Concurrent controls

No acute-duration oral MRL was derived for endosulfan because no suitable end point was available among the reliable acute-duration studies. The lowest LOAEL, 1.8 mg/kg/day, was for a serious end point, convulsions in pregnant rabbits, appearing 10 days after the start of daily gavage dosing in the EMC (1981) study. Because animals from both the control and the test groups developed ascites, and six rabbits were added without concurrent controls, the reliability of these results is questionable. 

The small number of animals used in a pyramiding dosage study makes it difficult to do standard statistical comparisons. This difficulty can be overcome to a certain extent by taking advantage of two design aspects of the pyramiding protocol. First, pretreatment data can and should be obtained on all animals for all parameters examined or determined. In-study comparisons should be made both to pretreatment data and to concurrent control animals. Such comparisons can be made not only on... 

Statistical analysis is a very useful tool for evaluating the effects of treatment on many developmental and reproductive toxicity parameters. For some parameters, such as maternal body weight changes, fetal weight, and horizontal activity in an open field, the comparison to the concurrent control is the primary consideration and, assuming adequate group size, the investigator relies heavily on the results of appropriate statistical analyses to interpret differences from control. 

In spite of its current popularity in the pharmaceutical industry, the use of two control groups is opposed by some statisticians on the grounds that a significant difference between the two groups may indicate that the study was compromised by excessive, uncontrolled variation. Haseman et al. (1986), however, analyzed tumor incidence data from 18 color additives tested in rats and mice and found that the frequency of significant pairwise differences between the two concurrent control groups did not exceed that which would be expected by chance alone. 

Initial therapeutic exploratory studies may use a variety of study designs, including concurrent controls and comparison with baseline status. Subsequent trials are usually randomized and concurrently controlled to evaluate the efficacy of the drug and its safety for a particular therapeutic indication. Studies in Phase II are typically conducted in a group of patients who are selected by relatively narrow criteria, leading to a relatively homogeneous population, and are closely monitored. 

Concurrent Control. Comparisons between treatments should be made to the maximum extent possible between experimental units from the same closely defined population. Therefore, animals used as a control group should come from the same source, lot, age, and so on as test group animals. Except for the treatment being evaluated, test and control animals should be maintained and handled in exactly the same manner. 

Finally, some thought must be given to the clear definition of what is meant by experimental unit and concurrent control. 

There is a continuing debate as to whether inbred or outbred strains of rodents should be used. In theory, inbred strains are preferable because a more accurate knowledge of back-grormd tumour incidence is available. It may be, however, that a particular inbred strain may metabolise the test material in a certain way or have a genetic resistance to the development of a specific tumour type. Usually outbred strains of rat or hamster are used, but occasionally inbred mice strains are included. An FI hybrid mouse strain is frequently employed. In some circumstances outbred Syrian hamsters may be the species of choice. The most important factor is to have a sound knowledge of the background incidence of tumours in the species or strain selected. This information complements the concurrent control data and provides information on the susceptibility of the strain to rare tumour t)rpes. Modif)dng factors, such as diet, cage density, etc., must be kept as constant as possible to enable correct interpretation of the results. ... 

Concurrent control information is the most important factor in the statistical analysis needed to confirm the presence of an oncogenic effect. 

The most important comparison is with concurrent control groups. However, there are occasions when it is necessary to use historical data, that is, information from control animals of the same strain on other studies. This is more relevant if the studies were conducted in the same laboratory under similar conditions and at the same time. The incidence of a particular neoplasm is often different between laboratories and may change with time. Historical data are most useful to get an idea of the variation in the background range of frequency and also to ascertain that rare tumour t)rpes can occur spontaneously. 

In all species/strains, there will be some pre- and postimplantation loss. In deciding whether the effects are substance-related, reference is made not only to the concurrent control, but also to historical values. It is impossible in this chapter to consider every possible outcome, but in general a slight increase in pre- and/or postimplantation loss that is within the typical control range, and does not show an obvious dose-related pattern, is more likely to be incidental than increases outside the control range and/or showing an obvious dose-relationship. 

For fetal variations that occur frequently, comparison of the incidences with the expected background range in addition to the concurrent control remains valid, but the concurrent control is now of greater importance. 

Since teratology studies in mice are far less frequent than in the rat, the amount of recent historical control data may be limited. If little or no recent reference data are available, the size of the concurrent control group should be increased. 

Each laboratory should compile its own historical control data from animals housed in their facility these animals can be concurrent controls, stock animals, or those used for training, depending... 

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