WASHINGTON _ The FDA has issued final regulations that willmake it easier for drug and biologics manufacturers to include dataabout a product's use for children on the label and to obtain FDAapproval for that use.

For diseases which take a similar course in adults and children,manufacturers may now obtain FDA approval for pediatric use basedon pharmacokinetic, pharmacodynamic and safety studies inchildren, rather than on full-blown efficacy studies. In addition,where appropriate, data from adult clinical trials can be extrapolatedto pediatric populations.

The new rules, which were first proposed in October 1992, will takeeffect Jan. 12, 1995. They will apply to the entire pediatric age group(birth to 16 years). If no substantial evidence exists to support adrug's pediatric use or its use in a particular pediatric population,labels will also have to include that information.

Current pediatric use regulations enacted in 1979 requiremanufacturers to conduct "two carefully controlled clinical studies"in children to win FDA approval for pediatric use. The requirementproved to be a major disincentive to drug makers, who rarelycompleted the additional pediatric clinical trials for various reasons,according to FDA spokesman Don McLearn. As a result,pediatricians were left guessing about how to alter dosages andregimens to treat children with drugs that were primarily studied inadults.

FDA commissioner David Kessler announced the new regulations(which were also published in the Federal Register) on Tuesday atthe annual conference of the Food and Drug Law Institute (FDLI)here.

"Children are not just miniature adults," said Kessler, who is apediatrician by training. "You can't simply calculate the pediatricdose based on the dose that is safe and effective in adults. We hopethis [new regulation] provides an incentive for manufacturers tosubmit pediatric information to us."

Part Of A Broader Effort

Kessler told FDLI conference attendees that the pediatric labelingrules are part of a broader FDA initiative to focus sponsors and theFDA on obtaining more pediatric data throughout the drugdevelopment process and in labeling. An informal 1990 surveyconducted by the American Academy of Pediatricians (AAP) foundthat 80 percent of the new molecular entities approved between 1984and 1989 had no information on pediatric use. In a speech at theannual AAP in 1992, Kessler called the situation "untenable."

Yet Kessler noted in the same speech that the FDA cannot forcecompanies to seek approval for indications, such as pediatric use,which they have not studied. Instead, the agency has opted to createincentives for manufacturers by easing the requirements.Pharmacokinetic and safety studies are less time-consuming and expensive than full-scale efficacy trials.

Under the new regulation, manufacturers must reexamine existinginformation to determine whether the pediatric labeling of theirmarketed products can be modified on the basis of adult studies andother available data. If so, they must submit an application forsupplemental pediatric use labeling within two years. The new rulealso gives the FDA authority to request pediatric use data for a drugthat is widely used, represents a safety hazard or is therapeuticallyimportant in the pediatric population. The rule does not limit howpractitioners may prescribe an approved drug, however.

The FDA will establish a special pediatric subcommittee to track theimplementation of the new regulation, as well as to draft policies andguidelines to promote pediatric testing of new drugs. In addition, theagency plans to work closely with the National Institutes of Health-funded Pediatric Pharmacology Research Units to conduct pediatricstudies on selected therapies.

For further information about the new pediatric use subsection of theprofessional labeling requirements for prescription drugs, contactErica L. Keys at the FDA's Center for Drug Evaluation and Researchat (301) 594-1046.

FDA Reports User Fee Act Performance

FDA Commissioner Kessler also told FDLI conference attendees onTuesday that his agency will eliminate its backlog of overdue drugand biologic submissions well before the deadline set by the 1992Prescription Drug User Fee Act (PDUFA). The act, which allows theFDA to collect fees from the pharmaceutical industry in order toexpedite the review of human drug applications, stipulates that theFDA must eliminate its user-fee defined application backlog by July2, 1995.

According to Kessler, a mere nine backlogged applications remainedat the FDA as of Nov. 30, 1994, down from 696 when PDUFA firstwent into effect on Oct. 1, 1992. "We are way ahead of schedule,"said Kessler. "We will meet this target, certainly, by July 2, 1995, ifnot sooner."

A central aim of PDUFA is accelerated review times for new drugapplications (NDA), biologic product license applications (PLA) andestablishment license applications (ELA). Specifically, the statuterequires that the FDA review and act upon 55 percent of completePLA, ELA and NDA submissions received during fiscal year 1994(fiscal year 1994) within 12 months of the submission date.

Although figures for fiscal year 1994 aren't yet complete, Kesslersaid that 1993 figures prove the agency is on track. In the 13 monthsdefined as by PDUFA as the fiscal year 1993, the FDA received 96complete NDA, PLA and ELA submissions (a 20 percent growth rateover previous years' submissions). Of those, 61 (63 percent) werereviewed within 12 months of submission _ that's higher than thegoals set out for 1994. Kessler noted that during the pre-PDUFAyears of 1990-91, only 42 percent of applications were reviewedwithin 12 months.

Although PDUFA doesn't prescribe approval targets or timelines, theexpectation of legislators and regulators has been that acceleratedreviews will ultimately translate into shortened approval times.Kessler claimed on Tuesday that the assumption is holding true. Infiscal year 1993, 20 NDAs and PLAs were approved within 14months of submission, as compared to 12 14-month approvals in1990-91.

The rate of affirmative outcomes _ either approved or approvable_ for NDA, PLA and ELA submissions more than doubled (to 35percent from 15 percent) between fiscal year 1993 and the pre-PDUFA reference years 1990-91. Likewise, affirmative outcomerates for efficacy and manufacturing supplements have risen. FDAreview of resubmissions is also moving closer to the PDUFA-setgoal of six months _ of 31 NDA, PLA and ELA resubmissionsreceived in fiscal year 1994, the FDA has reviewed 17 of themwithin six months. Of the 14 remaining, 13 are still within the 6-month review period and one required more than six months foraction.

Three Factors Contributed To Review Process

In a Dec. 1 report to Congress, the FDA listed "three measurablefactors that reflect greater sponsor attention to submissions" and thathave contributed significantly to the FDA's improving reviewperformance:

* Sponsors are filing fewer incomplete submissions, leading to adecrease in the number of "refuse-to-file" rulings by FDA;

* Sponsors are submitting a higher percentage of unamendedapplications. In fiscal year 1994, 77 percent of NDAs proceededthrough the first nine months of review or reached the point of FDAaction without a major amendment while 59 percent registered nominor amendments in the same period; and,

* Sponsors are resubmitting applications faster, especially for thoseapplications deemed approvable by FDA. The median resubmissiontime for approvable NDAs, PLAs and ELAs was less than threemonths in fiscal year 1993. n

-- Lisa Piercey Washington Editor

(c) 1997 American Health Consultants. All rights reserved.