Harmonization of medical products regulation: a key factor for improving regulatory capacity in the East African Community

The African continent constitutes 15% of the world’s population with a disproportionate disease burden of more than 25% [1, 2]. Africa’s high disease burden and high mortality from preventable and curable diseases are partly due to inadequate health systems, scarce financial and human resources as well as unavailability of and unaffordable medicines that are of good quality, safe and efficacious [3]. Lack of access to quality, safe, efficacious and affordable medicines is in part attributed to limited local pharmaceutical manufacturing base and weak medicines regulatory systems [3]. In 2005 the Heads of State and Government of the African Union (AU) mandated formulation of the Pharmaceutical Manufacturing Plan for Africa (PMPA) with the view of strengthening Africa’s ability to produce high quality and affordable medicines that will contribute to improved health and economic outcomes [4].

The coming into force of the African Continental Free Trade Area (AfCFTA) in 2019 serves as an impetus to boost intra-African trade through a single market of 1.2 billion people and a cumulative Gross Domestic Product (GDP) of over $3.4 trillion across the 55 member states of the AU [5, 6]. An estimated $259 billion health care and wellness sector by 2030 and the $45 billion projection African pharmaceutical market by 2020 are attributed to the changing economic profiles, rapid urbanization, increased healthcare spending and investment, and increasing incidence of chronic lifestyle diseases [7, 8]. The increasing demand of medicines in Africa due to population and economic growth as well as raising consumer awareness warrants governments’ investment in local production and effective regulation of medical products [6, 9].

For many years the capacity to regulate medicines in Sub-Saharan African countries has been confronted with fragmented legal frameworks, weak management structures and processes, and a severe lack of staff and resources. This led to subsequent proliferation of substandard and falsified medicines in various markets [10, 11]. A report in 2010 revealed that 7% of the 46 sub-Saharan African countries have moderately developed medicine regulatory capacity, about 63% have minimal capacities and the remaining 30% have an NMRA in place [12]. Poor inspection practices, ineffective licensing and product registration systems, inadequate access to quality control laboratories, non-existent pharmacovigilance, clinical trials oversight and drug promotion control systems, with subsequent 30% product quality failure rates are characteristic of regulatory systems in Africa [13]. This is coupled with inadequate communication and information exchange systems, lack of transparency and accountability and conflict of interest. Another study conducted in 2017 revealed that except for Sahrawi Republic, the remaining African countries have NMRAs with varying organizational setups and levels of functionality, operating either as units or departments within Ministries of Health, or as semi- or fully autonomous agencies [14].

Governments and partners are called to build and strengthen medicines regulatory systems with appropriate legal frameworks and institutions so as to carry out regulatory functions while supported by mechanisms for collaboration among agencies [11]. Effective and efficient regulation of medical products provides an opportunity for investment in manufacturing, trade, and sale of pharmaceutical products, as well as an increase in research and development of new medical products and technologies. In turn, these yield social and economic benefits to the patients and communities at large [4, 13, 14]. Building medical products regulatory capacity is also crucial for achieving Universal Health Coverage (UHC) goals, the AU Agenda 2063 aspirations and goals 1 and 3, as well as Sustainable Development Goals (SDGs) on access to quality, safe and efficacious health products to the people [15].

The African Medicines Regulatory Harmonization (AMRH) Initiative is an attempt by the AU to strengthen regulatory capacity, encourage harmonization of regulatory requirements and expediting access to good quality, safe, and effective medicines [16]. The initiative is implemented as part of the AU’s PMPA, a policy framework to provide an enabling regulatory environment for local production and contribute to the UHC, AU Agenda 2063 and SDGs goals [17, 18].

For the period between 2015 and 2016, countries in the East African Community (EAC) have recorded significant improvements in registration timelines from an average of 2 to 7 years to a median of 7 months [19, 20]. Within the Zazibona, the median timeline to product recommendation was 5 months in 2014 and 9 months for three consecutive years between 2015 and 2017. Zazibona is a collaborative procedure for registration of medicines initiated by Zambia, Zimbabwe, Botswana and Namibia in the Southern African Development Community SADC region.

The AMRH initiative is as well implemented in the Economic Community of West African States (ECOWAS), Intergovernmental Authority on Development (IGAD) and Economic Community of Central African States (ECCAS). It covers more than 85% of the Sub-Saharan African countries which are at different levels of its implementation. In order to address the problem of non-coherent medicines laws in African countries, the AMRH Initiative developed a Model Law on medical products regulation so as to ensure effective regulation and promotion of harmonization [20, 21]. The Model Law which among others promotes the establishment of autonomous agencies was adopted by the AU Assembly in January 2016 and has been domesticated by more than 12 AU Member States. Since 2014, eleven regional centers of regulatory excellence have been designated since 2014 to provide coordinated and structured regulatory science training programmes using the existing academic institutions in partnership with regulatory agencies [20].

Understanding the relevance of various regulatory interventions undertaken at country, regional and continental levels is important for informing regulatory policy reforms undertaken by the AU, governments, and partners [22]. For this reason, this study was done to evaluate the effect of medicines regulatory harmonization initiative in the EAC region and to provide insights on whether it is making an impact on national regulatory capacity. We aimed at determining factors related to the improving regulatory capacity in the EAC NMRAs. Specifically; to determine the level at which countries have: i) Implemented agreed Common Technical Document (CTD) for registration of medicines in the EAC Partner States. ii) Implemented common Information Management Systems (IMS) for medicines registration in each of the EAC Partner States’ NMRAs, and whether or not the IMS is linked in all Partner States and EAC Secretariat. iii) Implemented Quality Management Systems (QMS) in each of the EAC Partner States’ NMRAs. iv) The level of capacity attained at regional and national levels in implementing medicines registration harmonization in the EAC region. v) Whether or not a framework for mutual recognition procedure has been developed and implemented among the EAC Partner States, and lastly vi) Whether or not a platform for information sharing with key stakeholders at national and regional level has been established. The hypothesis is that the EAC MRH Project implemented under the AMRH Initiative has increased regulatory capacity in the EAC Partner States.

Fourteen (14) indicators were developed and grouped into 6 main categories to ensure objective assessment of performance of regional medicines regulatory harmonization initiatives, as indicated in the indicators matrix (Table 1) [23]. Each indicator was further refined and validated to facilitate users’ understanding, through validation workshops with monitoring and evaluation focal points from the EAC NMRAs, Regional Economic Communities (RECs) and the World Health Organization (WHO). The exercise aimed to ensure accuracy of data collected and to enable objective analysis.

This publication is a continuation from a previous paper which looked at factors affecting financial sustainability of NMRAs in the EAC region [24]. For the purpose of this paper, findings are categorised into five main categories namely policy and legal framework, NMRA governance, medicines registration and good manufacturing practice (GMP) systems, QMS and IMS.

The current environment of increased globalization imposed by the geo-economic-political situation warrants an advocacy for cooperation and harmonization among NMRAs across the world as basis for building and strengthening regulatory capacity. This is especially important given the fact that harmonization initiatives support regulators’ mandate to promote and protect public health when backed with clear governance structures and regulatory frameworks [37].

Medicines policies and laws serve as the foundation for effective regulation of medical products. A comparative study of medicines laws in the EAC region revealed that medicines laws exist in all EAC Partner States with varying legal provisions, key regulatory functions, and practices. These potentially affect availability of good quality, safe and efficacious medicines needed on the market [35]. In order to ensure effective regulation of medical products, convergence of regulatory practices through streamlining the existing legal frameworks is essential [35]. In this regard, it is important for countries to consider domestication of the AU Model Law on Medical Products Regulation which has the necessary provisions for a country to have a robust regulatory system such as core regulatory functions (as recommended by WHO), some level of autonomy, NMRA’s participation in harmonization initiatives and collaboration with other agencies. The increased advocacy under the EAC MRH Project has helped in creating awareness on the part of policy makers and politicians on the importance of investing in medical products regulation with subsequent improvement in policy and legal frameworks in all the countries of the EAC region.

Regulatory harmonization facilitates pharmaceutical companies’ submission of a single set of the dossier to several different countries with subsequent reduction of costs. Harmonization processes are also beneficial for public health as they facilitate open-minded technical discussions and the exchange of ideas and experience among regulators from different countries [38]. The EAC regulatory harmonization experience has enhanced regulatory science by increasing the rigour of the review process, with subsequent higher quality standards than national procedures. In turn, this has reduced the overall regulatory burden and led to less duplication of efforts [36, 39, 40]. These contribute to the strengthening of the capacity of the NMRAs in expedition of the assessments of priority medicines and filtering out of substandard or falsified products [38]. Sound, efficient, effective and transparent regulatory systems are as well important for the promotion of investment in pharmaceutical sector and socioeconomic advancement [11].

The decision to harmonise guidelines for registration of medicines and GMP inspections in the EAC region has simplified the process for manufacturers intending to lodge an application in any of the countries [59]. In addition, reliance mechanisms for registration of medicines employed by PPB, TMDA, ZFDA and NDA; reliance mechanisms for GMP inspection implemented by RFDA, NDA and ZFDA; and appropriate governance mechanisms to support sound and timely regulatory decisions by NMRAs are attributed to the improved efficiencies observed in these countries. For example, there has been a considerable improvement in the NMRA governance frameworks with a subsequent establishment of autonomous agencies in Kenya, Tanzania mainland, Rwanda, Uganda and Zanzibar.

The attainment of ISO certification by NMRAs is another factor that can be related to improved regulatory efficiency. With a resultant increase in the number of received applications as observed in Kenya, Tanzania mainland and Uganda. The ISO certification will also increase confidence in the quality of NMRAs work, increasing trust and facilitate reliance on registration and inspection processes as viewed by peer agencies in the region and across the continent [36]. It is important to note that ISO certification of the NMRAs is one of drivers of a robust medicines regulatory system. Similar means in place include being ranked by the WHO – GBT for evaluation of national regulatory systems. This was demonstrated by the TMDA by achieving the WHO – Maturity level 3 in 2018, becoming the first African NMRA to do so [41]. According to the WHO, the attainment of Maturity level 3 indicates that an agency has a stable well-functioning and integrated system of oversight for medical products. Further, it is of essence to recognise the progress made by the PPB, NDA and ZFDA, considering they had no QMS in place during the baseline survey. Rwanda is moving toward the attainment of the ISO 9001:2015 certifications while the NMRA in Burundi implemented quality objectives and standard operating procedures for some regulatory activities, including medicines evaluation and registration [36].

Furthermore, an operating IMS that links all Partner States is essential for improving efficiency as it assists the EAC Secretariat and NMRAs in tracking the progress of applications in their own as well as neighboring countries. All EAC Partner States now have a functioning IMS, and it is agreeable that this has boosted efficiency and strengthened cross-departmental linkages. The IMS platforms are designed to allow as many processes as possible to be conducted online through a single portal, whereby the PPB is the only agency which allows the electronic submission of dossier applications. Implementation of the EAC Cooperation Framework agreement also requires IMS platform for NMRAs to communicate and share information [36].

Harmonization initiatives are not spared of challenges. One of the challenges experienced by the EAC harmonization initiative is the unfamiliarity with regulatory systems of other NMRAs. This resulted into a lengthy process from development of harmonized guidelines to the actual coming into force in January 2015. The process involved eleven steps to familiarise all the key stakeholders such as regulators and industry with new guidelines and entailed additional costs for sensitization and training [40, 42]. Experience shows that sometimes countries are unwilling to commit to a uniform code due to differences in political economy and ethical systems. In a situation where there are differences in legal frameworks, it may imply that definitions of terms among countries are different (“generic”, “reference product”, “data exclusivity”, “pharmacopoeia”, “variations”, etc.) hence causing delays in the harmonization process. Medicines acceptable for market authorizations by the NMRAs as well as acceptable indications may also vary between countries based on differences in treatment guidelines and therapeutic traditions. Other challenges include differences in technical requirements, for example bioequivalence (BE) requirements for complex products and differences in aspects related to product and Active Pharmaceutical Ingredients (API) (e.g. source, method of manufacture and packaging). Moreover, divergence following joint approval due to separate handling of post-approval changes, variations in assessment timelines based on regulations and differences in data exclusivity/patent rules, are other factors to be well considered when implementing harmonization initiatives [40].

Although some countries have proven to be faster than others in granting marketing approval of products following the regional review process, many applicants are hesitant to use the joint product assessment procedure until efficiency improvements are made. While it has been reported that the regional procedure is of unexpectedly higher quality standards than national procedures, a common frustration is the time taken to receive the actual marketing authorization especially for smaller, less attractive markets [39]. These differences may be due to the diverse nature of governance (whether autonomous agency with its own Board or a department under the Ministry of Health) and execution of roles among the NMRAs, as well as the existence of non-streamlined policies, laws and guidelines in the respective countries. There is a need to further study factors hampering national uptake of joint review process as they affect marketing authorization timelines. Improvements are therefore required for the current EAC processes to meet the vision of harmonization.

Key performance indicators developed as part of this study have helped to identify gaps in the regional harmonization process. While the baseline assessment tool focused on the national regulatory system, legal framework, marketing authorization and regulatory inspection, the indicators tool developed during this study provided more insights into the interactions between NMRAs. These are mainly through regional processes like implementation of regional harmonised guidelines, execution of joint regulatory activities and subsequent uptake of the outcomes of the regional joint review and inspection processes.

Harmonizing regulatory standards across countries, work and cost-sharing arrangements, collaboration between NMRAs, as well as advocacy and information campaigns are key aspects in addressing the existing regulatory limitations in and across countries. The AMRH provides a platform to support RECs, Regional Health Organizations (RHOs) and Member States, in harmonizing medicines regulation with a view to build and strengthen regulatory capacity. These are achieved through mobilizing interested governments, donors and other stakeholders to invest in medicines regulation [18, 29]. The AMRH Initiative also serves as a foundation for the establishment of the African Medicines Agency (AMA) as enshrined in the AU Executive Council Decision EX.CL/872(XXVI) of January 2015 [20, 43]. It is expected that these initiatives will accelerate research and development of new or improved medical interventions for Poverty-Related Neglected Diseases (PRNDs), provide an enabling environment for local manufacturing, and contribute towards the AU Agenda 2063 and the global 2030 SDGs [18, 20].

The improved operational efficiencies with subsequent faster and more consistent review and approval process is a result of the regulatory harmonization, which has facilitated faster availability of products in the EAC market. It is expected that regulatory and product development costs will decrease and the industry submission practices will be aligned with fewer parallel registrations. Moreover, the resultant mutual learning and consistency in applying international guidelines for registration of medicines or inspection of manufacturing sites are anticipated.

The study has shown improved regulatory capacity in the EAC Partner States at varying degrees and timelines. The EAC Partner States have strived to put in place comprehensive policies and legal frameworks to support regulation of medical products with subsequent use of harmonised regional guidelines. Quality management system and information management systems have shown to be necessary tools for improving efficiency of regulatory processes. Moreover, the improved work-sharing through shared knowledge and skills among NMRAs has resulted in faster regulatory approvals and improved availability of safe, efficacious, and good quality medicines.

The developed indicators tool serves as basis for evaluation of regulatory harmonization networks on the African continent and beyond. We expect that the gaps identified, and lessons learnt from using the indicators tool in this study can be used as basis to refine it for further use.