FDA does not expect to issue written requests for studies of off-patent drugs at the same rate it has for patented drugs seeking pediatric exclusivity, Office of Counterterrorism & Pediatric Drug Development Director Dianne Murphy, MD, said.

"Please do not take the number of written requests that we have issued already as the rate at which we can do this in the future," Murphy told a Pediatric Advisory Subcommittee of the Anti-Infective Drugs Advisory Committee June 11.

"If we got one a month out we would be doing well...and I don't think that is going to happen," Murphy added.

FDA is working on issuing written requests for a portion of the 19 off-patent drugs on its "Preliminary Priority List" mandated by the Best Pharmaceuticals for Children Act passed in January.

"Some of them we will not be issuing written requests for because again, just because you're on the list, doesn't mean you're going to be able to" do the study "for all sorts of reasons that have been brought up around the table today....But we are going to try," Murphy said.

The list includes acyclovir, auralgan, lorazepam, ampicillin, diazoxide, digoxin, dobutamine, dopamine, nitroprusside, cimetidine, metoclopramide, amphetamine/dextroamphetamine, valproate, promethazine, bupropion, metaproterenol, terbutaline, metronidazole and azithromycin.

FDA has looked at the drugs by therapeutic category and collected use data to see how frequently drugs are being prescribed to children either on an inpatient basis (Children's Hospital Corporation of America data from 25 hospitals), or an outpatient basis (IMS data).

Of the five drugs in the cardio-renal category, dopamine had the most inpatient prescriptions in 2001 with about 10,000, followed by digoxin (4,700), dobutamine (3,800), nitroprusside (3,000) and diazoxide (117). "Right now, we are looking at a product out of this cluster to begin development of a written request," Murphy noted.

In the neuropharm category, lorazepam had the most inpatient prescriptions with 17,500. Amphetamine had only 401 inpatient scripts, but 3 mil. outpatient scripts. Promethazine was prescribed 940 times in hospitals and 360,000-1.3 mil. times in the outpatient setting. No data was presented for valproate and bupropion.

Murphy noted that for one of the neuropharm products "we really cannot issue a written request because there is actually part of the molecular entity that may still be under patent." GlaxoSmithKline has a patent for bupropion sustained release ( Wellbutrin SR/Zyban) that is still in litigation (¹ Also see "Wellbutrin SR Patent Case Will Be Early Application Of Festo Ruling" - Pink Sheet, 3 June, 2002., p. 12).

"We are now actively looking at a second product on this list to issue a written request for studies." Amphetamine/dextroamphetamine needs to be studied in children two to 16 years of age for attention deficit/hyperactivity disorder, FDA said.

Metaproterenol with 34 inpatient prescriptions and terbutaline with 968 inpatient prescriptions make up the pulmonary list.

Azithromycin tops the antimicrobial list with 5.2 mil. outpatient scripts (400 inpatient). Data needed on the drug include use under six years and prevention of mycobacterium avium infections. Inpatient scripts for ampicillin numbered 16,700 in 2001, followed by 5,600 for metronidazole, and 2,700 for acyclovir.

"We have already looked at one product on [the antimicrobial list] that we will not be issuing a written request, or sometimes when you dig into these more deeply, you find that there are actually other paths that you may want to develop or seek another way," Murphy said.

She noted that for I.V. ampicillin, "you are not going to do a placebo-controlled trial....So what is missing, then, may be just a little bit of pharmacokinetic/ pharmacodynamic data....With just a little bit of pharmacologic information...and that would come off that list."

Of the two gastrointestinal drugs on the list, metoclopramide had 16,000 inpatient prescriptions, while cimetidine had 660 (no outpatient scripts were listed). Data is needed for metoclopramide in patients up to 16 years in chemotherapy nausea and vomiting, post-operative use, and gastroesophageal reflux disease, FDA said.

Additional drug candidates and prioritization of the list have been suggested by a National Institute of Child Health & Human Development panel that met in April. The panel includes members and consultants to the FDA pediatric subcommittee.

The NICHD panel recommended for highest priority action: dopamine, lorazepam, dobutamine, acyclovir, cimetidine and morphine, which is not yet on the FDA list. A second-tier cluster cited by the panel included nitroprusside, valproate, nonionic contrast media and amphotericin B; the last two are not on FDA's list.

FDA faces a Jan. 4, 2003 deadline to produce the priority list, and $7 million has been appropriated for the process. Under the Act, $200 mil. is authorized for FY 2002 but has not yet been appropriated.

No funding for the program has yet been budgeted for FY 2003. "We don't have identified money in any budget for next year to pay for additional funding of meritorious applications coming in response to RFPs," Murphy explained.

Under the Act, FDA must issue written requests for the study of off-patent drugs to approved drug holders, who then have 60 days to agree or decline to conduct the studies. If the sponsor declines, the National Institutes of Health in consultation with FDA is to issue a request for proposal for pediatric studies.

GlaxoSmithKline has already declined a request to conduct studies for cimetidine and a written request has been issued to GSK for bupropion.

"I don't know what it's going to be for 2003 or who's going to weigh in on that issue. We're proceeding because we want to be ready to seize the opportunity if it's there," NICHD Center For Research For Mothers & Children Director Anne Willoughby, MD, said.

"Are we worried? Absolutely, but it's something we've done before with other diseases and other mandates and other concerns," Willoughby remarked.

Given the small budget appropriated and the expense of conducting trials, committee members expressed concern that studies may not be adequately funded.

Noting that committee industry representative Steven Spielberg, MD, Johnson & Johnson, "gave us a [figure] several years ago that it takes between $3 and $5 mil. to study a completely unstudied drug in pediatrics," committee consultant Richard Gorman, MD, Pediatric Partners, pointed out that, with $7 mil. appropriated, "after two months we'll be done."

"I will tell you without breaking confidentiality you can add a '0' behind some of the programs we're now involved in, and more, for a full pediatric development program," Spielberg responded.

FDA "has a daunting task ahead, to get each one of these done right, to ask for the information that is needed, to not ask for too much, and also certainly not to ask for too little, because at the end of the day we want to be able to write good labels for these drugs," Spielberg declared.

On the other hand, there may be certain drugs which "for relatively little investment you might get really major return," such as in the case of dopamine, he noted, "because there is already a lot of data there."

Costs could be kept down by using established clinical networks such as those funded by NIH, NICHD's Willoughby offered. "I think one of the things that is going to be important to do is with each of those networks is to make sure that pediatric drugs are on the radar screen and to see what advantage we can take of money already set aside."

Another potential financial stumbling block is the development of pediatric formulations, Spielberg noted. "I think it's a real quandary, and unless you can find somebody who's willing to take it on and do all the things necessary under [good manufacturing practices] to produce a marketable formulation and distribute that formulation...you've got a problem."

"We're not quite clear how we're going to implement [the formulation issue] at this point," Murphy said. "We're going to have to look at...the possibility of doing other approaches, carving out parts of it."

The committee also discussed selection criteria for adding drugs to the off-patent list. "What I hear people saying is that impact is the most important issue and to include in that volume of use, volume of disease, disease severity, the options and alternatives," adverse effects and symptoms, Committee Chair Joan Chesney, MD, University of Tennessee, said.

"Negatives, from our perspective, at this point would be 'me-toos,'" Murphy added. Also, "a narrow therapeutic index when alternatives are available might be considered a negative reason, or reason not to issue a written request."

Pediatric Off-Patent Study Requests Will Not Mirror Rate For Exclusivity

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