Towards early inclusion of children in tuberculosis drugs trials: a consensus statement

Sharon Nachman¹, Amina Ahmed², Farhana Amanullah³, Mercedes C Becerra⁴, Radu Botgros⁵, Grania Brigden⁶, Renee Browning⁷, Elizabeth Gardiner⁸, Richard Hafner⁷, Anneke Hesseling⁹, Cleotilde How¹⁰, Patrick Jean-Philippe¹¹, Erica Lessem¹², Mamodikoe Makhene⁷, Nontombi Mbelle¹³, Ben Marais¹⁴, Helen McIlleron¹⁵, David F McNeeley¹⁶, Carl Mendel⁸, Stephen Murray⁸, Eileen Navarro¹⁷, E Gloria Anyalechi¹⁸, Ariel R Porcalla¹⁷, Clydette Powell¹⁹, Mair Powell⁵, Mona Rigaud²⁰, Vanessa Rouzier²¹, Pearl Samson²², H Simon Schaaf⁹, Seema Shah²³, Jeff Starke²⁴, Soumya Swaminathan²⁵, Eric Wobudeya²⁶, Carol Worrell²⁷

Affiliations

¹ SUNY at Stony Brook, Stony Brook, NY, USA. Electronic address: sharon.nachman@stonybrook.edu.
² Levine Children's Hospital at Carolinas Medical Center, Charlotte, NC, USA.
³ Indus Hospital, Pakistan.
⁴ Harvard Medical School, Boston, MA, USA.
⁵ European Medicines Agency, London, UK.
⁶ Médecins Sans Frontières, Access Campaign, Geneva, Switzerland.
⁷ National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS, Bethesda, MD, USA.
⁸ TB Alliance, New York, NY, USA.
⁹ Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University, Cape Town, South Africa.
¹⁰ Department of Pharmacology and Toxicology, University of the Philippines, Manila, Philippines.
¹¹ Henry M Jackson Foundation-Division of AIDS, Contractor to National Institutes of Health, National Institute of Allergy and Infectious Diseases, Department of Health and Human Services, Bethesda, MD, USA.
¹² Treatment Action Group, New York, NY, USA.
¹³ Department of Medical Microbiology, University of Pretoria, Pretoria, South Africa.
¹⁴ Marie Bashir Institute for Infectious Diseases and Biosecurity and the Sydney Emerging Infectious Diseases and Biosecurity Institute and The Children's Hospital at Westmead, Sydney Medical School, University of Sydney, Sydney, Australia.
¹⁵ Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa.
¹⁶ Novartis Pharmaceuticals, East Hanover, NJ, USA.
¹⁷ Division of Anti-Infective Products; Office of Antimicrobial Products, Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
¹⁸ US Centers for Disease Control and Prevention, Division of Tuberculosis Elimination, International Research and Programs Branch, Atlanta, GA, USA.
¹⁹ US Agency for International Development, Washington, DC, USA.
²⁰ New York University School of Medicine, NY, USA.
²¹ GHESKIO, Port-au-Prince, Haiti.
²² Statistical and Data Analysis Center, Center for Biostatistics in AIDS Research and Frontier Science, Harvard School of Public Health, Boston, MA, USA.
²³ Department of Bioethics, NIH Clinical Center, Bethesda, MD, USA.
²⁴ Baylor College of Medicine, Houston, TX, USA.
²⁵ National Institute for Research in Tuberculosis, Chennai, India.
²⁶ Makerere University Johns Hopkins Research Collaboration, and Mulago National Referral Hospital, Kampala, Uganda.
²⁷ Eunice Kennedy Schriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD, USA.

PMID: 25957923
PMCID: PMC4471052
DOI: 10.1016/S1473-3099(15)00007-9

Review

Towards early inclusion of children in tuberculosis drugs trials: a consensus statement

Sharon Nachman et al. Lancet Infect Dis. 2015 Jun.

. 2015 Jun;15(6):711-20.

doi: 10.1016/S1473-3099(15)00007-9. Epub 2015 May 6.

Authors

Affiliations

¹ SUNY at Stony Brook, Stony Brook, NY, USA. Electronic address: sharon.nachman@stonybrook.edu.
² Levine Children's Hospital at Carolinas Medical Center, Charlotte, NC, USA.
³ Indus Hospital, Pakistan.
⁴ Harvard Medical School, Boston, MA, USA.
⁵ European Medicines Agency, London, UK.
⁶ Médecins Sans Frontières, Access Campaign, Geneva, Switzerland.
⁷ National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS, Bethesda, MD, USA.
⁸ TB Alliance, New York, NY, USA.
⁹ Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University, Cape Town, South Africa.
¹⁰ Department of Pharmacology and Toxicology, University of the Philippines, Manila, Philippines.
¹¹ Henry M Jackson Foundation-Division of AIDS, Contractor to National Institutes of Health, National Institute of Allergy and Infectious Diseases, Department of Health and Human Services, Bethesda, MD, USA.
¹² Treatment Action Group, New York, NY, USA.
¹³ Department of Medical Microbiology, University of Pretoria, Pretoria, South Africa.
¹⁴ Marie Bashir Institute for Infectious Diseases and Biosecurity and the Sydney Emerging Infectious Diseases and Biosecurity Institute and The Children's Hospital at Westmead, Sydney Medical School, University of Sydney, Sydney, Australia.
¹⁵ Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa.
¹⁶ Novartis Pharmaceuticals, East Hanover, NJ, USA.
¹⁷ Division of Anti-Infective Products; Office of Antimicrobial Products, Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
¹⁸ US Centers for Disease Control and Prevention, Division of Tuberculosis Elimination, International Research and Programs Branch, Atlanta, GA, USA.
¹⁹ US Agency for International Development, Washington, DC, USA.
²⁰ New York University School of Medicine, NY, USA.
²¹ GHESKIO, Port-au-Prince, Haiti.
²² Statistical and Data Analysis Center, Center for Biostatistics in AIDS Research and Frontier Science, Harvard School of Public Health, Boston, MA, USA.
²³ Department of Bioethics, NIH Clinical Center, Bethesda, MD, USA.
²⁴ Baylor College of Medicine, Houston, TX, USA.
²⁵ National Institute for Research in Tuberculosis, Chennai, India.
²⁶ Makerere University Johns Hopkins Research Collaboration, and Mulago National Referral Hospital, Kampala, Uganda.
²⁷ Eunice Kennedy Schriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD, USA.

PMID: 25957923
PMCID: PMC4471052
DOI: 10.1016/S1473-3099(15)00007-9

Abstract

Children younger than 18 years account for a substantial proportion of patients with tuberculosis worldwide. Available treatments for paediatric drug-susceptible and drug-resistant tuberculosis, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxic effects, and an overall scarcity of suitable child-friendly formulations. Several new drugs and regimens with promising activity against both drug-susceptible and drug-resistant strains have entered clinical development and are either in various phases of clinical investigation or have received marketing authorisation for adults; however, none have data on their use in children. This consensus statement, generated from an international panel of opinion leaders on childhood tuberculosis and incorporating reviews of published literature from January, 2004, to May, 2014, addressed four key questions: what drugs or regimens should be prioritised for clinical trials in children? Which populations of children are high priorities for study? When can phase 1 or 2 studies be initiated in children? What are the relevant elements of clinical trial design? The consensus panel found that children can be included in studies at the early phases of drug development and should be an integral part of the clinical development plan, rather than studied after regulatory approval in adults is obtained.

PubMed Disclaimer

Figures

**Figure 1. TB Drug Development phases**
Reproduced with permission

**Figure 2. Pediatric studies decision tree**
Reproduced from: http://www.fda.gov.ezproxy.nihlibrary.nih.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072109.pdf. Abbreviations: PK/PD: pharmacokinetics/pharmacodynamics; ER: exposure-response

See this image and copyright information in PMC

References

1. World Health Organization. [accessed 11/20/2013];Global tuberculosis report 2013. 2013 http://www.who.int/tb/publications/global_report/en/index.html.
1. Marais BJ, Graham SM, Maeurer M, Zumla A. Progress and challenges in childhood tuberculosis. The Lancet infectious diseases. 2013;13(4):287–289. - PubMed
1. Perez-Velez CM, Marais BJ. Tuberculosis in children. The New England journal of medicine. 2012;367(4):348–361. - PubMed
1. Marais BJ, Graham SM, Cotton MF, Beyers N. Diagnostic and management challenges for childhood tuberculosis in the era of HIV. The Journal of infectious diseases. 2007;196(Suppl 1):S76–S85. - PubMed
1. Marais BJ, Rabie H, Cotton MF. TB and HIV in children - advances in prevention and management. Paediatric respiratory reviews. 2011;12(1):39–45. - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Towards early inclusion of children in tuberculosis drugs trials: a consensus statement

Affiliations

Towards early inclusion of children in tuberculosis drugs trials: a consensus statement

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical