Letters
violence. Although previous studies have noted gender norms that promote male dominance and control as key factors, it must be acknowledged that these studies (including the recently published multicountry study2) only include men in their measures of perpetrators. We lack similar theories for females because they have largely been excluded from the perpetration research. As noted by Righthand and Welch,3 research on females who have committed sex offenses is rare. They suggest that “[t]he incidence of sex offending may be underestimated for female juveniles even more than for males, perhaps because of a societal reluctance (and even a reluctance among professionals) to acknowledge that girls are capable of committing such offenses.”3(p14) Thus, societal norms do encourage female perpetration, just in different ways than male perpetration. Until we acknowledge that women can be violent, we will not be able to develop gender-appropriate prevention programs that reduce rates of perpetration for men and women. We appreciate Dr Goodson’s observation that it is unlikely that all teenage perpetrators of sexual violence are making a conscious decision to commit a felony. Motivations certainly vary considerably. Future research could focus on illuminating this aspect of the perpetration. At the same time, sexual violence is sexual violence, regardless of motivation. Prevention programs that address this behavior are critical. Whether the motivation behind the violence was insidious or not, the data suggest that perpetrators often do not take responsibility for their actions and that many blame the victim to some extent. Taking responsibility for one’s actions may very well be related to the motivation behind the violence, and this combination could be a useful focus within prevention programs. The research on programs that focus on rethinking scripts for acceptable behavior is encouraging.4,5 And, as suggested in the implications of our study,1 we agree that bystander intervention could play a crucial role in both helping victims and identifying perpetrators. Michele L. Ybarra, MPH, PhD Kimberly J. Mitchell, PhD Author Affiliations: Center for Innovative Public Health Research, San Clemente, California (Ybarra); Crimes Against Children Research Center, University of New Hampshire, Durham (Mitchell). Corresponding Author: Michele L. Ybarra, MPH, PhD, Center for Innovative Public Health Research, 555 El Camino Real, Ste A347, San Clemente, CA 92672-6745 (michele@innovativepublichealth).
Survival at a Gestational Age of 24 Weeks in the Netherlands To the Editor Verhagen and Janvier1 have described the processes involved in the medical care of neonates who died. Although their article is highly relevant, we would like to comment on one aspect of it. They state that “[s]urvival for those born at 24 weeks…is as low as zero in some centers in the Netherlands.”1(p988) It is important to note that, in the Netherlands, views on the medical care of extremely preterm neonates have developed over time. Since September 2010, obstetricians and neonatologists nationwide agreed on offering parents active resuscitation for neonates from a gestational age of 24 weeks onwards. Since then, in the Netherlands, the mortality rate among neonates with a gestational age from 24 weeks and 0 days to 24 weeks and 6 days has decreased to between 45% and 50% in the neonatal intensive care units (data from the Netherlands Perinatal Registry), which is well in accordance with the rates in other European countries actively resuscitating neonates with such a low gestational age.2 Data on long-term morbidity are as yet unavailable but are being collected.3 In addition, data on perinatal deaths are collected to provide insight into the relevant ethical aspects of medical care at the limits of viability raised by Verhagen and Janvier.1 Floris Groenendaal, MD, PhD Rene Kornelisse, MD, PhD Chantal Hukkelhoven, PhD Author Affiliations: Department of Neonatology, University Medical Center Utrecht, Utrecht, the Netherlands (Groenendaal); Erasmus Medical Center, Rotterdam, the Netherlands (Kornelisse); Netherlands Perinatal Registry, Utrecht, the Netherlands (Hukkelhoven). Corresponding Author: Floris Groenendaal, MD, PhD, Department of Neonatology, University Medical Center Utrecht, PO Box 85090, Room KE 04.123.1, 3584 EA Utrecht, the Netherlands ([email protected]). Conflict of Interest Disclosures: None reported. 1. Verhagen AAE, Janvier A. The continuing importance of how neonates die. JAMA Pediatr. 2013;167(11):987-988.
Conflict of Interest Disclosures: None reported.
2. Costeloe KL, Hennessy EM, Haider S, Stacey F, Marlow N, Draper ES. Short term outcomes after extreme preterm birth in England: comparison of two birth cohorts in 1995 and 2006 (the EPICure studies). BMJ. 2012;345:e7976.
1. Ybarra ML, Mitchell KJ. Prevalence rates of male and female sexual violence perpetrators in a national sample of adolescents. JAMA Pediatr. 2013;167(12):1125-1134.
3. de Kluiver E, Offringa M, Walther FJ, Duvekot JJ, de Laat MW. Perinatal policy in cases of extreme prematurity; an investigation into the implementation of the guidelines [in Dutch]. Ned Tijdschr Geneeskd. 2013;157(38):A6362.
2. Jewkes R, Fulu E, Roselli T, Garcia-Moreno C; UN Multi-country Cross-sectional Study on Men and Violence research team. Prevalence of and factors associated with non-partner rape perpetration: findings from the UN Multi-country Cross-sectional Study on Men and Violence in Asia and the Pacific. Lancet Global Health. 2013;1(4):e208-e218. doi:10.1016/S2214-109X(13) 70069-X. 3. Righthand S, Welch C. Juveniles Who Have Sexually Offended: A Review of the Professional Literature. https://www.ncjrs.gov/pdffiles1/ojjdp/184739.pdf. Revised January 19, 2001. Accessed April 14, 2014. 4. Wolfe DA, Crooks C, Jaffe P, et al. A school-based program to prevent adolescent dating violence: a cluster randomized trial. Arch Pediatr Adolesc Med. 2009;163(8):692-699.
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5. Miller E, Tancredi DJ, McCauley HL, et al. One-year follow-up of a coach-delivered dating violence prevention program: a cluster randomized controlled trial. Am J Prev Med. 2013;45(1):108-112.
In Reply In their letter, Groenendaal and coauthors inform us about recent changes in attitudes and practice regarding the care of extremely preterm babies in the Netherlands resulting in optional active resuscitation for neonates from a gestational age of 24 weeks onwards. That is important news. We hope that they will soon publish these data internationally in a detailed manner and include the descriptions of medical care and the decisions that preceded the death or
JAMA Pediatrics June 2014 Volume 168, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Georgia User on 05/28/2015
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Letters
A. A. Eduard Verhagen, MD, PhD, JD Annie Janvier, MD, PhD
and modified with knowledge. Administrative matters need to always be improved. Since 2007, the Food and Drug Administration and the European Medicines Agency have closely collaborated on supporting the development of medicines for children. Guidance on the US Pediatric Study Plan and PIPs are already similar, and the timing of the submission of plans has been brought closer by the Food and Drug Administration Safety and Innovation Act. To conclude, we do not see evidence that the conduct of pediatric phase 1 trials has been jeopardized by the need for agreement of a PIP. Once pharmaceutical companies engage in developing medicines specifically for pediatric oncology purposes, we believe that regulators will speedily fulfill the public health objective of making medicines available for children with cancer.
Author Affiliations: Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (Verhagen); Division of Neonatology and Clinical Ethics, Sainte-Justine Hospital, University of Montreal, Montreal, Quebec, Canada (Janvier).
Ralf Herold, MD, PhD Agnès Saint-Raymond, MD Koenraad Norga, MD, PhD
survival of the babies studied. That would help us to understand what we can validly infer from comparison with other outcome studies. The remarks by Groenendaal et al illustrate that knowledge about how babies die is important because end-of-life decisions are heavily influenced by personal, local, and/or national values. Those values shape the patient mix, neonatal intensive care unit (NICU) outcomes, and the context of clinical and ethical decisions. Reflection on those values, as well as proper analysis of outcome data, can only take place if we start describing with more accuracy how babies die in the NICU or before they make it to the NICU.
Corresponding Author: A. A. Eduard Verhagen, MD, PhD, JD, Department of Pediatrics, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700RB Groningen, the Netherlands ([email protected]). Conflict of Interest Disclosures: None reported.
Too Few Medicines for Children With Cancer To the Editor We welcome the Viewpoint by Adamson1 on how regulatory agencies can improve the health of children through requirements and incentives for pediatric cancer medicines. This is done at the European Medicines Agency by the Pediatric Committee, which has overseen pediatric investigation plans (PIPs) since 2007.2 However, we do not share Dr Adamson’s views on 2 points. From our experience, difficulties in agreeing on a PIP are not owing to numerous study details, but more to stakeholders’ reluctance to accept that trials are needed when efficacy or safety in pediatric oncology indications differ from those in adults. Unfortunately, the European Union legislation gives regulators a single opportunity to set out PIP requirements. Phase 1 trials in childhood cancers should start early in development considering the few therapeutic options available; however, our analysis of phase 1 trials shows about 8 pediatric trials per year in the European Union and United States and 20 times more in adults, according to 2010 data. Dr Adamson suggests that completed phase 1 trials are not acceptable to regulators. In fact, completed trials have been and can be accepted, even if regulators would prefer to encourage more informative designs3,4 and to engage in early regulatory dialogue. Exchanging experiences, introducing pharmacokinetic or pharmacodynamic approaches with integrated modeling, or dose selection with integrated anticancer activity evaluation are of benefit to all. We welcome Dr Adamson’s suggestions on how to make more medicines available for childhood cancer. Early pediatric development should be encouraged in the revision of the European Union pediatric oncology guideline.5 Better communication and standard oncology PIPs will help define how pediatric medicine development can be efficiently managed
Author Affiliations: European Medicines Agency, London, United Kingdom (Herold, Saint-Raymond); Department of Paediatric Oncology, Antwerp University Hospital (UZA), Edegem, Belgium (Norga); Department of Medicine and Health Sciences, Antwerp University, Wilrijk, Belgium (Norga). Corresponding Author: Ralf Herold, MD, PhD, Product Development Scientific Support Department, European Medicines Agency, 7 Westferry Circus, Canary Wharf, London E14 4HB, United Kingdom ([email protected]). Conflict of Interest Disclosures: None reported. Disclaimer: The views expressed in this letter are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties. 1. Adamson PC. Unintended consequences of regulatory initiatives in childhood cancer drug development. JAMA Pediatr. 2013;167(10):886-887. 2. European Medicines Agency. Paediatric investigation plans agreed for anti-cancer medicines. http://www.ema.europa.eu/ema/index.jsp?curl=pages /medicines/landing/pip_search.jsp&mid=WC0b01ac058001d129. Accessed September 20, 2013. 3. Sleijfer S, Bogaerts J, Siu LL. Designing transformative clinical trials in the cancer genome era. J Clin Oncol. 2013;31(15):1834-1841. 4. Rogatko A, Schoeneck D, Jonas W, Tighiouart M, Khuri FR, Porter A. Translation of innovative designs into phase I trials. J Clin Oncol. 2007;25(31):4982-4986. 5. Addendum on paediatric oncology (CPMP/EWP/569/02) to the guideline “Evaluation of anti-cancer medicinal products in man.” http://www.ema.europa .eu/ema/index.jsp?curl=pages/regulation/general/general_content_000406 .jsp&murl=menus/regulations/regulations.jsp&mid=WC0b01ac0580034cf3. Accessed September 20, 2013.
In Reply I thank Herold et al for their thoughtful letter and their commitment to improving the drug development process for children with cancer. As a leader of an international collaborative childhood cancer research organization, in my experience— contrary to their conclusion—the process surrounding pediatric investigation plan approvals is delaying the onset of a number of pediatric phase 1 cancer trials. While it is fully appreciated that completed early-phase trials have been accepted in the past by the European Medicines Agency, it is likely the effect of regulatory uncertainty1 that leads a number of biopharmaceutical industry sponsors to delay the onset of pediatric clinical research until a pediatric investigation plan is approved.
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JAMA Pediatrics June 2014 Volume 168, Number 6
Copyright 2014 American Medical Association. All rights reserved.
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violence. Although previous studies have noted gender norms that promote male dominance and control as key factors, it must be acknowledged that these studies (including the recently published multicountry study2) only include men in their measures of perpetrators. We lack similar theories for females because they have largely been excluded from the perpetration research. As noted by Righthand and Welch,3 research on females who have committed sex offenses is rare. They suggest that “[t]he incidence of sex offending may be underestimated for female juveniles even more than for males, perhaps because of a societal reluctance (and even a reluctance among professionals) to acknowledge that girls are capable of committing such offenses.”3(p14) Thus, societal norms do encourage female perpetration, just in different ways than male perpetration. Until we acknowledge that women can be violent, we will not be able to develop gender-appropriate prevention programs that reduce rates of perpetration for men and women. We appreciate Dr Goodson’s observation that it is unlikely that all teenage perpetrators of sexual violence are making a conscious decision to commit a felony. Motivations certainly vary considerably. Future research could focus on illuminating this aspect of the perpetration. At the same time, sexual violence is sexual violence, regardless of motivation. Prevention programs that address this behavior are critical. Whether the motivation behind the violence was insidious or not, the data suggest that perpetrators often do not take responsibility for their actions and that many blame the victim to some extent. Taking responsibility for one’s actions may very well be related to the motivation behind the violence, and this combination could be a useful focus within prevention programs. The research on programs that focus on rethinking scripts for acceptable behavior is encouraging.4,5 And, as suggested in the implications of our study,1 we agree that bystander intervention could play a crucial role in both helping victims and identifying perpetrators. Michele L. Ybarra, MPH, PhD Kimberly J. Mitchell, PhD Author Affiliations: Center for Innovative Public Health Research, San Clemente, California (Ybarra); Crimes Against Children Research Center, University of New Hampshire, Durham (Mitchell). Corresponding Author: Michele L. Ybarra, MPH, PhD, Center for Innovative Public Health Research, 555 El Camino Real, Ste A347, San Clemente, CA 92672-6745 (michele@innovativepublichealth).
Survival at a Gestational Age of 24 Weeks in the Netherlands To the Editor Verhagen and Janvier1 have described the processes involved in the medical care of neonates who died. Although their article is highly relevant, we would like to comment on one aspect of it. They state that “[s]urvival for those born at 24 weeks…is as low as zero in some centers in the Netherlands.”1(p988) It is important to note that, in the Netherlands, views on the medical care of extremely preterm neonates have developed over time. Since September 2010, obstetricians and neonatologists nationwide agreed on offering parents active resuscitation for neonates from a gestational age of 24 weeks onwards. Since then, in the Netherlands, the mortality rate among neonates with a gestational age from 24 weeks and 0 days to 24 weeks and 6 days has decreased to between 45% and 50% in the neonatal intensive care units (data from the Netherlands Perinatal Registry), which is well in accordance with the rates in other European countries actively resuscitating neonates with such a low gestational age.2 Data on long-term morbidity are as yet unavailable but are being collected.3 In addition, data on perinatal deaths are collected to provide insight into the relevant ethical aspects of medical care at the limits of viability raised by Verhagen and Janvier.1 Floris Groenendaal, MD, PhD Rene Kornelisse, MD, PhD Chantal Hukkelhoven, PhD Author Affiliations: Department of Neonatology, University Medical Center Utrecht, Utrecht, the Netherlands (Groenendaal); Erasmus Medical Center, Rotterdam, the Netherlands (Kornelisse); Netherlands Perinatal Registry, Utrecht, the Netherlands (Hukkelhoven). Corresponding Author: Floris Groenendaal, MD, PhD, Department of Neonatology, University Medical Center Utrecht, PO Box 85090, Room KE 04.123.1, 3584 EA Utrecht, the Netherlands ([email protected]). Conflict of Interest Disclosures: None reported. 1. Verhagen AAE, Janvier A. The continuing importance of how neonates die. JAMA Pediatr. 2013;167(11):987-988.
Conflict of Interest Disclosures: None reported.
2. Costeloe KL, Hennessy EM, Haider S, Stacey F, Marlow N, Draper ES. Short term outcomes after extreme preterm birth in England: comparison of two birth cohorts in 1995 and 2006 (the EPICure studies). BMJ. 2012;345:e7976.
1. Ybarra ML, Mitchell KJ. Prevalence rates of male and female sexual violence perpetrators in a national sample of adolescents. JAMA Pediatr. 2013;167(12):1125-1134.
3. de Kluiver E, Offringa M, Walther FJ, Duvekot JJ, de Laat MW. Perinatal policy in cases of extreme prematurity; an investigation into the implementation of the guidelines [in Dutch]. Ned Tijdschr Geneeskd. 2013;157(38):A6362.
2. Jewkes R, Fulu E, Roselli T, Garcia-Moreno C; UN Multi-country Cross-sectional Study on Men and Violence research team. Prevalence of and factors associated with non-partner rape perpetration: findings from the UN Multi-country Cross-sectional Study on Men and Violence in Asia and the Pacific. Lancet Global Health. 2013;1(4):e208-e218. doi:10.1016/S2214-109X(13) 70069-X. 3. Righthand S, Welch C. Juveniles Who Have Sexually Offended: A Review of the Professional Literature. https://www.ncjrs.gov/pdffiles1/ojjdp/184739.pdf. Revised January 19, 2001. Accessed April 14, 2014. 4. Wolfe DA, Crooks C, Jaffe P, et al. A school-based program to prevent adolescent dating violence: a cluster randomized trial. Arch Pediatr Adolesc Med. 2009;163(8):692-699.
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5. Miller E, Tancredi DJ, McCauley HL, et al. One-year follow-up of a coach-delivered dating violence prevention program: a cluster randomized controlled trial. Am J Prev Med. 2013;45(1):108-112.
In Reply In their letter, Groenendaal and coauthors inform us about recent changes in attitudes and practice regarding the care of extremely preterm babies in the Netherlands resulting in optional active resuscitation for neonates from a gestational age of 24 weeks onwards. That is important news. We hope that they will soon publish these data internationally in a detailed manner and include the descriptions of medical care and the decisions that preceded the death or
JAMA Pediatrics June 2014 Volume 168, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Georgia User on 05/28/2015
jamapediatrics.com
Letters
A. A. Eduard Verhagen, MD, PhD, JD Annie Janvier, MD, PhD
and modified with knowledge. Administrative matters need to always be improved. Since 2007, the Food and Drug Administration and the European Medicines Agency have closely collaborated on supporting the development of medicines for children. Guidance on the US Pediatric Study Plan and PIPs are already similar, and the timing of the submission of plans has been brought closer by the Food and Drug Administration Safety and Innovation Act. To conclude, we do not see evidence that the conduct of pediatric phase 1 trials has been jeopardized by the need for agreement of a PIP. Once pharmaceutical companies engage in developing medicines specifically for pediatric oncology purposes, we believe that regulators will speedily fulfill the public health objective of making medicines available for children with cancer.
Author Affiliations: Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (Verhagen); Division of Neonatology and Clinical Ethics, Sainte-Justine Hospital, University of Montreal, Montreal, Quebec, Canada (Janvier).
Ralf Herold, MD, PhD Agnès Saint-Raymond, MD Koenraad Norga, MD, PhD
survival of the babies studied. That would help us to understand what we can validly infer from comparison with other outcome studies. The remarks by Groenendaal et al illustrate that knowledge about how babies die is important because end-of-life decisions are heavily influenced by personal, local, and/or national values. Those values shape the patient mix, neonatal intensive care unit (NICU) outcomes, and the context of clinical and ethical decisions. Reflection on those values, as well as proper analysis of outcome data, can only take place if we start describing with more accuracy how babies die in the NICU or before they make it to the NICU.
Corresponding Author: A. A. Eduard Verhagen, MD, PhD, JD, Department of Pediatrics, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700RB Groningen, the Netherlands ([email protected]). Conflict of Interest Disclosures: None reported.
Too Few Medicines for Children With Cancer To the Editor We welcome the Viewpoint by Adamson1 on how regulatory agencies can improve the health of children through requirements and incentives for pediatric cancer medicines. This is done at the European Medicines Agency by the Pediatric Committee, which has overseen pediatric investigation plans (PIPs) since 2007.2 However, we do not share Dr Adamson’s views on 2 points. From our experience, difficulties in agreeing on a PIP are not owing to numerous study details, but more to stakeholders’ reluctance to accept that trials are needed when efficacy or safety in pediatric oncology indications differ from those in adults. Unfortunately, the European Union legislation gives regulators a single opportunity to set out PIP requirements. Phase 1 trials in childhood cancers should start early in development considering the few therapeutic options available; however, our analysis of phase 1 trials shows about 8 pediatric trials per year in the European Union and United States and 20 times more in adults, according to 2010 data. Dr Adamson suggests that completed phase 1 trials are not acceptable to regulators. In fact, completed trials have been and can be accepted, even if regulators would prefer to encourage more informative designs3,4 and to engage in early regulatory dialogue. Exchanging experiences, introducing pharmacokinetic or pharmacodynamic approaches with integrated modeling, or dose selection with integrated anticancer activity evaluation are of benefit to all. We welcome Dr Adamson’s suggestions on how to make more medicines available for childhood cancer. Early pediatric development should be encouraged in the revision of the European Union pediatric oncology guideline.5 Better communication and standard oncology PIPs will help define how pediatric medicine development can be efficiently managed
Author Affiliations: European Medicines Agency, London, United Kingdom (Herold, Saint-Raymond); Department of Paediatric Oncology, Antwerp University Hospital (UZA), Edegem, Belgium (Norga); Department of Medicine and Health Sciences, Antwerp University, Wilrijk, Belgium (Norga). Corresponding Author: Ralf Herold, MD, PhD, Product Development Scientific Support Department, European Medicines Agency, 7 Westferry Circus, Canary Wharf, London E14 4HB, United Kingdom ([email protected]). Conflict of Interest Disclosures: None reported. Disclaimer: The views expressed in this letter are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties. 1. Adamson PC. Unintended consequences of regulatory initiatives in childhood cancer drug development. JAMA Pediatr. 2013;167(10):886-887. 2. European Medicines Agency. Paediatric investigation plans agreed for anti-cancer medicines. http://www.ema.europa.eu/ema/index.jsp?curl=pages /medicines/landing/pip_search.jsp&mid=WC0b01ac058001d129. Accessed September 20, 2013. 3. Sleijfer S, Bogaerts J, Siu LL. Designing transformative clinical trials in the cancer genome era. J Clin Oncol. 2013;31(15):1834-1841. 4. Rogatko A, Schoeneck D, Jonas W, Tighiouart M, Khuri FR, Porter A. Translation of innovative designs into phase I trials. J Clin Oncol. 2007;25(31):4982-4986. 5. Addendum on paediatric oncology (CPMP/EWP/569/02) to the guideline “Evaluation of anti-cancer medicinal products in man.” http://www.ema.europa .eu/ema/index.jsp?curl=pages/regulation/general/general_content_000406 .jsp&murl=menus/regulations/regulations.jsp&mid=WC0b01ac0580034cf3. Accessed September 20, 2013.
In Reply I thank Herold et al for their thoughtful letter and their commitment to improving the drug development process for children with cancer. As a leader of an international collaborative childhood cancer research organization, in my experience— contrary to their conclusion—the process surrounding pediatric investigation plan approvals is delaying the onset of a number of pediatric phase 1 cancer trials. While it is fully appreciated that completed early-phase trials have been accepted in the past by the European Medicines Agency, it is likely the effect of regulatory uncertainty1 that leads a number of biopharmaceutical industry sponsors to delay the onset of pediatric clinical research until a pediatric investigation plan is approved.
jamapediatrics.com
JAMA Pediatrics June 2014 Volume 168, Number 6
Copyright 2014 American Medical Association. All rights reserved.
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