Study Design Considerations For Special Populations

The goal of clinical pharmacology studies in special populations is to determine how the dose and dosage regimen should be adjusted in special populations so that the same systemic exposure that was found to be safe and effective in the pivotal clinical trial for the population it was tested in can be achieved. There are two approaches that can be adopted, a standard PK approach and a population PK proach.

In a standard PK Approach, a single dose or multiple dose(s) of the drug are administered (within the same study protocol) to the population being investigated, e.g., males and females; different ethnic and race groups, adult vs. elderly, and diffent age categories in the pediatric age groups. The number of subjects included should be enough to obtain a reasonable estimate of variability. Following the administration of the drug, frequent blood and urine samples are collected and pharmacokinetic parameters estimated and compared between the various populations of interest.

With the population PK (POPPK) approach, fewer samples are collected from a larger number of subjects as compared to the Standard PK approach, and PK parameters obtained are compared between the populations of interest. The conduct of Population Studies is described in Chapter 11 and in the FDA Guidance on Population PK [97]. Population PK studies are generally conducted as an add-on study to Phase II and III clinical trials. Some of the advantages of this approach include fewer bloodsample collections. Thus ethical concerns of collecting several blood samples from certain populations (e.g., pediatric) are reduced. The sample collections can be part of a routine clinical visit when blood and urine are being collected for other laboratory investigations. Since these studies are generally being conducted as part of Phase II and III trials, phramacodynamic endpoints can also be measured and exposure-response (safety and efficacy parameters) relationships could be evaluated in different populations of interest.

In order to decide which approach (standard PK vs. Population PK) is better suited for conducting studies in special populations one should consider the following. Regulatory agencies worldwide require the inclusion of representative special populations in clinical trials, thus special populations will be part of Phase II and III clinical trials. Therefore data which can provide exposure-response (safety and efficacy parameters) measures by including POPPK in the special population within pivotal clinical trials would be more valuable than simply collecting information on pharmacokinetic differences based on the standard PK approach. Based on simulation studies some researchers believe that the population PK approach is preferred over the traditional PK approach when characterizing

PK and PK/PD differences involving intrinsic (gender, race, age) factors. For assessing the effect of extrinsic factors (different drugs, smoking, food, etc.) one may not have enough subjects with the presence of that factor, enrolled in clinical trails to assess differences based on POPPK.

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