Pediatric Pharmacotherapy Part 1: The History of Pediatric Drug Therapy: Learning from Errors, Not Trials

Marcel J. Casavant; Jill R. K. Griffith


AccessMedicine from McGraw-Hill 

In This Article

Legal and Regulatory Developments: Pediatric Pharmacology in the United States

Federal drug regulatory efforts began in 1906; the role of the federal government has expanded several times since then, usually in response to a weakness of the process as demonstrated by some tragedy. Although, as we have seen at the beginning of this update, several of these tragedies involved the deaths of children, special regulatory attention to pediatrics has appeared only in recent decades. The major thrust of this extra regulatory attention has been to get drug manufacturers to conduct studies of their drugs in children. (See Table 1 )

Food and Drug Administration Modernization Act of 1997 (FDAMA)

The first of these recent regulatory efforts was the Food and Drug Administration Modernization Act. This law made many changes in U.S. Food and Drug Administration (FDA) operations and FDA interactions with drug manufacturers. Most important to our purposes, the FDAMA encouraged manufacturers of branded drugs to conduct pediatric studies. If studies were completed, the FDA would consider extending patent life another 6 months, termed “pediatric exclusivity.” Pediatric exclusivity is often called “the carrot;” an extra 6 months without competition in the marketplace constitutes a tremendous financial incentive.

Best Pharmaceuticals for Children Act (BPCA)[9]

Enacted in January 2002 after the FDAMA pediatric exclusivity provisions expired, BPCA not only encouraged manufacturers to conduct pediatric studies in exchange for an additional 6 months of exclusivity but also opened avenues for obtaining pediatric data on drugs the manufacturer declined to study. When the FDA feels pediatric data are needed, and the manufacturer chooses not to conduct the studies, BPCA allows the FDA to refer the study of an agent to either the National Institutes of Health (NIH) or the Foundation for the National Institutes of Health. BPCA requires the NIH to publish an annual list of drugs for which additional studies are needed. The FDA could then request drug sponsors to study drugs on the list. Pediatric study results submitted as Supplemental New Drug Applications (SNDA) undergo the same FDA review process as any other drug study result. FDA action could include approving the application; determining the application is approvable—meaning more information is required; or finding the application not approvable. Any negative pediatric safety or efficacy data is reflected in the product labeling.

Historically, drug manufacturers decline written FDA requests for the study of generic drugs because financial incentives are greatly reduced. As of 2005, the NIH identified 40 generic drugs it believed warranted more pediatric study; 16 requests went to drug manufacturers and all but one declined. The NIH funded 7 of the 15 declined written requests. 

Pediatric Final Rule and Pediatric Research Equity Act

Neither the FDAMA nor the BPCA encourages manufacturers to study their products in children early in the process during the initial licensing of the drug by the FDA. In 1997, the Pediatric Final Rule required manufacturers to submit pediatric data with every NDA if the drug had a potential use in children. Where FDAMA offers exclusivity as “the carrot,” the Pediatric Final Rule is “the stick” as it gives the FDA authority to mandate that a manufacturer conduct a pediatric drug study.

The rule went into effect in 1999 and was overturned by a federal court in 2002. The court ruled that the FDA did not have authority to issue this requirement. In response to the court ruling, Congress granted the authority via the 2003 Pediatric Research Equity Act (PREA), which reinstated and expanded the Pediatric Final Rule.

Thanks to FDAMA, the BPCA, the Pediatric Final Rule, and the PREA, hundreds of drug trials have been conducted in children. Many of these trials resulted in added FDA-approved indications for these drugs in children. Many provided data that let us prescribe medications for children with added confidence. Similarly, many of these studies resulted in critical new warnings and safety data, new pharmacokinetic data and dosing instructions, and even new designs to pediatric drug trials.[10] Congress recently recognized the value of all this extra work in getting safer drug therapy for children and, in the FDA Amendments Act of 2007 (FDAAA), renewed and extended these measures. At the same time, the FDAAA adds similar pediatric emphasis to medical devices. The FDA maintains a list of pediatric labeling changes resulting from these studies.[11]


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