Therapeutic exploratory trials

Therapeutic exploratory trials are conducted if the results of the human pharmacology trials are considered positive (someone has to decide that the results are positive). These trials involve the comprehensive assessment of the investigational drug s safety in perhaps 200-300 individuals with the disease or condition of interest. They are typically conducted by clinical pharmacologists, and participants in these trials are often hospitalized and can therefore be closely monitored. Extensive data are collected, including self-report assessments by the participants and biochemical assessments. 

If the therapeutic exploratory trials are successful (someone has to decide if this is the case), the... 

Tight experimental control is an extremely important goal in all experimental trials. Consequently, we talk a lot about how to maximize such control in these trials. However, it is simply a realistic consequence of the way that therapeutic confirmatory trials have to be conducted that the experimental control cannot be quite as tight in these trials as it is in human pharmacology trials and therapeutic exploratory trials. 

The advantage of very tight control in early Phase II (therapeutic exploratory) trials is that the "pure" efficacy of the drug can be assessed as well as possible. The drug has every chance to demonstrate its efficacy in these circumstances. 

A total of 290 participants were studied in the first therapeutic exploratory trial of on investigational antihypertensive drug. Of the 150 individuals treated with the test treatment, 32 reported fatigue. Of the 140 treated with placebo, 19 reported fatigue ... 

It is also appropriate to note that not all clinical trials utilize formal sample size estimation methods. In many instances (for example, FTIH studies) the sample size is determined on the basis of logistical constraints and the size of the study thought to be necessary to gather sufficient evidence (for example, pharmacokinetic profiles) to rule out unwanted effects. However, when the objective of the clinical trial (for example, a superiority trial) is to claim that a true treatment effect exists while at the same time limiting the probability of committing type I or II errors (a and P), there are computational methods used to estimate the required sample size. The use of formal sample size estimation is required in therapeutic confirmatory trials, this book s major focus, and strongly suggested in therapeutic exploratory trials. 

Therapeutic exploratory (Phase lb/II) Explore use for the targeted indication Estimate dosage for subsequent studies Provide basis for confirmatory study design, endpoints, methodologies Earliest trials of relatively short duration in well-defined narrow patient populations, using surrogate or pharmacological endpoints or clinical measures Dose-response exploration studies... 

Initial therapeutic exploratory studies may use a variety of study designs, including concurrent controls and comparison with baseline status. Subsequent trials are usually randomized and concurrently controlled to evaluate the efficacy of the drug and its safety for a particular therapeutic indication. Studies in Phase II are typically conducted in a group of patients who are selected by relatively narrow criteria, leading to a relatively homogeneous population, and are closely monitored. 

Therapeutic exploratory Explore use for the targeted Earhest trials of relatively... 

Human pharmacology and therapeutic exploratory studies define the most likely safe and effective dosage regimens for use in subsequent therapeutic confirmatory studies. These therapeutic confirmatory studies are typically run as double-blind, randomized, concurrently controlled clinical trials. 

Having considered these and other issues, what is a suitable dosing regimen for therapeutic exploratory and therapeutic confirmatory trials ... 

In addition to having an acceptable safety profile, an investigational drug needs to display beneficial therapeutic effects. This takes us into the realm of therapeutic exploratory and therapeutic confirmatory trials. The statistical approaches discussed in this chapter are characteristic of those employed in these trials. 

Trials that might otherwise be categorized as Phase I, II, III, and IV trials are referred to as human pharmacology, therapeutic exploratory, therapeutic confirmatory, and therapeutic use trials, respectively. 

A common design in therapeutic exploratory and confirmatory trials... 

Once we have assembled individual observations in a sample from a clinical study, our ability to understand the nature of those observations as a whole is limited by our ability to synthesize several disparate pieces of observation into an overall impression. Imagine that you have observed the following 10 observations of age of study participants in an early exploratory therapeutic clinical trial 45, 62, 32, 38, 77, 28, 25, 62, 41, and 50. 

To illustrate the coefficient of variation, consider the following (extremely simple and artificial) example. Imagine tliat there are two random variables in an early therapeutic exploratory clinical trial. One random variable is pulse (ranging from 50 to 80) and the other is age, which in this case is pulse minus 20. We can see that, from this example, values of pulse and age are just as disperse, but what differs between them is the mean. Hence, when we calculate the standard deviation, one random variable will appear to have more or less dispersion, but, after re-scaling the standard deviation with the sample mean, the measure of dispersion is the same. 

The view of the US Food and Drug Administration (FDA) concerning safety reviews is presented in their guidance document on the safety review of new drug applications (US FDA, 2005, p 5). As this guidance states, most therapeutic exploratory and therapeutic confirmatory trials are carefully designed to establish that a... 

Safety monitoring in clinical studies can be both data and labor intensive. In the context of later-stage therapeutic exploratory and therapeutic confirmatory trials, the collection of laboratory data is no exception. Typically, participants in clinical trials provide blood or urine samples at every clinic visit. There is an expansive range of clinical chemistry tests that can be conducted using these samples. 

When rather extreme departures from required assumptions are noted, our choice of an appropriate statistical method should be one of first validity and second efficiency. The difference between an extreme departure from required assumptions and any departure from required assumptions is again a matter of judgment. It should be noted that many of the parametric methods in this book are robust to departures from distributional assumptions, meaning that the results are valid under a number of conditions. This is especially true with the larger sample sizes encountered in therapeutic exploratory and confirmatory trials. We should also note that all the methods described in this book require that observations in the analysis are independent. There are statistical methods to be used for dependent data, but they are not described in this book. 

The term experimental means that researchers are systematically facilitating the administration of the drug of interest to some individuals and a control drug to others the preapproval therapeutic exploratory and therapeutic confirmatory trials discussed in previous chapters were experimental in nature. 

Additional objectives of clinical trials conducted in Phase II may include evaluation of potential study endpoints, therapeutic regimens (including concomitant medications) and target populations (e.g., mild versus severe disease) for further study in Phase II or III. These objectives may be served by exploratory analyses, examining subsets of data and by including multiple endpoints in trials. 

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