Opinion ID: 2161593
Heading Depth: 2
Heading Rank: 2

Heading: In vivo studies

Text: Dr. Done next turned to the in vivo (animal) studies relating to Bendectin. He first discussed a study entitled Reproductive Study of Offspring of Bendectin-Treated Dams, which was conducted by appellee and reported by a Dr. Staples. The study was designed to discover whether Bendectin would cause birth defects in the offspring of female rabbits. Dr. Done quoted the pertinent findings and conclusions of Dr. Staples: The limb alterations observed following Bendectin administration to female rabbits during gestation are considered to have been of no consequence in view of the mildness of the change and in view of its presence among the kits of controlled females. The sternal changes noted involving shifting ossification [bone formation] centers by past experience could point to the possibility of severe alterations should the dosage be increased above the levels employed here. This is of particular importance in view of the fact that that type of change was noted only at the highest dose administered. This possibility can be answered only if further experimentation employing increased dosage is conducted. Such experimentation would at least provide additional information concerning the significance of the abortions seen in this study following Bendectin administration to the rabbit. Dr. Done said that this study raised a suspicion of the teratogenicity of Bendectin which could be resolved only by further studies. Because appellee conducted no further studies, Dr. Done concluded that the Staples study must therefore be viewed as positive. [5] With regard to the sternal changes which Dr. Staples found, Dr. Done testified that the study could not be viewed as negative because the changes were found only at the highest dose used, which was not the highest dose possible. Teratologists, he said, use doses which fall just short of the amount which would start making the mothers ill. They then look for a dose-response relationship in which the number of effects increases with the dosage. Such a relationship helps to demonstrate that the effect is drug-related. The Staples study, however, was lacking the proper dose levels. Dr. Done also noted that the abortions mentioned by Dr. Staples ( i.e., spontaneous abortions or miscarriages) could have occurred because the babies were malformed and therefore couldn't survive.... Although the principal in vivo study on which Dr. Done relied was the one reported by Dr. Staples, he testified that two other in vivo studies strengthened his opinion that Bendectin is a teratogen. One was conducted by a Dr. Roll to test the effects of doxylamine, one of Bendectin's components, on mice and rats; the other was by a Dr. Hendricks and dealt with the effects of Bendectin on monkeys. Dr. Done did not discuss these studies at length, but he did say that they showed in my opinion evidence of teratogenicity in those particular species and that would just be further evidence of the potential of the drug to produce defects. As with the other types of scientific data on which he relied, Dr. Done readily acknowledged that he could not conclude that Bendectin was a teratogen on the basis of the in vivo studies alone. In this regard he testified on cross-examination: Q. Doctor, the observations of what is happening in people who receive a drug and to their offspring is crucial in getting what in the last analysis is the only meaningful answer whether the drug causes defects in people or not; wouldn't you agree with that? A. The only definitive answer in terms of absoluteness in humans, yes.       Q. Now, any time you have both human studies and animal studies, presuming that they are both properly performed, the human studies would be more valid, more reliable, wouldn't they? A. Well, it depends on how well performed they are compared to animal studies. In terms of pinning it down to the human being, if the studies are well performed they would have greater meaning.       Q. Now, in studies with human beings as distinguished from studies with animals, it is much more difficult to get perfect controls; is that correct? A. Yes. Q. And that is because animals can be kept in the same environment, given the same food and observed very closely; is that correct? A. That is part of the reason, yes. Q. You can control their breeding? A. That's right. Q. Whereas in human beings, they are much more different, much more difficult to control even if they are on a study; is that correct? A. That's right.       Q. Doctor, isn't it a fact that you cannot determine teratogenicity from animal studies? A. You can determine teratogenicity in the human being from animal studies. Q. But there is no direct correlation between the two? A. Well, there is a direct correlation... in the sense that no known human teratogen to my knowledge has failed to be teratogenic in at least one species of experimental animal. Dr. Done plainly did not state that in vivo data are useless, as the trial court apparently believed. Dr. Done acknowledged that, in theory, human studies may be better than animal studies for predicting a drug's effect on humans, but he also pointed out that animal studies have many advantages over human studies because better controls are possible. Moreover, he specifically said that [y]ou can determine teratogenicity in the human being from animal studies. Dr. Done did concede that [t]he fact that [a substance] is teratogenic in a species of animal does not necessarily mean that it will be in humans as far as we know. The extent of that concession, however, was simply that one cannot conclude that a drug is a human teratogen on the basis of animal studies alone. Dr. Done did not attempt to draw such a conclusion. Even Dr. William Scott, one of appellee's expert witnesses, testified that animal studies must not be considered alone, but in combination with all other available data, to determine the teratogenicity of a substance. That is precisely how Dr. Done arrived at his conclusion that Bendectin was a teratogen, as his testimony made very clear.