Milestones On Orphan Medicinal Products Development: The 100 First Drugs for Rare Diseases Approved Throughout Europe

Abstract

The internal systems for quality assure are being introduced in the health care environment, and especially in hospitals. The Clinical Pharmacology Service (CPS) at a University Hospital has implemented a quality management system, consistently with ISO 9001:2008 requirements and subjected to external audits by AENOR. The CPS defined 6 processes representing its activity in the hospital, and within each of those processes defined a number of indicators of the performance and its quality (process/n indicators): Clinical consultations (6), Safety of medicines and pharmacovigilance (7), Therapeutic Drug Monitoring (3), Policy and medicines selection (5), Clinical trials (4) and Clinical research (2). Three of the indicators were satisfaction surveys. The implantation period lasted 10 months. In a first phase (4 months), the design and documentation of the processes were developed; 24 procedures, 9 work instructions and 67 forms (or records) were documented and incorporated into the management system. In a second phase (6 months) the system was implemented. The internal and the external audits valued the performance and gave the higher standards to the CPS. The certification improved the activity of the CPS by using a structured process, analyzing the results, and introducing improvements. Furthermore the activity of the CPS was clearly visible for the rest of the Hospital and especially for the head physician team. The extra bureaucratic work pays off for the results obtained.

Interval estimation of the overall treatment effect in a meta-analysis of a few small studies with zero events

“…In MAs of RCTs, methodological challenges arise when the disease under examination is rare and only a few small RCTs are available [ 2 , 3 ]. This is mostly due to the large sample assumptions on which most MA methods are based.…”

Making the most of a few small population clinical trials

“…Even though most approved orphan drugs show that the conduct of reasonably sized trials is possible during an orphan drug development [100], this characteristic usually represents only the most prevalent among rare diseases. In very and ultra rare diseases, no more than two small trials become available.…”

“…We considered EPARs of approved orphan drugs, published from 2006 until today. Our selection of examples represents a range of rare conditions with different characteristics [100].…”

“…Usually, in an orphan drug evaluation procedure, no more than two randomized trials are available [100]. This was the case with the evaluation of Bronchitol® (mannitol) for cystic fibrosis [177].…”

“…Considering the number of people affected by a rare disease (prevalence between 1/2500 and 1/1000 [1]), in general a sufficiently sized RCT is not always feasible, while smaller trials produce underpowered and non-conclusive evidence [5,99]. When evaluating a novel intervention in rare diseases (orphan drug) the number of available trials is small; usually the number of participants per trial is limited as well [100]. Similarly to Chapter 2a, please note that the list of references is split into two parts: 1) references to other publications and 2) references to papers in the review ( ‡ ).…”