Feasibility of Randomised Clinical Trials in Rare Diseases: The Case of Polycythemia Vera

Abstract

Although it has long been recognised as the only reliable instrument for producing scientific evidence on the benefit/risk profile of therapeutic interventions, the technology of randomised clinical trials (RCT) is far from being the backbone of medical knowledge. Randomised clinical trials in polycythemia vera have been carried out when their methodology was being built up and, therefore, was rather unsatisfactory. Now we have aggressive cytoreductive treatments with chemotherapeutic agents loaded with doubts on long-term safety, while phlebotomy and preventive antiplatelet therapy are left to personal preferences because of debatable results of old, low-power clinical trials. A complex profile of uncertainties requires a simple, but articulated strategy of care and research to allow at the same time a reasonable transfer of the best available validated knowledge and a timely investigation of the most relevant questions. Without doubts, multi-country, collaborative RCTs is the key (not isolated or abstract) element of the current scenario. The declared background hypothesis is the willingness of a medical caring community of being, at the same time and with the same patients, a research community. The trial design comes in as the simplest technical way to deal with uncertainty. Data to be collected, criteria, contents, intensity of follow-up, and documentation of the events are exactly the same as those which are planned and adopted in routine care. One of the greatest achievements of the multicenter trials with this orientation has been to produce a “core” of data and practices, on which the main analyses will be made, but which at the same time reflect an optimal level of assistance to the majority of patients. The purpose of this paper is therefore twofold:

a) to provide a brief methodological review of the controlled evidence available for the direction of therapeutic practice for PV:

b) to outline and discuss the opportunity, general design, and feasibility of research strategies where a comparative large-scale trial between therapeutic alternatives could play a central role.

Key Words:

• Randomized clinical trials
• rare diseases
• polycythemia vera