BENEFIT THE ANIMALS

When government policies and regulations are considered, the guiding principle should be that it must help the animals. Lack of adherence to this principle can be construed as contributing to regulatory burden.

What contributes to regulatory burden? One of the main sources of regulatory burden is the lack of understanding of the scientific process. A good example of this lack of understanding is represented by USDA’s Policy 12. The goal of this policy is to provide guidance in enforcing the Animal Welfare Act, which requires investigators to minimize pain and distress by seeking alternatives to the use of animals in research. In the scientific process, the goal of the scientist is to test an hypothesis using the most rigorous scientific approaches possible. These approaches may require animals, cell cultures, mathematical models, and/or human subjects. The point is to do the best science possible. In reality, the scientist has already extensively considered alternatives to animals in designing the experiments. Good science requires more than a broad knowledge of the literature and a recent literature search. Unfortunately, there is a reality gap between the regulatory community and the scientific research community. Sessions like this workshop will contribute to closing that gap.

One of the suggestions from the study to help reduce regulatory burden was to prereview policies and regulations before implementation or commentary period. There should be discussion within the broad scientific community that includes investigators, IACUC coordinators, and laboratory animal veterinarians, all of whom will be affected by the policies or regulations.

In addition, there should be a sunset review of all policies and regulations that have been implemented. Every 5 or 10 years, policies and regulations should be reviewed by an external body to determine whether the policy has been effective and whether it should be revised.

The last aspect of what can contribute to regulatory burden is changing standards of compliance. In an environment where the rules keep changing, it becomes a constant challenge to remain in compliance, especially when there is no mechanism to directly inform investigators about the changes. Perhaps the rate of change should decrease so that everyone can understand what the standards are at this point in time.

If the factors I have described are the causes of regulatory burden, then what is the result of regulatory burden? What impact does regulatory burden have? Unfortunately, the impact is difficult to quantitate. However, issues such as lack of cooperation, feeling of distrust, and a general cynicism about the process can undermine the progress that has been made for animals.

Perhaps the most adverse effect of regulatory burden is the cost to the public. This cost is incurred with respect to financial loss due to reduced productivity as well as a loss of research. The burden of unnecessary regulations results in less research accomplished, fewer advances in health care, and fewer lives saved. Institutions and investigators have a shared responsibility with the regulatory agencies to minimize regulatory burden so that advances in health care can be made.

KEEP IT SIMPLE

The second message today is that any change in pain and distress definitions, categories, or reporting requirements must adhere to the dictum “keep it simple.” Compliance is facilitated by keeping regulations and policy simple.

The Animal Welfare Act contains the following very simple statement: “The Secretary shall promulgate standards for animal care, treatment and practices in experimental procedures to insure that animal pain and distress are minimized, including adequate veterinary care with appropriate use of anesthetic, analgesic, or tranquilizing drugs or euthanasia.” This simple statement has been made more complex than necessary.

The most effective means of minimizing pain and distress in research animals is not by federal regulation, but by an emphasis on the shared responsibility among investigators, veterinarians, laboratory animal care staff, and IACUCs to oversee the welfare of animals. There is an extensive process in place that, when operating effectively, ensures appropriate animal care. Pain and distress are considered in depth during the development of experimental protocols including veterinary prereview, IACUC review, and peer review by funding agencies and often by institutions. After protocols are approved and the work begins, animals are monitored throughout the study by animal care staff, research staff, and laboratory animal veterinarians. Consideration and observation by professionals in the institution are clearly the most effective means of minimizing pain and distress. In addition, this process is overseen by the IACUC during the semiannual inspection, the NIH assurance statement, the USDA in their annual inspection, and AAALAC International during the accreditation process.

With these assurances in place, why do we need to categorize experimental procedures and submit the numbers of animals in the respective categories to the USDA? As Barbara Rich of NABR pointed out at the SCAW meeting last month, the Animal Welfare Act only requires “. . . information on procedures likely to produce pain or distress in any animal and assurances demonstrating that the principal investigator considered alternatives to those procedures. . . .” I submit that quantitative information concerning animals experiencing pain and distress is not required by the Animal Welfare Act. In addition, because it fails to enhance the care and well-being of the animals, this requirement constitutes regulatory burden for the institutions. In their annual reports, institutions should be required to provide only qualitative information concerning the kinds of interventions performed on animals.

The question, “Do we need to change the classifications of pain and distress?” should be, “Do we need a classification system of pain and distress at all?” The answers are yes and no. No, we do not need one because the law does not require one, and the process of counting and reporting numbers of animals in different categories does not benefit the animals. Yes, we need a simple classification system to provide guidance and increase awareness of the investigators, laboratory animal veterinarians, and IACUCs. Such a system should be used only in the development, review, and implementation of a protocol to ensure that animals at risk receive extra attention.

The assessment of levels of pain and distress will always depend on individual interpretation. As Dr. Gebhart and Dr. Bayne told us this morning, the assessment will always depend on who is looking at the animals. This activity will be further complicated by the possible projection of personal feelings during the observations, which make it very difficult to categorize an animal regardless of how many subcategories are available. An additional complicating factor in the process is individual animal variation. As we heard earlier this morning, some animals recover from procedures better than others. This variation may relate to the differences in the individual sensitivity to pain, activity of the immune system, adaptation to stressful situations, or other factors we do not yet understand. The clear advantage of only reporting procedures is that the animal care team within an institution can focus on ensuring animal well-being instead of in which category an animal should be placed for reporting purposes.

ETHICAL ISSUES

My final message addresses the relation between biomedical research and the ethics of animal use. Jerrold Tannenbaum of the University of California, Davis, said at the PRIM&R meeting this spring, “Ethical issues in science are determined by advances in science.” In other words, complex diseases and complex approaches to understanding disease often raise ethical questions pertaining to science. A recent example of this effect is the use of gene therapy to treat clinical problems. This exciting new technology, a spin-off of the human genome project, has developed rapidly. We are starting to see ways to treat some patients who could never before be treated. However, the pace of the science has exceeded the pace of the ethical considerations.

The use of animals in research has reached a similar juncture. Our biomedical research effort over the years has been too successful, and this success has created problems. People live longer in a more quickly moving society. As a result, problems related to aging, such as neurodegenerative diseases, cancer, and diabetes, occur more frequently. Concurrently, diseases of a modern, growing urban society, such as cardiovascular disease, mental health problems, chronic fatigue, and infectious diseases like AIDS, are more prevalent. Consequently, science has moved to the more difficult questions. The challenge to the research community has been to test scientific hypotheses related to the cause and treatment of these diseases with the best animal models that mimic these disease states while minimizing the animals’ discomfort, distress, and pain.

Complex diseases require complex animal models. In response to this requirement, the scientific community has created disease models that could never have been developed without our rapid understanding of the genome. The explosive development of transgenic and gene knockout animals has opened up incredible new insights into previously difficult or impossible-to-study diseases. These new genetic models have been used with better pharmacological animal models, such as neurotoxin-treated animals to mimic Parkinson’s and Alzheimer’s diseases and surgically manipulated animals to replicate diseases like hypertension.

All of these approaches have permitted scientists to move to the next level of understanding, the cellular and molecular mechanisms of disease. In many laboratories, the use of animals has been replaced with alternative methods such as cell culture to study how signals are mediated within cells to change genetic expression or chemical interactions. An interesting dilemma is evolving. As we learn more about what happens inside a cell, it becomes more important to relate those findings to the whole animal. For example, the genome project is identifying hundreds of thousands of new genes that are responsible for the formation of a protein. After we learn what these proteins are, we will need to learn what they do, both at the cellular level and in the whole animal. In other words, the field of physiological genomics will likely require an even greater use of animals in research.

Again, it will be a shared responsibility in which the increasingly complex animal models of disease will mandate that investigators, veterinarians, and IACUCs have a greater responsibility ensuring animal well-being. Likewise, by helping to reduce regulatory burden and simplifying compliance with regulations in areas such as defining and reporting pain and distress, regulatory agencies will work with institutions to promote good animal care and good science.

QUESTIONS AND ANSWERS

DR. GLUCK (John Gluck, Kennedy Institute): I think your messages are very strong and important. You made the statement that regulatory burdens result in fewer advances in science. I have tried to document that premise in a number of different ways and have never been able to find any evidence. On what evidence is your statement based?

DR. HAYWOOD: I think it is Mark Twain who said, “So much conjecture on such a trifling of fact.” I base that association on my observation that we are spending more money on compliance issues in universities. We are spending more money on indirect costs to support the research effort, including compliance issues. When that happens, less of the NIH budget is available for research. I use an exercise in logic rather than looking at any numbers because I think those numbers would be very difficult to capture. The cost of doing research has increased tremendously in this country. As a result, the amount of research that actually gets done on a dollar basis has been reduced. Perhaps Dr. Rich will address some of this in his talk later.

DR. RICH (Robert Rich, Emory University School of Medicine): You said it perfectly.

DR. HAYWOOD: This concern is a continuing one for FASEB; for example, whether enough money is going to research versus the support of research.