Clinical research for rare disease: Opportunities, challenges, and solutions

When Ethics Constrains Clinical Research: Trial Design of Control Arms in “Greater Than Minimal Risk” Pediatric Trials

“…Indeed, as some have pointed out, the approval of drugs for rare diseases has depended less on randomized clinical trial studies than that of other drugs for more common diseases (Buckley, 2008;Mitsumoto et al, 2009;Griggs et al, 2009;Anonymous, 2010). Researchers and agencies such as the European Medicines Agency have acknowledged the difficulty of conducting randomized clinical trials when dealing with very rare diseases and have defended other types of trial designs, such as using external or historical controls or participants serving as their own control, in order to allow development of needed medicines (Buckley, 2008;Griggs et al, 2009;Anonymous, 2010).…”

“…Nonetheless, even when nonrandomized clinical trials are proposed as reasonable alternatives to a randomized clinical trial design for rare diseases, there is a still a tendency to think of these alternatives as providing evidence that does not rank as high as that of randomized trials (Buckley, 2008;Griggs et al, 2009 . Subjects with LINCL are evaluated in a ''screening protocol'' in which the diagnosis is confirmed and the clinical status of the child is assessed by a clinical rating scale and central nervous system magnetic resonance imaging.…”

“…Indeed, some argue that RCTs provide the most objective, legitimate, and genuinely scientific evidence about the effectiveness of any medical procedure (Guyatt et al, 2000;Devereaux and Yusuf, 2003). Hence, even when there is a clear recognition of the challenges that randomized clinical trials would impose on the development of drugs for rare, fatal diseases, and even when other trial designs are thought to be necessary in order to allow for needed medicines (Buckley, 2008;Griggs et al, 2009;Mitsumoto et al, 2009;Anonymous, 2010), the general agreement is that randomized clinical trials would provide the best evidence. But, as we show below, such belief is problematic.…”

Alkaptonuria: Leading to the Treasure in Exceptions

“…The design of clinical trials for rare diseases with few participants, and uncertainties about what outcomes will be informative over long periods of observation, is very challenging (Haffner 2006;Griggs et al 2009; European Committee for Orphan Medicinal Products 2011). Alkaptonuria, a neglected ultraorphan disease and the firstidentified inborn error of metabolism, represents an extreme case for therapeutic advance.…”

“…While in retrospect, it is not surprising that nitisinone failed to increase hip mobility in alkaptonuric patients with established ochronotic arthropathy, given the definitive effects of nitisinone on the primary biochemical defect in alkaptonuria, it is difficult to ignore the potential for clinical utility (Phornphutkul et al 2002;Suwannarat et al 2005;Introne et al 2011). However, the problem of how best to investigate its putative therapeutic and more likely preventative action on disease-related events that are meaningful for patientsand obtain appropriate funding for long-term studies and regulatory approval -remains (Buckley 2008;Griggs et al 2009). …”