Just a spoonful of sugar: Drug safety for pediatric populations

Journal of Law, Medicine and Ethics

Volumn 37, Issue 2, 2009, Pages 280-291

  Noah, Barbara A ^a  

^a WESTERN NEW ENGLAND UNIVERSITY   (United States)

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EID: 67650251822     PISSN: 10731105     EISSN: 1748720X     Source Type: Journal    
DOI: 10.1111/j.1748-720X.2009.00372.x     Document Type: Article

References (78)

1. See University of Michigan C.S. Mott Children's Hospital, National Poll on Children's Health, Apr. 14, 2008, available at http://health.med.umich.edu/ body.cfm?id=385 (last visited March 1, 2009) (explaining that, while less than one third of prescription drugs are actually FDA-approved specifically for use in children, 83% of parents believed that the last medication prescribed for their child was FDA-approved for pediatric use).
2. See General Accounting Office, GAO, Pediatric Drug Research, Studies Conducted Under Best Pharmaceuticals for Children Act 4 (2007) [hereinafter GAO BPCA Report] (describing the statutory testing scheme and describing the labeling changes that resulted from many of the studies); Food and Drug Administration (FDA), FDA Joins Children's Health Groups to Mark Historic Milestone for Pediatric Drugs, Dec. 19, 2005, available at http://www.fda.gov/ bbs/topics/News/2005 (last visited March 1, 2009) (explaining that, after eight years of legislative efforts "to enhance pediatric drug information, 100 pediatric drugs now include labeling information on safety, efficacy, dosing and unique risks for children.").
3. Increasing the quality and quantity of clinical trials on pediatric drugs represents a necessary but not sufficient response to the problems posed by widespread off-label prescribing and over-prescribing of certain drugs for pediatric patients. Although the carefully controlled environment of a clinical trial provides the most scientifically reliable data on drug safety and efficacy, these trials suffer from inherent limitations. Because most clinical trials are of relatively short duration, enroll only small numbers of participants, they are unlikely to uncover rare or delayed adverse drug reactions or interactions with other drugs. The compilation and analysis of adverse events reports for drugs already on the market provides another avenue for gathering data about a drug's safety and efficacy in a specific population of patients. There is also much that can be done to improve pediatric drug safety through the more efficient gathering of post-market safety data, but these issues are outside the scope of this essay.
4. See 21 C.F.R. § 201.57(f)(9).
5. See, e.g., L. K. Bachrach Bare-Bones Fact-Children Are Not Small Adults New England Journal of Medicine 351, no. 9 (2004 924 925, at 924-925 (discussing the results of a study that compares the effects of steroids on bone density in children with adults and recommending careful attention to decisions to use adult osteoporosis drugs in children with poor bone health).
6. See FDA Pediatric Patients: Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products 62 Fed. Reg. 43,900, 43,901 (1997) (hereinafter Proposed Pediatric Testing Rule); G. L. Kearns et al., "Developmental Pharmacology: Drug Disposition, Action, and Therapy in Infants and Children," New England Journal of Medicine 349, no. 12 (2003): 1157-1167 (providing a detailed discussion of differences in absorption and excretion of drugs in infants and children compared with adults).
7. See id., FDA, at 43,901 (explaining that the "effects of growth and maturation of various organs, maturation of the immune system, alterations in metabolism throughout infancy and childhood, changes in body proportions, and other developmental changes may result in significant differences in the doses needed by pediatric patients and adults.").
8. See id., at 43,901. For example, studies demonstrate that fentanyl, a powerful opoid painkiller that is commonly used to treat pain in infants and small children, is metabolized differently by neonates and babies two months or older because this early stage of development includes substantial improvement in the blood flow through the liver. Proportionate dosing with fentanyl in neonates produces a twofold or threefold higher blood concentration due to the immaturity of the liver at this early stage, and without adequate dosing information, these patients risk exposure to dangerously high levels of the drug. If, on the other hand, physicians err on the side of caution by providing very low doses of the drug, these patients may suffer the consequences of inadequate pain treatment. See id.; see also Kearns et al., supra note 6 (providing a detailed description, with examples, of the differences in drug absorption, distribution, and metabolism in infants and children).
9. See, e.g., R. Kaushal et al. Medication Errors and Adverse Drug Events in Pediatric Inpatients JAMA 285 (2001 2114 2120 T. J. Moore et al., "Reported Adverse Drug Events in Infants and Children Under 2 Years of Age," Pediatrics 110 (2002): e53, at 2, available at http://www.pediatrics. org/cgi/content/full/110/5/e52 (concluding that in a three year period, there were 769 deaths associated with a prescription drug product in infants and children under age 2 and that, although 183 different drugs were involved, 4 drugs accounted for an astonighing 38 percent of the deaths); F. James, "Drug-makers, Bush Clash on Kid Trials," Chicago Tribune, February 5, 2003, at A8 (describing a situation in 1999 when seven infants received the antibiotic erythromycin for pertussis and developed a serious digestive system complication requiring surgery, and the deaths of several infants from apparent overdosing of the anti-bacterial drug chloramphenicol); F. Lunzer Kritz, "Dose of Reality," Washington Post, September 10, 2002, at HE5 (describing serious side effects experienced by children after taking drugs that had not been evaluated for safety or effectiveness in pediatric populations); see also FDA, The Pediatric Exclusivity Provision: January 2001 Status Report to Congress, available at http://www.fda.gov/cder/pediatric/reportcong01.pdf at 2-3 [hereinafter FDA Status Report] (describing the risk of adverse reactions, often the result age-specific variables and instances of physicians resorting to "extemporaneous formulations" such as crushing tablets and mixing with food which can negatively affect the bioavailability of prescription drugs). (Pubitemid 32367829)
10. See FDA Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients 63 Fed. Reg. 66,632, 66,632 (1998) [hereinafter Final Pediatric Rule].
11. The off-label and long-term prescribing of psychoactive drugs for Attention Deficit Hyperactivity Disorder (ADHD) and mood disorders including anxiety and depression has generated fierce controversy. See, e.g., D. H. Barzman et al. Attention Deficit Hyperactivity Disorder Diagnosis and Treatment: Separating Myth from Substance Journal of Legal Medicine 25, no. 1 (2004 23-38; V. W. Henderson, "Stimulant Drug Treatment of Attention Deficit Disorder," Southern California Law Review 65, no. 1 (1991): 397-410, at 401-402, 407-409 (describing the debate about diagnosis of the condition and the controversy surrounding the use of psychoactive drugs to treat a conditions which is diagnosed primarily by observed behavior rather than using objective medical criteria); B. Vitiello, "Psychopharmacology for Young Children: Clinical Needs and Research Opportunities," Pediatrics 108, no. 4 (2001): 983-989. Approximately 3-5% of school aged children - more often boys than girls - are diagnosed with the disorder. See H. M. Schachter, "How Efficacious and Safe is Short-Acting Methylphenidate for the Treatment of Attention-Deficit Disorder in Children and Adolescents? A Meta-analysis," Canadian Medical Association Journal 165 (2001): 1475-1488; M. D. Rappley, "Attention Deficit-Hyperactivity Disorder," New England Journal of Medicine 352, no. 2 (2005): 165-173, at 165. Experts express concern about unknown long term effects. See M. D. Rappley et al., "Diagnosis of Attetion-Deficit/Hyper- activity Disorder and Use of Psychotropic Medication in Very Young Children," Archives of Pediatric Adolescent Medicine. 153, no. 10 (1999): 1039-1045, at 1039. Similar concerns exist with the use of a category of antidepressants known as selective serotonin re-uptake inhibitors (SSRIs). As with the use of stimulants for ADHD, physicians have expressed concern that the safety and efficacy of such drugs has not been established in very young children and that the long-term use of such drugs could inhibit normal brain development. J. T. Coyle, "Psychotropic Drug Use in Very Young Children," JAMA 283, no. 8 (2000): 1059-1060, at 1060 explaining that because "[e]arly childhood is a time of tremendous change for the human brain", "it would seem prudent to carry out much more extensive studies to determine the long-term consequences of the use of psychotropic drugs at this early stage of childhood" and adding that there is no empirical evidence to support the safety or efficacy of using psychotropic drugs in very young children).
12. See 21 U.S.C. § 353(b)(1)(B) (1994) (providing that a drug which, "because of its toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, is not safe for use except under the supervision of a practitioner licensed by law to administer such a drug... shall be dispensed only" by prescription); see also A. G. Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed. (Riverside, NJ: Pergamon Press, 1990): 1083 (describing anaphylactic reactions to penicillin that occur in approximately 300 people - 0.001% of treated patients - each year).
13. The FDA's formal system of monitoring and reporting adverse drug reactions is supplemented by an informal discourse within the medical community about the apparent side effects associated with newly-marketed drugs. See, e.g., Sildenafil in the Treatment of Erectile Dysfunction, New England Journal of Medicine 339, no. 10 (1998 699 702 (series of letters to the editor from physicians discussing early clinical experience with Viagra, including serious, unexpected adverse reactions); see also B. A. Noah, "Adverse Drug Reactions: Harnessing Experiential Data to Promote Patient Welfare," Catholic University Law Review 49, no. 2 (2000); 449-504 (describing and critiquing the FDA's post-market drug safety monitoring system).
14. See L. Noah Constraints on the Off-Label Uses of Prescription Drug Products Journal of Products & Toxics Liability 16, no. 2 (1994 139 165, at 142-43 (describing the FDA's regulatory authority over drug labeling and the relationship between approved labeling and off-label prescribing).
15. See J. M. Beck and E. D. Azari FDA, Off-Label Use, and Informed Consent Food & Drug Law Journal 53, no. 1 (1998 71 104, at 76-77 (1998) (providing examples of cases in which courts have recognized the validity of off-label prescribing; cf. Buckman Co. v. Plaintiffs' Legal Committee, 531 U.S. 341, 351 (2001) (acknowledging in the context of off-label uses of medical devices that the FDA's regulation of such products is not intended to interfere with off-label uses).
16. See, e.g., In re Williams, 573 NE.2d 638 (Ohio 1991) (reviewing a physician appeal from a state board of medicine determination that his off-label prescribing of a controlled substance to a number of patients constituted a failure to use reasonable care in the practice of medicine).
17. See, e.g., Washington Legal Found. v. Friedman, 13 F. Supp. 2d 51, 56-58 (D.D.C. 1998), vacated in part on other grounds, 202 F.3d 331 (D.C. Cir. 2000) (discussing the legal status of off-label prescribing and explaining that as "off-label uses are presently an accepted aspect of a physician's prescribing regimen, the open dissemination of scientific and medical information regarding these treatments is of great import" and adding that "off-label uses have, in some circumstances, proven to be harmful.") D. C. Radley et al. Off-Label Prescribing Among Office-Based Physicians Archives of Internal Medicine 166, no. 9 (2006 1021 1026 (concluding that off-label prescribing is common in outpatient settings and that it often occurs without adequate evaluation on questions of safety or necessity).
18. See American Academy of Pediatrics, Committee on Drugs Use of Drugs Not Described in the Package Insert (off-label uses) Pediatrics 110, no. 1 (2002 181 183, at 182.
19. See Noah, supra note 13, at 458-60 (describing the phases of new drug clinical trials) B. A. Noah Bioethical Malpractice: Risk and Responsibility in Human Research Journal of Health Care Law & Policy 7, no. 2 (2004 175 241, at 186 87.
20. See Associationn of American Physicians and Surgeons, Inc. v. FDA, 226 F. Supp. 2d 204, 206-07 (D.D.C. 2002).
21. See Beck and Azari, supra note 15, at 79 (explaining that "[o] ff-label use is not only legal and ethical, but is a common and integral feature of medical practice. The pace of medical discovery invariably runs far ahead of FDA's regulatory machinery, and off-label use is frequently 'state-of-the-art treatment.'".
22. Actually, the word "strategy" suggests a kind of deliberation that is mainly absent from the FDA's handling of post-market safety data. See Noah, supra note 13, at 449-504; see also P. B. Smith et al. Safety Monitoring of Drugs Receiving Pediatric Marketing Exclusivity Pediatrics 122, no. 3 (2008 e628 e633, at e629-e631 (describing efforts by the Pediatric Advisory Committee's efforts to monitor drug safety in 67 drugs granted pediatric exclusivity, concluding that most of the drugs produced no unexpectedly frequent or severe adverse events in pediatric patients and that routine adverse event monitoring was therefore appropriate, but urging physicians to be vigilant about reporting adverse events in children).
23. See 21 C.F.R. § 314.80.
24. See 21 C.F.R. § 201.57(f)(9)(vi).
25. See id.
26. See 21 U.S.C. § 355a(a). The statute also required FDA to publish a list of approved drugs for which the agency additional pediatric data would be beneficial. Id. at § 355a(b).
27. The National Pharmaceutical Alliance, a trade association representing generic drug manufacturers, sought a preliminary injunction to prevent the FDA from granting six-month patent extensions under the FDAMA provision. The U.S. District Court for the District of Columbia denied the motion. See National Pharmaceutical Alliance v. Henney, 47 F. Supp. 2d 37 (D.D.C. 1999).
28. See Best Pharmaceuticals for Children Act of 2002, Pub. L. No. 107-109, 115 Stat. 1408 (2002).
29. See 21 U.S.C. § 355a(a), (c).
30. See 21 U.S.C. § 355a. (d)(4)(B)(I). When the FDA determines that more data regarding a particular drug would prove helpful, the BPCA created two mechanisms through which third parties can be paid to conduct the research necessary to generate this data. The agency can refer the question to the NIH research Foundation and direct the Foundation to secure funds to pay a third party to conduct the research or, if the Foundation lacks the funds to support the requested testing, the BPCA created a large public fund to subsidize this research. See 42 U.S.C. § 284m(a), (d).
31. See GAO BPCA Report, supra note 2, at 4.
32. The latest available data show that the BPCA has generated more than 300 pediatric studies and that, based on the results, the FDA has approved labeling changes for more than 115 products. See J. S. Li et al. Economic Return of Clinical Trials Performed Under the Pediatric Exclusivity Program JAMA 297, no. 5 (2007 480 488, at 480. (Pubitemid 46220803)
33. GAO BPCA Report, supra note 2, at 4 (adding that many studies were still ongoing as of December 2005).
34. Id., at 4.
35. See FDA Status Report, supra note 9, at 15-16; 44-45 (attempting to estimate revenue losses for generic manufacturers); see also R. Zimmerman Pharmaceutical Firms Win Big on Plan to Test Adult Drugs on Kids Wall Street Journal, Feb. 5, 2001, at A12 (noting that the Bristol-Myers Squibb drug Glucophage received an extra $648 million in sales from extended market exclusivity despite the fact that fewer than 1 percent of prescriptions for the drug are for children).
36. See id. at 18, 47-48 (attempting to estimate additional costs for consumers of the delayed availability of generic drugs and suggesting that pediatric exclusivity will cost consumers $13.9 billion in higher drug costs over 20 years because of delayed market entry of generic equivalents).
37. See Ely Lilly Granted Extension for Prozac Los Angeles Times, November 16, 2000, at C2.
38. See C. Adams Drug Testing Incentives Are Scrutinized Wall Street Journal August 1, 2001, at B9; R. Zimmerman, "Pharmaceutical Firms Win Big on Plan to Test Adult Drugs on Kids," Wall Street Journal, February 5, 2001, at A1 (estimating that the additional six months of market exclusivity on the first 26 drugs to receive this extension will generate an extra $4 billion for the brand-name manufacturers, including nearly $1 billion each on Claritin and Prozac); "Generics in 2000 and 2001 Begin to Feel Pediatric Exclusivity Bite," Pink Sheet No. 63 (January 15, 2001): (explaining that Merck's drug, Pepcid (famotidine) was due to lose patent protection in October of 2000 but used the pediatric exclusivity provision to keep generic competition at bay until mid-April of 2001); Public Citizen, Patently Offensive: Congress Set to Extend Monopoly Patents for Cipro and Other Drugs (2001), available at http://www.citizen.org/congress/reform/drugpatents/pediatric/articles.cfm?ID= 6435 (last visited March 3, 2009). New data from pediatric studies also may lead to a significant alteration in the labeling for the pioneer drug such as the addition of a specific indication for use in adolescents. In theory, the sponsor of NDA supplement could get additional months of protection against any generic competition and/or three years of protection against generic competition on that labeling statement (but not on the drug itself). At one point, sponsors were attempting to claim both exclusivity periods, perhaps even running sequentially rather than concurrently. See J. Eilperin, "Bristol-Myers Presses for Patent," Washinton Post, November 28, 2001, at A33 (reporting that the manufacturer of Glucopage has argued that it deserves an additional 31/2 years of exclusivity, and against any generic competition, after discovering that children could benefit from this diabetes drug). When it extended the sunset date, Congress also closed this apparent loophole. See A. Dembner, "Pediatric Testing Program Extended: Drug Makers Keep Patent Incentive," Boston Globe, December 20, 2001, at A8.
39. See Li, supra note 32, at 482-85 (explaining that despite the uproar over the market exclusivity provision, most products that participated in the program were not blockbuster drugs with high annual sales); see also C. Baker-Smith et al. The Economic Returns of Pediatric Clinical Trials of Antihypertensive Drugs American Heart Journal 156, no. 4 (2003 682 688, at 683-688 (evaluating the net economic return of extended market exclusivity in the context of one drug category and concluding that although the net return was "highly variable," pediatric research proved generally to be a lucrative investment).
40. Only half of the ten drugs that physicians prescribe most often to children have been studied. See GAO BPCA Report, supra note 2, at 5. Nevertheless, drugs studied under the BPCA included those intended to treat a range of diseases, including cancer, neurological and psychiatric disorders, metabolic and endocrine disorders, and cardiovascular disease (including drugs for hypertension). Id., at 21.
41. The BPCA does, however, contemplate funding for studies of off-patent drugs. The latest data suggest that the National Institutes of Health will fund studies for ten such drugs at a cost of $68,500,000. See GAO BPCA Report, supra note 2, at 35, tbl. 6.
42. See FDA, Pediatric Patients: Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products, 63 Fed. Reg. 66,632 (1998).
43. See Assoc. of Am. Physicians & Surgeons, Inc. v. FDA, 226 F. Supp. 2d 204, 221-22 (D.D.C. 2002).
44. See 226 F. Supp. 2d. at 208.
45. See 21 C.F.R. §§ 314.55(c)(2); 601.27(c)(2). If the manufacturer succeeds with the burden of proving that a waiver is appropriate because the product would be ineffective or unsafe for pediatric use, the product's label must include this information. See id. § 201.23(c)(3). Manufacturers can also secure a partial waiver of the testing requirement if they certify that the product would not represent a meaningful therapeutic benefit for pediatric patients compared with existing treatments and is unlikely to be used in a substantial number of pediatric patients. See id. §§ 314.55(c)(2), 601.27(c)(2). Finally, if the manufacturer can demonstrate that it is unable to produce an appropriate formulation for a particular subpopulation, the agency may also grant a partial waiver of the study requirements. See id. at §§ 314.55(c)(3), 601.27 (c)(3).
46. See 226 F. Supp. 2d, at 221-22.
47. See C. Adams White House to Back Testing Drugs on Children Wall Street Journal, December 17, 2002, at D4, (noting that the American Academy of Pediatrics and the Elizabeth Glaser Pediatric AIDS foundation have intervened to appeal the ruling).
48. See Pediatric Research Equity Act of 2003, Public Law No: 108-155 (codified in scattered sections of 21 U.S.C. § 351 et seq.). As explained in a recent FDA guidance document, "PREA requires new drug applications (NDAs) and biologics licensing applications (BLAs) (or supplements to applications) for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration to contain a pediatric assessment unless the applicant has obtained a waiver or deferral (see section 505B(a) of the Act). It also authorizes FDA to require holders of applications for previously approved marketed drugs and biological products who are not seeking approval for one of the changes enumerated above (hereinafter 'marketed drugs and biological products'to submit a pediatric assessment under certain circumstances." See FDA, Guidance for Industry, How to Comply with the Pediatric Research Equity Act 1 (2005), available at http://www.fda.gov/Cder/ guidance/6215dft.pdf (last visited March 3, 2009).
49. See Guidance for Industry, supra note 48, at 2.
50. See Best Pharmaceuticals for Children Act of 2007, Pub. Law 110-85.
51. See FDA Joins Children's Health Group to Mark Historic Milestone for Pediatric Drugs FDA News, December 19, 2005, available at http://www.fda.gov/ bbs/topics/NEWS/2005 (last visited March 3, 2009).
52. See G. Harris Panel's Bi-Partisan View: FDA is Underfinanced New York Times, April 16, 2008 The FDA in Crisis: It Needs More Money and Talent," New York Times, February 3, 2008 (explaining that, in addition to funding issues, the FDA's effectiveness in carrying out its ever-increasing list of regulatory responsibilities is seriously compromised by lack of staff with expertise in emerging technologies, high staff turnover, and inadequate technological support, among other things). The FDA recently attempted to do something about the loss of scientific staff, hiring 1,300 new physicians and scientists in the fall of 2008. See R. Alonzo Zaldivar, "FDA Hires 1,300 New Doctors and Scientists," Associated Press, Sept. 11, 2008, available at http://www.usatoday.com/news/health/2008-08-11-fda-hiring-N.htm Recent concerns about pediatric use of certain medical devices, such as CAT scanners, suggest that pediatric studies for devices might also prove useful. Although medical device issues are outside the scope of this article, it is worth noting that certain devices pose risks to children that differ from those that they pose to adults. See, e.g., D. J. Brenner et al. Estimated Risks of Radiation-Induced Fatal Cancer from Pediatric CT American Journal of Roentgenology 176, no. 2 (2001 289 296 (explaining that "larger [radiation] doses and increased lifetime radiation risks in children produce a sharp increase, relative to adults, in estimated... lifetime cancer mortality risks"); see also S. Sternberg, "Kid's Medical Devices Need More Scrutiny," USA Today, July 19, 2005, available at http://www.usatoday.com (describing a National Academy of Sciences report that found that the FDA lacks the regulatory tools to monitor the safety of approved medical devices in children and that problems frequently arise when devices designed for adults are "jury-rigged" for pediatric use without adequate safety testing or ongoing safety evaluation); Institute of Medicine, Safe Medical Devices for Children 21 (2005) (explaining that "i]n many cases, medical devices used to help children have been initially developed for, tested with, and most frequently employed to treat adults... [and that]... implants and other devices may require modification for use with infants and children to account for differences in overall body size as well as the ftlinedimensions of body structures such as blood vessels), available at http://www.iom.edu (last visited April 15, 2009).
53. See FDA, FDA Joins Children's Health Groups to Mark Historic Milestone for Pediatric Drugs, December 19, 2005, available at http://www.fda.gov/bbs/ topics/News/2005 (last visited March 4, 2009) (explaining that, after eight years of legislative efforts "to enhance pediatric drug information, 100 pediatric drugs now include labeling information on safety, efficacy, dosing and unique risks for children."); see also R. E. Shaddy et al., "Carvedilol for Children and Adolescents with Heart Failure: A Randomized Controlled Trial," JAMA 298, no. 10 (2007): 1171-1179, at 1173-76 (finding little benefit compared with placebo for pediatric and adolescent patients despite the drug's well-document efficacy for health failure in adults); National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents, Pediatrics 114, no. 2 (2004): 555-576, at 557-62 (2004) (publishing recommended doses of various antihypertensive medications for children and.
54. See R. M. Nelson Ethics of Drug and Biologic Research in Children IOM, Rational Therapeutics for Infants and Children 2000) available at http://search.nap.edu/html/rational-therapeutics (last visited March 4, 2009) describing ethical and scientific complexities in pediatric study design including the special challenges of placebo controls and the difficulty of determining "meaningful therapeutic benefit"; see also American Academy of Pediatrics, "Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations," Pediatrics 95, no. 2 (1995): 286-294, at 287-289 (describing ethical challenges in pediatric drug research); A. R. Holder, "Constraints on Experimentation: Protecting Children to Death," Yale Law and Policy Review 6, no. 1 (1988): 137-156.
55. The FDA's regulations apply to all human subjects research involving articles such as drugs, medical devices, and biological products, that will eventually support a licensing application to the FDA, while the HHS regulations cover all research conducted or supported by a federal agency. See 21 C.F.R. § 50.1; 45 C.F.R. § 46.101. Many sections of the FDA and HHS regulations are nearly identical. For a useful comparison between the two sets of regulations, see FDA, Comparison of FDA and HHS Human Subject Protection Regulations, available at http://www.fda.gov/oc/gcp/comparison.html (last visited March 4, 2009).
56. The regulations define "children" as "persons who have not attained the legal age for consent to treatments or procedures involved in clinical investigations, under the applicable law of the jurisdiction in which the clinical investigation will be conducted." 21 C.F.R. § 50.3(o).
57. See 21 C.F.R. §§ 50.50-50.56.
58. See 21 C.F.R. § 50.51.
59. See 21 C.F.R. § 50.52.
60. See 21 C.F.R. § 50.53. The regulations also include a catch-all provision permitting research that is not otherwise approvable under one of the three foregoing categories but that "presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children" and that is conducted in accordance with sound ethical principles including appropriate consent of parents or guardians and assent of participants. See 21 C.F.R. § 50.54.
61. There is much debate about the definition of minimal risk, as well. The regulations define minimal risk to mean that "the magnitude and probability of harms or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests." 21 C.F.R. § 50.3(k). IRB members may believe that they can quantify risk encountered in daily life or to decide which aspects of physical exams are "routine" but there is no consensus on these questions. See D. Wendler et al. Quantifying the Federal Minimal Risk Standard: Implications for Pediatric Research without a Prospect of Direct Benefit JAMA 294, no. 7 (2005 826 832, at 827-828 (explaining that "absent empirical data, IRB members may rely on their own perceptions to assess whether research risks exceed this range. Unfortunately, individuals make systematic errors when they assess risks based on their own perceptions."). (Pubitemid 41178967)
62. See 21 C.F.R. § 50.52(a) - (b).
63. See 21 C.F.R. § 50.53(a) - (c).
64. See L. Friedman Ross et al., Placebo-Controlled Clinical Trials Put Children With Asthma at Risk 2004 available at http://www.uchospitals.edu/news/ 2004/20040105-ross.html (last visited March 4, 2009).
65. Cf. D. M. Smolin Nontherapeutic Research With Children: The Virtues and Vices of Legal Uncertainty Cumerland Law Review 33, no. 3 (2003 621 646, at 631 (noting that "it is unclear whether the perceived need for knowledge on pediatric populations could be satisfied through therapeutic research of direct benefit to research subjects, without substantial use of nontherapeutic research."); see also L. M. Kopelman, "What Conditions Justify Risky Nontherapeutic or "No Benefit" Pediatric Studies: A Sliding Scale Analysis," Journal of Law, Medicine & Ethics 32, no. 4 (2004): 749-756 at 752-53 (recommending a sliding scale to determine when a medical problem is serious enough to justify studies with real risks and no prospect of direct benefit to the pediatric participants and concluding that conditions with a high magnitude of harm more appropriately justify such research as long as the research poses "minimal hazard" to children with the medical condition and only a minor increase over minimal risk for healthy participants).
66. For example, a well-known child psychiatrist at Harvard Medical School whose research had supported the rapid rise in the use of antipsychotic medications in children admitted to taking at least $1.6 million in consulting fees from pharmaceutical manufacturers over a period of several years without reporting the income to the university. See G. Harris and B. Carey Researchers Fail to Reveal Full Drug Pay New York Times, June 8, 2008, available at http://www.nytimes.com/2008/06/08/us/08conflict.html (last visited April 15, 2009)(explaining that federal regulations require researchers to report earnings exceeding $10,000 per year to their universities in order to protect research integrity).
67. See G. Cohen Therapeutic Orphans, Pediatric Victims? The Best Pharmaceuticals for Children Act and Existing Pediatric Human Subject Protection Food & Drug Law Journal 58, no. 4 (2003 661 710, at 674 (discussion the difficulty in research ethics of protecting children as vulnerable subjects without creating "therapeutic orphans," that is, children for whom drug therapies have not been adequately tested); R. J. Katerberg, "Institutional Review Boards, Research on Children, and Informed Consent: Walking the Tightrope between Encouraging Vital Experimentation and Protecting Subjects' Rights," Journal of College & University Law 24, no. 3 (1998): 545-579.
68. See G. Harris Halt Is Urged for Trials of Antibiotic in Children New York Times, June 8, 2006, available at http://www.nytimes.com/2006/06/08/science/ 08drug.html (last visited April 15, 2009) (explaining that agency officials raised the alarm regarding a planned study of the antibiotic Ketek in 4000 infants and children after reports of liver failure in 12 adults [including four deaths] and 23 other cases of severe liver injury).
69. See id.
70. See 21 C.F.R. § 50.55(e). The regulations also contain special provisions for children who are wards of the state or other agency or institution. See 21 C.F.R. § 50.56 (requiring the appointment of an advocate to represent the child's best interests during the child's participation in clinical research for each child who is a ward).
71. See E. Rubinstein, Comment Going Beyond Parents and Institutional Review Boards in Protecting Children Involved in Nontherapeutic Research Golden Gate University Law Review 33, no. 3 (2003 251 294, 278 80 (describing a variety of contexts in which parental consent for a child's participation in research can be compromised by conflicts of interest such as emotional distress over the child's illness).
72. See 21 C.F.R. § 50.55(a). The regulations define "assent" as "a child's affirmative agreement to participate in a clinical investigation. Mere failure to object may not, absent affirmative agreement, be construed as assent." 21 C.F.R. § 50.3(n).
73. See id. at § 50.55(b).
74. See M. Healy Push to Test Drugs on Kids Comes With Reservations Chicago Tribune, March 7, 2004, at Q8 (explaining that drug companies benefit from the participation of children in research, through potential extended market exclusivity); see also S. S. Gidding, "The Importance of Randomized Controlled Trials in Pediatric Cardiology," JAMA 298, no. 10 (2007); 1214-1216, at 1215 (discussing a pediatric cardiology clinical trial and noting that "[r]ecruitment has been a significant problem for conducting randomized trials in pediatric cardiology" and that the study in question had a substantially smaller sample size compared with similar studies in adults).
75. See L. Friedman Ross Payment in Pediatric Research Journal of Medicine & Law 9, no. 1 (2005 1 24, at 1-2.
76. See id., at 3.
77. For example, an ethics panel at the FDA approved a study that would give a single dose of a stimulant drug to healthy children as young as nine years old and use an MRI to study their brain responses. Participants (or their parents) would receive $570 for the one-time study, prompting critics concerned with pediatric research ethics to protest that the study would draw in poorer families. See D. Henderson FDA Panel Says Child-Stimulant Study OK Associated Press, September 11, 2004 see also A. Dembner, "Teddy Bears and Veiled Threats to Attract Children into Medical Experiments," Boston Globe, March 20, 2001, at C1 (describing recruitment incentives including gift certificates to McDonalds or toy stores, and large cash payments and noting that many in the research field consider such incentives to be inappropriately coercive).
78. See E. L. Eisenstein Sensible Approaches for Reducing Clinical Trial Costs Clinical Trials 5, no. 1 (2008 75 84, at 76-84 (2008) (describing five important components of large-scale clinical trials and evaluating methods to improve cost-efficiency for each component, and projecting up to a 90 percent reduction in total clinical trial costs).