Two study designs

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. 

Various designs are used for the SRD sffidy. We will discuss the two study designs that are most frequently used. 

The combined fertility and embryo-fetal development study is described as a two study design in the ICH S5(R2) guideline (1) and is anticipated for use in rodents (usually rat but also the mouse) embryo-fetal development must still be evaluated in a second, nonrodent, species. 

According to the ICH Harmonized Tripartite Guideline, particularly in cases of low or no toxicity, but also in cases of chronic exposure, single and two study designs in rodents are also possible and acceptable. 

Preparing the study designs for each of the research studies to be contracted. The more details provided in the study designs, the better. The CROs use the provided information to prepare a draft study protocol and a proposal with time and cost estimates. Examples of two study designs are shown in Table 1. 

Gulati, D.K., E. Hope, J. Teague, and R.E. Chapin. 1991. Reproductive toxicity assessment by continuous breeding in Sprague-Dawley rats A comparison of two study designs. Fundam. Appl. Toxicol. 17(2) 270-279. 

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).

The two classes of epidemiological studies, case-control studies and cohort studies, are both based on the dose-effect relationship, i.e., the relationship between the magnitude of chemical exposure and the freqnency of disease. The two study designs approach the dose-effect relationship from different directions, case-control studies from the effect side and cohort studies from the exposure side. As might be expected, they meet somewhere in the middle. In fact, case-control studies may... 

Two studies resolved the Unresolved Safety Issue A-44, "Station Blackout." The first siudy, The Reliability of Emergency AC Power Systems in Nuclear Power Plants," when combined uh die lelevant loss-oToffsite-power frequency, provides estimates of station-blackout frequencies lor 18 nuclear power plants and 10 generic designs. The study also identified the design and operational features most important to the reliability of AC power systems. The second study, "Station Blackout Accident Analysis" (NUREG/CR-3226), focused on the relative importance to risk of laiion blackout events and the plant design and operational features that would reduce this risk. 

This early biological result spurred a variety of biochemical studies of the interactions of various polyamides with the basal transcription machinery and TE-DNA complexes. Two studies have used promoter scanning to identify sites where polyamide binding inhibits transcription [64, 65]. The method uses a series of DNA constructs with designed polyamide binding sites at varying distances from... 

In studies designed to examine dermal absorption of trichloroethylene, emersion of the hand (Sato and Nakajima 1978) or thumb (Stewart and Dodd 1964) for 30 minutes was reported to be pairrful. The pain was described as excruciating in one study (Sato and Nakajima 1978), and in another study it was described as mild by one subject and moderately severe by two subjects (Stewart and Dodd 1964). Occupational exposure to trichloroethylene that involved both dermal and inhalation exposure has been reported to result in dizziness, headache, insomnia, lethargy, forgetfulness, and loss of feeling in the hands and feet (Bauer and Rabens 1974 Kohlmuller and Kochen 1994). 

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). 

Forde et al.20 used a more complex study design to examine the effect of boiled coffee vs. paper-filtered coffee vs. coffee abstinence. The investigation involved 33 men with elevated baseline serum cholesterol levels (average 8.7 mmol/L [335 mg/dL]) who apparently were habitual boiled coffee drinkers (implied but not stated). The 10-week study was divided into two 5-week periods. Subjects were assigned to one of four groups (1) continuation of habitual consumption (control), (2) abstinence from coffee for the full 10 weeks, (3) abstinence from coffee for the first 5-weeks, followed by 5 weeks of paper-filtered coffee consumption, and (4) abstinence from coffee for the first 5 weeks, followed by 5 weeks of boiled coffee consumption. 

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