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Posted 11 May 2022 | By Denise Fulton 

Changes to pediatric, orphan drug regulations on European horizon

2831 AMSTERDAM - As regulators craft revisions to the European regulations governing pediatric and orphan drug development, the time is now for stakeholders to gather their thoughts and prepare their comments aimed at improving the impending draft documents.
That was the message that Karl-Heinz Huemer of the scientific office at the Austrian Medicines Agency (AGES) brought to delegates at RAPS Euro Convergence.
The European Paediatric Regulation 1901/2006 and amendments, as well as the Orphan Regulation 141/2000 and amendments, are both under review, with an aim to release revised drafts for public comment by approximately the end of 2022, Huemer told delegates. He highlighted several areas in the current regulations that could be revisited and clarified.
Huemer strongly noted that the views and ideas he presented were his own and not those of the European Medicines Agency (EMA), European Union (EU), Austrian Medicines Agency (AGES), or any organization with which he is affiliated.
One area worthy of reconsideration, according to Huemer, is the timing of submissions under each regulation. For example, the Paediatric Investigative Plan (PIP) must be submitted when the first human data are available – typically pharmacokinetic data in adults – at the end of Phase 1 development. The PIP then must be amended throughout Phase 2 and Phase 3.
If it were possible to file the PIP later, perhaps toward the end of Phase 2, there would be less need to revise and amend the PIP over time, Huemer noted, reducing the regulatory burden on the sponsor.
“If you see the PIP procedure, the outcome of the procedure is an opinion with key elements agreed on [by the regulator and the sponsor] at the end of Phase 1,” Heumer said. At that point, proof of concept has not been achieved, not even in adults, and the effect size is not yet known. “How can we seriously discuss Phase 3 in detail and agree on that at the end of Phase 1?”
Here, the EC seems willing to make some modifications, according to Huemer. One possibility is an evolutionary PIP that would allow the sponsor to amend the document as more evidence is gathered. “Hopefully, we will find a way that coming back [to the file] is an option, so that companies do not have to provide a [fully formed] program at the end of Phase 1 that limits the work,” he said, adding that “as far as I know, the discussion in the Commission is that this most likely will be addressed for the better.”
When it comes to seeking Orphan Drug Designation (ODD), the timing of submission is quite flexible, generally occurring at the beginning of Phase 1 or Phase 2 and allowing the sponsor to take advantage of reduced or even removed fees for scientific advisory submission.
Huemer noted that the bigger problem comes once ODD is confirmed. The current regulation allows no flexibility – ODD must occur at the time of marketing authorization.
For all these products, data on long-term benefit, long-term safety, and maintenance of effect may not be available at the initial marketing authorization, Huemer noted. “Finding options that, for example, would allow a company to redefine [an ODD application] based on what the status wants to show and not necessarily linked to initial marketing authorization would be a very good idea,” he said.
Drugs authorized under the Pediatric Regulation as well as the ODD must demonstrate that they provide a significant therapeutic benefit or meet an unmet need. Sponsors seeking ODD must demonstrate significant therapeutic benefit over standard of care and run a comparator trial. This can be very challenging because so few patients are impacted by a rare disease.
Is there a better way to obtain these data, Huemer asked. Could data extrapolation work, or perhaps modeling and simulation? And could there be a role for real-world evidence? All of these are areas that could be explored in comments on the impending draft regulations.
“So, in conclusion, there is some need for revision,” to both the Paediatric Regulation and the Orphan Regulation, Huemer said. “The European system still is one that has public consultation steps. And I really would suggest that you use this device when the draft regulations come out,” he said. “Try to make proposals as a company, as a person, as a physician, as a citizen of the European Union… all this is open, and this is really a chance that should be taken advantage of.”


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