In: Drug14 Jun 2010
The FDA, working under the aegis of the Congress, began to persuade pharmaceutical companies to provide pediatric labeling information on drugs if such data were available. Initially, a 1979 FDA regulation required full clinical trials in pediatric populations as the basis for drug labeling for chil-dren, but progress in achieving this goal was made very slowly. The 1979 regulation permitted pediatric claims only if there had been adequate and well-controlled studies of the drug in children. This regulation, contrary to its purpose, stymied the hope that drug labels would provide adequate information for using drugs in children. For the words “Pediatric Use” to appear on the label, there needed to be “substantial evidence derived from adequate and well-controlled studies.”
Thus, most prescription drugs did not contain pediatric doses on labels because the required clinical trials of children were not available at the time. The 1979 regulation said that if a specific pediatric indication existed, it should be described in the “Indications and Usage” section of the labeling and the appropriate pediatric dosage should be listed in the “Dosage and Administration” section. tadalis sx
Even with this regulation, it was disappointing to the FDA and to pediatricians that only 20% to 25% of all drug labels included pediatric information; this reinforced the fact that very few drugs were being tested for safety and effectiveness in children. Although little testing was done and sparse information appeared on labels, health professionals could still prescribe a drug for children for “off-label” uses. Without pediatric drug data, however, physicians were sometimes reluctant to treat children.
Because of the continued slow progress in pediatric drug studies as well as in meaningful pediatric drug labeling, it took significant congressional pressure to achieve passage of a new legislative rule in 1994. The rule revised the “Pediatric Use” subsection of the prescription drug-labeling requirements.
The new regulation seemed to promise that drugs would be labeled with additional pediatric information that was crucial to the well-being of many of the nation’s children. The rule allowed companies, in some situations, to base pediatric labeling on data extrapolated from adequate and well-controlled adult studies along with other information on treating children. However, the rule specified that such pediatric-use statements could be made only if the course of the disease and the drug’s effects were sufficiently similar in children and adults. The manufacturers were required to take the necessary steps to modify existing labeling. Triggered by the need for additional information that might produce health benefits in children, the regulation included a six-month pediatric exclusivity that prolonged the patent life of the active moiety. Manufacturers were required to submit supplemental pediatric dosing information on their products to the FDA by December of 1996.
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The 1994 regulation also clarified the FDA’s “final rule” requesting specific pediatric-use information from the drug manufacturers. For example, the FDA might request pedi-atric-use data for a drug that was widely used, was a safety hazard, or was therapeutically important in children. The rule, however, did not limit the manner in which a practitioner prescribed an approved drug. Further, if there was not substantial evidence to support a pediatric indication or a pediatric-use statement for any children (or for a specific age group), the Pediatric Use subsection had to state that the “safety and effectiveness in pediatric patients [or the age group] have not been established.”
A special pediatric FDA subcommittee staff tracks the implementation of the regulations and takes steps to ensure that the various possibilities of pediatric testing and use are explored. Its Center for Drug Evaluation and Research made efforts to increase the number of pediatric studies included in submissions for new prescription medicines. The agency also works closely with the National Institute of Child Health and Human Development (NICHHD) to conduct pediatric trials and with sponsors of new products to ensure that the necessary pediatric data are included. Manufacturers whose products were clearly not of benefit to children or whose pediatric dosage formulations were not feasible could apply for waivers exempting them from these requirements.
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The response to the 1994 rule did not adequately address the lack of pediatric-use information for marketed drugs and biological products. Manufacturers submitted pediatric labeling supplements for approximately 430 drugs and biologicals, a small fraction of the thousands of prescription drugs and biological products on the market. Of the supplements submitted, approximately 75% did not substantially improve pediatric-use information. More than 50% of the total supplements submitted simply requested the addition of the statement that the “safety and effectiveness in pediatric patients have not been established.” Others requested minor wording changes or submitted unorganized, unanalyzed collections of potentially relevant data. Almost 15% (approximately 65) of the supplements provided adequate pediatric information for all relevant pediatric age groups, and another 8% (approximately 35) provided adequate pediatric information for some, but not all, relevant age groups. The rule did not work well.
The FDA’s Modernization Act (FDAMA) of 1997 required the FDA to specify which drugs needed to carry pediatric labeling. The intent of the list was to focus on those products that were widely used in children and for which the absence of labeling information might lead to serious misuse.
In 1998, the FDA listed the drugs that it said needed to carry pediatric labeling. Some drugs that met the labeling criteria and that did not carry a pediatric indication included albuterol inhalation solution, ampicillin (e.g., Unasyn®, Pfizer) for intravenous use, fluoxetine (Prozac®, Eli Lilly), and methylphenidate (e.g., Ritalin®, Novartis) in children younger than six years of age. Although the FDA expects the six-month marketing exclusivity offered by the Modernization Act to provide a substantial incentive for sponsors to conduct some pediatric studies, the voluntary nature of the incentive provided by this Act is likely to leave many drugs, age groups, and indications unstudied.
The Modernization Act provides no incentive to conduct studies on certain categories of products, including most antibiotics, biologicals, and off-patent products. Under the Best Pharmaceuticals for Children Act (BPCA), off-patent drugs that are no longer the property of any single drug firm will undergo pediatric drug trials sponsored by the U.S. Department of Health and Human Services (DHHS). Under Section 1789, a fund would be created for off-patent pediatric research in instances when manufacturers of off-patent drugs decline to conduct pediatric research. The FDA and the manufacturers would negotiate the wording of pediatric labeling for off-patent drugs and approvable new drugs within a six-month period. The bill would reauthorize pediatric exclusivity incentives until October 1, 2007.
Following is a summary of the legislation signed and approved by Congress on January 4, 2002. On January 1, 2002, Congress had passed the “Pediatric Rule” for the FDA to follow (see “Pediatric Exclusivity” later). As of January 31, 2003, the status of the FDA’s Pediatric Rule was as follows:
The current Pediatric Rule (BCPA) requires pharmaceutical companies to study new and marketed drugs and biologi-cals in children to determine their safety, efficacy, and dosing. The FDA could apply the rule if an agent promised to bring a “meaningful therapeutic benefit” over current treatments or if more than 50,000 children were affected. Approximately 12,400 children are found to have cancer each year in the U.S., and the rule might have applied in pediatric oncology only if an agent represented a therapeutic advance. Another requirement of the rule is that the disease or an agent’s indication or mechanism of action must be the same in children and adults.
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