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Alternatives to Monoclonal Antibody Production (Proceedings)

Presentation

Nelson L. Garnett, DVM
Director, Division of Animal Welfare
 Office for Protection from Research Risks
 National Institute of Health

It is a pleasure to be here with you today in Baltimore. As some of you may know, I did my postdoctoral training in laboratory animal medicine at JHU, and later directed the lab animal program at University of Maryland School of Medicine right here in Baltimore. I always enjoy the opportunity to "return to the well."

I've been asked to make a brief presentation this morning, about the issues involved in monoclonal antibody production, from OPRR's perspective.

To me, today's meeting is both an ordinary event and an extraordinary event.

What makes it ordinary is that it is part of an ongoing animal welfare education program that OPRR has been sponsoring for many years. It is cosponsored in the traditional way with a PHS-funded academic institution. It will focus on an area of interest that is quite relevant to the day-to-day workings of Institutional Animal Care and Use Committees, and it has a direct impact on the welfare of animals involved in PHS-funded research.

What makes it extraordinary is the stimulus for this particular meeting at this particular time. The precipitating event was a petition to the Director of NIH from an animal protectionist group, represented here today by Dr. John McArdle, whose perspectives on the use of animals in research are generally thought of as being very different from those of the biomedical research community. Now that is unusual enough, but I want to share with you my initial impressions when, with some trepidation, I first read the petition. After carefully studying it, with what I hope was an open mind, what struck me as being most extraordinary was that there were more areas of agreement than disagreement.

The official NIH response to the petition has been issued, and I'll defer to Dr. Louis Sibal to address the specifics of that response in more detail later. But let's take a moment now to go through the major elements of the petition, and I think you'll see what I mean about the large amount of common ground:

  1. "Prohibit the use of animals in the production and use of monoclonal antibodies resulting from the ascites method."

    As you might guess, this petition item is one where there may be some disagreement. I believe there are statutory prohibitions against the federal government prescribing methods of research, which Dr. Sibal is likely to address in his talk. However, I think that if it could be demonstrated that the mouse ascites antibody production method was completely unnecessary, and that in-vitro methods were always superior both scientifically, and humanely, and practically, there would be few scientists (or government funding sources) and even fewer IACUCs, who would support its use. There are many others on the program today who are far more qualified than I am to address some of these issues so I will defer to them on those.

  2. "...confirm the validity and reliability of alternative methods of MAB production described below."

    This petition item is of central importance to the whole question of alternatives, and it's one that I believe NIH and the biomedical community are committed to, as we will hear later on. Validation is clearly the first step in gaining general acceptance of any new methodology. From the scientist's standpoint, an alternative is not an alternative if it can't accomplish the same scientific aims as the procedure that is being replaced. Conversely, if a method is shown to be better, faster, cheaper, and more humane, I believe that it will rapidly become the method of choice. The interesting thing to me is that this evolution is an inherent part of the scientific process. Indeed, I think that others today will show that the in-vitro methods we are discussing exist in large part because of scientific needs and long term NIH sponsorship. I expect to learn today, along with you, what the current state of the art is in MAB production, and what some of the latest developments are in the validation of this and other alternatives as well.

  3. "Encourage acceptance of the alternative methods by the scientific community by initiating an education outreach program on them and by proposing a regulation requiring all NIH scientists and grantees to allow the alternatives."

    Education is the cornerstone of OPRR's approach to improved animal welfare, so this challenge is one that we gladly embrace. The alternatives theme is one that has been prominent in many meetings and workshops that OPRR has either sponsored or participated in recent years. Indeed, this meeting today should add to the resources available to all scientists and IACUCs who design and evaluate research proposals involving monoclonal antibodies.

    An interesting sidebar on the alternatives issue is that OPRR's Director, Dr. Gary Ellis, directed the 1986 Office of Technology Assessment report to Congress on "Alternatives to Animal Use in Research, Testing, and Education," and was advised in that effort by Dr. John McArdle.

    With respect to proposing new regulations, it appears that that approach may be inconsistent with statutory limitations. I expect Dr. Sibal will address that later on today.

    However, the current regulatory and policy expectations clearly indicate a requirement to consider alternatives and to minimize animal pain and distress where possible, consistent with the aims of the research.

  4. "Initiate a training program at NIH to train scientists in the use of the alternatives."

    Here is another area of agreement. There is already a clear requirement, as a condition for PHS support, for all institutions to provide training in the concept, availability, and use of research or testing methods that limit the use of animals or limit animal distress. Every institution receiving PHS support for animal-related activities, including the NIH intramural program, has signed a formal Assurance document with OPRR promising to do just that. A number of resources exist today, and more are in the planning stages, that will assist all investigators and IACUCs in their efforts to address the alternatives training and literature search requirements. One such resource, the USDA Animal Welfare Information Center, is represented here today and has a display. Another project that is under development is a Johns Hopkins Center For Alternatives To Animal Testing initiative, with support from Proctor & Gamble, Humane Society of the United States, OPRR, and others. It is an attempt to integrate all of the existing alternatives databases and to provide a user friendly web-based search engine. These are just a few examples.

If we can agree with the petition on the areas of validation, education, and training, and the basic principles of humane animal experimentation as stated in federal policy, then the remaining issues that I'd like to see addressed today are these:

To what degree does the mouse ascites MAB production cause pain and distress? This is a crucial question to address because the answer is really at the heart of what we're talking about, from the animal welfare standpoint. I suspect that we all have our opinions on this and that they may not always agree. I also suspect that the real answer will vary according to the individual circumstances. Hopefully we will hear some objective data on this question today.

How can that pain or distress be minimized? Assuming that there is pain and distress involved, what can be done to eliminate or mitigate it? This may be an area where specialized training and institutional policies could be of benefit.

Another question that I'm hoping will be answered today is this very basic one: Is there a continuing need for the mouse ascites antibody production method?

If so, are there certain circumstances under which it should, or should not, be utilized?

What criteria should the IACUC apply to the approval of a project involving the ascites method?

We still occasionally hear the assertion "that's a scientific issue and our IACUC doesn't get into the review of the science". In the case of MAB production methods, the decision to use the mouse ascites method may be a scientific one, but the requirement to consider alternatives and to minimize pain and distress make it imperative that the IACUC critically review the scientific justification and reject the proposal if the IACUC is not convinced of the validity of that justification.

I'd like to close now with a comment about performance standards and accountability. This audience should be very familiar with the concept of performance-based standards, as exemplified by the most recent edition of the Guide for the Care and Use of Laboratory Animals. Outcome-based performance standards, despite their complexity of interpretation and difficulty of implementation, have been embraced by the regulatory, laboratory animal, and biomedical research communities as being the best way to enhance animal welfare and science. In the case of monoclonal antibody production, the desired animal welfare outcome, in addition to the scientific objective of the study, is the minimization of animal pain and distress. If we are to convince an objective observer that our system of animal welfare oversight is effective, we must ensure that the mechanisms in place at the local level include the critical review of all animal use, and that we adhere to all applicable regulations, policies, and guidelines. In many respects, I think that is what the petitioner has asked of us.

Judging from the speakers lined up for the rest of the day, I can predict that all of the issues that I have outlined will be thoroughly addressed. I'll close now and look forward to a challenging and enjoyable program.

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