**Frequently Asked Questions About the Public Health Service Policy on**

**Humane Care and Use of Laboratory Animals**

*Axel Wolff, MS, DVM, Nelson Garnett, DVM, Stephen Potkay, VMD, Carol
Wigglesworth, Denis Doyle, MA, and Venita Thornton, DVM, MPH*

The authors answer eight questions commonly asked of the Office of
Laboratory Animal Welfare concerning the Public Health Service Policy on
Humane Care and Use of Laboratory Animals.

\[The authors are affiliated with the Office of Laboratory Animal
Welfare, National Institutes of Health. Please send reprint requests to
Wolff at OLAW, NIH, RKL1, Suite 360, MSC 7982 6705 Rockledge Dr.,
Bethesda, MD 20892.\]

*LBNL Researchers please note: the **IACUC** refers to the Institutional
Animal Care and Use Committee, which at LBNL is the **AWRC**, the Animal
Welfare and Research Cmtee.*

The Office of Laboratory Animal Welfare (OLAW) of the National
Institutes of Health (NIH) develops, implements, and oversees compliance
with the US Public Health Service (PHS) Policy on Humane Care and Use of
Laboratory Animals 1 (Policy). The PHS Policy and the US Department of
Agriculture\'s (USDA\'s) Animal Welfare Regulations 2 are the two
principal federal documents that set forth requirements for animal care
and use by institutions using animals in research, testing, and
education. One of OLAW\'s primary functions is to assist institutions in
implementing PHS Policy by responding to policy-related questions. This
is accomplished by collaborating with organizations and individuals in
preparing guidance for Institutional Animal Care and Use Committees
(IACUCs) 3-5, supporting the publication of monographs on various
aspects of animal care and use programs 6,7, and publishing Policy
interpretations in articles 8-18 and other formats 19-30. OLAW also
sponsors seminars and training that specifically address current topics
covering animal care and use, and issues guidance notices in the NIH
Guide for Grants and Contracts (formerly as "Dear Colleague"letters),
all of which are found on the OLAW website
(http://grants.nih.gov/grants/olaw/olaw.htm). The following represent
several additional questions frequently asked by institutions and the
OLAW responses.

[1. Does the IACUC need to require that the investigator submit the
grant application, or portions thereof, along with the IACUC animal use
protocol form for review by the IACUC? Is the IACUC required to compare
the two for consistency?]{.underline}

PHS Policy (IV.D.) requires the institution to verify, before award,
that the IACUC has reviewed and approved those components of grant
applications and contract proposals related to the care and use of
animals. This position is reiterated in NIH Grants Policy Statement
under Part II, Terms and Conditions. Most institutions have developed an
IACUC protocol form and require investigators to provide detailed
information about the proposed use of the animals on this form. The
signature of the authorized institutional official on any PHS
application or proposal indicates the organization\'s commitment to
comply with the laws, regulations, and policies to which an activity is
subject. Institutional submission of IACUC approval, subsequent to
submission of the application/proposal, must represent approval of the
information originally submitted in the application/proposal, or include
notification of any significant changes required by the IACUC.

Although there is no explicit requirement for the IACUC to do a
side-by-side comparison of the application/proposal and the IACUC
protocol review form, it is an institutional responsibility to ensure
that the information the IACUC reviews and approves is consistent with
that contained in the application/proposal to be funded. Institutions
are free to devise a workable mechanism to accomplish this end. One
excellent way to prevent problems of inconsistencies between the
information submitted to the PHS and that on the IACUC protocol review
form is to implement a procedure for direct comparison 23. If a
procedure of direct comparison is adopted, the individual(s) charged
with conducting the comparison should be appropriately qualified to
identify inconsistencies. Some institutions have delegated this
responsibility to a particular office or position ( e.g. , sponsored
programs office, compliance office); others have asked Departmental
Chairs to verify consistency 31.

[2. Our IACUC has several categories for the approval of animal study
protocols. Which one to use depends on the kinds of issues it identifies
during review. We are sometimes unsure how best to characterize the
approval status of these projects. Can OLAW provide any advice as to
what constitutes appropriate terminology for approval of a
protocol?]{.underline}

The PHS Policy recognizes only three outcomes of IACUC reviews of
proposed activities (protocols) related to animal care and use, as well
as proposals for significant changes in previously approved ongoing
activities. They are 'approve\', 'withhold approval\', and 'require
modifications to secure approval\'. OLAW is aware that some institutions
have chosen to use different words and phrases to characterize the
latter of these outcomes, such as 'conditionally approved\', 'approval
pending\', 'provisionally approved\', 'approved with stipulations\',
'administrative approval\', and 'limited approval\'. We should note that
several incidents of suspensions and noncompliance are reported by
institutions to OLAW each year that are related to the conduct of
unauthorized animal studies by investigators who have misinterpreted
IACUC responses or the approval categorization of their proposals. To
avoid such misunderstandings and the subsequent necessities to take
corrective actions and report to OLAW, this Office recommends that
IACUCs use language that is as unambiguous as possible in communicating
the results of their reviews of animal study protocols. We suggest that
institutions can do this by adhering to the language of the Policy and
avoiding use of the words 'approved\' and 'approval\' to describe the
outcome of any review that is not an unequivocal approval and making it
known that no animal work may commence without an unequivocal approval.
In addition, the IACUC approval date submitted to PHS agencies as part
of a grant application or contract proposal must reflect the date of
final approval.

[3. Are the scientists at our institution allowed to use
non-pharmaceutical-grade chemical compounds in physiological
preparations involving laboratory animals? Please clarify whether this
is an allowable practice and whether it makes a difference if the
compounds are used in survival versus nonsurvival
experiments.]{.underline}

The use of non-pharmaceutical-grade chemical compounds in experimental
animals under certain circumstances has been, and will continue to be, a
necessary and acceptable component of biomedical research. OLAW and the
USDA have determined that their use should be based on (1) scientific
necessity, (2) nonavailability of an acceptable veterinary or human
pharmaceutical-grade compound, and (3) specific review and approval by
the IACUC 32. In preparing and reviewing proposals to use
non-pharmaceutical-grade products, investigators and IACUCs should
consider a number of related animal welfare and scientific issues
including safety, efficacy, and the inadvertent introduction of
research-complicating variables. Although one can assume that issues
such as sterility, pyrogenicity, stability, pharmacokinetics, and
quality control have been addressed during the course of producing
pharmaceutical-grade drugs, one cannot say the same for substances
produced in the research laboratory using non-pharmaceutical-grade
chemical compounds. Cost savings alone do not adequately justify the use
of non-pharmaceutical-grade compounds in animals. Although the potential
animal welfare consequences of complications are less evident in
nonsurvival studies, the scientific issues remain the same. The
principles and need for professional judgment just outlined still apply.

[4. Because of time constraints and the needs of our investigators, our
IACUC reviews some protocols by sending each member a copy and then
polling them to determine whether they approve. Is this procedure in
compliance with the PHS Policy if the IACUC members, at a subsequent
full-Committee meeting, are asked to reaffirm their votes? Is this
procedure appropriate, and if not, what must we do to correct the
situation?]{.underline}

No. The initial polling of members is not sufficient for approval and
initiation of work on animals. Only full Committees or designated
members can approve animal study protocols, in accordance with the PHS
Policy (IV.C.2). IACUC members may use electronic or other forms of
polling to call for a full-Committee review, but not to vote 12,17. Any
animal studies undertaken on the basis of approvals resulting from such
polling would not be compliant with the PHS Policy. Recognizing that
urgency may sometimes be an issue in considering animal study protocols,
the PHS Policy allows for designated review by at least one qualified
member, appointed by the IACUC Chair, provided that all other voting
members have had an opportunity to request full review and that no
member requests a full-Committee review.

[5. Several investigators at our institution wish to use surgically
modified anmals in their research but do not want to perform the surgery
in-house. We are considering the purchase of such animals and would like
to know whether the PHS Policy applies to customized surgery peformed at
vendor facilities.]{.underline}

The PHS Policy is applicable to all PHS- supported activities involving
animals, whether the activities are performed at a PHS agency, an
awardee institution, or other institution (PHS Policy at I., II., III.,
and V.B.). OLAW has provided guidance regarding animal use (antibody
production) that takes place outside the applicant/assured institution
through subgranting or subcontracting 33. That guidance may also serve
as a template for determining whether other activities such as
customized surgery are covered by the PHS Policy. In this regard, and
with respect to applicability of the PHS Policy , a determining issue is
whether the surgery is conducted in response to a specific custom
request or whether the animals were previously modified and available
before the request was made. If an investigator requests that a specific
custom surgical procedure or procedures be performed on an animal for
use in activities funded by the PHS, then the organization that conducts
the procedure(s) is considered a performance site and must either have
on file with OLAW an approved Animal Welfare Assurance or be included as
a component of the applicant organization\'s Assurance.

[6. We are a small antibody producer using rabbits, mice, and goats, and
our work supports numerous clients, including some funded by the PHS.
When we applied for an Assurance, OLAW informed us that we could not
approve one 'blanket protocol\' to cover all of our antibody production
procedures, even though the work is essentially always the same. Please
clarify.]{.underline}

Provisions of the PHS Policy apply to all Assured institutions
regardless of their size or mission. They include the requirement for
the IACUC to "review and approve, require modifications in (to secure
approval) or withhold approval of those components of PHS-conducted or
supported activities related to the care and use of animals," (PHS
Policy at IV.B.6.) on a project-specific basis. Consequently, each
proposed protocol involving antibody production as well as significant
changes (e.g., amendments) to previously approved protocols must be
submitted for IACUC review and approval, taking into account the aims of
the study and the methods proposed to avoid or minimize pain or distress
to the animals (PHS Policy at IV.C.1.). For example, reviews of proposed
ascites monoclonal antibody production in mice must also critically
address alternative (in vitro) methods as well as pain and distress
issues 6,33. Another example would be a request for a custom antibody
against a specific protein for the purpose of vaccine development,
followed by a request for an antibody against a different protein to be
used for the same purpose. In both instances, Policy would require
either an amendment or a new protocol. As is the case with any new
protocol or proposed significant change to a previously approved
protocol, the PHS Policy allows for either full-Committee or
designated-member review. OLAW recognizes that many aspects of antibody
production are routine and recommends that institutional Standard
Operating Procedures (SOPs) be developed that describe species-specific
techniques for immunization, titer determinations, volume blood
collection, and associated procedures. One may cite IACUC-approved SOPs
in proposed project-specific protocols or proposed amendments to avoid
needless repetition. Under these circumstances, it is possible to
combine multiple projects, or even multiple investigators, under a
single protocol. However, for PHS Policy purposes, IACUC approval of
each project-specific protocol submission or amendment must be readily
identifiable and amenable to tracking.

[7. May a former employee or former student of our institution be
considered for appointment to our IACUC as a nonaffiliated
member?]{.underline}

PHS Policy (IV.A.3.b.4.) defines the nonaffiliated member as an
"individual who is not affiliated with the institution in any way other
than as a member of the IACUC, and is not a member of the immediate
family of a person who is affiliated with the institution," and the
USDA\'s Animal Welfare Regulations expect the individual to "provide
representation for the general community interest 34." The Guide 3 ,
which calls this person the "public member," requires additionally that
the individual not be a current laboratory animal user. Regarding the
service of a former employee in the capacity of a nonaffiliated member,
the appointing official would have to receive assurance that the person
is not in any way conflicted or beholden to the institution 35. If there
are no discernable ties or ongoing affiliation with the institution,
then it would be permissible to consider appointment of the former
employee or former student to the IACUC. It is important for officials
who appoint IACUC members to determine whether real or perceived
conflicts of interest exist and make the appropriate choices to avoid
criticism about the institution\'s or the Committee\'s integrity.
Choosing an individual who is unambiguously 'nonaffiliated\' is the best
way to fulfill the letter and the spirit of this provision.

[8. Our IACUC has encountered a problem with investigators who do not
submit their protocols for review in time to gain approval before the
three-year expiration date. Is it permissible to grant an administrative
extension of IACUC approval so as to avoid expiration?]{.underline}

No. For PHS purposes, IACUC review following the provisions at IV.C.2.
of the PHS Policy must be accomplished at least once every three
years 1. The IACUC may not extend the three-year approval by any means
other than IACUC review and approval using the procedures of IV.C.2.
When IACUC approval expires, it is no longer valid. Continuation of
animal activities beyond the expiration is a serious and reportable
violation of PHS Policy.

**References**

1\. Public Health Service. Policy on Humane Care and Use of Laboratory
Animals (US Department of Health and Human Services, Washington, DC,
revised August, 2002).

2\. 9 CFR Chapter 1, Subchapter A-Animal Welfare, Parts 1-3.

3\. Institute of Laboratory Animal Resources, National Research Council.
Guide for the Care and Use of Laboratory Animals 8 (National Academy
Press, Washington, DC, 1996).

4\. ARENA/OLAW. Institutional Animal Care and Use Committee Guidebook ,
2nd edn (2002). http://grants.nih.gov/grants/olaw/GuideBook.pdf.

5.Silverman, J., Suckow, M.A. & Murthy, S. (eds.) The IACUC Handbook
(CRC Press, Washington, DC, 2000).

6\. Institute for Laboratory Animal Research. Monoclonal Antibody
Production (National Academy Press, Washington, DC, 1999).

7\. Institute for Laboratory Animal Research. Occupational Health and
Safety in the Care and Use of Research Animals (National Academy Press,
Washington, DC, 1997).

8\. Division of Animal Welfare, Office for Protection from Research
Risks. The PHS responds to commonly asked questions. ILAR News 33, 68-70
(1991).

9\. Division of Animal Welfare, Office for Protection from Research
Risks. Frequently asked questions about the PHS Policy on Humane Care
and Use of Laboratory Animals. ILAR News 35, 47-49 (1993).

10\. Wolff, A.V. & Smith, P.D. Compliance at the institutional and
programmatic level. Lab Anim. (NY) 23, 28-29 (1994).

11\. Potkay, S., Garnett, N.L., Miller, J.G., Pond, C.L. & Doyle, D.J.
Frequently asked questions about the PHS Policy on Humane Care and Use
of Laboratory Animals. Lab Anim. (NY) 24, 24-26 (1995).

12\. Garnett, N. & Potkay, S. Use of electronic communications for IACUC
functions. ILAR J . 37, 190-192 (1995).

13\. Garnett, N.L. & Schwindaman, D. A note from the NIH and USDA. Lab
Anim. (NY) 25 , 22-26 (1996).

14\. Oki, G.S., Prentice, E .D., Garnett, N.L., Schwindaman, D.F., &
Wigglesworth, C.Y. Model for performing institutional animal care and
use committee; continuing review of research. Contemp. Top. Lab. Anim.
Sci. 35, 33-36 (1996).

15\. Potkay, S., Garnett, N.L., Miller, J.G, Pond, C.L. & Doyle, D.J.
Frequently asked questions about the PHS Policy on Humane Care and Use
of Laboratory Animals. Contemp. Top. Lab. Anim. Sci. 37, 47-50 (1997).

16\. Potkay, S. OLAW\'s compliance oversight: noncompliance with PHS
Policy. Lab Anim. (NY) 29, 32-35 (2000).

17\. Wolff, A.V. Correct conduct of full-committee and designated-member
protocol reviews. Lab Anim. (NY) 31, 28-31 (2002).

18\. Alderson, C. & Garnett, N.L. Disaster recovery: "Who ya gonna
call?" Lab Anim. (NY) 31, 27-30 (2002).

19\. Garnett, N.L. & DeHaven, W.R. OPRR and USDA/Animal Care response on
applicability of the animal welfare regulations and the PHS Policy to
dead animals and shared tissues. Lab Anim. (NY) 26, 21 (1997).

20\. Garnett, N.L. & DeHaven, W.R. A word from the government \[IACUC
authority\]. Lab Anim. (NY) 27, 21 (1998)

21\. Garnett, N.L. & DeHaven, W.R. OPRR and USDA commentary \[protocol
review\]. Lab Anim. (NY) 27, 18 (1998).

22\. Garnett, N.L. & DeHaven, W.R. The view from USDA and OPRR
\[suspension authority\]. Lab Anim. (NY) 27, 17 (1998).

23\. Garnett, N.L. & DeHaven, W.R. A word from OPRR and USDA \[protocols
and grant applications\]. Lab Anim. (NY) 28, 21 (1999).

24\. Garnett, N.L. A word from OPRR \[protocol extensions\]. Lab Anim.
(NY) 29, 18-19 (2001).

25\. Garnett, N.L. Letter to the editor: innovative but not compliant
\[electronic protocol review\]. Lab Anim. (NY) 30, 15 (2001).

26\. Taylor, K. & Wolff, A. Pass the baton \[research transfers and
pilot studies\]. Lab Anim. (NY) 30, 21 (2001).

27\. Garnett, N.L. & DeHaven, W.R. A word from OLAW and APHIS \[protocol
approval\]. Lab Anim. (NY) 30, 18-20 (2001).

28\. Garnett, N.L. & DeHaven, W.R. A word from OLAW and USDA \[IACUC
minutes\]. Lab Anim. (NY ) 30, 21-23 (2001).

29\. Garnett, N. & Gipson, C. Letter to the editor: Suggestions to bring
electronic protocol system into compliance. Contemp. Top. Lab. Anim.
Sci. 40, 8 (2001).

30\. Garnett, N.L. A word from OLAW \[unapproved animal use\]. Lab Anim.
(NY) 31, 19-21 (2002).

31\. Klemfuss, H. Matching protocols to grant proposals. Lab Anim. (NY)
31, 36-39 (2002).

32\. U.S. Department of Agriculture, Animal and Plant Health Inspection
Service, Animal Care, Policy 3-Veterinary Care, April 14, 1997.

33\. Garnett, N.L & Ellis, G.B Sources of custom antibody production.
OPRR Reports, Number 95-02 - February 12, 2001.

34\. US Department of Agriculture, Animal and Plant Health Inspection
Service, Animal Care, Policy 15, IACUC Membership-Veterinary Care, April
14, 1997.

35\. Silverman, J., Suckow, M.A. & Murthy, S. (eds.) The IACUC Handbook
Section 5:25 (CRC Press, Washington, DC, 2000).