- Email: [email protected]
The ethics of innovation in pediatric surgery
Seminars in Pediatric Surgery (2006) 15, 319-323
The ethics of innovation in pediatric surgery Daniel J. Riskin, MD, MBA,a,b Michael T. Longaker, MD, MBA,a Thomas M. Krummel, MDa From the aBiodesign Surgical Innovation Program, Department of Surgery, Stanford University School of Medicine, Stanford, Califonia; and the b Department of Surgery, University of California, Los Angeles, Los Angeles, California. INDEX WORDS Ethics; Pediatric; Innovation; Research; Experiment
Ethical issues in pediatric research have long been debated, and experimentation in pediatric surgery is under intense scrutiny. Extensive legislation and institutional systems that attempt to protect children while supporting necessary research are at times ineffective. Pediatric surgery has less funding and resources for innovation than fields with higher clinical volume. Not unlike pediatrics in general, innovation in pediatric surgery must be beyond criticism. And yet, for the sake of patients, innovation should not only be maintained, but must be encouraged. © 2006 Elsevier Inc. All rights reserved.
Innovation is the introduction of something new. Research and innovation are different. Research requires study and analysis, but application is not critical. Innovation requires an act of use, but previous study need not be involved. Still, medical innovation and research are intertwined, and one cannot proceed effectively without the other. This brief review will necessarily focus on progress made through research since so little is known about innovation outside the context of research. Successful medical innovation generally incorporates research and publication, whereas failed innovation is most often neither published nor discussed. Innovation in pediatric surgery comes in many forms with correspondingly different ethical standards. Innovation can be a new way of tying a knot, a better way of directing light, or a different way of laying out surgical drapes. Most day-to-day innovation is low risk, low reward, and has few ethical implications. When an innovation entails patient risk, patients and parents rely on the physician, the medical Address reprint requests and correspondence: Thomas M. Krummel, MD, Stanford University School of Medicine, Department of Surgery, 257 Campus Drive West, Stanford, CA 94305-5148. E-mail: [email protected].
1055-8586/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2006.07.012
institution, and society to assess safety and efficacy while protecting the individual. The pull between societal progress and individual protection is fundamental to the ethics of health care innovation. Unresolved ethical issues are pervasive in pediatric surgery research and innovation. From historical injustice to legal debate to fundamental questions about autonomy and assent, innovation in pediatric surgery is a fascinating and perplexing area of bioethics.
History It is difficult for physicians to accept that our training and culture have led not only to impressive successes, but also to historic tragedies. Nowhere is this more clear than in the history of child experimentation. For more than a century, critics have noted that children and other vulnerable populations, such as prisoners and the mentally ill, have been subjects of medical experimentation without consent. Child experimentation is well documented in the 19th century. Examples are numerous and include subjects such as James Phipps, an 8-year-old boy who took part in Edward Jenner’s first trials of cowpox injections to
320 prevent smallpox, and Joseph Meister, a 10-year-old French child who first was inoculated with Louis Pasteur’s rabies vaccine.1 Inadequate child protection was not limited to the 19th century.2 In the first half of the 20th century, American protesters shed light on the use of orphans in trials of diagnostics tests and vaccines for syphilis, tuberculosis, and other infectious diseases. These tests often involved inoculation of the child, where future sequellae described include hemorrhage, blindness, and death.1,3,4 In the early 20th century, children at the Hebrew Orphan Asylum were given selected diets to induce scurvy and rickets so disease progression could be better understood. Between 1958 and 1960, mentally challenged residents at Willowbrook State School were exposed to hepatitis so researchers could follow its course.2 If history generates concern over experimentation in pediatrics, concern for the field of pediatric surgery should be even more stringent. Surgery, in contrast to other areas in medicine, has been free to develop new operations and treatments without strict requirements of animal testing and prospective human clinical trials.5 Sham operations,6 nonbeneficial research,7 and experimentation with little oversight8 in children and adults are a real part of our surgical past. Many operations in children were developed without prior study; current outcomes are all too often unknown because of a lack of prospective data. Whereas by modern standards many past experiments are unethical, it should be noted that there has long been a complex relationship between pediatric researchers and their patients. Edward Jenner, a researcher who inoculated his gardner’s son with smallpox virus, subsequently housed the boy and provided for his future.1 In 1940, John Lentz wrote in an American Medical Association journal, celebrating the “little medical heroes” who had been so important in advancing medical knowledge.9 Medical history highlights countless physicians driven to help children, making life-saving advances in surgical care. In 1944, Dr. Alfred Blalock developed the first palliative operative treatment for Tetralogy of Fallot,10 forming a foundation for operative correction which today permits more than 85% of children with the disease to reach adulthood.11 Dr. Thomas Starzl’s initial liver transplant in 1963 in a 3-year-old boy with biliary atresia did not save the child,12 but led to advances that now save the lives of thousands of children and adults a year.13
The law Despite notable heroes, unacceptable ethical breaches of the past have been acknowledged. One must ask whether we are adequately protected against such acts in the future. In the US and most developed countries, laws exist to protect the medical rights of children. Although the legal system does not define all protections surrounding innovation in
Seminars in Pediatric Surgery, Vol 15, No 4, November 2006 pediatric care, it is a starting point to understand current societal thought. US laws will be examined for the sake of simplicity, but many countries have detailed laws and protections. US federal regulations outline requirements for consent from both a parent and the child who is contemplating participating as a human subject in research. The requirement that the child give permission, which is referred to as “assent,” gives to two different sources, both parent and child, the power to veto the child’s participation in research.14 Assent becomes a critical ethical issue as it underlies the child’s autonomy. Federal regulations define assent as “positive agreement,” of children who are able to provide it.15 The federal code defines research categories which the Department of Health and Human Services (DHHS) is permitted to fund. Since most academic research incorporates DHHS funding, this code effectively defines acceptable criteria. Table 1 details the current federal regulations. Code 46.407 defines the most controversial area of research: study with more than minor risk and little benefit to the patient but significant benefit to the health or welfare of children. This form of research requires public review and comment as well as direct support from the DHHS Secretary after conferring with experts in science, ethics, and law. The bar was intentionally set high and, although the regulations have been in place for two decades, as of 2004, less than 10 such reviews had been undertaken.16 Risk standards, outlining regulation of trials according to perceived patient risk, largely determine which studies will be approved and funded. These standards continue to be hotly debated.17,18
Assent, consent, and dissent Thought about medical ethics has evolved over time19 (Figure 1). Current law highlights one of the most often discussed areas of child bioethics: the right to assent, consent, and dissent. Pediatric surgeons have a unique relationship with their patients. Parents also assume an essential role. Together with the child, there are at least three critical decision-makers, each with unique rights and responsibilities.20 The child’s role changes based on age and apparent decision-making ability. The Belmont Report, a more recent defining document in bioethics, suggests that respect for persons, beneficence, and justice are fundamental.21 Subsequent discussion has led to four basic principles that underpin modern medical ethics: autonomy, beneficence, nonmaleficence, and justice. Although the principles of beneficence, nonmaleficence, and justice apply to pediatrics and other medical fields equally, the principle of autonomy is more challenging. Children, particularly young children, cannot always make personal decisions effectively. In place of autonomy, ethicists have leaned toward protecting the “best interests of the child.”2 In this view, a combination of permission by the parent and assent by the child substitutes for informed consent. The American Academy of Pediatrics follows this model, recom-
Riskin et al Table 1
Ethics of Innovation
321
Summary of US code relating to research the Department of Health and Human Services may fund
§46.404 Requirements for research not involving greater than minimal risk. Only if the IRB finds that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians. §46.405 Requirements for research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects. (a) The risk is justified by the anticipated benefit to the subjects; (b) The relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches; and (c) Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians. §46.406 Requirements for research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition. (a) The risk represents a minor increase over minimal risk; (b) The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; (c) The intervention or procedure is likely to yield generalizable knowledge about the subjects’ disorder or condition which is of vital importance for the understanding or amelioration of the subjects’ disorder or condition; and (d) Adequate provisions are made for soliciting assent of the children and permission of their parents or guardians. §46.407 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. (a) The IRB finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; and (b) The Secretary, after consultation with a panel of experts in pertinent disciplines (for example; science, medicine, education, ethics, law) and following opportunity for public review and comment, has determined that: (i) The research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; (ii) The research will be conducted in accordance with sound ethical principles; (iii) Adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians.
mending viewing informed consent in children as composed of assent of the child and a proxy consent by the parent.22 It is difficult to know when a child first has the ability to consent to medical care, particularly if the treatment is nonvalidated. In old English law, rights were defined by the rule of sevens. Under this rule, children under 7 had no capacity to consent, children age 7 to 14 were assumed not to have the capacity to consent, and children age 14 and above were presumed to have capacity to consent.23 According to the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research (1977), people who understand and determine their future should be allowed to enroll in research based on their own view of a positive life.24 Conversely, individuals who cannot understand the suggested research cannot make an informed decision.7 A fixed legal line of age 18, although commonly used, may not be the best marker for the ability to consent. Studies have shown that many children are as mature and emotionally developed at 14 as they are at age 18. The American Academy of Pediatrics has supported the view that children have capacity to decide much earlier than the law recognizes and recommends that adolescents be more involved in their own health care decisions.22 To consider involvement in a trial, a possible subject must understand multiple elements of informed consent, including the study’s purpose, risks, anticipated benefits, requirements, and alternatives.25 An individual may reach this state at age 14 or may never be able to give truly informed consent for nonvalidated treatment.
Another complicating factor in child assent is the reason a child may want to be involved in a clinical trial. Many adults choose to be involved in research studies hoping to
MILESTONES IN THOUGHT About Medical Ethics Patient Care & Research
Hammurabi
1750 BC
Hippocrates
400 BC
Nuremberg Medical Trial
1946
Helsinki Declaration
1964
Beecher Exposé (19)
19 66
Belmont Report
1979
Figure 1 Milestones in thought: about medical ethics in patient care and research.
322 give back to society. Few studies have assessed why children help others at various ages.7 The existing data suggest that children younger than 10 to 12 years old behave altruistically for varying reasons. They help others because they expect to be rewarded, to comply with the request of an adult, or because they feel compelled by social rules. Children under age 10 may not possess the concept of altruism.26 This should be taken into account when assessing a child’s ability to assent. Just as assent is important, the concept of dissent is also critical. Dissent is defined as patient rejection of treatment.27 This concept overlaps autonomy and nonmaleficence. A child must be able to express pain or displeasure to stop involvement in a research trial. In the most straightforward situation, a child clearly expresses discomfort or pain during a study. But, distress in children may not be obvious, either in cause or effect. A situation requiring uncomfortable decisions or outside observation may be deeply disturbing to a child. The child may express discomfort through belligerence or even silence.7 Although the importance of a dissent requirement seems clear, it may not always be obvious when a child’s statements or behavior actually reflect distress.28 A basic dissent requirement includes clearly telling children to inform investigators or nurses if they experience any discomfort. Individuals involved in pediatric research should also be trained to recognize more subtle signs of distress in a child.22 The principles of assent, consent, and dissent underlie ethical innovation and research. These principles can be difficult to evaluate and apply in the field of pediatric surgery.
Institutional involvement In working through ethical issues, the medical community has come to rely on medical institutions to take a leading role, much like the US Federal Government relies on states for regional decisions. The Joint Commission on Accreditation of Healthcare Organizations requires that each hospital have in place a mechanism to solve ethical issues. Many hospitals have ethics committees to handle areas of clinical concern.29 Physicians and administrators work hard to assure appropriateness. Institutional Review Board (IRB) oversight is standard. In some institutions, interactive computers are used to augment information in informed consent.2 Institutions are banding together to support organized research. Networks such as Pediatric Research in Office Settings (PROS) and Center for Child Health Research (CCHR) have been created to make large trials possible and support assessment of interventions.30 However, institutions are by no means perfect. There is generally little oversight to the process of obtaining consent. Many agree that we must clearly discuss with our patients and their parents the nonvalidated nature of possible treat-
Seminars in Pediatric Surgery, Vol 15, No 4, November 2006
Figure 2 care.
Francis D. Moore, MD. Ethics of innovative surgical
ments, including newness, past experience, and even the disclosure that “I have never done this before.”33 However, this important discussion does not always take place when introducing innovative treatments. Also disturbing, it has been shown that institutions share little information with researchers on ethical issues beyond written regulations.17 Accordingly, the principles outlined by Dr. Francis D. Moore31,32 more than 30 years ago remain valid (Figure 2). Aside from ineffective oversight, institutional mechanisms put into place to protect children often limit innovation. Physicians within research networks must independently seek IRB approval at each institution where a study is performed. IRBs follow NHHS guidelines as outlined earlier. However, they tend to act conservatively, limiting or preventing trials that may involve risk to the child.33 According to federal regulations, studies must be determined by IRB to present minimal risk or direct benefit. However, in one study of IRBs, 81% of respondents categorized only one procedure, a single blood draw, as minimal risk.15 This suggests that many important studies, where parent and child would participate with fully informed consent, may never be approved. Current institutional mechanisms to support appropriate innovation are a step in the right direction. But, what institutions are doing is not enough, either to promote innovation or limit its abuse.
Conclusion It is obvious that many, if not most, innovative pediatric operations were not developed through animal studies and controlled trials. Whereas surgeons generally tend toward caution, the real benefits, complications, and efficacy of these operations may be unclear without prospective study.20 In 1968, pediatrician Harry Shirkey described infants and children as “therapeutic or pharmaceutical orphans” because few interventions had been developed and studied in the pediatric population.34,35 There is a moral imperative to continue innovation in pediatric surgery and
Riskin et al
Ethics of Innovation
prevent children from once again becoming therapeutic orphans. Appropriate studies and progress must be promoted.36 Safety is an utmost concern. It has been suggested that the chain of progression of studies should be: animal–adult– older children–infant.36 Such a constrained system may be inappropriately limiting, but trials in children should be entered with as much preexisting data as possible. At the very least, epidemiological or clinical data should strongly suggest that a new measure will be effective before instituting a clinical trial.37 Clear protections and regulation are also important. Society must continue to discuss risk standards and ages for assent and consent. It is possible that federal regulations combined with IRB conservatism have gone too far toward hindering needed studies. Risk levels must be evaluated conscientiously and shared clearly with all involved parties. Finally, we should do everything possible to remove hidden agendas and financial conflicts of interest from clinical trials and assessment of innovative technologies.33 Innovation in pediatric surgery, like any experimentation in children, draws public attention and concern. In particular, surgical intervention is high stakes and difficult to assess. The combination makes innovation in pediatric surgery a hotbed for ethical debate. It is incumbent on us to assure that questions are debated openly and answered clearly so that ethical innovation can progress for the benefit of all of our patients.
References 1. Lederer S. Children as guinea pigs: historical perspective. Account Res 2003;10(1):1-16. 2. Barfield RC, Church C. Informed consent in pediatric clinical trials. Curr Opin Pediatr 2005;17(1):20-4. 3. Belais D. Vivisection: animal and human. Cosmopolitan 1910;49: 267-73. 4. Beecher H. Experimentation in Man. Springfield, IL: Charles C. Thomas, 1959. 5. Frader J, Flanagan Klygis E. Innovation and research in pediatric surgery. Semin Pediatr Surg 2001;10(4):198-203. 6. Beecher H. Surgery as placebo: a quantitative study of bias. J Am Med Assoc 1961;176:1102-7. 7. Shah S. Should children decide whether they are enrolled in nonbeneficial research? Am J Bioethics 2003;3(4):1-6. 8. Souba WW, Wilmore DW. Judging surgical research: how should we evaluate performance and measure value? Ann Surg 2000; 232(1):32-41. 9. Lentz J. Little medical heroes. Hygeia 1940;18:888-90, 914, 941-2. 10. Merrill W. What’s past is prologue. Ann Thorac Surg 1999;68: 2366-75. 11. Murphy J, Gersh BJ, Mair DD, et al. Long-term outcome in patients undergoing surgical repair of tetralogy of fallot. N Engl J Med 1993; 329(9):593-9. 12. Starzl T, Marchiaro TL, et al. Homotransplantation of the liver in humans. Surg Gynecol Obstet 1963;117:659-64.
323 13. Schafer D. Liver transplantation: looking back, looking forward. In: Transplantation of the Liver. Philadelphia, PA: Lippincott, Williams & Wilkins, 2001. 14. Schwartz R. Why a teenager over age 14 should be able to consent, rather than merely assent, to participation as a human subject of research. Am J Bioethics 2003;3(4):38-40. 15. Shah S, Whittle A, Wilfond B, et al. How do institutional review boards apply the federal risk and benefit standards for pediatric research? J Am Med Assoc 2004;291(4):476-82. 16. Kopelman L, Murphy TF. Ethical concerns about federal approval of risky pediatric studies. Pediatrics 2004;113(6):1783-9. 17. Wolf L, Zandecki J, Lo B. Institutional review board guidance on pediatric research: missed opportunities. J Pediatr 2005;147(1): 84-9. 18. Whendler D. Risk standards for pediatric research: rethinking the Grimes rules. Kennedy Inst Ethics J 2004;14(2):187-98. 19. Beecher H. Ethics and clinical research. N Engl J Med 1966;274(24): 1354-60. 20. Caniano D. Ethical issues in the management of neonatal surgical anomalies. Semin Perinatol 2004;28(3):240-5. 21. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979. Department of Health, Education, and Welfare, Office of Human Subjects Research, Washington, DC. Available from: http://ohsr.od. nih.gov/guidelines/belmont.html. 22. Kohrman A, Clayton EW. Informed consent, parental permission, and assent in pediatric practice. Pediatrics 1995;95(2):314-7. 23. Schlam L, Wood JP. Informed consent to the medical treatment of minors: law and practice. Health Matrix 2000;141(10), 54. 24. Levine RJ. Recommendations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research: impact on research in pharmacology. Fed Proc 1977;36(10): 2341-3. 25. Berg J, Appelbaum PS, Lidz CW, et al. Informed Consent: Legal Theory and Clinical Practice. Oxford: Oxford University Press, 2001. 26. Raviv A, Lewis EN, Levin IW. Motivations for Donation Behavior by Boys of Three Different Ages. Child Development 1980;51:610-13. 27. Boudreaux AM, Tilden SJ. Ethical dilemmas for pediatric surgical patients. Anesthesiol Clin North Am 2002;20(1):227-40. 28. Council BMR: The ethical conduct of research in children. In: Brody B, ed. The Ethics of Biomedical Research: An International Perspective. New York, NY: Oxford University Press 1991;320-1. 29. Comprehensive Accreditation Manual for Hospitals 2000. Oakbrook Terrace, IL: JCAHO, 2000. 30. Greenberg R. Community pediatrics research. Pediatrics 2003;112(3): 766-9. 31. Moore FD. Three ethical revolutions: ancient assumptions remodeled under pressure of transplantation. Transplant Proc 1988;20:1061-2 (suppl 1). 32. Moore FD. The desperate case: CARE (costs, applicability, research, ethics). J Am Med Assoc 1989;261(10):1483-4. 33. Levin A. IOLs, innovation, and ethics in pediatric ophthalmology: let’s be honest. J AAPOS 2002;6(3):133-5. 34. Hampton T. Experts ponder pediatric research ethics. J Am Med Assoc 2005;294(17):2148-51. 35. Shirkey H. Therapeutic orphans. J Pediatr 1968;72(1):119-20. 36. White R. Ethical issues in pediatric surgical research. America 1997; 176(4):17-20. 37. Ijichi S, Ijichi N. The scientific establishment of a new therapeutic intervention for developmental conditions: practical and ethical principles. Child’s Nervous Syst 2003;19(10):711-5.
The ethics of innovation in pediatric surgery Daniel J. Riskin, MD, MBA,a,b Michael T. Longaker, MD, MBA,a Thomas M. Krummel, MDa From the aBiodesign Surgical Innovation Program, Department of Surgery, Stanford University School of Medicine, Stanford, Califonia; and the b Department of Surgery, University of California, Los Angeles, Los Angeles, California. INDEX WORDS Ethics; Pediatric; Innovation; Research; Experiment
Ethical issues in pediatric research have long been debated, and experimentation in pediatric surgery is under intense scrutiny. Extensive legislation and institutional systems that attempt to protect children while supporting necessary research are at times ineffective. Pediatric surgery has less funding and resources for innovation than fields with higher clinical volume. Not unlike pediatrics in general, innovation in pediatric surgery must be beyond criticism. And yet, for the sake of patients, innovation should not only be maintained, but must be encouraged. © 2006 Elsevier Inc. All rights reserved.
Innovation is the introduction of something new. Research and innovation are different. Research requires study and analysis, but application is not critical. Innovation requires an act of use, but previous study need not be involved. Still, medical innovation and research are intertwined, and one cannot proceed effectively without the other. This brief review will necessarily focus on progress made through research since so little is known about innovation outside the context of research. Successful medical innovation generally incorporates research and publication, whereas failed innovation is most often neither published nor discussed. Innovation in pediatric surgery comes in many forms with correspondingly different ethical standards. Innovation can be a new way of tying a knot, a better way of directing light, or a different way of laying out surgical drapes. Most day-to-day innovation is low risk, low reward, and has few ethical implications. When an innovation entails patient risk, patients and parents rely on the physician, the medical Address reprint requests and correspondence: Thomas M. Krummel, MD, Stanford University School of Medicine, Department of Surgery, 257 Campus Drive West, Stanford, CA 94305-5148. E-mail: [email protected].
1055-8586/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2006.07.012
institution, and society to assess safety and efficacy while protecting the individual. The pull between societal progress and individual protection is fundamental to the ethics of health care innovation. Unresolved ethical issues are pervasive in pediatric surgery research and innovation. From historical injustice to legal debate to fundamental questions about autonomy and assent, innovation in pediatric surgery is a fascinating and perplexing area of bioethics.
History It is difficult for physicians to accept that our training and culture have led not only to impressive successes, but also to historic tragedies. Nowhere is this more clear than in the history of child experimentation. For more than a century, critics have noted that children and other vulnerable populations, such as prisoners and the mentally ill, have been subjects of medical experimentation without consent. Child experimentation is well documented in the 19th century. Examples are numerous and include subjects such as James Phipps, an 8-year-old boy who took part in Edward Jenner’s first trials of cowpox injections to
320 prevent smallpox, and Joseph Meister, a 10-year-old French child who first was inoculated with Louis Pasteur’s rabies vaccine.1 Inadequate child protection was not limited to the 19th century.2 In the first half of the 20th century, American protesters shed light on the use of orphans in trials of diagnostics tests and vaccines for syphilis, tuberculosis, and other infectious diseases. These tests often involved inoculation of the child, where future sequellae described include hemorrhage, blindness, and death.1,3,4 In the early 20th century, children at the Hebrew Orphan Asylum were given selected diets to induce scurvy and rickets so disease progression could be better understood. Between 1958 and 1960, mentally challenged residents at Willowbrook State School were exposed to hepatitis so researchers could follow its course.2 If history generates concern over experimentation in pediatrics, concern for the field of pediatric surgery should be even more stringent. Surgery, in contrast to other areas in medicine, has been free to develop new operations and treatments without strict requirements of animal testing and prospective human clinical trials.5 Sham operations,6 nonbeneficial research,7 and experimentation with little oversight8 in children and adults are a real part of our surgical past. Many operations in children were developed without prior study; current outcomes are all too often unknown because of a lack of prospective data. Whereas by modern standards many past experiments are unethical, it should be noted that there has long been a complex relationship between pediatric researchers and their patients. Edward Jenner, a researcher who inoculated his gardner’s son with smallpox virus, subsequently housed the boy and provided for his future.1 In 1940, John Lentz wrote in an American Medical Association journal, celebrating the “little medical heroes” who had been so important in advancing medical knowledge.9 Medical history highlights countless physicians driven to help children, making life-saving advances in surgical care. In 1944, Dr. Alfred Blalock developed the first palliative operative treatment for Tetralogy of Fallot,10 forming a foundation for operative correction which today permits more than 85% of children with the disease to reach adulthood.11 Dr. Thomas Starzl’s initial liver transplant in 1963 in a 3-year-old boy with biliary atresia did not save the child,12 but led to advances that now save the lives of thousands of children and adults a year.13
The law Despite notable heroes, unacceptable ethical breaches of the past have been acknowledged. One must ask whether we are adequately protected against such acts in the future. In the US and most developed countries, laws exist to protect the medical rights of children. Although the legal system does not define all protections surrounding innovation in
Seminars in Pediatric Surgery, Vol 15, No 4, November 2006 pediatric care, it is a starting point to understand current societal thought. US laws will be examined for the sake of simplicity, but many countries have detailed laws and protections. US federal regulations outline requirements for consent from both a parent and the child who is contemplating participating as a human subject in research. The requirement that the child give permission, which is referred to as “assent,” gives to two different sources, both parent and child, the power to veto the child’s participation in research.14 Assent becomes a critical ethical issue as it underlies the child’s autonomy. Federal regulations define assent as “positive agreement,” of children who are able to provide it.15 The federal code defines research categories which the Department of Health and Human Services (DHHS) is permitted to fund. Since most academic research incorporates DHHS funding, this code effectively defines acceptable criteria. Table 1 details the current federal regulations. Code 46.407 defines the most controversial area of research: study with more than minor risk and little benefit to the patient but significant benefit to the health or welfare of children. This form of research requires public review and comment as well as direct support from the DHHS Secretary after conferring with experts in science, ethics, and law. The bar was intentionally set high and, although the regulations have been in place for two decades, as of 2004, less than 10 such reviews had been undertaken.16 Risk standards, outlining regulation of trials according to perceived patient risk, largely determine which studies will be approved and funded. These standards continue to be hotly debated.17,18
Assent, consent, and dissent Thought about medical ethics has evolved over time19 (Figure 1). Current law highlights one of the most often discussed areas of child bioethics: the right to assent, consent, and dissent. Pediatric surgeons have a unique relationship with their patients. Parents also assume an essential role. Together with the child, there are at least three critical decision-makers, each with unique rights and responsibilities.20 The child’s role changes based on age and apparent decision-making ability. The Belmont Report, a more recent defining document in bioethics, suggests that respect for persons, beneficence, and justice are fundamental.21 Subsequent discussion has led to four basic principles that underpin modern medical ethics: autonomy, beneficence, nonmaleficence, and justice. Although the principles of beneficence, nonmaleficence, and justice apply to pediatrics and other medical fields equally, the principle of autonomy is more challenging. Children, particularly young children, cannot always make personal decisions effectively. In place of autonomy, ethicists have leaned toward protecting the “best interests of the child.”2 In this view, a combination of permission by the parent and assent by the child substitutes for informed consent. The American Academy of Pediatrics follows this model, recom-
Riskin et al Table 1
Ethics of Innovation
321
Summary of US code relating to research the Department of Health and Human Services may fund
§46.404 Requirements for research not involving greater than minimal risk. Only if the IRB finds that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians. §46.405 Requirements for research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects. (a) The risk is justified by the anticipated benefit to the subjects; (b) The relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches; and (c) Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians. §46.406 Requirements for research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition. (a) The risk represents a minor increase over minimal risk; (b) The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; (c) The intervention or procedure is likely to yield generalizable knowledge about the subjects’ disorder or condition which is of vital importance for the understanding or amelioration of the subjects’ disorder or condition; and (d) Adequate provisions are made for soliciting assent of the children and permission of their parents or guardians. §46.407 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. (a) The IRB finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; and (b) The Secretary, after consultation with a panel of experts in pertinent disciplines (for example; science, medicine, education, ethics, law) and following opportunity for public review and comment, has determined that: (i) The research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; (ii) The research will be conducted in accordance with sound ethical principles; (iii) Adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians.
mending viewing informed consent in children as composed of assent of the child and a proxy consent by the parent.22 It is difficult to know when a child first has the ability to consent to medical care, particularly if the treatment is nonvalidated. In old English law, rights were defined by the rule of sevens. Under this rule, children under 7 had no capacity to consent, children age 7 to 14 were assumed not to have the capacity to consent, and children age 14 and above were presumed to have capacity to consent.23 According to the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research (1977), people who understand and determine their future should be allowed to enroll in research based on their own view of a positive life.24 Conversely, individuals who cannot understand the suggested research cannot make an informed decision.7 A fixed legal line of age 18, although commonly used, may not be the best marker for the ability to consent. Studies have shown that many children are as mature and emotionally developed at 14 as they are at age 18. The American Academy of Pediatrics has supported the view that children have capacity to decide much earlier than the law recognizes and recommends that adolescents be more involved in their own health care decisions.22 To consider involvement in a trial, a possible subject must understand multiple elements of informed consent, including the study’s purpose, risks, anticipated benefits, requirements, and alternatives.25 An individual may reach this state at age 14 or may never be able to give truly informed consent for nonvalidated treatment.
Another complicating factor in child assent is the reason a child may want to be involved in a clinical trial. Many adults choose to be involved in research studies hoping to
MILESTONES IN THOUGHT About Medical Ethics Patient Care & Research
Hammurabi
1750 BC
Hippocrates
400 BC
Nuremberg Medical Trial
1946
Helsinki Declaration
1964
Beecher Exposé (19)
19 66
Belmont Report
1979
Figure 1 Milestones in thought: about medical ethics in patient care and research.
322 give back to society. Few studies have assessed why children help others at various ages.7 The existing data suggest that children younger than 10 to 12 years old behave altruistically for varying reasons. They help others because they expect to be rewarded, to comply with the request of an adult, or because they feel compelled by social rules. Children under age 10 may not possess the concept of altruism.26 This should be taken into account when assessing a child’s ability to assent. Just as assent is important, the concept of dissent is also critical. Dissent is defined as patient rejection of treatment.27 This concept overlaps autonomy and nonmaleficence. A child must be able to express pain or displeasure to stop involvement in a research trial. In the most straightforward situation, a child clearly expresses discomfort or pain during a study. But, distress in children may not be obvious, either in cause or effect. A situation requiring uncomfortable decisions or outside observation may be deeply disturbing to a child. The child may express discomfort through belligerence or even silence.7 Although the importance of a dissent requirement seems clear, it may not always be obvious when a child’s statements or behavior actually reflect distress.28 A basic dissent requirement includes clearly telling children to inform investigators or nurses if they experience any discomfort. Individuals involved in pediatric research should also be trained to recognize more subtle signs of distress in a child.22 The principles of assent, consent, and dissent underlie ethical innovation and research. These principles can be difficult to evaluate and apply in the field of pediatric surgery.
Institutional involvement In working through ethical issues, the medical community has come to rely on medical institutions to take a leading role, much like the US Federal Government relies on states for regional decisions. The Joint Commission on Accreditation of Healthcare Organizations requires that each hospital have in place a mechanism to solve ethical issues. Many hospitals have ethics committees to handle areas of clinical concern.29 Physicians and administrators work hard to assure appropriateness. Institutional Review Board (IRB) oversight is standard. In some institutions, interactive computers are used to augment information in informed consent.2 Institutions are banding together to support organized research. Networks such as Pediatric Research in Office Settings (PROS) and Center for Child Health Research (CCHR) have been created to make large trials possible and support assessment of interventions.30 However, institutions are by no means perfect. There is generally little oversight to the process of obtaining consent. Many agree that we must clearly discuss with our patients and their parents the nonvalidated nature of possible treat-
Seminars in Pediatric Surgery, Vol 15, No 4, November 2006
Figure 2 care.
Francis D. Moore, MD. Ethics of innovative surgical
ments, including newness, past experience, and even the disclosure that “I have never done this before.”33 However, this important discussion does not always take place when introducing innovative treatments. Also disturbing, it has been shown that institutions share little information with researchers on ethical issues beyond written regulations.17 Accordingly, the principles outlined by Dr. Francis D. Moore31,32 more than 30 years ago remain valid (Figure 2). Aside from ineffective oversight, institutional mechanisms put into place to protect children often limit innovation. Physicians within research networks must independently seek IRB approval at each institution where a study is performed. IRBs follow NHHS guidelines as outlined earlier. However, they tend to act conservatively, limiting or preventing trials that may involve risk to the child.33 According to federal regulations, studies must be determined by IRB to present minimal risk or direct benefit. However, in one study of IRBs, 81% of respondents categorized only one procedure, a single blood draw, as minimal risk.15 This suggests that many important studies, where parent and child would participate with fully informed consent, may never be approved. Current institutional mechanisms to support appropriate innovation are a step in the right direction. But, what institutions are doing is not enough, either to promote innovation or limit its abuse.
Conclusion It is obvious that many, if not most, innovative pediatric operations were not developed through animal studies and controlled trials. Whereas surgeons generally tend toward caution, the real benefits, complications, and efficacy of these operations may be unclear without prospective study.20 In 1968, pediatrician Harry Shirkey described infants and children as “therapeutic or pharmaceutical orphans” because few interventions had been developed and studied in the pediatric population.34,35 There is a moral imperative to continue innovation in pediatric surgery and
Riskin et al
Ethics of Innovation
prevent children from once again becoming therapeutic orphans. Appropriate studies and progress must be promoted.36 Safety is an utmost concern. It has been suggested that the chain of progression of studies should be: animal–adult– older children–infant.36 Such a constrained system may be inappropriately limiting, but trials in children should be entered with as much preexisting data as possible. At the very least, epidemiological or clinical data should strongly suggest that a new measure will be effective before instituting a clinical trial.37 Clear protections and regulation are also important. Society must continue to discuss risk standards and ages for assent and consent. It is possible that federal regulations combined with IRB conservatism have gone too far toward hindering needed studies. Risk levels must be evaluated conscientiously and shared clearly with all involved parties. Finally, we should do everything possible to remove hidden agendas and financial conflicts of interest from clinical trials and assessment of innovative technologies.33 Innovation in pediatric surgery, like any experimentation in children, draws public attention and concern. In particular, surgical intervention is high stakes and difficult to assess. The combination makes innovation in pediatric surgery a hotbed for ethical debate. It is incumbent on us to assure that questions are debated openly and answered clearly so that ethical innovation can progress for the benefit of all of our patients.
References 1. Lederer S. Children as guinea pigs: historical perspective. Account Res 2003;10(1):1-16. 2. Barfield RC, Church C. Informed consent in pediatric clinical trials. Curr Opin Pediatr 2005;17(1):20-4. 3. Belais D. Vivisection: animal and human. Cosmopolitan 1910;49: 267-73. 4. Beecher H. Experimentation in Man. Springfield, IL: Charles C. Thomas, 1959. 5. Frader J, Flanagan Klygis E. Innovation and research in pediatric surgery. Semin Pediatr Surg 2001;10(4):198-203. 6. Beecher H. Surgery as placebo: a quantitative study of bias. J Am Med Assoc 1961;176:1102-7. 7. Shah S. Should children decide whether they are enrolled in nonbeneficial research? Am J Bioethics 2003;3(4):1-6. 8. Souba WW, Wilmore DW. Judging surgical research: how should we evaluate performance and measure value? Ann Surg 2000; 232(1):32-41. 9. Lentz J. Little medical heroes. Hygeia 1940;18:888-90, 914, 941-2. 10. Merrill W. What’s past is prologue. Ann Thorac Surg 1999;68: 2366-75. 11. Murphy J, Gersh BJ, Mair DD, et al. Long-term outcome in patients undergoing surgical repair of tetralogy of fallot. N Engl J Med 1993; 329(9):593-9. 12. Starzl T, Marchiaro TL, et al. Homotransplantation of the liver in humans. Surg Gynecol Obstet 1963;117:659-64.
323 13. Schafer D. Liver transplantation: looking back, looking forward. In: Transplantation of the Liver. Philadelphia, PA: Lippincott, Williams & Wilkins, 2001. 14. Schwartz R. Why a teenager over age 14 should be able to consent, rather than merely assent, to participation as a human subject of research. Am J Bioethics 2003;3(4):38-40. 15. Shah S, Whittle A, Wilfond B, et al. How do institutional review boards apply the federal risk and benefit standards for pediatric research? J Am Med Assoc 2004;291(4):476-82. 16. Kopelman L, Murphy TF. Ethical concerns about federal approval of risky pediatric studies. Pediatrics 2004;113(6):1783-9. 17. Wolf L, Zandecki J, Lo B. Institutional review board guidance on pediatric research: missed opportunities. J Pediatr 2005;147(1): 84-9. 18. Whendler D. Risk standards for pediatric research: rethinking the Grimes rules. Kennedy Inst Ethics J 2004;14(2):187-98. 19. Beecher H. Ethics and clinical research. N Engl J Med 1966;274(24): 1354-60. 20. Caniano D. Ethical issues in the management of neonatal surgical anomalies. Semin Perinatol 2004;28(3):240-5. 21. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979. Department of Health, Education, and Welfare, Office of Human Subjects Research, Washington, DC. Available from: http://ohsr.od. nih.gov/guidelines/belmont.html. 22. Kohrman A, Clayton EW. Informed consent, parental permission, and assent in pediatric practice. Pediatrics 1995;95(2):314-7. 23. Schlam L, Wood JP. Informed consent to the medical treatment of minors: law and practice. Health Matrix 2000;141(10), 54. 24. Levine RJ. Recommendations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research: impact on research in pharmacology. Fed Proc 1977;36(10): 2341-3. 25. Berg J, Appelbaum PS, Lidz CW, et al. Informed Consent: Legal Theory and Clinical Practice. Oxford: Oxford University Press, 2001. 26. Raviv A, Lewis EN, Levin IW. Motivations for Donation Behavior by Boys of Three Different Ages. Child Development 1980;51:610-13. 27. Boudreaux AM, Tilden SJ. Ethical dilemmas for pediatric surgical patients. Anesthesiol Clin North Am 2002;20(1):227-40. 28. Council BMR: The ethical conduct of research in children. In: Brody B, ed. The Ethics of Biomedical Research: An International Perspective. New York, NY: Oxford University Press 1991;320-1. 29. Comprehensive Accreditation Manual for Hospitals 2000. Oakbrook Terrace, IL: JCAHO, 2000. 30. Greenberg R. Community pediatrics research. Pediatrics 2003;112(3): 766-9. 31. Moore FD. Three ethical revolutions: ancient assumptions remodeled under pressure of transplantation. Transplant Proc 1988;20:1061-2 (suppl 1). 32. Moore FD. The desperate case: CARE (costs, applicability, research, ethics). J Am Med Assoc 1989;261(10):1483-4. 33. Levin A. IOLs, innovation, and ethics in pediatric ophthalmology: let’s be honest. J AAPOS 2002;6(3):133-5. 34. Hampton T. Experts ponder pediatric research ethics. J Am Med Assoc 2005;294(17):2148-51. 35. Shirkey H. Therapeutic orphans. J Pediatr 1968;72(1):119-20. 36. White R. Ethical issues in pediatric surgical research. America 1997; 176(4):17-20. 37. Ijichi S, Ijichi N. The scientific establishment of a new therapeutic intervention for developmental conditions: practical and ethical principles. Child’s Nervous Syst 2003;19(10):711-5.