Artesunate-Mefloquine, Partnerships in Drug Development
Artesunate-Mefloquine, Partnerships in Drug Development
Artesunate and mefloquine are well known treatments for falciparum malaria in loose combination. Since 2001, the ASMQ combination has been one of the WHO-recommended forms of ACT for first-line treatment to provide adequate cure-rates and delay the development of resistance. DNDi and partners decided to improve this therapy by developing a FDC of ASMQ, as the convenience afforded by reducing tablet numbers to once daily over three days is expected to lead to increased patient compliance and adherence. Such an undertaking required both pharmaceutical and industrial development as well as clinical studies. The subsequent technology transfer from Farmanguinhos, Brazil to Cipla Ltd, India facilitated access in endemic regions of Asia.
Development of a FDC of ASMQ has depended on close collaborations between industrial, academic, governmental and NGO research organizations, involving partnerships with and between developing countries, with independent funding provided by both public (EU's INCODEV FP5, French AFD, Dutch DGIS, Spanish AECID, Swiss SDC, UK DFID and the European Commission's EDCTP) and private (Médecins Sans Frontières, MSF) sources. The global cost of the development of ASMQ FDC, including pharmaceutical development costs, clinical studies, technology transfer and some implementation activities, is expected to amount to approximately 15 million Euros. This figure does not include in kind contributions by Farmanguinhos and Cipla Ltd, who contributed to the industrialization of the fixed dose combination.
The Universiti Sains Malaysia developed analytical and bio-analytical methods for use in quality control and clinical pharmacological studies. The analytical techniques were transferred to Farmanguinhos/Fiocruz who formulated a fixed-dose combination product with appropriate stability and biopharmaceutical characteristics, together with a viable manufacturing process and the required validated control methods. Clinical batches were produced and toxicology, bio-equivalence, bio-availability and pharmacokinetic studies performed for inclusion in registration and prequalification files.
Artesunate and MQ have been used in combination for over 20 years, involving more than 38,000 patients in 91 studies in 22 countries across Southeast Asia, the Western Pacific, Africa and Latin America. The fixed dose combination of these has been demonstrated to be efficacious and safe for treating uncomplicated malaria in more than 25,000 patients in Thailand, Myanmar, India and in a large intervention study in Brazil (Table 1). Of these, the safety and efficacy study carried out on 500 patients in Thailand was pivotal, with efficacy of the FDC comparable to that of the loose tablet combination, better toleration and a lower incidence of vomiting. In addition, the Myanmar study (808 patients) compared the effectiveness of the four ACT FDCs recommended by WHO at the time and showed the ASMQ FDC to have the highest cure rate and the lowest rate of gametocyte carriage, providing the greatest post-treatment suppression of recurrent falciparum malaria and the most effective suppression of blood-stage Plasmodium vivax malaria.
Mefloquine has been associated with an increased incidence of nausea, vomiting, dizziness, dysphoria and sleep disturbance in clinical trials and adverse reactions of varying severity have been experienced by a number of patients when taking AS and MQ in a loose combination or the FDC, primarily in the first 28 days of treatment. However, WHO notes that mefloquine-related adverse effects are seldom debilitating and where this ACT has been deployed it has been well tolerated. There were no serious adverse effects reported in the Brazilian intervention study involving more than 23,000 patients, including children, confirming the safety of the combination. In addition, ASMQ FDC was designed to provide an optimized, short-term, gastro-intestinal tolerance, reducing the overall risk of vomiting. The risk of increased neuropsychiatric reactions following the use of MQ within 60 days of treatment is not an issue in Southeast Asia, Western Pacific and Latin America, areas with low to medium transmission.
The initial targeting of Southeast Asia and Latin America was based on the low to middle intensity transmission and multidrug resistance forms of malaria in these regions. Further studies involving ASMQ FDC are now ongoing with a number of partners in African countries (Figure 1; Table 2), including children and pregnant women, and patients with sickle cell anaemia, which will provide additional information for areas with a different epidemiological profile. A large-scale study in pregnant women is also ongoing in Thailand. Children and pregnant women are among the most vulnerable of those affected by malaria.
(Enlarge Image)
Figure 1.
International partners involved in the development of ASMQ FDC. FACT Core Members: DNDi, TDR of WHO, Farmanguinhos/Fiocruz (BR), Université Bordeaux Segalen (FR), Universiti Sains Malaysia (MY), Mahidol University (TH), Mahidol Oxford Tropical Medicine Research Unit, Shoklo Malaria Research Unit (TH), Centre National de Recherche et de la Formation sur le Paludisme (CNRFP) (BF), University of Oxford (UK). Preclinical Development: Universiti Sains Malaysia (MY), Farmanguinhos/Fiocruz (BR), Cipla Ltd (IN). Clinical Development: Southeast Asia: University of Oxford (UK), Mahidol University (TH), Mahidol Oxford Tropical Medicine Research Unit (TH), University Sains Malaysia (MY), Shoklo Malaria Research Unit (TH), Mae Sot Clinic (TH), Indian Council for Medical Research (IN), Médecins Sans Frontières, Medical Action Myanmar (MM); Latin America: Amazon Network for the Surveillance of Anti-malarial Drug Resistance (RAVEDRA)/Ministry of Health (BR), National Malaria Control Program Brazil; Africa: CNRFP (BF), Kenya Medical Research Institute (KEMRI) (KE), Institute of Tropical Medicine Anvers (BE), National Institute for Malaria Research (TZ), Kwame Nkrumah University (GH), Centre Muraz (BF), University of Malawi (MW), Tropical Medicines Research Centre (ZM), Royal Tropical Institute (KIT) (NL), Liverpool School of Tropical Medicine (UK), Ifakara Health Institute (TZ). Manufacturers: Farmanguinos/Fiocruz (BR), Cipla Ltd (IN).
ASMQ FDC could also play a role within the strategy of multiple first-line therapies to delay emergence and spread of disease where, in areas of high transmission, repeat treatments are likely to be necessary within 60 days of the initial treatment. A recent model predicts that in areas with high transmission, combining a gametocytocidal artemisinin derivative with a longer-acting partner drug will protect patients from re-infection and reduce transmission more effectively than some common currently used ACT regimens which are gametocyte-killing but short-acting.
Plasmodium vivax is the second most important species causing human malaria, accounting for about 40% of malaria cases worldwide. It is the dominant malaria species outside Africa, prevalent in endemic areas in Asia, Central and South America, Middle East and Oceania but rare in Africa. WHO recommends treating uncomplicated vivax malaria with chloroquine in combination with primaquine, where chloroquine is effective. However, in areas of chloroquine resistance an appropriate ACT (but not artesunate-sulphadoxine/pyrimethamine) combined with primaquine is to be used, particularly where ACT is first line therapy for P. falciparum, although primaquine is counter-indicated with severe glucose-6-phosphate dehydrogenase (G6PD) deficiency. Experience indicates that it is likely that primaquine combined with ASMQ will result in high cure rates against vivax blood stage infection and relapse. In Brazil, the Tropical Pathology Research Institute (IPEPATRO) is studying the efficacy of ASMQ FDC in treating P. vivax malaria compared to chloroquine or artemether-lumefantrine when each is administered with primaquine.
Within the FACT consortium, Farmanguinhos/Fiocruz was the first manufacturer of ASMQ FDC. The technology transfer of ASMQ FDC between Farmanguihos/Fiocruz in Brazil and Cipla Ltd (2007–2009) in India was undertaken to facilitate access to ASMQ in Southeast Asia. There were some problems encountered during this first-time process. A halt in the production of MQ API by the original manufacturer led to significant delays whilst a new manufacturer was identified and the product evaluated. There were differences in the particle size and flow compatibility of this replacement API compared with the original product necessitating changes to the manufacturing process, which required some time. In addition, Cipla's equipment differed from that used by Farmanguinhos, requiring further modifications to the process. However these improvements ultimately resulted in faster tablet manufacture of ASMQ to GMP-standards. With the resolution of these problems the transfer was completed in 2010, and as such it is a prime example of a successful south-south technology transfer.
With Cipla Ltd in charge of manufacturing in Asia, together with Indian registration granted in November 2011, the supply of ASMQ in Asia and in other parts of the world is ensured at pre-agreed prices.
DNDi worked with the Brazilian regulatory authorities, the Agencia Nacional de Vigilancia Sanitaria (ANVISA), in order to register ASMQ FDC for use in the country. In late 2006, a new piece of Brazilian registration incorporated an expedited review process for the drugs to treat neglected diseases. ASMQ FDC was granted Brazilian registration approval in March 2008 and adopted as treatment policy by the Ministry of Health as an alternative to first-line treatment for uncomplicated P. falciparum malaria.
On 29 March, 2012, the Malaysian National Pharmaceutical Control Bureau of the Ministry of Health approved the use of ASMQ FDC for the treatment of acute uncomplicated malaria resulting either from P. falciparum mono-infection or mixed infections with P. vivax. This approval is a step for ASMQ FDC within the ASEAN (Association of Southeast Asian Nations) Harmonization Scheme between health authorities, and as Malaysia is a Pharmaceutical Inspection Convention country, it should facilitate registration in the other countries. DNDi is coordinating the review of ASMQ with ASEAN regulatory authorities to obtain drug registration, which will in turn lead to adoption by malaria control programmes. The registration of ASMQ FDC is underway in countries in Southeast Asia and the Western Pacific where AS+MQ is part of a national policy for uncomplicated malaria.
WHO pre-qualified the Cipla ASMQ FDC product in September 2012. This recognition of a high-quality product will enable procurement agencies to bulk-buy goods for use in resource-poor settings. A recent analysis found that a large percentage of anti-malarial drugs in Asia and sub-Saharan Africa are either fake or of inferior quality, leading to vulnerable populations receiving poor treatment and adding to the threat of resistance developing.
The DNDi model works through collaboration and cooperation between international partners from a wide range of research settings. As such it has required the management of collaborators spread over different research centres across Europe, USA, Asia, South America and Africa. This has led to management problems not necessarily encountered in a conventional industrial setting, notably in terms of communication between the various project groups. Bi-annual project meetings were held in order to communicate results effectively between all project partners, interspersed with local research group meetings held at the relevant sites. This dispersal of knowledge and personnel meant that it took one to two years before a team could be sufficiently well established to work together efficiently and effectively, and adaptation to differing political and cultural influences was required. However, the overall belief in the value of the project, together with a desire to succeed, was highly motivating for all involved, and much was achieved.
This virtual model gave rise to some complications which would have been simpler to resolve in a traditional pharmaceutical setting, based on existing infrastructure and know-how. For example, in addition to those problems described above relating to the production of mefloquine API, another change of manufacturer had to be managed very late in development due to a halt in production of artesunate API by the selected supplier. It was essential to demonstrate the identity of the new API selected and its GMP status, as well as ensuring the Drug Master File (DMF) acceptability by regulatory authorities and WHO. In both cases, as the FACT partnership did not represent a potential big customer this made negotiations more difficult and required good will from the suppliers, who became, to some extent, members of the partnership. These API changes had an impact on the development and registration timelines. A further complication was more typical of those experienced by international organizations. The partner in Brazil, Farmanguinhos, developed the FDC according to local specifications, or to the specification in force in production. This required vigilance and adaptation, with additional analysis and documentation subsequently necessary in order for the manufactured product to fulfill development and quality specifications for worldwide use.
Finally, working with a number of different partners magnified the effects of natural turnover in personnel, at different levels. There was occasionally a risk of lack of continuity in vision which required a prolongation of project management beyond the initial years of early development, and the sustained support from the executive level management of the participating partners.
Partnerships have been set up with and between developing countries, where there has been the added benefit of building capacity of resources and knowledge in countries in South America, Southeast Asia and Africa. This in turn may lead to increased product uptake, and to local scientists and pharmaceutical firms pursuing follow-on innovations that could address local access issues.
Farmanguinhos/Fiocruz has acquired much useful knowledge and experience in its involvement with the project. ASMQ FDC was the first new product fully developed by the company, taking it through from development of the manufacturing and control processes, validation of control methods and manufacturing processes, industrial scale up and production, compilation of the regulatory file and on to successful product registration in Brazil. One employee received training in the preparation of the analytical methods related to AS at Universiti Sains Malaysia. This knowledge was passed on to Farmanguinhos/Fiocruz, as an enabling step in the control of the production process and product development. Other members of the Brazilian development team received training in toxicology studies.
During the course of this project, team members at the University Sains Malaysia learned how to perform bio-analytical work under GLP conditions, and those involved in clinical development acquired a better understanding of the requirements in developing a drug to ICH standards for regulatory approval. In India, staff involved in clinical trials were trained to GCP standards, including training in maintaining correct documentation and the completion of case record forms.
Discussion and Evaluation
Artesunate and mefloquine are well known treatments for falciparum malaria in loose combination. Since 2001, the ASMQ combination has been one of the WHO-recommended forms of ACT for first-line treatment to provide adequate cure-rates and delay the development of resistance. DNDi and partners decided to improve this therapy by developing a FDC of ASMQ, as the convenience afforded by reducing tablet numbers to once daily over three days is expected to lead to increased patient compliance and adherence. Such an undertaking required both pharmaceutical and industrial development as well as clinical studies. The subsequent technology transfer from Farmanguinhos, Brazil to Cipla Ltd, India facilitated access in endemic regions of Asia.
Development of a FDC of ASMQ has depended on close collaborations between industrial, academic, governmental and NGO research organizations, involving partnerships with and between developing countries, with independent funding provided by both public (EU's INCODEV FP5, French AFD, Dutch DGIS, Spanish AECID, Swiss SDC, UK DFID and the European Commission's EDCTP) and private (Médecins Sans Frontières, MSF) sources. The global cost of the development of ASMQ FDC, including pharmaceutical development costs, clinical studies, technology transfer and some implementation activities, is expected to amount to approximately 15 million Euros. This figure does not include in kind contributions by Farmanguinhos and Cipla Ltd, who contributed to the industrialization of the fixed dose combination.
Pharmaceutical and Preclinical Development
The Universiti Sains Malaysia developed analytical and bio-analytical methods for use in quality control and clinical pharmacological studies. The analytical techniques were transferred to Farmanguinhos/Fiocruz who formulated a fixed-dose combination product with appropriate stability and biopharmaceutical characteristics, together with a viable manufacturing process and the required validated control methods. Clinical batches were produced and toxicology, bio-equivalence, bio-availability and pharmacokinetic studies performed for inclusion in registration and prequalification files.
Clinical Development
Artesunate and MQ have been used in combination for over 20 years, involving more than 38,000 patients in 91 studies in 22 countries across Southeast Asia, the Western Pacific, Africa and Latin America. The fixed dose combination of these has been demonstrated to be efficacious and safe for treating uncomplicated malaria in more than 25,000 patients in Thailand, Myanmar, India and in a large intervention study in Brazil (Table 1). Of these, the safety and efficacy study carried out on 500 patients in Thailand was pivotal, with efficacy of the FDC comparable to that of the loose tablet combination, better toleration and a lower incidence of vomiting. In addition, the Myanmar study (808 patients) compared the effectiveness of the four ACT FDCs recommended by WHO at the time and showed the ASMQ FDC to have the highest cure rate and the lowest rate of gametocyte carriage, providing the greatest post-treatment suppression of recurrent falciparum malaria and the most effective suppression of blood-stage Plasmodium vivax malaria.
Mefloquine has been associated with an increased incidence of nausea, vomiting, dizziness, dysphoria and sleep disturbance in clinical trials and adverse reactions of varying severity have been experienced by a number of patients when taking AS and MQ in a loose combination or the FDC, primarily in the first 28 days of treatment. However, WHO notes that mefloquine-related adverse effects are seldom debilitating and where this ACT has been deployed it has been well tolerated. There were no serious adverse effects reported in the Brazilian intervention study involving more than 23,000 patients, including children, confirming the safety of the combination. In addition, ASMQ FDC was designed to provide an optimized, short-term, gastro-intestinal tolerance, reducing the overall risk of vomiting. The risk of increased neuropsychiatric reactions following the use of MQ within 60 days of treatment is not an issue in Southeast Asia, Western Pacific and Latin America, areas with low to medium transmission.
The initial targeting of Southeast Asia and Latin America was based on the low to middle intensity transmission and multidrug resistance forms of malaria in these regions. Further studies involving ASMQ FDC are now ongoing with a number of partners in African countries (Figure 1; Table 2), including children and pregnant women, and patients with sickle cell anaemia, which will provide additional information for areas with a different epidemiological profile. A large-scale study in pregnant women is also ongoing in Thailand. Children and pregnant women are among the most vulnerable of those affected by malaria.
(Enlarge Image)
Figure 1.
International partners involved in the development of ASMQ FDC. FACT Core Members: DNDi, TDR of WHO, Farmanguinhos/Fiocruz (BR), Université Bordeaux Segalen (FR), Universiti Sains Malaysia (MY), Mahidol University (TH), Mahidol Oxford Tropical Medicine Research Unit, Shoklo Malaria Research Unit (TH), Centre National de Recherche et de la Formation sur le Paludisme (CNRFP) (BF), University of Oxford (UK). Preclinical Development: Universiti Sains Malaysia (MY), Farmanguinhos/Fiocruz (BR), Cipla Ltd (IN). Clinical Development: Southeast Asia: University of Oxford (UK), Mahidol University (TH), Mahidol Oxford Tropical Medicine Research Unit (TH), University Sains Malaysia (MY), Shoklo Malaria Research Unit (TH), Mae Sot Clinic (TH), Indian Council for Medical Research (IN), Médecins Sans Frontières, Medical Action Myanmar (MM); Latin America: Amazon Network for the Surveillance of Anti-malarial Drug Resistance (RAVEDRA)/Ministry of Health (BR), National Malaria Control Program Brazil; Africa: CNRFP (BF), Kenya Medical Research Institute (KEMRI) (KE), Institute of Tropical Medicine Anvers (BE), National Institute for Malaria Research (TZ), Kwame Nkrumah University (GH), Centre Muraz (BF), University of Malawi (MW), Tropical Medicines Research Centre (ZM), Royal Tropical Institute (KIT) (NL), Liverpool School of Tropical Medicine (UK), Ifakara Health Institute (TZ). Manufacturers: Farmanguinos/Fiocruz (BR), Cipla Ltd (IN).
ASMQ FDC could also play a role within the strategy of multiple first-line therapies to delay emergence and spread of disease where, in areas of high transmission, repeat treatments are likely to be necessary within 60 days of the initial treatment. A recent model predicts that in areas with high transmission, combining a gametocytocidal artemisinin derivative with a longer-acting partner drug will protect patients from re-infection and reduce transmission more effectively than some common currently used ACT regimens which are gametocyte-killing but short-acting.
Plasmodium vivax is the second most important species causing human malaria, accounting for about 40% of malaria cases worldwide. It is the dominant malaria species outside Africa, prevalent in endemic areas in Asia, Central and South America, Middle East and Oceania but rare in Africa. WHO recommends treating uncomplicated vivax malaria with chloroquine in combination with primaquine, where chloroquine is effective. However, in areas of chloroquine resistance an appropriate ACT (but not artesunate-sulphadoxine/pyrimethamine) combined with primaquine is to be used, particularly where ACT is first line therapy for P. falciparum, although primaquine is counter-indicated with severe glucose-6-phosphate dehydrogenase (G6PD) deficiency. Experience indicates that it is likely that primaquine combined with ASMQ will result in high cure rates against vivax blood stage infection and relapse. In Brazil, the Tropical Pathology Research Institute (IPEPATRO) is studying the efficacy of ASMQ FDC in treating P. vivax malaria compared to chloroquine or artemether-lumefantrine when each is administered with primaquine.
Technology Transfer
Within the FACT consortium, Farmanguinhos/Fiocruz was the first manufacturer of ASMQ FDC. The technology transfer of ASMQ FDC between Farmanguihos/Fiocruz in Brazil and Cipla Ltd (2007–2009) in India was undertaken to facilitate access to ASMQ in Southeast Asia. There were some problems encountered during this first-time process. A halt in the production of MQ API by the original manufacturer led to significant delays whilst a new manufacturer was identified and the product evaluated. There were differences in the particle size and flow compatibility of this replacement API compared with the original product necessitating changes to the manufacturing process, which required some time. In addition, Cipla's equipment differed from that used by Farmanguinhos, requiring further modifications to the process. However these improvements ultimately resulted in faster tablet manufacture of ASMQ to GMP-standards. With the resolution of these problems the transfer was completed in 2010, and as such it is a prime example of a successful south-south technology transfer.
With Cipla Ltd in charge of manufacturing in Asia, together with Indian registration granted in November 2011, the supply of ASMQ in Asia and in other parts of the world is ensured at pre-agreed prices.
Product Registration and Prequalification
DNDi worked with the Brazilian regulatory authorities, the Agencia Nacional de Vigilancia Sanitaria (ANVISA), in order to register ASMQ FDC for use in the country. In late 2006, a new piece of Brazilian registration incorporated an expedited review process for the drugs to treat neglected diseases. ASMQ FDC was granted Brazilian registration approval in March 2008 and adopted as treatment policy by the Ministry of Health as an alternative to first-line treatment for uncomplicated P. falciparum malaria.
On 29 March, 2012, the Malaysian National Pharmaceutical Control Bureau of the Ministry of Health approved the use of ASMQ FDC for the treatment of acute uncomplicated malaria resulting either from P. falciparum mono-infection or mixed infections with P. vivax. This approval is a step for ASMQ FDC within the ASEAN (Association of Southeast Asian Nations) Harmonization Scheme between health authorities, and as Malaysia is a Pharmaceutical Inspection Convention country, it should facilitate registration in the other countries. DNDi is coordinating the review of ASMQ with ASEAN regulatory authorities to obtain drug registration, which will in turn lead to adoption by malaria control programmes. The registration of ASMQ FDC is underway in countries in Southeast Asia and the Western Pacific where AS+MQ is part of a national policy for uncomplicated malaria.
WHO pre-qualified the Cipla ASMQ FDC product in September 2012. This recognition of a high-quality product will enable procurement agencies to bulk-buy goods for use in resource-poor settings. A recent analysis found that a large percentage of anti-malarial drugs in Asia and sub-Saharan Africa are either fake or of inferior quality, leading to vulnerable populations receiving poor treatment and adding to the threat of resistance developing.
Working With a Virtual Model
The DNDi model works through collaboration and cooperation between international partners from a wide range of research settings. As such it has required the management of collaborators spread over different research centres across Europe, USA, Asia, South America and Africa. This has led to management problems not necessarily encountered in a conventional industrial setting, notably in terms of communication between the various project groups. Bi-annual project meetings were held in order to communicate results effectively between all project partners, interspersed with local research group meetings held at the relevant sites. This dispersal of knowledge and personnel meant that it took one to two years before a team could be sufficiently well established to work together efficiently and effectively, and adaptation to differing political and cultural influences was required. However, the overall belief in the value of the project, together with a desire to succeed, was highly motivating for all involved, and much was achieved.
This virtual model gave rise to some complications which would have been simpler to resolve in a traditional pharmaceutical setting, based on existing infrastructure and know-how. For example, in addition to those problems described above relating to the production of mefloquine API, another change of manufacturer had to be managed very late in development due to a halt in production of artesunate API by the selected supplier. It was essential to demonstrate the identity of the new API selected and its GMP status, as well as ensuring the Drug Master File (DMF) acceptability by regulatory authorities and WHO. In both cases, as the FACT partnership did not represent a potential big customer this made negotiations more difficult and required good will from the suppliers, who became, to some extent, members of the partnership. These API changes had an impact on the development and registration timelines. A further complication was more typical of those experienced by international organizations. The partner in Brazil, Farmanguinhos, developed the FDC according to local specifications, or to the specification in force in production. This required vigilance and adaptation, with additional analysis and documentation subsequently necessary in order for the manufactured product to fulfill development and quality specifications for worldwide use.
Finally, working with a number of different partners magnified the effects of natural turnover in personnel, at different levels. There was occasionally a risk of lack of continuity in vision which required a prolongation of project management beyond the initial years of early development, and the sustained support from the executive level management of the participating partners.
Capacity Building
Partnerships have been set up with and between developing countries, where there has been the added benefit of building capacity of resources and knowledge in countries in South America, Southeast Asia and Africa. This in turn may lead to increased product uptake, and to local scientists and pharmaceutical firms pursuing follow-on innovations that could address local access issues.
Farmanguinhos/Fiocruz has acquired much useful knowledge and experience in its involvement with the project. ASMQ FDC was the first new product fully developed by the company, taking it through from development of the manufacturing and control processes, validation of control methods and manufacturing processes, industrial scale up and production, compilation of the regulatory file and on to successful product registration in Brazil. One employee received training in the preparation of the analytical methods related to AS at Universiti Sains Malaysia. This knowledge was passed on to Farmanguinhos/Fiocruz, as an enabling step in the control of the production process and product development. Other members of the Brazilian development team received training in toxicology studies.
During the course of this project, team members at the University Sains Malaysia learned how to perform bio-analytical work under GLP conditions, and those involved in clinical development acquired a better understanding of the requirements in developing a drug to ICH standards for regulatory approval. In India, staff involved in clinical trials were trained to GCP standards, including training in maintaining correct documentation and the completion of case record forms.
