Regulatory Focus™ > News Articles > PREA Non-Compliance Letters Call out Companies for Failure to Submit Required Pediatric Studies

PREA Non-Compliance Letters Call out Companies for Failure to Submit Required Pediatric Studies

Posted 11 September 2013 | By Alexander Gaffney, RAC

The US Food and Drug Administration (FDA) has released three additional non-compliance letters to two major pharmaceutical companies, chiding them for having not met their pediatric study commitments under federal law.


Historically, many companies seeking product approval in the US avoided clinical studies involving children, wary of the ethical problems, the lack of incentives, and the potential consequences if the testing brought up new adverse problems. As a result, many products lacked adequate dosing or safety information for children.

This, as regulators will tell you, is a problem. "We all know that children are not just small adults," wrote Lynne Yao, associate director of Pediatric and Maternal Health Staff in FDA's Center for Drug Evaluation and Research's (CDER) Office of New Drugs (OND). Some drugs may be super-potent in children relative to adults, while others may not work at all. In either case, there are inherent safety risks.

To remedy this situation, the US Congress passed into law two critical pieces of legislation: The Best Pharmaceutical for Children Act (BPCA) and the Pediatric Research Equity Act (PREA), which combined had the effect of providing new exclusivity-based incentives to conduct studies (additional six months for pediatric written requests by FDA), as well as the ability for FDA to require companies to conduct pediatric studies as a condition of approval.

The effects of this legislation, Yao continued, have been substantial. "Before BPCA and PREA became law, more than 80% of the drugs approved for adult use were being used in children, even though the safety and effectiveness had not been established in children. Today that number has been reduced to about 50%."

Initial Letters: Many Delays, Many Reasons Why

But despite the law's requirement that some drug manufacturers must conduct studies as a condition of marketing approval, some companies have failed to do so. In August 2013, FDA announced that rather than simply pressure these companies privately, it would begin posting its letters to the offending companies on a public webpage along with the companies' responses to FDA.

The initial batch of letters included five to three manufacturers: Genzyme (3), Amedra Pharmaceuticals (1) and The Medicines Company (1).

The response letters indicated a range of reasons for delays.

Genzyme, for example, lists a long history of trying to get its studies off the ground, and notes that it has 40 patients enrolled awaiting the initiation of a trial for two drugs, and has been waiting since December 2010 to hear back from FDA on another proposed study.

Amedra, by contrast, had acquired the drug in question from another company, and said it is of the opinion that it needs a waiver due to unspecified reasons (contained in the letter but redacted, presumably to protect trade secrets). The Medicines Company, however, said safety issues and drug shortages had delayed its attempts to fulfill its pediatric study requirements, and is now seeking a deferral from FDA.

New Letters: Same Old Story

Now FDA has posted an additional three letters to two manufacturers: Pfizer (2) and Sunovion Pharmaceuticals.

The letter to Sunovion references the company's Xoponex (levabuterol HCl) Inhalation Solution, approved to treat asthma, chronic bronchitis and other lung conditions. FDA said that while the company had applied for a deferral extension for its PREA-required study, the agency decided it "does not qualify for an extension."

Sunovion's response indicates that it is in the midst of conducting testing, which will conclude in March 2014. The date by which FDA had originally expected to receive the study was 31 July 2003, making the study more than a decade behind schedule. A reason was not given for the delays.

The letters to Pfizer, meanwhile, reference the company's Protonix IV (pantoprazole sodium) for Injection, a proton pump inhibitor. Pfizer's studies are long overdue, having originally been due by 1 April 2004. A request by Pfizer to further defer the studies was denied by FDA, which found the company did "not qualify for an extension."

A second letter to the company again cited Pfizer for non-compliance, this time for failing to complete a study for a supplemental indication for Protonix required to be completed by 19 July 2009.

As opposed to Sunovion, Pfizer's response letters to FDA go into far more detail about its efforts thus far. In response to the first letter, Pfizer explains it has already submitted three study reports (in 2004, 2005 and 2008) to FDA on the pharmacokinetics, efficacy and safety of the drug of pediatric patients with gastroesophageal reflux disease.

FDA found this data to be insufficient in August 2011, Pfizer recounted, and a year later the company asked FDA to clarify what studies would be required, which FDA did in May 2013. The second letter recounts nearly identical information, perhaps indicating that the studies submitted by Pfizer were intended to address multiple indications.

Delays and Other Details

Pfizer's letters do indicate one rather disturbing point: There is a massive delay in response times by both FDA and the companies themselves with respect to pediatric studies. FDA took several years to analyze and respond to Pfizer's data submission, while the company took almost a year to respond to FDA's letter indicating deficiencies in the data submitted for Protonix.

As in the case of Amedra, part of this delay could be caused by Pfizer's 2009 purchase of Wyeth, the original NDA holder of Protonix. However, Pfizer's response letters make no attempt to rationalize the delays except to say that it is "fully committed" to meeting its obligations under PREA and plans to submit draft study protocols within 15 days.

FDA Non-Compliance Letters

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