Clinical trials rare diseases

If the drug proves safe and effective, phase III trials are initiated. (In the context of clinical trials, safe and effective are rarely used in the absolute sense. Safe generally refers to a favourable risk beneht ratio, i.e. the benefits should outweigh any associated risk. A drug is rarely 100 per cent effective in all patients. Thus, an acceptable level of efficacy must be defined, ideally prior to trial commencement. Depending upon the trial context, efficacy could be defined as prevention of death/prolonging of life by a specific time-frame. It could also be defined as alleviation of disease symptoms or enhancement of the quality of life of sufferers (often difficult parameters to measure objectively). An acceptable incidence of efficacy should also be defined (particularly for phase II and III trials), e.g. the drug should be efficacious in, say, 25 per cent of all patients. If the observed incidence is below the minimal acceptable level, then clinical trials are normally terminated. 

Natalizumab was approved by the U.S. FDA for the treatment of MS in November 2004, and is being evaluated in Phase 3 clinical trials for IBD and CD.105 Based on Phase 3 clinical trials in MS patients, natalizumab appeared to be safe, since an increased rate of infection was not observed after 1 year of treatment.106 The safety of combined treatment with immunosuppressants, other than short courses of corticosteroids, was not evaluated and was not recommended because of the potential for an increased risk of infections. Flowever, barely three months after its approval, natalizumab was voluntarily withdrawn from the MS market by its manufacturer and all ongoing clinical trials were suspended due to the occurrence of a rare neurological disease, progressive multifocal leukoencephalopathy (PML), in 3 out of approximately 3,000 patients enrolled in clinical trials (2 in MS and 1 in CD).107 108 109... 

Nearly 25% of malignant glial neoplasms are of the AA histology with approx 2500 patients in the US diagnosed yearly (10). The relative rareness of this disease makes accrual to clinical trials challenging. Histologic confirmation of the diagnosis and central... 

The most common adverse reaction to etanercept is mild to moderate erythema, pain, or pruritus at the injection site (37%). Headaches and abdominal pain can also occur. New positive autoantibodies, such as antinuclear antibodies (ANA), anti-dsDNA antibodies, and anticardiolipin antibodies, can develop in patients treated with etanercept. Although there is so far no association between this and the development of autoimmune diseases or malignancies, long-term studies have yet to be done. Rare cases of pancytopenia may be associated with this drug. Although clinical trials showed no increased risk of infection with etanercept treatment, postmarketing reports of serious infections, sepsis, and associated fatalities exist. 

DoD is not just another purchaser in a commercial market, however. It becomes a developer of drugs when demand is mainly or exclusively for military use. Under these circumstances, DoD requirements for CBW defense drugs involve the department in the full spectrum of research, development, testing for safety and effectiveness through clinical trials or alternate means, production, acquisition, and issues of medical use. (This may also be the case for naturally occurring diseases that rarely appear in the United States and for which the domestic civilian market is limited.)... 

Modernizing the Critical Path Sciences Clinical Trials Pediatric Therapeutics Rare Diseases Toxicological Research... 

Products for a rare disease or condition may be too small to recover their development and registration cost from sales. If this situation is expected, the developer may ask the FDA for written recommendations for the required preclinical and clinical trials. In addition, the manufacturer and sponsor can ask for an official designation as "orphan drug" (also for biological products). Orphan drugs are entitled to tax reductions and a 7 year monopoly on their use for the designated indication. 

The list of factors that come into play is indicative of the complexity. For example, the absolute risks of different trials ranges from no improvement while on the drug to actual increased mortality. The length of trials is different antibiotics, 14 days, an Alzheimer drug, at least 24 months, and an osteoporosis drug is 36 to 48 months. The size of trials depends on the improvement one wishes to demonstrate and the natural rate of disease progression. One might only need 30 to 40 patients for a trial on some rare tumor disease, in stroke or sepsis, from 60 to 200 patients, but in cardiovascular medicine or obesity, one needs 2,000 to 10,000 patients to have some idea of efficacy. As a reminder, the key for these clinical trials is Is there a sufficient number of patients who are well characterized and who could enter the trial so that we will have the statistical power to... 

When the patients who received a drug candidate have the disease manifestations completely eradicated and experience no other effects while patients treated with a placebo have a continuation of the disease process, the evaluation is not difficult. However, that is rarely, if ever, the case, and evaluation requires detailed statistical analysis of the collected data. An ICH guide-line covers statistical issues related to the scope of clinical trials, design techniques to minimize bias, types of clinical trial designs, conduct considerations, data analysis for efficacy, evaluation of safety and tolerance, and reporting. 

The therapeutic use and safety of etanercept have been reviewed (3). Mild-to-moderate injection site reactions were the most common adverse effects (42-49%), with a frequency 3.8 to 6 times greater than with placebo. Nonneutralizing antibodies to etanercept were rarely detected. Etanercept-treated patients more often developed new antinuclear antibodies or anti-double-stranded DNA antibodies, but no patient developed symptoms suggestive of an autoimmune disease during clinical trials. 

Preclinical and clinical trial data and data from phase IV studies have shown that levofloxacin, moxifloxacin, and gatifloxacin cause prolongation of the QT interval, but that the potential for torsade de pointes is rare and is influenced by several independent variables (for example concurrent administration of class la and III antidysrhyth-mic agents) (25). There is a moderate increase in the QT interval associated with sparfloxacin, averaging 3%, and the few serious adverse cardiovascular events that have been reported during postmarketing surveillance all occurred in patients with underlying heart disease (26). 

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