Développement d une approche de régulation des essais cliniques dans les pays en développement

Programme spécial de bourses internationales 2008-2009 de l Institut International de Recherche en Éthique Biomédicale Rapport de Stage à l Organisation Mondiale de la Santé (du 15 juin au 7 août 2009 à Genève) Montréal, le 20 août 2009 Pour le projet de recherche intitulé Développement d une approche de régulation des essais cliniques dans les pays en développement Étudiant : Diadié Maïga, Université de Montréal, candidat PhD en santé publique, Tél. 514-259-1949, diadie.maiga@umontreal.ca Sous la direction de : Régis Blais, Ph.D., Professeur titulaire, Département d administration de la santé, Université de Montréal. Téléphone: (514) 343-5907 Courriel: regis.blais@umontreal.ca Lise Lamothe, Ph.D., Professeure agrégée, Département d'administration de la santé, Université de Montréal. Téléphone: (514) 343-6111 poste 3141. Courriel: lise.lamothe@umontreal.ca Bryn Williams-Jones, Ph.D., Professeur adjoint, Département de médecine sociale et préventive, Université de Montréal. Tel: (514) 343-6111 poste 4881; Courriel: bryn.williams-jones@umontreal.ca

1. Problématique et objectifs Depuis la seconde moitié du 20 ème siècle, les essais cliniques randomisés sont considérés comme le meilleur instrument pour déterminer la valeur thérapeutique des traitements médicaux [1]. Cette situation s est renforcée en 1992 avec l avènement en particulier de la médecine basée sur les données probantes [2]. Cependant, les essais cliniques de médicaments s accompagnent nécessairement d un certain niveau de risque pour la sécurité des participants [3]. Ces risques se trouvent majorés dans les pays en développement, en particulier parce que leurs populations sont faibles du point de vue économique ou politique et par conséquent susceptibles d être exploitées. Parallèlement, on note que dans les pays en développement la conduite des essais cliniques est de plus en plus fréquente. La plupart des essais conduits dans ces pays sont des projets de recherche de promoteurs étrangers des pays industrialisés qui externalisent les essais de médicaments des phases I à IV vers les pays du tiers monde. Sur l ensemble des essais commandités par des compagnies américaines, la proportion de sites d essais cliniques aux États-Unis a régressé de 90% en 1999 à 47% en 2007 [4]. Plusieurs facteurs expliquent cette externalisation dont l endémicité des maladies cibles, les coûts moins élevés de réalisation des essais, la facilité de recrutement de participants aux essais, mais aussi l absence ou la faiblesse de contraintes réglementaires [5, 6]. Sans un contrôle indépendant du déroulement des essais, on manque d information pertinente sur l efficacité des médicaments, leur innocuité, leur qualité et la protection des sujets humains contre les abus dans la recherche. Malheureusement, la plupart des pays en développement ne disposent d aucune législation pour la conduite des essais. Lorsqu une législation existe, elle ne précise pas à qui revient le mandat d autoriser les essais, de procéder à la surveillance de leur déroulement et d y mettre fin.

3 En somme, plusieurs essais cliniques sont conduits dans les pays en développement, sans garantie de respect des exigences scientifiques et éthiques, ni suivi et surveillance réglementaire. Ceci constitue, d une part, un risque à la sécurité sanitaire mondiale, en particulier à celle des sujets de recherche, et, d autre part, une menace à l'intégrité des données cliniques qui sont par la suite soumises à une évaluation en vue de l'obtention d une autorisation de mise sur le marché international. De plus, on peut ajouter qu il y a, pour les futurs utilisateurs des pays étrangers promoteurs de ces essais, un manque de gage d efficacité et de sécurité des médicaments. Pour ces raisons, il est donc important de comprendre les enjeux de la dynamique pour suggérer une régulation appropriée des essais cliniques en pays en développement. C est l objet du travail de recherche proposé dans ce protocole. Objectifs : Le principal objectif de cette recherche est d analyser et comprendre les enjeux individuels et organisationnels de la régulation des essais cliniques dans les pays en développement. Elle vise les objectifs spécifiques suivants : (i) appréhender la dynamique des acteurs et celle des organes de régulation des essais cliniques; (ii) identifier les obstacles et les facteurs facilitant la mise en place de mécanismes appropriés de régulation des essais cliniques ; (iii) Proposer un système de régulation des essais cliniques pour les pays en développement. 2. Méthode Après discussions avec l équipe de l OMS, il a été mis à notre disposition différents rapports de réunion et des projets de directives et rapports divers. Nous avons identifié et rassemblé comme sources de données les documents portant sur la réglementation des essais cliniques ainsi que des documents pertinents des systèmes de santé en Afrique et ceux décrivant les activités des services impliqués dans la réglementation pharmaceutique et dans la recherche utilisant des sujets humains. L examen documentaire nous a offert la possibilité d analyser les dynamiques des pays telles que rapportées par leurs autorités réglementaires pharmaceutiques 3

4 et les responsables des comités d éthiques ainsi que des représentants de différents programmes de lutte contre la maladie lors des consultations inter-pays organisées par l OMS pendant les cinq dernières années. 3. Déroulement du stage et réalisations par rapport aux résultats visés. Pour répondre aux objectifs de la recherche, nous avons effectué du 15 juin au 7 août 2009 le stage auprès du département Immunization, Vaccines and Biologicals (IVB), Quality, Safety and Standards Team (QSS). La recherche nous a permis d identifier la production en 1999 de deux rapports de l OMS précisant les mandats des autorités sanitaires relativement aux vaccins et à leur régulation. Ce qui devrait théoriquement marquer une étape importante à la réflexion sur le contrôle des essais cliniques en Afrique voire à sa mise en œuvre. Apparemment cette influence n a pu se réaliser. Il nous est apparu que ce n est qu en 2005 que l OMS entreprend des initiatives réelles de mise en œuvre, à travers le département Immunization, Vaccines and Biologicals (IVB), Quality, Safety and Standards Team (QSS). En effet ce dernier a initié depuis septembre 2005 des activités de renforcement dans le domaine de la réglementation des essais cliniques en Afrique pour promouvoir la collaboration entre les pays africains pour leur permettre de discuter les défis communs, de partager leurs expertises et de rapprocher les procédures d évaluation et de surveillance des essais cliniques de vaccins. Nous avons identifié deux domaines d action qui recouvrent l essentiel des intérêts, initiatives et activités entreprises par l OMS dans le domaine de la régulation des essais cliniques en région Africaine. Il s agit (i) de la revue et de l inspection conjointes des essais cliniques et (ii) d une idée d intégration des aspects éthiques, réglementaires et des registres d essais cliniques. En plus d un état des lieux qui va permettre de mieux comprendre le contexte et l évolution de la situation en région Africaine nous avons analysé la contribution de la revue et de 4

5 l inspection conjointes à la régulation des essais cliniques en Afrique. Quant au projet d intégration des aspects éthiques, réglementaires et des registres d essais cliniques, il ne sera pas examiné dans le cadre de ce travail puisqu il est encore en phase de discussion et d élaboration entre différents départements de l OMS. Finalement, les 2 analyses suggérées sont formulées sous format d articles qui traiteront respectivement de l état des lieux de la régulation des essais cliniques en Afrique; et de la revue et l inspection conjointes en tant que modèle de collaboration stratégique à la régulation des essais cliniques en Afrique. Dans le premier article nous dresserons, à partir de l analyse des rapports de réunions de l OMS avec des pays africains, un portrait de l état de la régulation des essais cliniques afin de mieux comprendre les perspectives de développement pour le futur du contrôle des essais cliniques dans cette partie du monde. À partir des comptes-rendus de réunion que nous avons corrélés avec notre revue de la littérature nous avons relevé des limites du cadre de réglementation avant 2005 et identifié les progrès réalisés depuis 2005. Nous terminons l analyse par identifier quelques enjeux pour les intervenants. Dans le deuxième article nous analysons les initiatives de revue et d inspection conjointes. Le papier décrit ces stratégies en montrant comment celles-ci contribuent au renforcement des capacités des autorités de réglementation des essais cliniques en Afrique. Les limites de la revue et de l inspection conjointes sont enfin abordées en suggérant des mécanismes correctifs aux lacunes identifiées. Ces deux articles ont été soumis à l obtention de la clairance de la Direction à l OMS. Le 1 er a déjà obtenu cette clairance et est soumis à publication dans une revue internationale avec comité de lecture. Le 2 ème article est encore dans le circuit d obtention de la clairance de l OMS avant soumission à une revue pour publication. 5

6 Références 1. Marks, H.M., La médecine des preuves : histoire et anthropologie des essais cliniques (1900-1990). Les Empêcheurs de penser en rond. 1999, Le Plessis-Robinson: Institut Synthélabo pour le progrès de la connaissance. 352. 2. Evidence-Based Medicine Working Group, Evidence-based medicine. A new approach to teaching the practice of medicine. Evidence-Based Medicine Working Group.[see comment]. JAMA, 1992. 268(17): p. 2420-5. 3. Doucet, H., L'éthique de la recherche : guide pour le chercheur en sciences de la santé. Paramètres;. 2002, Montréal: Presses de l'université de Montréal. 265. 4. Karlberg, J.P. (2008) Sponsored Clinical Trial Globalization Trends. Clinical Trial Magnifier 1. 5. Acharya, K. (2007) Health-India: Prime Destination for Unethical Clinical Trials. 6. Wemos Foundation (2007) The risks of carrying out clinical drug trials in developing countries. 6

7 Regulatory oversight of clinical trials in Africa: Progress over the past five years Abstract Randomized controlled clinical trials represent the best way to establish the therapeutic or preventive value of medicines. This decade has seen a strong shift in the location of clinical trials from industrialized countries to developing countries, including many in Africa. However, without independent strong regulatory and ethical oversight of clinical trials the safety of research subjects, and scientific integrity of clinical data cannot be verified. This article draws up a portrait of clinical trials regulation in Africa in support of development of 7

8 priority medicines, highlights challenges and presents the progress made by countries under WHO guidance over the past five years Key words: Clinical trials regulation. Africa. National Drug Regulatory Authorities. Ethical committees. 8

9 I. Introduction Rousseau & Casals define regulation as a means aimed at ensuring a good functioning of a system and keeping its balance [1]. Within the framework of this study we understand by regulation a legal framework properly implemented, that gives mandate to defined bodies to exert the oversight over clinical trials, including the authorization of applications submitted for their approval, effective follow-up of their execution, and their termination if necessary. Recent statistics show that pharmaceutical companies are changing their strategies by moving their sites of clinical trials to developing countries. For example, out of all clinical trials sponsored by American companies, the proportion of the clinical trials sites within the United-States regressed from 90% in 1999 to 47% in 2007 [2]. The European Medicines Agency (EMEA) estimates that a quarter of the subjects recruited as participants for pivotal clinical trials conducted to build evidence of safety and efficacy of medicines, to support an application for marketing authorization for the period 2005 to 2008 came from developing countries, many of them in Africa [3]. Two publications in 1999 by WHO, specifying the mandates of national regulatory authorities (NRAs) for vaccine regulation [4, 5] marked the need for a change to ensure that there is full regulatory oversight of all clinical trials in Africa. However, this change could not occur without the implementation of initiatives of WHO to support the regulatory authorities of these countries in the process of establishing a regulatory framework. Indeed before 2005, with exception of very few countries, legislation on regulation of clinical trials was quasi-non-existent in Africa [6]. The same report showed that, where legislation existed, it did not specify who had the mandate to authorize the clinical trials, carry out inspections and to terminate them if found non compliant with GCP standards and with the approved protocol. Consequently, when an authority authorized the trials, it seldom carried out their follow-up and inspection; the monitoring of their implementation was always limited 9

10 [6]. In September 2005, WHO organized a workshop on regulatory procedures for clinical evaluation of vaccines in Addis Ababa. This meeting revealed that out of 13 participating African countries, 10 had an ethics committee, which examined clinical trial applications, 4 had National Regulatory Authorities (NRAs) which were involved in the process of clinical trials review and/or authorized the importation of the clinical batches, and /or carried out the inspection of the clinical trial sites. These roles were not always clearly defined in the national legislation. Regulatory structures and review processes varied significantly among countries, in most cases they less than optimal and they lacked the necessary expertise to conduct the activities involved in the regulation of clinical trials. The NRAs and the ethics committees (ECs), except in 2 cases, acted in parallel and no interaction existed between them [6]. Where NRAs existed there were no proper and complete guidelines for the relevant activities. This article seeks to draw up a portrait of clinical trials regulation in Africa and presents the progress made by African countries in this regard, under WHO guidance over the past five years. II. Method We have identified, gathered and analyzed data sources including documents related to the regulation of clinical trials as well as relevant documents from health systems in Africa, and those describing the activities of the services involved in the regulation of clinical research. The review of documents including meeting reports made it possible to analyze the changes in regulation in African countries as reported by representatives from NRAs and ECs. Progress was assessed by comparing the situation before 2005 and in 2009, almost five years after the introduction of the WHO initiatives to support NRAs. III. Results 1. Limitations of the regulatory framework for clinical trials before 2005 Legal and regulatory framework for clinical trials 10

11 The various stages of development of a drug or vaccine are: (i) discovery and development, including testing in animals; (ii) evaluation in human subjects through clinical trials (phases 1 to 3); (iii) obtaining the marketing authorization; (iv) and post-marketing surveillance through phase 4 clinical trials [7]. In the industrialized countries, these stages of development of a drug or vaccine, including the clinical trials, are governed by many legislative and regulatory measures. In general, to exert regulation these countries refer to a competent authority in charge of the regulation of the pharmaceutical sector. All clinical trials must be declared to this authority, which is legally entitled to give the authorization to start a clinical trial. The WHO GCP guideline mention that the " The role of governments is to provide the legal framework for clinical trials" [8]. The European directive 2001/20/CE is the legal document for clinical trials of medicines for human use in European countries [9]. One of the objectives of this directive which is to harmonize the legal and administrative framework of the Member States, stipulates that before commencing any clinical trial, the sponsor shall be required to submit a valid request for authorisation to the competent authority of the Member State in which the sponsor plans to conduct the clinical trial (European directive 2001/20/CE, article 9, paragraph 2). For example, in France, the competent authority to give this authorization to start a clinical trial on any medicine is AFSSAPS (Agence Française de Sécurité Sanitaire des Produits de Santé) [10]. In Canada, the Health Products and Food Branch (HPFB) represents the regulatory body within Health Canada (Ministry for Health) responsible for approval or rejection of an application for a clinical trial. In addition to the authorization to start a clinical trial, the administrative procedures include obtaining proof of the authorization by the EC. The involvement of the bioethics community in the establishment of these ethics committees have come in part from the adoption of several international provisions or guidelines governing clinical experimentation in humans. Three of these are the Code of Nuremberg, the declaration of Helsinki and the international 11

12 CIOMS guidelines for biomedical research involving human beings [11]. These documents do not constitute an exhaustive list of international regulations or guidelines but represent the principal ethical standards required for clinical research. For the application of these standards, the ECs play an important role in guaranteeing the protection of human research subjects. In Africa these guidelines or principles are yet to be fully translated into national laws in order to protect research participants. Regulatory capacity of African countries and the operation of the ECs The various studies carried out on the existence and the capacities of ethics committees reveal a disparity between countries [12, 13]. A study led by the WHO Regional Office for Africa (WHO/AFRO) highlighted the absence of national ECs for medical research in 36% of its member states [14]. The same source indicated that only one of these countries ensured that the clinical trials financed by either external governmental or private sponsors were subject to an ethical evaluation and received approval in the country of origin. The recurring results underline failures, which relate to the absence of ECs, directives, staff, procedures and other resources [14, 15]. It is also noted that, when several ethics committees coexist, it is difficult to define the respective roles and responsibilities. Moreover, in certain cases, the investigators were unaware of the existence of the EC. A study conducted in Sudan in 2007 showed that 53 out of the 116 researchers who were interviewed were unaware of the existence of ECs in the country [16]. However, the first EC was established in this country in 1979 [17]. In addition, the method of decision-making within the committees, their independence, the follow-up of the requests for amendments to the protocols and the monitoring of the performance of the clinical trials after ethical approval also constitute elements of concern in many countries in Africa [18]. According to a study conducted in 14 countries in West and Central Africa, what should urgently be addressed is the question of countries considered unable to exercise efficient control of research implemented on their territory, and thus obliged to depend on those who finance or conduct such research [19]. 12

13 In short, before 2005 the regulation of clinical trials was, at its best, perceived as, and limited to the ethical function of review for which the responsibility was allocated to the ECs, in most African countries. The framework for regulation of medicines was lacking for clinical trials, including the roles and responsibilities of the various relevant parties. Moreover, the NRAs did not seem to be aware of their responsibility and their authority in the process of approval and inspections. The sponsors and the investigators lacked interlocutors clearly designated by the national legislations. However, South Africa contrasted with this situation in Africa. The NRA of this country, according to an amended legislative act going back to 1965, requires both regulatory and ethical approval and carries out inspections of the clinical trial sites. The sponsors know exactly the requirements and a Web site disseminates the relevant information. However, in spite of the existence of a legal framework in South Africa, some clinical trials without regulatory approval are reported [6]. 2. Progress made in the regulation of clinical trials in Africa in the last 5 years Objective of WHO strengthening initiatives The initiatives of WHO to support the African region aims at promoting collaboration among the African countries to enable them to identify and discuss common challenges, share their expertise and to harmonize the procedures for evaluation and regulatory oversight of clinical trials of vaccines. Implementation The department of Immunization, Vaccines and Biologicals of WHO (IVB), Quality, Safety and Standards Team (QSS) initiated activities of strengthening in the field of the regulation of the clinical trials by organizing a meeting in Addis Ababa in September 2005, in collaboration with WHO/AFRO and involving representatives of regulatory authorities from 13 African countries. The workshop reviewed the legal framework of each country, discussed the regulatory procedures for evaluation of vaccines and other common concerns. Following this meeting, model procedures were developed for submission of clinical trial applications and 13

14 for importation and release of clinical batches. These procedures were used for joint reviews of clinical trial applications and joint inspections of clinical trial sites, facilitated by WHO, These activities involving several countries with common challenges, led to the establishment of a platform called the African Vaccine Regulatory Forum (AVAREF). Since its beginning in 2006, AVAREF has met annually, in Accra (Ghana), Ouagadougou (Burkina Faso) and Zanzibar (United Republic of Tanzania) respectively. AVAREF includes representatives of NRAs and ECs from 19 countries and may extend to more African countries. During the first three meetings, in addition to the NRAs and ECs of represented countries, several experts from strong regulatory authorities like, Food and Drug Administration of the United States, Health Canada and the EMEA (European Medicines Evaluation Agency) as well as other partners like the Program for Appropriate Technology for Health (PATH) and the European and Developing Countries Clinical Trial Partnership (EDCPT) have participated. The goal of the forum is to build the capacity of the participating countries to implement their full responsibility for the regulation of vaccine trials, it promotes the communication between NRAs and ECs, as well as between NRAs of industrialized countries, which are manufacturers of vaccines and their African counterparts where the clinical trials take place. It has also provided an opportunity for identification of gaps in regulation of clinical trials of vaccines, that require support from WHO. For example, the respective roles and responsibilities of the NRAs and the ECs are discussed and clarified to avoid the duplication of tasks, to optimize the use of resources and to reinforce the communication and collaboration. The process proves to be a stage towards the harmonization of procedures at the regional level, to ensure observance of the Good Clinical Practices enacted in the international guidelines of the ICH adopted in 1996. Table 1 gives some activities carried out within the framework of the initiative since 2005. 14

15 Table 1: Examples of achievements within the regulatory framework of the initiatives of strengthening of WHO in the field of the clinical trials regulation in Africa. Field of regulation Before 2005 Since 2005 Observance of ethical standards Observance of international scientific standards - Diversity of the context (absence of ethics committees, unclear roles and responsibilities, unawareness of their existence). - No collaboration between NRAs and ECs. - Absence of standards. - No harmonization of procedures in the African region. - Awareness of the need to revise or develop the legal/regulatory framework. - Clarification of the mandates of the NRAs and ECs - Annual forum for NRAs and ECs since 2006 (AVAREF) - Training on GCP inspections since 2007. - Joint review of 3 clinical trials and joint inspections of 3 clinical trial sites. Advocacy for regulatory oversight - Minimal or weak - Stronger advocacy through annual AVAREF Forum Regulatory oversight of clinical trials - Limited in the best cases to the ethics committees. - Few NRAs in existence (4) - NRAs not involved. - Evolution of the roles and the responsibility for the NRAs. - Annual forum for interaction between African NRAs and those of developed (product manufacturing) countries since 15

- Limited interaction 2006. 16 between African NRAs and those of developed (product manufacturing) countries - Better definition of the roles and responsibilities for the intervening parties. - Positive interaction between NRAs and ECs. - Interlocutors known for sponsors and researchers. - Networking between countries and with independent experts through the AVAREF. 3. Priority clinical trials of vaccines in Africa: challenges of regulation for the different stakeholders The regulation of clinical trials in developing countries contributes to the development of new products to tackle the myriad of health problems, which specifically affect these countries [20, 21]. For example, clinical trials are required to test new drugs and vaccines within Africa in the fight against the major endemic diseases, namely malaria, tuberculosis and HIV/AIDS. The Declaration of Helsinki [22] which represents the most quoted ethical framework, recalls in several of its articles that human experimentation constitutes a source of improvement for prophylactic, diagnostic and therapeutic procedures as well as providing better understanding of the aetiology and pathogenesis of diseases, including new and emerging diseases. WHO, by initiating these projects of building capacity of African NRAs perceived well in advance the fundamental obligation for African countries to have effective oversight of all the clinical trials which take place in their territories. It is important to understand that the responsibilities of the countries that will host clinical trials and where new drugs and vaccines will be introduced cannot be replaced by the regulatory approval of the manufacturing countries. 16

17 In spite of the regulatory strengthening initiatives of NRAs by WHO, many countries have not succeed yet in the implementation of a regulatory framework. The legislations in place in most African countries do not assign a clear mandate for regulation and oversight of clinical trials to a specific body within the health authorities. The new-institutional theory suggests that any organization should adopt structures in response to external expectations [23]. In addition, constitution and law are crucial factors of context and contents of activities of public organizations, on one hand because their structures and their goals are mainly stipulated in the laws which created them and on the other hand because the roles of the public agencies and their managers, as well as the resources placed at their disposal, are the subject of regulations in these laws. In fact, public administration is subordinate to the law [24, 25]. Since the lines of authority in the oversight of the clinical trials are multiple and unclear, each part assumes that it does not have all the necessary levers to take up the challenge of regulation. It is thus essential at the national level to pay important and particular attention to the development of the legal body within a framework of dialogue of all interested parties in order to integrate the whole essential dimensions in a harmonious way. In addition to the enacted international standards, the legal authorities must take initiatives to implement them because the partners, including WHO, cannot impose on them a model for the regulatory procedures. That pertinently raises the question of the legal framework of cooperation. It is important to take into consideration such a question to promote collaboration and to encourage the exchange of information and expertise among NRAs and the various partners. The African countries which are selected to host the clinical trials often do not have enough experience with regards to legal framework for the oversight of the clinical trials. It is apparent that from a cognitive point of view, staff from NRAs and members of ECs need a basic academic and professional development level to enable them to make the best possible use of the capacity building opportunities offered by WHO. In this respect it has to be stressed that many countries, which are targets for the introduction of new 17

18 vaccines do not have the full competence and the necessary expertise to evaluate the quality, safety and efficacy of these vaccines for which they have the responsibility of evaluating [26]. That represents a challenge but also an opportunity to take advantage of the support by experts from WHO and partners. It was suggested that WHO serves as a means to facilitate the access to these external resources. Some examples are the participation of international experts in the joint reviews and joint inspections of clinical trials to support the reviewers and inspectors from the African NRAs and ECs, as well as the participation of experts at the AVAREF meetings, and the development of regulatory procedures made available for AVAREF countries to adapt and/adopt into their national regulatory frameworks. This list of documents includes guidelines for sponsors for the submission of clinical trials application, procedures for GCP inspections and models of legislation. This approach indeed makes it possible to optimize the use of international standards, to reinforce the activities of the regulatory authorities of African countries. Moreover, the participating countries are given the chance to develop their own experience from the acquired expertise [27-29]. IV. Conclusion The globalisation of clinical trials and their fast expansion in emerging countries, the lack of a mandate by the regulatory authorities of the industrialized countries to provide regulatory oversight of clinical trials outside of their territories and the weaknesses of the NRAs of the host countries are all factors which contribute to adversely affect the clinical trial environment in Africa. Despite these challenges WHO, through its multiple initiatives including the AVAREF, is resolutely committed to an approach of strengthening of the activities of National Regulatory Authorities in African countries. The success of these initiatives lies on the responsibility of the participating countries to secure the implementation of the activities relevant to their mandate to regulate clinical trials, which will guarantee the protection of research subjects. 18

Acknowledgements 19 Diadié Maïga benefitted from an internship at WHO with financial support from the International Institute of Research in Ethics and Biomedicine and the AnÉIS (Analyse et évaluation des interventions en santé). The authors gratefully acknowledge the contribution of Dr. Modibo Dicko who worked in the IVD programme of the WHO Regional Office for Africa when AVAREF was conceived and established. The views expressed herein are those of the authors, and may not represent the views of WHO and the founders. 19

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References 21 1. Rousseau, L. and L. Cazale, Réforme ou évolution? Enjeux et opinions sur la régulation et la transformation, in Le système sociosanitaire au Québec : gouvernance, régulation et participation, M.-J. Fleury, Editor. 2007, Gaëtan Morin: Montréal. p. xxxv, 513. 2. Karlberg, J.P. (2008) Sponsored Clinical Trial Globalization Trends. Clinical Trial Magnifier 1. 3. European Medicines Agency, EMEA strategy paper: Acceptance of clinical trials conducted in third countries, for evaluation in Marketing Authorisation Applications. 2008: London. 4. Organisation Mondiale de la Santé, Réglementation des vaccins - S'appuyer sur les autorités de réglementation pharmaceutique existantes. 1999: Genève. 5. World Health Organization, Informal consultation of experts on national regulation of vaccines existantes. 1999: Geneva. 6. Chocarro, L. and P. Folb, Workshop on regulatory procedures for clinical evaluation of vaccines, Addis Ababa, Ethiopia, 21-23 September 2005. 2005, World Health Organization. 7. Mathieu, M.P. and C.-P. Milne, New drug development : a regulatory overview. Rev. 7th ed. 2005, Waltham, MA: Parexel International Corp. 389. 8. World Health Organization, Guidelines for good clinical practice (GCP) for trials on pharmaceutical products, in WHO Technical Report Series, volume 850 Annexe 3. 1995, World Health Organization: Geneva. 9. Parlement Européen et Conseil de l'union Européenne, Directive 2001/20/CE du Parlement européen et du conseil du 4 avril 2001 concernant le rapprochement des dispositions législatives, réglementaires et administratives des États membres 21

22 relatives à l'application de bonnes pratiques cliniques dans la conduite d'essais cliniques de médicaments à usage humain. 2001. 10. Agence Française de Sécurité Sanitaire des Produits de Santé. Essais cliniques de médicaments et de produits biologiques. 2007 Page consultée le 10 mars 2008]; Available from: http://agmed.sante.gouv.fr/htm/5/essclin/indesscl.htm. 11. Doucet, H., L'éthique de la recherche : guide pour le chercheur en sciences de la santé. Paramètres;. 2002, Montréal: Presses de l'université de Montréal. 265. 12. Kass, N.E., et al., The structure and function of research ethics committees in Africa: a case study.[see comment]. PLoS Medicine / Public Library of Science, 2007. 4(1): p. e3. 13. See, C.M., D.R. Wassenaar, and C.M. Slack, Perceived Capacity of Selected African Research Ethics Committees to Review HIV Vaccine Trial Protocols. IRB, 2006. 28(2): p. 1-9. 14. Kirigia, J.M., C. Wambebe, and A. Baba-Moussa, Status of national research bioethics committees in the WHO African region. BMC Medical Ethics, 2005. 6: p. E10. 15. Ahmad, K., Developing countries need effective ethics review committees.[see comment]. Lancet, 2003. 362(9384): p. 627. 16. Elsayed, D.E.M. and N.E. Kass, Assessment of the ethical review process in Sudan. Developing World Bioethics, 2007. 7(3): p. 143-148. 17. Elsayed, D.E.M., The current situation of health research and ethics in Sudan. Developing World Bioethics, 2004. 4(2): p. 154-159. 18. Effa, P., et al., Ethics committees in Western and Central Africa : Concrete foundations. Developing World Bioethics, 2007. 7(3): p. 136-142. 19. Networking for Ethics on Biomedical Research in Africa (NEBRA) (2006) Rapport d'enquête. 22

23 20. Council for International Organizations of Medical, S., International ethical guidelines for biomedical research involving human subjects. Bulletin of Medical Ethics, 2002(182): p. 17-23. 21. Organisation Mondiale de la Santé, Lignes Directrices Opérationnelles pour les Comités d'éthique chargés de l'évaluation de la Recherche Biomédicale. 2000: Genève. 22. World Medical Association General, A., World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. International Journal of Bioethics, 2004. 15(1): p. 124-9. 23. Meyer, J.W. and B. Rowan, Institutional organizations: Formal structure as myth and ceremony. American Journal of Sociology, 1977. 2(83): p. 340-363. 24. Berkley, G.E., The craft of public administration. 2d ed. 1978, Boston ; Toronto: Allyn and Bacon. x, 555. 25. Gortner, H.F., J. Mahler, and J.B. Nicholson, La gestion des organisations publiques. 1994, Sainte-Foy: Presses de l'université du Québec. xxii, 587. 26. Brennan, M.J., et al., Development of new tuberculosis vaccines: a global perspective on regulatory issues. PLoS Medicine / Public Library of Science, 2007. 4(8): p. e252. 27. World Health Organization, First meeting of the African vaccine regulatory forum (AVAREF), Accra, Ghana, 19-22 September 2006. 2006, World Health Organization. 28. World Health Organization, Second meeting of the African vaccine regulatory forum (AVAREF), Ouagadougou, Burkina Faso, 25-28 September 2007. 2007, World Health Organization. 29. World Health Organization, Third meeting of the African vaccine regulatory forum (AVAREF), Zanzibar, United Republic of Tanzania, 28-31 October 2008. 2008, World Health Organization. 23

24 Joint Reviews and Inspections: Strategic forms of collaboration for strengthening the regulatory oversight of clinical trials in Africa 24

Summary 25 The existing regulatory oversight of clinical trials in Africa seems insufficient to ensure safety and protection of trial subjects, while promoting the generation of quality data for market authorization of medicines. Clear guidelines are required for sponsors, so they would submit a clinical trial application to the Ethics Committees and National Regulatory Authorities, and only after appropriate clearance by both can the clinical trial commence. This paper describes two specific strategies, joint reviews of vaccine clinical trial applications and joint inspections of clinical trial sites as part of a WHO initiative to strengthen capacity for the regulatory oversight of clinical trials in Africa. Significantly, the joint reviews and inspections contributed to reinforcing the capacities of the regulatory authorities as well as defining an efficient process to maximize the quality of the reviews and minimize undue delays. Finally we will suggest complementary mechanisms to overcome the limitations of the joint reviews and inspections. Key words: Clinical trials regulation. Joint review. Joint inspection. Africa. 25

26 1. Introduction The promotion of research and development in Africa has the potential to lead to the identification of appropriate medicines to tackle priority diseases, including HIV/AIDS, malaria and tuberculosis [1, 2]. A trend reported in recent statistics show that pharmaceutical companies are moving their sites for clinical trials to developing countries [3, 4]. Clinical trials of vaccines are uniquely different from those of drugs. First, the subjects, in vaccine clinical trials, comprise healthy individuals, mostly children or even infants. Secondly, the selected location must be in areas, endemic for the relevant disease, and these in most cases are in countries were poverty is high and regulatory oversight is weak or nonexistent [5-9]. This constitutes a potential risk, in particular for research subjects, and a threat to the quality and the integrity of the clinical data generated to support the marketing authorization of the product. Consequently the governments of African countries face the challenge to identify and implement suitable mechanisms to ensure oversight of clinical trials, consistent with international guidelines and standards. By doing this, they will ensure the safety of their populations, while promoting the benefits of research for those who will eventually use the new vaccines. One of the goals of the World Health Organization (WHO) is to ensure global access to the highest possible level of health, achieved in part by helping governments to increase the capacities of their health systems, and providing appropriate technical assistance. WHO has initiated activities for strengthening the National Regulatory Authorities (NRAs) and Ethics Committees (ECs) in Africa to overcome the challenges previously enumerated. Two main strategies of the initiative developed in the African region are the joint reviews of clinical trial applications and the joint inspections of clinical trial sites. Using all the documents related to these activities as well as the experiences of those who were directly involved, we present the approach and methodology used by WHO to facilitate 26

the process. Furthermore, we discuss these strategies, by analyzing their successes, weaknesses and limitations and propose means of improvement. 27 2. Strategic objective and emergence of the joint review and inspection Very few countries in Africa had the capacity to review clinical trial applications and to inspect clinical trial sites, prior to the introduction of WHO initiatives for strengthening of regulatory oversight of clinical trials. Since in many cases countries host multicenter trials [10-13] and face similar challenges of lack of technical expertise and established procedures, it made sense to use the regional approach to build capacity in the countries involved in a given clinical trial. The joint review and inspection respectively consisted of a joint evaluation by the NRAs and members of ECs of a group of countries, of an application for clinical trial authorization and the clinical trial sites. This was facilitated by WHO and with the agreement of the sponsor. During a workshop organized by WHO on regulatory procedures for the clinical evaluation of vaccines involving 13 African countries in Addis Ababa in 2005 [14], WHO first proposed the joint review of a clinical trial application as a means to help the selected target countries and to prepare other potential target NRAs and ECs to evaluate future clinical trials. Participating countries agreed that this would be the best approach to strengthen their capacity for oversight of clinical trials in a collaborative manner. Three reviews of clinical trials and two joint inspections were carried out, facilitated by WHO. a) Conjugate Meningitis A Vaccine Clinical trials The first two joint reviews were for clinical trial applications of phase II and II-III studies of a conjugate meningitis A vaccine, produced by the Serum Institute of India and sponsored by PATH/MVP (Meningitis Vaccine Project) 1. The first trial took place in Mali and The Gambia. Both countries had participated in the workshop in Addis Ababa in September 2005 that 1 The MVP was born out of an initiative of the WHO aiming at improving the health coverage of the epidemics of meningitis in sub-saharan Africa after the epidemic devastator of 1996-1997. It is about a partnership between WHO and Program for Appropriate Technology in Health (PATH) born in 2001. 27

28 resulted in the development of regulatory procedures for submission and review of clinical trial applications and for importation and release of clinical batches. These model procedures were used to inform the sponsor on the documentation required by the NRAs. The joint review was done in Banjul, The Gambia in June 2006. The participants were from the NRAs and ECs from the two target countries and representatives from other countries where trials were planned in the future (Senegal, Ghana, Ethiopia and Burkina Faso). The joint inspection of this study was done in Mali in January 2007 with the same participants. Independent experts were recruited by WHO to support the processes of review and inspection. Invited countries (those invited to learn from the process but had not received the application) as well as the consulting experts signed confidentiality agreements. The second joint review was done in Dakar, Senegal in June 2007 and the second inspection in two sites in Senegal, following a similar format. The third site involved in this particular study was in The Gambia. The country participants were encouraged to conduct their own inspection following the same procedure, without the presence of an external expert. However, WHO provided support by facilitating a consultation with the lead expert in Senegal, before and after the visit to the clinical trial site. This allowed them to validate their preparations for the inspection and the interpretation of the observations. Representatives from the countries that participated in the joint reviews and the inspections, reported to WHO to have successfully applied the knowledge and methodology to other clinical trial applications and for the inspections of sites in their territories. b) RTS, S Malaria vaccine clinical trial The third joint review was for a phase III clinical trial of the RTS, S Malaria vaccine manufactured by GSK Biologicals, in Belgium. In this case the study involved 11 sites in seven countries (Burkina Faso, Malawi, Tanzania, Ghana, Kenya, Mozambique, Gabon). The complexity of the arrangements due to the number of countries involved required a lengthy process of preparation to seek agreement from all participating countries, reach consensus on 28

29 the use of a harmonized format for the dossier to be submitted by the manufacturer and to design the review process in a way that would build on the already existing capacities in the target countries. The first stage was the presentation of the project by the vaccine manufacturer (GSK) and the neutral partner to WHO, Program for Appropriate Technology in Health, Malaria Vaccine Initiative (PATH/MVI) during the second meeting of the African Vaccine Regulatory Forum (AVAREF) in September 2007. Countries agreed that a joint review would be a good opportunity to enhance the quality of the evaluation process. They also agreed that the model procedure developed by WHO would be used so the manufacturer would prepare one single dossier for all target countries, and on the minimum information that should be presented in each of the sections of the application. In April 2008, a new timeline was agreed upon by the manufacturer, and four of the seven target countries. NRAs requested that a period of two months be given to them to perform their own review in preparation for the joint review. This was a significant difference from the first two experiences, where no individual country review was done prior to the joint review. Another difference was that in this instance, expert reviewers from the NRA of the country of manufacture provided technical support to the seven African countries. In October 2008, the joint review was conducted. A joint report with observations from all reviewers was prepared, and presented to the manufacturer. The outcome of the review was a joint report of observations, which were either clarified or became a commitment for submission of additional information to each of the countries, to allow them to complete the evaluation process and issue approvals of the application independently. 5. Key stakeholders in joint reviews and inspections All the joint reviews and inspections have been facilitated by WHO with the intention of creating a mechanism that countries could follow in the future, if the format proved efficient in enhancing the quality of the review and reducing undue delays in the process between 29

30 submission of the applications and the issuance of an approval (or rejection), while at the same time the experience served as a unique leaning opportunity for the participating countries. In order to coordinate all the activities and resources required, there are a few elements that must be in place: a) Consensus from the manufacturer and sponsors as owners of the information. b) A neutral partner to support WHO with funding and/or with negotiations with the owner of the information through their unbiased commitment to ensure that the clinical trials would go through the highest possible level of regulatory oversight. c) Consensus from the countries involved to review the application together, and to use the common report as the basis for their national decision. d) Focal persons for the NRA and the EC in each participating country, to communicate with. e) Experts that support the country regulators by sharing their knowledge and experience, but do not influence their decision-making. Neutral partners support the clinical development of priority vaccines without a vested interest in a particular vaccine candidate, and to accomplish their commitment to support the strengthening of the regulatory oversight of such trials they request WHO to facilitate the review and inspections, thus not exerting any influence on the evaluation process. They provide support to WHO with funding, and/or in setting the stage to get the consensus from the manufacturers to allow all participating countries to share information and views. The ideal format involves experts from the regulatory authority of the country where the vaccine is manufactured to strengthen the interaction between regulators of manufacturing and trial host countries. The process must not invade the sovereignty of the participating countries; it helps in the decision making process by enhancing the quality of the review. The end result is a summation of the expertise and views of all participants in the activity, who in turn bring 30

31 along the views of their colleagues who have already done a preliminary assessment of the submitted dossier. The final report is in a way, an almost exhaustive list of concerns, which after satisfactory response from the manufacturer to each country involved should result in the authorization of the clinical trial. 3. Advantages of the joint reviews and inspections Historically, joint activities or common arrangements or various forms of networks have allowed the continuity and the coordination of medical care and services between various stakeholders of the health system [15]. Joint reviews and inspections are an example of this productive manner to deal with common challenges in the area of regulatory oversight of clinical trials through a two-fold approach: training of the reviewers of the participating countries and sharing of knowledge and views which lead to the compilation of observations in a common report. For the participating countries, the first advantage of the joint review and inspection was the awareness of the complexities of the review process and the improvement of their knowledge on the methodological, scientific and ethical considerations involved in the evaluation. With regards to the ECs, the joint review allowed them to revise existing methods or procedures and to validate activities already conducted by them. For example, some participants from ECs reported that they did not distinguish ethical approval from the regulatory authorization of the clinical trial or did not realize that it was their responsibility to look at the scientific aspects of the protocol, even in the absence of a body providing such a function. Thus after ethical approval, the trials were likely to start without sufficient scientific evaluation. Secondly, the benefit for the sponsor is that the whole process follows for a pre-determined timeline facilitated by WHO, thus avoiding undue delays in the review process itself. Generally the sponsors expect short timelines to avoid delays in the commencement of the clinical trials. From the public health point of view, we can admit that the decisions of the NRAs should be made within a reasonable time to avoid a negative impact on the clinical 31