Comments Submitted to NIH on the Proposed Eighth Edition of the Guide for the Care and Use of Laboratory Animals
May 24, 2011 – Comments submitted to the National Institutes of Health Office of Laboratory Animal Welfare in response to Federal Register Notice on “Laboratory Animal Welfare: Proposed Adoption and Implementation of the Eighth Edition of the Guide for the Care and Use of Laboratory Animals” [76 FR 91 (May 11, 2011)] (PDF, 180KB).
The American Psychological Association (APA) submits these comments to the National Institutes of Health (NIH) Office of Laboratory Animal Welfare (OLAW) on the proposed adoption and implementation of the 8th edition of the Guide for the Care and Use of Laboratory Animals (new Guide) as Public Health Service (PHS) Policy. The APA Committee on Animal Research & Ethics (CARE) has reviewed and compared the new Guide to existing PHS Policy, which is based on the 7th edition of the Guide (1996 Guide). As a standing committee of APA committed to the humane treatment of laboratory animals for over 85 years and representing a membership of over 154,000 researchers, educators, clinicians, consultants, and students, CARE has been involved in developing and updating guidelines for the humane care and treatment of nonhuman animals in research. Because research with laboratory animals is an integral component of the science of behavior, APA has strongly supported past efforts to improve laboratory animal welfare while ensuring that proposed policies do not compromise scientific research.
While APA recognizes that the new Guide is a well-crafted resource that aims to strike a balance between the needs of research and the welfare of laboratory animals, at this time we cannot recommend that NIH adopt the 8th edition of Guide as PHS Policy. APA is concerned that: 1) the new Guide contains many recommendations that will, in effect, function like regulations, rather than the guidelines for the care and use of research animals authorized by the Health Research Extension Act of 1985; 2) insufficient scientific evidence is presented regarding impact on animal welfare for some major revisions in the new Guide; and 3) the additional provisions will have a significant economic impact on PHS-assured institutions.
Furthermore, the rationale for having federal funds allocated to prepare this new Guide is not clear. In November 2005, the NIH Office of Scientific Affairs issued a call for public comments (NOT-OD-06-011) on the need to update the laboratory animal welfare standards of the 7th edition of the Guide. Comments received were reviewed by a working group of scientists and laboratory animal veterinarians who concluded that there was “no evidence to warrant revising the performance standards of the 1996 Guide. These standards have allowed individual institutions the flexibility to adapt policies and procedures to their own institutional environments” (NOT-OD-07-016). The report of the working group also indicated that the Guide should become a web-based document that would make it possible to revise the Appendix periodically with current references and reports to be included after critical review for scientific validity. Despite this conclusion, a Guide revision project was initiated in the fall of 2008. Rather than merely updating references and providing new information on animal husbandry, however, the 8th edition contains new requirements that impose substantial financial and paperwork burden on investigators, institutional animal care and use committees (IACUCs), and animal housing programs without commensurate improvement in the welfare of the laboratory animals. Furthermore, it strays further from its traditional domain of guiding institutions on appropriate housing, facility construction and veterinary care of vertebrates in research into new policies that have the effect of imposing restrictions on research design and on the exercise of scientific judgment by federally funded researchers.
Thus, APA recommends that the 1996 Guide remain PHS policy and that the new Guide be used as a reference document. If contrary to the CARE recommendation, OLAW does decide to adopt the new Guide as PHS Policy, CARE believes that the March 2012 deadline for compliance with the new standards is unrealistic. In that event, CARE recommends a more gradual 4-5 year phase-in, which will allow for collection of relevant data that can inform and guide OLAW policy decisions that impact all PHS-funded research with laboratory animals.
The new Guide contains more than 40 statements about what institutions “must” do (defined as “actions that are imperative and mandatory duty requirements”), including 29 new requirements. In addition, there are approximately 660 recommendations that researchers “should” do (defined as “a strong recommendation for achieving a goal” but noting that “individual circumstances might justify an alternative strategy”). Both sets of statements have the unintended consequence of being viewed and implemented as policy rather than guidance – policies that the research community has not had a chance to comment on in a substantive manner. Moreover, some of these mandatory requirements are particularly problematic because they constrain the exercise of scientific and professional judgment by investigators and laboratory animal veterinarians.
The new Guide is extraordinarily prescriptive on a number of topics, without adequate empirical evidence that the recommended action enhances the welfare of laboratory animals. Compliance with these new standards will greatly increase the cost of conducting research with laboratory animals with no evidence of commensurate improvement in animal welfare. The increased cost will be further compounded by increased regulatory and paperwork burden, in terms of justifications for elements in the research protocol and recordkeeping by both investigators and institutions.
The APA’s response highlights areas of concern for psychologists who conduct research with laboratory animals.
- Changes in Animal Housing and Physical Plant Recommendations - New recommendations that detail specifications for cage sizing and recommended use of solid bottom cages particularly for rats and mice are based on weak to nonexistent evidence. Mandatory requirements for social housing for all species are also not evidence-based and do not recognize space and other practical constraints on institutions. Further, for many institutions, particularly smaller institutions, these and many other physical plant/environment recommendations will be prohibitively expensive, with no documented evidence of commensurate improvement in lab animal welfare. For example, modifying the existing facility to include double barrier doors, monitoring systems for environmental and space pressurization control, or security and access control to the facility present a financial burden that, in the case of many smaller institutions with strong research programs, will be insurmountable.
- Increased IACUC Responsibilities – Newly introduced requirements for post-approval monitoring of protocols (e.g., direct observation of “laboratory practices and procedures and comparisons with approved protocols”) and formal review of “unexpected outcomes” are examples of items requiring additional IACUC staffing and researcher effort. These new requirements increase the regulatory and paperwork burden on both the IACUC and investigators.
- Changes in Recommendations Regarding Survival Surgery – A major change in the new Guide is the introduction of language cautioning against multiple survival surgery procedures, in addition to the continuing caution against multiple major survival surgeries. This echoes a newly introduced caution against animal reuse as a “reduction” strategy. Restrictions against using animals in multiple procedures surely increases the number of animals needed, thus increasing research costs as well as the number of animals used in research. The caution against multiple survival surgical procedures not only increases the costs and number of animals required, but also interferes with the scientific integrity of established and acceptable research by restricting the use of within-subject and single subject designs that have proven to be particularly powerful for behavioral research.
- New Requirements for Food/Fluid Regulation – The section on “Food and Fluid Regulation” now requires daily recording of food and fluid consumption for all animals on either type of restriction, which ignores the fact that animals for which one commodity is restricted have unrestricted access to the other. The 1996 Guide has the requirement for recording daily fluid intake only for fluid restriction experiments; it does not require this for food restriction. This requirement will necessitate use of calibrated water bottles or flow-meters rather than the now common automated watering systems, thus incurring additional equipment costs. The new requirement can further be interpreted to mean that the food consumption of each animal needs to be recorded (e.g., weigh the food given to animals on fluid restriction and then weigh what is left). This is unnecessary micromanagement of food and fluid restriction procedures, which generally are carefully worked out based on needs of the species and the experience of the investigator.
In addition, specific direction is given to record body weights at least weekly for food restriction (‘Body weights should be recorded at least weekly"). In contrast, the 1996 Guide states that "Precautions that should be used in case of fluid restriction to avoid acute or chronic dehydration include…recording of body weight at least once a week." Not only is the new requirement overly prescriptive but weekly recording is not a good general recommendation. For example, in some protocols, such as with rodents, weighing should occur more often than weekly. In others, such as for non-human primates, weekly recording of body weights may not be necessary under stable feeding conditions, and is not desirable if the animal has to be anesthetized to be weighed.
The guidance to use "treats" (“highly preferred food or fluid”) for behavioral training (“conditioned-response…protocols”) is made despite information provided in the two of the scholarly reviews cited in that same paragraph that such strategies do not work well to train behaviors. This example of inappropriate guidance may represent only imprecise drafting, rather than intent, but this is only one example of how the 8th edition is unsuitable as federal policy.
- New Requirements on the Use of Non-Pharmaceutical Grade Chemicals and Other Substances – The new section “Use of Non-Pharmaceutical Grade Chemicals (NPC) and Other Substances” is of particular concern and adds new policy to the Guide that is unwarranted with respect to both animal welfare and good research practice. Albeit well intended, this policy is not well informed regarding the conduct of research that uses drugs in laboratory animals. This section essentially bans researchers from using standard source drugs for research (e.g., compounds from the National Institute on Drug Abuse (NIDA) drug supply program; reliable private vendors; and chemists) or requires additional paperwork burden to justify and detail their use if a version of that same drug is available in a human clinical or veterinary formulation. The recommendation is also based on the erroneous assumption that clinical preparations are available for most drugs used in laboratory animal research. Further, clinical formulations are generally inappropriate for research as these can make dose manipulations and vehicle comparisons difficult. Additional details about these specific concerns are described below.
One problem with the new guidance on NPC is that the term “pharmaceutical grade” is not defined, nor does an accepted definition exist. Two conflicting definitions are implied by citation of the USDA/APHIS Policy 3: an interpretive rule for use of “medications” to prevent pain/distress and the intramural NIH program policy on “non-pharmaceutical grade drugs.” USDA/APHIS enforcement makes clear that Policy 3 is interpreted as requiring use of commercially prepared solutions for the stated purpose, rather than investigator-prepared, and the first sentence of the new Guide section on this topic is consistent with this interpretation. Yet the NIH intramural policy defines “pharmaceutical grade” as manufactured according to USP standards, thus accommodating investigator-prepared solutions. Even the intramural NIH policy ignores that the NIDA drug supply program and other standard sources do not prepare to USP standards, as these have more to do with documenting drug manufacture than drug quality. As with other sections, the contradictions in guidance are problematic. Reconciling definitions is one obstacle to interpretation, but the clear requirement that investigators justify the use of certain types of compounds and provide elaborate detail on their preparation and characteristics for IACUC review is only one example of the new Guide’s intrusion into the realm of the scientific and professional judgment of NIH-funded researchers.
Specifically, APA notes the following with respect to the four sentences on NPC in the Guide:
- “The use of pharmaceutical grade chemicals...ensures that toxic or unwanted side effects are not introduced into studies. . . .” The apparent premise of this sentence that the use of commercial drug solutions ensures that the toxic or unwanted side effects are avoided is, in fact, false. There are many examples of commercial solutions being recalled, and mass manufacture of pharmaceutical grade drugs only amplifies these errors.
- “They [pharmaceutical grade chemicals] 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. Even with solutions that may be useful for a particular project, the need to conduct dose-effect evaluations inevitably means the commercial solution would need to be diluted or concentrated in the laboratory to accomplish this purpose. Unlike clinical use, volume of drug delivery needs to be held constant. Given the need for dose and volume modifications, 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. In addition, many commercial formulations, such as those in pill or capsule form, contain filler material that could confound experimental effects, especially when used by alternative routes of administration.
- “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 that the need for an NPC is unusual; whereas in reality, it is the rule. A primary goal of psychopharmacology research is to find new treatments for neuropsychiatric illnesses. A critical step in much of this research is to give drugs with novel mechanisms of action to laboratory animals. Most of these drugs are, by definition, unavailable from commercial sources and must be prepared by the investigator. These new chemical entities are key 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 as well as biotechnology and pharmaceutical firms make controlled substances and other compounds not formulated for use in humans available to researchers at no cost. The requirement also inappropriately presumes that any preparation of drug solutions by the researcher can be assumed to be inferior to commercial preparation.
Finally, 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 both researchers and on the IACUC. It inappropriately defers the scientific judgment of the researcher to the IACUC. This recommendation also presumes that the IACUC has expertise, or retains someone with such expertise, to evaluate the details of formulations planned by the researcher.
“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.
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 use can be significant (e.g., up to 10-fold). Review of the Guide indicates that this new section uniquely micromanages pharmacological research. Further, 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.
- Expanded Attending Veterinarian (AV) Responsibilities – In general, the new Guide mandates increased consultation with and oversight by the AV, beyond that required under current PHS Policy. This expansion in AV responsibilities greatly increases institutional economic burden, with no data or rationale to support these changes. Although few would object to having more AV involvement in animal care and use, there are no data to indicate that these changes are necessary, nor were any cost/benefit analyses for mandating such changes cited. The cost burden of increasing the involvement of an AV may be too high for some institutions to continue to conduct animal research. There are already many institutions with strong research programs that are on the brink of closing their animal facilities because of the escalating costs. The educational, societal, and economic impact that these closings could have may far outweigh whatever unspecified shortcomings the proposed new guidelines have been created to address, especially when there is no evidence to indicate that the changes in the new Guide will result in a significant improvement to the welfare of the animals at these institutions.
Constraints on Professional Judgment The section on “non-pharmaceutical grade drugs” and the constraints against using animals in more than one survival procedure along with multiple other sections of the new Guide preempt scientific and professional judgment on the design and conduct of research. This seems especially inappropriate for a document that will govern the research of scientists whose funding has been granted based to a significant degree on the peer-reviewed determination of their expertise and ability to carry out specialized research. The new version of the Guide goes significantly beyond the traditional value of this document for setting standards for animal housing, husbandry, and veterinary care of research animals.
The 2011 Guide also introduces new policies that constrain the exercise of scientific and professional judgment by laboratory animal veterinarians and others experienced in laboratory animal management. One example is the new policy that social housing must be the default for all species. Although exceptions include needs of research and welfare of the animal, no provision is made for practical considerations, such as duration of housing of a nonhuman primate in a facility compared to the time necessary to adapt the animal to a social housing situation.
APA concurs with the National Association for Biomedical Research (NABR) that the new Guide represents a significant “guidance document,” as defined by the Office of Management and Budget (OMB). It is the position of the APA that an opportunity for comment in greater detail from the research community on the substance of the new Guide and its financial consequences is necessary before a decision on its adoption as PHS Policy is made and an implementation strategy instituted.