Therapeutic exploratory studie

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. 

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. 

Suppose that an investigational antihypertensive drug is evaluated at multiple doses in a parallel-group placebo-controlled study. Participants in this therapeutic exploratory study were randomly assigned to receive either placebo or one of three possible doses of the test treatment (low, medium, or high). The treatment period was for 6 weeks. The number and percentage of participants experiencing any AE, and particular AEs, are displayed in Table 8.2. 

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... 

What information from early phase trials may be used to inform the study designs of therapeutic exploratory and therapeutic confirmatory trials ... 

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 ... 

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. 

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. 

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. 

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. 

Sample size estimation requires the input of a number of specialists involved with the development of new drugs. The estimate of the standard deviation can be informed by exploratory therapeutic trials of the same drug or by literature reviews of similar drugs. Synthesis of these data from a number of sources requires statistical and clinical judgments. As was seen in Figure 12.1 the estimate of the standard deviation has an important effect on the sample size. Study teams should understand the sources of variability in... 

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