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Executive Summary

FDA is encouraging pharmaceutical companies to submit supplements updating their pediatric use labeling as soon as possible to comply with a proposed rule published in the Oct. 16 Federal Register. The proposal is a revision of the "pediatric use" subsection in prescription drug labeling. FDA is proposing that any final rule take effect one year after publication. "After this date, products whose labeling is not in compliance with the rule will be misbranded drugs," FDA said. The comment period on the proposed rule closes Dec. 15. As a result of the implementation schedule,"FDA urges manufacturers to consider what labeling revisions, if any, will be necessary before FDA publishes the final rule, and to submit supplements proposing any revised labeling at the earliest opportunity." Generic drug manufacturers will have four months after any labeling changes in the referenced innovator products to bring their labels into compliance. The Oct. 16 proposal would allow FDA to "approve a drug for pediatric use based on adequate and well-controlled studies in adults, with other information supporting pediatric use" in cases where the agency has "concluded that the course of the disease and the effects of the drug are sufficiently similar in children and adults to permit extrapolation from the adult data to children." "Other information, such as data from pharmacodynamic studies of the drug in children, controlled or uncontrolled studies confirming the safety or effectiveness of the drug in children, pertinent premarketing or postmarketing studies or experience, may be necessary to establish the applicability of the adult data to children," the proposed rule continues. The expanded "pediatric use" section of labeling would also include "brief" statements of other available information and, where appropriate, references to other sections of labeling, such as "warnings" or "clinical pharmacology." Commissioner Kessler announced the new rule at the American Academy of Pediatrics annual meeting in San Francisco Oct. 14. FDA worked with the AAP in developing the proposal: representatives of the association met with FDAers last September to discuss pediatric drug labeling ("The Pink Sheet" Dec. 2, 1991, T&G-3). The prologue to the proposed rule refers to an AAP study that showed that 80% of new molecular entities approved by FDA between 1984 and 1989 had no information on pediatric use. "The labeling of drugs and biologics for use in children lags well behind clinical patterns of use," Kessler declared at the AAP meeting. "For many approved drugs, the labeling carries little or no information about use in children." "The problem of pediatric labeling results from the fact that most drugs are tested by their manufacturers in the vast majority of applications that are submitted to the FDA contain little or no data from clinical trials in children," Kessler said. Citing Bristol-Myers Squibb's Videx (ddI), which was approved simultaneously in adults and children, Kessler said: "That is the way the system should work." After outlining the proposed rule, Kessler acknowledged that "there are real limits to this policy...There are many pediatric diseases where we cannot extrapolate from studies in adults." "In those instances," Kessler said, "drug manufacturers, the pediatric research community and sponsors of clinical research need to step up to the plate and make sure that the necessary studies are done." "FDA has undertaken a number of initiatives to encourage sponsors to study prescription drugs in children and to stimulate development of sufficient information to support labeling that promotes the safe and effective use of drugs in children," Kessler said. "FDA now routinely reviews INDs to determine whether studies in children should be undertaken. Where appropriate, we have encouraged sponsors of certain investigational drugs to perform studies in children before marketing. But," he added, "jawboning has its limits." The proposed rule would establish boilerplate language for an expanded pediatric use section: "The safety and effectiveness of drug name have been established in children age to ; (note any limitations, e.g., no data for children under [age] two). Use of drug name in children is supported by evidence from adequate and well-controlled studies of drug name in adults with additional data (insert wording that accurately describes the data submitted to support a finding of substantial evidence of effectiveness in children)." If there is not enough information to support a pediatric indication, the "pediatric use" section will declare that "safety and effectiveness in children below the age of have not been established." The section will also include a discussion of any "specific hazard" associated with pediatric use even if the drug is not indicated in children. Finally, any excipients that "present an increased risk of toxic effects to neonates or other pediatric subgroups" will be specially noted in either the "contraindications," "warnings" or "precautions" section of the label under the proposed rule. Kessler's public exhortation of drug companies to provide pediatric data for the agency to review is similar to an earlier effort by the commissioner to generate supplements for off-label uses of cancer therapies. In January, Kessler told the National Cancer Advisory Board that the agency was actively soliciting off-label use data for oncology drugs ("The Pink Sheet" Feb. 3, p. 8). Kessler also has been preparing an article for publication in a medical journal emphasizing the agency's willingness to approve oncology supplements ("The Pink Sheet" May 4, p. 3). That effort, however, has yet to get off the ground; the proposed journal article remains unpublished. The apparent first sign of activity came when one firm, Lederle Labs, decided to proceed with a submission on its own ("The Pink Sheet" Oct. 12, T&G-7). For pediatric labeling, however, Kessler has more to rely on than public encouragement of sponsors. In addition to the proposed rule, FDA also has participated in the development of a legislative incentive for firms to conduct pediatric trials sponsored by Kansas Republican Sen. Kassebaum (see following story). Kessler used the discussion of pediatric labeling as a springboard to talk about AIDS. "Whenever separate pediatric studies are needed, we must be ready to meet the situation head on," Kessler said. "And in the face of the most terrible of epidemics, in the face AIDS, we all must be ready to meet the situation head on." "I fear this nation is in danger of slipping back into the complacent attitude toward AIDS that existed during the early days of the epidemic," Kessler said. "We as a nation seem to be learning to live with AIDS, while others are dying from it, and that is a frightening concept." With the Presidential election less than three weeks away, Kessler countered a remark by candidate Ross Perot made during the Oct. 11 debate: "The other night, Mr. Perot said that it takes 10 years for FDA to approve an AIDS drug. That is false. This Administration's review times for AZT, ddI and ddC are measured in months, not years. I promise you this. Bring me a drug that is a true cure for AIDS, and I will have it approved so fast it will make your head swim." The commissioner pointed out that "FDA cannot require firms to submit applications." He added: "It is particularly unfortunate when, after two years of planning and counseling and cooperation between the Public Health Service and a private firm, a firm pulls back from its planned trial." The agency also "cannot require companies to conduct trials on products they no longer want to pursue," Kessler continued. "Nothing concerns me more than when firms with an idea, firms with talented and energetic people, refuse to step up to the plate and accept their share of responsibility. If those firms do not stand up and do what is right, nothing we can do at FDA, at NIH [the National Institutes or Health] or at CDC [the Centers for Disease Control] will make one whit of difference."

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