COMMENTARY |
Congress, the FDA, and the Fair Development of New Medications for Children
Department of Pediatrics, Division of Infectious Diseases
Duke University School of Medicine
Durham, NC 27710
Abbreviations: FDA, Food and Drug Administration • FDAMA, Food and Drug Administration Modernization Act • NIH, National Institutes of Health • HIV, human immunodeficiency virus • AUC, area under the curve • PACTG, Pediatric AIDS Clinical Trials Group
The engine driving the amazing progress in new therapeutic agents in the late 20th century has been the major pharmaceutical companies, which in turn are fueled by the desire to make profits for their stockholders. With a few exceptions, like oral antibiotics and antihistamines, children and new drugs for pediatric indications are too small a market to draw the attention of the major pharmaceutical houses, and the profit motive fails to provide the necessary impetus to perform the studies needed to understand how to use new drugs in children. To rectify this imbalance, Congress and the Food and Drug Administration (FDA) have tried a variety of tacks. In 1979, the FDA began to require pediatric information in the product label and package insert, but this did little to motivate pediatric studies. In 1994, the FDA allowed companies to obtain pediatric labeling if they established a dosing regimen for children and the disease process was biologically comparable to the same process in adults. Although it looked like an inexpensive way to expand a company’s market, the actual effect was minimal, and few companies pursued pediatric trials. The result of this nonresponsiveness was the inclusion of pediatric regulations in another law, the 1997 Food and Drug Administration Modernization Act (FDAMA). The FDAMA offered a 6-month extension to a company’s exclusive ability to market a drug if they performed studies in children that enabled a change in the drug’s labeling (ie, indications and dosing). This law was often referred to as "the carrot" in pediatric drug development, drawing companies toward a societally desired goal. To complement this approach, in 1998 the Pediatric Final Rule ("the stick") was promulgated by the FDA. This rule allowed the FDA to require pharmaceutical companies to perform studies in children as part of new drug development if the drug had potential for pediatric utility. The Pediatric Final Rule was critical because the pharmaceutical companies had no reason to rush pediatric studies as part of the FDAMA. Patent holders have 17 years of exclusivity after patenting, with a provision they can have a minimum of 5 years of marketing exclusivity if the prelicensing development process has left them with <5 years of patent protection. Although much of the 17 years is typically used up in development process, companies may still have a decade or more to determine if their drug is going have sufficient market size to justify the cost of a pediatric study to obtain an additional 6 months at the end of their normal exclusivity. The Pediatric Final Rule enabled the FDA to push companies to do pediatric studies earlier in the drug development process.
Unfortunately, in October 2002, the Federal District Court for the District of Columbia ruled that the FDA had overstepped its authority by issuing the Pediatric Final Rule. The result of the suit, brought by 3 conservative groups (the Association of American Physicians and Surgeons, Inc, the Competitive Enterprise Institute, and Consumer Alert), abruptly led several companies to postpone or halt planned pediatric trials. The plaintiffs in the District Court case felt that requiring pediatric drug testing made medications more expensive (because of the cost of pediatric drug testing), and would delay release of new medications (although the FDA had generally required a plan for pediatric drug testing, rather than completion of the studies). As a result of this court case, Congress, rather than the FDA, will need to act to produce a new pediatric rule with teeth. In 2002, Congress did enact the "Best Pharmaceuticals for Children Act," which extends the 6-month exclusivity extension provision to 2007 and authorizes the National Institutes of Health (NIH) to work with the FDA and fund pediatric studies of drugs that no longer have exclusivity or patent protection, but neither strategy is an optimal vehicle to encourage companies to test new drugs in children during the licensing process.
Why are pediatric studies needed? Because, quite simply, adult pharmacokinetic data cannot be extrapolated to children in a predictable manner. In this month’s Pediatrics electronic pages, the results from Pediatric AIDS Clinical Trials Group Protocol 377, described by Floren et al,1 are an excellent illustration of this important truism. This article is particularly illustrative because of the complexity of the relationships between the weight of the children and the metabolism of 2 different drugs. In this instance, weight is probably a surrogate for age and maturation, particularly of hepatic function.
The treatment of human immunodeficiency virus (HIV) involves administering complicated regimens for long periods of time. Typically, 1 to 3 nucleoside reverse transcriptase inhibitors (eg, zidovudine [formerly called "AZT"], lamivudine, and didanosine), will be combined with either a non-nucleoside reverse transcriptase inhibitor (exemplified by nevirapine or efavirenz), or with a protease inhibitor like nelfinavir, ritonavir, indinavir, or Lopinavir/r (Kaletra). In some cases, particularly where patients have advanced disease and no demonstrable resistance to non-nucleoside reverse transcriptase inhibitors, the combination regimen will include all 3 of these classes of antiretroviral drugs. Such was the case in PACTG Protocol 377.
The most critical finding in PACTG 377 was that the nelfinavir area under the curve ([AUC], a measure of drug concentration over time) for children <25 kg who received nelfinavir without nevirapine was very decreased relative to children >25 kg (the difference was 2.6-fold). When children received nelfinavir with nevirapine, this weight-stratified differential went away. The other important finding was that the AUC0–24 hours for nelfinavir dosed twice daily was comparable to a thrice-daily regimen in larger children (>25 kg), but was 2.7-fold greater than the AUC0–24 hours for children <25 kg dosed thrice daily. In short, the easier to administer twice-daily dose was pharmacokinetically superior to the more cumbersome thrice-daily regimen, particularly in smaller, younger children. Given the tight relationship between poor medication adherence and the development of resistance, the fact that an easier to administer regimen provides a superior pharmacokinetic profile is particularly important.
PACTG 377 was performed by the NIH-funded Pediatric AIDS Clinical Trials Group (PACTG). The federal government has considered HIV infection and its management a priority, so studies of new drugs for HIV treatment tend to occur relatively early. But the situation in HIV disease is an exception. Most pediatric health problems are not investigated by funded research groups, and new drug development depends on corporate sponsorship. Even the PACTG is limited in that new drugs must be provided by the pharmaceutical companies, purchased by the research group (too expensive for all but the smallest studies), or must await licensure and availability through Medicaid and other funding agencies. Increasingly the pharmaceutical industry has decided to move slowly into pediatric studies, and the NIH lacks the resources to fund drug purchases. This is particularly true in international trials.2 The result is that in most cases only licensed drugs will be investigated, and those trials won’t begin until the FDA has approved licensure for adults. The delay in critical information in children may be years. In the meantime, drugs may be used in a way that compromises their effectiveness, a problem that was clearly true for nelfinavir.
It is reasonable to hope that Congress will respond to the important need to require the evaluation of new medications in children when there are children who could benefit. Studies like PACTG 377 are an illustration of the reason to evaluate drugs in children as well as adults, proof that the pharmacokinetics of some medications is distinct in younger, smaller individuals. Pediatricians and those who care for children should encourage Congress to do what’s right and to reinstitute the Pediatric Final Rule, this time permanently.
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FOOTNOTES |
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Received for publication Jun 3, 2003; Accepted Jun 3, 2003.
Address correspondence to Ross E. McKinney, Jr, Department of Pediatrics, Division of Infectious Diseases, Duke University School of Medicine, Box 3461, DUMC, Rm 117A, Dean’s Suite, Davison Bldg, Durham, NC 27710. E-mail: ross.mckinney{at}duke.edu
Dr McKinney is a member of the Pediatric AIDS Clinical Trials Group.
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REFERENCES |
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 TOP REFERENCES |
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- Floren LC, Wiznia A, Hayashi S, et al. Nelfinavir pharmacokinetics in stable human immunodeficiency virus-positive children: Pediatric AIDS Clinical Trials Group Protocol 377.
Pediatrics.2003; 112
:e220
–e227
[Abstract/Free Full Text] - Cohen J. Drug trials without the drugs?
Science.2003; 300
:1212
–1213
[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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