Abstract
Background
To improve the supply of health care and health care products, traditional herbal medicines that are safe, effective, and of good quality need marketing authorizations. This study aims to determine the contribution of ethnomedical evidence to the marketing of traditional herbal medicines in Mali.
Methods
This was a descriptive cross-sectional study conducted from December 2023 to March 2024 supplemented by a literature review of the legislative and regulatory provisions relating to traditional medicine and the requirements for marketing authorization of traditional herbal medicines in Mali and the West African sub-region.
Results
The regulatory framework for marketing authorization is governed by decree no. 04-557/P-RM of 01 December 2004 and interministerial order no. 05-2203/MS-MEP-SG of 20 September 2005 in Mali. These texts set out the specific requirements for the marketing authorization of traditional plant-based medicines, depending on the category. They consider ethnomedical evidence drawn from long experience of traditional use as proof of efficacy and tolerance for category 2 traditional medicines. As a result, marketing authorizations were issued for 15 products derived from traditional medicine and pharmacopeia, 5 of which are included in the National List of Essential Medicines and the National Therapeutic Formulary of Mali.
Conclusion
The use of ethnomedical evidence provides a good opportunity to obtain marketing authorization for phytomedicines derived from traditional medicine without having to go through long and costly non-clinical and clinical studies.
Introduction
Equitable access to health care remains a challenge in many African countries. 1 In 1978 the Alma-Ata Declaration recommended integrating traditional remedies, which efficacy has been established, into national pharmaceutical policies and appropriate regulatory measures. 2 In addition, traditional medicine (TM) could make a significant contribution to achieving universal health coverage in Africa, where around 80% of the population still uses traditional herbal medicines (THMs).3,4
According to the World Health Organization (WHO), TM is effective in several areas, including mental health, disease prevention, treating non-communicable diseases, and improving the quality of life of people with chronic diseases and the aging population. 5 Notwithstanding this recognition of TM, THMs present potential risks (inherent toxicity of herbs, contamination, adulteration, interactions with other products, etc.) commensurate with their growing use worldwide.6-8 Also, THMs are not regulated as widely as conventional medicines and there are limited clinical trials to determine their efficacy and safety. 9
Clinical trials are the last step in the drug discovery and development pathway. 10 However, other research and validation methods applicable to TM are possible and could enable them to be widely disseminated. One alternative is ethnomedical studies, which look at illness and health across different cultures, and the use specific methods to treat disease and achieve cure. 11
In Mali, research into THMs is carried out under the aegis of the National Research Institute for Traditional Medicine and Pharmacopoeia (NRITMP), the former Department of Traditional Medicine (DTM).12,13 This structure works closely with TM practitioners to conduct research into the development of THMs, commonly known as improved traditional medicines, for the treatment of the most common pathologies. 14 Based on national regulatory texts,15,16 some of these products have already been granted marketing authorization in Mali and are included on the National List of Essential Medicines (NLEM). 17
National regulations distinguish 4 categories of THMs
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: − − − −
According to the same regulations, traditional medicines of categories 2, 3, and 4 must undergo prior marketing authorization before marketing. Only category 2 medicines may be authorized without clinical trials but based on ethnomedical evidence of long experience of use of the medicine in an updated or traditional form.15,18 Ethnomedical evidence is the sum of information presented based on a retrospective study to provide the scientific basis for the practice of traditional African medicine or the use of a herbal remedy. 19 In practice, the collaboration between a TM practitioner and a health care professional is necessary to establish it, as close monitoring of the treatment of at least 30 patients per disease over 4 months is required. This follow-up is sanctioned by a report containing, among other things, information on the cases treated (patients, reasons for consultation, adverse effects, etc.), the percentage of successful treatment, and the reasoned decision confirming or not the competence of the traditional health practitioner.20-22
Good use of ethnomedical evidence should make obtaining marketing authorizations for THMs easier, preventing long, tedious, and costly conventional clinical trials. It is in this context that the present study was initiated with the general objective of determining the real contribution of ethnomedical evidence to the THMs marketing authorization process in Mali. More specifically, the aim was to (i) describe the methodology of THMs research and development at NRITMP, (ii) analyze the national regulatory requirements applicable to THMs marketing authorization, and (iii) determine the proportion of category 2 THMs that have obtained marketing authorization using ethnomedical evidence, and the difficulties associated with marketing authorization.
Materials and methods
Study Framework
The study was carried out at the NRITMP (formerly DTM) and the Pharmacy and Medicines Directorate in Bamako (Mali) on the one hand and on the other at the Drug Development Laboratory of the Sciences and Health Doctoral School of Joseph KI-ZERBO University in Ouagadougou (Burkina Faso).
Type and Period of Study
This was a descriptive cross-sectional study, supplemented by a literature review, which took place from December 2023 to March 2024.
Study Population
The participating structures were the NRITMP and the Pharmacy and Medicines Directorate in Mali. They were included on a purposive basis, on the assumption that they were involved in THMs research and the regulation of marketing authorization for these products. Within the structures, the participants were the person in charge of the THMs research process at NRITMP and the staff in charge of marketing authorization application files (including the head of the homologation section and 3 of her collaborators) at the Pharmacy and Medicines Directorate.
Study Materials
The study material consisted of: − legislative, regulatory, and administrative texts relating to THMs − technical notes and reports on the ethnomedical evaluation process − technical files on marketing authorization applications for registered THMs − minutes of the sessions of the National Commission for Medicinal Product Marketing authorizations − regulatory texts governing THMs marketing authorizations in Mali and the West African sub-region − theses on developing traditional medicine resources and THMs registered or applying for marketing authorization.
Data Collection Techniques and Tools
Using qualitative methods, data were collected in 2 ways: − The document review focused on the legislative and regulatory provisions relating to traditional medicine and the requirements for marketing authorization for THMs in Mali and the sub-region. These provisions were collected directly with the national participants and on the institutional websites of the West African sub-regional regulatory authorities. − Semi-structured face-to-face interviews using cross-sectional survey questionnaires were conducted with the main players involved in the THMs research process at NRITMP and the evaluation of THMs marketing authorization applications submitted to the Malian Directorate of Pharmacy and Medicines.
The survey questionnaire administered to NRITMP was structured in 4 parts: (i) the methodological approach used for THMs research, (ii) essential data for THMs marketing authorization and applicable regulatory requirements, (iii) main constraints (including regulatory) for marketing authorization, and (iv) proposals for optimal adaptation of marketing authorization legislative and regulatory provisions to THMs. For the Directorate of Pharmacy and Medicines, it mainly concerned: (i) the current legislative and regulatory provisions covering THMs marketing authorization, (ii) the essential data for THMs marketing authorization and the regulatory requirements applicable to THMs marketing authorization, and finally (iii) the main constraints (including regulatory) which limit THMs marketing authorization in Mali compared with conventional medicines (see ././fullquestionnaire.docx).
Data Analysis
For the literature review, the national and sub-regional legislative and regulatory provisions identified were analyzed using a comparison table in Microsoft Excel 2016 software. This made it possible to highlight all the requirements for THMs marketing authorization in terms of the applicable regulatory framework, the categories of THMs eligible for marketing authorization, the types of dossiers required, registration fees, and so on.
As for the other qualitative data from the participant interviews (completed questionnaires and written notes), these were analyzed using a content analysis approach (thematic). 23 Thus, the first step was familiarization with the data collected, followed by coding. The second was the identification and grouping of similar themes in the responses in order to develop the analysis grid using Microsoft Excel 2016 software. The final step was the synthetic analysis of the data in line with the study objectives.
Ethical Considerations
The study was conducted following the ethical principles of the Declaration of Helsinki. All participants were informed about the study and gave their written consent. The study protocol was also approved by the Ethics Committee of the University of Sciences, Techniques and Technologies of Bamako under no. 2020/275/CE of 07 December 2020 and the National Ethics Committee for Health Research of Burkina Faso under no. 2023-07-186 of 11 July 2023. The confidentiality of personal data and the anonymity of respondents were guaranteed during this study.
Results
Methodological Approach to Research and Development of THMs at the NRITMP
Research at the NRITMP begins with ethnobotanical surveys to select plants and traditional recipes for a targeted disease. This is followed by a literature search to gather all the relevant information on the plants selected. The plant material is then harvested and prepared to facilitate the next phases. These phases include pharmaceutical studies (quality control of raw materials, preparation of extracts, characterization of chemical constituents) and pre-clinical studies (determination of the toxicity and activity of extracts). The results will be used to produce plant monographs and compile the technical dossiers required for marketing authorization applications.
Based on preclinical studies of safety, efficacy, and quality, formulations are then proposed. Given the complexity, duration, and high cost of clinical trials, most of these formulations are category 2 THMs for which there is sufficient ethnomedical evidence for marketing authorization. Thereafter, experimental production for use by patients in general and those undergoing consultation in the medical departments of the NRITMP. This experimental production therefore concerns both registered THMs and new products whose technical files for marketing authorization applications have been finalized.
The Regulatory Framework Governing Marketing Authorization for THMs in Mali
In Mali, the regulatory framework governing marketing authorization for medicinal products for human and veterinary use consists of: − Decree no. 04-557/P-RM of 01 December 2004 instituting marketing authorization for medicines for human and veterinary use: this defines a medicine derived from traditional pharmacopeia as being “any medicine developed by a traditional practitioner or researcher using knowledge or information derived from traditional pharmacopeia”. − Interministerial Order no. 05-2203/MS-MEP-SG of 20 September 2005 determining the procedures for applying for marketing authorizations for medicinal products for human and veterinary use: articles 10 and 11 of Interministerial Order no. 05-2203/MS-MEP-SG respectively specify the different categories of THMs and the dossiers required for each category. In addition to the administrative documents (marketing authorization application, deed of creation of the production structure, partnership agreement between producer and research institute for categories 3 and 4), the technical documents to be submitted are grouped into pharmaceutical, pharmaco-toxicological and clinical dossiers (Table 1). The pharmaceutical dossier includes an analytical report including quality control of raw materials and finished products, as well as stability tests on the finished product, which are required for category 2, 3, and 4 THMs. Pharmacological, toxicological, and clinical data may be replaced by ethnomedical evidence for category 2 THMs only. Technical dossiers must also be submitted in the Common Technical Document (CTD) format following regional requirements
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and national procedures for the registration of medicinal products for human use.
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− Order no 95-1319 /Mss-Pa/Sg of 22 June 1995 laying down the rules for the organization and operation of private traditional consultation and care practices, herbalist shops, and production units for improved traditional medicines
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: Article 30 of this Order stipulates that “the manufacture and marketing of category 2 and higher THMs are subject to obtaining a visa…”. Other articles of this Order specify the documents to be supplied and their characteristics. Essential Data to be Provided in Marketing Authorization Applications for Categories 2, 3, and 4 Traditional Medicines.
THMs That Have Obtained Marketing Authorization Using Ethnomedical Evidence and the Difficulties Involved in Obtaining Marketing Authorization
Category 2 THMs Manufactured in Mali With Marketing Authorizations and Obtained based on Ethnomedical Evidence.
During the interviews, two participants noted in particular the difficulties involved in obtaining marketing authorizations for THMs. Thus, the participant from NRITMP reported “the failure of the regulatory body to apply the texts effectively...” and “...the absence of specific sessions of the national marketing authorization commission dedicated to THMs”. At the Pharmacy and Medicines Directorate, one of the participants spoke of “the lack of collaboration between traditional health practitioners and research institutions, including NRITMP... many traditional health practitioners come directly to the regulatory authority in the hope of obtaining a marketing authorization...”.
Discussion
The main objective of this study was to determine the real contribution of ethnomedical evidence to the THMs marketing authorization process. Our results show that the THMs registered in Mali are largely the result of NRITMP research and have benefited from specific regulations and the contribution of ethnomedical evidence.
NRITMP carries out THMs research and development activities, particularly the preparation of marketing authorization dossiers. The content of these dossiers is similar to that of the African Intellectual Property Organization (AIPO) directive 27 which was the subject of Bony’s dissertation in Ivory Coast on the draft registration dossier for herbal medicines derived from the African Pharmacopoeia. 28 This is a light dossier, as recommended by the WHO, for the assessment of herbal medicinal products in herbal tea form, considering their long history of use by the public. 2 NRITMP’s research activities also include conducting clinical trials in collaboration with specialized hospital departments on certain THMs. These trials have involved GASTROSEDAL, which has already been registered, and products not yet registered, particularly CALMOGASTRYL, which was proposed for the treatment of peptic ulcer disease in 1989,29,30 SAMANERE for the treatment of Hepatitis B in 1992, 31 PSOROSPERMINE ointment for the treatment of eczema in 1993 32 and SOUMAFOURA TIEMOGO BENGALY for the treatment of uncomplicated malaria in 2006. 33
The regulations governing marketing authorization are based on a decree and two specific orders. These texts define THMs and specify the categories eligible for marketing authorization, as well as the files to be submitted. Among these documents is an expert report attesting to long experience of use of the drug in its current or traditional form (at least 20 years). 15 This provision is thus applied to category 2 THMs, and in particular to those resulting from NRITMP research, which do not require clinical trials according to WHO recommendations. 1 But unlike in Mali, the long experience of use was still not taken into account in the regulation of THMs marketing authorization in Zimbabwe, in 2021 34 despite WHO recommendations.
In addition, the regulatory system for marketing authorization of medicinal products has evolved16,26,35 to take account of the technical requirements relating to the safety and quality of pharmaceutical products in general and THMs in particular. 15 This situation is in line with De Smet study, which recommends the introduction of a special system for granting marketing authorization for phytomedicines, with an obligation for operators to report suspected adverse reactions. 36 In Mali, this special regime for the marketing authorization of THMs is included in the general regulatory provisions for medicines for human and veterinary use. However, specific regulations also define the conditions for marketing traditional medicines in certain countries of the West African Economic and Monetary Union (WAEMU), including Benin, Burkina Faso and Niger.37-39 They specify, among other things, the categories of medicines derived from traditional pharmacopeia, the categories eligible for marketing authorization, the types of dossiers required, the information to be included in the marketing authorization application, and the registration and renewal fees. In Ivory Coast, it is only noted no. 0972/AIRP of 26 May 2023 from the Ivorian Pharmaceutical Regulatory Authority that sets out the procedures for registering products derived from traditional pharmacopeia in terms of the types of required (administrative and technical) files with the constituent elements for categories 2 to 4 and the related fees. 40 These national regulations, inspired by the various harmonization initiatives aimed at marking out the registration of THMs, have been promoted at the level of the African continent and the West African sub-region by the WHO and African sub-regional organizations. These include the 2010 WHO guidelines for the registration of traditional medicines in the African region, the 2003 reference framework for the harmonization of registration procedures for medicines derived from traditional pharmacopeia in AIPO member countries, which is the result of the initiative for the protection and promotion of African inventions in the field of medicines (endorsed by the countries), the 2013 West African Health Organization (WAHO) guidelines for the registration of traditional medicines, etc.1,27,41,42 In addition, WAEMU Community Regulation No. 04/2020/CM, which applies to all pharmaceutical products, is mandatory and immediately applicable to member countries. 43
Based on ethnomedical evidence, only 15 category 2 THMs manufactured in Mali have obtained marketing authorizations issued by the Malian health authorities. Of these, 7 currently have a valid marketing authorization and 5 are registered on the NLEM and included in the national therapeutic formulary 17 for the treatment of common pathologies. Application of the WHO recommendations have therefore led to an increase in the number of marketing authorizations issued in Mali for category 2 THMs produced in Mali or other WAEMU countries such as Burkina Faso (n = 4) and Ivory Coast (n = 1). 44 It also led to the issue of 3 marketing authorizations for products from the WAEMU region in Niger 45 and an increase in the number of category 2 THMs marketing authorizations issued in Burkina Faso, rising from six in 2020 46 to 12, including 11 produced by national industries and one from the WAEMU region in 2024. 47 Unlike the WAEMU countries, where the marketing authorization process for herbal products is well advanced, a recent study carried out in Ethiopia showed that no THMs had yet been registered, due to the absence of a favorable regulatory framework. 48 On the other hand, despite ethnomedical evidence being considered in Mali and the slimmed-down dossier recommended by the WHO as proof of safety and efficacy in the marketing authorization dossier, the number of categories 2 THMs with valid marketing authorization remains low. The same applies to Brazil, where a study revealed a low number of authorized herbal medicinal products in 2021. 49 In the case of Mali, the absence of new dossiers for locally manufactured THMs submitted to the Directorate of Pharmacy and Medicines for marketing authorization since 2016 could explain this situation. Another cause is the direct consequence of the non-validity of the marketing authorizations of the 8 category 2 THMs previously registered by NRITMP due to the absence of additional studies to support the marketing authorizations over the years according to the NRITMP participant. This situation would nevertheless be detrimental to achieving the general objective of the national pharmaceutical policy, which is to guarantee equitable access to quality essential medicines for the population, as well as to the development of industrial production of THMs. 50 From a regulatory point of view, the validity of the marketing authorization is limited to 5 renewable years, and failure to market an authorized product within 2 years of the marketing authorization could result in its withdrawal from the market.16,25 As a result, new applications will have to be submitted by NRITMP for the re-use of products with invalid marketing authorizations.
Regarding the difficulties encountered in obtaining marketing authorizations for THMs, the failure of the regulatory body to apply the texts effectively, the absence of specific sessions of the national marketing authorization commission dedicated to THMs and the lack of collaboration between traditional health practitioners and research institutions were cited. Collaboration between traditional healers and research institutions is essential to generate the additional safety, efficacy, and quality data required to obtain marketing authorizations under the regulatory framework. 15 As for the absence of specific sessions for THMs, this is partially taken into account by the regulations through ad hoc expert appraisals carried out following general sessions of the national marketing authorization commission. Article 17 of Interministerial Order no. 05-2203/MS-MEP-SG states that “For new products and traditional herbal medicines, and where necessary, the Directorate of Pharmacy and Medicines will carry out an expert appraisal of the dossiers submitted...the results of these appraisals will be included in the dossiers for the following session… ”15. However, unlike in Mali, where the non-application of legislation is reported, some authors emphasize the inability of certain manufacturers to demonstrate the harmlessness of THMs in Tanzania 51 and the difficulty for applicants to provide all the information required for registration in Ivory Coast. 52 The opportunities offered by Community procedures for the registration of THMs, already highlighted by Boka in 2018 53 should be exploited to find solutions to the difficulties. They should also make it possible to harmonize registration practices and promote mutual recognition of THMs marketing authorizations issued by the various countries in the sub-region. Harmonization of THMs registration practices could also make it easier for file evaluators in the different countries to take ethnomedical evidence into account and facilitate mutual recognition of the marketing authorizations issued. This need for harmonization of the marketing authorization process is also emphasized in Asia 54 and worldwide 55 for herbal medicines, in order to produce accepted standardized herbal medicines with the same safety, quality and efficacy requirements.
Conclusion
This study shows that there are simplified regulations for the registration of THMs in Mali. This is an integral part of the general regulations governing the marketing authorization of medicines for human and veterinary use. It considers ethnomedical evidence for granting marketing authorizations for category 2 THMs, an alternative to clinical trials that require more financial, technical, and time resources.
Ethnomedical evidence has enabled 15 category 2 THMs to be placed on the market. The marketing authorizations for 7 THMs are still valid, and 5 of them are currently registered on the NLEM and included in the national therapeutic formulary.
In the future, there is a need for effective application of the texts by the regulatory authority, through capacity building for regulatory agents on the approval of THMs, and better collaboration between traditional health practitioners and research institutions. This will make it possible to strengthen the ethnomedical use data, with evidence of safety and efficacy to increase the number of THMs with marketing authorization, as well as the provision of care, and to improve the better keeping of registers of patients treated, which are sources of high-quality ethnomedical evidence.
Footnotes
Author Contributions
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Partial financial support was received from the Training program for university trainers in Mali.
Data Availability Statement
Data will be made available on request.