Clinical trials study sample

In pharmaceutical and medical device development, clinical trials are classified into four main phases designated with Roman numerals 1,11, III and lY The various phases of development trials differ in purpose, length and number of subjects involved. Phase I trials are conducted to determine safe dose levels of a medication, treatment or product (National Institutes of Health, 2002). The main purpose is often to determine an acceptable single dosage - how much can be given without causing serious side-effects. Phase I trials will also involve studies of metabolism and bioavailabity (Pocock, 1983). The sample size of a Phase 1 clinical trial is usually small, ranging from 10-80 subjects (National Institutes of Health, 2002 Pocock, 1983). 

Statistical methods are often employed to determine the study sample size and optimize power. Outlining the methods for calculating sample size and power for clinical trials is beyond the scope of this chapter. Interested readers are referred to texts by Chow and Liu (1998), Hulley and Cummings (1988), and Shuster (1990) for specific information on sample size and power estimation methods. 

Clinical trials are costly to conduct, and results are often critical to the commercial viability of a phytochemical product. Seemingly minor decisions, such as which measurement tool to use or a single entry criterion, can produce thousands of dollars in additional costs. Likewise, a great deal of time, effort and money can be saved by having experts review the study protocol to provide feedback regarding ways to improve efficiency, reduce subject burden and insure that the objectives are being met in the most scientifically sound and cost-effective manner possible. In particular, I recommend that an expert statistician is consulted regarding sample size and power and that the assumptions used in these calculations are reviewed carefully with one or more clinicians. It is not uncommon to see two studies with very similar objectives, which vary by two-fold in the number of subjects under study. Often this can be explained by differences in the assumptions employed in the sample size calculations. 

The study termination form collects patient exit information from the clinical trial. Here is a sample study termination form ... 

For development of bioequivalence studies (in which different formulations have been used in clinical trials), it would seem that normally there would be no need to conduct bioequivalency studies using a stereoselective assay for the evaluation of the concentrations of drug in the plasma samples. We would not usually expect any noticeable difference in the ratio of R to S isomer exiting in plasma samples derived at the same postdosing time point from different... 

All drugs will pose some degree of risk, and completed clinical trials are the primary source of information in this subject. Clinical trials do, of course, have limitations. The principal one concerns the everpresent problem of sample size. Rare side effects, if they exist, cannot generally be detected in clinical trials involving limited numbers of patients. Adverse drug reports and case-reports provide early clues to such effects so-called pharmacoepidemiology studies may be mounted to evaluate such risks. 

WeU accepted Provides rich and high quahty data Can establish a causal link between altered pharmacokinetics and the variable of interest Early results from specific studies enable expansion of patient population in Phase 3 studies not usually difficult to perform Relatively straightforward and simple data analysis Not usually useful for screening Frequent sampling is very difficult in patients in large clinical trials or in children Relationship between altered pharmacokinetics and clinical response may not be established Study sample usually does not represent the target population Small sample may fail to elicit extremes of altered kinetics... 

The impact of these considerations on study subject selection, sample size and endpoint measures will need to figure in future clinical trial designs. 

Clinical trials generate vast quantities of data, most of which are processed by the sponsor. Assessments should be kept to the minimum that is compatible with the safety and comfort of the subject. Highest priority needs to be given to assessment and recording of primary endpoints, as these will determine the main outcome of the study. The power calculation for sample size should be based on the primary critical endpoint. Quite frequently, trials have two or more evaluable endpoints. It must be stated clearly in the protocol whether the secondary endpoints are to be statistically evaluated, in which case power statements will need to be given, or are simply... 

The therapeutic benefits and risks of a medicine, and therefore the choice of treatment for an individual patient, stem from evidence from a series of clinical trials. Taken together, these trials should reflect all likely therapeutic situations. From time to time, a particular problem arises that generates a new hypothesis. In order to obtain an answer to the specific question, we sometimes restrict the population sample to study subjects who do not possess a number of variables that may confound the outcome. In this manner, we move away from the realities of everyday clinical practice to an idealised, but artificial, environment. This is justifiable if the restriction is logical and if, with it, the hypothesis testing can be successfully completed. Otherwise, the issue may never be settled. 

Sample sizes for clinical trials are discussed more fully elsewhere in this book and should be established in discussion with a statistician. Sample sizes should, however, be sufficient to be 90% certain of detecting a statistically significant difference between treatments, based on a set of predetermined primary variables. This means that trials utilising an active control will generally be considerably larger than placebo-controlled studies, in order to exclude a Type II statistical error (i.e. the failure to demonstrate a difference where one exists). Thus, in areas where a substantial safety database is required, for example, hypertension, it may be appropriate to have in the programme a preponderance of studies using a positive control. 

The new GCP requires that sponsors shall compile plan and operating procedures on auditing and implement auditing in conformity with the plan and the procedures, thus auditors audit not only the sponsor s in-house process but also processes at study sites. Within the sponsoring company, usually aU CRFs and study reports are subject to the audit. Study sites are selected for audit based on auditors SOP, usually based on sampling methodology. Audit certificate for each clinical trial is required to be incorporated into new drug submission dossier. 

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