Peyvandi et al. reply:

We were pleased that our opinion piece1 triggered the interests of the Pediatric Center of Excellence at Quintiles2 and the European Medicines Agency (EMA)3. Our writing did refer to the manner in which clinical studies are planned, but we have not suggested that these studies are unnecessary in pediatric patients. Our main point was that if studies in children are a prerequisite before coagulation factor concentrates become available in adults, then adults will face an undue delay in access to new drugs, particularly because pediatric studies take a long time owing to the small number of children with inherited coagulation disorders.

It is true that 50 years ago patients with hemophilia seldom reached adulthood. However, these patients currently enjoy a normal life expectancy. As a result, managing hemophilia in the aging adult in the presence of considerable co-morbidities (e.g., heart disease or cancer) has become a major challenge4. So it is important that these adult patients have access to new drugs with no undue delay.

Mentzer et al.3 state that coagulation factors with a long half-life are potentially more interesting for prophylactic use than on-demand use and thus more relevant for pediatric use than adult use. However, most adults in the European Union with hemophilia are now treated prophylactically (as many as 60% of adults with severe hemophilia are). The prophylactic regimen entails at least three intravenous administrations each week5 that are usually self-administered despite arthropathy in the shoulders, elbows and hands. Many of these individuals have damaged veins due to a lifetime of needle sticks and concomitant vein scarring, which subsequently results in considerable difficulties for successful self-infusions.

Mentzer et al.3 correctly point out that the risk of immunogenicity, the main current complication of hemophilia treatment, is more relevant in children than adults. To evaluate the immunogenicity of new products, the most suitable cases would be previously untreated patients (PUPs). However, PUPs are very few in number, making their recruitment an obstacle in conducting such clinical studies6. Accordingly, the EMA currently requires clinical trials in at least 50 and 20 previously treated children (PTPs) aged <12 years for factors VIII and IX, respectively, for 50 exposure days (i.e., a day on which treatment is administered). With long-acting factors, administrations take place less frequently, so it will also take more time to complete the studies. All these aspects add to the delay before new factor products become available in adults, a snag that can be overcome by relaxing the requirement for pediatric trials and allowing clotting factor concentrates to be used in adults after studies in adults are completed.

We agree with Huff2 that adequate planning, including early interactions with regulatory agencies, would make it possible to provide timely access in adults; this could help provide sufficient information to support use in children. However, this approach will not overcome the delays we mentioned in our piece because for now, children cannot be included in clinical trials until adult studies have been completed. Therefore, there remains a mandatory delay in initiating pediatric studies.

In conclusion, we fully agree with the urgency of completing clinical trials in pediatric populations, and we believe that doctors should be vigilant against prescribing drugs to children off-label. However, these objectives should not detract from the health of adults with hemophilia. In the context of hemophilia, we believe that a rigid adherence to the principles of the Pediatric Investigation Plan does more harm than good.