MTI Review Volume 9, Issue 1--A Publication of Medical & Toxicological Information (MTI)

THE ANIMAL RULE: ANIMAL v. HUMAN STUDIES AS SCIENTIFIC EVIDENCE

THE ANIMAL RULE: In May 2002 the Food and Drug Administration (FDA), with little fanfare, published its final rule in the Federal Register regarding testing of new drug products that has since become known as “the Animal Rule.” This new rule allows for certain types of drugs to be brought to market without being tested first on human subjects. Although this rule purports only to deal with “efficacy,” which is the power or capacity to produce a desired effect, agencies like the FDA are charged with safeguarding our food supply and seeing that the drugs we use are effective and safe for human consumption. Testing of chemical compounds for effectiveness and toxic or adverse effects is an integral part of this safety process. Before the imposition of this rule on July 1, 2002 (summarized below) drugs could only be marketed to the public after completion of human clinical trials.

SUMMARY: The Food and Drug Administration (FDA) is amending its new drug and biological product regulations to allow appropriate studies in animals in certain cases to provide substantial evidence of the effectiveness of new drug and biological products used to reduce or prevent the toxicity of chemical, biological, radiological, or nuclear substances. This rule will apply when adequate and well-controlled clinical studies in humans cannot be ethically conducted and field efficacy studies are not feasible. In these situations, certain new drug and biological products that are intended to reduce or prevent serious or life-threatening conditions may be approved for marketing based on evidence of effectiveness derived from appropriate studies in animals and any additional supporting data.

Under this rule, FDA can rely on the evidence from animal studies to provide substantial evidence of the effectiveness of these products when:
1. There is a reasonably well-understood pathophysiological mechanism for the toxicity of the chemical, biological, radiological, or nuclear substance and its amelioration or prevention by the product;
2. The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model (meaning the model has been adequately evaluated for its responsiveness) for predicting the response in humans;
3. The animal study endpoint is clearly related to the desired benefit in humans, which is generally the enhancement of survival or prevention of major morbidity; and
4. The data or information on the pharmacokinetics and pharmacodynamics of the product or other relevant data or information in animals and humans is sufficiently well understood to allow selection of an effective dose in humans, and it is therefore reasonable to expect the effectiveness of the product in animals to be a reliable indicator of its effectiveness in humans.

The rule goes on to further state the “Safety evaluation of products is not addressed in this rule…FDA recognizes that some safety data, such as data on possible adverse interactions between the toxic substance itself and the new product, may not be available. This is not expected to keep the agency from making an adequate safety evaluation.”

On the surface it appears that scientists of at least one federal agency believe that animal evidence can take the place of well controlled clinical trials on human subjects. However, one reason the debate is continuing is that the followers of sound science know this is not the case. Scientists find themselves caught in a politically driven system and at the same time recognize that they must deal with very real bioterrorism issues.

SCIENTISTS MEET : In November 2003 the National Capital Area Chapter of the Society of Toxicology (NCAC-SOT) held a symposium in Washington, DC to generate discussion about this very issue of using only animal models for testing chemical compounds that are destined for human use. Representatives from the FDA, EPA and private industry gave their varying views on the tremendous challenge this regulatory rule has created for the scientific community and examples of ways they are dealing with the resulting problems. At first examination, it seems reasonable to allow drug manufacturers to rely more heavily on animal experiments for chemical or bioterrorism remedies in cases such as anthrax where human tests would be considered unethical. However, testing solely in animals regardless of the species or strain can never completely replicate human clinical trials. And many critics worry that the wording of the rule that includes the ambiguous phrases “certain new drug and biological products” and “life-threatening conditions” leaves a wide open avenue for pushing more drugs ever faster through the regulatory phase to an unsuspecting public. In such a scenario, compared by some to the 1996 film Extreme Measures in which homeless New Yorkers were unwittingly medical experiment “volunteers,” the rule change means that there will still be human clinical trials; however, they will not be controlled nor will the participants know they are the test cases.

Although this conference took place at a highly scientific level and the legal community was not an active participant the issues discussed underscore the tremendous complexity facing attorneys challenged by scientific issues as they represent their clients and judges who must rule on specific circumstances and the acceptability of scientific evidence when the regulatory law appears to deviate from sound science. U.S. Supreme Court Justice Stephen Breyer, in his introduction to the Reference Manual on Scientific Evidence, stated that “there is an increasingly important need for law to reflect sound science.” At the risk of being reductive with very complex issues such as the new “Animal Rule,” it might be worthwhile to step back and look at the fundamental basics of testing new therapeutic products to arrive at a sound science conclusion regarding whether evidence from animal studies can supplant evidence from human studies. For the purposes of this discussion we will use the broad definition of “drug” to be any chemical agent that affects living processes.

ANIMAL STUDIES: It cannot be underestimated the incredibly valuable contribution that animals have had in the discovery and testing of new drug products. For example, in the early part of this century, Canadian scientists were able to isolate insulin and were successfully able to keep diabetic dogs alive. This success led to its use in a human test case of a fourteen year-old dying of diabetes and the dramatic evidence that insulin could effect the same therapeutic result as it did in the beagles. Millions of people have since benefited by healthier, longer lives because of these very important animal studies. Animal studies allow us to look at the full pharmacological spectrum of a new drug to test its efficacy and safety to see if the drug has promise for man. We have now even advanced to the point where we have a full range of alternative testing methods that are available and are continually adding new ones such as genomics and proteomics to our arsenal of testing procedures. New methods are helping reduce the number of animals needed for testing which is not only a cost saving measure but also recognized as more humanitarian.

EXTRAPOLATING ANIMAL DATA TO HUMANS: In her now classic work The Dose Makes The Poison Dr. Alice Ottoboni addresses this issue of extrapolating data from animal studies to humans:

“If there were absolutely no relationship between man and other mammals in their response to chemicals, we would have no methodology for evaluating adverse effects or, for that matter, beneficial effects of drugs, nutrients, etc. for the human species. The consequences of such a situation for human health and well being would be incomprehensibly tragic, and the billions of dollars spent yearly by government and industry in programs for conducting and evaluating animal toxicity tests would be a useless and unjustified waste.

“Fortunately, such is not the case. There are many common threads woven through the fabric of bioevolution. Humans are not unique in their anatomy, physiology or biochemistry. The similarities among mammals are far more numerous than are their differences. And, at the molecular level, man even shows a kinship with single celled organisms in cellular anatomy and biochemistry. For example, one of the final pathways for converting sugars, fats, and some amino acids to their end products of energy, carbon dioxide and water is the same for almost all living organisms whether they be plants, microorganisms, or animals. This pathway, known as the Krebs cycle or the tricarboxylic acid (TCA) cycle, was first studied in yeasts—the same kind of organisms that are used to raise our bread and carbohydrate our beer.

[However,] the proposition that data obtained from animal experimentation can be applied directly and quantitatively to man is so obviously flawed that it had no proponents until relatively recently. There is sufficient species variation in the toxicity of chemicals to make a blind transfer of data from animals to man very dangerous.”

ANIMAL STUDIES CANNOT SUBSTITUTE: In fact, there is no reputable scientist that would argue that animal studies can exactly replicate human studies. Every standard textbook or reference work in pharmacology or toxicology concurs with this statement. In the well-known publication The Goodman & Gilman Pharmacological Basis of Therapeutics the authors state: “Before initial studies in man are permitted, the full pharmacological spectrum of a new drug and its pharmacokinetic characteristics must be thoroughly and extensively explored in animals, and both acute and chronic toxicity tests must be conducted on several species. Because of species variations, such studies are considered useful merely as evidence that the drug has promise and is sufficiently safe to warrant testing in man. Even the most extensive studies in animals cannot substitute for successful clinical trials as evidence of therapeutic efficacy.”

SPECIES DIFFERENCES: Mammals are largely similar in the metabolic pathways at the cellular level, but the degree to which they use one biochemical pathway over another can vary dramatically between species. And, there are physiologic differences peculiar to a given species. For instance, rats are unable to vomit and dogs can expel their stomach contents at will, while with man it is an largely involuntary mechanism of action. There are very real species differences that make relying solely on animal data for therapeutic products that will be used by humans very dangerous indeed.

EXAMPLES OF DIFFERENT SPECIES:

RATTUS NORVEGICUS

HOMO SAPIEN

POLITICS OF REGULATORY LAW: The public demands a ready supply of high quality drugs that they perceive will enhance or extend their quality of life and at the same time protect them from acts of bioterrorism. Unfortunately drug safety is not at the top of most people’s list; in fact, safety is directly contradictory to the increasing demand of drug availability. The pharmaceutical companies are trying to meet this increased demand brought on in large part by their aggressive advertising to consumers. And they, as profit-centered corporations are trying to please their shareholders and bring new products to market as quickly and efficiently as possible in order to produce a satisfactory economic return. Consequently, drug safety is not at the top of their list either. Added to this mix is the fact that most of the funding for new drug approvals is provided by the manufacturers who have a vested interest in seeing that the process is accelerated. In fact, the FDA’s Center for Drug Evaluation and Approval (CDER) now makes an annual report to its “shareholders,” touting their success at speeding up the process for their corporate investors. Bringing a new drug to market is an expensive process at best and eliminating human trials in one area is one step closer to relying totally on post marketing data for drug efficacy and safety evaluations. Is it any wonder that many scientists are concerned with the direction this brave new world is taking us?

SOUND SCIENCE CONCLUSION: But at the end of the day, regulatory agencies are not courtrooms and they are bound by political decisions, not sound science. Can animal evidence take the place of human evidence when dealing with a human case? Of course not--if you intend to use sound science. Have the regulatory rules changed ? Yes, they have but let us hope the rules of scientific evidence stand solidly on the side of sound science.

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