- Email: [email protected]
EU Clinical Trials Regulation
Correspondence
essential for facility-based MDRs. Without confidentiality and openness in reporting, valuable insights and lessons are lost. We declare that we have no conflicts of interest.
*Vincent De Brouwere, Gwyneth Lewis, Véronique Filippi, Thérèse Delvaux, Jolly Beyeza-Kashesya, Yirgu Gebrehiwot, Cassimo Bique, David Taylor [email protected] Institute of Tropical Medicine, Antwerp, Belgium (VDB, TD); London School of Hygiene and Tropical Medicine, London, UK (VF); Mulago National Referral Hospital, Kampala, Uganda (JB-K); Institute of Women’s Health, University College London (GL); Addis Ababa University, School of Medicine, Addis Ababa, Ethiopia (YG); Hospital Central de Maputo, Maputo, Mozambique (CB); and International Federation of Obstetrics and Gynaecology, London, UK (DT) 1
2
3
4
Hounton S, de Bernis L, Hussein J, et al. Towards elimination of maternal deaths: maternal deaths surveillance and response. Reprod Health 2013; 10: 1. WHO. Beyond the numbers. Reviewing maternal deaths and complications to make pregnancy safer. Geneva: World Health Organization; 2004. Swick HM, Szenas P, Danoff D, Whitcomb ME. Teaching professionalism in undergraduate medical education. JAMA 1999; 282: 830–32. Danel I, Graham WJ, Boerma T. Maternal death surveillance and response. Bull World Health Organ 2011; 89: 779A.
Counting the dead: properly and promptly Registration of deaths in England and Wales is not fit for purpose, as the Royal Statistical Society makes clear1 with ten arguments against late registration, and calls to action by national statisticians, health and social care information centres, and ministers. Late registrations, mainly of inquest deaths, occur because the fact of death is not even registered in England and Wales until the inquest verdict has determined cause of death. Legislation is needed to uncouple registration of the fact of death from registering cause. Without exception, all deaths in Scotland must be registered within 8 days of death having been ascertained. www.thelancet.com Vol 381 May 18, 2013
The Chief Medical Officer’s first report on public health in England failed to differentiate between registrationyear and death-year for deaths from illicit drugs. Of drug-related deaths registered in 2011, half occurred in preceding years.2 Differentiation also failed in the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA)’s annual report.3 Carefully chosen words in the Editorial on suicides in the UK (Feb 2, p 348)4 disguised the problem: “6045 suicides were recorded in UK in 2011”. Most readers would not realise that nearly half the suicides registered in England and Wales in 2011 had occurred in preceding years.5 Only around 10 000 of the half million deaths per year in England and Wales have a registration delay of at least 6 months.1 Parliamentary questions by Patrick Mercer revealed that one in five deaths of people aged 5–44 years is subject to at least 6 months registration delay.1 Indeed, registration delay varies by cause of death, age and sex,1 and have lengthened in the past decade. Record linkage is a powerful means of making discoveries about public health, including at the interface with other jurisdictions. But in England and Wales, this is challenged by our being unable to correctly establish the survival status of study participants. Paid-for checks against the death register in England and Wales on whether study participants have died by a specified date yielded information on deaths that have both occurred and been registered by the check date, while Scotland’s statistical system would retrieve all deaths that occurred. As a consequence, in England and Wales, analyses have to be delayed to allow for registration delays, and the discovery potential from NHS record linkage is held back. Reports on deaths in England and Wales should differentiate registration-year from death-year. Researchers doing death registration checks in England and Wales should
specify both analysis date and check date because participants who died before the analysis date, but whose death was not registered before the check date, could be analysed wrongly as alive at the analysis date. I lead for the Royal Statistical Society on late registration of deaths.
Sheila M Bird [email protected] Biostatistics Unit, Medical Research Council, Cambridge, CB2 0SR, UK 1
2
3
4 5
Royal Statistical Society. Late registration of deaths in England and Wales—further statement. http://www.rss.org.uk/site/cms/newsarticle. asp?chapter=15&nid=79 (accessed May 1, 2013). Office for National Statistics. Deaths related to drug poisoning in England and Wales, 2011. http://www.ons.gov.uk/ons/rel/subnationalhealth3/deaths-related-to-drug-poisoning/ 2011/stb-deaths-related-to-drugpoisoning-2011.html (accessed May 1, 2013). EMCDDA. 2012 Annual report on the state of the drugs problem in Europe.http://www. emcdda.europa.eu/publications/annualreport/2012 (accessed May 1, 2013). The Lancet. Suicide in the UK: questioning ourselves. Lancet 2013; 381: 348. Office for National Statistics. Suicides in the United Kingdom, 2011. http://www.ons.gov. uk/ons/rel/subnational-health4/suicides-inthe-united-kingdom/2011/stb-suicidebulletin.html (accessed May 1, 2013).
EU Clinical Trials Regulation The upcoming debate on the proposal for European regulation on clinical trials will have to unravel many knots. In addition to removing any reference to Ethics Committees, the proposal, released by the EU Commission, established ground for a single scientific assessment for the authorisation to conduct a clinical trial. This one-entry evaluation, which will then be valid for all concerned member states, has been artificially dissociated from national ethical assessments.1 Other deregulation measures were also put forward, introducing provisions that will negatively impact on the protection of trial participants, such as narrowing the definition of a clinical trial. This change would allow some post-authorisation trials to fall outside the scope of the new regulation 1719
Correspondence
Science Photo Library
or to be labelled as low-intervention clinical trials, thus exempting sponsors from having to provide any compensation for damages incurred by trials participants. Many interested parties have expressed their dissent with the EU Commission’s proposal.2,3 The draft report by Glenis Willmott (Member of the European Parliament) is heading in the right direction, having partly responded to some of the ethical and transparency concerns.4 Yet, the revision of the Clinical Trials Regulation offers a major opportunity to redirect clinical research and development towards a model that meets real public health needs, by: (1) requiring comparative clinical trials in accordance with the Declaration of Helsinki which specifies that “The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention”, and warns against the use of placebocontrolled clinical trials, stating that “extreme care must be taken to avoid abuse of this option”; (2) granting public access to raw data and clinical study reports, which would allow independent analysis and early detection of safety problems; (3) discouraging the conduct of unethical trials in countries outside the EU by demanding that clinical data submitted in the Common Technical Document (when applying for a medicine’s marketing authorisation) is obtained from registered clinical trials that duly comply with the provisions of the new regulation; and (4) enacting and enforcing effective monitoring of clinical trials, to prevent any omission and data withholding. I declare that I have no conflicts of interest.
Bruno Toussaint [email protected] Prescrire, 75558 Paris Cedex 11, FRANCE 1
1720
European Commission. Proposal for a regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. Brussels: European Commission, 2012.
2
3
4
AIM, ISDB, MiEF, WEMOS. Proposed regulation on clinical trials: joint analysis. http://english. prescrire.org/en/79/207/46302/2507/2506/ SubReportDetails.aspx (accessed April 24, 2013). Gøtzche PC. Deficiencies in proposed new EU regulation of clinical trials. BMJ 2012; 345: e8522. Willmott G. Draft Report on the proposal for a regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. http://www.europarl.europa.eu/ sides/getDoc.do?pubRef=-//EP//NONSGML% 2BCOMPARL%2BPE-504.236%2B01%2BDOC% 2BPDF%2BV0//EN (accessed April 24, 2013).
Road traffic injuries are on the increase. There is a need for more accurate cause-specific data. Both data collection and ways to tackle road traffic injuries will require cross-sectoral cooperation between various ministries.4 Cooperation between ministries will be especially challenging given the current political climate in Iraq. We declare that we have no conflicts of interest.
*Najwan Abu Al Saad, Egbert Sondorp [email protected]
Road traffic injuries in Iraq Road traffic injuries are an emerging public health priority for Iraq that will need to be addressed. Although reliable data on the incidence of road traffic injuries in Iraq are lacking, it is an important public health issue, and information can be derived from indirect indicators. Road traffic injury risk is the product of motor vehicles per person and injuries or fatalities per vehicle.1 In countries with accelerated economic growth like Iraq, the number of vehicles tends to increase accompanied by an increase in road traffic injuries. It will take improvements in vehicle safety and implementation of traffic legislation to counter this increase.1 Data from former East Germany show that, after reunification and subsequent economic change, a 41% increase in car numbers was associated with a four-fold increase in road traffic injury associated mortality between 1989 and 1991.2 In 1989, there were an estimated 1 million registered vehicles in Iraq.3 This number did not change significantly during sanctions, bacause vehicle imports ceased. Between 1990 and 2003, road use and mortality associated with road traffic injuries declined.4 Between 2003 and 2004 alone, an estimated 500 000 to 800 000 vehicles were imported into Iraq.3
Peterborough City Hospital, Peterborough PE3 9GZ, UK (NAAS); and London School of Hygiene and Tropical Medicine, London, UK (ES) 1
2
3
4
Kopits E, Cropper M. Traffic fatalities and economic growth. Accid Anal Prev 2005; 37: 169–78. Winston FK, Rineer C, Menon R, Baker SP. The carnage wrought by major economic change: ecological study of traffic related mortality and the reunification of Germany. BMJ 1999; 318: 1647–50. World Bank. Iraq–Emergency road rehabilitation project.http://documents. worldbank.org/curated/en/2005/11/6493885/ iraq-emergency-road-rehabilitation-project (accessed March 30, 2013). WHO. Global status report on road safety: time for action. Geneva, World Health Organization, 2009.
Department of Error Langer A, Horton R, Chalamilla G. A manifesto for maternal health post-2015. Lancet 2013; 381: 601–02—In this Comment, the final point of the panel should read: “Finally, we must fulfil all of these actions sustainably, which means universal access to services free at the point of demand within a strong health system—to family planning, to emergency obstetric care, to safe abortion, to properly trained health individuals, especially midwives and those providing midwifery services.” This correction has been made to the online version as of May 17, 2013. Palmu AA, Jokinen J, Borys D, et al. Effectiveness of the ten-valent pneumococcal Haemophilus influenza protein D conjugate vaccine (PHiD-CV10) against invasive pneumococcal disease: a cluster randomised trial. Lancet 2013; 381: 214–22—The total number of children enrolled was 47 366, not 47 369 (data pertaining to three participants had been entered into the database twice). The results were checked after exclusion of the duplicates; the error did not affect any of the results of the vaccine effectiveness and safety endpoints. These corrections have been made to the online version as of May 17, 2013.
www.thelancet.com Vol 381 May 18, 2013
essential for facility-based MDRs. Without confidentiality and openness in reporting, valuable insights and lessons are lost. We declare that we have no conflicts of interest.
*Vincent De Brouwere, Gwyneth Lewis, Véronique Filippi, Thérèse Delvaux, Jolly Beyeza-Kashesya, Yirgu Gebrehiwot, Cassimo Bique, David Taylor [email protected] Institute of Tropical Medicine, Antwerp, Belgium (VDB, TD); London School of Hygiene and Tropical Medicine, London, UK (VF); Mulago National Referral Hospital, Kampala, Uganda (JB-K); Institute of Women’s Health, University College London (GL); Addis Ababa University, School of Medicine, Addis Ababa, Ethiopia (YG); Hospital Central de Maputo, Maputo, Mozambique (CB); and International Federation of Obstetrics and Gynaecology, London, UK (DT) 1
2
3
4
Hounton S, de Bernis L, Hussein J, et al. Towards elimination of maternal deaths: maternal deaths surveillance and response. Reprod Health 2013; 10: 1. WHO. Beyond the numbers. Reviewing maternal deaths and complications to make pregnancy safer. Geneva: World Health Organization; 2004. Swick HM, Szenas P, Danoff D, Whitcomb ME. Teaching professionalism in undergraduate medical education. JAMA 1999; 282: 830–32. Danel I, Graham WJ, Boerma T. Maternal death surveillance and response. Bull World Health Organ 2011; 89: 779A.
Counting the dead: properly and promptly Registration of deaths in England and Wales is not fit for purpose, as the Royal Statistical Society makes clear1 with ten arguments against late registration, and calls to action by national statisticians, health and social care information centres, and ministers. Late registrations, mainly of inquest deaths, occur because the fact of death is not even registered in England and Wales until the inquest verdict has determined cause of death. Legislation is needed to uncouple registration of the fact of death from registering cause. Without exception, all deaths in Scotland must be registered within 8 days of death having been ascertained. www.thelancet.com Vol 381 May 18, 2013
The Chief Medical Officer’s first report on public health in England failed to differentiate between registrationyear and death-year for deaths from illicit drugs. Of drug-related deaths registered in 2011, half occurred in preceding years.2 Differentiation also failed in the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA)’s annual report.3 Carefully chosen words in the Editorial on suicides in the UK (Feb 2, p 348)4 disguised the problem: “6045 suicides were recorded in UK in 2011”. Most readers would not realise that nearly half the suicides registered in England and Wales in 2011 had occurred in preceding years.5 Only around 10 000 of the half million deaths per year in England and Wales have a registration delay of at least 6 months.1 Parliamentary questions by Patrick Mercer revealed that one in five deaths of people aged 5–44 years is subject to at least 6 months registration delay.1 Indeed, registration delay varies by cause of death, age and sex,1 and have lengthened in the past decade. Record linkage is a powerful means of making discoveries about public health, including at the interface with other jurisdictions. But in England and Wales, this is challenged by our being unable to correctly establish the survival status of study participants. Paid-for checks against the death register in England and Wales on whether study participants have died by a specified date yielded information on deaths that have both occurred and been registered by the check date, while Scotland’s statistical system would retrieve all deaths that occurred. As a consequence, in England and Wales, analyses have to be delayed to allow for registration delays, and the discovery potential from NHS record linkage is held back. Reports on deaths in England and Wales should differentiate registration-year from death-year. Researchers doing death registration checks in England and Wales should
specify both analysis date and check date because participants who died before the analysis date, but whose death was not registered before the check date, could be analysed wrongly as alive at the analysis date. I lead for the Royal Statistical Society on late registration of deaths.
Sheila M Bird [email protected] Biostatistics Unit, Medical Research Council, Cambridge, CB2 0SR, UK 1
2
3
4 5
Royal Statistical Society. Late registration of deaths in England and Wales—further statement. http://www.rss.org.uk/site/cms/newsarticle. asp?chapter=15&nid=79 (accessed May 1, 2013). Office for National Statistics. Deaths related to drug poisoning in England and Wales, 2011. http://www.ons.gov.uk/ons/rel/subnationalhealth3/deaths-related-to-drug-poisoning/ 2011/stb-deaths-related-to-drugpoisoning-2011.html (accessed May 1, 2013). EMCDDA. 2012 Annual report on the state of the drugs problem in Europe.http://www. emcdda.europa.eu/publications/annualreport/2012 (accessed May 1, 2013). The Lancet. Suicide in the UK: questioning ourselves. Lancet 2013; 381: 348. Office for National Statistics. Suicides in the United Kingdom, 2011. http://www.ons.gov. uk/ons/rel/subnational-health4/suicides-inthe-united-kingdom/2011/stb-suicidebulletin.html (accessed May 1, 2013).
EU Clinical Trials Regulation The upcoming debate on the proposal for European regulation on clinical trials will have to unravel many knots. In addition to removing any reference to Ethics Committees, the proposal, released by the EU Commission, established ground for a single scientific assessment for the authorisation to conduct a clinical trial. This one-entry evaluation, which will then be valid for all concerned member states, has been artificially dissociated from national ethical assessments.1 Other deregulation measures were also put forward, introducing provisions that will negatively impact on the protection of trial participants, such as narrowing the definition of a clinical trial. This change would allow some post-authorisation trials to fall outside the scope of the new regulation 1719
Correspondence
Science Photo Library
or to be labelled as low-intervention clinical trials, thus exempting sponsors from having to provide any compensation for damages incurred by trials participants. Many interested parties have expressed their dissent with the EU Commission’s proposal.2,3 The draft report by Glenis Willmott (Member of the European Parliament) is heading in the right direction, having partly responded to some of the ethical and transparency concerns.4 Yet, the revision of the Clinical Trials Regulation offers a major opportunity to redirect clinical research and development towards a model that meets real public health needs, by: (1) requiring comparative clinical trials in accordance with the Declaration of Helsinki which specifies that “The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention”, and warns against the use of placebocontrolled clinical trials, stating that “extreme care must be taken to avoid abuse of this option”; (2) granting public access to raw data and clinical study reports, which would allow independent analysis and early detection of safety problems; (3) discouraging the conduct of unethical trials in countries outside the EU by demanding that clinical data submitted in the Common Technical Document (when applying for a medicine’s marketing authorisation) is obtained from registered clinical trials that duly comply with the provisions of the new regulation; and (4) enacting and enforcing effective monitoring of clinical trials, to prevent any omission and data withholding. I declare that I have no conflicts of interest.
Bruno Toussaint [email protected] Prescrire, 75558 Paris Cedex 11, FRANCE 1
1720
European Commission. Proposal for a regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. Brussels: European Commission, 2012.
2
3
4
AIM, ISDB, MiEF, WEMOS. Proposed regulation on clinical trials: joint analysis. http://english. prescrire.org/en/79/207/46302/2507/2506/ SubReportDetails.aspx (accessed April 24, 2013). Gøtzche PC. Deficiencies in proposed new EU regulation of clinical trials. BMJ 2012; 345: e8522. Willmott G. Draft Report on the proposal for a regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. http://www.europarl.europa.eu/ sides/getDoc.do?pubRef=-//EP//NONSGML% 2BCOMPARL%2BPE-504.236%2B01%2BDOC% 2BPDF%2BV0//EN (accessed April 24, 2013).
Road traffic injuries are on the increase. There is a need for more accurate cause-specific data. Both data collection and ways to tackle road traffic injuries will require cross-sectoral cooperation between various ministries.4 Cooperation between ministries will be especially challenging given the current political climate in Iraq. We declare that we have no conflicts of interest.
*Najwan Abu Al Saad, Egbert Sondorp [email protected]
Road traffic injuries in Iraq Road traffic injuries are an emerging public health priority for Iraq that will need to be addressed. Although reliable data on the incidence of road traffic injuries in Iraq are lacking, it is an important public health issue, and information can be derived from indirect indicators. Road traffic injury risk is the product of motor vehicles per person and injuries or fatalities per vehicle.1 In countries with accelerated economic growth like Iraq, the number of vehicles tends to increase accompanied by an increase in road traffic injuries. It will take improvements in vehicle safety and implementation of traffic legislation to counter this increase.1 Data from former East Germany show that, after reunification and subsequent economic change, a 41% increase in car numbers was associated with a four-fold increase in road traffic injury associated mortality between 1989 and 1991.2 In 1989, there were an estimated 1 million registered vehicles in Iraq.3 This number did not change significantly during sanctions, bacause vehicle imports ceased. Between 1990 and 2003, road use and mortality associated with road traffic injuries declined.4 Between 2003 and 2004 alone, an estimated 500 000 to 800 000 vehicles were imported into Iraq.3
Peterborough City Hospital, Peterborough PE3 9GZ, UK (NAAS); and London School of Hygiene and Tropical Medicine, London, UK (ES) 1
2
3
4
Kopits E, Cropper M. Traffic fatalities and economic growth. Accid Anal Prev 2005; 37: 169–78. Winston FK, Rineer C, Menon R, Baker SP. The carnage wrought by major economic change: ecological study of traffic related mortality and the reunification of Germany. BMJ 1999; 318: 1647–50. World Bank. Iraq–Emergency road rehabilitation project.http://documents. worldbank.org/curated/en/2005/11/6493885/ iraq-emergency-road-rehabilitation-project (accessed March 30, 2013). WHO. Global status report on road safety: time for action. Geneva, World Health Organization, 2009.
Department of Error Langer A, Horton R, Chalamilla G. A manifesto for maternal health post-2015. Lancet 2013; 381: 601–02—In this Comment, the final point of the panel should read: “Finally, we must fulfil all of these actions sustainably, which means universal access to services free at the point of demand within a strong health system—to family planning, to emergency obstetric care, to safe abortion, to properly trained health individuals, especially midwives and those providing midwifery services.” This correction has been made to the online version as of May 17, 2013. Palmu AA, Jokinen J, Borys D, et al. Effectiveness of the ten-valent pneumococcal Haemophilus influenza protein D conjugate vaccine (PHiD-CV10) against invasive pneumococcal disease: a cluster randomised trial. Lancet 2013; 381: 214–22—The total number of children enrolled was 47 366, not 47 369 (data pertaining to three participants had been entered into the database twice). The results were checked after exclusion of the duplicates; the error did not affect any of the results of the vaccine effectiveness and safety endpoints. These corrections have been made to the online version as of May 17, 2013.
www.thelancet.com Vol 381 May 18, 2013