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Including African data in drug discovery and development

Clinton G.L. Veale, Adrienne L. Edkins, Susan Winks, Mathew Njoroge & Kelly Chibale


The low number of clinical trials in Africa and biomedical datasets that disproportionately represent populations of European ancestry contribute to the suboptimal efficacy and safety of some medicines in African populations. To address these disparities, we propose greater incorporation of African data into drug discovery and development, as well as the development of African-centric preclinical and clinical models and tools.


Introduction

Large biomedical databases house priceless patient-derived information, which, when combined with sophisticated analysis techniques such as machine learning, provide key insights into disease causes and progression, genetic variation in populations and drug target identification. This integrated information is supporting the emergence of precision medicine, and, when combined with advances such as organs-on-chips, could improve preclinical screening models and thereby enhance the speed and effectiveness of drug research and development (R&D).


Unfortunately, African populations are less likely to benefit from these advances because they are largely absent from biomedical research. Reasons include the small proportion of clinical trials conducted on the African continent - currently only 3.7% of global trials - and the predominance of individuals with European ancestry in datasets 1. The lack of data from African populations in drug R&D may result in medicines that are less effective and/or safe in African populations compared with populations that are better represented during drug development 2.


Efforts to address this using the limited but growing data sets on African populations have focused on the pharmacogenomics of drug-metabolizing enzymes and transporters. Collectives such as the African Pharmacogenomics Consortium have revealed substantial diversity in genetic variants linked to drug responses even between African population groups 2,3. So far, such research has identified opportunities to ‘retro-optimize’ the use of marketed drugs that show toxicity and/or low efficacy in individuals with particular genetic variants 3, but use during drug R&D has not been a focus. In this article, we highlight the importance of collecting clinical trial and genetic data from African populations and discuss opportunities to harness this data to inform drug R&D.


Increasing African population participation in clinical trials

Data from clinical trials not only establishes the effectiveness and safety of drugs in patients; it also provides insights into variations in drug effects in population groups, facilitating the development of modelling tools for dosing and pharmacokinetics that support treatment optimization. It is well established that involving relevant population groups in drug development improves treatment outcomes for that population. The low participation of African populations in clinical trials restricts the applicability of such data and meta-data in drug R&D.


Historically, Africa has not been an attractive location for major funders of clinical trials. The reasons for this are varied, but long timelines and unpredictable regulatory and ethics approvals are two major contributing factors. In addition, each of Africa’s 54 countries represents a regulatory jurisdiction and a separate health-care market. Efforts to overcome this through collaboration among African sites are gradually growing, starting with the African Medicines Regulatory Harmonization (AMRH) programme, the African Vaccine Regulatory Forum (AVAREF) and, more recently, the African Medicines Agency (AMA). There is a need for further standardization and mutual recognition, aligned to universally acclaimed certification, to help overcome the bureaucratic burden. Importantly, increasing clinical development capacity and strengthening and harmonizing the regulatory environment are synergistic; progress in one will encourage development in the other.


Efforts are ongoing to establish regional hubs focused on clinical trials to enable increased collaboration, visibility and capacity strengthening. For example, the Clinical Trials Community (CTC) maps out and connects the African clinical trial community, and the Pandemic Preparedness Platform for Health and Emerging Infections Response (PANTHER) aims to have clinical trial frameworks in place before a disease outbreak, with the remaining work focused on adapting trials to local contexts and disease characteristics. However, there is an urgent need for an African clinical trials forum to articulate the unique opportunities in the continent and its key role in the global R&D ecosystem.


Now is an opportune time for locations in Africa to become more popular for clinical trials. There are several factors driving this, including the recent FDA draft guidance pushing for an increase in racial and ethnic diversity in clinical trials; the large number of patients (including treatment-naive patients), which may facilitate rapid recruitment; the unique and diverse genetics of patients; and the lower costs compared to countries in the Global North once clinical trial sites are established.


Collecting African genomic data that can inform drug R&D

A recent genomic survey of 426 individuals, from 50 ethnic groups in 15 African countries, identified - 3 million previously undescribed genetic variants, highlighting the extraordinary genetic diversity in Africa 4. Such genetic variants might have various effects relevant to drug R&D, including effects on disease-associated proteins and pathways, on drug absorption, distribution, metabolism, excretion and toxicity (ADMET), and on the responses to drugs that modulate particular targets.


For example, studies of cytochrome P450 enzymes (CYPs) have revealed functional variants that are more common in some African populations, such as CYP2B6*6, an allele of CYP2B6 with reduced function that occurs at higher frequencies in African populations 3. Patients with this allele are at higher risk of dose-related adverse effects from drugs metabolized by this enzyme, such as efavirenz. Polymorphisms in the same enzyme with unknown functional relevance that have not been observed beyond African populations have also been identified 3.


In addition, the high genetic diversity and relatively low intermixing with non-African populations may make genetic variants associated with disease easier to find in African populations. This unexplored genetic information could include variants with previously unappreciated therapeutic relevance, which could lead to identification of new drug targets.


So, although understanding of the therapeutic relevance of genetic variation in African populations is currently limited, it could have a crucial role in both optimizing the use of existing drugs in patients from African populations and in developing future drugs that are safer and/or more effective in these patients. The Human Heredity and Health in Africa (H3Africa) consortium and the Three Million African Genomes (3MAG) projectare aiming to drastically increase the representation of Africans in large biomedical datasets, which could offer insights into African disease and support the growth of translational medicine on the continent 5. This calls for the establishment of a robust translational medicine network in Africa to realize the potential value of its rich genomic diversity. For example, this could enable African researchers to initiate longitudinal real-world data studies to understand the role of the genomic diversity of African populations in disease progression and drug response.


Harnessing African data and African-centric drug discovery

Optimizing the use of available drugs in African populations is vital for improving therapeutic outcomes in the near term. Achieving this goal requires the expansion of pharmacogenomics capacity in the continent, bridging clinical trials to identify clinically relevant phenotypes in African populations, and support for the translation and implementation of African pharmacogenomics knowledge into routine medical use.


However, while the pharmacogenomics-based retro-optimization of the use of existing drugs in African populations recognizes the biases in biomedical data, it does not address the underlying issue—that data relevant to African populations need to be incorporated across the R&D process. To that end, drug discovery and development programmes should incorporate regionally relevant genetic and clinical trial data that reflect population-level genetic variations. For example, in the context of drug metabolism, it would be valuable to derive in vitro systems from African donors, selected to represent widespread Africa- specific genotypes. This would help identify and address potential sources of ADMET variability, and design ethnobridging strategies for drugs for which clinical development was conducted in other populations. In the broader drug discovery context, this would also need to include developing models based on cells derived from African populations, and the development of virtual African populations in pharmacometric approaches. ln addition, for infectious diseases and cancer, when selective pressures could have a strong influence on genetic variants of potential drug targets, target sequences from relevant African populations should be used in the earliest stages of drug discovery.


In addition, clinical trials need to be designed with insights from African real-world data that capture the comorbidities of infectious and non-communicable diseases in African patients, in order to improve understanding of the impact of drug-drug interactions on efficacy and safety. From such knowledge, African-centric drug discovery hypotheses around targeting disease could be derived. Frontloading African centricity into common drug discovery tools could be key to addressing inherent variability and optimizing and selecting preclinical candidates that could be more suitable for clinical trials in African populations.


Outlook

Through ongoing advances in biomedical sciences and big-data analysis, it is hoped that drug discovery tools will become more representative of human physiology and disease biology and increase the likelihood of successful translation into the clinic. However, without suitable African biomedical data to feed into them, the potential of these tools to improve the suitability of drugs for African patient populations will be undermined.


The United Nations projects that by 2050 nearly 25% of the world’s population will live in Africa, increasing the medical need and the market for drugs that are optimized for patients in these countries, as well as their diaspora. Given the continuing impact on health outcomes and economic losses due to medicines with suboptimal safety and efficacy, in addition to providing authentic, high-quality medicines, it is now prudent to revisit approaches to drug discovery and development in the spirit of health equity. Greater emphasis on improving the participation of Africans in clinical trials, increasing the representation of data derived from Africans in global data sets, and developing African-centric models and tools for early drug discovery and clinical development are required to allow African patients to derive maximum benefit from modern drug discovery and development. COVID-19 has emphasized the need to bolster Africa’s local innovative R&D and manufacturing capacity, as well as the need to strengthen and harmonize regulatory systems on the continent. Although it will not replace national medicine regulatory authorities, establishment of the AMA will increase harmonization of standards, reduce duplication and improve the efficiency of regulatory processes in African countries. For African-centric drug discovery to blossom, increased effort, and investment by African governments to support R&D, eschewing nationalism, is needed to facilitate collection and sharing of biomedical data from African populations, and development of expertise in harnessing it for the benefit of patients in the continent and beyond.


Clinton G. L. Veale 1, Adrienne L. Edkins 2, Susan Winks 3, Mathew Njoroge 3 &

Kelly Chibale 1,3,4

1 Department of Chemistry, University of Cape Town, Rondebosch, South Africa.

2 The Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry and Microbiology, Rhodes University, Makhanda, South Africa.

3 Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa.

4 South African Medical Research Council Drug Discovery and Development Research Unit and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa.



References

1. Sirugo, G., Williams, S. M. & Tishkoff, S. A. The missing diversity in human genetic studies.

Cell 177, 26-31 (2019).

2. Dandara, C. et al. African Pharmacogenomics Consortium: Consolidating pharmacogenomics knowledge, capacity development and translation in Africa. AAS Open Res. 2, 19 (2019).

3. Rajman, I., Knapp, L., Morgan,T. & Masimirembwa, C. African genetic diversity: implications for cytochrome P450-mediated drug metabolism and drug development. EBioMedicine 17, 67-74 (2017).

4. Choudhury, A. et al. High-depth African genomes inform human migration and health. Nature 586, 741—748 (2020).

5. Winks, S., Woodland, J. G., Pillai, G. ‘Colin’ & Chibale, K. Fostering drug discovery and development in Africa. Nat. Med. 28, 1523—1526 (2022).


Acknowledgements

The authors gratefully acknowledge the contributions of Colin Pillai and David Mukanga (CTC), Nicola Mulder (H3Africa), Bernhards Ogutu (PANTHER), Collet Dandara and Collen Masimirembwa (African Pharmacogenomics Consortium), who provided valuable feedback during the preparation of this article. K.C. is the Neville Isdell Chair in African-centric Drug Discovery and Development and thanks Neville Isdell for generously funding the Chair.


Competing interests

The authors declare no competing interests.


This article was featured in Nature Reviews Drug Discovery.


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