Clinical outcome data

In the approach of CLSI to setting CB (CLSI, 2007,2008) two primary data sets are used. The first are clinical outcome data and the second are the distribution of in vitro susceptibility data. These can be used to generate cut-off values COd and CO,vt, respectively. COd values are the smallest susceptibility inhibition zone (largest MIC) measures that are determined for bacteria associated with successful therapies. CO t are the lower limit of the distribution of in vitro inhibition zones (upper limit MIC) of fully susceptible strains. If these two cut-off values are in agreement they can be used to set CB. Cut-off values (COpd) can also be generated from a consideration of pharmacokinetic data and pharmacodynamic data. CLSI (2007) recommend that COpd be used in the setting of CB only to resolve disagreements, if any, between COd and COwt. 

In practice clinical outcome data have rarely been produced from commercial aquaculture and even more rarely have they been associated with data on the susceptibility of the target bacterium using CLSI methods. The authority that can be given to estimates of COd is proportional to the number of studies of clinical outcomes that were used to generate them. Thus, the paucity of data of the type needed to set COd raises serious questions as to whether precise CB can, in the short or medium term, be set using the procedures outlined in M37-A3 (CLSI, 2007). 

Diagnosis and procedure codes may reflect reimbursement strategies instead of clinically accurate diagnoses Limited information on important covariates Sparse outcomes data Lack of representativeness Lack of structure for research purposes... 

The Stroke-Thrombolytic Predictive Instrument (Stroke-TPI) has recently been developed in order to provide patient-specific estimates of the probability of a more favorable outcome with rt-PA, and has been proposed as a decision-making aid to patient selection for rt-PA." The estimates from this tool should, however, be treated with caution. The prediction rule is dependent on post hoc mathematical modeling, uses clinical trial data from subjects randomized beyond 3 hours who are not rt-PA-eligible according to FDA labeling and current best practice, and has not been externally validated. It is, therefore, not appropriate to exclude patients from rt-PA treatment based solely on Stroke-TPI predictions. 

We found only one published systematic study of outpatient treatment for PCP abusers, involving 158 patients (73 percent male) of a private clinic (Bolter et al. 1976). This study gave no treatment outcome data, but the authors did comment that treatment was difficult because of the patients strong psychological dependence on PCP. 

Current data suggest little benefit on clinical outcomes beyond symptom relief for calcium channel blockers in the setting of ACS.43 Moreover, the use of first-generation shortacting dihydropyridines, such as nifedipine, should be avoided because they appear to worsen outcomes through their negative inotropic effects, induction of reflex sympathetic activation, tachycardia, and increased myocardial ischemia.43 Therefore, calcium channel blockers should be avoided in the acute management of MI unless there is a clear symptomatic need or a contraindication to p-blockers. 

Acute HIV Infection Diagnosis of acute HIV infection is difficult, since many patients are asymptomatic, or have nonspecific clinical symptoms similar to other common respiratory infections. If acute HIV infection is suspected, HIV antibody tests and a plasma HIV RNA concentration should be obtained. A clear diagnosis is made when an HIV antibody test is negative and the plasma HIV RNA concentration is high. There are limited outcomes data for treating acutely infected patients. Treatment of acute infection can decrease the severity of acute disease and decrease the viral set point this may decrease progression rates and reduce the rate of viral transmission.18-22 Limitations include an increased risk of chronic drug-induced toxicides and the development of viral resistance. 

Clinical trial data supporting the use of specialty formulas in niche populations typically are unconvincing in terms of patient outcomes. 

Specialty formulas designed for use in specific clinical situations generally are much more expensive than standard polymeric formulas. Strong clinical trial data supporting use of these specialty formulas in niche populations typically are unconvincing in terms of patient outcomes. 

Raloxifene, a more complete uterine antagonist than tamoxifen or clomiphene, significantly reduces leiomyoma size in post-menopausal women [31], yet it is less efficacious at reducing tumor volume in pre-menopausal women [32], This result has been attributed to the poor pharmacokinetic properties of this compound in which extensive conjugative metabolism of the phenol(s) limits the circulating levels of the parent drug. In addition, clinical outcomes in premenopausal women treated with raloxifene suggest that this compound, like tamoxifen and clomiphene, can affect the ovaries via the HPO axis [33]. These data, taken collectively, indicate that current SERMs lack the efficacy, pharmacokinetic, and ovarian safety properties needed to treat leiomyoma in ovulatory women. 

Sun D, Lawrence XY, Hussain MA, Wall DA, Smith RL, Amidon GL (2004) In vitro testing of drug absorption for drug developability assessment Forming an interface between in vitro preclinical data and clinical outcome. Curr. Opin. Drug Discov. Dev. 7 75-85. 

Exposure-response data, however, are not likely to obviate the need for clinical data when formulation or manufacturing changes result in altered PKs, unless the relationships between measured responses and relevant clinical outcomes are well understood. The sponsors of studies need to make a financial evaluation of these studies as well often. 

The biomarker is not used because no synthetic analysis has been done. The data need to be pooled, synthesized, and analyzed. We have to xmderstand what the data are telling us about that biomarker and what the remaining gaps in understanding are. Studies have to be identified that will fill those gaps, and then somebody has to do that work, whatever it is and for a surrogate endpoint, of course, that work involves correlation with clinical outcomes. 

One possible solution to this problem is the inclusion of a usual care arm appended as a third arm of a clinical trial. In such a three-arm study, patients randomized to the usual care arm of the study would be treated as they would be outside of the trial, rather than as mandated by the study protocol, and economic and outcomes data from usual care could thus be collected. These data would make it possible to quantify the number of outcomes that likely would be detected in usual care and the costs of these outcomes. 

It should be noted that polypharmacy per se is not necessarily an inappropriate practice. Most medical disorders, from asthma to AIDS to allergies, are managed with medication combinations. However, it is important to note that the use of multiple concurrent medications appears to rising substantially, suggesting that there is a great need for research data and well-designed studies to inform this practice. In some instances, it may be that the combination, while popular, may be more likely to result in side effects and not particular advantages in treatment efficacy and clinical outcomes (Connor et ak, 2000). 

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