BYLINE: Wechsler, Jill

HIGHLIGHT:

The FDA is developing a program to encourage pediatric research in order to make pediatric drug development a routine part of R&D

BODY:

The Littleton high school shootings in Colorado that happened early 1999 gave rise to the need for more research on the use of prescription drugs in children.

Apparently, one of the attackers had taken a selective serotonin reuptake inhibitor at one time and the side effects of this drug have not yet been determined of late

due to the lack of definitive data. To fill such gaps and reduce medication errors, the Food and Drug Association (FDA) is urging manufacturers to conduct the studies needed to develop pediatric labeling for new drugs as well as those already on the market. At the same time, it implemented a two-pronged program to encourage pediatric research and a pediatric "final rule" to "fill the gaps" in the FDAMA voluntary pediatric labeling program. Under the rule, manufacturers are being required to conduct pediatric studies on products that are not positioned to take advantage of the FDAMA exclusivity program. The FDA will measure the success of its initiatives by monitoring whether changes in product labeling have transpired.

Jill Wechsler, Washington Correspondent

The possibility that off-label prescribing of an antidepressant for a troubled teenager may be linked to the Littleton (CO) high school shootings in April has focused attention on the need for more research on the use of prescription drugs in children. One of the Littleton attackers had taken a selective serotonin reuptake inhibitor at one time, and mental health experts continue to note that there are few definitive data on the side effects of such medications on young patients.

To fill such data gaps and reduce medication errors, the FDA is urging manufacturers to conduct the studies needed to develop pediatric labeling for new drugs as well as those already on the market. Up to now, inadequate prescribing information for young patients has made children "therapeutic orphans" according to Murry

Lumpkin, deputy director of the FDA's Center for Drug Evaluation and Research (CDER). Moreover, a lack of standardized pediatric formulations requires considerable product compounding by pharmacists, Lumpkin noted at the first meeting of the FDA's Pediatric Advisory Subcommittee, hem in late April. Now the agency is seeking to streamline pediatric research requirements as part of its broader goal of pediatric prescribing that's based more on science than on a practitioner's bias or hope, Lumpkin observed.

Prior agency efforts to stimulate clinical research on children have had little success, reported FDA associate director of pediatrics Diane Murphy, MD, who heads CDER's Pediatrics Team. Over the past decade, only about 30% to 35% of new molecular entities have come to market with adequate labeling for children.

Meanwhile, policies to encourage sponsors to conduct pediatric studies after gaining market approval for a new therapy largely have been unsuccessful. One analysis estimates that information on pediatric use is inadequate for almost three-fourths of prescription drugs, Murphy told the advisory panel.

Two-Pronged Approach

To alter this situation, the FDA is busy implementing a two-pronged program to encourage pediatric research. The main stimulus is the FDA Modernization Act (FDAMA) of 1997, which offers drug manufacturers 6 months of additional market exclusivity for conducting studies that will provide useful pediatric information on product labels. This "carrot" has prompted manufacturers to send in more than 100 proposals to conduct pediatric studies, reported CDER Pediatrics Team medical officer Rosemary Roberts, MD. She told the advisory panel that, as a result, CDER has issued 49 formal written requests specifying what information a sponsor must submit to qualify for added exclusivity. As of March, the FDA had granted exclusivity on five products that fulfilled stated study requirements, and three more applications were pending review.

At the same time, the agency is implementing the pediatric "final rule" that it adopted in 1998 to "fill the gaps" in the FDAMA voluntary pediatric labeling program.

This rule permits the FDA to require manufacturers to conduct pediatric studies on products not positioned to take advantage of the FDAMA exclusivity program--antibiotics, biologics, and other older or off-patent therapies. The final rule went into effect April 1, 1999, but the agency cannot require studies for another 2 years, a delay designed to show whether the incentive policy produces the desired results. The FDA plans to wave the "stick" of the final rule only after it gives exclusivity a chance to play out, Roberts said.

To show that the voluntary incentives will work--and that the FDA need not implement the mandatory policy--industry is responding to the call for pediatric studies.

A recent survey by the Pharmaceutical Research and Manufacturers of America (PhRMA) found that 109 companies have 207 drugs and vaccines in development for children, up from 187 medicines in 1998 and 146 in 1997. PhRMA president Alan Holmer attributed the rise to the FDAMA incentive program, which he predicted will encourage research on even more medicines, plus new formulations and treatment information for existing therapies.

Provider Perspectives

The true measure of the program's success will be whether it improves and makes substantive changes in product labeling, according to health care professionals.

American Academy of Pediatrics (AAP) representative Daniel Notterman, MD, of Princeton University urged the advisory panel to examine whether the new initiatives really add new information to drug labels. The AAP wants to see labels with dosing guidelines for additional age groups and information on new pediatric formulations. To spur the efforts, the AAP is developing a list of 80 to 100 drugs that its members consider most in need of pediatric labeling. One objective is to better focus the FDA's "pediatric priority list," which currently includes some 475 drugs and biologics, on those therapies with "substantial use" in young patients.

Pharmacists also are providing input on which drugs are most often used for children and in need of new formulations. A group of children's hospitals is developing the Pediatric Health Information Systems Database, reported Dave Grinder, director of pharmacy at All Children's Hospital, St. Petersburg, FL. The database was started by the Child Health Corporation of America (CHCA) and now includes 28 children's hospitals.

A major concern for pharmacists and patients is the lack of commercially available pediatric formulations of drugs commonly used in children, added Grinder, who represented the Pediatric Pharmacy Advocacy Group (PPAG) at the panel meeting. Payers and health plans often fail to realize that most drug utilization data do not capture the widespread need for extemporaneous compounding. Grinder reported that the 2 minutes it takes to prepare an extemporaneous oral liquid adds up to more than 11 hours of pharmacy compounding per day at children's hospitals, according to CHCA data. He explained how pharmacists often have to "invent ways to do things," which can be stressful and risky. He cited one study that found that 20% of medication errors in pediatrics are related to oral liquid medications. The PPAG has developed a list of drugs drugs most frequently compounded for pediatric use at participating hospitals for internal use as well as FDA reference.

Trials Can Be Tricky

The lack of pediatric products and labeling arises from the cost and difficulties of conducting studies on young patients. Designing clinical trials for children raises a host of ethical questions about whether parental consent is sufficient and how much data on adults should be collected before beginning tests on children. The role of placebo-controlled trials and whether it's ethical to study children who don't have the condition in question also draw attention.

Another challenge is to identify young patients willing and able to participate in studies. One result of the surging interest in sponsoring pediatric studies is that the demand is "saturating" the nation's pediatric research infrastructure, Lumpkin said. Experts advised study sponsors to look to HMOs, vaccine trial centers, and patient advocacy groups for help in addressing the universal difficulty of finding enough eligible subjects for pediatric trials.

In some cases where manufacturers have trouble designing studies, they will be able to defer submitting pediatric data with an NDA or obtain a waiver from having to conduct pediatric studies altogether. The FDA insists that it will not delay approval of a new therapy for adults just because there is insufficient pediatric information. The agency has granted deferrals for products already in the pipeline, but usually with a stipulation in the approval letter as to what pediatric studies will be conducted and when they are due. The FDA also will note the potential for gaining market exclusivity for doing the stated research in order to use "every opportunity" to discuss both the incentive and the mandatory programs, CDER's Murphy added. But if sponsors do not meet time frames for submitting promised pediatric data, there will be a "very public" discussion of the situation, she predicted.

The waiver option will be available to sponsors after the mandatory final rule policy kicks in 2 years from now. To require pediatric studies, the agency first must demonstrate a "compelling need" and that "meaningful therapeutic benefit" will result. Sponsors may gain a waiver if they can document a lack of benefit major difficulties conducting pediatric studies that the medication is unsafe or ineffective in children or that, after "reasonable attempts" a suitable formulation cannot be developed.

Because of the importance of pediatric labeling, patient and provider groups want the FDA to use the waiver option "very sparingly," said Timothy Westmoreland of the Pediatric AIDS Foundation. He noted that 6 months of added exclusivity is a "plenty sufficient" incentive for manufacturers to conduct needed studies, and that the agency should take legal action against companies that refuse to comply with specific research requests.

Manufacturers, on their part, want some kind of appeals mechanism for resolving scientific and medical disputes, pointed out Michael Horan of PhRMA. Sponsors also are asking the FDA to provide additional guidance on how it will implement the final rule so that it meshes with the FDAMA exclusivity program. FDA officials hope to issue a guidance for implementing the pediatric rule this summer, along with a more specific guidance on designing and conducting pediatric clinical trials.

A Routine Part of Research

The ultimate goal for the FDA and the health care community is for pediatric drug development to become a routine part of pharmaceutical research and development. To accomplish this goal, Murphy and her staff have begun to discuss pediatric study requirements with sponsors at regular meetings scheduled for reviewing clinical protocols and discussing pending applications. The aim is to clarify data expectations and timing while also providing information on exclusivity opportunities to further encourage sponsor compliance.

The CDER Pediatrics Team is developing a tracking system to collect data on the number of pediatric proposals from sponsors, the resulting written requests from the FDA, the types of studies requested and conducted, and the number of deferrals and waivers. The listing also will indicate to what extent the program results in changed labels and more prescribing information for physicians. These data will be important for the FDA as it updates its pediatric drug priority list each year and files a report to Congress by January 1, 2001. If the added exclusivity program does not yield the expected results, the program is slated to "sunset" in January 2002.

Jill Wechsler covers Washington for professional journals. She specializes in the health care and pharmaceutical industries.

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