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 &
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.