Therapeutic confirmatory studie

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. 

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... 

Therapeutic confirmatory (Phase III) Demonstrate/confirm efficacy Establish safety profile Provide an adequate basis for assessing the benefit/risk relationship to support licensing Establish dose-response relationship Adequate and well controlled studies to establish efficacy Randomized parallel dose-response studies Clinical safety studies Studies of mortality/morbidity outcomes Large simple trials Comparative studies... 

Therapeutic confirmatory Demonstrate/confirm efficacy Adequate, and well controlled studies to establish efficacy... 

Safety analyses are not typically prespecified in the study protocol and/or the study analysis plan. Studies are typically powered on efficacy outcomes (the primary objective in therapeutic confirmatory trials see Chapter 9), and the sample size that results from this sample-size estimation may be considerably smaller than would be needed for a thorough investigation of safety data. 

All of the studies that are performed before a therapeutic confirmatory trial is started collect information that facilitates a logical scientific progression from FTIH studies to the point where the therapeutic confirmatory trial is appropriate. In a real sense, all of these studies, and all of the information gained to date, have had one purpose to allow the primary objective in the therapeutic confirmatory trial to be stated as simply as possible. In this context, the word simple is not pejorative. To the contrary, a primary objective that can be stated simply can be tested simply, i.e., in a straightforward and unambiguous manner. This is a highly desirable attribute in a primary objective. 

The following are some of the fundamental components in a study protocol for a therapeutic confirmatory trial for an investigational antihypertensive drug ... 

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

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. 

The term "responders analysis" was first introduced in Chapter 9 with regard to clinical laboratory data. A responders analysis approach can be used in the context of efficacy data, as well. Consider a double-blind, placebo-controlled, therapeutic confirmatory trial of an investigational antihypertensive ("test drug"). Based on earlier experience, a period of 12 weeks is considered sufficient to observe a clinically meaningful treatment effect that can be sustained for many months. In this study, a participant whose SBP is reduced by at least 1 0 mmHg after 1 2 weeks... 

In this chapter we highlight additional statistical considerations relevant to therapeutic confirmatory trials, and other study designs that also provide important information upon which to base decision-making. These additional insights and information build upon the material presented so far. As this chapter is largely conceptual rather than computational, we have included a number of references to guide your further reading. 

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. 

We have seen that relatively small numbers of participants are recruited for early phase trials (perhaps 20-80 in FTIH studies and 200-300 in early Phase II studies), and relatively larger numbers are recruited for therapeutic confirmatory trials (perhaps 3000-5000). It is relatively easy to recruit between 20 and 80 participants at... 

Phase 3 After phase 2, there are still other questions that must be answered. Is the drug effective Does the drug have some benefit beyond that of similar drugs already on the market What is the relationship between risk and benefit All of these questions are answered with the Phase 3 study (or therapeutic confirmatory). In this case, there are no longer few dozen patients enrolled, but hundreds or thousands. The effectiveness of the drug on symptoms, quality of life, or survival was compared with a placebo (a dummy therapeutic efficacy), with other drugs already in use, or no treatment. 

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