Comparator drugs, clinical trials

Physicians are also more likely to know their patients well compared to clinical trial investigators and, like family members, may be better able to notice personality changes and other more subtle adverse drug reactions. Also, physicians are more likely to be in touch with family members who are largely ignored during controlled clinical trials. 

However, already in an early clinical trial, rofecoxib was found to produce four times the number of myocardial infarctions than its comparator drug, naproxen. A subsequent trial of rofecoxib compared to placebo in colorectal cancer prevention demonstrated, after 18 months of study, that a greater number of myocardial infarctions occulted in the rofecoxib group. In 2004 the manufacturers of rofecoxib withdrew the diug from the market. A similar study of celecoxib compared to placebo in cancer prevention, showed that celecoxib also increased the risk of cardiovascular embolisms [3]. 

Celecoxib, which has a low selectivity for COX-2 compared to COX-1, is still available, although its more selective successor, valdecoxib has been withdrawn. Etoricoxib, the successor to rofecoxib, is marketed in Europe but not in the USA. In a large multinational clinical trial, etoricoxib caused no more thromboembolic events than diclofenac, but after 18 months the incidence of gastrointestinal ulcers and bleeding was the same for both drugs [4]. 

However, compared with the traditional analytical methods, the adoption of chromatographic methods represented a signihcant improvement in pharmaceutical analysis. This was because chromatographic methods had the advantages of method specihcity, the ability to separate and detect low-level impurities. Specihcity is especially important for methods intended for early-phase drug development when the chemical and physical properties of the active pharmaceutical ingredient (API) are not fully understood and the synthetic processes are not fully developed. Therefore the assurance of safety in clinical trials of an API relies heavily on the ability of analytical methods to detect and quantitate unknown impurities that may pose safety concerns. This task was not easily performed or simply could not be carried out by classic wet chemistry methods. Therefore, slowly, HPLC and GC established their places as the mainstream analytical methods in pharmaceutical analysis. 

For any intervention intended to impact favorably upon human health, it is important to evaluate its safety and efficacy in order to demonstrate that it does not cause harm and it does provide the expected benefit. The gold standard method for evaluating any intervention, whether it be a botanical product, dietary supplement, drug, medical device or medical procedure, is the randomized, clinical trial (RCT). A clinical trial is a type of experiment conducted in human subjects where the effects of at least two interventions are compared. Often, the clinical trial takes the form of an active treatment compared to an inactive control or placebo. 

Appropriate empiric anti-infective therapy decreases 28-day mortality compared to inappropriate empiric therapy (24% versus 39%).22 23,30 Additionally, appropriate therapy administered within 1 hour of sepsis recognition also decreases complications and mortality.22-23,30 Empiric anti-infective therapy should include one, two, or three drugs, depending on the site of infection and causative pathogens (Table 79-3). Anti-infective clinical trials in sepsis and septic shock patients are scarce and have not demonstrated differences among agents therefore, factors that determine selection are ... 

At first, Sapirstein and I found the equivalence between antidepressants and other drugs puzzling, to say the least. Why should drugs that are not antidepressants be as effective as antidepressants in treating depression To answer this question, we asked another. What do all these diverse drugs have in common that they do not share with inert placebos What do SSRIs have in common with the older tricyclic antidepressants, with other less common antidepressants, and even with tranquillizers, depressants and thyroid medication The only common factor that we were able to note was that they all produce easily noticeable side effects - the one thing that was lacking in Merck s new treatment for depression. Placebos can also produce side effects, but they do so to a much lesser extent than active medication. Clinical trials show that whereas the therapeutic benefits of antidepressants are relatively small when compared to placebos, the difference in side effects is substantial.7... 

---