Daniel S. Levine

Ten years ago, regulators in Europe set out to address a problem. Drug companies often weren’t pursuing pediatric indications for the drugs they developed. Instead, young patients in need of treatment, often had to rely on doctors prescribing medicines never tested in pediatric patients and used outside of their approved use.

That can be a problem as developmental issues can be important considerations when treating pediatric patients and these issues can vary depending on the stage of development of a patient ranging from newborns to teenage patients. The variations in this population can also make developing medicines for this population complex.

The reasons why drug developers didn’t do more to conduct clinical trials in pediatric population is a matter of both ethics and economics. Until the 1980s, many people considered it unethical to subject children to clinical research. That view has changed overtime as there has been a gradual movement toward the belief that children, like others, deserve to have drugs prescribed to them on the basis of scientific evidence.

The economic considerations, though, have been more problematic. Companies make decisions about what drugs to pursue based in part on market opportunities. The good news is that the Europe has met with some success in addressing the issue.

Regulations instituted in Europe ten years ago to address the lack of drugs developed and researched for use in pediatric patients have produced encouraging results and suggest they will reduce the off-label use of adult medications in pediatric populations, according to a new European Commission report. But the benefits are concentrated in certain therapeutic areas suggesting that research priorities in adult, rather than children, drive development decisions and suggest more work may be needed to address gaps in drug development. 

The report follows a 2013 report aimed at evaluating the impact of the so-called “Paediatric Regulations” to determine whether revisions are necessary. Both reports were mandated by the regulations.

The regulations require companies at an early-stage of development to agree to a pediatric research and development program with the European Medicines Agency. Failure to comply with the agreement could put a marketing approval at risk, providing a stick to go along with carrots providing a six-month extension of market exclusivity, as well as benefits provided by other measures, such as orphan drug designation. There are waivers for medicines that are unlikely to benefit children.

The current report notes that ten years is a short-period to measure the impact of regulation on drug development, but it did find signs of encouragement. From 2007 to 2016, more than 260 new medicines for use by children (new marketing authorizations and new indications) were approved, more linked to the regulation’s requirements, the report said. The number of agreed pediatric investigation plans grew to more than 1,000 in 2017, of which 131 were completed at the end of 2016. The report called this a “clear upward trend.”

“The last 10 years have seen some considerable progress in the availability of medicines for children in certain therapeutic fields because of the Regulation. Rheumatology or infectious diseases are often referred to as prime examples,” the report said. “The significant surge of new treatments for children with rheumatologic diseases following the completion of [pediatric investigation plans] has transformed a sector, which was previously neglected.”

But the report also found that the positive developments do not follow a strategic plan, but instead are often linked to development in adult markets. The reality is that most pediatric investigation plans] grow out of research and development programs for adults. Progress in the pediatric field, the report said, is “dependent on companies’ adult product pipeline and influenced by revenue prospects in a specific market segment.”

“Where the adult needs or market expectations overlap with pediatric needs, children will benefit directly,” the report said. “However, there are a considerable number of diseases that are biologically different in adults and children, where the disease burden differs, or that only exist in children. It is in those diseases, where the mechanism introduced by the Regulation sometimes struggles with scientific, clinical and market realities.”

The bad news is that the area where the regulations have failed to bring strong benefit is in diseases that are unique to pediatric populations where strategic decisions to invest occur independently of ongoing adult programs. “This is particularly true for rare diseases in children, such as pediatric cancer,” the report said.

The report says that in diseases unique to children that are supported by orphan drug regulation, those benefits failed to drive development in the same way that orphan drug regulation did so for adult populations. The commission plans to take a closer look at that question through a join evaluation of the combined effects of the orphan drug and pediatric regulations before considering changes.

The European rare disease patient alliance Eurodis, in comments submitted in response to the report said that companies overlook and underutilize these regulations and, argued that there is a need to better educate industry about them. “Considering that more than half of rare diseases affect children,” the group said, “deep understanding of both regulations will tremendously help medicine developers to optimize their pediatric investigation plans and make the most of the incentives and rewards.”

November 1, 2017

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