Pediatric Wish List: Longer Exclusivity Reviews, More Public Data

Future legislation should mandate increased public availability of pediatric trial data, Office of Pediatric Therapeutics Director Dianne Murphy said at a June 13 Institute of Medicine drug forum in Washington, D.C.

Murphy stressed the need for greater transparency of data from studies submitted in support of pediatric exclusivity.

"This data needs to be available," Murphy said, maintaining that it is "morally wrong that we have these studies conducted and the data is not available."

Murphy's comments, offered during a panel discussion entitled, "Addressing the Barriers to Development in Pediatrics," represented her personal opinion as a pediatrician rather than her role as an FDA official, she stressed.

Pediatric trial requirements and exclusivity are regulated under the Best Pharmaceuticals for Children Act (2002) and the Pediatric Research Equity Act (2003) (¹ (Also see "Barr Expects Metformin Launch By Early February; Pediatric Bill Signed" - Pink Sheet, 14 Jan, 2002.), p. 5 and ² (Also see "FDA Pediatric Study Bill Clears Senate, Will Sunset With Exclusivity Grants" - Pink Sheet, 28 Jul, 2003.), p. 4). Both are scheduled to sunset on Oct.1, 2007.

The Government Accountability Office is in the process of drafting a report, mandated by BPCA, on the effectiveness of the law, including any recommendations for changes. The report is due by the end of September.

Current BPCA Transparency Rules Opaque

BPCA only requires that FDA make publicly available a "summary of the medical and clinical pharmacology reviews of pediatric studies conducted for the supplement."

"There's a real quandary, though, in how much information" can or should be provided, Murphy observed.

"A medical review after it is redacted for trade secrets" would be more useful than the current summary system, she said. "The next step would be all the data," which presents issues of practicality and available storage capacity. "Where would you put all that?"

Furthermore, labeling should provide information about any pediatric trials "irrespective of the approval status and irrespective of the process," Murphy said. Under BPCA, "that information is locked inside the FDA."

Other panelists identified FDA's written requests for pediatric studies as another element of the process that should be made freely available under future law.

"Written requests should be public," Robert Nelson, University of Pennsylvania, said. "Knowing what the FDA asks people to do is very helpful to evaluate what they have in fact done, in the interest of transparency."

FDA Division of Pediatric Drug Development Acting Director Lisa Mathis said she and Murphy concurred.

Murphy also identified the timing of exclusivity incentives as a primary area for improvement in the legal framework governing pediatric studies.

Looking To Europe For Guidance

Recently passed legislation in the European Union may provide a model for the handling of several exclusivity issues, she noted.

The EU has "some very interesting approaches," Murphy said. "If I could wave my magic wand, I'd adopt some of the things they are doing."

The European Parliament passed legislation June 1 designed to facilitate the development of pediatric medicines.

Among the provisions in the EU regulation, sponsors will be required to submit applications for pediatric extensions no later than six months before the expiration of relevant protections.

By comparison, the deadline for FDA to make pediatric exclusivity determinations is three months.

"Right now we have 90 days; all pediatric submissions are a priority review," Murphy said. "Six months is tight...to get to a decision. Now, on top of that, you have half that amount of time, and you are supposed to make an assessment whether the commission has 'fairly responded' to our written process."

"We have now crossed over from medicine into law. 'Fairly responded' means that they have simply submitted what we asked them to submit."

"So, did they do two randomized controlled trials?" she asked as an example. "Well, yeah, but how well controlled? We can't tell you that in the 60 to 90 days that we have."

In the event a generic equivalent is being delayed market entry by the process, "we would try to do the review in a shorter period of time," she added.

As a result of the time crunch, the evaluation lacks "the in-depth assessment of what actually happens during the trial," Murphy said.

One potential result is that the agency will grant exclusivity based on data later deemed to be weak.

"When we get into some of these trials, after we made that exclusivity determination - and fortunately this is not common, but it's unfortunate when it happens - we have found that we probably would have not thought that this trial was conducted with good scientific principles," Murphy explained. "We need that full period of time."

The law should be changed to require that the exclusivity determination be made at the time of the action on the application, she said.

The tight review time in BCPA represents lawmakers' desire not to grant "a long period of de facto exclusivity," Murphy maintained.

EU Adopts Six-Month Exclusivity Incentive

Under the new EU reg, which will be enacted Jan. 1, 2007, companies that develop safe and effective pediatric drugs will receive a six-month patent extension under the regulation - on par with the current incentive in the U.S.

The European system will likely benefit from combining "the incentive and the requirement into one process," Murphy said. In the U.S., "we have two separate legislative processes" under PREA and BPCA. "They are handled very differently, both legislatively and within the agency."

The EU legislation should yield a "much more cohesive approach for pediatric drug development," Murphy commented.

The EU pediatric medicines reg establishes an expert group that works on the development of all pediatric studies.

"Right now, under BCPA we have the pediatric implementation team," Murphy noted. Drug divisions within the agency are urged to bring all written requests to the team for continuity.

Pediatrics Surveillance Plan Is Key

Murphy emphasized the importance of post-marketing surveillance to the pediatric drug development field in particular.

"We need to continue to have an additional emphasis on pediatric safety after there has been this attention on the exclusivity and the studies," she said.

In particular, ongoing studies can illuminate a drug's affect within specific sub-populations, she noted.

"The public needs to understand that drugs are studied in a very limited population, in a very defined way, and we really find out a lot about our safety information after a product is marketed."

With pediatric drugs in a pre-market context, "you are dealing with rather short-term trials, you are dealing with a very select population," Murphy explained.

"You are not going to know what's going to happen to children [going] through all these developmental stages until it's out there in the market."

"Post-marketing safety surveillance, active surveillance, which we wish we had, is really a critical phenomena, and something you'll hear people say we need more of, and I think particularly in pediatrics," she asserted.

Ethicist On Board

Looking forward, Murphy highlighted additional items on her wish-list for a successful pediatric drug development program: continued development of endpoints; real time inspection of pediatric trials; focused pediatric safety reviews; and continued development of best practices for juvenile animal models.

Strong ethics programs are "critical" as well, she said. When BPCA was passed, lawmakers insisted FDA have an "ethicist on board," Murphy said. "It's been a really important component to our program; it's added a lot to the way that we've been moving forward."