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Malaria drug and vaccine trials in Africa: obstacles and opportunities
Transactions of the Royal Society of Tropical Medicine and Hygiene (2008) 102, 7—10
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/trst
REVIEW
Malaria drug and vaccine trials in Africa: obstacles and opportunities T.A. Lang a,∗, G.O. Kokwaro b,c a
KEMRI/Wellcome Trust Programme, P.O. Box 230, Kilifi, Kenya Department of Pharmaceutics and Pharmacy Practice, Faculty of Pharmacy, University of Nairobi, Nairobi, Kenya c KEMRI/Wellcome Trust Programme, Nairobi, Kenya b
Received 10 May 2007; received in revised form 24 August 2007; accepted 24 August 2007 Available online 29 October 2007
KEYWORDS Malaria; Trials; Public—private partnerships; Drug development; Vaccine development; Capacity building; Africa
Summary There are several new treatments and vaccine technologies in clinical development for childhood malaria that have arrived in the clinical phase of evaluation during the past 5—10 years. This is a long-awaited change as until this time there had been little in the pipeline. As these products progress, evaluating them in the populations for whom they are being developed is becoming increasingly challenging. Many more capable trial sites are required and thousands of children and their parents need to be willing to take part in all the clinical trials that will be necessary if even a handful of these products make it through to obtaining a marketing approval license. Then, beyond licensure, these products will need to be assessed in more ‘real-life’ phase IV trials to establish whether they can truly impact the high level of mortality that malaria brings to the under-five population in Africa. Here we explore the issues that face both the trial sites and the product developers and present how this opportunity should be utilised to develop experienced African clinical researchers and facilities alongside getting these products through into public health use. © 2007 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
1. Introduction Until recently, there had been a desperate lack of new candidate treatments for Plasmodium falciparum malaria and there were few vaccine candidates showing encouraging signs of immunogenicity (Ballou, 2005; Trouiller and Olliaro,
∗
Corresponding author. Tel.: +254 415 22063; fax: +254 415 522390. E-mail address: tlang@kilifi.kemri-wellcome.org (T.A. Lang).
1999). This situation is improving (White, 2006) and the largest two public—private partnerships that exist to address these deficits have made significant progress. Medicines for Malaria Venture (MMV) has four candidate drugs in phase III, five in phases I and II with a further 11 pre-clinical programmes in their pipeline (MMV, 2006). The Malaria Vaccine Initiative (MVI) has taken three varying vaccine technologies into phase I, has another two that have progressed into phase II and has six pre-clinical programmes in its portfolio (MVI, 2006). Typically, a new malaria drug requires testing in at least 2000 participants to demonstrate enough safety data for licensure (Lang and Greenwood, 2003). Efficacy can
0035-9203/$ — see front matter © 2007 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.trstmh.2007.08.008
8 usually be demonstrated in small comparative phase II trials with 200—400 participants. Phase III trials are designed to confirm the efficacy shown in phase II and to achieve the number of exposures required to prove safety and so require thousands of participants across several sites. As a vaccine for malaria is yet to be registered, there is still discussion on the data required. Many thousands of participants would be needed to prove efficacy against severe malaria (Greenwood, 2005), although for uncomplicated malaria far fewer participants would be required (Aide et al., 2007). If in the next few years these candidate drugs and vaccines are to progress to registration there will be many multicentre trials running concurrently across Africa. Furthermore, those drugs and vaccines that succeed will then need large-scale effectiveness phase IV programmes. This raises exciting opportunities whilst also presenting a testing scenario both to the developers and those responsible for the field trial sites. The developers of malaria drugs and vaccines carefully select their trial sites. They evaluate them against criteria such as experience of the investigators in conducting international regulatory standard trials, level of malaria in their location, standard of their laboratories and whether there are any potentially competing trials planned or ongoing. There is a trend for developers to use the same sites and often those with a European or American affiliation (Kilama, 2003). However, if there are to be enough sites to cope with this demand, a larger number of sites are needed from more diverse areas, and if this is to provide increased capacity for the long-term they should have strong local affiliations and leadership.
2. Daily realities of malaria trials Most malaria deaths occur in children under 5 years of age in rural Africa (Snow et al., 1999). Therefore, efficacy and safety needs to be measured in this age group and, if the data are to be relevant for the true target population, trials should be conducted in the type of setting where most malaria occurs. The problem is that these populations are difficult to reach. Evaluating new drugs and vaccines requires trials with high levels of intervention in terms of number of visits for the participants, observed taking of therapies or giving of vaccine as well as the taking of samples and giving medical examinations. Blood samples are essential for measuring parasite levels and for assessing the safety and pharmacokinetics of the investigational product. Other assays are also crucial to product development, especially in vaccine development where immune responses need to be measured. Laboratory facilities for such procedures are rarely available near the participants, so systems are needed either to hospitalise subjects or preferably to establish complex transport logistics to transfer the samples under the necessary conditions to the laboratory. Many laboratory assays need the samples transported at a cold temperature, further complicating and limiting the practicalities. Mapping and census systems need to be in place well before a trial begins in order to find possible participants and then to identify subject’s enrolment in a trial. This is important in the likely scenario of drug and vaccine trials competing for the same populations as well as to recognise trial participants
T.A. Lang, G.O. Kokwaro if they present at another health facility. Practical measurers such as issuing trial identification photo cards can help. It needs to be possible to find and transfer participants for the detection and management of any adverse events. This can become very difficult in the rainy seasons when roads can quickly become impassable. These are just some of the practical operational issues. From a design, recruitment and operational perspective, there are some interesting developments that should be considered by clinical programme developers. There has been a significant increase in the use of insecticide-treated bed nets and introduction of artemisinin-containing combination therapy drugs (Breman et al., 2004). Since both may impact malaria incidence rates, recent epidemiological data should be obtained at the protocol development stage, rather than relying on enrolment figures from previous trials. This is because the situation is rapidly changing and varies greatly between locations. Most published data on current bed net coverage or uptake of new drugs is only broadly relevant and therefore each site needs to evaluate its own true malaria levels to find the best trial ‘hotspots’. Another increasingly complex issue is that of coordinating research into uncomplicated malaria alongside the important question of studying severe disease. The drug and vaccine registration trials typically occur in communitybased studies and have protocols that follow children through a malaria season or longer. A usual exclusion criterion is inclusion into another trial and/or receiving another investigational product. This requires wider thinking as it is most often the experienced centres conducting large fieldbased trials that have concurrent ward-based programmes looking at severe diseases. Drug and vaccine trials could seriously reduce the number of eligible children available for the severe disease trials, thereby impeding advancement in knowledge in how to treat and manage children with life-threatening malaria.
3. Opportunities for building capacity Alongside the increase in new products through public—private partnerships, there has also been an influx of funding for capacity building to bring African trial sites up to international regulatory standard and to make them ready for this predicted flood of new products (Croft, 2005). This presents an interesting dilemma: to conduct a drug or vaccine trial there needs to be a product and a protocol, but for a site to conduct a trial they should ideally be experienced and well trained (ICH, 1996). It may be quite difficult to increase capacity quickly at inexperienced sites by using programmes not related to products. It may be better to use smaller, early-phase trials in adults or pragmatic phase IV studies to build and develop less experienced sites and thereby increase the number of sites with the potential to conduct more complex regulatory standard phase II and III trials later. There are several, large, highly experienced trial units in Africa, but many more are needed not only to allow for more multicentre trials but also to reflect the changing malaria ecologies. Development of new sites will provide opportunities not only for general infrastructure upgrade, but also for relevant training of more African trialists, monitors
Conducting African malaria drug and vaccine trials and Institutional Review Boards. Personnel training needs to be better linked with opportunities for career advancement since it is currently proving difficult to recruit African trial monitors, co-ordinators and clinicians with existing experience in the absence of proper career advancement opportunities. The few that have these skills are highly sought after by the internationally funded research units, leave research for posts in the private sector or leave Africa altogether for better paid posts in Europe and the US (Bundred and Levitt, 2000). Training capacity within Africa is also low and sponsoring organisations generally bring in their own training teams from Europe and the USA, or send their staff overseas for training. If African sites are to be able to retain their staff to direct and lead their own research agendas, they must improve their ability to train and develop clinical trial staff locally and independently. Infrastructure upgrading should include laboratories to support clinical trials on-site and avoid the current logistical problems of transporting samples to reference laboratories outside the country. Few of the current initiatives on capacity strengthening are addressing the issue of laboratory upgrading at the various sites being developed. Lastly, there is a need for a central repository where information about past, ongoing and planned clinical trials can be obtained. This database would be a good resource to search for details on site experience, training opportunities and where previous trials have been conducted, for example. There is funding available to develop trial sites and this is very welcome, although it is possibly not to a high enough level or is too tightly constrained for practical use. To be able to improve their operations, trial sites must be able to access money that they can spend where they see it is needed. It is hard to get funding for core support staff or general infrastructure. Importantly, it is the sites that are currently least engaged in internationally funded research that need to be most actively pursued and targeted. These smaller and fledgling research sites have access to populations that have not previously been part of trial programmes and are typically staffed by younger African clinicians and scientists who are keen to develop and build their capacity. Such sites are currently not able to compete with the larger and better established sites that conduct the lion’s share of the regulatory pathway trials in Africa. Organisations such as African Malaria Network Trust (AMANET), Malaria Clinical Trials Alliance (MCTA) and European & Developing Countries Clinical Trials Partnership (EDCTP) are making good progress in improving trial site capacity across Africa (http://Elearning.AmanetTrust.Org/). The e-learning tools available on the AMANET website are a huge step forward and this will hopefully expand to offer ICH Good Clinical Practice (GCP) and trial management training. If such qualifications can be obtained via the Internet, there is much greater potential for developing many more African trialists. Mentoring would be a further improvement, not only at the individual level, but perhaps it could even work at the site level by partnering younger sites with established programmes. Schemes such as posting trialists from experienced sites to the new centres they are mentoring could work well. Mentoring could be built into site selections and tendering systems, thereby integrating this into development programmes and improving sustainability.
9 Raising the capacity of sites to conduct trials must be accompanied by harmonisation and increased abilities for African countries to conduct appropriate ethical review of proposed trials. The Pan-African Bioethics Initiative recognises there is a need to establish a networking system between African ethics committees to share resources and to improve how they operate (http://www.pabin.org/Survey.aspx). Trial sponsors and capacity building organisations should be encouraged to support these efforts better as it must progress alongside the number of trials being planned and sites being expanded. Ethical review standards and resources must not lag behind.
4. Conclusions There is an incoming wave of new malaria drugs and vaccines that need testing. This is compounded by the apparent reduction (or at least change) in malaria incidence which may have resulted from to better access to new drugs and increased bed net use (although this has yet to be proved). Product developers and clinical trial sites need to be prepared and adaptable. Drug trials might required longer recruitment times and more sites in order to enrol enough children with uncomplicated malaria, and vaccine trials may need a longer period of follow-up to capture enough cases for efficacy endpoints. Investigators will need to be flexible and prepared to move locations (possibly often) by adapting to data on localised incidence rates. It might appear that the obvious answer is to conduct malaria trials in even less accessible areas where bed nets and newer treatments have not yet reached. This is no easy solution as this brings a substantial ethical requirement for making available the best standard of care along with the trial infrastructure. In practice, this would be making bed nets available to the whole community and addressing the issue of sustaining the benefits of improved access to medical care once the trial has been completed. From the perspective of protocol design and product development, potential investigators should be exposed in detail to the drug or vaccine’s clinical development plan and feedback from the regulatory agencies. This will give sites a better understanding of the rationale for each individual protocol and in turn this will help them contribute to protocol design more strategically. The result should be better protocols that reflect the practicalities of disease, local epidemiology and standard of care, yet still remain focused on capturing the data required for registration. Dialogue and recognition of the issue are needed between the product developers and investigators to limit the negative impact of large field-based regulatory trials on ward-based studies of severe disease. The issue might be resolved by altering trial designs. By making severe disease an endpoint, participants would be free to take part in wardbased studies without compromising the data of the original regulatory study. Co-enrolment to more than one trial is an easier solution if it would be acceptable to the regulatory authorities and developers or change the ability of either trial to measure their endpoints. As these new products come through the pipeline from partnerships engaged in malaria drug and vaccine development, the number of international standard clinical trial
10 sites should grow proportionately. This presents exciting new opportunities for African trialists that should be used to their maximum potential. Acknowledgement: This work has been conducted with the permission of the Director of the KEMRI-Wellcome Programme, Kilifi, Kenya. Funding: None. Conflicts of interest: None declared. Ethical approval: Not required.
References Aide, P., Bassat, Q., Alonso, P.L., 2007. Towards an effective malaria vaccine. Arch. Dis. Child. 92, 476—479. Ballou, W.R., 2005. Malaria vaccines in development. Expert Opin. Emerg. Drugs 10, 489—503. Breman, J.G., Alilio, M.S., Mills, A., 2004. Conquering the intolerable burden of malaria: what’s new, what’s needed: a summary. Am. J. Trop. Med. Hyg. 71, 1—15. Bundred, P.E., Levitt, C., 2000. Medical migration: who are the real losers? Lancet 356, 245—246.
T.A. Lang, G.O. Kokwaro Croft, S.L., 2005. Public—private partnership: from there to here. Trans. R. Soc. Trop. Med. Hyg. 99 (Suppl. 1), S9—S14. Greenwood, B., 2005. Malaria vaccines. Evaluation and implementation. Acta Trop. 95, 298—304. ICH, 1996. Good Clinical Practice: consolidated guideline. ICH Harmonised Tripartite Guideline. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Geneva. http://www.ich.org/ [accessed 8 August 2007]. Kilama, W.L., 2003. Malaria vaccines in Africa. Acta Trop. 88, 153—159. Lang, T., Greenwood, B., 2003. The development of Lapdap, an affordable new treatment for malaria. Lancet Infect. Dis. 3, 162—168. MMV, 2006. Portfolio 3rd Q 2006. Medicines for Malaria Venture, Geneva. http://www.mmv.org/IMG/pdf/Portfolio 2006 3QV4 3 .pdf [accessed 8 August 2007]. MVI, 2006. Development Projects. Malaria Vaccine Initiative, Bethesda, MD. http://www.malariavaccine.org/ab-current projects.htm [accessed 8 August 2007]. Snow, R.W., Craig, M., Deichmann, U., Marsh, K., 1999. Estimating mortality, morbidity and disability due to malaria among Africa’s non-pregnant population. Bull. World Health Organ. 77, 624—640. Trouiller, P., Olliaro, P.L., 1999. Drug development output: what proportion for tropical diseases? Lancet 354, 164. White, N.J., 2006. Developing drugs for neglected diseases. Trop. Med. Int. Health 11, 383—384.
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/trst
REVIEW
Malaria drug and vaccine trials in Africa: obstacles and opportunities T.A. Lang a,∗, G.O. Kokwaro b,c a
KEMRI/Wellcome Trust Programme, P.O. Box 230, Kilifi, Kenya Department of Pharmaceutics and Pharmacy Practice, Faculty of Pharmacy, University of Nairobi, Nairobi, Kenya c KEMRI/Wellcome Trust Programme, Nairobi, Kenya b
Received 10 May 2007; received in revised form 24 August 2007; accepted 24 August 2007 Available online 29 October 2007
KEYWORDS Malaria; Trials; Public—private partnerships; Drug development; Vaccine development; Capacity building; Africa
Summary There are several new treatments and vaccine technologies in clinical development for childhood malaria that have arrived in the clinical phase of evaluation during the past 5—10 years. This is a long-awaited change as until this time there had been little in the pipeline. As these products progress, evaluating them in the populations for whom they are being developed is becoming increasingly challenging. Many more capable trial sites are required and thousands of children and their parents need to be willing to take part in all the clinical trials that will be necessary if even a handful of these products make it through to obtaining a marketing approval license. Then, beyond licensure, these products will need to be assessed in more ‘real-life’ phase IV trials to establish whether they can truly impact the high level of mortality that malaria brings to the under-five population in Africa. Here we explore the issues that face both the trial sites and the product developers and present how this opportunity should be utilised to develop experienced African clinical researchers and facilities alongside getting these products through into public health use. © 2007 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
1. Introduction Until recently, there had been a desperate lack of new candidate treatments for Plasmodium falciparum malaria and there were few vaccine candidates showing encouraging signs of immunogenicity (Ballou, 2005; Trouiller and Olliaro,
∗
Corresponding author. Tel.: +254 415 22063; fax: +254 415 522390. E-mail address: tlang@kilifi.kemri-wellcome.org (T.A. Lang).
1999). This situation is improving (White, 2006) and the largest two public—private partnerships that exist to address these deficits have made significant progress. Medicines for Malaria Venture (MMV) has four candidate drugs in phase III, five in phases I and II with a further 11 pre-clinical programmes in their pipeline (MMV, 2006). The Malaria Vaccine Initiative (MVI) has taken three varying vaccine technologies into phase I, has another two that have progressed into phase II and has six pre-clinical programmes in its portfolio (MVI, 2006). Typically, a new malaria drug requires testing in at least 2000 participants to demonstrate enough safety data for licensure (Lang and Greenwood, 2003). Efficacy can
0035-9203/$ — see front matter © 2007 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.trstmh.2007.08.008
8 usually be demonstrated in small comparative phase II trials with 200—400 participants. Phase III trials are designed to confirm the efficacy shown in phase II and to achieve the number of exposures required to prove safety and so require thousands of participants across several sites. As a vaccine for malaria is yet to be registered, there is still discussion on the data required. Many thousands of participants would be needed to prove efficacy against severe malaria (Greenwood, 2005), although for uncomplicated malaria far fewer participants would be required (Aide et al., 2007). If in the next few years these candidate drugs and vaccines are to progress to registration there will be many multicentre trials running concurrently across Africa. Furthermore, those drugs and vaccines that succeed will then need large-scale effectiveness phase IV programmes. This raises exciting opportunities whilst also presenting a testing scenario both to the developers and those responsible for the field trial sites. The developers of malaria drugs and vaccines carefully select their trial sites. They evaluate them against criteria such as experience of the investigators in conducting international regulatory standard trials, level of malaria in their location, standard of their laboratories and whether there are any potentially competing trials planned or ongoing. There is a trend for developers to use the same sites and often those with a European or American affiliation (Kilama, 2003). However, if there are to be enough sites to cope with this demand, a larger number of sites are needed from more diverse areas, and if this is to provide increased capacity for the long-term they should have strong local affiliations and leadership.
2. Daily realities of malaria trials Most malaria deaths occur in children under 5 years of age in rural Africa (Snow et al., 1999). Therefore, efficacy and safety needs to be measured in this age group and, if the data are to be relevant for the true target population, trials should be conducted in the type of setting where most malaria occurs. The problem is that these populations are difficult to reach. Evaluating new drugs and vaccines requires trials with high levels of intervention in terms of number of visits for the participants, observed taking of therapies or giving of vaccine as well as the taking of samples and giving medical examinations. Blood samples are essential for measuring parasite levels and for assessing the safety and pharmacokinetics of the investigational product. Other assays are also crucial to product development, especially in vaccine development where immune responses need to be measured. Laboratory facilities for such procedures are rarely available near the participants, so systems are needed either to hospitalise subjects or preferably to establish complex transport logistics to transfer the samples under the necessary conditions to the laboratory. Many laboratory assays need the samples transported at a cold temperature, further complicating and limiting the practicalities. Mapping and census systems need to be in place well before a trial begins in order to find possible participants and then to identify subject’s enrolment in a trial. This is important in the likely scenario of drug and vaccine trials competing for the same populations as well as to recognise trial participants
T.A. Lang, G.O. Kokwaro if they present at another health facility. Practical measurers such as issuing trial identification photo cards can help. It needs to be possible to find and transfer participants for the detection and management of any adverse events. This can become very difficult in the rainy seasons when roads can quickly become impassable. These are just some of the practical operational issues. From a design, recruitment and operational perspective, there are some interesting developments that should be considered by clinical programme developers. There has been a significant increase in the use of insecticide-treated bed nets and introduction of artemisinin-containing combination therapy drugs (Breman et al., 2004). Since both may impact malaria incidence rates, recent epidemiological data should be obtained at the protocol development stage, rather than relying on enrolment figures from previous trials. This is because the situation is rapidly changing and varies greatly between locations. Most published data on current bed net coverage or uptake of new drugs is only broadly relevant and therefore each site needs to evaluate its own true malaria levels to find the best trial ‘hotspots’. Another increasingly complex issue is that of coordinating research into uncomplicated malaria alongside the important question of studying severe disease. The drug and vaccine registration trials typically occur in communitybased studies and have protocols that follow children through a malaria season or longer. A usual exclusion criterion is inclusion into another trial and/or receiving another investigational product. This requires wider thinking as it is most often the experienced centres conducting large fieldbased trials that have concurrent ward-based programmes looking at severe diseases. Drug and vaccine trials could seriously reduce the number of eligible children available for the severe disease trials, thereby impeding advancement in knowledge in how to treat and manage children with life-threatening malaria.
3. Opportunities for building capacity Alongside the increase in new products through public—private partnerships, there has also been an influx of funding for capacity building to bring African trial sites up to international regulatory standard and to make them ready for this predicted flood of new products (Croft, 2005). This presents an interesting dilemma: to conduct a drug or vaccine trial there needs to be a product and a protocol, but for a site to conduct a trial they should ideally be experienced and well trained (ICH, 1996). It may be quite difficult to increase capacity quickly at inexperienced sites by using programmes not related to products. It may be better to use smaller, early-phase trials in adults or pragmatic phase IV studies to build and develop less experienced sites and thereby increase the number of sites with the potential to conduct more complex regulatory standard phase II and III trials later. There are several, large, highly experienced trial units in Africa, but many more are needed not only to allow for more multicentre trials but also to reflect the changing malaria ecologies. Development of new sites will provide opportunities not only for general infrastructure upgrade, but also for relevant training of more African trialists, monitors
Conducting African malaria drug and vaccine trials and Institutional Review Boards. Personnel training needs to be better linked with opportunities for career advancement since it is currently proving difficult to recruit African trial monitors, co-ordinators and clinicians with existing experience in the absence of proper career advancement opportunities. The few that have these skills are highly sought after by the internationally funded research units, leave research for posts in the private sector or leave Africa altogether for better paid posts in Europe and the US (Bundred and Levitt, 2000). Training capacity within Africa is also low and sponsoring organisations generally bring in their own training teams from Europe and the USA, or send their staff overseas for training. If African sites are to be able to retain their staff to direct and lead their own research agendas, they must improve their ability to train and develop clinical trial staff locally and independently. Infrastructure upgrading should include laboratories to support clinical trials on-site and avoid the current logistical problems of transporting samples to reference laboratories outside the country. Few of the current initiatives on capacity strengthening are addressing the issue of laboratory upgrading at the various sites being developed. Lastly, there is a need for a central repository where information about past, ongoing and planned clinical trials can be obtained. This database would be a good resource to search for details on site experience, training opportunities and where previous trials have been conducted, for example. There is funding available to develop trial sites and this is very welcome, although it is possibly not to a high enough level or is too tightly constrained for practical use. To be able to improve their operations, trial sites must be able to access money that they can spend where they see it is needed. It is hard to get funding for core support staff or general infrastructure. Importantly, it is the sites that are currently least engaged in internationally funded research that need to be most actively pursued and targeted. These smaller and fledgling research sites have access to populations that have not previously been part of trial programmes and are typically staffed by younger African clinicians and scientists who are keen to develop and build their capacity. Such sites are currently not able to compete with the larger and better established sites that conduct the lion’s share of the regulatory pathway trials in Africa. Organisations such as African Malaria Network Trust (AMANET), Malaria Clinical Trials Alliance (MCTA) and European & Developing Countries Clinical Trials Partnership (EDCTP) are making good progress in improving trial site capacity across Africa (http://Elearning.AmanetTrust.Org/). The e-learning tools available on the AMANET website are a huge step forward and this will hopefully expand to offer ICH Good Clinical Practice (GCP) and trial management training. If such qualifications can be obtained via the Internet, there is much greater potential for developing many more African trialists. Mentoring would be a further improvement, not only at the individual level, but perhaps it could even work at the site level by partnering younger sites with established programmes. Schemes such as posting trialists from experienced sites to the new centres they are mentoring could work well. Mentoring could be built into site selections and tendering systems, thereby integrating this into development programmes and improving sustainability.
9 Raising the capacity of sites to conduct trials must be accompanied by harmonisation and increased abilities for African countries to conduct appropriate ethical review of proposed trials. The Pan-African Bioethics Initiative recognises there is a need to establish a networking system between African ethics committees to share resources and to improve how they operate (http://www.pabin.org/Survey.aspx). Trial sponsors and capacity building organisations should be encouraged to support these efforts better as it must progress alongside the number of trials being planned and sites being expanded. Ethical review standards and resources must not lag behind.
4. Conclusions There is an incoming wave of new malaria drugs and vaccines that need testing. This is compounded by the apparent reduction (or at least change) in malaria incidence which may have resulted from to better access to new drugs and increased bed net use (although this has yet to be proved). Product developers and clinical trial sites need to be prepared and adaptable. Drug trials might required longer recruitment times and more sites in order to enrol enough children with uncomplicated malaria, and vaccine trials may need a longer period of follow-up to capture enough cases for efficacy endpoints. Investigators will need to be flexible and prepared to move locations (possibly often) by adapting to data on localised incidence rates. It might appear that the obvious answer is to conduct malaria trials in even less accessible areas where bed nets and newer treatments have not yet reached. This is no easy solution as this brings a substantial ethical requirement for making available the best standard of care along with the trial infrastructure. In practice, this would be making bed nets available to the whole community and addressing the issue of sustaining the benefits of improved access to medical care once the trial has been completed. From the perspective of protocol design and product development, potential investigators should be exposed in detail to the drug or vaccine’s clinical development plan and feedback from the regulatory agencies. This will give sites a better understanding of the rationale for each individual protocol and in turn this will help them contribute to protocol design more strategically. The result should be better protocols that reflect the practicalities of disease, local epidemiology and standard of care, yet still remain focused on capturing the data required for registration. Dialogue and recognition of the issue are needed between the product developers and investigators to limit the negative impact of large field-based regulatory trials on ward-based studies of severe disease. The issue might be resolved by altering trial designs. By making severe disease an endpoint, participants would be free to take part in wardbased studies without compromising the data of the original regulatory study. Co-enrolment to more than one trial is an easier solution if it would be acceptable to the regulatory authorities and developers or change the ability of either trial to measure their endpoints. As these new products come through the pipeline from partnerships engaged in malaria drug and vaccine development, the number of international standard clinical trial
10 sites should grow proportionately. This presents exciting new opportunities for African trialists that should be used to their maximum potential. Acknowledgement: This work has been conducted with the permission of the Director of the KEMRI-Wellcome Programme, Kilifi, Kenya. Funding: None. Conflicts of interest: None declared. Ethical approval: Not required.
References Aide, P., Bassat, Q., Alonso, P.L., 2007. Towards an effective malaria vaccine. Arch. Dis. Child. 92, 476—479. Ballou, W.R., 2005. Malaria vaccines in development. Expert Opin. Emerg. Drugs 10, 489—503. Breman, J.G., Alilio, M.S., Mills, A., 2004. Conquering the intolerable burden of malaria: what’s new, what’s needed: a summary. Am. J. Trop. Med. Hyg. 71, 1—15. Bundred, P.E., Levitt, C., 2000. Medical migration: who are the real losers? Lancet 356, 245—246.
T.A. Lang, G.O. Kokwaro Croft, S.L., 2005. Public—private partnership: from there to here. Trans. R. Soc. Trop. Med. Hyg. 99 (Suppl. 1), S9—S14. Greenwood, B., 2005. Malaria vaccines. Evaluation and implementation. Acta Trop. 95, 298—304. ICH, 1996. Good Clinical Practice: consolidated guideline. ICH Harmonised Tripartite Guideline. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Geneva. http://www.ich.org/ [accessed 8 August 2007]. Kilama, W.L., 2003. Malaria vaccines in Africa. Acta Trop. 88, 153—159. Lang, T., Greenwood, B., 2003. The development of Lapdap, an affordable new treatment for malaria. Lancet Infect. Dis. 3, 162—168. MMV, 2006. Portfolio 3rd Q 2006. Medicines for Malaria Venture, Geneva. http://www.mmv.org/IMG/pdf/Portfolio 2006 3QV4 3 .pdf [accessed 8 August 2007]. MVI, 2006. Development Projects. Malaria Vaccine Initiative, Bethesda, MD. http://www.malariavaccine.org/ab-current projects.htm [accessed 8 August 2007]. Snow, R.W., Craig, M., Deichmann, U., Marsh, K., 1999. Estimating mortality, morbidity and disability due to malaria among Africa’s non-pregnant population. Bull. World Health Organ. 77, 624—640. Trouiller, P., Olliaro, P.L., 1999. Drug development output: what proportion for tropical diseases? Lancet 354, 164. White, N.J., 2006. Developing drugs for neglected diseases. Trop. Med. Int. Health 11, 383—384.