EDCTP’s support for ethical and regulatory activities in Africa was presented by Dr Thomas Nyirenda, (EDCTP Manager for Strategic Partnerships and Capacity Development). The EDCTP capacity development programme for enabling the African environment for clinical trials includes supporting sub-Saharan African countries to strengthen ethics capacities, regulatory frameworks, and pharmacovigilance activities in collaboration with European partners.

Between 2014 and 2018, EDCTP supported ethics and regulatory activities to the amount of €5.8 million through 20 grants. New ethics committees were established in institutions where they did not exist, and funding was provided for improved oversight by existing NECs, NRAs, and regional ethics committees. EDCTP support has resulted in:

• increased public awareness of research ethics review and regulatory oversight of clinical trials;
• improved compliance with international standards of legal frameworks by NECs and NRAs;
• improved staff qualification at NECs and NRAs to conduct ethics and regulatory evaluations, respectively;
• faster turnaround times of study protocol evaluations and effective pharmacovigilance reporting, including through the use of electronic systems.

EDCTP is also funding pharmacovigilance networks and EDCTP Regional Networks of Excellence which could strengthen the links between NRAs, national public health programmes, and local research and academic institutes.

Dr Mukanga (Bill & Melinda Gates Foundation) presented the Gates Foundation’s funding to support regulatory and ethics activities; this is done through grants to the African Vaccine Regulatory Forum (AVAREF), the African Academy of Sciences (AAS), and ethics committees.

The objective of the investment in AVAREF is to accelerate access to global health products through optimisation of the African regulatory landscape, targeting a 50% timeline reduction in five years. This is also important to address the need for an emergency mechanism which may facilitate rapid review of clinical trial applications during pandemics.

The Gates Foundation is supporting the African Academy of Sciences to develop a database of African clinical research site capabilities. This is to address a situation in which clinical research activity appears to be unevenly distributed with advanced capacity concentrated in 28 sites across nine countries. An open database with information about African clinical trial capacities and research sites will promote African research centres and their visibility, as such a platform would:

• offer a robust, open access, up-to-date database regarding the African clinical research landscape, including a catalogue of existing clinical trial capacity, regulatory requirements, performance, and predictability in the field of clinical and translational sciences across countries;
• optimise collaboration across the clinical research ecosystem;
• reduce duplication of feasibility assessments conducted to identify, collect and submit data on clinical trial site capacity at the beginning of every new project;
• improve visibility of African clinical research capacity to global investors;
• increase the capacity to identify duplication and gaps in capacity and funding, and thus enable transparency of future investments and their impact;
• provide additional support to ethics committees.

Ms. Margareth Ndomondo-Sigonda (Head Health Programmes, AUDA-NEPAD, and coordinator of its African Medicines Regulatory Harmonisation (AMRH) programme) gave an overview of AMRH and the AMRH Partnership Platform.

The AUDA-NEPAD agency, in collaboration with WHO and other partners represented in PACTA, has established a coordination mechanism that will oversee the strengthening of medicines regulatory systems and the harmonisation activity in Africa, using a single platform. This platform is vital to avoid duplication of work, ensure optimal utilisation of resources, and establish a consensus on priority areas of intervention.

AMRH aims to improve access to the needed medical products and technologies for the African people by creating an enabling environment for pharmaceutical industry to grow, and supporting regulatory reforms in the pharmaceutical sector through evidence-informed studies, policies, laws and regulations, guidelines, and technical requirements.

The African Vaccine Regulatory Forum (AVAREF) is aligned with AMRH on clinical trials ethics and regulatory oversight and more than 85% of sub-Saharan Africa is covered by projects for medicines registration harmonisation at different levels. The AMRH platform will leverage the harmonisation and alignment of AMRH and AVAREF in Africa to build on the proven model of working through the National Regulatory Authorities (NRAs) for medicines and Research Ethics Committees (RECs), Regional Economic Communities, and Regional Health Organisations, and the African Union Commission to address gaps in regulatory capacity at national, regional and continental levels.

The AMRH platform currently has a total of 35 members in different specialised areas of medicines regulation from dossier review and registration, clinical trials, blood and blood products, to post-marketing surveillance and pharmacovigilance, quality control and assurance. Other areas include medical devices and diagnostics, Good Manufacturing Practices, policy and regulatory reform, regulatory capacity, etcetera.

The vision of the African Union is to transition the AMRH programme into the African Medicines Agency (AMA) which will be responsible for areas such as management and coordination of emergencies, and multi-country clinical trial oversight.

Professor Bartholomew Dicky Akanmori (WHO-AFRO Regional Focal point for Vaccine Research and Development) gave an overview of AVAREF during the second session on the first day. In 2006, AVAREF was created by WHO with support from EDCTP. It started as an informal capacity building platform aimed at improving the regulatory oversight of interventional clinical trials conducted in Africa. AVAREF was to serve as a network of NRAs and NECs to build their capacity and improve the harmonisation of practices in support of product development and regulation of clinical trials. 

The forum has since demonstrated its value in strengthening regulatory and ethics reviews, promoting harmonised standards and approaches, and accelerating the review of vaccines of high public health value – most recently in relation to vaccines against Ebola. The strategic objectives for the renewed AVAREF are to:

• increase the efficiency and quality of reviews and inspections, and improve the timeliness and transparency of regulatory decisions for all interventional trials conducted in Africa;
• promote the safety of patients;
• accelerate the AMRH process, linking all regional economic communities;
• stimulate innovation and research in Africa;
• enhance emergency preparedness on the continent, in regional economic communities, and in individual countries;
• strengthen AVAREF’s capacity building role;
• promote awareness, sustainability, and monitoring of AVAREF.

Professor Issiaka Sombie (Principal Professional Officer of Research and Health Information of the West African Health Organization), presented the approach his organisation has used to improve research ethics in West Africa. The West African Health Organization (WAHO) is a specialised health institution of ECOWAS, the Economic Community of West African States, the intergovernmental regional body made up of fifteen West African countries. WAHO is responsible for the harmonisation of the health policies of the ECOWAS member states.

All ECOWAS member states have National Ethics Committees (NECs) and Institutional Review Boards. WAHO has the mandate to convene meetings of the representatives of NECs for health research of the ECOWAS member states. WAHO has used this convening power to establish the West African Network of National Ethics Committees (WANEC). WANEC is used to:

• harmonise the operations of NECs in the regional community including their operational guidelines and standard operating procedures;
• strengthen the capacity of NECs;
• develop a functional guideline for multi-site projects and their evaluation;
• strengthen the relationship between the NECs and Institutional Review Boards; and
• mobilise funds for the functioning of the NECs.
  

Nonetheless, WAHO faces major challenges, including lack of funding; lack of relevant national legislation; lack of an established operational secretariat; limited awareness of the functions of ethics committees; inadequate continuous education for members, researchers and administrators; limited opportunities for networking both through electronic media and face-to-face; insufficient monitoring of research and inactive follow-up for final reports from principal investigators.

OCEAC – the organisation to coordinate the fight against endemic diseases in Central Africa - is an agency of the Central African Economic and Monetary Community (CEMAC). It is responsible for the harmonisation of national pharmaceutical policies and research ethics in the central African region. Members include Cameroon, the Central African Republic, Congo, Gabon, Equatorial Guinea, and Chad. OCEAC has adopted a common pharmaceutical policy; a framework regulation and additional regulations on standard operating procedures, guidelines on specific areas of the pharmaceutical sector (adopted by the member states), and a regional operational plan adopted by the Ministers of Health of the CEMAC members.

Challenges faced by OCEAC countries include weakness of legislation and pharmaceutical regulation in the region; low capacity of national medicines regulatory authorities; insufficient human resources in the pharmacy sector; weakness of national drug supply systems; poor coordination of interventions to fight against fake medicines and illicit drug routes; and limited funding. There is also a low level of cooperation from National Ethics Authorities in Equatorial Guinea, Gabon, and the Central African Republic.

Moving ahead, OCEAC is proposing: joint evaluation of applications for market approval; joint inspections, development of regional standards for the harmonisation of sanctions in the fight against counterfeit medicines and illicit supply routes; empowerment of Directors of Pharmacy Boards; and establishment of drug quality control systems at the regional level.

Global perspective

Members of Cochrane South Africa from the South African Medical Research Council (SAMRC) presented the global perspective on clinical registration starting with the general concept of a clinical trial registry. WHO defines - for the purpose of registration - a clinical trial as any research study that prospectively assigns human participants or groups of humans to studies of one or more health-related interventions (diagnostics, behavioural interventions, or new drugs) which can be used to evaluate (in Phase I to Phase IV trials) the effects on health outcomes. A clinical trials registry was described as a database in which key administrative and scientific information is stored about planned, ongoing and completed trials, sufficient to identify the trial’s existence.

The establishment of a clinical trials registry followed the 2004 Ministerial Summit on Health Research by WHO which led to the formation of a network of international clinical trial registries - the International Clinical Trials Registry Platform (ICTRP). The platform ensures a single point of access and the unambiguous identification of trials. It reduces public bias and selective outcome reporting while fulfilling the ethical mandate of publication and allowing transparency to enhance public trust. A clinical trial register provides a tool to assess the research being conducted, in order to reduce duplication, particularly in resource-limited settings, and direct research to what is needed.

Aspects of clinical trials registration are much discussed, most recently the topic of data sharing. Many hold that it is unethical to conduct research in humans without publication and dissemination of the results of that research. WHO has made it mandatory for all primary registers to have a data field in which trialists can add their plans to share the data resulting from the proposed clinical trial.

Regional perspective

Elizabeth Pienaar, (SAMRC and project manager of PACTR), gave an overview of PACTR and its relevance to Africa. PACTR was initiated in 2006 as the Aids, TB and Malaria Registry with support from EDCTP. It grew over the years and in 2009, after a call from AVAREF, it expanded its scope to receive data on clinical trials for all diseases and conditions. Accordingly, it was renamed to PACTR and became a Primary Registry of the WHO-ICTRP.

PACTR receives strategic advice from an Advisory Group comprising technical and strategic stakeholders, such as SAMRC, the National Department of Health of South Africa, the Australia New Zealand Clinical Trials Registry, and WHO. In 2018, PACTR was redeveloped to include improved search and trial submission functions. The administrative processes have also been improved. Four new data fields required by WHO-ICTRP were also included, making it one of the first registries to comply with current WHO standards.

PACTR also offers the opportunity for networking as it provides access to researchers as well as trial sites. Moreover, it provides information on the funders of the various research projects and it is a resource for potential trial participants to find specialists researching their condition, thereby providing the opportunity to be involved with a trial. Data from PACTR has been used for the mapping of clinical trial activity regarding several disease conditions relevant to Africa, e.g. Ebola, HIV/AIDS, Tuberculosis, and neglected tropical diseases.

To date, approximately 1800 clinical trials have been registered in PACTR by 1841 principal investigators (34 trials listing multiple principal investigators). The majority of these investigators (1673) are from 38 African countries; the others are mainly from Europe and the United States of America. The registration has grown from five trials in 2008 to 79 trials in the first quarter of 2019. Retrospective registration remains a challenge; it accounts for 48% of registrations. Analysis of the trials indicated that most are funded by universities. This is followed by the category of so-called ‘self-funded’ trials. Currently, 67 trials in the registry are EDCTP-funded, a number lower than the total of trials funded by EDCTP.

PACTR sees as opportunities for further development, the establishment of a network with ethics and regulatory authorities and the development of the capacity of all stakeholders. Maintaining Primary Registry status, within the WHO-ICTRP as well as securing sufficient funding to sustain and develop the functionality of PACTR, remain constant challenges.

National perspectives

Participants from South Africa, Nigeria, Kenya, and Australia presented national perspectives.

Duduzile Ndwandwe (Project Coordinator from Cochrane South Africa, SAMRC) described a national registry example. The South African National Clinical Trial Register (SANCTR) monitors and manages the conduct of clinical trials in South Africa. A clinical trial must have ethical and all other regulatory approvals, where required, before the trial can be registered. Registration of clinical trials in SANCTR is currently a difficult and tedious process and does not conform to WHO standards. SANCTR oversight is being transitioned to the SAMRC including support for the re-development of SANCTR. This seeks to ensure that the process for registration will be streamlined and that SANCTR will conform to WHO standards by partnering with the WHO primary registry, PACTR. All clinical trials registered in SANCTR will be uploaded to PACTR, receive a PACTR number, and will be subsequently fed to the WHO International Clinical Trial Registry (ICTRP).

The aim of this redevelopment of SANCTR is to ensure a single point of entry for clinical trials conducted in South Africa and facilitate registration of trials in accordance with global requirements. This redevelopment requires broad collaboration. To make the SANCTR registry work, collaborations have been established with national ethics committees, regulatory authorities, and funders; good communication with clinical trialists is also very important.

The Nigerian perspective was presented by Professor Martin Meremikwu. In Nigeria, the National Agency for Food and Drug Administration and Control (NAFDAC) is responsible for protocol review and authorisation of clinical trials before they are conducted. It is also responsible for the inspection of trial sites to monitor the conduct of authorised studies to ensure that the well-being and safety of the participants are protected, and credible data is obtained from the study. The National Health Research Ethics Committee is responsible for the accreditation of Independent Ethics Committees and/or Institutional Review Boards that review study protocols for research ethics, depending on the number of trial sites involved. More information on its website: nhrec.net). Currently, there are 43 registered Health Research Ethics Committees in Nigeria.

Clinical trial authorisation by NAFDAC is mandatory for new or relatively new drug products, herbal formulations or cosmetics for which a safety and efficacy profile has not been determined, especially in Nigerian populations; drugs for new indications; drugs for new patient groups (e.g. age, race etc.); new combination-drugs products; new dosage schedules or regimens; new drug delivery systems; new medical devices; new medical procedures, bioequivalence studies, and academic clinical trials on any of the above.

Professor Walter Jaoko, from the University of Nairobi, presented the Kenyan perspective. In Kenya, the Pharmacy & Poisons Board (PPB) is the regulator of clinical trials based on published guidelines for the conduct of clinical trials in Kenya.

Ethical approval of a clinical trial protocol is mandatory for submission for regulatory review by the PPB. The approval must be given by a research ethics committee accredited by the National Bioethics Committee. Review of the on-line submitted proposal is done by the Expert Committee on Clinical Trials of the PPB.

Clinical trials which are approved by the PPB, are uploaded to the national clinical trials registry where the public can access the trial information. The PPB only registers clinical trials of drugs, vaccines, and medical devices. The PPB is upgrading its system to introduce new features in line with international requirements for clinical trials registries. The decision of Kenyan researchers to register studies in other clinical trials registries is largely driven by the requirements of funding agencies or scientific journals. As a result, some trials conducted in Kenya are registered in PACTR but most are registered on ClinicalTrials.gov.

Professor Davina Ghersi (Australian Clinical Trials Alliance) is a leader in clinical trials, implementation science, and policy in the Australian Clinical Trials Alliance (ACTA) and she shared her experiences with the ACTA model. This Australian organisation, ACTA, promotes effective and cost‐effective healthcare in Australia through investigator‐initiated clinical trials and clinical quality registries that generate evidence to support decisions made by health practitioners, policy‐makers, and consumers. This is a model that PACTA could emulate: contribute deliver high-quality and cost‐effective care through the systematic generation and application of evidence derived from clinical research.

Industry perspective

Dr Anthony Man (Novartis Global Health Development Unit, Switzerland) presented an industry perspective on clinical trials approvals in Africa. The pharmaceutical industry promotes the documentation and dissemination of information about clinical research studies including elements of trial design, sponsorship and trial results. Multiple trial registries are used with different legal frameworks, data collection methods, reporting requirements, connectivity (ICTRP) and search functions.

The main registry used by industry is ClinicalTrials.gov (U.S. National Library of Medicine) which (at the time of writing) had information on more than 299,902 privately and publicly funded research studies in 208 countries. The pharmaceutical industry also uses the EU Clinical Trials Register with information on 34,289 clinical trials with a EudraCT protocol. Other registries used are individual company databases (e.g. Novartis Clinical Trial Results; GSK Study Register; the Yale University Open Data Access Project) and national or local registries established according to local laws and practices. Some registries require ethical approval before registration. Ethical approvals could involve multiple countries and several Institutional Review Boards and sometimes efforts have to be duplicated.

Acceleration of the trial approval process is needed to avoid delays in recruitment (e.g. in view of the malaria season), expiration of usable products, and the risk of staff turnover. In the long term, delays in trial approval could affect the implementation of protocol amendments, duration, costs, the registration of new medicines, and patient access to new treatments. Delays could be lessened through advance translation, simplification of forms, and good-quality documents prior to negotiations with governments for customs clearance and import licenses. From the perspective of industry, there is an urgent need for a transparent and harmonised process for ethics and regulatory review and approval of clinical trials within and across African countries.

The Cochrane initiatives on systematic reviews and evidence synthesis were presented by Kathelene Weiss and Tamara Kredo. Cochrane Africa promotes the use of evidence to inform decision making on healthcare and capacity development in sub-Saharan Africa. It supports the production of high-quality, relevant Cochrane reviews; makes relevant evidence accessible; and advocates for evidence-informed policy and practice. Cochrane Africa tries to maintain a sustainable network of experienced Cochrane review contributors which includes authors, editors, mentors, and trainers. The network aims to build the capacity to conduct systematic reviews, advance teaching and learning of evidence-informed healthcare, and to promote knowledge translation. Cochrane reviewers from South Africa, Nigeria and Cameroon shared their views.

Cochrane Global and Cochrane South Africa highlighted the emergence of a digital and trustworthy evidence ecosystem. Cochrane is working hard to move evidence synthesis and dissemination forward in the Africa ecosystem for evidence synthesis. Progress is being made to ensure that digital, structured data can efficiently feed living systematic reviews into living guidelines.nCochrane is laying the foundations for generating ‘fair’ research data, based on the FAIR data principles (Findable, Accessible, Interoperable, and Reusable).

Martin Meremikwu (Director of Cochrane Nigeria and Professor at Calabar University, Nigeria) reported that In Nigeria clinical trial registers contain important information on ongoing clinical trials and trials that may have been completed but not published. Cochrane systematic reviews include published and unpublished clinical trials. Published protocols provide reviewers with the opportunity to compare outcomes reported in published trial reports with those originally expected and thus to identify the risk of bias that may arise from selective reporting of trial outcomes.

Professor Pierre Ongolo-Zogo (Cameroon/AACHRD/EVIPNet; University of Yaoundé, Cameroon) spoke about evidence-informed policy. Based on his experience as a member of WHO AFRO’s African Advisory Committee for Health Research and Development (AACHRD) and the WHO Evidence-Informed Policy Network (EVIPNet), he posed the following questions. Are reviews and trials in alignment with the Universal Health Care agenda? Are there funding opportunities to create or to sustain the enabling climate for knowledge translation?

Prof Ongolo-Zogo stated that systematic reviews are a must to justify any clinical trial, especially in product and intervention development to address poverty-related diseases in Africa. There should be evidence briefs for policy and practice to inform policymakers and critical health stakeholders on the value of clinical trials for product development. Evidence-informed deliberative dialogues and stakeholder engagement before clinical trials are essential to leverage appropriate support and mitigate some of the bureaucratic barriers. Trial registration and review registration should be linked and online tools made available for easier access to policy-relevant evidence. Engaging the media and the consumers is important and should be viewed as an integral part of capacity building to sustain the enabling climate for clinical trials and knowledge translation.