To the Editor:

In the February Opinion “Pediatric requirements in Europe stymie help for hemophilia,” Peyvandi et al.1 challenged the European requirements for the development of recombinant and human plasma–derived factor VIII (FVIII) and factor IX (FIX) products in children. In their view, the sequential clinical trial process for FVIII and FIX products as defined in the scientific guidelines2,3 of the European Medicines Agency (EMA) will delay the availability of new products for adults in the European Union. Similar considerations by one of the authors4 have already been addressed elsewhere5.

Hemophilia is a disease that in the past typically affected only children, as the vast majority of affected individuals never reached adult age; it became a greater concern in adults only after the development of effective and safe treatments6. Considering this, the EU guideline requests that sufficient pediatric data be available when a new medicinal product for hemophilia is submitted for marketing authorization. This approach ensures that in cases of a significant pediatric medical need, the target pediatric population is not deprived of high-quality, safe and effective medicinal products.

The authors pointed out an urgent need for long-acting coagulation factors, which would reduce the frequency of intravenous administrations and may be less immunogenic than other treatments. Although less frequent administrations certainly would benefit patients, many safe and effective FVIII and FIX products are already authorized in the European Union for adult and pediatric patients with hemophilia. Newer products with a longer half-life are potentially more interesting for prophylactic use rather than on-demand use and are consequently more relevant for pediatric use because prophylactic administration is more common in children.

The EU requirement to include in the pediatric studies a minimum number of doses does increase the duration of studies for long-acting products, which are administered less often. However, this requirement is needed to evaluate the potential for immunogenicity, which is a major risk factor in the treatment of hemophilia A, more so in children than adults.

Consequently, timely access in adults has to be balanced with the need to assess the safety of a product before it is used in children. The EMA has demonstrated flexibility in its approach to balance these competing requirements in the guidelines, for example, by requesting inclusion of only a limited number of pediatric patients in the studies and particularly by specifying that more than half of the required doses in pediatric studies can be administered after marketing authorization has been requested in adults. Such an approach aims to prevent unnecessary delays in authorization.

Commencing the requested pediatric trials as early as possible in the overall medicinal product development process is therefore the key to avoiding or reducing the delay of marketing authorization.

The use of new medicinal products in children should rely on sufficient evidence for pharmacokinetics, safety and efficacy in all age groups. Experience has shown that pharmaceutical companies encounter considerable difficulties when trying to enroll children and complete pediatric studies once a medicinal product is available on the market for adults because of widespread off-label use in children.

We strongly believe that with appropriate planning, including early interaction with regulators, it is possible to reconcile timely product access for adults with sufficient information to support the treatment's use in children.