A checklist for clinical trials in rare disease: obstacles and anticipatory actions-lessons learned from the FOR-DMD trial.

BACKGROUND: Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. METHOD: The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. RESULTS: Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. CONCLUSION: Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate.

An open-label assessment of aripiprazole in the treatment of PTSD.

BACKGROUND: Recent studies suggest that atypical antipsychotics may be effective augmentation strategies for the treatment of posttraumatic stress disorder (PTSD). Limited data were available on the newest agent, aripiprazole, so we aimed to evaluate its efficacy and tolerability in the treatment of PTSD. METHODS: A 12-week, prospective, open-label, flexible-dose, adjunctive trial of aripiprazole was conducted in military veterans meeting DSM-IV criteria for PTSD. Concomitant psychiatric medications continued unchanged, except for other neuroleptics which were not allowed. The primary outcome variable was change from baseline in the Clinician Administered PTSD scale (CAPS). RESULTS: All 17 subjects were male, with an average age of 57 years. Total CAPS scores decreased from 78.2 (SD = 17.8) at baseline to 60.0 (23.5) at study end (p = 0.002). Re-experiencing (CAPS-B) and avoidance/numbing symptoms (CAPS-C) were significantly improved, and trend level reductions were observed in hyperarousal symptoms (CAPS-D). Fifty-three percent (9/17) were considered responders, as defined by a decrease in total CAPS scores of at least 20%. Reductions in the Positive and Negative Symptom Scale (PANSS) total score and positive and general psychopathology subscale scores were statistically significant. The final average dose of aripiprazole was 13.06 (SD = 6.45) mg daily. Nine patients discontinued because of side effects. The most common adverse events consisted of gastro-intestinal disturbances, sedation, and psychomotor activation. Tolerability was improved with lower starting doses (e.g., 5 mg daily) and slow titration. CONCLUSIONS: Addition of aripiprazole to ongoing treatment further reduced PTSD symptoms in military veterans with severe PTSD. These preliminary findings await confirmation in randomized, controlled trials.