BMJ 2015;350:h2867 doi: 10.1136/bmj.h2867 (Published 27 May 2015)
Page 1 of 2
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NEWS Indian rotavirus vaccine concern over intussusception is unfounded, say researchers Priyanka Pulla Bangalore
Researchers testing an Indian rotavirus vaccine have said that concerns linking it to an increased risk of intussusceptions are unfounded. They were responding to an online campaign that has called for them to release raw data on the rates of intussusception seen during the trial.1
Gagandeep Kang, professor of gastrointestinal sciences at Christian Medical College, Vellore, who worked on the trial, said that the trial data cannot be used to estimate the risk of intussusception from the vaccine as the campaigners have argued. “This was not a study powered to detect rare events. If you want to find the rate of intussusception, you need to evaluate the vaccine in hundreds of thousands of children,” she told The BMJ.
Kang’s group conducted the trial in 6800 children to measure the efficacy of the Indian rotavirus vaccine, Rotavac, which was developed by the Hyderabad based company Bharat Biotech and tested with funding from India’s Department of Biotechnology. During the two year trial Kang’s team also collected data on intussusception, a rare side effect in which the intestine folds into itself, causing symptoms such as bloody stools. Because intussusception is seen in only one in more than 20 000 of the children receiving currently licensed rotavirus vaccines such as Merck’s RotaTeq, it is misleading and statistically incorrect to use rates of intussusception from a 6800 child study to claim that the vaccine is risky, Kang said. The online petition posted on 12 May on the campaign website Avaaz.org has demanded that the Christian Medical College, which led the clinical trials on Rotavac in 2011, release raw data from the trial.2 The petition argued that the rate of intussusception in the control arm, at 17 of 4532 children, was high compared with the six intussusceptions in 2267 children in the placebo arm. It also noted that the rate of intussusceptions detected at the Vellore centre of the trial, estimated at 581 of 100 000 child years, is far higher than the rate at the Delhi centre, at 27.7 of 100 000 child years, and it urged the trial researchers to share the control and placebo components of both numbers. The petition cited a letter3 to the journal Vaccine from Jacob M Puliyel, a paediatrician at Delhi’s St Stephen’s Hospital, in which he argued that these numbers could point to a heightened risk of intussusception from the vaccine in the long term.
Puliyel told The BMJ that, even though the intussusceptions did not occur in the risk window immediately after administration of the vaccine, they were higher across two years For personal use only: See rights and reprints http://www.bmj.com/permissions
than in the placebo arm. “A risk window is only relevant to a study if you don’t have a control group. If you have a control group, all intussusceptions that happen in the vaccinated group, over and above the placebo, are said to be due to the vaccine,” he said. Because the researchers have not yet released trial data from individual centres from the previous trial, a planned 100 000 children trial of the same vaccine by the Department of Biotechnology would be unethical, Puliyel added.
Given that the side effect is so rare and that intussusception is fairly commonly seen in children, the World Health Organization recommends that vaccine manufacturers collect data on rates of intussusception after the vaccine is launched, Kang said, because it is very hard to detect the condition in small scale pre-launch trials. WHO has also said that existing data on Rotavac do not point to an increased risk from intussusception.4
However, Puliyel said that, even if all of these arguments are correct, the researchers should release the raw data, such as the break-up of intussusceptions in the Vellore centre. When asked whether these data would be released K VijayRaghavan, secretary of the Department of Biotechnology, told The BMJ in an email that the data had already been shared with the Drug Controller General of India, as well as with experts who constitute the National Technical Advisory Group on Immunization (NTAGI) and with WHO. “However, in response to various queries that we have received, the DBT [Department of Biotechnology] will work with the NTAGI to review the questions being asked, and ensure that data [are] available for analysis by a competent body, meeting the requirements of analytical rigor and transparency. This will happen soon,” he wrote.
T Jacob John, an independent paediatrician and virologist who was not associated with the Rotavac studies, told The BMJ that the data on 6800 children showed absolutely no risk of intussusception. In the trial the researchers took an aggressive approach to detect intussusception: instead of waiting for children to be brought to hospitals with symptoms they used broad criteria such as abdominal distension to perform ultrasounds on them, thus picking up many more mild cases of intussusception than would otherwise have been identified. John added that it was incorrect to attribute intussusceptions occurring more than a month after the administration of the vaccine to Rotavac, as the campaigners had implied. Subscribe: http://www.bmj.com/subscribe
BMJ 2015;350:h2867 doi: 10.1136/bmj.h2867 (Published 27 May 2015)
Page 2 of 2
NEWS
Kang told The BMJ that the upcoming study of 100 000 children would be conducted in the same locations as the previous trial so that the paediatricians who monitored intussusception the last time could draw on their experiences to care for any cases that may arise this time. “We are trying to be as responsible as possible. I don’t see what else we could we doing,” she said. 1
Avaaz.org petition. Director, Christian Medical College, Vellore: release Indian rotavirus vaccine trial data. 12 May 2015. https://secure.avaaz.org/en/petition/To_The_Director_ Christian_Medical_College_Vellore_632004_Release_Indian_Rotavirus_Vaccine_Trial_ Data/.
For personal use only: See rights and reprints http://www.bmj.com/permissions
2 3 4
John J, Kawade A, Rongsen-Chandola T, et al. Active surveillance for intussusception in a phase III efficacy trial of an oral monovalent rotavirus vaccine in India. Vaccine 2011;32 (suppl 1):A104-9. Bajaj J, Puliyel JM. Intussusception risk with 116E rotavirus vaccine in Vellore, south India. Vaccine 2015;pii:S0264-410X(15)00293-5; doi:10.1016/j.vaccine.2015.03.007. World Health Organization. Safety profile of a novel live attenuated rotavirus vaccine. July 2014. www.who.int/vaccine_safety/committee/topics/rotavirus/rotavac/Jun_2014/en/ .
Cite this as: BMJ 2015;350:h2867 © BMJ Publishing Group Ltd 2015
Subscribe: http://www.bmj.com/subscribe
Page 1 of 2
News
NEWS Indian rotavirus vaccine concern over intussusception is unfounded, say researchers Priyanka Pulla Bangalore
Researchers testing an Indian rotavirus vaccine have said that concerns linking it to an increased risk of intussusceptions are unfounded. They were responding to an online campaign that has called for them to release raw data on the rates of intussusception seen during the trial.1
Gagandeep Kang, professor of gastrointestinal sciences at Christian Medical College, Vellore, who worked on the trial, said that the trial data cannot be used to estimate the risk of intussusception from the vaccine as the campaigners have argued. “This was not a study powered to detect rare events. If you want to find the rate of intussusception, you need to evaluate the vaccine in hundreds of thousands of children,” she told The BMJ.
Kang’s group conducted the trial in 6800 children to measure the efficacy of the Indian rotavirus vaccine, Rotavac, which was developed by the Hyderabad based company Bharat Biotech and tested with funding from India’s Department of Biotechnology. During the two year trial Kang’s team also collected data on intussusception, a rare side effect in which the intestine folds into itself, causing symptoms such as bloody stools. Because intussusception is seen in only one in more than 20 000 of the children receiving currently licensed rotavirus vaccines such as Merck’s RotaTeq, it is misleading and statistically incorrect to use rates of intussusception from a 6800 child study to claim that the vaccine is risky, Kang said. The online petition posted on 12 May on the campaign website Avaaz.org has demanded that the Christian Medical College, which led the clinical trials on Rotavac in 2011, release raw data from the trial.2 The petition argued that the rate of intussusception in the control arm, at 17 of 4532 children, was high compared with the six intussusceptions in 2267 children in the placebo arm. It also noted that the rate of intussusceptions detected at the Vellore centre of the trial, estimated at 581 of 100 000 child years, is far higher than the rate at the Delhi centre, at 27.7 of 100 000 child years, and it urged the trial researchers to share the control and placebo components of both numbers. The petition cited a letter3 to the journal Vaccine from Jacob M Puliyel, a paediatrician at Delhi’s St Stephen’s Hospital, in which he argued that these numbers could point to a heightened risk of intussusception from the vaccine in the long term.
Puliyel told The BMJ that, even though the intussusceptions did not occur in the risk window immediately after administration of the vaccine, they were higher across two years For personal use only: See rights and reprints http://www.bmj.com/permissions
than in the placebo arm. “A risk window is only relevant to a study if you don’t have a control group. If you have a control group, all intussusceptions that happen in the vaccinated group, over and above the placebo, are said to be due to the vaccine,” he said. Because the researchers have not yet released trial data from individual centres from the previous trial, a planned 100 000 children trial of the same vaccine by the Department of Biotechnology would be unethical, Puliyel added.
Given that the side effect is so rare and that intussusception is fairly commonly seen in children, the World Health Organization recommends that vaccine manufacturers collect data on rates of intussusception after the vaccine is launched, Kang said, because it is very hard to detect the condition in small scale pre-launch trials. WHO has also said that existing data on Rotavac do not point to an increased risk from intussusception.4
However, Puliyel said that, even if all of these arguments are correct, the researchers should release the raw data, such as the break-up of intussusceptions in the Vellore centre. When asked whether these data would be released K VijayRaghavan, secretary of the Department of Biotechnology, told The BMJ in an email that the data had already been shared with the Drug Controller General of India, as well as with experts who constitute the National Technical Advisory Group on Immunization (NTAGI) and with WHO. “However, in response to various queries that we have received, the DBT [Department of Biotechnology] will work with the NTAGI to review the questions being asked, and ensure that data [are] available for analysis by a competent body, meeting the requirements of analytical rigor and transparency. This will happen soon,” he wrote.
T Jacob John, an independent paediatrician and virologist who was not associated with the Rotavac studies, told The BMJ that the data on 6800 children showed absolutely no risk of intussusception. In the trial the researchers took an aggressive approach to detect intussusception: instead of waiting for children to be brought to hospitals with symptoms they used broad criteria such as abdominal distension to perform ultrasounds on them, thus picking up many more mild cases of intussusception than would otherwise have been identified. John added that it was incorrect to attribute intussusceptions occurring more than a month after the administration of the vaccine to Rotavac, as the campaigners had implied. Subscribe: http://www.bmj.com/subscribe
BMJ 2015;350:h2867 doi: 10.1136/bmj.h2867 (Published 27 May 2015)
Page 2 of 2
NEWS
Kang told The BMJ that the upcoming study of 100 000 children would be conducted in the same locations as the previous trial so that the paediatricians who monitored intussusception the last time could draw on their experiences to care for any cases that may arise this time. “We are trying to be as responsible as possible. I don’t see what else we could we doing,” she said. 1
Avaaz.org petition. Director, Christian Medical College, Vellore: release Indian rotavirus vaccine trial data. 12 May 2015. https://secure.avaaz.org/en/petition/To_The_Director_ Christian_Medical_College_Vellore_632004_Release_Indian_Rotavirus_Vaccine_Trial_ Data/.
For personal use only: See rights and reprints http://www.bmj.com/permissions
2 3 4
John J, Kawade A, Rongsen-Chandola T, et al. Active surveillance for intussusception in a phase III efficacy trial of an oral monovalent rotavirus vaccine in India. Vaccine 2011;32 (suppl 1):A104-9. Bajaj J, Puliyel JM. Intussusception risk with 116E rotavirus vaccine in Vellore, south India. Vaccine 2015;pii:S0264-410X(15)00293-5; doi:10.1016/j.vaccine.2015.03.007. World Health Organization. Safety profile of a novel live attenuated rotavirus vaccine. July 2014. www.who.int/vaccine_safety/committee/topics/rotavirus/rotavac/Jun_2014/en/ .
Cite this as: BMJ 2015;350:h2867 © BMJ Publishing Group Ltd 2015
Subscribe: http://www.bmj.com/subscribe
