Playing by the Rules
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Protocol Review
Jerald Silverman, DVM, Column Coordinator

Lab Animal 27(3), 1998
Playing by the Rules
Al Miller, the new director of the county animal shelter, was pumped up about his appointment as the unaffiliated member of the Great Eastern University IACUC. He viewed himself as a true animal lover, but one who was pragmatic about animal use in research. Al played by the book: he read and memorized all the pertinent laws, regulations, and policies he could locate. If you are going to use animals in research, you better not try to pull a fast one on Al.

As part of a new protocol involving naturally occurring ulcerative colitis in primates, Dr. Cheryl Heering proposed to surgically reverse a segment of the colon. Numerous recording and sampling devices would monitor and obtain early changes in intestinal neural and secretory activity. She would not administer analgesics post-operatively, however, since the first 72 hours after surgery were critical to her research.

Heering was an established investigator at Great Eastern, and had previously submitted related protocols to the IACUC for review, all of which did not incorporate analgesics. Each time the IACUC had intervened, and each time, after some give and take, Heering modified her protocol to include analgesics—it was almost an IACUC ritual. Again, the IACUC thought that post-operative analgesia would not interfere with the scientific question posed in the new protocol, and the committee chair told the secretary to “send Sherry the usual letter.” This time, however, Heering repeatedly balked. She provided her usual documentation which only weakly justified not using analgesics. The chair of the IACUC finally solicited the opinion of two outside experts, but both gave equivocal responses. Frustrated, the IACUC requested pilot studies with and without analgesia.

Heering wasn’t interested in a pilot study. She repeated that any analgesic would potentially modify the parameters she was studying, and even quoted the ambiguous responses from the two external consultants. It hurt Al Miller, the unaffiliated member, to support her, but as an honest person, he quoted section 2.31a of the Animal Welfare Act (AWA) regulations: “nothing in this part shall be deemed to permit the...IACUC to prescribe methods or set standards for the design, performance, or conduct of actual research or experimentation by a research facility…”

Unhappy but unperturbed, the IACUC chair opened his copy of the regulations and quoted a part of section 2.31a which Miller had omitted: “…except as specifically authorized by law or these regulations.” The chair went on to quote the regulations of section 2.31c(6), which, he said, clarifies 2.31a: “[the IACUC shall] require modifications in [to secure approval]...or withhold approval of those components of proposed activities related to the care and use of animals...” He also quoted 2.31d, which indicates that painful procedures must “be performed with appropriate sedatives, analgesics or anesthetics, unless withholding such agents is justified for scientific reasons...by the principal investigator...”

Miller knew the regulations, but did not agree with the chairperson’s interpretations. He said that the investigator had indeed presented scientific justification. The chair countered that the IACUC didn’t have to accept any flimsy justification given by an investigator, and, in this case, the justification was too weak. The regulations are clear, he said, and the IACUC—not the investigator—has final say, since it has the authority to “review and approve, and require modifications...to secure approval.” The chair emphasized the word “require.” Is there an inherent conflict in the AWA regulations? How would you resolve the questions raised in this case?

Money Should not be an Object
Richard C. Van Sluyters, OD, PhD and Nikki Simpson

IACUCs are specifically charged with ensuring that, consistent with sound research design, investigators avoid or minimize pain and distress to animals. One of the more challenging tasks IACUC members face is evaluating proposals that allege that administering analgesics to animals subjected to painful procedures would interfere with the scientific needs of the research. As the IACUC chair from Great Eastern University points out, unless the justification for withholding analgesia is compelling, federal regulations require steps to avoid or alleviate pain for protocol approval.

The equivocal opinions rendered by the two outside experts consulted by the IACUC, and the investigator’s refusal to conduct a pilot study, complicate the issue. The IACUC has previously ruled that the investigator’s evidence fails to adequately support the claim that analgesics would interfere with the study. Assuming the present study is similar to those performed in the past, it is difficult to see how the IACUC could reverse its decision in the absence of new information.

There are some issues that need clarification, but it’s doubtful that any of them would lead the IACUC to overturn its decision. Apparently, the investigator has managed to collect useful data in the past from animals that received analgesics. If analgesics weren’t a problem for her in previous studies, why are they now? Has the investigator independently sought expert opinion on the actions of contemporary analgesics, and does this information solidly support her contention that all analgesics would potentially modify the parameters she wants to measure? How does the investigator rationalize her claim that administering analgesics would be a source of uncontrolled variability in the immediate post-surgical period, when she apparently is not controlling for the variable effects of the pharmacological agents and the physical manipulation of the abdominal contents that are required by her initial surgery? Alternatively, if her experimental design includes controls for these other potential sources of variability, why is she unwilling to also include a control for the possible side-effects of post-surgical analgesics (i.e., a pilot study)?

As things now stand, there are no happy outcomes to this unfortunate stalemate. If the IACUC sticks to its guns and forces the investigator to include analgesics in her study, she’s unlikely to be pleased with its decision. On the other hand, if the committee members bow to the investigator’s wishes, it seems likely at least some will feel that they have unjustifiably compromised animal welfare. What’s needed is additional information. In this case, a pilot study seems the most straightforward way to get an answer that’s unequivocal.

It’s not clear why the investigator objected to the pilot study, but a common reason is the extra cost it would engender to the research grant. Sympathetic IACUC members will understand this argument, but they also will recognize that when it comes to animal welfare, cost should not be the only issue. Institutional officials could resolve this dilemma by recognizing that they have a responsibility for promoting the highest standards of animal welfare, while at the same time providing a supportive environment for their researchers. In this case, the institution could cover the cost of conducting the pilot study. The data the pilot study yields could only enhance Heering’s research. Indeed, she may be able to publish the data as part of her larger study. More importantly, the understanding they provide would allow the IACUC and the investigator to make an informed decision about the use of analgesics in her experimental paradigm.

Van Sluyters is a professor of optometry and IACUC chair at the University of California, Berkeley. Simpson is the IACUC coordinator at the University of California, Berkeley.

Pilot First
Les Rolf, PhD, DVM

Miller raised a good point with his citation; however, the AWA also mandates the IACUC to “...set standards of design and performance of biomedical research...” in a number of areas, including the appropriate use of post-operative analgesics and sedatives. This responsibility would extend to:
  • requiring statements indicating that in vitro techniques and methodologies cannot satisfy the scientific question and hypothesis being tested;
  • reviewing the number of animals the protocol requires, based on: IACUC expertise, statistical tools used in the protocol, the investigator’s previous animal mortality experience, and similar protocols from cited literature;
  • precluding the use of paralytic agents unless the animal is fully anesthetized;
  • requiring justification for more than one major procedure on an experimental animal;
  • and determining appropriate methods of euthanasia with respect to the specific species involved.
The IACUC may, for example, require an investigator to follow specific guidelines on the volume of blood that he or she may withdraw at one time; the amount of weight loss an animal can sustain on a protocol; on food and water restrictions related to a reward system paradigm; or on imposing overnight fasting on an animal prior to anesthesia.

In terms of the above scenario, the AWA certainly invests the IACUC with the authority to demand justification for potentially painful or distressing protocols. Nevertheless, Heering may indeed have a valid point in this case, even if her supporting documentation is “flimsy.” The most appropriate analgesics for the anticipated pain associated with this type of soft tissue surgery would be opioids or alpha-2 agonists. Both of these agents have well-documented effects on motility of the gastrointestinal tract. It is not known how much influence motility has on normal neural reflexes locally and regionally, and on function of the secretion of the mucosal lining. On the other hand, the fact that Heering’s previous objections to analgesia presumably did not compromise her research undermines this possibility.

Since the external consultants were ambiguous, and Heering has not actually found analgesics to be detrimental to her past research, the optimal solution would be for the IACUC to require one or two pilot studies before it approves the protocol:

  • Heering could use a short-lived opioid or alpha-2 agonist for the first 24 hours after surgery, followed by an analgesic-free 24-hour period and a second 24-hour analgesic period (she might repeat the study with two analgesia-free periods and one period of analgesia);
  • or she could selectively block the nerves of the abdominal musculature at the end of surgery, using either regional nerve blocks or epidural anesthesia to eliminate pain perception from the abdominal musculature and soft tissue, without interfering with autonomic nervous system flow to and from the resected intestinal tract.
Rolf is chief of laboratory animal surgical services, University of Pennsylvania, ULAR, Philadelphia, PA.

Bound by Law
Gary L. Francione, Esq. and Anna E. Charlton, Esq.

Under the 1985 amendments to the federal AWA, the individual researcher must justify to the IACUC withholding pain relief, and must also provide written assurances that she has considered alternatives to animal use and that her experiment is not merely an unnecessary duplication. Despite these requirements, the ultimate determination whether to provide pain relief to the animal still rests with the individual researcher, who is permitted to withhold pain relief “when scientifically necessary” and for “the necessary period of time.” That is, once the investigator justifies the position that infliction of pain is required by the experiment, the IACUC must abide by the researcher’s decision, and has absolutely no authority to interfere with actual scientific decisions or to undertake any ethical merit review of the experiment.

The hypothetical involving Heering and Miller does not challenge the notion that the IACUC has no authority to perform ethical merit reviews. Rather, the hypothetical asks about what counts as an adequate justification on the investigator’s part. Neither the statute itself, nor the interpreting regulations, could be read to require that the IACUC accept “any flimsy justification given by an investigator.” A “flimsy” justification may be tantamount to no justification at all, and there is a requirement for some justification. In this case, Heering’s justification seems to be colorable. In the first place, she, presumably a qualified investigator, has made the determination that the analgesic would modify the experimental parameters. Second, she has “equivocal” responses from two inside experts.

In such a case, the burden is now on the IACUC either to gainsay Heering and the experts on specific empirical grounds concerning the effect of analgesics on the experiment, or to approve the experiment. The 1985 amendments to the federal law carefully preserved what has been a consistent theme of the law since its inception: that there be no interference with the actual conduct or design of research, and that the individual investigator be free to pursue the experiment as she thinks required. This theme of the freedom of the individual investigator is also contained in the PHS law that forbids the IACUC from “prescrib[ing] methods of research,” and reflects the fact that throughout the history of animal welfare regulation in the US, the research community has taken the position that free scientific inquiry is protected as a matter of constitutional right. If such a right does exist (and we have argued elsewhere that it does not), then it is held by the individual investigator.

Nothing in 1985 changed this notion that regulation under the AWA extends largely to animal husbandry issues alone. Indeed, the USDA, in promulgating IACUC regulations, noted that some within the scientific community claimed that IACUC review “would deprive researchers of the scientific discretion necessary for the conduct of research.” The USDA rejected this concern, responding that IACUC authority is “limited to the animal care and use portion of a proposal,” and “does not extend to evaluating the design, outlines, guidelines, and scientific merit of research.”

The IACUC may ask the investigator for a justification, and the investigator is required to provide one. But to the extent that reasonable minds may differ as to whether the justification suffices, the IACUC must defer to the investigator. To do otherwise would be to interfere in the conduct of the research, and violate the statutory, regulatory, and perhaps constitutional proscriptions against interference with research design and methodology.

We should state in closing that we are opposed to the use of all nonhumans for biomedical research, irrespective of expected benefit for humans.

Francione is a professor of law and Nicholas deB. Katzenbach Scholar of Law & Philosophy at Rutgers University, School of Law, Newark, NJ. Charlton is staff attorney and co-director of the Rutgers Animal Rights Law Clinic.

A Word from the Government
The USDA/APHIS/Animal Care (USDA/AC) and the NIH Office for Protection from Research Risks (OPRR) are authorized to interpret and implement the USDA Animal Welfare Regulations and the Public Health Service Policy on Humane Care and Use of Laboratory Animals, respectively. USDA/AC and OPRR have determined that the AWA and PHS Policy do not require an IACUC to approve a proposed project against its will.

—Nelson L. Garnett, DVM, director, Division of Animal Welfare, Office for Protection from Research Risks, National Institutes of Health

—W. Ron DeHaven, DVM, acting deputy administrator, Animal Care, Animal Plant, Health, Inspection Service, US Department of Agriculture

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