Dual draft guidances outline FDA vision for pediatric drug development, exclusivity

In a move that could ruffle the feathers of pharmaceutical companies, the US Food and Drug Administration (FDA) says it aims to be more selective when awarding six-month exclusivity extensions for the written request (WR) studies that are required under the Pediatric Research Equity Act (PREA).

The 43-page draft guidance – Pediatric Drug Development: Regulatory Considerations—Complying with the Pediatric Research Equity Act and Qualifying for Pediatric Exclusivity Under the Best Pharmaceuticals for Children Act – is one of two draft guidances released by the FDA on 17 May. A second 19-page draft document offers the agency’s current thinking on scientific considerations for drugs meant for children.

The FDA says the draft guidance on exclusivity aims to help companies comply with PREA study requirements and describes the process for gaining pediatric exclusivity. It also includes information on adverse event reporting, pediatric study plans, deferral extensions and more.

PREA, enacted in 2003 and reauthorized and expanded in 2007, calls for studies for specific pharmaceuticals and biologics to determine appropriate drug labeling for people under 18 years of age. As an incentive for running these studies, makers of novel drugs have historically been given an additional six months of exclusivity before generic versions can be sold. That exclusivity was established by the Best Pharmaceuticals for Children Act (BPCA), enacted in 2002 and, like PREA, reauthorized in 2007. PREA and BPCA were made permanent as part of FDASIA, 2012’s Food and Drug Administration Safety and Innovation Act.

The new draft guidance notes that the agency has collected a large amount of data on pediatric labeling changes over the years and has concluded that such data would have made its way to the FDA, notwithstanding the exclusivity incentive.

“PREA requirements have resulted in an increase in pediatric labeling, even without the added incentive of the BPCA,” according to the draft guidance. “In light of the data on pediatric labeling changes pursuant to the BPCA and/or PREA, FDA believes WRs should be reserved for those sponsors who conduct additional pediatric studies – beyond what is required under PREA – that may produce health benefits in children.”

The draft guidance concludes, “Thus, upon finalization of this guidance, FDA does not expect to issue WRs solely for studies or planned studies that are required under PREA.”

The bottom line is that “if a company is only doing what’s already required, then the FDA doesn’t need to give that company an incentive. And that facilitates earlier entry of generic or certain piggyback competition,” Chris Markus, partner at the law firm King & Spalding, said in an interview. “This is something that companies should consider when thinking through their regulatory strategy. In the world of pharma, exclusivities are very important incentives.”

Markus stressed, however, that the draft guidance is not putting the kibosh on all WR studies. “The FDA says the written request can be provided for sponsors to conduct additional studies beyond what’s required, so they’re not saying that they’re never going to offer that incentive. They’re just saying they’re not going to do it in all cases,” she said.

Congress tucked the six-month exclusivity into the BPCA because, at the time, companies weren’t conducting enough pediatric research.

Drug manufacturers “were reluctant to perform research on children for a variety of reasons, and the problem that created was that doctors didn’t have appropriate information,” Markus said. “For example, some drugs would work for the same cancer that adults would have, but a child might need less of that drug, or sometimes need more because they would metabolize it faster.”

Exclusivity was the tool devised by Congress for gaining that additional data. “Congress said, ‘We’re going to create this incentive where, if FDA issues a written request for certain studies involving children and you fairly comply with the request within certain time frames, then you can have an extension of your patent protection and other exclusivities that exist that delay certain competitors from entering the marketplace for six additional months,’” Markus said.

The exclusivity line that the FDA has drawn in its new draft guidance could mean that some pharmaceutical companies stand to lose a boatload of money, says Robert Pollock, president and chief scientific officer for Melbourne Laboratories LLC, and a senior advisor for Lachman Consultant Services.

“Those six months of exclusivity are very important to companies, especially if they have a blockbuster drug,” he told Focus. “Just imagine that you have a drug that is making $2 billion a year in profits – if you get six more months of protection, that’s another $1 billion in your pocket.”

Despite the exclusivity issue, Markus said the draft guidance would be helpful for industry. The document “refreshes the standards and the interaction of several different regulatory rubrics that govern the study of drugs and children,” she said. “And they’ve evolved – there have been different requirements enacted or put into place via regulation over the last 20 to 25 years. The draft pulls together in one place a current perspective on how [the regulations] interrelate and what FDA’s current thoughts are on how they interrelate. It’s beneficial for everybody.”

Pollock agreed. “It’s a compilation of what the FDA has learned from [PREA and BPCA] and outlines the agency’s current thinking,” he said. “It identifies some new situations that might not have come up before and how the FDA has dealt with them. FDA’s just putting out there the ground plan it has developed over the course of time since these pieces of legislation were originally approved.”

A second FDA draft guidance

Meanwhile, the second draft guidance released by the FDA on 17 May – Pediatric Drug Development Under the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act: Scientific Considerations – “addresses selected clinical, scientific, and ethical issues regarding the development of drugs for pediatric use when such drugs are subject to” PREA and/or BPCA, according to the document.

This draft guidance “talks about formulation development and what companies should consider when doing that activity for the pediatric population,” Pollock said. “It expresses what kind of nonclinical information you’re going to have for pediatric patients. It talks about extrapolation for pediatric patients if there’s literature out there that can be extrapolated.”

He pointed out that physicians routinely review the literature on specific older, approved drugs to determine if they’ve been used in pediatric patients.

“If a drug is metabolized the same way in adults and children, a physician can pretty much predict what’s going to happen,” Pollock said.

New draft guidances replace 2005 draft document

The FDA says these new draft guidances “revise and replace” a 2005 draft guidance, How to Comply with the Pediatric Research Equity Act. The agency notes, however, that the new draft documents do not replace “any other pediatric guidance already published.”

“The substantial lag between approval of a drug for adult use and the approval in children,” Lynne Yao, director of the Division of Pediatrics and Maternal Health, said in a statement. She added that the drafts will help industry comply with PREA and BPCA and “help increase the availability and timeliness of safe and effective medicines and vaccines for children in the US.”

FDA is accepting comments on both draft guidance until 17 July at www.regulations.gov. The docket ID is FDA-2005-D-0460.

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