f6098d8b__and_Use_of_Laboratory_Animals__Comments
[ID] 264 [Entry Date] 04/20/2011 at 01:03:46 PM [Affiliation] Organization [Organization Name] American Society for Pharmacology & Experimental Therapeutics [Organization City and State] Bethesda, MD [Comments] 
Comment 1: The Association for Pharmacology and Experimental Therapeutics (ASPET) comprises 4800 members who are experts in research across a wide range of specialties, as indicated by the names of its divisions: Behavioral Pharmacology, Cardiovascular Pharmacology, Drug Discovery & Development Drug Metabolism, Molecular Pharmacology, Neuropharmacology, Toxicology, and Translational & Clinical Pharmacology. ASPET urges OLAW not to adopt the 2011 edition of the Guide. Its deviation from the 1996 Guide will result in a significant increase in regulatory and paperwork burden and expense without benefit to animal welfare. ASPET supports the comments of NABR that were submitted to Francis Collins, Director of NIH. Our comments will focus on the newly added section "Use of Non-Pharmaceutical Grade Chemicals [NPC] and Other Substances," which adds new policy to the Guide that is unwarranted with respect to animal welfare or good research practice. Albeit well intended, this policy is not well informed regarding the conduct of research that uses drugs in laboratory animals. One problem with the new guidance on NPC is that the term "pharmaceutical grade" is not defined, nor does an accepted definition exist. An indication of its intended meaning is Guide citation of USDA/APHIS Policy 3, which covers "sedatives, analgesics, or anesthetics" used to prevent pain/distress with regulated species. Its use of "non-pharmaceutical grade" refers to medications not prepared for clinical use. The Guide extends Policy 3 terminology to all vertebrates and all chemicals used in research. The implication is that all solutions prepared by a researcher are considered of inferior quality and that clinical solutions are ideal for research, neither of which is accurate. Specifically, ASPET notes the following with respect to the four sentences on NPC in the Guide: (1) "The use of pharmaceutical grade chemicals. . .ensures that toxic or unwanted side effects are not introduced into studies. . . ." The use of commercially prepared solutions does not ensure this. There are many examples of commercial solutions being recalled. Mass manufacture of pharmaceutical grade drugs amplifies any error. (2) "They should therefore be used, when available, for all animal-related procedures. . ." The assertion that clinical formulations are superior for all-animal-related procedures is neither logical nor supported by scientific evidence. Laboratory-prepared formulations have been the norm in research for the last century. There is no evidence that research or animal welfare would be improved by changing this research practice. The way in which drugs are formulated for clinical use make them poor choices for research. For example, dose manipulations are essential to research. Unlike clinical use, volume of drug delivery needs to be held constant. The single concentrations of solutions sold commercially inevitably need to be diluted to manipulate dose. The assumed benefit of using a commercial solution is lost. Another element of good research is comparison of the effects of the drug with that of vehicle alone. Vehicles of commercial solutions cannot easily be duplicated. (3) "The use of [NPCs] should be described and justified in the animal use protocol and be approved by the IACUC. . . for example, the use of [NPC] may be necessary to meet the goals of a project or when a veterinary or human pharmaceutical-grade product is unavailable." The wording implies the need for an NPC is unusual. In reality, it is the rule. The vast majority of animal research involves compounds that are not used clinically. New chemical entities are keys to advances in science and public health. Collaborations with academic, government, or industry chemists are common; many high purity compounds are available from highly regarded commercial sources. Drug supply programs at NIH make controlled substances and other compounds not formulated for use in humans available to researchers without cost, as do biotechnical and pharmaceutical firms. To require that each use of an "NPC" be justified in writing and reviewed and approved by an IACUC places an unwarranted paperwork burden on researchers and on the IACUC. (4) "Consideration should be given to the grade, purity, sterility, pH, pyrogenicity, osmolality, stability, site and route of administration, formulation, compatibility, and pharmacokinetics of the chemical or substance to be administered, as well as animal welfare and scientific issues relating to its use (NIH 2008)." These considerations are applicable to veterinary care, but are of more variable relevance to research. A part of each research project that uses chemical compounds necessarily involves determining details of their use that will assure the meaningful characterization of the effects of the compound. ASPET suggests that requiring these to be spelled out in advance, and reviewed and approved by the IACUC singles out pharmacology research for micromanagement--a function that has not been the traditional goal or value of the Guide. Note also that the citation is to an intramural NIH guideline, which defines "pharmaceutical grade" differently than does USDA/APHIS Policy 3. In summary, the newly added Guide requirement to use drugs formulated for clinical use in research animals is not realistic. For the few situations in which such a drug might be available, the practical needs of research make them unsuitable, and the cost, compared to one suited for laboratory can be significant (e.g., up to 10-fold). To require NIH's drug supply programs to substitute clinical-use solutions for all those it currently provides via its drug supply programs would be an expense that does not justify use of scarce research dollars. Should OLAW adopt the 2011 Guide, ASPET urges that it consult NIH Institute Directors regarding the wisdom of including the NPC section as PHS Policy. Comment 2: ASPET concurs with NABR that the 2011 Guide represents a significant "guidance document," as defined by the Office of Management and Budget (OMB), which "may reasonably be anticipated to lead to an annual effect on the economy of $100 million or more. . ." Therefore, setting a date by which PHS-Assured institutions must comply with the new Guide prior to an OMB analysis of its financial impact on those institutions and NIH itself is premature.
Listing of Public Comments on Proposed Adoption and Implementation of the Eighth Edition of the Guide for the Care and Use of Laboratory Animals