In 1937, the S. E. Massengill Company mixed a popular and effective antibiotic called sulfanilamide with diethylene glycol, a chemical used in antifreeze, to produce Elixir Sulfanilamide. The sweet-tasting but toxic syrup wound up killing over 100 people, including many children, before it could be entirely recalled. The scandal led to the 1938 passage of congressional legislation that gave the U.S. Food and Drug Administration the power to require safety testing before new medicines could be marketed. Less than a quarter-century later, another major drug-safety disaster occurred, this time involving thalidomide, a sedative widely prescribed in Europe and Japan for morning sickness. Though the drug was never approved for sale in the United States, Congress responded to the thalidomide tragedy by expanding the FDA’s powers again—this time through the 1962 Kefauver Harris Amendment, which required that companies prove efficacy as well as safety in pre-market testing through FDA-regulated clinical trials.

While safety and health issues surrounding children’s medicines shaped the modern FDA’s evolution, the drug research and approval process that Congress put into place in the 1930s and 1960s has failed to serve children’s interests. The reason, in part, is that children aren’t just tiny adults. Their metabolism may process drugs differently, leading to problems with under-dosing (producing no effect) or overdosing (producing toxic effects). Prolonged exposure to drugs for chronic illnesses could short-circuit early growth processes and cause long-term developmental problems. Pediatricians can often only make an informed guess as to how drugs designed and tested for adults would affect “children,” a fuzzy category that also includes newborns and adolescents. In fact, by the mid-1990s, about 80 percent of all drugs used for children were prescribed “off label”—that is, doctors prescribed them without any specific guidance about whether the drug was safe and effective for its intended use (or any use) in children.

Compounding these challenges is a dearth of pediatric drug research, a function of both economics and health. Children for the most part are a healthy population and represent a much smaller potential market for drug companies than older, sicker adults. The FDA’s copious safety and efficacy requirements make the cost of developing new medicines staggering—approximately $1 billion over a 10- to 15-year process. Thus, companies have less incentive to produce drugs for the relatively tiny population of very sick children, since they have little hope of recouping their investments before a drug’s patent expires. And children’s unique biology poses another complication, making drug testing in pediatric populations particularly daunting, time-consuming, and expensive.

Thankfully, in 1997, Congress recognized these obstacles and passed the Best Pharmaceuticals for Children Act (BPCA), which offers increased incentives for drug manufacturers to test new medicines in pediatric populations. Companies that propose (or are asked by the FDA to conduct) studies of new medicines in children can receive six months of added patent protection for the drug after it receives FDA approval (assuming the pediatric studies meet FDA requirements). The law delays generic competition for such drugs, potentially bringing in millions of dollars in added revenues for widely used medicines.

Still, BPCA is voluntary, and drug makers can decline the FDA’s request for studies under the legislation. Acting to close this loophole, the FDA issued the Pediatric Rule in 1999, which required manufacturers to perform at least some basic testing of new medicines in children. Courts later overturned the Pediatric Rule, but President Bush signed the 2003 Pediatric Research Equity Act (PREA), which gave the FDA the authority to require pediatric testing as part of the new drug review-and-approval process.

These two laws—carrot and stick—have worked to expand testing of new children’s medicines and helped physicians prescribe pediatric medicines with more confidence that their benefits are worth the potential risks. To date, the Institute of Medicine estimates that BPCA and PREA have made available 180 new drugs for use in pediatric indications and prompted over 400 label changes to help physicians prescribe drugs more effectively. Off-label prescribing has also declined significantly, to roughly 50 percent of all prescriptions written for children.

The current environment for pediatric research, however, remains fragile, in no small part due to the uncertainty about BPCA’s and PREA’s permanence. Both laws face congressional reauthorization every five years—but it can take six years to complete a pediatric study. Companies would have to commit to expensive research without knowing whether Congress will change the rules before the study is even completed.

Thankfully, bipartisan legislation proposed in Congress in late March would make PREA and BPCA permanent, while clarifying some key aspects of the programs and reforming others. The bill has the support of industry stakeholders and patient groups like the Elizabeth Glaser Pediatric AIDS Foundation. The bill would require companies to submit proposed BPCA trial designs to the FDA sooner than they do now, after relatively early safety and efficacy testing—but not so early as in Europe, where firms often must revise their testing plans after additional data are generated. If companies don’t complete their BPCA studies in a timely fashion, the FDA can disclose the failure—essentially “naming and shaming” the company, but not pulling the drug from the market. The Government Accounting Office (GAO) would be required to submit regular reports on the programs’ impact on pediatric research and drug labeling.

But the key achievement of the legislation would simply be to let the FDA and the inventors of new medicines advance pediatric research more efficiently, without having to obtain legislative approval every five years.


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