Pediatric Protocol In Written Agreement Should Be Strictly Followed - FDA

NDA sponsors will be expected to precisely adhere to study protocols included in pediatric written agreements, FDA's revised guidance on pediatric exclusivity states.

"If a sponsor incorporates a protocol into a written agreement but does not follow the protocol exactly, the sponsor would not earn pediatric exclusivity unless it obtained an amendment to the written agreement," the guidance for industry states.

FDA does not, however, recommend that sponsors "routinely" include protocols in the written agreement, the Oct. 4 guidance adds.

The agency acknowledged that "sponsors do not always follow protocols to the letter," and cautioned that "although the studies completed are still good, scientifically sound studies," strict adherence to the protocol outlined in the written agreement will be expected.

Pediatric written agreements are intended to clarify ambiguities that may exist in a written request for pediatric studies.

The pediatric incentive grants sponsors an additional six months of exclusivity for conducting pediatric studies if FDA issues a written request soliciting them. Pediatric exclusivity may be obtained whether or not the studies demonstrate safety and efficacy in children. A written request from FDA is required for a sponsor to qualify for exclusivity.

Written agreements between FDA and the sponsor are not required for exclusivity, but may be used to "confirm that a particular method of fulfilling a term of the written request is acceptable when multiple options are available," the guidance states.

FDA's first guidance on pediatric exclusivity, issued in June 1998, did not have elaborate detail regarding written agreements (¹ (Also see "Pediatric Data Not Included In Label May Be Made Public By Alternate Means" - Pink Sheet, 6 Jul, 1998.)). "Written agreements are not an issue until there are written requests," FDA Center for Drug Evaluation & Research Regulatory Policy Staff member Leanne Cusumano commented Oct. 4 at the Regulatory Affairs Professionals Society annual meeting in Washington, D.C. "Written agreements are a big issue, which [FDA is] still working out," she added.

Cusumano noted that the importance of this issue is mounting as more written requests are being issued. She suggested that a confirmation about how many patients in a study would be adequate might be something a firm would seek from a written agreement.

She acknowledged that it is not perfectly clear whose responsibility it is to initiate a written agreement, but recommended that "if a sponsor is interested, they should talk to FDA about it."

Novartis Associate Director-Regulatory Liaison, Drug Regulatory Affairs and former FDAer Sharon Olmstead remarked that FDA has also been strictly adhering to disease specific templates designed to guide pediatric studies. "I can tell you that they are sticking very closely to the template," Olmstead said, "so if you deviate from the template [in a proposal] and you get your written request, it will say exactly what is in the template."

FDA's pediatrics website has posted templates for pediatric studies of anti-depressants, anti-hypertensives, obsessive compulsive disorder therapies and antiretroviral drugs (² (Also see "Antihypertensive Pediatric Sample Request Describes "Meaningful" Data" - Pink Sheet, 15 Mar, 1999.)).

In its most recent update on the progress of the pediatric incentive program, the agency reported that it has received 159 proposed pediatric study requests as of Oct. 1. FDA has issued 101 written requests, 35 incomplete responses and 20 written request amendments. One proposed study request was withdrawn and action on 33 are pending.

Olmstead acknowledged FDA's efforts, noting that the agency has implemented the incentives program despite an effective decrease in resources, since the FDA Modernization Act states that user fees for all pediatric supplements will be waived.

An FDA report on pediatric exclusivity is due to Congress on Jan. 1, 2001, and Olmstead said she is "not sure that by the end of next year we are going to have fully appreciated the impact of the incentive....I just hope that we will be able to present it to Congress in such a way that if this is really successful...they can understand that it is successful based on what is going on at the time, because just the raw numbers may not tell the whole picture."