IACUC Administrators Best Practices Meeting

Thursday, August 27, 2015

Thank you to our Supporters

Funding for this meeting was made possible in part by

IACUC Administrators Association (IAA)

* Office of Laboratory Animal Welfare, National Institutes of Health, Department of Health and Human Services

The Pennsylvania State University

* The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official views of the Department of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government.

Special Thanks to our Guest Facilitators!

Doreen Bartlett, Senior Assurance Officer, Division of Assurances, OLAW

Pat Brown, Executive Director, OLAW

Carol Clarke, Research Specialist Staff Officer, APHIS, USDA

Chris Newcomer, Executive Director, AAALAC International

Susan Silk, Director, Division of Policy and Education, OLAW

Axel Wolff, Director, Division of Compliance Oversight, OLAW

Updates (OLAW, USDA, and AAALAC)

Pat Brown, OLAW

Carol Clarke, USDA

Chris Newcomer, AAALAC

OLAW Update

Patricia BrownDirector, Office of Laboratory Animal WelfareNational Institutes of Health

August 26, 2015IAA 10th Anniversary Best Practices MeetingState College, PA

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Updates

•Recent OLAW Guidance

•Educational Resources

•New NIH Initiatives

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Recent OLAW Guidance

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MOU Between NIH and NSF

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• Effective October 1, 2015 for institutions receiving NSF support

• What to do?• If you have a PHS Assurance and NSF-supported

animal activities:• Do not submit a new Assurance!• In your 2015 annual report to OLAW, check that

you have a program change & attach an update to your Assurance Part I. Applicability section indicating NSF support.

• If you have an incident of noncompliance or adverse event on an NSF-supported animal activity, you must report these situations to OLAW.

MOU Between NIH and NSF

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• Effective October 1, 2015 for institutions receiving NSF support

• What to do?• If you have NSF-supported animal activities and no

PHS Assurance: • NSF will notify OLAW that a PHS Assurance is

needed. • OLAW will contact your institution to negotiate

an Assurance.• If you have an incident of noncompliance or

adverse event on an NSF-supported animal activity: • You must report these situations to OLAW.

Qualifications of IACUC Nonscientific and Nonaffiliated Members

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• Intent of the PHS Policy for a diversity of perspectives on the IACUC

• Assured institutions must comply by the 2015 annual report, due January 31, 2016, or by the next Assurance renewal, whichever comes first.

• Nonscientific member:• naïve attitude with regard to science & scientific

activities• person without scientific training• If not apparent based on their occupation or training,

written documentation of reason

Qualifications of IACUC Nonscientific and Nonaffiliated Members

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• Nonaffiliated member:• has no discernible ties or ongoing affiliation with the

institution• is not in any way obligated to the institution• has no real or perceived conflicts of interest• is not an laboratory animal user or former user• is not an immediate family member of an individual

affiliated with the institution

• Notice number: NOT-OD-15-109Release date: June 9, 2015

Update to the PHS Policy

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• 2015 Revision changes:• Adoption of the Guide, 8th edition• Implementation of 2013 AVMA Guidelines• Modification to footnotes requiring that institutions

comply with USDA regulations as applicable• Change in OLAW contact information• Minor grammatical corrections

• Formats available:• Electronic: HTML, PDF and eBook files at:

http://grants.nih.gov/grants/olaw/references/phspol.htmhttp://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf

http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.epub

• Print: print copies requested by e-mail to olaw@od.nih.gov

Notice of OLAW Policy on Shared Animal Welfare Concerns

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• Under MOU with USDA, OLAW shares self-reports involving USDA regulated species:• Unanticipated death of animal(s) • Unexpected and unrelieved pain or distress• Issues of interest to both agencies

• Reports shared after OLAW case is closed• AC will not cite for past self-reports if certain criteria

are met• Complaints concerning previously reviewed cases

or events over 3 years old will not be reexamined• OLAW webinar available for viewing

Significant Changes to Animal Activities

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• Significant changes to animal activities may now be handled by several methods

• Did not change what constitutes a significant change• OLAW & USDA in agreement on this change• OLAW Significant Changes webpage

– http://grants.nih.gov/grants/olaw/significant_changes.htm

• OLAW Special Seminars: Guidance on Significant Changes to Animal Activities: recording, transcripts and resources– http://grants.nih.gov/grants/olaw/educational_resources/webinar_08212014.htm

• Notice number: NOT-OD-14-126Release date: August 26, 2014

Change in Criteria for Renewal of Domestic Animal Welfare Assurances

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• Current direct or indirect PHS funding for activities involving animals

• Funding via grant, contract, or subaward• Letter of inactivation, if no current funding• If selected for a future award, a new Assurance will

be negotiated• Notice number: NOT-OD-14-099

Release date: May 29, 2014

Educational Resources

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Commentary in Lab Animal

August 2014, Vol. 43, No. 8, pp 265-267Animal care and use programs for multiple campuses

January 2015, Vol. 44, No. 1, pp 13-15Authority to euthanize

March 2015, Vol. 44, No. 3, pp 85-88Interpreting guidance on significant changes

April 2015, Vol. 44, No. 4, pp 129-131Congruence between grants and protocols

May 2015, Vol. 44, No. 5, pp 167-169Control of IACUC meeting minutes

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OLAW Web Resources

OLAW Web Resources

OLAW Webpages: Education Resources – Webinars list - Updated Significant Changes – New

PHS Policy Tutorial – Good for new membersFrequently Asked QuestionsTopic IndexUseful Links – alternatives, ethics, reports, etc.

Sample Documents:Semiannual Facility & Program Review

Checklist Semiannual Report to the Institutional Official Animal Study ProposalAnimal Welfare Assurances Annual Report19

2015 Workshops & Conferences

IACUC 101 Series Workshops

September 3-4 – Honolulu, HI

SCAW Workshops & Conferences September 18 – New York, NYOctober 8 – Chicago, ILDecember 7-8 – San Antonio, TX

USDA AWIC Workshops – Beltsville, MDOctober 28-29

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OLAW Online Seminars

Online seminars quarterly at 1pm ETSeptember 24 – Resources for the 3RsDecember 3 – Q & A with OLAW

About the program:http://grants.nih.gov/grants/olaw/e-seminars.htm

Recordings of previous online seminars:http://grants.nih.gov/grants/olaw/educational_resources.htm

Webinars now sorted by Category, Date and Name

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OLAW Online Seminars

Recordings and transcripts of recent online seminars:June 4, 2015 - Regulatory Considerations for Using Pharmaceutical Products in Research Involving Laboratory AnimalsMarch 12, 2015 – Zebrafish 101 for IACUCsDecember 4, 2014 – Openness & Transparency and Biomedical Research Oversight

http://grants.nih.gov/grants/olaw/educational_resources.htm

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New NIH Initiatives

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•Nature, Collins FS & Tabak LA, 505:612-13, 2014•NIH training modules emphasizing good

experimental design•Principles for enhanced rigor in publishing•Revise application instructions and review criteria:▫Scientific premise▫Rigorous design▫Consideration of sex and other relevant biological

variables▫Authentication of key biological and chemical

resourceshttp://www.nih.gov/science/reproducibility/index.htm

Enhancing Rigor and Reproducibility in NIH-funded science

Thank You

• E-mail: olaw@od.nih.gov• Phone: 301-496-7163• Website: http://olaw.nih.gov• Twitter: @NIH_OLAW• ListServ or RSS feed:

subscribe through OLAW webpage for current announcements, notices, policy interpretations.

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USDA Updates

Carol Clarke, DVM, DACLAMResearch Staff OfficerUSDA-APHIS Animal Care

Animal Care

National Policy Staff Riverdale, MD

Emergency ProgramsRiverdale, MD

Animal Welfare Operations Raleigh, NC Fort Collins, CO

Center for Animal Welfare Kansas City, MO

Total: ~224 employees

Animal Welfare Operations [Formerly the Regional Offices and

Inspectors]

•Contact information unchanged• Fort Collins and Raleigh offices

• Duties remain the same• Oversight of the inspection process• Oversight of licensure and registration • Processes the annual reports • Participates in outreach and education

The Collaboratory• Center for Animal Welfare:

• Training arm for inspectors, licensees & registrants • Veterinarians on staff with specialties by species

• National Policy Staff: • Establishes policy, and direction of AC programs. • Veterinarians on staff are SMEs for a regulated entity

• The Regulatory Support Staff: • Consist of lawyers that ensure case management,

program and policy analysis. • Works with APHIS Investigative & Enforcement Services

and the Office of the General Council.

Changes to Inspection Guide

Chapter 4: Specific Types of Inspections

Revisions in 2015

•Inspection of Inactive Facilities [4-24]• Facilities with no regulated activity for 2 years

• Registration dictates inspection• Registration can be canceled and reactivated

before animal use begins.• Contact the regional office for guidance

Chapter 7-Research Facility Inspection

Revisions made in 2015

•Exceptions and the Annual report• Requirements for reporting [7-26]

•Protocol Selection Process [7-29]• Protocol Selection Worksheet

Regulatory Updates

Importation of Live Dogs

Final rule: Docket No. APHIS–2009–0053 Effective 11/14/2014•Animal Welfare Act amended to ensure health and welfare of imported dogs

Prohibits the importation of dogs into the US for resale unless the Secretary determines the dogs:•are in good health, •received all necessary vaccinations,•are at least 6 months of age.

Dogs Imported for Research

• Importers of dogs for research must submit:

• Animal Care import permit [ APHIS 7040B]• Continuation Sheet [APHIS 7040C]• Health certification for each animal [APHIS 7041]

• Submit evidence where necessary why age, vaccination, or health exemptions are necessary [e.g. IACUC-approved protocol]

Contact: Dr. Gerald Rushin Gerald.L.Rushin@aphis.usda.govContact: Julian Prager Julian.D.Prager@aphis.usda.gov

Petitions

Federal Register: APHIS - 2014-0050:

PCRM: Develop clear and more stringent requirements for identifying and using alternatives.

•Comment period: 3/30/2015- 5/29/2015 250 comments received

•Recommendations will be made to APHIS after all comments reviewed

Federal Register: APHIS 2014- 0098

New England Anti-vivisectionist Society:• Ethologically appropriate environments for

nonhuman primates in research

Comment period re-opened for an additional 60 days until 8/31

Recommendations will be made to APHIS after comments are reviewed

Federal Register: APHIS-2015-0033NAVS: Petition to Amend the Reporting Requirements for Research Facilities Under the Animal Welfare Act Regulations

Comment period: 6/24/2015 to 8/24/2015

Comments will be reviewed and recommendations will be made to APHIS.

Note

• Publication in the Federal Register is not an indication there will be a regulatory change• A regulatory change requires following the rulemaking

process which is dictated by the Administrative Procedures Act

Animal Care Always Available for Guidance

Your VMO or Regional Office is available to listen!

Get updates through our stakeholder registry

https://public.govdelivery.com/accounts/USDAAPHIS/ https://public.govdelivery.com/accounts/USDAAPHIS/ subscriber/new subscriber/new

Update from Update from AAALAC AAALAC InternationalInternationalChristian E. Newcomer, VMD, DACLAM Christian E. Newcomer, VMD, DACLAM Executive DirectorExecutive Directorcnewcomer@aaalac.orgcnewcomer@aaalac.org

Today’s Topics

AAALAC reaches a landmark! Items involving accreditation Items involving the industry and modifying

our work environment Items internal to AAALAC (with spillover

effects on you)

Cage/Rack Washer & Sterilizer Safety

http://www.aaalac.org/accreditation/faq_landing.cfm#E10

This FAQ has had several revisions “…..it is easy to become confused and

disoriented during an emergency situation when seconds can make a difference. All safety features should be clearly identified and be easily distinguishable or have legible instructional or identification signage. In addition, a sign should be located on the outside of the rack washer or bulk sterilizer that identifies all of the safety features of the equipment.”

Harm-Benefit Analysis

Carbon Dioxide (CO2) Euthanasia http://

www.aaalac.org/accreditation/faq_landing.cfm#D5

Because of their metabolic differences, great care should be taken with CO2 euthanasia of neonatal rodents, ensuring minimization of pain and distress, with due consideration of applicable laws and regulations.

1This also applies to those rare cases when CO2 is used for anesthesia.

Committee to Review the Program Description Template

As part of continuous improvement, the Council had determined that after a full cycle of site visits, the PD template would be reviewed for improvements.

Using comments provided by units to the AAALAC Office or identified by Office staff as well as Council suggestions, work continues to refine the PD.

Adoption of the new PD will be considered in at the September 2015 COA Meeting.

Key Findings

• Avoid implementing unnecessary requirements

• Disseminate “model program” information (from Federal agencies)

• Review and refine IACUC processes and staff to promote rapid approval of high quality scientific proposals

• Irritants regarding IACUC administrative work:

• Escalating regulations• Prescriptive guidance• Duplicative oversight on

grants and protocols• IACUC hyper-regulation• Liability paranoia• Added effort-welfare neutral• OLAW’s lack of should/must

dichotomy• Many other specific gripes

AAALAC Perspective – the AAALAC “club”

“The AV said I now had to obtain my own DEA registration to obtain ketamine, instead of getting it from the veterinary staff…..”

“When asked why, the AV replied that on the next site visit, AAALAC will require that PI’s have their own registrations...”

What About the JAAWS Article?

News Flash!!!The authors have declined to share their dataset with us.

Dear Chris,

Justin and I conferred about the discussion that we had with you yesterday. Based on that discussion, in which you made clear that you would use our data in a premeditated attempt to exonerate AAALAC, rather than conduct an objective analysis, we will not be sharing our data with you. Thank you.

Sincerely,

Alka Chandna, Ph.D.Senior Laboratory Oversight SpecialistLaboratory Investigations DepartmentPeople for the Ethical Treatment of Animals(202) 829-0974 | AlkaC@peta.org

http://www.tandfonline.com/eprint/ujcEqFhRxzKDRMSgkqDY/fullNewcomer & McGlone commentary in JAAWS

New/Revised Reference Resources

No new RRs added AVMA Guidelines on Euthanasia NIH Guidelines for Research Involving

Recombinant or Synthetic Nucleic Acid Molecules

CCAC Guidelines on the Care and Use of Fish in Research, Teaching, and Testing

CIOMS-ICLAS International Guiding principles for Biomedical Research Involving Animals

Thank you!Thank you!www.aaalac.org

accredit@aaalac.org

Additional Questions?

Colorado State UniversityElaine K. Kim, BS, CPIA

Lon V. Kendall, DVM, PhD, DACLAM

Implementation of OLAW Guidance on Significant Changes to Animal Activities, NOT-OD-14-126

What documents need to be created to implement VVC process? “The specific significant changes…may be handled administratively according to IACUC-reviewed and -approved policies in consultation with a veterinarian authorized by the IACUC. The veterinarian is not conducting DMR, but is serving as a subject matter expert to verify that compliance with the IACUC-reviewed and -approved policy is appropriate for the animals in this circumstance. Consultation with the veterinarian must be documented. The veterinarian may refer any request to the IACUC for review for any reason and must refer any request that does not meet the parameters of the IACUC-reviewed and -approved policies.”

Transcript, page 4: “We mean guidance documents, standard operating procedures and drug formularies.”

NOT-OD-14-126: What does it say?

Implementation of NOT-OD-14-126 at CSU: Should we do it? If so, how? •VVC Process developed by IACUC—2 documents:

• Protocol Review Process• Performance of Repeat Procedures

•Included items identified in NOT-OD-14-126• Anesthesia, analgesia, sedation • Euthanasia method• Duration, frequency, type and number of procedures

•Additional considerations: • Experimental substance administration• Animal disposition• Source of animals• Space requirements

Veterinary Verification and Consultation (VVC)

• Updated contact information • Typographical errors • Change funding information • Change in personnel (not PI)• Increase in animal numbers of non-USDA covered species, not to exceed

10% of the approved protocol number • Change in housing location within an IACUC approved facility

Administrative Review

CSU Metrics

• CSU ACUP: 620 protocols • Infectious disease, biomedical research, veterinary school, veterinary clinical

studies, no medical school, ag satellite facilities, increasing private sponsors, and FDA regulated work

• DR/FCR amendments vs. VVC amendments: • Average turnaround time: 3-4 weeks vs. 7 days or less • Percentage of total amendments from January-July 2015:

• 29 out of 120 = ~24%• Type of amendments submitted influenced revisions of 2 policies.

Document Revisions and Review Documentation • Revisions since implementation in October 2014:

• VVC section: • additional strains/sources of animals • space requirement changes • final disposition clarification • examples of “duration, frequency, type of procedures” • number of procedures • reference materials used with the policy

• Language adjustments, e.g. from “approval” to “verification” • Performance of Repeat Procedures:

• clarification of how the document is used• nasal, buccal, fecal collections

• eProtocol—VVC Panel, Protocol Notes section, AV notes rationale. • Included in monthly meeting minutes, allowing entire IACUC to review. • Any question about DR/FCR vs. VVC/administrative review goes to the IACUC.

Scenarios

• PI approved for use of ketamine/xylazine anesthesia; wants to expand the dose range listed in the protocol.

• PI approved for final disposition of euthanasia; wants to add transfer to another approved IACUC protocol.

• PI approved for euthanasia of mice via isoflurane overdose + cervical dislocation; wants to add secondary method of exsanguination.

• PI approved for monthly blood collection in cats; wants to decrease the time between blood collections (collect every 2 weeks), same amount of blood collected.

• PI to add 2 rats (Genus Rattus) to the protocol (total n=30 rats). • PI to change housing location of aquatic species to personal lab space. • PI to add transfer to another approved IACUC protocol as final disposition:

• Recipient protocol has at least one pain category D procedure • Original protocol has pain category C procedures only.

Break-Time

Overview: USDA Inspection Process

Carol Clarke, DVM, DACLAMAPHIS-Animal Care

Animal Welfare Act (AWA)

Public Law 89-544, US Code 7 § 2131-2159,

A statute enacted by Congress in 1966.

This law governs the care & use of animals in research for both gov’t& non-gov’t facilities

Animal Welfare Regulations

Code of Federal Regulations 9 CFR Chapter 1 Subchapter A

Every regulation listed in the CFR must have an enabling statute (AWA).

The regulations describe in greater detail how an agency should interpret the law.

Animal Care Resource Guide Policies Guidelines for regulation interpretation updated 3/2014

Our Data Systems

• Animal Care Information System (ACIS)• Database open to the public where inspection and

annual reports are posted

• Risked Based Information System (RIBIS)• Proprietary property of Animal Care• Determines inspection frequency

• factors: regulatory requirements, non-compliances

The Inspectors

• Only veterinarians (VMOs) inspect facilities that use animals for teaching, testing, & experimentation

• VMOs receive training in the regulatory requirements through our Center for Animal Welfare.

Terms: Citation Vs. Violation

• A ‘citation’ occurs when a VMO determines a regulatory requirement was not followed• Animal Care uses the term Non-compliance, or

Non-compliance item [NCI]

• A ‘violation’ is the term used after a judge has made a ruling • ‘Alleged violation’ is the term before a ruling is made

More Terminology

•Direct NCI: A noncompliance that currently and directly affects animal health and well-being

•Repeat NCI: A noncompliance that has been cited on a previous inspection report.

• Not necessarily the last inspection report

• AWA § 2146a mandates one annual visit Includes inactive facilities or those that

did not use or handle animals in 2 years

• VMOs can visit more often: Due to complaints Based on the history of compliance As a result of on-going investigations

Inspection Frequency

Complaints

A VMO will evaluate allegations when: They involve serious animal welfare impacts They are < 3 years old They were not investigated previously

The VMO will not evaluated allegations:If they are the same ones previously looked into If the allegations are > 3 years old.

Inspection of Research FacilitiesAgency/ Organization

Frequency of visitation

Announced Regulatory Authority

Focus

USDA-APHIS Annual Inspections Or as often as needed

No Animal Welfare Act:P.L. 89-544 § 2146a

Minimize pain/distress

NIH-OLAW Site visits are Ad hoc or for cause

Yes Health Ext Research Act P.L. 99-158 § 495

PHS policy & ILAR Guide 8th ed

FDA Inspections every 2-3yrsDepending on # of GLP studies

No Food, Drug, & Cosmetics ActP.L. 75-717

Compliance with GLP mandates

AAALAC Site visits are every 3yrs

Yes None Program accreditation

Animal Welfare Inspection Guide• A reference document to assist the inspector.

• Does not supersede the Animal Welfare Act (AWA) or the AWA Regulations

• Does not supersede professional judgment.

• Chapters relevant to research facilities:• 2: Required Inspection Procedures• 3: General Inspection Procedures• 4: Specific Types of Inspections• 7: Research Facility Inspections

Preparation Before Inspection

• Preparation may include but is not limited to:

• Review of past inspection reports• Attention to veterinary care and Direct NCIs

• Current enforcement actions• Exemptions

• i.e. additional major operative procedures

Required Procedures

• Outlined in Chapter 2 of Inspection Guide• VMO must:

• arrive during the normal business hours• be accompanied by the facility’s designated

representative• follow the facility’s biosafety procedures

Inspectors are allowed access §2.38 (b): Access of records & property•During business hours APHIS official allowed to:

• Enter the business, • Examine required records and make copies,• Inspect where deemed necessary, • Document findings of noncompliance (pictures, other

means)

A Common Citation

§2.38 (b): Access of records & property

•Citation-No access to records • Cause: Person with access (keys or codes) is out• Prevention: have a back-up person

Photos

Photos will be taken when:

• there are “Direct” or “Repeat” NCIs• facility is under investigation • there is some concern or dispute

The facility will have 24 – 48 hrs. to review & request redactions of records

Inspection includes but limited to:

Facility:•Animals and enclosures• Equipment, • Transportation vehicles/equipment

Documents:•IACUC minutes•Acquisition records•Program of veterinary care•Dog Exercise plan•Plan for Environmental Enhancement” for primates.

Protocol Review Sheet-NEW

• Research Facility Protocol Selection Sheet

• Summarizes protocol sampling procedures• Protocol numbers not required • Becomes attached to the inspection report• Will not be posted to the website but can be

requested through FOIA.

Teachable moments-New

•Purpose: to gain compliance through education

• May become a citation on next visit if not adhered

•Disposition:• Scanned into ACIS and sent to the VMO’s Supervisor• Kept for 3 years or longer if there is an ongoing

investigation

Inspection of ‘Inactive’ Facilities• Registration dictates inspection:

• Includes facilities on inactive status by request• Includes facilities with no regulated activity for 2 years

• The Inspector :• Confirms no regulated activity• Ensures an IACUC is in place• Checks to see if an Annual Reports as filed

• The Inspection Report:• Will indicate no regulated activity

Tip: Avoid inspection by canceling registration

Self - Identification & Correction

No Citation• The IACUC/facility found the problem in a timely

manner, • Took timely and appropriate corrective action,• There is not an ongoing pattern of violations, and• No serious animal welfare impacts.

Citation• If all of the above criteria are not met

Self Reporting of Adverse Events

Self reporting of adverse events is voluntary•Does not impact citations for noncompliance. •Is viewed however as a sign of “good faith” which may be taken into consideration during an investigation

Required Reporting1. Change in operation2. Annual Report.3. IACUC protocol suspension4.Failure to adhere to the plan and schedule to correct a significant deficiency

Exit Briefing

•Each NCI is reviewed with corrections discussed• If no NCIs, just a summary of events will occur • If there is information that leads to a change,

the report must be modified before it is issued.• Can be done immediately or mailed later

•The inspector and the registrant sign report • Signature ≠ agree but a facility can opt not to sign

•A copy of the report is left with the facility • an amended report can be sent by certified mail

Exit Briefing: Facility Opportunities

• Ask questions

• Present additional information that may influence the determination of compliance.

Delivery of the Inspection Report

• Required: Hand delivery of reports with Direct NCIs • Other reports can be delivered by E-mail or

certified mail.

• Required: the report must arrive at the facility before the earliest correction deadline or within 5 days post inspection

The Appeal Process1. Must receive appeal within 21 days of receipt of report

2. The report remains off-line during the process

3. An Appeal team is formed: The Regional Director (RD)& Asst. RD (opposite offices)A Subject matter expert

4. The Ruling: Usually within 30 days and is final

5. Disposition of the report post-ruling:If a change occurs only the modified report is posted The original report is kept in the regional office

Investigative Actions

• Investigative and Enforcement Services (IES) may become involved in severe cases of noncompliance

• The IES website explains the process, go to:• http://

www.aphis.usda.gov/wps/portal/aphis/resources/enforcement-actions

• Select: Investigative Process, Enforcement Process

• Questions can be directed to Christine Jones • Christine.B.Jones@aphis.usda.gov

Your VMO or Regional Office is available to listen!

Get updates through our stakeholder registry

https://public.govdelivery.com/accounts/USDAAPHIS/ https://public.govdelivery.com/accounts/USDAAPHIS/ subscriber/new subscriber/new

Animal Care is Available for Guidance

Questions and Answers

Notice of Memorandum of Understanding Between NIH and NSF Concerning Laboratory Animal Welfare (NOT-OD-15-139)

Issued by National Institutes of Health (NIH)

Purpose

This Notice announces a memorandum of understanding (MOU) between the NIH Office of

Laboratory Animal Welfare (OLAW) and the National Science Foundation (NSF).

Memorandum of Understanding

NIH and NSF operate under a MOU to ensure consistent and effective oversight of the welfare of

animals used in activities funded by the NSF. The agreement provides a framework to enhance

communication and harmonize the agencies' efforts while reducing regulatory burden to supported

institutions. The MOU is posted at http://grants.nih.gov/grants/olaw/references/mou_nsf.htm.

Impact on NSF-supported institutions

Effective October 1, 2015, institutions receiving NSF support must:

include NSF-supported activities with live vertebrate animals as covered activities in their OLAW

Animal Welfare Assurance (Assurance); and promptly report situations involving NSF-supported

animal activities to OLAW as required by the Public Health Service (PHS) Policy on Humane Care

and Use of Laboratory Animals (Policy) Section IV.F.3.

NOT-OD-15-139 (Continued)OLAW will:

negotiate new Assurances for institutions with pending NSF awards;

review and evaluate noncompliance reports and the actions taken involving NSF-supported activities; and

report findings to NSF.

Background

OLAW is responsible for administration and implementation of the PHS Policy. The Policy requires

institutions to establish and maintain proper measures to ensure the appropriate care and use of all animals

involved in research, research training, and biological testing activities. Institutions receiving PHS funding

through grants, contracts or cooperative agreements for research involving vertebrate animals are required

to comply with the PHS Policy.

NSF holds its awardees responsible for the humane care and treatment of any vertebrate animal used or

intended for use in such activities as field or laboratory research, development, training, experiments,

biological testing or for related purposes supported by NSF grants, contracts or cooperative agreements.

Any NSF awardee performing research on vertebrate animals must comply with the Animal Welfare Act

(AWA) [7 U.S.C. 2131 et seq.], the AWA regulations [9 CFR 1.1-4.11], the PHS Policy, and the U.S.

Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and

Training. The awardee must follow the guidelines described in the Guide for the Care and Use of

Laboratory Animals and the AVMA Guidelines for the euthanasia of Animals.

NOT-OD-15-139: Questions1. If an organization does not receive funding from PHS, but

receives it from NSF will it need to negotiate and maintain an Assurance?

2. Will the NIH Grants Terms and Conditions also apply to NSF grants?

3. An Assured organization subcontracts NSF funds to a non-Assured organization. Does the non-Assured organization need to establish an Assurance, be listed as a performance site?

4. Does this affect AAALAC and accreditation requirements?

5. Will OLAW/NIH govern NSF funds?

Any Recommendation for Handling the NIH Congruency Requirements?

What is the Expectation for Documenting Training?

Any concerns with the following?

1.On the approved IACUC protocol, the PI “ASSURES” all of his/her staff will be appropriately trained to conduct all animal activities before initiation.

2.The PI indicates on the protocol that all are experienced and no training is necessary.

3.Each animal user maintains his or her own training logs, which are made available upon request.

4.Any other ideas?

How do institutions fulfill the requirement for maintaining an Occupational Health and Safety Program?

What mechanisms are used to assure that researchers recognize an unexpected outcome and know when and how to

report it?

How do institutions determine when to use the Guide vs. the Ag Guide?

How are researchers educated to recognize pain and distress in animals, especially in prey species that may hide it, and to provide pre-

emptive treatments when appropriate?

Time for Lunch!!

Ron E. Banks, DVMDiplomate, American College of Animal WelfareDiplomate, American College of Laboratory Animal MedicineDiplomate, American College of Veterinary Preventive Medicine

Director, Office of Animal Welfare AssuranceDuke University & Duke University Medical CenterDurham, North Carolina

Webster defines merit as;… the state of having worth, value or excellence.

When the noun merit is combined with the adjective scientific it means:

… of scientific worth, scientific value, or scientific excellence.

Legal Basis:Public Health Service Policy on Humane Care and Use of Laboratory Animals (PHS Policy), which applies to all PHS-supported animal research through the U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research and Training:

Principle II: Procedures involving animals should be designed and performed with due consideration of their relevance to human or animal health, the advancement of knowledge, or the good of society.Principle III: The animals selected for a procedure should be of an appropriate species and quality and the minimum number required to obtain valid resultsPrinciple VIII: Investigators and other personnel shall be appropriately qualified and experienced for conducting procedures on living animals.Principle IX: Where exceptions are required in relation to the provisions of these Principles, the decisions should not rest with the investigators directly concerned but should be made, with due regard to Principle II, by an appropriate review group such as the institutional animal care and use committee.

Legal Basis:USDA: AWA, USDA regs, USDA Policy

e.g., Use animals when justified.

Legal Basis:AAALAC:

AAALAC: 3. Harm-benefit analysis: On page 27, the Guide for the Care and Use of Laboratory Animals (NRC 2011) indicates that for studies that have the potential for unrelieved pain or distress, there are special considerations for IACUC review. Specifically, the Guide indicates that "the IACUC is obliged to weigh the objectives of the study against potential animal welfare concerns." This seems to indicate that for studies involving the potential for pain and distress, the IACUC should conduct a "harm/benefit" analysis. What does AAALAC expect with regard to Committee evaluation of these kinds of studies?

The 2011 Guide specifies that the Committee is obliged to weigh study objectives against animal welfare concerns in accordance with the tenets of the Three R's. This analysis is typically already performed by IACUCs in their reviews of proposed animal studies. AAALAC International expects that IACUC's (or comparable oversight body), as part of the protocol review process, will weigh the potential adverse effects of the study against the potential benefits that are likely to accrue as a result of the research. This analysis should be performed prior to the final approval of the protocol, and should be a primary consideration in the review process. For animal use activities potentially involving pain and/or distress or other animal welfare concerns, the AAALAC International site visitorswill assess how the Committee conducts this analysis.

Institutional review of merit:Particularly important when:

Using in-house funds, Initiates a research project whose review is pending at the NIH, or Could be published.

Can do two different levels of review for merit: The fundamental level (the smell test), and The knowledge-based level (science potential).

1. State the specific scientific objectives (aims) of the research;

2. State the potential value of the study with respect to human or animal health, the advancement of knowledge, or the good of society. Identify the information gaps the project is intended to fill. If the research duplicates previous experiments, explain why the duplication is necessary;

3. Justify the species selection;

4. Provide detailed justification for the number of experimental and control animals requested. Include a brief description of the experimental design and state the number and species/strain of animals per group/subgroup in each experiment/procedure;

5. Describe sequentially, with a reasonable degree of detail, all procedures (surgical and nonsurgical) to be carried out on live animals. The end points of procedures and the time frame must be clearly defined; and

6. Address familiarity of all involved personnel with behavioral/physiological/ anatomical characteristics of the selected species, and describe their experience with regard to the specific procedures to be applied to live animals.

Scientific Merit is Not Sufficient AloneThe relative value of the study must be consideredMorbidity is an ethical costMortality may also be an ethical cost

Some studies may have scientific value but be insufficiently meritorious due to the ethical cost required.

IACUCs Cannot transfer this decision to the research subjects IRBs may be able to transfer some decision-making to the research subjects

http://vetmed.duhs.duke.edu/PDF/Guidelines%20&%20Suggestions/Guidance_%20for_Merit_Reviewers.pdf

Considerations:Tailor merit reviews to an individual reviewer or the proposed activity being reviewed. Significance: Does the project address an important problem in the field? If the aims of the project are achieved, will the new knowledge potentially affect concepts or methods that drive this field? Investigator: Are the PI and associates considered capable of completing the proposed activities? Is the principal investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? Innovation: Do the experiments challenge current scientific paradigms? Does the project employ novel concepts, approaches, or method? Are the aims original and innovative? Approach: Is it plausible that the overall strategy, methodologies, and analyses will accomplish the specific aims of the project? Does the principal investigator acknowledge potential problem areas and consider alternative approaches? Environment: Is the scientific environment and support considerations adequate for successful completion of the work? Does the research take advantage of unique features of the environment or employ useful collaborative arrangements? Is there evidence of institutional support?Ethical Cost-Benefit: Is the use of animals in the described context result in an acceptable ethical cost-benefit outcome?

Afternoon BreakAfternoon Break

Proposed New OLAW Non-pharmaceutical-grade

Substance Policy

Susan Silk, OLAW, NIHIAA Best Practice Meeting

State College, PAAugust 27, 2015

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Draft, Not Final Policy

• The following slides are proposed (not final) policy.

• OLAW would appreciate your feedback on our proposed policy.

• You can help by sharing your opinion:– Will this empower humane animal care and use? – Will this work administratively at your institution?– Do you understand the proposed policy?– Have you experienced exceptional circumstances that

we should consider in drafting this policy?

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Proposed Definition

OLAW and USDA define a pharmaceutical-grade substance as any active or inactive drug, biologic, reagent, etc., manufactured under FDA Current Good Manufacturing Practices (CGMP) regulations.

Substances that were not manufactured under FDA CGMP are non-pharmaceutical-grade.

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FAQ F4 Revision: May investigators use non-pharmaceutical-grade substances in animals?

Yes. It is frequently necessary to use non-pharmaceutical-grade substances in animals to meet scientific and research goals. OLAW and USDA require investigators to use pharmaceutical-grade substances in PHS Assured and USDA regulated research unless it is necessary to use a non-pharmaceutical-grade substance for scientific reasons or because a pharmaceutical-grade substance is not available. The agencies require the investigator to justify, and the IACUC to review and approve, the use of non-pharmaceutical-grade substances.

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(F20) How can I determine whether a particular drug is available in a pharmaceutical-grade?

If a substance is manufactured under CGMP or conditions that meet the standards1 of CGMP, OLAW considers it to be pharmaceutical-grade. Substances such as drugs, reagents, biologics, etc., that cannot be demonstrated to have been manufactured under CGMP are considered non-pharmaceutical-grade by OLAW.

1Such as INAD file drugs or FDA registered drugs.

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(F21) May investigators use non-pharmaceutical-grade substances because they cost less than an expensive pharmaceutical-grade product?

No. Cost savings alone is not an adequate justification for the use of non-pharmaceutical-grade substances. Researchers are required to administer pharmaceutical-grade substances to animals in PHS Assured or USDA registered animal care and use programs, when available, unless a non-pharmaceutical-grade substance is required for scientific reasons.

Unavailability or shortages of pharmaceutical-grade substances may lead to cost increases and the IACUC may determine that this justifies the use of the non-pharmaceutical-grade substitution.

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(F22) How can we determine if drugs we order from chemical or reagent suppliers are pharmaceutical-grade?

Products obtained from chemical or reagent suppliers are not pharmaceutical-grade because they are not manufactured under CGMP.

Frequently the supplier provides a chemical purity standard of the reagent in the catalog listing. Chemical purity standards provide information about the purity of a substance, but no information about the safety or efficacy of the substance when administered to animals.

If the use of a reagent or chemical is justified in the animal study proposal (scientific or pharmaceutical-grade not available), IACUCs may approve the use of substances that have a chemical purity grade of “N.F.” or above. Substances rated “Lab” grade or below are not appropriate for administration to animals.

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Chemical Purity Standards

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Category DefinitionA.C.S. A chemical grade of highest purity and meets or exceeds purity standards set by American

Chemical Society (ACS).

Reagent High purity generally equal to A.C.S. grade and suitable for use in many laboratory and analytical applications.

U.S.P. A chemical grade of sufficient purity to meet or exceed requirements of the United States Pharmacopeia (USP); acceptable for food, drug, or medicinal use; may be used for most laboratory purposes.

N.F. A grade of sufficient purity to meet or exceed requirements of the United States National Formulary. (Was acquired in 1975 by the United States Pharmacopeia, USP-NF. NF contains excipient standards that also call for reference materials.)

Lab A chemical grade of relatively high quality with exact levels of impurities unknown; usually pure enough for educational applications. Not pure enough to be offered for food, drug, or medicinal use of any kind.

Purified Also called pure or practical grade, and indicates good quality chemicals meeting no official standard; can be used in most cases for educational applications. Not pure enough to be offered for food, drug, or medicinal use of any kind.

Technical Good quality chemical grade used for commercial and industrial purposes. Not pure enough to be offered for food, drug, or medicinal use of any kind.

(F23) Are substances compounded in a pharmacy pharmaceutical-grade?

If a substance is compounded by a pharmacy from pharmaceutical-grade substances, OLAW considers the substance to be pharmaceutical-grade.

A substance that is compounded by a pharmacy that contains one or more non-pharmaceutical-grade substances, such as reagents or chemicals, is considered by OLAW to be non-pharmaceutical-grade.

Institutions are expected to comply with the state and federal regulations applicable to compounding and would be wise to evaluate the compounding pharmacies under consideration to determine if they are quality providers.

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(F24) Are investigators required to use a compounding pharmacy when they require a specific mixture of substances? No. It is sometimes necessary for researchers to compound investigational substances in their laboratories.

It is also sometimes necessary for investigators to dilute or add vehicles (adulteration) to pharmaceutical-grade substances in their laboratories.

If investigators compound or adulterate substances from either pharmaceutical-grade or non-pharmaceutical-grade substances, OLAW considers the resulting substances non-pharmaceutical-grade.

Compounding and adulteration conducted by investigators in the laboratory should be described in the protocol, reviewed and approved by the IACUC.

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(F25) Is dilution of a drug with saline considered compounding?

No, dilution of a drug with saline or other appropriate diluent is an adulteration of the original product.

Adulteration is frequently necessary to ensure that the appropriate dosage is administered.

Although this adulteration will have to be reviewed and approved by the IACUC, if proper sterile technique and a sterile diluent are used, there should be no issues of concern for the IACUC.

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(F26) Must a vehicle or diluent be pharmaceutical grade?‑ It depends on the route of administration and the need to maintain sterility.

For oral administration, the vehicle or diluent should be food grade.

For injections such as intramuscular, intraperitoneal, or subcutaneous, the diluent or vehicle should be sterile and physiologic.

Our concern is that it doesn't injure the animals and is appropriate for the science. IACUCs and investigators should use professional judgment in making this determination.

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(F27) When we add a substance to the animal’s feed, does it have to be pharmaceutical-grade?

No. However, as stated on the Chemical Purity Standard Table, chemicals classified as Lab, Purified, and Technical grades may not be administered to animals in the food.

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(F28) Can non pharmaceutical grade substances ‑ ‑be administered to animals for clinical use?

No. For veterinary clinical use, animal or human drugs manufactured under CGMP are required. If there is a scientific reason to use an non-pharmaceutical-grade substance, the use is no longer considered veterinary clinical use.

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(F29) May we use euthanasia solutions, such as Fatal Plus, for perfusions? Procedures in which researchers administer a commercial euthanasia product followed immediately by an irreversible procedure (terminal perfusion, tissue harvest, or exsanguination) is acceptable.

The irreversible procedure confirms death of the animal. Under these circumstances, the euthanasia solution is being used as intended with death as the final outcome.

Any delay in the terminal step(s) to conduct other potentially painful procedures changes the euthanasia to non-survival surgery and is unacceptable.

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(F30) May we use diluted euthanasia solution for anesthesia? No. The use of commercial euthanasia products for anesthesia is specifically prohibited by FDA, as indicated on the product label. The extra-label use of a euthanasia product for its pentobarbital content is unacceptable and violates the PHS Policy and Animal Welfare Act and Regulations. Such proposed use is not to be approved by the IACUC.

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(F31) What are acceptable scientific criteria for institution-wide use of non-pharmaceutical-grade substances?

The IACUC may develop and implement institution-wide policies regarding use of non-pharmaceutical-grade substances. The following are examples of situations in which it would be reasonable for the IACUC to review and approve the use of non-pharmaceutical-grade substances. IACUCs may use these examples as the basis for developing their own criteria.

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Examples of Scientific Justification

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1. If no equivalent CGMP veterinary or human drug is available for experimental use, then an equivalent chemical reagent of N.F. standard or above should be used. It should be formulated aseptically with a non-toxic vehicle as appropriate for the route of administration.

2. Although an equivalent CGMP veterinary or human drug is available for experimental use, the chemical-grade reagent is required to replicate methods from previous studies because results are directly compared to those of replicated studies.

3. Although an equivalent CGMP veterinary or human drug is available, dilution or change in formulation is required.

a. If adulteration by dilution, addition, or other change in formulation is required, there may be no additional advantage to be gained by using a pharmaceutical-grade substance.

b. Use of the highest-grade reagent may have the advantage of single-stage formulation and also result in purity that is equal to or higher than the CGMP human or veterinary drug.

c. Professional judgment should be used to determine the appropriate test material and to ensure use of an agent with the least likelihood for causing adverse effects.

4. The available CGMP human or veterinary drug is not concentrated enough to meet experimental requirements.

5. The available CGMP human or veterinary drug does not meet the non-toxic vehicle requirements for the specified route of injection.

F32. Do ALL substances administered to research animals have to be identified on the protocol?

Drugs used for veterinary clinical reasons on research animals must be pharmaceutical-grade and do not have to be listed in the protocol.

Any drugs, biologics, or reagents that are administered to animals as part of an experiment must be included on the protocol and reviewed and approved by the IACUC.

Use of non-pharmaceutical-grade substances must be justified (scientific reason or pharmaceutical-grade not available) and reviewed by the IACUC.

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(F33) Must we use pharmaceutical-grade vehicles to get non-pharmaceutical-grade test articles into solution?

Vehicles used to administer test articles to animals must be pharmaceutical-grade, if available.

Use of non-pharmaceutical-grade vehicles must be justified, reviewed and approved.

The IACUC and investigator must consider the route of administration of the substance. Products administered orally must be appropriate for food.

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(F34) OLAW says that the IACUC may consider grade, purity, sterility, acid-base balance, pyrogenicity, osmolality, stability, site & route of administration, compatibility of components, side effects and adverse reactions, storage and pharmacokinetics. Are researchers required to provide information about each factor for every substance?

No. The IACUC is responsible for evaluating the potential adverse consequences of non-pharmaceutical-grade substances when used in animals. The IACUC may consider factors including the grade, purity, sterility and acid-base balance, pyrogenicity, osmolality and stability, the site and route of administration, compatibility of components, side effects and adverse reactions, storage and pharmacokinetics.

Not all of these factors may be applicable in all circumstances and the IACUC may not need to request all of this information in every situation.

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Thoughts?

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Wrap-up

Please, complete your Evaluation Forms and offer suggests!