Clinical trials historical

It would be comforting to be able to state that the causes of postmarketing withdrawals from drugs were substantially different from those of failure of drugs in clinical trials. While the last few years (refer back to Table 1.1) are seemingly somewhat different from those in the past, the historic causes for the modem era (the last 40 years) are lead off by hepatic toxicity, also the primary cause for safety failure in early clinical trials. 

Historically, CROs have a mixed record of IT adoption some have developed in-house custom IT soluhons designed to accommodate their internal workflow and comply with their standard operating procedures (SOPs). Like sponsors, many have now acquired systems from large IT software providers, especially when such systems are employed by their clients and required by their clients for their clinical trial service providers. 

S.5.5.2.3 Historical controls Since many clinical trials are conducted in the same diseases, with the same control treatments there is an obvious desire to make the most use of this potentially valuable information. Can we compare the results of a new treatment in a group of patients with a group of control patients extracted from a historical database For example, suppose we are testing a new treatment for migraine headache and 60% of patients improve in the first 2 h post-treatment, compared to 30% in a group of historical control patients treated who had been treated with the current gold standard. Are we able to conclude that the new treatment is preferable to the gold standard ... 

Japanese GCP requires that the head of the medical institute and the sponsor must execute a study contract, and does not allow the investigator to directly contract with the sponsor. Historically, a clinical trial is considered as an activity of the hospital as a whole, not of an individual investigator. The reason behind this is that the investigator cannot conduct any study without the full support of hospital staff and access to hospital facilities. The head of the medical institute is responsible for organising an IRB in-house or to make it available outside the hospital, if the hospital is not large enough to maintain an IRB. Once the sponsoring company submits the clinical study plan to the hospital, the head of the medical institute should submit the study document to the IRB for their opinion. The head cannot be a member of the IRB, is not allowed to discuss or vote on the clinical trial, but nevertheless attendance to the IRB is not prohibited. 

As with carbamazepine, the historical use of valproate for anxiety is not supported by robust clinical trials. A randomised study showed efficacy in panic disorder (Lum et al. 1991) and benefit has been reported in open studies in OCD and PTSD. The major side-effects are tremor, nausea, ataxia and weight gain and there is the potential for drug interactions via inhibition of hepatic enzymes. 

Historically, embryo-fetal development studies were mandatory to support inclusion of women of childbearing potential (WOCBP) in clinical trials. More recently, it has become admissible under appropriate circumstances to include WOCBP in early clinical trials before performing the embryo-fetal toxicity studies, provided that effective contraception is used. In Japan and Europe, data from adequately designed preliminary embryo-fetal toxicity studies, with as few as six females per group, may be used to support the inclusion of WOCBP in short-term clinical trials (18). The predictivity of such preliminary mammalian studies has not been established (see below), but it could be argued that they may be less predictive than alternative methods such as FETAX. We therefore expect FETAX to play an evermore important role in pharmaceutical development in the future. 

In clinical trials the cumulative risk of death 35 days after starting treatment was 9% in the lepirudin-treated patients, compared with 18% in historical controls cumulative risk of new thromboembolic complications was 6% with lepirudin and 22% in historical controls... 

One of the largest trials ever conducted took place in the US in 1954 and concerned the evaluation of the Salk Polio Vaccine. The trial has been reported extensively by Meier (1978) and is used by Pocock (1983) in his discussion of the historical development of clinical trials. 

A further phrase that is used in this area is historical evidence of sensitivity to drug effects. This idea, introduced initially in ICH ElO, refers to the ability of effective treatments to consistently show an advantage over placebo in appropriately designed and conducted clinical trials. As mentioned in the previous paragraph, there are certain therapeutic settings where this is not the case. 

TABLE 3.4. Historical data on clinical trial success rates as compared to clinical leverage strategy... 

E. Therapeutic response Thrombin-dependent tests show dose dependency [aPTT rise proportionally to dose of Refludan]. The key criteria of efficacy in two pivotal clinical trials from a laboratory standpoint were platelet recovery and effective anticoagulation. Seven days after the start of treatment with Refludan in patients with HIT, the cumulative risk of death, limb amputation, or new thromboembolic complication was substantially lower than in a historical control group. 

The key parameter for any drug product is its efficacy as demonstrated in controlled clinical trials. The time and expense associated with such trials make them unsuitable as routine quality control methods. Therefore, in vitro surrogate tests are often used to assure that product quality and performance are maintained over time and in the presence of change. A variety of physical and chemical tests commonly performed on semisolid products and their components (e.g., solubility, particle size and crystalline form of the active component, viscosity, and homogeneity of the product) have historically provided reasonable evidence of consistent performance. More recently, in vitro release testing has shown promise as a means to comprehensively assure consistent delivery of the active component(s) from semisolid products. 

Justice. This principle requires that the burdens and benefits of participation in clinical trials are distributed evenly and fairly. Historically, populations that were easily and conveniently accessed by researchers, such as prison inmates, nursing home residents, and people with poor access to general health care, have been used when they should not have been. Vulnerable populations should not be deliberately chosen for participation in clinical trials when nonvulnerable populations would also be appropriate. The benefits of... 

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