Correspondence
We declare no competing interests.
*Claire Leppold, Tetsuya Tanimoto, Akihiko Ozaki, Tomohiro Morita, Putri Viona Sari [email protected] Department of Research, Minamisoma Municipal General Hospital, Fukushima 975-0033, Japan (CL); Department of Internal Medicine, Jyoban Hospital of Tokiwakai Group, Fukushima, Japan (TT); Department of Surgery, Minamisoma Municipal General Hospital, Fukushima, Japan (AO); Department of Internal Medicine, Soma Central Hospital, Fukushima, Japan (TM); and Global Public Health Unit, School of Social and Political Science, University of Edinburgh, Edinburgh, UK (PVS) 1
Zeng M, Mao XH, Li JX, et al. Efficacy, safety, and immunogenicity of an oral recombinant Helicobacter pylori vaccine in children in China: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2015; 386: 1457–64.
Authors’ reply We are pleased to read the letter by Claire Leppold and colleagues, which suggests doing a further analysis of the data from our study on Helicobacter pylori vaccination in children in China1 to explore any patterns between age and vaccine efficacy. In our study, we reported that the oral recombinant H pylori vaccine was effective in H pylori-naive children aged between 6 years and 15 years. We also noticed that H pylori naivety was associated with younger age during screening before enrolment.1 One explanation is that as the children grew older, they had more chances of being exposed to H pylori, which suggests they need to be immunised www.thelancet.com Vol 387 February 20, 2016
with H pylori vaccine early in their childhood.2 However, the possible effects of age on vaccine efficacy have not been discussed. As requested by Leppold and colleagues, we further analysed the data at months 24 and 36 during the extended follow-up, stratified by sub-age groups. At 24 months, six events of H pylori infection in the vaccine group versus 15 events in the placebo group were recorded, with an efficacy of 60·1% (95% CI –8·8 to 87·3) in children aged younger than 10 years. In children aged 10 years or older, four events of H pylori infection occurred in the vaccine group versus seven events in the placebo group, which resulted in an efficacy of 44·2% (–199·5 to 88·0). At 36 months, in children aged younger than 10 years, five events of H pylori infection occurred in the vaccine group compared with 13 events in the placebo group, showing an efficacy of 63·9% (–8·1 to 89·9), whereas only one event in the vaccine group was observed in the subgroup of children aged 10 years or older, resulting in an absence of vaccine efficacy. In terms of immunogenicity, a significantly higher antibody response was noted in the vaccine group than in the placebo group, but the decrease in antibody concentrations was very similar between the sub-age groups at months 24 and 36 (appendix). We agree with Leppold and colleagues about the importance of the associations between age and vaccine protection. Unfortunately, we were not able to identify any statistically significant patterns because of the restricted sample size and high rate of older children lost to follow-up, causing an insufficient statistical power and some unexpected bias. Moreover, the participants involved in our study were of a narrow age range of 6 to 15 years at enrolment. Therefore, well designed long-term studies are warranted for the confirmation of the possible
effects of age on H pylori vaccine protection.
Biomedical Imaging Unit, Southampton General Hospital/ Science Photo Library
IgA concentrations might be used as surrogate immunological criteria for protection. Vaccine protection waned over 3 years, and further analysis of the concentrations of serum IgG and salivary IgA levels for each follow-up period, stratified by age, would be useful. Any elucidated patterns between age and vaccine protection could be used to investigate optimum time periods and dosing schedules for vaccination of children, information that would be of great value to future studies.
X-HM and Q-MZ have a patented oral recombinant Helicobacter pylori vaccine and preparation method licensed to Chongqing KangWei Biotechnology. All other authors declare no competing interests.
Jing-Xin Li, Ming Zeng, Xu-Hu Mao, Quan-Ming Zou, *Feng-Cai Zhu [email protected] Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu 210009, China (F-CZ, J-XL); College of Pharmacy, Third Military Medical University, Chongqing, China (J-XL, Q-MZ, X-HM); and National Institute for Food and Drug Control, Beijing, China (MZ) 1
2
Zeng M, Mao XH, Li JX, et al. Efficacy, safety, and immunogenicity of an oral recombinant Helicobacter pylori vaccine in children in China: a randomised, double-blind, placebocontrolled, phase 3 trial. Lancet 2015; 386: 1457–64. Sutton P. At last, vaccine-induced protection against Helicobacter pylori. Lancet 2015; 386: 1424–25.
Implementing health policy and systems research in Myanmar We agree with Karen Eggleston and colleagues’ (Nov 21, p 2053)1 assertion that one of the greatest challenges facing Myanmar is the optimum allocation of scarce resources, and add that evidence to inform this is needed urgently. We started working to generate such evidence shortly after the move to a nominally civilian government in 2011 opened the country up to more international collaborations. Here, we summarise the insights gained while doing one of the first multidisciplinary research programmes on the health system and tuberculosis control in Myanmar, which included two literature reviews, a mixed-methods situational assessment, a case-control study of risk factors for emergence of drug resistance, a qualitative study of barriers to accessing health services, and an economic analysis of patient costs. We think that the trust between local stakeholders and international
See Online for appendix
749
Correspondence
Published Online January 8, 2016 http://dx.doi.org/10.1016/ S0140-6736(16)00033-7
research groups should be strengthened. At present, local ethical approvals for gathering crucial data such as patient costs might be altogether denied, if determined by the Ministry of Health. Studies on certain regions, groups, and topics with potentially the most need for research are extremely restricted; the 2014 suspension of Médecins Sans Frontières Holland shows how carefully political sensitivities must be managed.2 Monitoring of data collection at health facilities by external researchers can be discouraged by authorities, which means making strong partnerships with local implementers is essential. Finally, many parallel institutions have to be navigated, including departments of medical research, universities, and vertical disease control programmes. As the world watches Myanmar transform, a rising pressure from competing demands and stakeholders might be alleviated, but could potentially also magnify these constraints. Myanmar presents unparalleled new opportunities for doing research, informing policy, and capacitybuilding. However, gathering unbiased data and disseminating potentially controversial findings to achieve a positive effect requires experience and partnership, now more than ever. We declare no competing interests.
*Mishal Khan, Joanne Yoong, Zaw Myo Tun, Richard Coker [email protected] Communicable Diseases Policy Research Group, London School of Hygiene & Tropical Medicine, London, UK (MK, RC); Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549, Singapore (MK, JY, ZMT, RC); Center for Economic and Social Research, University of Southern California, Los Angeles, CA, USA (JY); and Faculty of Public Health, Mahidol University, Bangkok, Thailand (RC) 1
750
Zaw PPT, Htoo TS, Pham NM, Eggleston K. Disparities in health and health care in Myanmar. Lancet 2015; 386: 2053.
2
Médecins Sans Frontières. Myanmar: MSF to resume HIV/AIDS and all other activities in Kachin, Shan and Yangon but concerns remain. March 2, 2014. http://www.msf.org.uk/article/ myanmar-msf-resume-hivaids-and-all-otheractivities-kachin-shan-and-yangon-concernsremain (accessed Nov 30, 2015).
editorials to help readers interpret the studies remain the best available methods for ensuring the dissemination of scientifically sound clinical trial data. I declare no competing interests. I am an employee of Fresenius Kabi, but the views expressed in this letter are mine.
Prepublication culture in clinical research
Edward Tabor [email protected] Bethesda, MD, USA
In their Comment, Michael Lauer and colleagues (Dec 19, p 2447)1 make several fundamental errors in their case for prepublication of clinical studies on the internet before peer review. By suggesting that clinical studies should be prepublished in the same way that studies in astronomy are, the authors fail to note that clinical studies of poor quality can harm patients who might start or stop therapy in response to faulty data, whereas little short-term harm would be expected from an unreviewed astronomy study. The authors denigrate the Ingelfinger rule, which discourages clinicians from giving press conferences about new discoveries before the data are peer reviewed, thus protecting patients from making potentially life-threatening changes in their treatment solely on the basis of unreviewed news reports. They assert that prepublication would permit open-source review on the internet, but in fact, these comments and suggestions from interested readers cannot be as stringent as a thorough review by a scientific peer. The authors also belittle journal publications as being “based on cleaned data and [reflecting] the views of the trial’s lead investigators”, but peer review does not result in “cleaned data” any more than prepublication would, nor would prepublication remove the views of the lead investigators. Ultimately, peer review and (in some cases) the publication of accompanying
1
Lauer MS, Krumholz HM, Topol EJ. Time for a prepublication culture in clinical research? Lancet 2015; 386: 2447–49.
Department of Error Reich MR, Harris J, Ikegami N, Maeda A, Takemi K, Evans TG. Moving towards universal health coverage: lessons from 11 country studies. Lancet 2016; 387: 745–50—In this Health Policy paper, Cheryl Cashin and Edson C Araujo should also have been listed as authors. The author list should have read as follows: “Michael R Reich, Joseph Harris, Naoki Ikegami, Akiko Maeda, Cheryl Cashin, Edson C Araujo, Keizo Takemi, Timothy G Evans”. The author affiliations list, Contributors section, and Declaration of interests section have been updated accordingly. These corrections have been made to the online version as of Jan 8, 2016, and the printed report is correct. Dreyling M, Jurczak W, Jerkeman M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet 2016; 387: 770–83—The affiliation for Cristina Joao should have included Instituto Português de Oncologia, Lisbon, Portugal. This correction has been made to the online version as of Feb 18, 2016, and the printed Article is correct.
www.thelancet.com Vol 387 February 20, 2016
We declare no competing interests.
*Claire Leppold, Tetsuya Tanimoto, Akihiko Ozaki, Tomohiro Morita, Putri Viona Sari [email protected] Department of Research, Minamisoma Municipal General Hospital, Fukushima 975-0033, Japan (CL); Department of Internal Medicine, Jyoban Hospital of Tokiwakai Group, Fukushima, Japan (TT); Department of Surgery, Minamisoma Municipal General Hospital, Fukushima, Japan (AO); Department of Internal Medicine, Soma Central Hospital, Fukushima, Japan (TM); and Global Public Health Unit, School of Social and Political Science, University of Edinburgh, Edinburgh, UK (PVS) 1
Zeng M, Mao XH, Li JX, et al. Efficacy, safety, and immunogenicity of an oral recombinant Helicobacter pylori vaccine in children in China: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2015; 386: 1457–64.
Authors’ reply We are pleased to read the letter by Claire Leppold and colleagues, which suggests doing a further analysis of the data from our study on Helicobacter pylori vaccination in children in China1 to explore any patterns between age and vaccine efficacy. In our study, we reported that the oral recombinant H pylori vaccine was effective in H pylori-naive children aged between 6 years and 15 years. We also noticed that H pylori naivety was associated with younger age during screening before enrolment.1 One explanation is that as the children grew older, they had more chances of being exposed to H pylori, which suggests they need to be immunised www.thelancet.com Vol 387 February 20, 2016
with H pylori vaccine early in their childhood.2 However, the possible effects of age on vaccine efficacy have not been discussed. As requested by Leppold and colleagues, we further analysed the data at months 24 and 36 during the extended follow-up, stratified by sub-age groups. At 24 months, six events of H pylori infection in the vaccine group versus 15 events in the placebo group were recorded, with an efficacy of 60·1% (95% CI –8·8 to 87·3) in children aged younger than 10 years. In children aged 10 years or older, four events of H pylori infection occurred in the vaccine group versus seven events in the placebo group, which resulted in an efficacy of 44·2% (–199·5 to 88·0). At 36 months, in children aged younger than 10 years, five events of H pylori infection occurred in the vaccine group compared with 13 events in the placebo group, showing an efficacy of 63·9% (–8·1 to 89·9), whereas only one event in the vaccine group was observed in the subgroup of children aged 10 years or older, resulting in an absence of vaccine efficacy. In terms of immunogenicity, a significantly higher antibody response was noted in the vaccine group than in the placebo group, but the decrease in antibody concentrations was very similar between the sub-age groups at months 24 and 36 (appendix). We agree with Leppold and colleagues about the importance of the associations between age and vaccine protection. Unfortunately, we were not able to identify any statistically significant patterns because of the restricted sample size and high rate of older children lost to follow-up, causing an insufficient statistical power and some unexpected bias. Moreover, the participants involved in our study were of a narrow age range of 6 to 15 years at enrolment. Therefore, well designed long-term studies are warranted for the confirmation of the possible
effects of age on H pylori vaccine protection.
Biomedical Imaging Unit, Southampton General Hospital/ Science Photo Library
IgA concentrations might be used as surrogate immunological criteria for protection. Vaccine protection waned over 3 years, and further analysis of the concentrations of serum IgG and salivary IgA levels for each follow-up period, stratified by age, would be useful. Any elucidated patterns between age and vaccine protection could be used to investigate optimum time periods and dosing schedules for vaccination of children, information that would be of great value to future studies.
X-HM and Q-MZ have a patented oral recombinant Helicobacter pylori vaccine and preparation method licensed to Chongqing KangWei Biotechnology. All other authors declare no competing interests.
Jing-Xin Li, Ming Zeng, Xu-Hu Mao, Quan-Ming Zou, *Feng-Cai Zhu [email protected] Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu 210009, China (F-CZ, J-XL); College of Pharmacy, Third Military Medical University, Chongqing, China (J-XL, Q-MZ, X-HM); and National Institute for Food and Drug Control, Beijing, China (MZ) 1
2
Zeng M, Mao XH, Li JX, et al. Efficacy, safety, and immunogenicity of an oral recombinant Helicobacter pylori vaccine in children in China: a randomised, double-blind, placebocontrolled, phase 3 trial. Lancet 2015; 386: 1457–64. Sutton P. At last, vaccine-induced protection against Helicobacter pylori. Lancet 2015; 386: 1424–25.
Implementing health policy and systems research in Myanmar We agree with Karen Eggleston and colleagues’ (Nov 21, p 2053)1 assertion that one of the greatest challenges facing Myanmar is the optimum allocation of scarce resources, and add that evidence to inform this is needed urgently. We started working to generate such evidence shortly after the move to a nominally civilian government in 2011 opened the country up to more international collaborations. Here, we summarise the insights gained while doing one of the first multidisciplinary research programmes on the health system and tuberculosis control in Myanmar, which included two literature reviews, a mixed-methods situational assessment, a case-control study of risk factors for emergence of drug resistance, a qualitative study of barriers to accessing health services, and an economic analysis of patient costs. We think that the trust between local stakeholders and international
See Online for appendix
749
Correspondence
Published Online January 8, 2016 http://dx.doi.org/10.1016/ S0140-6736(16)00033-7
research groups should be strengthened. At present, local ethical approvals for gathering crucial data such as patient costs might be altogether denied, if determined by the Ministry of Health. Studies on certain regions, groups, and topics with potentially the most need for research are extremely restricted; the 2014 suspension of Médecins Sans Frontières Holland shows how carefully political sensitivities must be managed.2 Monitoring of data collection at health facilities by external researchers can be discouraged by authorities, which means making strong partnerships with local implementers is essential. Finally, many parallel institutions have to be navigated, including departments of medical research, universities, and vertical disease control programmes. As the world watches Myanmar transform, a rising pressure from competing demands and stakeholders might be alleviated, but could potentially also magnify these constraints. Myanmar presents unparalleled new opportunities for doing research, informing policy, and capacitybuilding. However, gathering unbiased data and disseminating potentially controversial findings to achieve a positive effect requires experience and partnership, now more than ever. We declare no competing interests.
*Mishal Khan, Joanne Yoong, Zaw Myo Tun, Richard Coker [email protected] Communicable Diseases Policy Research Group, London School of Hygiene & Tropical Medicine, London, UK (MK, RC); Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549, Singapore (MK, JY, ZMT, RC); Center for Economic and Social Research, University of Southern California, Los Angeles, CA, USA (JY); and Faculty of Public Health, Mahidol University, Bangkok, Thailand (RC) 1
750
Zaw PPT, Htoo TS, Pham NM, Eggleston K. Disparities in health and health care in Myanmar. Lancet 2015; 386: 2053.
2
Médecins Sans Frontières. Myanmar: MSF to resume HIV/AIDS and all other activities in Kachin, Shan and Yangon but concerns remain. March 2, 2014. http://www.msf.org.uk/article/ myanmar-msf-resume-hivaids-and-all-otheractivities-kachin-shan-and-yangon-concernsremain (accessed Nov 30, 2015).
editorials to help readers interpret the studies remain the best available methods for ensuring the dissemination of scientifically sound clinical trial data. I declare no competing interests. I am an employee of Fresenius Kabi, but the views expressed in this letter are mine.
Prepublication culture in clinical research
Edward Tabor [email protected] Bethesda, MD, USA
In their Comment, Michael Lauer and colleagues (Dec 19, p 2447)1 make several fundamental errors in their case for prepublication of clinical studies on the internet before peer review. By suggesting that clinical studies should be prepublished in the same way that studies in astronomy are, the authors fail to note that clinical studies of poor quality can harm patients who might start or stop therapy in response to faulty data, whereas little short-term harm would be expected from an unreviewed astronomy study. The authors denigrate the Ingelfinger rule, which discourages clinicians from giving press conferences about new discoveries before the data are peer reviewed, thus protecting patients from making potentially life-threatening changes in their treatment solely on the basis of unreviewed news reports. They assert that prepublication would permit open-source review on the internet, but in fact, these comments and suggestions from interested readers cannot be as stringent as a thorough review by a scientific peer. The authors also belittle journal publications as being “based on cleaned data and [reflecting] the views of the trial’s lead investigators”, but peer review does not result in “cleaned data” any more than prepublication would, nor would prepublication remove the views of the lead investigators. Ultimately, peer review and (in some cases) the publication of accompanying
1
Lauer MS, Krumholz HM, Topol EJ. Time for a prepublication culture in clinical research? Lancet 2015; 386: 2447–49.
Department of Error Reich MR, Harris J, Ikegami N, Maeda A, Takemi K, Evans TG. Moving towards universal health coverage: lessons from 11 country studies. Lancet 2016; 387: 745–50—In this Health Policy paper, Cheryl Cashin and Edson C Araujo should also have been listed as authors. The author list should have read as follows: “Michael R Reich, Joseph Harris, Naoki Ikegami, Akiko Maeda, Cheryl Cashin, Edson C Araujo, Keizo Takemi, Timothy G Evans”. The author affiliations list, Contributors section, and Declaration of interests section have been updated accordingly. These corrections have been made to the online version as of Jan 8, 2016, and the printed report is correct. Dreyling M, Jurczak W, Jerkeman M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet 2016; 387: 770–83—The affiliation for Cristina Joao should have included Instituto Português de Oncologia, Lisbon, Portugal. This correction has been made to the online version as of Feb 18, 2016, and the printed Article is correct.
www.thelancet.com Vol 387 February 20, 2016
