Single study design

Except for the embryo and fetal development component in rabbits, the components described above can be combined into fewer, larger studies instead of conducting each component separately. Acceptable alternatives include the single-study design and two-study design. The choice may be made based on when study results are needed (how soon are females to be incorporated in clinical studies) and compound availability. 

However, combining different phases of the reproductive cycle into a single study design increases the risk of an adverse event compromising the evaluation of subsequent stages, e.g., any impact on fertility of the male or female could result in too few litters for the embryo-fetal development evaluation. Under such circumstances, a separate embryo-fetal development study would have to be scheduled with the associated added cost and use of animals. Further, a separate embryo-fetal development study is recommended if the test item is poorly tolerated with repeated dosing in order to limit the duration of the administration period. 

A typical feature of Phase [lb are dose response trials regarding a drug s safety, efficacy and side effects. No single study design can address all aspects of dose response relationships for a new drug, and so a number of different... 

As the most probable option, three study protocols are indicated. It is also possible to plan a single study design (rodents) or two study design (rodents). 

Figure 4 International Conference on Harmonisation guidelines on detection of toxicity to reproduction for medicinal products, (a) Study of fertility and early embryonic development (4.1.1) (b) study for effects on prenatal and postnatal development, including maternal function (4.1.2) (c) study for effects on embryo-fetal development (4.1.3) (d) single-study design (4.2) (e) two-study design (4.3).

J.H. Massey and S.K. Singles, Photostability of two fungicides on spray application monitors, in Terrestrial Field Dissipation Studies Design, Interpretation and Purpose, ed. E.L. Arthur, V.E. Clay, and A. Barefoot, ACS Symposium Series No. 842, American Chemical Society, Washington, DC (2003). 

The critical effect of intermediate-duration exposure to -hexane in humans is neurotoxicity, specifically peripheral neuropathy. No inhalation MRL was derived for this duration because the reports of neurological effects in humans were predominantly case reports with inadequate documentation of exposure levels or comparison with unexposed groups. A large database on neurological effects in rats exists for this duration however, the design of these experiments precluded documentation of clear dose-response relationships within a single study. Because of the limited database for oral exposure to -hexane and the lack of toxicokinetic data for this route, no MRL was derived for oral exposure to -hexane. 

Overview of Study Design. Four groups of five adult rabbits each receive a single vaginal exposure daily for 10 days. The genitalia are examined daily. Animals are then euthanized and the vagina is examined macroscopically and microscopically. 

In a study designed to investigate the mechanism of renal toxicity for 1,4-dichlorobenzene reported in the NTP (1987) studies, 1,4-dichlorobenzene administered by gavage to male Fischer 344 rats at 7 daily doses of 120 or 300 mg/kg/day significantly increased the level of protein droplet formation in the kidneys of males but not females (Charbonneau et al. 1987). Administration of a single dose of... 

The FDA allows single-dose human studies based on single-dose animal studies. A rodent and non-rodent species are required and signs of major toxicity must be demonstrated. The study design is outlined in the publication by Munro and Mehta and requires an observation period of 14 days after dosing. 

The likely effectiveness of the product, derived from the preclinical and early clinical work, will determine study design, complexity and size. It is a mistake to try to answer too many questions in a single study, despite the apparent commercial attractiveness of such a strategy. A study overburdened by many secondary objectives is more likely to fail when the design is implemented in many centres worldwide. What seems a good idea in head office can often be hard to implement in the clinic. Statistical advice is vital, and statisticians offer excellent opinions about the utility of complex study designs. 

Numerous studies have been conducted in which animals were exposed to 2-hexanone via inhalation. However, the purpose of many of these studies was to assess the potential effects of combined exposure to 2-hexanone and another substance (usually chloroform or methyl ethyl ketone [MEK]). Study design has consequently involved exposure to only one concentration of 2-hexanone as a control exposure. A single high dose of 2-hexanone was used in several other studies in order to elicit and study histopathological changes in the affected nervous tissue. In addition, the grade or purity of the 2-hexanone administered was not stated in many studies, or in some cases, hexanone with purity as low as 70% was used. As a result of these various complications, the usefulness of the available data is limited. 

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