National ethics guidance in Sub-Saharan Africa on the collection and use of human biological specimens: a systematic review

Abstract

Background

Ethical and regulatory guidance on the collection and use of human biospecimens (HBS) for research forms an essential component of national health systems in Sub-Saharan Africa (SSA), where rapid advances in genetic- and genomic-based technologies are fueling clinical trials involving HBS and the establishment of large-scale biobanks.

Methods

An extensive multi-level search for publicly available ethics regulatory guidance was conducted for each SSA country. A second review documented active trials listed in the WHO International Clinical Trials Registry Platform as of January 2015 in which HBS collection was specified in the protocol. Findings were combined to determine the extent to which countries that are study sites for HBS-related research are supported by regulatory guidance language on the collection, use, ownership and storage of biospecimens.

Results

Of the 49 SSA countries, 29 had some form of national ethics guidance, yet only 17 provided language relating to HBS-related research, with specific guidance on consent (14), ownership (6), reuse (10), storage (9), and export/import/transfer (13). Ten countries accounted for 84 % of the active clinical trials involving the collection of HBS in SSA. All except one of these countries were found to have some national guidance in the form of regulations, codes of ethics, and/or standard operating procedures; however, only seven of the ten offered any language specific to HBS.

Conclusions

Despite the fact that the bulk of registered clinical trials in SSA involving HBS, as well as existing and proposed sites for biorepositories under the H3Africa Initiative, are currently situated in countries with the most complete ethics and regulatory guidance, variability in the regulations themselves may create challenges for planned and future pan-African collaborations and may require legislative action at the national level to revise. Countries in SSA that still lack regulatory guidance on HBS will require extensive health system strengthening in ethics governance before they can be full participants in the modern research enterprise.

Background

Exponential growth in the fields of pharmacogenetics and genomics research over the past decade is fueling worldwide interest in the establishment of biorepositories of human biological specimens. Biorepositories already exist in three SSA countries—The Gambia, South Africa, Zimbabwe [1–3]. Major expansion in this domain is occurring in Sub-Saharan Africa, largely driven by the Human Heredity and Health in Africa Initiative (H3Africa), a joint effort of the National Institutes of Health (NIH), the Wellcome Trust, and the African Society for Human Genetics [4]. The ‘hub and spoke’ model adopted by this initiative calls for the development of four pilot regional biobanks – two in South Africa and one each in Nigeria and Uganda – which will serve as multi-country repositories of specimens collected under sponsored research activities taking place throughout the region [5]. The H3Africa Initiative reflects significant efforts by the international community of researchers, funding agencies, and African academic institutions to build a foundation for sophisticated, state-of-the-art genomic research on burdensome diseases in Africa; the ultimate goal of the initiative is to improve the health of the African peoples.

From its inception, the initiative has sought broad consensus on topics relating to ethics and governance A Joint NIH and Wellcome Trust Policy document sets forth high-level principles on ethics, governance, and resource sharing with which research networks and programs funded by the initiative are expected to comply [6]. A standing working group on ethics and regulatory issues comprising ethicists and other members of the scientific community meets periodically to discuss and develop recommendations on a wide range of topics including community engagement strategies, cultural issues, informed consent, participant safety, return of results, intellectual property, material transfer agreements, and other regulatory issues. While such guidance has the potential to serve as a model framework for all countries in Africa to consider as they develop their own national guidelines, the current focus of the initiative is on those entities that it supports. Applied more broadly, the pan-continental approach espoused by H3Africa and similar initiatives may require a level of ethical guidance at the country level explicitly addressing the collection and use of HBS which is currently not to be found in most national ethics regulatory guidance. In many African countries, such systems are in their infancy; policies that address emerging technologies such as whole genome sequencing and association studies are absent [7, 8].

The International Declaration on Human Genetic Data, promulgated by UNESCO in 2003, recognized the importance of national policies to guide the collection, processing, use, and storage of human genetic data, as well as the review by local and institutional ethics committees of protocols involving such data [9]. In Africa specifically, a growing body of literature has focused on the need to have ethical and legal governance structures in place to oversee research involving HBS and the operation of biobanks [10, 11].

If the H3Africa vision of a pan-continental genomic enterprise is to be fully realized, ethics guidelines at the national level must align in ways that support interoperability among African countries. In cases where no guidelines presently exist, investment in institutional capacity-building by such entities as H3Africa and others may be needed to support their development. In cases where national guidelines do exist, some may require the addition of new language specific to research involving HBS; such revisions may require legislative approval. There may be instances where national values simply will not support the transnational transfer of genetic information, broad data sharing within research communities (however relevant to their populations), or the delegation of decision-making on future use to an outside authority. The lack of interoperability among African nations in their ethics guidance as well as differences in interpretation of meaning in instances where international recommendations have been adopted has the potential to slow, even derail, the realization of benefit from new advances and approaches in biomedical research [10, 12].

Although a number of scholars have examined the ethical, legal, and social issues associated with the collection and use of biospecimens in research, there has been far less focus on the existence and nature of regulatory guidance on HBS at the national level in Sub-Saharan Africa [8, 11–17]. Of particular importance is the identification of national ‘gaps’ in ethics guidance, as well as inconsistencies and national differences among those countries where guidance does exist.

Methods

This study involved two systematic reviews designed to determine the availability of publicly accessible regulatory HBS guidance at the national level in SSA countries and to assess the extent to which it addressed ethical and regulatory issues relating to consent, ownership, reuse, storage, and export/import/transfer. Two reviews were conducted as part of this project. The first involved a multi-level search to identify publicly available national research ethics guidance on the collection and use of HBS in countries in Sub-Saharan Africa. This process, detailed in Table 1, involved keyword searches, on-line reviews of international ethics databases and regional and national government websites, and, in those instances where on-line efforts yielded no results, direct contact via email with national ethics committees and scans of ethics review statements included in previously published journal. National ethics guidance was operationalized to include enabling legislation for the creation and constitutions of national research institutes and national research ethics committees, codes of ethics, national ethics guidelines, and standard operating procedures. We excluded those documents that only provided instructions to researchers on how to submit their protocols, instruction on writing consent documents, and organizational information from research ethics committees that were not identified as being national in jurisdiction. Materials Transfer Agreements (MTA) and Specimen Transfer Agreements (STA) for specific countries were included in our search but were only used as a source of guidance if we could find a specific reference to “human” biological specimens. We limited our results to those national documents that we could access publicly on-line or secure through contact with the national regulatory body, reasoning that guidelines that were inaccessible via such mechanisms would be of limited utility to the research community.

Table 1 Search strategy and selection criteria

A second review was conducted using the WHO International Clinical Trials Registry Platform (ICTRP) to identify registered clinical trials taking place in Sub-Saharan Africa as of January 1, 2015, and, of these, the number of clinical trials in each country that called for the collection of HBS as part of the study protocol [18]. The ICTRP is a web-based, publicly accessible compilation of studies that have been registered in any of the following databases: Australian New Zealand Clinical Trials Registry (ANZCTR); Chinese Clinical Trial Registry (ChiCTR); ClinicalTrials.gov; EU Clinical Trials Register (EU-CTR); ISRCTN; The Netherlands National Trial Register (NTR); Brazilian Clinical Trials Registry (ReBec); Clinical Trials Registry – India (CTRI); Clinical Research Information Service - Republic of Korea (CRiS); Cuban Public Registry of Clinical Trials (RPCEC); German Clinical Trials Register (DRKS); Iranian Registry of Clinical Trials (IRCT); Japan Primary Registries Network (JPRN); Pan African Clinical Trial Registry (PACTR); Sri Lanka Clinical Trials Registry (SLCTR); and Thai Clinical Trials Register (TCTR). Included in the count of active clinical trials were those trials listed in the database as active/not recruiting; recruiting; not yet recruiting; authorized-recruitment/may be ongoing or finished; and pending. Studies were excluded if identified as not recruiting; complete; terminated; closed/follow-up continuing; closed to recruitment/follow-up complete; temporary halt or suspension; other; not applicable; or withdrawn. The process used to identify active trials calling for HBS collection is illustrated in Fig. 1.

Fig. 1

Research process for identifying active clinical trials in SSA involving HBS collection (Source: WHO-ICTRP as of January 1, 2015)

Results

Table 2 summarizes the availability of national ethics guidance irrespective of content as well as guidance language specific to HBS in each of the 49 countries included in the WHO region constituting Sub-Saharan Africa. Detailed information on the specific content of any HBS-related language is provided in Table 3. Twenty-nine (60 %) of the countries in the region had some national ethics guidance, either in the form of laws, regulations, codes, guidelines, or standard operating procedures. Of these 29 countries, however, twelve did not have regulations that addressed specific guiding principles or rules for ethics research or review. Six (Congo DRC, Equatorial Guinea, Republic of Guinea, Lesotho, Madagascar, and Mali) had regulatory language that was limited to establishing or defining the functions and constitution of research ethics committees. One (Mauritius) had drafted a code of research ethics that was distributed for public comment in 2003, but no documentation could be found that it had been operationalized. Three countries (Cameroon, Mozambique, Rwanda) offered limited language specific to guiding principles or ethical conduct of research, but link their review processes to the ethical guidance contained in the Declaration of Helsinki, CIOMS, or the ICH-GCP [19–21]. No national guidelines for general ethical conduct of research could be found for The Gambia, but the Medical Research Council – The Gambia had published very detailed guidelines for the collection and use of biospecimens stored in the National DNA Bank of The Gambia which we have included in our analysis [22]. In addition, two countries (Chadand Gabon) had been working with UNESCO on the establishment of national ethics committees but no regulatory documentation could be found [23, 24].

Table 2 SSA countries with HBS-related information in legislative/regulatory/guidance ethics documents

Table 3 National regulatory guidance language on collection and use of HBS by country*

More than one half (59 %) of the countries whose guidelines articulated ethical principles or guidelines for ethical review include some language to guide the collection and use of HBS for biomedical research. Fourteen of these offered some language with respect to informed consent; 10 addressed the subject of reuse; and 12 contained specific language relating to export/import/transfer. Only six countries offered language with respect to HBS ownership and nine contained language regarding storage. Thirteen required that a Materials or Specimens Transfer Agreement be executed. Table 4 reports the findings with respect to registered, active clinical trials in Sub-Saharan Africa that called for the collection of HBS. Of the 5319 studies identified in the WHO International Clinical Trials Registry Platform, 1802 of were currently active as of January 1, 2015. Three hundred sixty-six (366) of these involved the collection of a biosample from research subjects. The distribution of these trials across the region are illustrated in Fig. 2.

Table 4 Clinical trials in SSA involving HBS collection (Source: WHO-ICTRP as of January 1, 2015)

Fig. 2

Distribution of active clinical trials in SSA involving HBS collection (Trial information Source: WHO-ICTRP as of January 1, 2015; Map source: Wikimedia Commons)

Table 5 reports on the ethics system guidance on HBS found in the countries where the largest number of studies involving HBS are currently taking place in Sub-Saharan Africa. These 10 countries account for nearly 82 % of the active clinical trials involving the collection of HBS in the region that were registered in the WHO International Clinical Trials Registry Platform as of January 1, 2015. They included the five countries that either have existing biorepositories (The Gambia, South Africa and Zimbabwe) or planned to establish regional biorepositories in the near future as part of the H3Africa Initiative (Nigeria, South Africa and Uganda). All ten of these countries had some form of ethics system guidance in the form of regulations, codes of ethics, standard operating procedures, or guidelines, and, with the exception of Mali, provided some regulatory language at the national level as to the collection and use of HBS. Notably only four of these countries (The Gambia, Kenya, Uganda, and Zambia) included language in their national ethics documents on the ownership of HBS. Mali, where at the time of our study there were currently 10 registered active trials requiring a biosample, had no guidance language on HBS in its national ethics documents. Although most of the countries in which large biorepositories existed or are planned as part of H3-Africa contain fairly detailed HBS language in their guidelines, only two (The Gambia and Uganda) spoke to issues of ownership. After Mali, Zimbabwe offered the least guidance within this group of countries, with no language on HBS-specific consent, ownership, or reuse.

Table 5 National ethics guidance on 10 countries host to the most registered clinical trials

Discussion

This study examined the availability of national ethics and regulatory guidance on biomedical research in Sub-Saharan African countries and identified the extent to which national regulatory systems provided ethics guidance on specific aspects of HBS collection and use to inform research design and ethics review. Ethical principles and regulatory guidance regarding HBS consent, ownership, reuse, storage, and export/import/transfer are foundational elements in national health systems as research activities calling for the collection and use of biospecimens in Africa expand and ethics committees are increasingly called on to review and respond to rapidly advancing innovation in research and research technologies.

Our research found that despite efforts at the international, regional, and national levels, 20 of the countries in Sub-Saharan Africa (41 %) at the time of our study still lacked articulated national ethical principles and regulatory guidance for policy-making, review, and monitoring of research. Among those countries where ethical and regulatory guidance existed, specific language with respect to HBS collection and use was often lacking or incomplete. While in 17 of the countries in Sub-Saharan Africa (59 %), some form of national regulatory guidance relating to HBS did exist, a number of these lacked explicit guidance on HBS-related issues such as consent (3), ownership (11), reuse (7), storage (8), and export/import/transfer (5).

Gaps in national ethical and regulatory guidance in the region on the collection and use of HBS for research may result in inconsistent reviews within ethics committees and pose challenges for full participation by African countries in genomic research. In the absence of guiding principles and regulatory direction, ethics committees may delay or deny HBS-related research of potential benefit to their communities, or they may approve such research without due exploration of its implications for its citizenry or its cultural values.

Differences in ethical and regulatory requirements among African countries where guidance does exist also appear to raise impediments to the interoperable pan-African approach to genomic research espoused by H3Africa. Despite the fact that the bulk of registered clinical trials involving HBS in Sub-Saharan Africa, as well as existing sites and those sites proposed for future biorepositories, are currently situated in countries with the most complete ethics and regulatory guidance on HBS, variability in the regulations themselves may create challenges for pan-African collaborations that rely on transnational sharing of specimens and data or that delegate decision-making responsibility with respect to future use to repository-centric ethics or scientific review committees. Malawi, for example, contained language in its guidelines that all forms of studies and testing aimed at collecting and storing HBS for future unspecified genetic research/analysis is ‘non-permissible’ [25]. Tanzania required that a new consent be secured for each new research protocol in which a sample will be reused [26]. Uganda, where one of the H3Africa repositories is intended to be located, required that all requests for transfers of HBS be made by a legal resident of Uganda who was affiliated with a locally registered and recognized Ugandan organization [27].

While these and other potential sources of regulatory tension may be resolved in the future, for now they represent potential constraints on research that calls for a more ‘regional’ perspective of specimen and data sharing, and are likely to require legislative action at the national level to revise. At the same time, gaps in HBS-related guidance within countries that are already research-intensive sites may give rise to lengthy or inconsistent review decisions by local ethics committees left to make their own policy decisions in the absence of clearly stated regulations or principles at the national level.

Future growth in the fields of pharmacogenetics and genomic research is likely to generate demand for HBS from a more representative pool of the African peoples and to prompt researchers to look for new communities in countries where research is currently not active. The transnational movements of diseases themselves, as seen in the 2014 Ebola outbreak in Western Africa, may identify new target populations for study beyond those of interest at present. Such expansion will require system-wide capacity-building in these settings and will need to be guided by clearly articulated national regulatory guidance to ensure ethical and thoughtful research governance.

Resources to assist national governments in developing ethics capacity may be available through such programs as UNESCO’s Assisting Bioethics Committees (ABC) program, which aims to build and strengthen bioethics infrastructure within its member states and which is already working to build capacity in Chad, Gabon, and Madagascar [23, 24, 28]. H3Africa’s working group on ethics and regulatory issues and its work to date in articulating broad principles and regulatory guidance regarding HBS collection and use [6] would, were its focus to extend beyond its own funded research networks and programs, be a valuable starting point for countries as they begin to build national consensus on the value of genomics research for their communities and the region as a whole.

Limitations of this study

Data used in this study were largely derived from publicly accessible sources. Despite an extensive search, some of the countries in Sub-Saharan Africa that we report as lacking national ethics regulatory guidelines may, in fact, have them. Given the central role that national policies play in shaping the research landscape in the region, it is important that researchers and ethics committees have ready access to country-level guidance on the collection and use of HBS as the scope of genomics research in Sub-Saharan Africa expands. In addition, the mapping of active clinical trials that involve HBS in Sub-Saharan Africa relied on publicly accessible international registries. It therefore did not take into account those studies which are not required to register, and serves more as an illustration of a potential regulatory ‘gap’ between research and national governance than as a comprehensive source of data on HBS-related research in the region.

Conclusion

Despite substantial capacity-building efforts, many countries still lack regulatory guidance on the collection and use of human biological specimens in research. Although the African countries currently most in demand as HBS-related clinical research sites number among those offering the most guidance, extensive health system strengthening will be needed to ensure that regulatory language is available to guide the ethical extension of HBS-related research into other countries in the region. Efforts to create interoperability across national policies to meet international and regional research goals of Pan-African research collaboration must be on-going, recognizing that some differences may be value-based choices by representative governments while others, although malleable to change, will require legislative action to amend.