Going through the phases

Best America Pharmaceuticals was an NIH/OLAW-Assured institution. Dr. Joy Holmes of Best America studied diseases of the pancreas. In a preliminary test with a very a small number of rats, a new compound, P20R, was found to cause pancreatic damage similar to what she had sought for many years for her research. Consequently, in her IACUC application, Holmes proposed an initial 'up and down' acute oral toxicity test with P20R to calculate an estimate of its lethal dose for 50% of the rats (LD₅₀). On her application, she called this test Phase I. Once Phase I was completed, she proposed Phase II, a larger study with 50 rats. Using the information from Phase I, Phase II would determine the dose and frequency of use of P20R that would cause pancreatic lesions in approximately 90% of her rats (ED₉₀). The final part of her study, Phase III, would use the results of Phase II in conjunction with her ongoing studies pertaining to the treatment of pancreatic injury. For Phase III, 500 rats were requested; however, her protocol stated that if an ED₉₀ could not be established in Phase II, the project would be terminated. Holmes clearly justified the number of animals she would need for all three phases of her study, and the IACUC was satisfied with the significance of the study and all aspects of animal care and use.

The primary question facing the IACUC was whether to approve the entire study as requested by Holmes or to wait until the two earlier testing phases were completed before releasing the animals for Phase III. The researchers on the committee wanted to approve the entire study because, they said, Holmes was required to follow her protocol: if Phase II did not provide the needed ED₉₀, she was obligated not to use the remaining animals, even if they had been approved for potential use. As one member put it, “The entire IACUC system is based on self-regulation, and if we can't trust Joy Holmes to do what she said she will do, why do we even have an IACUC?” Others on the committee felt differently. For example, one said, “The IACUC is based on self-regulation by our company as a whole; it's not focused on any one person. If everybody always did the right thing—which is naïve thinking—only then would there be no need for an IACUC.” Those members wanted to release the 500 rats for Phase III only if Phase II was reported to the IACUC as being successful. A third group wanted Phase III to be a separate protocol or a major amendment to the existing protocol if Phase II was successful.

If you were a member of the Best America IACUC, how would you approach approving the requested number of animals in Holmes' protocol?

Response to Protocol Review Scenario: Post-approval monitoring

Response to Protocol Review Scenario: Approve and monitor