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

doi:10.21203/rs.3.rs-35630/v3

Background: Limited capacity to regulate medical products is associated with circulation of products which do not meet standards of quality, safety and efficacy with negative public health and economic outcomes. This study focused on assessing the effect of the East African Community (EAC) medicines regulatory harmonization initiative on the capacity of national medicines regulatory agencies, with a focus on registration and inspection systems.

Methods: An exploratory mixed-method design using both qualitative and quantitative data, was employed. Data was collected from six national medicines regulatory authorities (NMRAs) and the EAC Secretariat through a combination of semi-structured interviews, questionnaires, and checklists for the period 2010/11-2015/16 whereas 2010/11 data served as baseline. Interviews were conducted with heads of NMRAs, regulatory and monitoring and evaluation experts, and the EAC Secretariat Project Officer. A set of 14 indicators grouped into 6 categories were used to measure NMRAs performance.

Results: Policy and legal frameworks provide a foundation for effective regulation. Collaboration, harmonization, joint dossier reviews and inspections of manufacturing sites, reliance and cooperation are key factors for building trust and capacity among NMRAs. Five out of six of the EAC Partner States have comprehensive medicines laws with autonomous NMRAs. All the NMRAs have functional registration and good manufacturing practice inspection systems supported by regional harmonised guidelines for registration, inspection, quality management and information management systems with four NMRAs attaining ISO 9001:2015 certification.

Conclusions: The EAC regulatory harmonization initiative has contributed to improved capacity to regulate medical products. The indicators generated from this research can be replicated for evaluation of similar initiatives across and beyond the African continent and contribute to public health policy.

Health Economics & Outcomes Research

Health Policy

East African Community

medical products regulation

regulatory capacity

Africa regulatory harmonization

registration

regulatory inspection

efficiency

governance

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 African Union (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 and increased 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 African Union (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 Pharmaceutical Manufacturing Plan for Africa (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 2015-2017. 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 East African Community 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 for medicines registration in each of the EAC Partner States’ NMRAs, and whether or not the country’s information management system (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 East African Community 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.

To measure the performance of regional medicines regulatory harmonization initiatives and to ensure objective assessment of the EAC MRH initiative, 14 indicators were developed and grouped into 6 main categories as indicated in indicators matrix (Table 1) (S1). Each indicator was further refined and validated to facilitate users’ understanding, to ensure accuracy of data collected and to enable objective analysis. This was done through validation workshops with monitoring and evaluation focal points from the EAC NMRAs, Regional Economic Communities (RECs) and the World Health Organization (WHO).

Table 1 Indicators Matrix

	Indicator Title	Type	Reporting Level	Frequency	Data Sources
Category 1	Policy and legal framework
Indicator 1	National Medicines Policy (NMP)	Input	NMRA	Three yearly	WHO NMRA GBT, Government gazette, Ministry of Health
Indicator 2	Legal framework governing the regulation of medical products	Input	NMRA	Three yearly	WHO NMRA GBT, Government Gazette, National Law, Ministry of Justice library, NMRA records
Category 2	NMRA governance
Indicator 3	NMRA level of autonomy	Output	NMRA	Three yearly	WHO NMRA GBT, CIRS OpERA programme, Government gazette, NMRA Financial report, Governance structure
Indicator 4	Availability of structures to support NMRA decision making process	Process	NMRA	Three yearly	NMRA Organisation/governance structure, Medicines law
Category 4	Medicines evaluation and registration, and good manufacturing practice (GMP) inspection systems
Indicator 5	Availability of guidance and procedures for registration of medicines	Process	NMRA	Annually	WHO NMRA GBT, CIRS OpERA programme, NMRA records, Government policies and legislation
Indicator 6	NMRAs using regionally harmonized guidelines for product registration	Output	Regional	Annually	CIRS OpERA programme, NMRA Records; REC Records
Indicator 7	Availability of a process to track product registration applications and timelines	Process	NMRA	Annually	WHO NMRA GBT, CIRS OpERA programme, NMRA records
Indicator 8	Number of products applications with registration decisions per annum	Outcome	Regional	Annually	CIRS OpERA programme, NMRA records
Indicator 9	Proportion of NMRAs participating in joint assessments	Output	Regional	Annually	CIRS OpERA programme, REC records
Indicator 10	Proportion of product applications jointly assessed/ reviewed at regional level	Outcome	Regional; continental	Annually	CIRS OpERA programme, REC records
Indicator 11	Availability of a Good Manufacturing Practice (GMP) inspection guidance and procedure	Process	NMRA	Annually	WHO NMRA GBT, NMRA records, Government policies and legislation, WHO Assessment Reports
Category 5	Functional Quality Management Systems (QMS)
Indicator 12	Implementation of Quality Management System (QMS) requirements by NMRA	Process	NMRA; regional	Annually	CIRS OpERA programme, NMRA QMS Records
Indicator 13	Percentage of NMRAs ISO 9001: 2015 Certification	Output	NMRA; regional	Annually	NMRAs QMS Records
Category 6	Information Management Systems (IMS)
Indicator 14	Implementation of requirements for an integrated IMS	Output	NMRA; regional	Annually	WHO NMRA GBT, NMRA IMS

Study design: An exploratory, mixed method design using both qualitative and quantitative data was employed in this study. Data was collected from all the six NMRAs in the EAC partner States namely, the Republic of Burundi, Republic of Kenya, Republic of Rwanda, the United Republic of Tanzania (with two NMRAs), and the Republic of Uganda. Data from the six NMRAs was collected through a combination of semi-structured interviews, questionnaires and checklists (as indicated in S1 Table). Annual data collection was conducted during the 2010/11-2014/15 period whereas for some indicators, a three yearly data collection was done during the 2010/11– 2015/16 period. In each case, data from the starting year served as baseline. Questionnaire and checklist were developed based on the information obtained from the preliminary situational analysis study [23,24]. Moreover, additional questions were adopted from the WHO Global benchmarking tool for evaluation of national regulatory systems [25]. Validation of the questionnaire and checklists was done through a pilot study in all 6 NMRAs using some of the prospective respondents.

The first phase of data collection involved self-administration of the questionnaire and checklists (S1) by the selected informants. These included the NMRA’s head, one monitoring and evaluation personnel from each NMRA and a project officer from the EAC MRH project, making a total of 13 respondents. All informants were purposefully selected based on their respective roles and participation in medicines policy and regulation of medical products in the respective NMRAs.

Semi-structured interviews, also involving the above-mentioned respondents, were conducted following the successful completion of the questionnaire and checklists data collection phase. Each interview session involved one to two respondents from a particular department/unit. In addition, one NMRA staff responsible for medicines registration, GMP inspections, legal affairs, human resource, and finance were also interviewed in each NMRA. An invitation letter and interview topic guide were sent to the interviewees in advance. A permission record the responses in a written form was obtained from all respondents, moreover, confidentiality of all respondents was observed. Interviews were conducted on face to face basis, each session lasting for 1 to 2 hours. Responses were recorded by means of selective written notes, which were thereafter subjected to qualitative analysis. Follow up visits were conducted aiming at collecting the missing data and validating the previously collected data.

Data analysis: Qualitative data analysis and interpretation was carried out on all indicators involving the availability and corresponding details of the National policies, laws, guidelines, provisions, legal frameworks, level of autonomy, references and regulatory standards, GMP guidance and procedures as well as status of implementation of different modules. Qualitative data obtained using questionnaires, interviews and desk reviews of documents was organized, analysed and evaluated manually with the help of tables on MS Excel^®.

On the other hand, quantitative data on aspects related to numbers of applications, joint assessments, products registered, timelines to registration of products, and number of NMRAs under a particular aspect were tabulated and analysed using MS Excel^® for means, standard deviations, frequencies and proportions. Where only a single point/year data was provided by the respondent(s), it was reported as such. Due to lack of data from some agencies in some of the studied aspects, only the available data was used in statistical analysis.

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, quality management systems and information management systems.

Policy and legal frameworks: Progress has been observed in National Medicines Policies (NMPs) and Medicines Laws by the EAC Partner States as exemplified in Table 2. While only three countries indicated the availability of NMPs during the baseline study, currently all six countries have NMPs with a clear vision and indications for establishment of a semi- or autonomous NMRA. With respect to medicines laws, Tanzania-Mainland and Zanzibar amended their national laws in 2014 and 2016 respectively, while the Rwanda Food and Drugs Law was enacted in 2013 [26–31].

Table 2 Status of indicators under policy and legal frameworks category (2010/11 – 2015/16)

	National Medicines Regulatory Agency
	Burundi	Kenya	Rwanda	Tanzania	Uganda	Zanzibar
Indicator 1: National Medicines Policy (NMP)
Availability of a National Medicines Policy (NMP)	Yes	Yes	Yes^Δ	Yes	Yes	Yes^Δ
Year of approval of the NMP by the Cabinet of Ministers	2012	2012	2016^sd	2007	2015	2014
Availability of a provision in the NMP for establishment of an autonomous national medicines regulatory agency (NMRA)	Yes	Yes	Yes^Δ	Yes	Yes	Yes^Δ
Existence of a vision for the NMRA	Yes	Yes	Yes^Δ	Yes	Yes	Yes^Δ
Policy comprehensiveness	Yes	Yes	Yes^Δ	Yes	Yes	Yes^Δ
Indicator 2: Legal framework governing the regulation of medical products
Legal framework availability	Yes	Yes	Yes^Δ	Yes	Yes	Yes^Δ
Availability of a Law for regulating medicines in your country	Yes	Yes	Yes^Δ	Yes	Yes	Yes^Δ
Year of enactment of medicines law	1980	1957 (as amended in 2009)	2013	1978, (repealed 2003 and amended in 2004 & 2014)	1993	1986 (repealed in 2006 & amended in 2016)
Legislation comprehensiveness	No	-	Yes^Δ	Yes	Yes	Yes^Δ

NB: - = No data available/submitted; ^sd = Secondary data from the EAC MRH Project SC Meeting Report (2018); Yes^Δ = a change from No at baseline

Governance: A baseline study revealed that, the Tanzania Medicine and Medical Devices Authority (TMDA), the Zanzibar Food and Drugs Board (ZFDB) and the Kenya Pharmacy and Poisons Board (PPB) were semi-autonomous entities, and that the head of the PPB also served as a Chief Pharmacist combining both regulatory and policy roles as the technical arm of the Ministry of Health . For Rwanda and Burundi, the respective Ministries of Health Departments administered regulatory functions. Moreover, for the TMDA, PPB and the Uganda National Drug Authority (NDA), the agencies had powers to charge fees for regulatory services and received very little or no government subvention [23,24].

Results have shown a significant improvement in the level of autonomy of the NMRAs. Currently, four NMRAs are operating as semi-autonomous agencies namely: the Rwanda Food and Drugs Authority (RFDA), TMDA, ZFDA, and PPB; while NDA operates as a fully autonomous agency. Furthermore, the National Pharmaceuticals Regulation Law of Burundi was under consideration by the Burundian Parliament, provides for the establishment of a semi-autonomous NMRA to be called the Drug and Food Regulatory Authority of Burundi (ABREMA) [32]. Table 3 provides analysis of the NMRAs governance framework including the level of autonomy.

Moreover, there was a progressive trend in the development of regulations and guidelines among the EAC Partner States (Figure 1). While baseline data showed three out of the six NMRAs had regulations and guidelines, the end-line data, shows five out six NMRAs reported having regulations and guidelines in place.

Table 3 Status of indicators NMRA governance category (2010/11 – 2015/16)

	National Medicines Regulatory Agency
	Burundi	Kenya	Rwanda	Tanzania	Uganda	Zanzibar
Indicator 3: NMRA level of autonomy
NMRA’s level of autonomy	Department within the Ministry of Health	Semi-Autonomous	Semi-Autonomous	Semi-Autonomous	Autonomous		Semi-Autonomous
Indicator 4: Availability of structures to support NMRA decision making process
Medicine Law	Republic of Burundi. Decret No. 100/150 du 30 September 1980 portant Organization de I’exercise de la Pharmacie au Burundi. 1980.	Republic of Kenya. The Pharmacy and Poisons Act, Chapter 244. 1957, as amended in 2009.	Republic of Rwanda. Law No. 47/2012 of 14/01/2013 relating to the Regulation and Inspection of Food and Pharmaceutical Products. 2013	United Republic of Tanzania (Mainland). Tanzania Food, Drugs and Cosmetics Act, Cap 219. 2003, as amended in 2004, 2014 & 2019	Republic of Uganda. The National Drug Policy and Authority Act. 1993.		United Republic of Tanzania (Zanzibar). The Zanzibar Food, Drugs and Cosmetics Act. No. 2 of 2006 as amended in 2016
Existence of NMRA Governing Board	No	Yes	Yes	Yes	Yes		Yes^Δ

NB: Yes^Δ = a change from No at baseline

Medicines registration system: Comparison of baseline data show improvement in registration systems in Rwanda and Burundi. All six NMRAs currently have a legal mandate to register medicines and a system to manage applications from receipt of a dossier to the issuance of a marketing authorization. In addition, all the NMRAs use the EAC harmonized guidelines for registration and Standard Operating Procedures (SoPs) for joint review of dossiers (Table 4). Also, all NMRAs participate in the EAC joint review of dossiers. However, the time taken to register a product based on the outcome of the joint review process still varies from country to country. For instance, out of fifteen applications received through the regional procedure, The TMDA registered all the products, whereas the proportion of products registered by other NMRAs was as shown in the brackets: PPB (13/15), Burundi (1/15), RFDA (9/15), ZFDA (1/15), and NDA (7/15) (Table 4). A reliance mechanism (where an agency relies on others in making a regulatory decision) exists in Kenya, Tanzania-Mainland, Tanzania-Zanzibar and Uganda while it was not the case for Burundi and Rwanda. Results on number of products applications received per annum (Table 4, under indicator 8) indicated the highest five years average of 800 new applications were received by the TMDA, followed by NDA (458), Burundi (70) and ZFDA (16). The PPB and RFDA indicated to have received 1030 and 833 applications respectively in 2016.

Table 4 Medicines Registration and GMP Inspection Systems in the EAC Partner States NMRAs (2011/12 – 2015/16)

	National Medicine Regulatory Agency
	Burundi	Kenya	Rwanda	Tanzania	Uganda	Zanzibar
Indicator 5: Availability of guidance and procedures for registration of medicines
Legal mandate to register medicines	Yes	Yes	Yes	Yes	Yes		Yes
Availability of a system for receiving applications, evaluating and providing marketing authorisation for medicines	Yes	Yes	Yes	Yes	Yes		Yes
Indicator 6: NMRAs using regionally harmonized guidelines for product registration
Availability and use of EAC Harmonized guidelines for registration of medicines	Yes^Δ	Yes^Δ	Yes^Δ	Yes^Δ	Yes^Δ		Yes^Δ
Year EAC Harmonized Guidelines for Registration of Medicines came into force	2015	2015	2015	2015	2015		2015
Indicator 7: Availability of a process to track product registration applications and timelines
Availability of mechanism for tracking registration timelines	No	Yes (2011)	No	Yes (2011)	No		Yes (2015)
Average timelines range attained for Fast-tracked products	-	3 months	-	4-6 months	-		-
Average timeline range attained for normal review	-	12 months*	-	12 months*	-		12 months*
Indicator 8: Number of products applications with registration decisions per annum (Mean ± SD)
Applications received per annum	70.0±42.0	1,030*	833*	799.7±275.2	457.80±148.73		16.00±18.89
Application carried over from previous reference year(s)	0.0±0.0	1000*	575*	443.0±301.4	-		0
Medicines registered by the NMRA per annum	0.0±0.0	514*	175*	463.0±224.6	344.40±243.87		6.20±4.76
Indicator 9: Proportion of NMRAs participating in joint assessments
Participation in EAC joint assessments	Yes (2015)	Yes (2015)	Yes (2015)	Yes (2016)	Yes (2015)		Yes (2015)
Number of joint assessments participated by NMRA	1	1	1	3	1		3
Existence of policy on abridged procedure for registration of medicines	No	No	No	Yes (2011)	Yes (2016)		No. It is happening but there is no written policy yet.
Reference regulatory standard used on abridged procedure for registration of medicines	None	WHO-PQ	EAC & WHO-PQ	In-house SOP	EAC, SRAs & WHO-PQ		WHO-PQ
Indicator 10: Proportion of product applications jointly assessed/ reviewed at regional level
Number of products registered based on EAC joint dossier review^sd	1/15	13/15	9/15	15/15	7/15		1/15
Time taken to register medicines based on joint review outcome^sd	-	-	-	-	-		-
Indicator 11: Availability of a Good Manufacturing Practice (GMP) inspection guidance and procedure
Legal mandated to conduct GMP inspection	No	Yes (2011)	Yes (2015)	Yes (2011)	Yes (2011)		Yes (2015)
NMRA using EAC Harmonized guidelines for good manufacturing practice (GMP) inspections	No	Yes (2015)	Yes (2015)	Yes (2015)	Yes (2015)		Yes (2015)
Year EAC GMP inspection guidelines came into force	-	2015	2015	2015	2015		2015
Participating in EAC joint GMP inspections	Yes (2014&16)	Yes (2015)	Yes (2015)	Yes (2015)	Yes (2012)		Yes (2012)
Availability of policy on GMP assessment of pharmaceutical manufacturing sites using document review	No	No	Yes	No	Yes		No (it is happening but there is no written policy yet)
Reference regulatory standard used for GMP document review	-	-	EAC, PICs & WHO-PQ	-	EAC, WHO-PQ, US-FDA, EMA, PICS Inspection Reports		EAC GMP inspection report, WHO-Prequalification GMP inspection reports-

NB: Year in the bracket indicating the time from which the indicator started to apply; Yes^Δ = a change from No at baseline; * = only 2015/16 data (not average); - = No data available/ submitted; ^sd = Secondary data from the EAC MRH Project SC Meeting Report (2018)

GMP Inspection System: All six NMRAs have a legal mandate to conduct GMP inspection (Table 4, indicator 11). Except for Burundi NMRA, other NMRAs reported to be conducting inspections of manufacturing sites. While Kenya, Tanzania and Uganda NMRAs had conducted inspections since during the baseline study, Rwanda and Zanzibar NMRAs started in 2015. Moreover, All NMRAs indicated to be using the EAC harmonized guidelines for GMP inspection from 2015 when they came into force. Each NMRA reported having participated at least once in the EAC joint inspections. Additionally, the RFDA, NDA and ZFDA employ a reliance models by using GMP inspection reports from other agencies such as the EAC, Stringent Regulatory Authorities (SRAs), Pharmaceutical Inspection Convention (PIC), and the WHO Pre-Qualification Programme (WHO-PQ) (Table 4).

Functional Quality Management System: The International Standards Organization (ISO) certification is a globally recognized accreditation of the maturity and functionality of the QMS of an organization. The EAC MRH Projects advocates for implementation of QMS to facilitate delivery of quality and consistent services to customers. The NMRAs in Zanzibar, Burundi, Rwanda and Kenya had no QMS in place during baseline survey, the TMDA was ISO 9001:2008 certified and the NDA had initiated the ISO certification process. Evaluation of QMS implementation data from the EAC Partner States NMRAs indicated different levels of implementation as indicated in Table 5. However, currently the NMRAs in Kenya, Tanzania mainland, Uganda and Zanzibar are ISO 9001:2015 certified, while Rwanda and Burundi NMRAs are working towards the certification [33].

Table 5 Status of the Quality Management System in the EAC Partner States NMRAs (2011/12 – 2014/15)

	National Medicine Regulatory Agency
	Burundi	Kenya	Rwanda	Tanzania	Uganda	Zanzibar
Indicator 12: Implementation of EAC QMS in the NMRA based on ISO-9001 standard	No	Yes (2011)	No	Yes (2014)	Yes (2014)	Yes
Indicator 13: ISO-9001 Certification of NMRA medicines regulatory system	No	No	No	Yes (2010)	No	No

NB: Year in brackets indicates the time from which the indicator started to apply

Functional Information Management Systems: One of the objectives of the EAC MRH is to have all the Partner States’ NMRAs implementing a common information management system (IMS) for medicines registration, which is linked in all Partner States and the EAC Secretariat. A robust IMS is key for supporting the technical aspects of medicines regulation, to facilitate efficiency and effectiveness of business processes, improve transparency, facilitate decision-making process, sharing and exchange of information among NMRAs and stakeholders, and timeliness of approval of registration decisions. During the baseline survey, the TMDA had an integrated system which was locally developed whereas the PPB used SIAMED®. The NDA, on the other hand, used a combination of SIAMED®, ACCESS® and a locally developed software. Burundi had a manual IMS, which was not functioning, ZFDA had a functional manual registry and Rwanda had both a manual and an electronic system. The method of capturing information in NMRAs in the EAC Partner States was variable and unreliable. The electronic systems were not user friendly, difficult to integrate with other IMS platforms, could not automatically generate or print certificates or be linked to websites. The existed manual systems were labour intensive.

A comparison of IMS implementation status with baseline data shows a significant improvement in all countries, with Burundi and Zanzibar moving from manual to electronic systems. All the EAC NMRAs are currently using a harmonized IMS whereby four out of five NMRAs reported sharing regulatory information amongst each other as indicated in Figure 2 and Table 6.

Table 6 Status of implementation of different key modules by the NMRAs under Information Management Systems (IMS) category in by 2015

	National Medicine Regulatory Agency
	Burundi	Kenya	Rwanda		Tanzania	Uganda	Zanzibar	EAC Secretariat
Indicator 14: Status of key modules in Implementation of requirements for an integrated IMS
Premises	✓	✓		✓	✓	✓	✓	✕
Products	✕	✓		✓	✓	✓	✓	✕
GMP	✓	✓		✓	✓	✓	✓	✕
Inspection	✕	✓		✓	✓	✓	✓	✕
Import and Export	✕	✓✓		✓✓	✓	✓✓	✕	NA
Finance Module	✓✓✓	✓✓✓		✓	✓✓✓	✕	✕	NA
Report Module	✓✓✓✓	✓✓✓✓		✓✓✓✓	✓✓✓✓	✓✓✓✓	✓✓✓✓	✓✓✓✓

Key: ✓= fully functional; ✓✓ = fully functional and integrated to National Revenue Authority; ✓✓✓= fully functional and integrated to e-banking and/or Mobile money; ✓✓✓✓=fully functional and reports customized according to the national and regional needs; ✕ = non-functional; NA = not applicable (Source: EAC Secretariat MRH Project Progress Report, 2015

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 [33].

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 entailed additional costs for sensitization and training [37,39]. 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 [37].

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 [36]. 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 inspections. 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 regional economic communities (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 [18,26]. 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 [20,40]. 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 African Union Agenda 2063 and the global 2030 sustainable development goals [18,20].

Way forward for the Initiative

Review of the EAC MRH Project in 2017 identified three key challenges including limited access to public information about the process; limited information flow from regulators to industry during the joint assesment process; and a significant lag time between a joint assessment recommendation and national registration decisions.

As a result of these challenges, the EAC Partner States came up with a package of solutions. First, the NMRAs of the Partner States agreed on a cadre of regional technical officers (RTOs) who are responsible for the day-to-day management of joint activities and recommending programmatic changes to the initiative’s Steering Committee. The Partner States also agreed on implementing the Cooperation Framework Agreement for the NMRAs, as also approved by the EAC’s Council of Health Ministers in May of 2018. This serves as an intermediary step toward a binding mutual recognition agreement between all Partner States. The cooperation framework will facilitate implementation of joint assessment or inspection decision and ensure that regulatory decisions are made in a timely manner and honoured throughout the region. On funding the Initiative, the region will introduce a framework for contributions from the Partner States’ NMRAs. This includes a coordination fee to support regional assessment and inspection processes to complement donor funding. The long-term goal is to establish a semi-autonomous EAC Medicines Agency which will ensure that the program continues to grow and improve [41].

The process of widening the scope of medical products has started with harmonization of regulation of in vitro diagnostics (IVDs), and medical devices with a view to include vaccines, biologics and biosimilars. Regulatory activities will also be expanded to cover clinical trials oversight, safety and quality surveillance initiatives. Furthermore, the initiative has welcomed the South Sudan’s new NMRA towards addressing the regulatory challenges in the youngest member of the EAC [41].

Study limitations

Missing some of the data from some of the NMRAs led to the lack of a complete regional picture in several aspects of this study.

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, 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.

ABREMA Drug and Food Regulatory Authority of Burundi

ACCESS Drug Registration Software Solutions

AFDRAN African Drug Regulatory Authorities Network

AMA African Medicines Agency

AMQF African Medicines Quality Forum

AMRH African Medicines Regulatory Harmonization Initiative

API Active Pharmaceutical Ingredient

AU African Union

AUC African Union Commission

AUDA African Union Development Agency

AVAREF African Vaccines Regulatory Forum

BMGF Bill and Melinda Gates Foundation

CIRS Centre for Innovation in Regulatory Science

CNF Committee on National Formulary

CTD Common Technical Document

DPML Directorate of Pharmacy, Medicines and Laboratory

EAC East African Community

ECCAS Economic Community of Central African States

ECOWAS Economic Community of West Africa States

e-CTD Electronic Common Technical Document

GDP Gross Domestic Product

GMP Good Manufacturing Practice

GRevP Good Review Practice

GVP Good pharmacovigilance practice

ICH International Council on Harmonization of Technical Requiremets for Registration of Pharmaceuticals for Human Use

IGAD Intergovernmental Authority on Development

ISO International Standards Organization

IMS Information Management System

KPPB Kenya Pharmacy and Poisons Board

LMIC Low- and Middle-Income Countries

MA Marketing Authorization

MDGs Millennium Development Goals

MoH Ministry of Health

MoU Memorandum of Understanding

NDA Uganda National Drug Authority

NDQCL National Drug Quality Control Laboratory

NEPAD New Partnership for Africa’s Development

NMP National Medicine Policy

NMRA National Medicines Regulatory Agencies

NOMCOL A Network of Official Medicines Quality Control Laboratories

PMPA Pharmaceutical Manufacturing Plan for Africa

QMS Quality Management System

RECs Regional Economic Community

RFDA Rwanda Food and Drug Authority

RHO Regional Health Organizations

SADC Southern African Development Community

SDGs United Nations Sustainable Development Goals

SIAMED WHO Model System for Computer-assisted Drug Registration

SoPs Standard Operating Procedures

SRAs Stringent Regulatory Authorities

TFDA Tanzania Food and Drugs Authority

TMDA Tanzania Medicine and Medical Devices Authority

TGA Therapeutic Goods Administration of Australia

UHC Universal Health Coverage

UNECA United Nations Economic Commission for Africa

USP United States Pharmacopoeia

WB World Bank

WHO World Health Organization

WHO-GBT World Health Organization Global Benchmarking Tool for evaluation of national regulatory systems

WHO-PQ World Health Organization Pre-Qualification Programme

Zazibona Zambia, Zimbabwe, Botswana and Namibia collaborative procedure on registration of medicines

ZFDA Zanzibar Food and Drugs Agency

ZFDB Zanzibar Food and Drugs Board

Ethics approval and consent to participate

Ethics approval was granted by the WITS Human Research Ethics Committee on 31^st July 2015 through clearance certificate No. M150751. In addition, national ethical clearances and approval were granted by the respective national research ethics committees and the EAC Secretariat. Informed consent forms were signed by individual respondents from NMRAs in the EAC Partner States and the Secretariat.

Consent for publication

Respondents gave consent to publish results of this study

Availability of data and materials

All relevant data are within the manuscript and its supporting information files. The data collection instruments, and the datasets used during the current study are available from the corresponding author upon request.

Competing interests

Authors have declared that no competing interests exist.

Funding

This work was funded by the African Union Development Agency-The New Partnership for Africa’s Development (AUDA-NEPAD).

Acknowledgements

Authors would like to express their sincere gratitude to the Heads and officials in the NMRAs of Burundi, Kenya, Rwanda, Tanzania (Mainland and Zanzibar), Uganda and the EAC Secretariat for their support during the data collection and conduct of this study.

Author Contributions

MS was responsible for the study conception design of the work, acquisition, analysis, interpretation of data for the work and initial drafting of the report. NB and NN were responsible for data collection while NEM did data analysis and provided critical revision of the manuscript. MJ, NS and EK provided critical revision of the manuscript including analyses, interpretation of data and final approval of the version to be published.

Authors' information

Not applicable

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S1QuestionnaireChecklist.pdf
S1 Table: Questionnaire and checklist for heads of NMRAs and M&E experts.

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

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Abstract

Figures

Background

Methods

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Supplementary Files

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