FDA MANDATORY PEDIATRIC LABELING RULE WOULD APPLY TO FIRST INDICATION FOR NMEs, MARKETED PRODUCTS WITH WIDE USE OR IMPORTANT BENEFITS IN CHILDREN

FDA's authority to require pediatric trials prior to approval of an NDA would apply only to the first indication of a new molecular entity or new biological product, an Aug. 15 Federal Register notice states.

"In an effort to limit the scope of the rule to those products for which pediatric labeling is most urgently needed and to minimize the burden on manufacturers and on agency resources available to review new product applications, FDA has tentatively concluded that the pediatric study requirement would not apply to subsequent applications for the drug or biological product, e.g. to supplements for new indications or dosage forms," FDA said in the proposed rule.

The structure of the proposed rule could influence companies' decision-making when choosing among first indications to seek for products in development. If proposed legislation to allow limited off-label promotions is enacted, companies could have even more flexibility in selecting an indication for which to seek formal approval.

"The proposed rule would require an assessment of safety and effectiveness in one subpopulation (pediatric patients) only for the indications already claimed by the manufacturer," the agency continued. "It would not require a manufacturer to study its product for unapproved (`off-label') indications, even if the product were widely used in pediatric patients for those indications."

Based on analysis of recent approval data, FDA estimated that the study requirements will affect an average of 14 drugs and about 1,850 pediatric patients annually at new research costs to industry "of between $9.3 mil. and $16.7 mil. per year." The Administration expects comments on its cost estimate. White House Deputy Assistant to the President for Health Policy Development Chris Jennings told an Aug. 13 press briefing that he "assumes that the industry will raise questions about [FDA's cost] estimate." Among its objections to the proposal, the Pharmaceutical Research & Manufacturers of America has suggested that the proposal will cost more than FDA estimates . The comment period on the proposed rule expires November 13.

For products already on the market, FDA is going to require pediatric labeling "where there is a compelling need for more information," the proposal states.

Specifically, FDA will require studies when "(1) the product was widely used in pediatric populations and the absence of adequate labeling could pose significant risks to pediatric patients; or (2) the product was indicated for a very significant or life threatening illness, but additional dosing or safety information was needed to permit its safe and effective use in pediatric patients."

Based on 1994 data from IMS America, FDA lists 10 drugs in the proposed rule that were most widely prescribed in pediatric patients without adequate pediatric labeling. Included in the list are asthma drugs: albuterol inhalation solution for nebulization in patients under 12; Rhone-Poulenc Rorer's Intal (cromolyn) in patients under five; and Boehringer Ingelheim's Alupent (metaproterenol sulfate) in patients under six.

Treatments for allergic reactions and infections included in the list are: Wyeth-Ayerst's Phenergan (promethazine) for treatment of allergic reactions in patients under two and Auralgan (antipyrine/benzocaine/glycerin otic solution) for treatment of ear pain in patients under 16; ampicillin injections for treatment of infections in patients under 12 and Schering's Lotrisone (clotrimazole and betamethasone dipropionate) for the treatment of topical infections in patients under 12.

Psychotropics on the list include: Lilly's Prozac (fluoxetine) for the treatment of depression and obsessive compulsive disorder in patients under 16; Pfizer's Zoloft (sertraline) for the treatment of depression in patients under 16; and CibaGeneva's Ritalin (methylphenidate) for the treatment of attention deficit disorders and narcolepsy in patients under six.

Studies in pediatric populations will often be geared to determine proper dosage and formulation for pediatric patients, FDA said. The agency emphasized "the importance of studying the pharmacokinetics of a drug in pediatric patients of different ages before they are widely exposed to it," and the fact that "a standardized pediatric formulation ensures bioavailability and consistency of dosing, and permits meaningful testing of safety and effectiveness."

Manufacturers may receive waivers for pediatric studies if the product does not represent a meaningful therapeutic benefit over existing therapies or is not likely to be used widely in pediatric populations, the proposal states.

"FDA also does not intend to require pediatric assessments in other situations where the study(ies) necessary to carry out the assessment are impossible or highly impractical or would pose undue risks to pediatric patients," the proposed rule states.

Sponsors can apply for full or partial waivers based on FDA's division of the pediatric population into four age group categories: neonates (birth to one month old), infants (one month to two years old), children (two years to 12 years old) and adolescents (12 to 16 years old) and its assessment of the need for studies in all or some of the groups.

"In addition to the other grounds for waiver, the proposed rule would authorize FDA to grant a partial waiver for those age groups for which a pediatric formulation was required, if reasonable attempts to produce a pediatric formulation had failed," FDA said. However, "if a waiver were granted on the ground that it was not possible to develop a pediatric formulation, the waiver would cover only those pediatric age groups requiring a pediatric formulation."

FDA is asking for comments on whether cost should be considered as a grounds for a waiver. In addition, the agency solicits views on how to determine the threshold for pediatric use to require studies. FDA is suggesting either a calculation of the number of pediatric prescriptions expected for the product annually, with 100,000 or more considered substantial, or an estimate of the prevalence of the disease, with a total population of 100,000 considered substantial.

The agency pledged to work with sponsors during development to produce a plan for studies, and to consult with sponsors before deciding what types of studies to require. The agency is planning a public workshop in early 1998 to discuss pediatric labeling, and has already put in place pediatric teams as part of the review process ("The Pink Sheet" July 7, p. 8).

FDA may also allow companies to defer submission of pediatric data until after a new molecular entity or a new biologic product application for approval has been approved.

"If FDA concluded that there were adequate justification for deferring the submission of pediatric use studies, the agency could approve the product for use in adults subject to a requirement that the applicant submit the required pediatric studies within a specified time after approval," the agency said. "FDA would consult with the sponsor in determining a deadline for the deferred submission, but would ordinarily require the submission not more than two years after the date of initial approval." The agency plans to require manufacturers to provide annual updates on the status of pediatric commitments.