Anti-infective trials

This quote also makes a further important point relating to anti-infective trials. It is not uncommon in such trials to be including patients on clinical grounds... 

Generally speaking we power based on the per-protocol set and then increase the sample size requirement to give the number required in the full analysis set. Under some circumstances, for example in anti-infective trials, we factor up further to take into account the patients that are recruited, but are not eligible for the full analysis set. 

As with sample size in superiority trials we generally power on the basis of the per-protocol set and increase the sample size to account for the non-evaluable patients. This is particularly important in non-inferiority trials where the full analysis set and the per-protocol set are co-primary analyses. Note also, as before in superiority trials further factoring up may be needed if there are randomised patients who are being systematically excluded from the full analysis set, as is the case, for example, in anti-infective trials. 

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 ... 

Clinical success rates and attrition rates by phase of clinical trial for new drugs are important indicators of how effectively companies are utilising drug development resources. The proficiency with which this is done reflects a complex set of regulatory, economic and company-specific factors. Success rates differ by therapeutic class, and t)q)ically vary from about 28% success rate for an anti-infective compound to 12% for respiratory drugs. Table 9.3 shows the details. 

A success/failure approach will be particularly effective if the endpoint is already binary, for example cured/not cured in a trial of an anti-infective. In the earlier discussion of modified ITT the CPMP (1997) Note for Guidance on the Evaluation of New Anti-bacterial Medicinal Products goes on to say Patients who have no measurements after baseline are included as failures in the analysis. ... 

For anti-infective and antiviral drugs, provide a summary of the results of the microbiology trials conducted with the drug. This should include the following ... 

Indeed, two orally delivered, carbohydrate-based, silica-linked, gastrointestinal anti-infective therapies were advanced to clinical trials. Synsorb Pk was developed for the treatment of E. coli infections to prevent hemolytic uremic syndrome. The target E. coli variant produces verotoxin,the toxin in "hamburger disease." The other silica-linked oligosaccharide drug, Synsorb Cd, was for the treatment of C. difficile-associated diarrhea. Both compounds were discontinued in development. 

Biopharmaceuticals in Clinical Trials as Anti-infective Agents... 

Of the 57 patients, 28 were treated with vitamin E during the period of the trial and 29 had dummy tablets. Local treatment consisted of the use of anti-infective agents and pressure bandaging. 

Walz JM, Avelar RL, Longtine KJ, Carter KL, Mermel LA, Heard SO. Anti-infective external coating of central venous catheters a randomized, noninferiority trial comparing 5-fluorouracil with chlorhexidine/silver sulfadiazine in preventing catheter colonization. Crit Care Med 2010 38(11) 2095-102. 

Skepticism concerning the anti-infective role of vitamin D focuses upon the fact that much of the anti-TB effect is an in vitro phenomenon, rather than in vivo (Bruce et al. 2010). As Bruce et al. note, there is little evidence that vitamin D affects the course of human infection. It is conflicting information such as this that indicates the need for prospective trials in groups of patients with TB. 

The recognition that vitamin A could be used as a treatment for infections dates to antiquity. Fish liver oils, a potent source of vitamin A, were used as a treatment for infections in Greek and Roman medicine. Experiments in the 1920 s suggested that vitamin A-deficient animals were more susceptible to infections, and Green and Mellanby dubbed vitamin A the anti-infective vitamin in 1928 [5]. At least thirty trials were conducted between 1920 and 1940 which examined the use of vitamin A as a therapy for a wide variety of infections in humans. Although these early trials were encouraging, the emergence of sulfa antibiotics in the late 1930 s and the disappearance of malnutrition in industrialized countries led to a caesura in research on vitamin A as an anti-infective therapy. The description of an association between mild vitamin A deficiency and increased child mortality renewed interest in vitamin A [6], and further controlled clinical trials were conducted in the 1980 s which provided more definitive evidence for vitamin A as a public health intervention [2]. 

A number of chimerized, humanized, and one human mAb have now been approved for therapeutic use in humans in the treatment of autoimmunity, malignancy, infection and cardiovascular disease (Table 1). Some of the currently licensed mAb will be discussed here. A much larger number of mAb are currently being evaluated in Phase I, II and III trials. In general, chimeric, humanized and human mAb are very well tolerated with few side effects. Chimeric or humanized mAb still have the potential to evoke host immune response to the variable domains or CDRs of the antibody so-called HACA (human anti-chimeric antibody) or HAHA (human anti-human antibody) responses, although these responses are uncommon. Short-lived and occasionally severe infusion-related acute hypersensitivity reactions such as fever, skin itching, shivering, respiratory compromise and low blood pressure sometimes occur-. Such effects may... 

---