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ICH E-1 suggests that a database of about 1500 patients (300-600 for 6 months, 100 for 1 year) is usually sufficient for chronically administered drugs, but as suggested in that guideline; this may be too small for the very long, very wide exposure in an asymptomatic population intended for antihypertensive drugs. [15] In addition to the usual safety assessments, attention should be paid to excessive fall in blood pressure (hypotension), especially on standing (orthostatic hypotension), and rebound phenomena. Depending on the particular drug and other observations, studies of effects on heart rhythm or cardiac conduction, coronary steal effects, effects on risk factors for cardiovascular disease (e.g., blood glucose, lipids), and effects on target organ damage are of interest.

As antihypertensive treatments are often used in combination, it is important to study the efficacy and safety of the new drug in this situation. Information on combination use can be obtained in formal factorial studies and in combined use in the course of long- and short-term clinical studies. Specific requirements regarding clinical co-administration studies may vary among regions. Studies in patients with inadequate blood pressure control on other agents will provide information on the effect of the test drug when added to other agents (add on studies). Studies in which additional drugs are added to the test drug to achieve an adequate response may also be useful.

There are two approaches to the combination studies needed to obtain safety and efficacy data to support fixed combination products. It is essential to consult with regional regulatory authorities regarding the specific data needed to support the specific indications.

5.1 Factorial study:  In a factorial study, placebo, and one or more doses of the test drug T and another drug D are studied alone and in the combination in a short-term randomized controlled trial. Such a trial can be used to show that the combination has a greater effect than either drug alone. Most informative for identifying the appropriate dosages for a fixed combination is a factorial D/R study in which several doses of each drug, e.g., a test drug T and another drug D, and their combinations are compared, as shown below.

This design reveals D/R relationships for the test drug and other drug alone and in combination with each dose of the other treatment and may support one or more fixed combinations. These studies reveal "response surface" relationships that use data from all groups. It may be necessary to study separately the low doses and low dose combinations to establish their specific usefulness.[16]

5.2 Studies in non-responders to each drug
The safety and efficacy of combinations can also be assessed by examining the effect of the combination in patients failing to respond to both of the single drugs, e.g., diastolic blood pressure > 90 mmHg on that component. In some cases, regional authorities only require trials in patients failing to respond to one of the components.

This article deals with control and design principles that guide the conduct and conclusion of a meaningful HT trial. The international guidelines and current clinical and biostatistical practices were reviewed for relevant clinical, design, end-point assessments and regulatory issues.

The results are grouped mainly into ethical, protocol and assessment issues. Each trial is as meaningful as the number of scientific questions it answers and paves the direction of future trials in that field.

Compliance to GCP opens up the data for correct interpretation. Any neglect toward this end of abiding by the GCP principles can raise a batch of critical questions, eventually rendering the entire data to be uninteresting or suspect.

Principles of study design and analysis mentioned in this article can give the trial lists an advantage of a well-designed study, providing the crucial evidence of safety and efficacy of the agent under testing.

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16. EARLY: first functional class II population study emphasizes need to diagnose and treat PAH early [media release]. Allschwil, Switzerland: Actelion Pharmaceuticals; 2007.



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