- Email: [email protected]
Misleading report on clinical trials in India
Correspondence
The Editors of The Lancet [email protected] www.thelancet.com Vol 379 May 26, 2012
32 Jamestown Road, London NW1 7BY, UK 1
2 3
4
Pronyk PM, Muniz M, Nemser B, et al, for the Millennium Villages Study Group. The effect of an integrated multisector model for achieving the Millennium Development Goals and improving child survival in rural sub-Saharan Africa: a non-randomised controlled assessment. Lancet 2012; published online May 8. DOI:10.1016/S0140-6736(12)60207-4. Editorial. With transparency comes trust. Nature 2012; 485: 147. Malenga G, Molyneux M. The Millennium Villages project. Lancet 2012; published online May 8. DOI:10.1016/S0140-6736(12)60369-9. Bryce J, Gilroy K, Jones G. The Accelerated Child Survival and Development programme in west Africa: a retrospective evaluation. Lancet 2010; 375: 572–82.
Misleading report on clinical trials in India We are sorry to note that Amy Yee, in her World Report (Feb 4, p 397),1 did not consider it proper to seek comment from the principal investigators whose ethics she questions. Her report is biased and portrays the clinical trial scenario in India in general and at Indore, Madhya Pradesh, in particular in an unjust, negative matter. The report falls into the type of partisan coverage noted more often in the lay press.2 All trials in which we participated were legal, ethical, and done as per the norms of clinical practice and guidelines set out by the Indian Council of Medical Research (ICMR) and the Medical Council of India. The protocols for all trials, including the Hindi version of the informed consent form, were approved by the Institutional Ethics Committee, which had been constituted and was working as per the ICMR guidelines. All patients were insured by the sponsors against trial-related adverse events and outcomes. All the trials in which we participated were multicentre and multinational in nature, being simultaneously conducted at many prestigious institutions in India and other countries (including in North America, Europe, Australia). The same protocol, same informed consent form, and same insurance policies were applicable at all centres.
Since none of the serious adverse events or deaths were related to investigational products or the process of participation in the trial, there was no reason to offer compensation. The 81 adverse events and a few deaths out of 3300 patients over a span of 4 years were due to the natural history of the illness or unrelated circumstances. The money received by six doctors over the same period reflects the gross receipt of the trial budget, most of which is spent on doing the trial, and a 10% share which is deposited in the respective departments as per the orders of the Dean of the college. The residual income is duly audited and tax is paid. The Government of Madhya Pradesh and the Economic Offence Wing of the police have conceded this money as being a legitimate professional income. Similar practices are prevalent in other parts of India and the world over. The Government of Madhya Pradesh did ban initiation of new trials in October, 2010, owing to reports in the media, but permitted continuation of ongoing trials, which are still ongoing to date. No vulnerable patients were exploited by us. The demographic profile of patients enrolled in our studies reflects that of the population attending government clinics. The “improper procedures” for which a fine of Rs5000 was selectively imposed on 12 doctors comprise a trivial technicality of failing to provide information to (another part of) the health department about some details of the clinical trials. However, all information had already been submitted on more than one occasion to other more relevant departments and agencies. The fine had nothing do with the legality, ethics, or proper conduct of the trials as per norms of good clinical practice. There is no restriction in the ICMR guidelines on principal investigators also being members of ethics committees. The ICMR guideline says that members who also happen to be
Getty Images
As was made clear in the accompanying Comment by Grace Malenga and Malcolm Molyneux,3 these interim findings should be judged with appropriate caution. The comparison between Millennium and matched villages was not randomised, and so no causal attribution of measured changes can be conclusively ascribed to the interventions. That said, the results presented, in the words of one of the original reviewers of the paper, are “encouraging evidence—a big intervention rapidly leading to measurable results.” And, in fairness to those attempting to evaluate the effects of complex health programmes, non-randomised comparisons do have the power to illuminate—one example being the retrospective non-randomised assessment of UNICEF’s Accelerated Child Survival and Development programme in west Africa.4 The next phase of the Millennium Villages project will involve the monitoring of actual vital events (instead of relying on recall). To ensure that all future data from the project are fully and fairly evaluated, Prof Jeffrey Sachs, the Principal Investigator of the Millennium Villages project, is establishing new internal and external oversight procedures, including the creation of an International Scientific Expert Advisory Group, chaired by Prof Robert Black, Chairman of the Department of International Health, Johns Hopkins Bloomberg School of Public Health, which will report to the Principal Investigator and also communicate its findings to The Lancet. The goal is to provide a further independent means of verifying the quality of the project’s design and analysis. It is important that this work, which is of considerable significance for understanding how countries scale up multiple complex interventions across sectors, receives proper scientific evaluation before, during, and after publication.
1947
Correspondence
investigators should not be involved in the process of decision making about approval of the trial. This guideline has always been followed. We are proud in saying that we have been associated with many important clinical trials related to coronary artery disease, stroke, Alzheimer’s dementia, parkinsonism, and asthma, leading to many publications and subsequent approval of a few new molecules or formulation by licensing authorities in India, the USA, and other countries. A prime example was published in The Lancet,3 and WHO and the Government of India have acknowledged the role of this vaccine in making India polio free for the past year, for the first time in the history of the nation. We declare that we have no conflicts of interest.
*Apoorva Pauranik, Anil Bharani, Salil Bhargava, Ashok Bajpai, Hemant Jain, Pushpa Verma
fine is regarded as an improper procedure; the World Report did not directly link the penalty to ethical violations. Activists claim that Hindi translations of consent forms were far shorter than the English versions and were not exact. Pauranik and colleagues state that there is no restriction in the Indian Council of Medical Research guidelines on principal investigators also being members of ethics committees. But Clinical Trials Registry India (CTRI) itself has raised concerns about strengthening ethics committees and called for investigators and committee members to declare conflicts of interest. I phoned and emailed CTRI and the Ministry of Health multiple times, but never received a reply. If The Lancet does a follow-up story on clinical trials, we will be sure to contact Pauranik and colleagues.
[email protected]
I declare that I have no conflicts of interest.
MGM Medical College, Indore, Madhya Pradesh 452001, India
Amy Yee
1
A 9/8 Vasant Vihar, New Delhi 110057, India
2
3
Yee A. Regulation failing to keep up with India’s trials boom. Lancet 2012; 379: 397–98. Yuji K, Narimatsu H, Tanimoto T, Komatsu T, Kami M. Sharing information on adverse events. Lancet 2011; 377: 1654. Sutter RW, John TJJ, Jain H, et al. Immunogenicity of bivalent types 1 and 3 oral poliovirus vaccine: a randomised, double-blind, controlled trial. Lancet 2020; 376: 1682–88.
[email protected]
Pregnancy should not rule out 18FDG PET/CT for women with cancer
First, the measured absorbed doses we reported (3·3–4·0×10–2 mGy/MBq)3 are actually higher than current dosimetric standards (about 2·0×10–2 mGy/MBq), but our measurements were obtained from women in the first weeks of pregnancy. The first trimester is characterised by rapid cellular proliferation, which leads to a higher glucose consumption and consequently a high absorbed dose of 18FDG. Indeed, more recent data from women at a later stage of pregnancy show much lower fetal 18FDG uptake, and the absorbed dose is about 1·0×10–2 mGy/MBq or less.4 Second, dosimetry extrapolations from monkeys should be taken with extreme caution. Data from monkeys might not be a good dosimetric model for man, since they often significantly and unpredictably overestimate human values.5 Finally, it should not be forgotten that, for the range of doses delivered by a PET/CT examination, especially when appropriate measures are taken to minimise the dose, there are no clearly proven health effects on the fetus. Therefore, when medically indicated, 18FDG PET should not be avoided, since the benefit for the mother is likely to outweigh the very small fetal radiation risk. I declare that I have no conflicts of interest.
Author’s reply Apoorva Pauranik and colleagues’ points are well taken. However, it is a fact that activists have made formal allegations of ethical violations and filed complaints with the Indian Supreme Court and other agencies. The Court will decide how to proceed, and whether clinical trials were legal and ethical. My World Report acknowledged that patients’ deaths were not found to be linked to the trials. It also acknowledged that the money received by six doctors was to run clinical trials. But large amounts of money are clearly involved. A “trivial technicality” relating to the Rs5000 1948
In the excellent Series papers about the management of pregnant women with gynaecological and haematological cancers (Feb 11, pp 558 and 580)1,2 the authors discourage the use of fluorine-18labelled fluorodeoxyglucose (18FDG) PET/CT during pregnancy, because of the potential risks associated with radiation exposure to the fetus. These recommendations were partly inspired by the fetal dosimetric measurements in pregnant women we previously published,3 and partly by data from monkey models. It is my contention that these data do not justify such strong recommendations.
Paolo Zanotti-Fregonara [email protected] CNRS UMR 5287, INCIA, Université de Bordeaux, 33076 Bordeaux, France 1
2
3
4
5
Morice P, Uzan C, Gouy S, Verschraegen C, Haie-Meder C. Gynaecological cancers in pregnancy. Lancet 2012; 379: 558–69. Brenner B, Avivi I, Lishner M. Haematological cancers in pregnancy. Lancet 2012; 379: 580–87. Zanotti-Fregonara P, Jan S, Taieb D, et al. Absorbed F-18-FDG dose to the fetus during early pregnancy. J Nucl Med 2010; 51: 803–05. Takalkar AM, Khandelwal A, Lokitz S, Lilien DL, Stabin MG. (18)F-FDG PET in pregnancy and fetal radiation dose estimates. J Nucl Med 2011; 52: 1035–40. Zanotti-Fregonara P, Innis RB. Suggested pathway to assess radiation safety of (11) C-labeled PET tracers for first-in-human studies. Eur J Nucl Med Mol Imaging 2012; 39: 544–47.
www.thelancet.com Vol 379 May 26, 2012
The Editors of The Lancet [email protected] www.thelancet.com Vol 379 May 26, 2012
32 Jamestown Road, London NW1 7BY, UK 1
2 3
4
Pronyk PM, Muniz M, Nemser B, et al, for the Millennium Villages Study Group. The effect of an integrated multisector model for achieving the Millennium Development Goals and improving child survival in rural sub-Saharan Africa: a non-randomised controlled assessment. Lancet 2012; published online May 8. DOI:10.1016/S0140-6736(12)60207-4. Editorial. With transparency comes trust. Nature 2012; 485: 147. Malenga G, Molyneux M. The Millennium Villages project. Lancet 2012; published online May 8. DOI:10.1016/S0140-6736(12)60369-9. Bryce J, Gilroy K, Jones G. The Accelerated Child Survival and Development programme in west Africa: a retrospective evaluation. Lancet 2010; 375: 572–82.
Misleading report on clinical trials in India We are sorry to note that Amy Yee, in her World Report (Feb 4, p 397),1 did not consider it proper to seek comment from the principal investigators whose ethics she questions. Her report is biased and portrays the clinical trial scenario in India in general and at Indore, Madhya Pradesh, in particular in an unjust, negative matter. The report falls into the type of partisan coverage noted more often in the lay press.2 All trials in which we participated were legal, ethical, and done as per the norms of clinical practice and guidelines set out by the Indian Council of Medical Research (ICMR) and the Medical Council of India. The protocols for all trials, including the Hindi version of the informed consent form, were approved by the Institutional Ethics Committee, which had been constituted and was working as per the ICMR guidelines. All patients were insured by the sponsors against trial-related adverse events and outcomes. All the trials in which we participated were multicentre and multinational in nature, being simultaneously conducted at many prestigious institutions in India and other countries (including in North America, Europe, Australia). The same protocol, same informed consent form, and same insurance policies were applicable at all centres.
Since none of the serious adverse events or deaths were related to investigational products or the process of participation in the trial, there was no reason to offer compensation. The 81 adverse events and a few deaths out of 3300 patients over a span of 4 years were due to the natural history of the illness or unrelated circumstances. The money received by six doctors over the same period reflects the gross receipt of the trial budget, most of which is spent on doing the trial, and a 10% share which is deposited in the respective departments as per the orders of the Dean of the college. The residual income is duly audited and tax is paid. The Government of Madhya Pradesh and the Economic Offence Wing of the police have conceded this money as being a legitimate professional income. Similar practices are prevalent in other parts of India and the world over. The Government of Madhya Pradesh did ban initiation of new trials in October, 2010, owing to reports in the media, but permitted continuation of ongoing trials, which are still ongoing to date. No vulnerable patients were exploited by us. The demographic profile of patients enrolled in our studies reflects that of the population attending government clinics. The “improper procedures” for which a fine of Rs5000 was selectively imposed on 12 doctors comprise a trivial technicality of failing to provide information to (another part of) the health department about some details of the clinical trials. However, all information had already been submitted on more than one occasion to other more relevant departments and agencies. The fine had nothing do with the legality, ethics, or proper conduct of the trials as per norms of good clinical practice. There is no restriction in the ICMR guidelines on principal investigators also being members of ethics committees. The ICMR guideline says that members who also happen to be
Getty Images
As was made clear in the accompanying Comment by Grace Malenga and Malcolm Molyneux,3 these interim findings should be judged with appropriate caution. The comparison between Millennium and matched villages was not randomised, and so no causal attribution of measured changes can be conclusively ascribed to the interventions. That said, the results presented, in the words of one of the original reviewers of the paper, are “encouraging evidence—a big intervention rapidly leading to measurable results.” And, in fairness to those attempting to evaluate the effects of complex health programmes, non-randomised comparisons do have the power to illuminate—one example being the retrospective non-randomised assessment of UNICEF’s Accelerated Child Survival and Development programme in west Africa.4 The next phase of the Millennium Villages project will involve the monitoring of actual vital events (instead of relying on recall). To ensure that all future data from the project are fully and fairly evaluated, Prof Jeffrey Sachs, the Principal Investigator of the Millennium Villages project, is establishing new internal and external oversight procedures, including the creation of an International Scientific Expert Advisory Group, chaired by Prof Robert Black, Chairman of the Department of International Health, Johns Hopkins Bloomberg School of Public Health, which will report to the Principal Investigator and also communicate its findings to The Lancet. The goal is to provide a further independent means of verifying the quality of the project’s design and analysis. It is important that this work, which is of considerable significance for understanding how countries scale up multiple complex interventions across sectors, receives proper scientific evaluation before, during, and after publication.
1947
Correspondence
investigators should not be involved in the process of decision making about approval of the trial. This guideline has always been followed. We are proud in saying that we have been associated with many important clinical trials related to coronary artery disease, stroke, Alzheimer’s dementia, parkinsonism, and asthma, leading to many publications and subsequent approval of a few new molecules or formulation by licensing authorities in India, the USA, and other countries. A prime example was published in The Lancet,3 and WHO and the Government of India have acknowledged the role of this vaccine in making India polio free for the past year, for the first time in the history of the nation. We declare that we have no conflicts of interest.
*Apoorva Pauranik, Anil Bharani, Salil Bhargava, Ashok Bajpai, Hemant Jain, Pushpa Verma
fine is regarded as an improper procedure; the World Report did not directly link the penalty to ethical violations. Activists claim that Hindi translations of consent forms were far shorter than the English versions and were not exact. Pauranik and colleagues state that there is no restriction in the Indian Council of Medical Research guidelines on principal investigators also being members of ethics committees. But Clinical Trials Registry India (CTRI) itself has raised concerns about strengthening ethics committees and called for investigators and committee members to declare conflicts of interest. I phoned and emailed CTRI and the Ministry of Health multiple times, but never received a reply. If The Lancet does a follow-up story on clinical trials, we will be sure to contact Pauranik and colleagues.
[email protected]
I declare that I have no conflicts of interest.
MGM Medical College, Indore, Madhya Pradesh 452001, India
Amy Yee
1
A 9/8 Vasant Vihar, New Delhi 110057, India
2
3
Yee A. Regulation failing to keep up with India’s trials boom. Lancet 2012; 379: 397–98. Yuji K, Narimatsu H, Tanimoto T, Komatsu T, Kami M. Sharing information on adverse events. Lancet 2011; 377: 1654. Sutter RW, John TJJ, Jain H, et al. Immunogenicity of bivalent types 1 and 3 oral poliovirus vaccine: a randomised, double-blind, controlled trial. Lancet 2020; 376: 1682–88.
[email protected]
Pregnancy should not rule out 18FDG PET/CT for women with cancer
First, the measured absorbed doses we reported (3·3–4·0×10–2 mGy/MBq)3 are actually higher than current dosimetric standards (about 2·0×10–2 mGy/MBq), but our measurements were obtained from women in the first weeks of pregnancy. The first trimester is characterised by rapid cellular proliferation, which leads to a higher glucose consumption and consequently a high absorbed dose of 18FDG. Indeed, more recent data from women at a later stage of pregnancy show much lower fetal 18FDG uptake, and the absorbed dose is about 1·0×10–2 mGy/MBq or less.4 Second, dosimetry extrapolations from monkeys should be taken with extreme caution. Data from monkeys might not be a good dosimetric model for man, since they often significantly and unpredictably overestimate human values.5 Finally, it should not be forgotten that, for the range of doses delivered by a PET/CT examination, especially when appropriate measures are taken to minimise the dose, there are no clearly proven health effects on the fetus. Therefore, when medically indicated, 18FDG PET should not be avoided, since the benefit for the mother is likely to outweigh the very small fetal radiation risk. I declare that I have no conflicts of interest.
Author’s reply Apoorva Pauranik and colleagues’ points are well taken. However, it is a fact that activists have made formal allegations of ethical violations and filed complaints with the Indian Supreme Court and other agencies. The Court will decide how to proceed, and whether clinical trials were legal and ethical. My World Report acknowledged that patients’ deaths were not found to be linked to the trials. It also acknowledged that the money received by six doctors was to run clinical trials. But large amounts of money are clearly involved. A “trivial technicality” relating to the Rs5000 1948
In the excellent Series papers about the management of pregnant women with gynaecological and haematological cancers (Feb 11, pp 558 and 580)1,2 the authors discourage the use of fluorine-18labelled fluorodeoxyglucose (18FDG) PET/CT during pregnancy, because of the potential risks associated with radiation exposure to the fetus. These recommendations were partly inspired by the fetal dosimetric measurements in pregnant women we previously published,3 and partly by data from monkey models. It is my contention that these data do not justify such strong recommendations.
Paolo Zanotti-Fregonara [email protected] CNRS UMR 5287, INCIA, Université de Bordeaux, 33076 Bordeaux, France 1
2
3
4
5
Morice P, Uzan C, Gouy S, Verschraegen C, Haie-Meder C. Gynaecological cancers in pregnancy. Lancet 2012; 379: 558–69. Brenner B, Avivi I, Lishner M. Haematological cancers in pregnancy. Lancet 2012; 379: 580–87. Zanotti-Fregonara P, Jan S, Taieb D, et al. Absorbed F-18-FDG dose to the fetus during early pregnancy. J Nucl Med 2010; 51: 803–05. Takalkar AM, Khandelwal A, Lokitz S, Lilien DL, Stabin MG. (18)F-FDG PET in pregnancy and fetal radiation dose estimates. J Nucl Med 2011; 52: 1035–40. Zanotti-Fregonara P, Innis RB. Suggested pathway to assess radiation safety of (11) C-labeled PET tracers for first-in-human studies. Eur J Nucl Med Mol Imaging 2012; 39: 544–47.
www.thelancet.com Vol 379 May 26, 2012