefore decided to focus initially on generic MAs and later on to include other kinds of medical products (included branded medicines) and to extend the initiative to cover clinical trials and pharmacovigilance. There was also the question of how to fund such a venture in a continent with many very resource-poor countries.
“What I am talking about is hugely complex and very detailed and laborious set of activities that had to be put in place,” Ahonkhai says. “We structured a financing system not only to enable our funds but also to encourage other funders to put their contributions into a trust fund. We then approached the World Bank and they agreed to manage the trust fund under certain conditions, and this has been helpful as it is a reputable global body that donors are not scared to put their funds into.”
The trust fund is meant to allow the pooling of donor funds, ensure fiscal accountability, and drive projects through the World Bank’s in-country management expertise, with RECs receiving the necessary resources “in a flexible and coordinated manner,” the AMRH says.
The AMRH is actually the first project to be funded from the Global Medicines Regulatory Harmonization (GMRH) Multi-Donor Trust Fund, which was established in 2011 with an initial contribution of $12.5m from the BMGF. Funding for the AMRH is also being provided by DFID, the US PEPFAR (President’s Emergency Plan for AIDS Relief), GAVI and the Swiss Agency for Development and Cooperation.
The goal, says Ahonkhai, is “not to equalize capacity in all the countries – that is not possible – but to leverage a sense of collaboration and working together to enable all member states to benefit from the pool of resources that is now available. The resources were designed with actual needs in mind, rather than the theoretical need for a strong regulatory body.”
He says it is also vital that the direction of the initiative should be dictated by the needs and priorities of the countries themselves, rather than trying to impose one regulatory model on them all.
Model Law
In order to help countries in their harmonization efforts, a new “Model Law on Medical Product Regulation” was adopted by governments of the African Union (AU) in January 2016. The law is intended to be a template for the RECs wanting to strengthen their regulatory practices and align themselves with other countries in the region.
Paul Dearden, head of emerging markets at AbbVie in the UK, explained the need for such a move. “We have seen a lot of regulators who are very keen to collaborate but can only go so far because national legislation prevents them from doing so,” he said. “The Model Law allows them to collaborate in a formal way.”
According to Mercè Caturla, global access regulatory lead for Africa and the WHO at the Johnson & Johnson subsidiary Janssen Pharmaceutica, the Model Law was put in place to address legislative gaps in African Union states that were hampering effective medicines regulation. “It would be a guide to follow when developing their own local laws,” she told the Pink Sheet. “Some countries have already adopted the model law.”
For example, Lesotho, Seychelles, Swaziland and Zimbabwe have used the Model Law to review and develop their own laws, although there are concerns that the regions are not taking a comprehensive and systematic approach to meeting the needs of their member states.
Caturla agrees that this is work in progress. “From an industry perspective it is good to have the Model Law, but we would like to see harmonized regional and local laws. The regions should be talking to each other so that, for example, the EAC (East African Community) can also learn from ECOWAS [Economic Community of West African States] and vice-versa. It is not happening that much yet.”
Ahonkhai adds that in order to foster sustainability and consistency of regulatory practices, the procedures need to be approved at the legislative level and published, and all RECs should adopt the same policies.
East African Joint Review Pilot
In order to keep things on a manageable scale, the stakeholders agreed at the outset that it made sense to start small and gradually expand the initiative. This was mainly because financial resources might be inadequate to support full-scale execution of all regulatory functions at the beginning, and even when they were sufficient, staffing and other resources might be in short supply. Taking on a single work stream would allow for trust building across NRAs and for early learning, and “quick wins” would help to build up enthusiasm and committee to this “transformative effort,” according to the AMRH.
The focus was therefore narrowed to marketing authorizations in the East African Community, which comprises Burundi, Kenya, Rwanda, Tanzania, Uganda (and – since April 2016 – South Sudan).
With help from the WHO, the EAC launched a pilot project in 2012 to test out joint assessments by the countries’ regulators, focusing on high-priority medicines including those from essential medicines lists of member countries. It involved a common technical document, a platform for sharing information, a team of assessors conducting joint assessments, and a framework for mutual recognition of regulatory decisions. The manufacturer had to agree to the sharing of information on dossier assessment results among the member countries.
Following successful trials with a number of generics, in 2013-14 EAC ministers endorsed the joint review procedure as well as a set of harmonized requirements and guidelines for drug registration that had been drawn up and reviewed by stakeholders including the IFPMA.
It was also agreed to extend the procedure to branded originator products, beginning with a review in October 2015 of Roche’s Avastin (bevacizumab) and Herceptin (trastuzumab). As of December 2016, more than 27 MA applications had been received through the EAC regional system, and four products with regionally-agreed positive MA opinions had been approved at national level.
Historically, the time taken to submit separate applications to each NRA and gain separate approvals had historically taken one to two years. Under the joint review procedure, the median time from filing to country-level MA was seven months for these four products, representing a reduction in timelines of 40-60%. Several joint good manufacturing practice inspections were also carried out.
Expansion Time
The AMRH is now in a geographical expansion phase. The initiative has been launched in ECOWAS, which has 15 member countries and could present more challenges given that a number of different languages are spoken, including English, French and Portuguese. Nonetheless, the AMRH stakeholders say harmonization of technical standards and requirements “is already nearing completion” in ECOWAS and that “joint product marketing application review and authorization will follow.”
Harmonization efforts have also begun in the Southern African Development Community (SADC), starting with the ZaZiBoNa group (Zambia, Zimbabwe, Botswana and Namibia). “Modest” activities are under way in the Economic and Monetary Community of Central Africa (CEMAC) covering six countries, and in the Intergovernmental Authority for Development (IGAD) in the Horn of Africa (eight).
AbbVie’s Dearden says that the initiative is bearing fruit, not only for the regulators and patients but for industry too. “Now the agencies are beginning to ask challenging questions, probably because they are being assisted by WHO and supporting each other. They are asking robust questions which suggests that they are learning from the process.”
Moreover, he notes, approvals should be faster so that drugs become available more quickly to patients. “There are delays of up to four or five years in some countries compared with rest of the world, but this is just a process issue that could be avoided to a great extent. Also, there is more awareness of the agencies’ review activities and what information is needed for their decision, and more transparency in the process.” And for companies “there is also more reliability and predictability. It’s good to know what timeframes are going to look like.”
Coming soon in part 2 of this article: Janssen Pharmaceutica’s experience with collaborative regulatory procedures, expansion of the AMRH to clinical trials and pharmacovigilance, and the challenge of funding African regulatory harmonization efforts into the future.
From the editors of Scrip Regulatory Affairs.