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Just a Spoonful of Sugar: Drug Safety for Pediatric Populations

Published online by Cambridge University Press:  01 January 2021

Barbara A. Noah
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Extract

Children deserve optimal medical care. Although prescription drugs play a prominent and essential role in pediatric health care delivery, health care providers often must make prescribing decisions for their young patients based on imperfect or absent safety and efficacy data for pediatric populations. Until relatively recently, the Food and Drug Administration (FDA) made surprisingly little effort to improve the quality or quantity of clinical research data for this patient group. Despite recent agency efforts to improve the situation, only one-third of drugs prescribed to children currently have been studied for safety and efficacy in pediatric populations. Moreover, recent agency initiatives to encourage pediatric drug research have generated mixed results and unintended consequences. The complex of issues surrounding the testing and prescribing of prescription drugs used for children will require that pharmaceutical companies, the FDA, and health care providers examine current practices, acknowledge their shortcomings, and consider cooperative, creative solutions.

Type
Symposium
Information
Journal of Law, Medicine & Ethics , Volume 37 , Issue 2 , Summer 2009 , pp. 280 - 291
Copyright
Copyright © American Society of Law, Medicine and Ethics 2009

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References

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). (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).' href=https://scholar.google.com/scholar?q=See+University+of+Michigan+C.S.+Mott+Children's+Hospital,+National+Poll+on+Children's+Health,+Apr.+14,+2008,+available+at++(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).>Google Scholar
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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 overprescribing 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.Google Scholar
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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 Noah, B. A., “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).Google Scholar
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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).Google Scholar
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See “Ely Lilly Granted Extension for Prozac,” Los Angeles Times, November 16, 2000, at C2.Google Scholar
See Adams, C., “Drug Testing Incentives Are Scrutinized,” Wall Street Journal, August 1, 2001, at B9; Zimmerman, R., “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/drug_patents/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 Eilperin, J., “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 3½ 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 Dembner, A., “Pediatric Testing Program Extended: Drug Makers Keep Patent Incentive,” Boston Globe, December 20, 2001, at A8. (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 Eilperin, J., “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 3½ 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. 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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.Google Scholar
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.Google Scholar
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).Google Scholar
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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).Google Scholar
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See Adams, C., “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).Google Scholar
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).+(last+visited+March+3,+2009).>Google Scholar
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See Harris, G., “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 Zaldivar, R. Alonzo, “FDA Hires 1,300 New Doctors and Scientists,” Associated Press, Sept. 11, 2008, available at <www.usatoday.com/news/health/2008-08-11-fda-hiring-N.htmGoogle Scholar
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., Brenner, D. J. 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 Sternberg, S., “Kid's Medical Devices Need More Scrutiny,” USA Today, July 19, 2005, available at <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 <www.iom.edu> (last visited April 15, 2009).CrossRefGoogle Scholar
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 Shaddy, R. E. 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 andCrossRefGoogle Scholar
See Nelson, R. M., “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); Holder, A. R., “Constraints on Experimentation: Protecting Children to Death,” Yale Law and Policy Review 6, no. 1 (1988): 137-156.Google Scholar
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 <www.fda.gov/oc/gcp/comparison.html> (last visited March 4, 2009). (last visited March 4, 2009).' href=https://scholar.google.com/scholar?q=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++(last+visited+March+4,+2009).>Google Scholar
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).Google Scholar
See 21 C.F.R. §§ 50.50 – 50.56.Google Scholar
See 21 C.F.R. § 50.51.Google Scholar
See 21 C.F.R. § 50.52.Google Scholar
See 21 C.F.R. § 50.53. The regulations also include a catchall 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.Google Scholar
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 Wendler, D. 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.”)CrossRefGoogle Scholar
See 21 C.F.R. § 50.52(a) - (b).Google Scholar
See 21 C.F.R. § 50.53(a) - (c).Google Scholar
See Ross, L. Friedman 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).+(last+visited+March+4,+2009).>Google Scholar
Cf. Smolin, D. M., “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 Kopelman, L. M., “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).Google Scholar
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 Harris, G. and Carey, B., “Researchers Fail to Reveal Full Drug Pay,” New York Times, June 8, 2008, available at <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).+(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).>Google Scholar
See Cohen, G., “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); Katerberg, R. J., “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.Google Scholar
See Harris, G., “Halt Is Urged for Trials of Antibiotic in Children,” New York Times, June 8, 2006, available at <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).+(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).>Google Scholar
See id.Google Scholar
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).Google Scholar
See Rubinstein, E., 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).Google Scholar
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).Google Scholar
See id. at § 50.55(b).Google Scholar
See Healy, M., “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 Gidding, S. S., “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).Google Scholar
See Ross, L. Friedman, “Payment in Pediatric Research,” Journal of Medicine & Law 9, no. 1 (2005): 1–24, at 1–2.Google Scholar
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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 Henderson, D., “FDA Panel Says Child-Stimulant Study OK,” Associated Press, September 11, 2004; see also Dembner, A., “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).Google Scholar
See Eisenstein, E. L., “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).CrossRefGoogle Scholar