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As disease-modifying therapies near realization, there are concerns about the criteria by which these therapies will be judged. It is not yet clear what kind of evidence (clinical, biomarker, or otherwise) will be required to support a disease-modifying claim. When such a drug is approved, regulators must be certain that the claims in the label are factual and unambiguous, yet a definition for “disease modification” remains to be established. One strong potential definition is: “a therapy that affects the underlying pathology and structure of the disease”. However, this is only one possibility, and a consensus definition must be codified before criteria to evaluate it can be determined.
There is room for informed speculation, however. Criteria to evaluate disease-modifying effects have been proposed, and typically involve one of two approaches (neither of which has yet been endorsed by regulators). The first is a clinical approach, in which clinical designs are employed that would ideally force a conclusion that a drug has a disease-modifying effect. In one proposed design, patients would be randomized to drug or placebo for an appropriate duration. At the end of that period, and if a difference in outcome between drug and placebo on an appropriate clinical measure or measures has been achieved, patients originally randomized to drug would then be treated with placebo, while patients originally treated with placebo would remain on placebo.
The evidentiary standards for the approval of drugs to treat human disease are set forth in the relevant sections of the Food, Drug, and Cosmetic Act. This chapter focuses on some of the more important and current issues related to the demonstration of effectiveness of drugs and biologics. In essentially all cases, drugs to treat neurological disease are approved on the basis of clinical trials that examine the drug's effects on a face valid measurement with clinical meaning. The FDA defines orphan diseases as those with a prevalence of less than 200000 in the US. In the case of a trial designed to establish the superior safety profile of one drug compared to another, it is also critical that the trials examine a full range of adverse events, and employ methods sensitive enough to adequately assess them.
There is significant interest in the development of new drugs to treat vascular dementia. However, before US approval of new drugs for this entity is possible, certain issues with regulatory implications need to be addressed. Is vascular dementia a distinct clinical syndrome with valid diagnostic criteria? Can this entity be distinguished from Alzheimer's disease (AD) and other causes of dementia? What design features are important for clinical trials in this disorder? The US Food and Drug Administration (FDA) convened a special meeting of the Peripheral and Central Nervous System Advisory Committee in an attempt to answer these questions. The conclusions from this meeting indicate that vascular dementia (VaD) is a pathologically heterogeneous disorder but appears to be reasonably distinguishable from AD dementia. The NINDS-AIREN diagnostic criteria are suitable as entry criteria for vascular dementia trials. Trials should be similar in duration to AD dementia trials and should employ a dual outcome strategy (cognitive + global/functional measures). For drugs that are believed to have a disease-modifying effect, clinical trials should study specific vascular dementia subtypes and would need to employ substantially different designs from those used currently. The term “vascular dementia” may not be entirely appropriate to describe this population.
This paper describes a method to construct a standardized health care
resource use database. Billing and clinical data were analyzed for 916
patients who received liver transplantations at three medical centers over a
4-year period. Data were checked for completeness by assessing whether each
patient's bill included charges covering specified dates and for specific
services, and for accuracy by comparing a sample of bills to medical records.
Detailed services were matched to a standardized service list from one of the
centers, and a single price list was applied. For certain services, clinical
data were used to estimate service use or, if a match was not possible,
adjusted charges for the services were used. Twenty-three patients were
eliminated from the database because of incomplete resource use data. There
was very good correspondence between bills and medical records, except for
blood products. Direct matches to the standardized service list accounted for
69.3% of services overall; 9.4% of services could not be matched to the
standardized service list and were thus adjusted for center and/or time
period. Clinical data were used to estimate resource use for blood products,
operating room time, and medications; these estimations accounted for 21.3% of
A database can be constructed that allows comparison of standardized
resource use and avoids biases due to accounting, geographic, or temporal
factors. Clinical data are essential for the creation of such a database. The
methods described are particularly useful in studies of the cost-effectiveness
of medical technologies.
Commercially available computer-aided sperm analysis (CASA) was introduced to research laboratories and laboratory medicine nearly 10 years ago. The first instruments were CellSoft (Cryo Resources, Montgomery, NY) and ExpertVision (later called CellTrak, Motion Analysis Corp., Santa Rosa, CA). There soon followed the HTM-2000 (Hamilton Thorn Research, Beverly, MA), the SM-CMA instrument from Europe (Stromberg-Mika, Bad Feilnbach, Germany), and others. There are now over 120 papers which verify CASA technology for semen analysis or apply it in basic and clinical studies. However, despite this enormous body of work, and the considerable time since its introduction, CASA's potential has not been realized for two basic reasons. First, manufacturers have been unwilling or unable to address a fundamental limitation of the technology, namely the inability of CASA instruments to obtain accurate counts and percent motilities when the concentration of a specimen is greater than about 50 x 106 sperm/ml or less than about 20 x 106 sperm/ml, or when a specimen is laden with debris. These common conditions require laboratories to either dilute, concentrate, or wash specimens, significantly limiting routine clinical application of the technology. Second, professional societies and organizations have been slow to develop and recommend performance and operating standards for CASA instruments. Appeals have been made by industry spokesmen and individual scientists (Schrader et al., 1992; Chapin et al., 1992) to achieve this end, but no stance has been taken by any professional group on the performance, use, calibration, or standardization of CASA technology.
The application of CASA in clinical laboratory medicine is hindered by these continuing technical limitations and the lack of involvement by professional organizations.
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