Study populations, defining

Resistance to Tetracyclines. The tetracyclines stiU provide inexpensive and effective treatment for several microbial infections, but the emergence of acquired resistance to this class of antibiotic has limited their clinical usehilness. Studies to define the molecular basis of resistance are underway so that derivatives having improved antibacterial spectra and less susceptibiUty to bacterial resistance may be developed. Tetracyclines are antibiotics of choice for relatively few human infections encountered in daily clinical practice (104), largely as a result of the emergence of acquired tetracycline-resistance among clinically important bacteria (88,105,106). Acquired resistance occurs when resistant strains emerge from previously sensitive bacterial populations by acquisition of resistance genes which usually reside in plasmids and/or transposons (88,106,107). Furthermore, resistance deterrninants contained in transposons spread to, and become estabUshed in, diverse bacterial species (106). 

Concomitant or prior medications may be used in either safety or efficacy analyses. The presence of specific medications may be used as covariates for inferential analyses. Also, medications are often summarized to show that the therapies under study come from medically comparable populations. Medications may be used to determine protocol compliance and to help define a protocol-compliant study population. Concomitant medications may be examined to determine whether they interact with study therapy or whether they can explain the presence of certain adverse events. From a CDISC perspective, prior medications would be considered a finding while concomitant medications would be considered an intervention. 

Key Concepts for Creating Analysis Data Sets 84 Defining Variables Once 84 Defining Study Populations 85 Defining Baseline Observations 85 Last Observation Carried Forward (LOCF) 86 Defining Study Day 89 Windowing Data 91 Transposing Data 94... 

The written informed consent form should be presented to potential participants in a language that they understand and written in terms that they can comprehend. This is one of the important functions of an IRB. The IRB members review every informed consent form to determine if it contains all of the required elements and any additional required elements of an informed consent form as sef forth in the governing regulations. The informed consent form is also reviewed to determine that complete, accurate, and pertinent study-related information is being provided to the potential participants and that medical terms are clearly defined, in simple language at the study population can understand. 

Choosing the study population is obviously critical to adequate trial design. The specific criteria of patient eligibility should be clearly pre-defined as part of the primary question the trial strives... 

Table 2.8. Typical issues addressed when designing a clinical trial protocol. The trial objectives should clearly define what questions the trial should answer. The study design section should contain comprehensive information detailing trial size, criteria used to choose the study population, and enrolment procedures. Description of intervention section should give the background to the intervention itself, its therapeutic rationale and how it is to be administered. Measurement of response should detail the data to be collected, how it will be collected and analysed. The organization and administration section should give full details of all the investigators, where the trial is being run, and its project management details...

Firstly, the study population, disease (or diseases) and exposure should have been well defined by the authors. Cases of disease in the study population should have been identified in a way that was independent of the exposure of interest, and exposure should have been assessed in a way that was not related to disease status. 

Inclusion and exclusion criteria strictly define the nature of the subject sample that participates in a clinical trial. Accordingly, they also strictly define the study population to which statistical inferences may be made (see Chapter 7 for discussion of statistical inference). For now, this statement can be expressed as follows The inclusion and exclusion criteria strictly define the study population to whom the results of the clinical trial can reasonably be generalized. This study population may or may not be a good representation of the entire population of patients with the disease or condition of interest. Chapter 11 provides more detailed discussion of the implications of this statement. (See also www.clinicaltrials.gov for examples of inclusion and exclusion criteria in clinical trials.)... 

The Art of Defining a Study Population in Preapproval Clinical Trials... 

It is somewhat of an art, albeit a very important one, to carefully define a study population so that a new treatment can be shown to be effective but not so carefully that the treatment effects are not applicable to more heterogeneous populations. It is a balancing act to optimize design in early studies to demonstrate an effect but to make sure that later studies are not so optimized that their results do not generalize well (see Friedman et al., 2006, for additional discussion of generalization). 

Examples of commonly used clinical tools or tests that may be appropriate for children s health issues are summarized in Table 8. This table underscores the utility in evaluating children s overall health status rather than restricted focus on specific organ systems, except for circumstances when a particular exposure or health concern exists for a defined study population. 

As the bioequivalence rules are clearly defined, the study population must ensure a high level of standardization, making it sometimes difficult to extrapolate to patient settings. Typical enrolment criteria are ... 

The review of the protocol ensures that there are adequate selection criteria and procedures to protect vulnerable study populations. In addition, information within the protocol, the informed consent, and the Investigator s Brochure are reviewed to assess safety information that may affect subjects. Institutional review boards are empowered with the authority to approve or disapprove research activities that are covered by regulations, as well as to require modifications to secure approval. Informed consents will be reviewed to assure that all the information provided is in accordance with 21 CFR 50.25 the IRB may also require that additional information be provided to study subjects in a separate format, such as a patient information sheet. If this requirement is waived, a written statement may be given to the subject. If a very short window of opportunity exists to dispense a research treatment to avoid a devastating or fatal outcome, a waiver for this requirement may be requested. It is important to note, however, that the sponsor must clearly describe or define the situations that would require testing without administering a written informed consent. Also, provisions that will be made to obtain the consent from family members must be in place. This issue will be discussed in more detail in the section on informed consent. In summary, the following criteria are used by IRBs to approve research ... 

After careful statistical, clinical, and pragmatic evaluation, the study population may be defined. 

Methods of patient selection from study population described nclusion and exclusion criteria defined Diagnostic criteria defined... 

In the DARC/PELCO method (1), the structural variable makes use of graph theory. It is based on simultaneous representation of ail structures (15) whose structural modifications are to be correlated with variations in property and of the population containing these structures. The environment concept is used to describe each structure as an ordered chromatic graph. The principle of syn chronous generation of a structure and of the series which contains it, called hyperstructure is used to describe the population to be studied. This concept and this principle, when applied to an isofocal population, define a multidimensional variable characterizing the chemical structure. 

Only well-defined strains, products, and study populations should be used in trials. 

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