RCTs and observational studies to determine the effect of prophylaxis in severe haemophilia

Abstract

It has been suggested that more RCTs should be conducted in the evaluation of haemophilia treatment, including prophylaxis. To draw valid conclusions from experimental or observational studies, internal validity should be ensured. In particular, similarity of prognosis between treatment groups compared in a particular study is needed. Because the use of prophylaxis in observational studies is nonrandomized by definition, special efforts should be made to achieve comparability of prognosis, that is, to avoid 'confounding by indication'; in RCTs this is ensured by randomized allocation of treatment. However, the high costs of an RCT results in a limitation of both patient numbers and length of follow up. Observational studies tend to be more generalizable and cheaper, as they may include a wider spectrum of morbidities, use treatment protocols in agreement with routine care, and use available data. Therefore, observational studies can be much larger and of longer duration than RCTs; and are the preferred design for the evaluation of long term treatment effects. Several valid observational studies comparing prophylaxis and on demand treatment have reported both a short term reduction of 75-90% in bleeding frequency, and significant improvement in arthropathy, quality of life, and socioeconomic parameters after more than 20 years of prophylactic treatment. RCTs provide the most powerful tool for the evaluation of short term effects of any treatment, but are infeasible for the evaluation of long term effects. The definitive assessment of the long-term benefits of prophylaxis requires observational studies that should be performed according to rigorous standards.

Intermediate-dose versus high-dose prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s

“…15 Comparing birth cohorts from centers in 2 countries provides the best alternative to a randomized controlled trial to assess long-term outcomes of the Dutch intermediate-dose and Swedish high-dose prophylactic regimens. Selection bias was avoided, as the choice of prophylactic regimen depended on country of birth only.…”

A modeling approach to evaluate long-term outcome of prophylactic and on demand treatment strategies for severe hemophilia A

“…Randomized controlled clinical trials comparing treatments into adulthood are not feasible and retrospective studies are likely to suffer from confounding by indication as they compare selected groups of patients. 9,10 In cases in which true experiments are unfeasible or impracticable, modeling techniques can be used to synthesize information from different sources. Moreover, experiments can be simulated to explore alternative strategies both for short-and long-term outcomes.…”

The Economics of Hemophilia Treatment

“…Another limitation of RCTs is that the limited duration of follow-up may fail to capture important consequences [13]. Decisions in the health sector have consequences for the family, community care, employers, and so on.…”