Development of standardized laboratory methods and quality processes for a phase III study of the RTS, S/AS01 candidate malaria vaccine

Christine Swysen, Johan Vekemans, Myriam Bruls, Sunny Oyakhirome, Chris Drakeley, Peter Kremsner, Brian Greenwood, Opokua Ofori-Anyinam, Brenda Okech, Tonya Villafana, Terrell Carter, Barbara Savarese, Adriano Duse, Andrea Reijman, Charlotte Ingram, John Frean, Bernhards Ogutu, Clinical Trials Partnership Committee, Seth Owusu-Agyei, Kwaku Poku Asante, Salim Abdulla, Eusebio Macete, Jahit Sacarlal, Philip Bejon, Trudie Lang, Kevin Marsh, Patricia Njugana, Ally Olotu, Tinto Halidou, Selidji Todagbe Agnandji, Bertrand Lell, Jennifer Evans, Tsiri Agbenyega, Daniel Ansong, Mary Hamel, Simon Kariuki, David Jones, Walter Otieno, Francis Martinson, Cheikh Sadibou-Sokhna, Jean-François Trape, Samwel Gesase, Martha Lemenge, John Lusingu, Umberto D'Allessandro, Peter Kremsner, John Aponte, Marcel Tanner, Brian Greenwood, Lorenz von-Seidlein, Laurence Slutsker, Irving Hoffman, W Ripley Ballou, Alice Grasset, Didier Lapierre, Amanda Leach, Johan Vekemans, Laurence Vigneron, Anne Walsh, Alan Brooks, Filip Dubovsky, Santiago Ferro Carol Hooks, Christian Loucq, Melinda Moree, John McNeil, Carolyn Petersen, David Poland, Patricia Atkinson, Barbara Savarese, Marla Sillman, Tonya Villafana, Christine Swysen, Johan Vekemans, Myriam Bruls, Sunny Oyakhirome, Chris Drakeley, Peter Kremsner, Brian Greenwood, Opokua Ofori-Anyinam, Brenda Okech, Tonya Villafana, Terrell Carter, Barbara Savarese, Adriano Duse, Andrea Reijman, Charlotte Ingram, John Frean, Bernhards Ogutu, Clinical Trials Partnership Committee, Seth Owusu-Agyei, Kwaku Poku Asante, Salim Abdulla, Eusebio Macete, Jahit Sacarlal, Philip Bejon, Trudie Lang, Kevin Marsh, Patricia Njugana, Ally Olotu, Tinto Halidou, Selidji Todagbe Agnandji, Bertrand Lell, Jennifer Evans, Tsiri Agbenyega, Daniel Ansong, Mary Hamel, Simon Kariuki, David Jones, Walter Otieno, Francis Martinson, Cheikh Sadibou-Sokhna, Jean-François Trape, Samwel Gesase, Martha Lemenge, John Lusingu, Umberto D'Allessandro, Peter Kremsner, John Aponte, Marcel Tanner, Brian Greenwood, Lorenz von-Seidlein, Laurence Slutsker, Irving Hoffman, W Ripley Ballou, Alice Grasset, Didier Lapierre, Amanda Leach, Johan Vekemans, Laurence Vigneron, Anne Walsh, Alan Brooks, Filip Dubovsky, Santiago Ferro Carol Hooks, Christian Loucq, Melinda Moree, John McNeil, Carolyn Petersen, David Poland, Patricia Atkinson, Barbara Savarese, Marla Sillman, Tonya Villafana

Abstract

Background: A pivotal phase III study of the RTS,S/AS01 malaria candidate vaccine is ongoing in several research centres across Africa. The development and establishment of quality systems was a requirement for trial conduct to meet international regulatory standards, as well as providing an important capacity strengthening opportunity for study centres.

Methods: Standardized laboratory methods and quality assurance processes were implemented at each of the study centres, facilitated by funding partners.

Results: A robust protocol for determination of parasite density based on actual blood cell counts was set up in accordance with World Health Organization recommendations. Automated equipment including haematology and biochemistry analyzers were put in place with standard methods for bedside testing of glycaemia, base excess and lactacidaemia. Facilities for X-rays and basic microbiology testing were also provided or upgraded alongside health care infrastructure in some centres. External quality assurance assessment of all major laboratory methods was established and method qualification by each laboratory demonstrated. The resulting capacity strengthening has ensured laboratory evaluations are conducted locally to the high standards required in clinical trials.

Conclusion: Major efforts by study centres, together with support from collaborating parties, have allowed standardized methods and robust quality assurance processes to be put in place for the phase III evaluation of the RTS, S/AS01 malaria candidate vaccine. Extensive training programmes, coupled with continuous commitment from research centre staff, have been the key elements behind the successful implementation of quality processes. It is expected these activities will culminate in healthcare benefits for the subjects and communities participating in these trials.

Trial registration: Clinicaltrials.gov NCT00866619.

Figures

Figure 1
Figure 1
Parasite density counting methodology (method 1).
Figure 2
Figure 2
Parasite density counting: criteria for concordance of readings and determination of final result.

References

    1. Abdulla S, Oberholzer R, Juma O, Kubhoja S, Machera F, Membi C, Omari S, Urassa A, Mshinda H, Jumanne A, Salim N, Shomari M, Aebi T, Schellenberg DM, Carter T, Villafana T, Demoitié MA, Dubois MC, Leach A, Lievens M, Vekemans J, Cohen J, Ballou WR, Tanner M. Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N Engl J Med. 2008;359:2533–2544. doi: 10.1056/NEJMoa0807773.
    1. Agnandji ST, Asante KP, Lyimo J, Vekemans J, Soulanoudjingar SS, Owusu R, Shomari M, Leach A, Fernandes J, Dosoo D, Chikawe M, Issifou S, Osei-Kwakye K, Lievens M, Paricek M, Apanga S, Mwangoka G, Okissi B, Kwara E, Minja R, Lange J, Boahen O, Kayan K, Adjei G, Chandramohan D, Jongert E, Demoitié MA, Dubois MC, Carter T, Vansadia P, Villafana T, Sillman M, Savarese B, Lapierre D, Ballou WR, Greenwood B, Tanner M, Cohen J, Kremsner PG, Lell B, Owusu-Agyei S, Abdulla S. Evaluation of the safety and immunogenicity of the RTS,S/AS01 malaria candidate vaccine when integrated in the Expanded Program of Immunization. J Infect Dis. 2010;202:1076–1087. doi: 10.1086/656190.
    1. Alonso PL, Sacarlal J, Aponte JJ, Leach A, Macete E, Aide P, Sigauque B, Milman J, Mandomando I, Bassat Q, Guinovart C, Espasa M, Corachan S, Lievens M, Navia MM, Dubois MC, Menendez C, Dubovsky F, Cohen J, Thompson R, Ballou WR. Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial. Lancet. 2005;366:2012–2018. doi: 10.1016/S0140-6736(05)67669-6.
    1. Aponte JJ, Aide P, Renom M, Mandomando I, Bassat Q, Sacarlal J, Manaca MN, Lafuente S, Barbosa A, Leach A, Lievens M, Vekemans J, Sigauque B, Dubois MC, Demoitié MA, Sillman M, Savarese B, McNeil JG, Macete E, Ballou WR, Cohen J, Alonso PL. Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial. Lancet. 2007;370:1543–1551. doi: 10.1016/S0140-6736(07)61542-6.
    1. Bejon P, Lusingu J, Olotu A, Leach A, Lievens M, Vekemans J, Mshamu S, Lang T, Gould J, Dubois MC, Demoitié MA, Stallaert JF, Vansadia P, Carter T, Njuguna P, Awuondo KO, Malabeja A, Abdul O, Gesase S, Mturi N, Drakeley CJ, Savarese B, Villafana T, Ballou WR, Cohen J, Riley EM, Lemnge MM, Marsh K, von Seidlein L. Efficacy of RTS,S/AS01 vaccine against malaria in children 5 to 17 months of age. N Engl J Med. 2008;359:2521–2532. doi: 10.1056/NEJMoa0807381.
    1. Asante KP, Abdulla S, Agnandji S, Lyimo J, Vekemans J, Soulanoudjingar S, Owusu R, Shomari M, Leach A, Jongert E, Salim N, Fernandes J, Dosoo D, Chikawe M, Saadou I, Osei-Kwakye K, Lievens M, Paricek M, Möller T, Apanga S, Mwangoka G, Dubois M-C, Tigani M, Kwara E, Minja R, Houkpatin A, Boahen O, Kayan K, Adjei G, Chandramohan D, Carter T, Vansadia P, Sillman M, Savarese B, Loucq C, Lapierre D, Greenwood B, Cohen J, Kremsner P, Owusu Agyei S, Tanner M, Lell B. Safety and efficacy over 19 months of the RTS,S/AS01E candidate malaria vaccine co-administered with Expanded Program of Immunization vaccines: an open randomized controlled trial. Lancet Infect Dis. in press .
    1. Sacarlal J, Aide P, Aponte JJ, Renom M, Leach A, Mandomando I, Lievens M, Bassat Q, Lafuente S, Macete E, Vekemans J, Guinovart C, Sigaúque B, Sillman M, Milman J, Dubois MC, Demoitié MA, Thonnard J, Menéndez C, Ballou WR, Cohen J, Alonso PL. Long-term safety and efficacy of the RTS,S/AS02A malaria vaccine in Mozambican children. J Infect Dis. 2009;200:329–336. doi: 10.1086/600119.
    1. Schluger N, Karunakara U, Lienhardt C, Nyirenda T, Chaisson R. Building clinical trial capacity for tuberculosis drugs in high-burden countries. PLoS Med. 2007;4:e302. doi: 10.1371/journal.pmed.0040302.
    1. Moorthy V, Reed Z, Smith PG. on behalf of the WHO Study Group on Measures of Malaria Vaccine Efficacy. Measurement of malaria vaccine efficacy in phase III trials: Report of a WHO consultation. Vaccine. 2007;25:5115–5123. doi: 10.1016/j.vaccine.2007.01.085.
    1. Greenwood BM, Armstrong JRM. Comparison of two simple methods for determining malaria parasite density. Trans R Soc Trop Med Hyg. 1991;85:186–188. doi: 10.1016/0035-9203(91)90015-Q.
    1. Planche T, Krishna S, Kombila M, Engel K, Faucher JF, Ngou-Milama E, Kremsner PG. Comparison of methods for the rapid laboratory assessment of children with malaria. Am J Trop Med Hygiene. 2001;65:599–602.
    1. World Health Organization. Informal consultation on quality control of malaria microscopy. Geneva: WHO; 2006.
    1. Westgard JO. Basic QC Practices: Training in Statistical Quality Control for Medical Laboratories. 3. Madison WI: Westgard Quality Corporation; 2010.
    1. Vekemans J, Marsh K, Greenwood B, Leach A, Kabore W, Soulanoudjingar S, Asante KP, Ansong D, Evans J, Sacarlal J, Bejon P, Kamthunzi P, Salim N, Njuguna P, Hamel M, Otieno W, Gesase S, Schellenberg D. Assessment of severe malaria in a multicentre, phase III, RTS,S/AS01 malaria candidate vaccine trial: case definition, standardization of data collection and patient care. Malar J. in press .
    1. Mahon CR, Manuselis G. Textbook of Diagnostic Microbiology. 2. Philadelphia: Saunders; 2000.
    1. Winn W, Allen S, Janda W, Koneman E, Procop G, Schreckenberger P, Woods G. Koneman's Color Atlas and Textbook of Diagnostic Microbiology. 6. Philadelphia: Lippincott Williams and Wilkins; 2006.
    1. Participants in the 2001 Conference on Ethical Aspects of Research in Developing Countries [Participants]. Fair benefits for research in developing countries. Science. 2002;298:2133–2134. doi: 10.1126/science.1076899.
    1. Participants in the 2001 Conference on Ethical Aspects of Research in Developing Countries [Participants]. Moral standards for research in developing countries. From "reasonable availability" to "fair benefits". Hastings Cent Rep. 2004;34:17–27.
    1. Schulz-Baldes A, Vayena E, Biller-Andorno K. Sharing benefits in international research. EMBO Reports. 2007;8:8–13. doi: 10.1038/sj.embor.7400886.

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