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Alternatives to Monoclonal Antibody Production (Proceedings)

Alternatives in Monoclonal Antibody Production

Jerry D. DePoyster, DVM
Veterinary Medical Officer
U.S. Department of Agriculture

AC's Position General comments about positions

The LAW

Animal Care's position on the use of alternatives to monoclonal antibodies is simple - it is the LAW. The AWA requires that every research protocol involving animals include a justification for the use of animals as well as the number and species of animals to be used.

In addition, if an animal protocol will employ painful or distressful procedures, the principal investigator must provide a written narrative assuring that a search for any alternatives to the painful or distressful procedures has been conducted. Further, scientific justification must be provided when nonpainful or non-distressful alternatives exist but are not used.

Congressional statements on conducting research and the use of alternatives

In enacting the AWA, Congress, in Section 13 of the AWA, specified that USDA is not to interfere with the performance of research or experimentation. The Secretary of USDA is not authorized to: (1) promulgate rules, regulations, or orders with regard to the design, outlines, or guidelines of actual research or experimentation; (2) promulgate rules, regulations, or orders with regard to the performance of actual research or experimentation; and (3) not interrupt the conduct of actual research or experimentation during inspection.

But, Congress, was clear in that alternatives are to be used when available. Section 1 states "methods of testing that do not use animals are being and continue to be developed which are faster, less expensive, and more accurate than traditional animal experiments..." And in Section 13, Congress specifies that "the principal investigator considers alternatives to any procedure likely to produce pain or distress in an experimental animal..."

Conclusion

To conclude, it is clear that Congress meant alternatives to be used when available and acceptable. Regarding this issue of monoclonal antibodies, it does appear that - in many cases - there are acceptable alternatives, to the use of live animals.

We have made sure that our field personnel are aware of this issue. They will expect to see solid justification if live animals (regulated) are used for the production of monoclonal antibodies.

I also might mention that AWIC has prepared a very large biography on the monoclonal antibody alternatives. It is available either from AWIC or from their Web Site.

USDA Response to the Petition from the American Anti-Vivisection Society

August 6, 1997
Mr. Andrew Kimbrell, Esq.
International Center for
Technology Assessment
310 D Street, NE.
Washington, D.C. 20002


Dear Mr. Kimbrell:

Thank you for the opportunity to respond to the very important issues raised in the petition from the American Anti-Vivisection Society (AAVS), requesting that the U.S. Department of Agriculture (USDA):

  1. Modify the current definition of "animal" as found in the animal welfare regulations (Title 9, Code of Federal Regulations, 1.1) that excludes mice, rats, and birds from coverage under the Animal Welfare Act (AWA).
  2. Prohibit the use of animals in the production and use of monoclonal antibodies resulting from the ascites method.

Regulation of Rats, Mice, and Birds

As the petition correctly states, rats, mice, and birds are included in the AWA definition of "animal." However, the statute gives the Secretary of Agriculture broad discretionary authority to exclude rats of the genus Rattus, mice of the genus Mus, and birds.

In 1990, USDA analyzed the impact of bringing rats, mice, and birds under regulation, USDA concluded that there were 1,735 facilities regulated under the AWA that use rats, mice, and other species, and estimated there were an additional 2,324 unregistered research facilities that use only rats and mice--these figures are for research and do not include breeders, dealers, carriers, intermediate handlers, or exhibitors. The analysis was an estimation, because there is no (known) reliable method to determine how many facilities or businesses are using rats and mice in biomedical research. If these facilities were regulated, they would represent a 96 percent increase in the number of animal research sites under USDA inspection authority. USDA estimated that the cost to provide coverage to those animals at research facilities was $3,425,366 per year--in 1990 dollars. Approximately 60 percent of this cost would be due to the regulation of rats and mice, with the balance for birds. There would be additional costs for the coverage of breeders, dealers, carriers, intermediate handlers, and exhibitors of rats, mice, and birds. Other costs, such as first-year training and vehicle and equipment purchases for additional inspectors, were not included in the above estimate.

The Animal Care unit of APHIS has experienced relatively flat funding since 1992, increasing only 0.10 percent during this time period. With budget-eroding factors such as inflation and "high-cost area" salary increases, this modest increase actually represents a significant decrease in buying power, resulting in a net decrease in the number of inspectors. Nevertheless, Animal Care has become more efficient. We are now inspecting 883 (9.3 percent) more facilities than in 1992 with 15 fewer inspectors (-21 percent). We are continually striving to make the most efficient use of available funds as possible, and believe we are conducting better quality inspections despite the static funding and reduced workforce.

Due to the factors described above, we believe that the additional workload associated with the regulation of rats, mice, and birds would severely compromise our ability to provide protection to the species we currently cover. Nevertheless, we have started implementation of several initiatives in our Strategic Direction for the Animal Care Program that will enable us to realize even greater efficiency within existing resource allocations. For example, these initiatives include a risk-based inspection program that is currently under a field-based pilot study. Risk-based inspections will allow us to focus our limited inspection resources where there is the greatest need and the greatest potential for inadequate animal care. Similarly, we are developing a merit program that will enable us to recognize exceptional facilities, and further economize inspection resources by inspecting such facilities less frequently. Other potential actions, such as the consideration that is currently being given to the assessment and collection of AUser Fees@ from facilities licensed and registered under the AWA, could provide for additional resources in the future.

Given the relevant issues and factors described above, we do not believe that it is prudent for USDA to extend AWA coverage to rats, mice, and birds at this time. Nevertheless, Animal Care will continue to evaluate its available resources and reassess its ability to regulate these species in the future.

Use of Animals in the Production and Use of Monoclonal Antibodies

As you stated, animals have been used for years to produce monoclonal antibodies (MAB) via the ascites method. Animal Care recognizes that alternative methods that do not use live animals have been developed in recent years, and this technology is continually improving.

In enacting the AWA, Congress specified that USDA is not to interfere with the design or performance of research or experimentation (Section 13 (a) (6)). For USDA to prohibit an often used, proven research procedure such as MAB production in animals would constitute interference, and is an action that USDA does not have the legal authority to take. The AWA does require that every research protocol involving animals include a justification for the use of animals as well as the number and species of animals to be used. If an animal protocol will employ painful or stressful procedures, the principal investigator must provide a written narrative assuring that a search for any alternatives to the painful or distressful procedures have been conducted. Further, scientific justification must be provided when nonpainful or nondistressful alternatives exist but are not used. As you know, all such protocols must be reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) before any animal research commences. In addition, animal protocol and IACUC records that contain this information are reviewed by our Veterinary Medical Officers (VMOs) on routine, unannounced inspections of research facilities. Any justification that seems incomplete or improper is investigated and enforcement action initiated where appropriate. These requirements as set forth in the current regulations are sufficient to preclude the unnecessary use of regulated species in the production of monoclonal antibodies. I will emphasize this concern with all Animal Care VMOs in order to ensure thorough evaluations during future inspections of research facilities using animals to produce MAB in regulated species.

We feel this approach, i.e., not "banning" the ascites method of MAB production but enforcing existing regulations through our current inspection system, is consistent with our legal authority. It is also consistent with our review of the current literature, which included the articles submitted with the petition. Most of the research suggests that in vitro methods need further development and evaluation. While we concur that in vitro MAB production is fast becoming the Astate of the art, at some of the production methods are not fully developed and in vitro methods cannot always produce specific MAB in the quantities needed. We feel that through the oversight provided by the internal IACUCs, NIH, and USDA, unnecessary use of the ascites method of MAB can be prevented.

Animal Care recently released a new policy manual which I have enclosed for your information. Policies 11 and 12 deal specifically with the issues of painful and distressful procedures and searching for alternatives to such procedures. Also, I should mention that the Animal Welfare Information Center (AWIC) of the National Agricultural Library has been very proactive in the area of alternatives, and they have a large collection of materials relevant to the issues of antibody production and alternatives to painful and distressful procedures. AWIC is just one of several information sources currently used on a routine basis by the biomedical research community.

USDA appreciates your concern for the well-being of research animals. We recognize the valuable contributions provided by organizations such as the AAVS as we all strive to make ongoing improvements toward animal well-being. Thank you for the opportunity to address the issues raised in the AAVS petition.

Sincerely,
W. Ron DeHaven
Acting Deputy Administrator
Animal Care

Enclosure

cc:
T. Medley
K. Vail

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