1. Guidance on Significant Changes to Animal Activities
Notice Number: NOT-OD Release Date: August 26, 2014
On August 26, 2014, NIH released OLAW’s new Guidance related to Significant Changes to Animal Activities that can only be described as watershed or as one of my colleagues stated “It’s a game changer”.

2. Resources: Significant Changes to Previously Approved Animal Activities
NIH Guide Notice NOT-OD
OLAW Webpage Significant Changes
You can find the OLAW Guidance at these links. The first URL is a landing page that has links to all the resources OLAW offers regarding the significant change guidance. You can find it within the FAST FACTS section of the OLAW website. That is the first thing on the OLAW website.

3. Resources: Significant Changes to Previously Approved Animal Activities
OLAW Special Seminars: Guidance on Significant Changes to Animal Activities: Recording, transcripts and resources
Susan Silk, MS, OLAW
George Babcock, PhD, U of Cincinnati
Jerry Collins, PhD, Yale University
Betty Goldentyer, DVM, USDA, APHIS, AC
Mary Lou James, BS, IACUC 101 Series
Cynthia Gillett, DVM, University of Minnesota
This link will take you to a relevant OLAW seminar transcript and slides and ultimately to a recording of an electronic fireside chat. During that chat, representatives of the biomedical research community review the Guidance with OLAW’s Susan Silk and USDA’s Betty Goldentyer, and ask questions. I recommend listening to the webinar or reading the transcript because questions discussed on the webinar may include questions that you have, too.

4. Major Points
Significant changes to animal activities may now be handled by several methods as per NOT-OD
Certain specific significant changes MUST be reviewed and approved by either FCR or DMR.
Other specific significant changes MAY be administratively handled using an IACUC-established mechanism of veterinary verification and consultation (VVC) when there is an IACUC approved policy that addresses the specific significant change.
Requests for increases in animal numbers MAY be administratively handled using an IACUC established mechanism for doing so and according to an IACUC policy describing allowable increases.
This slide reviews the major points of the new Guidance. It is important to keep in mind that both OLAW and the USDA agree on this guidance. So USDA-regulated ONLY institutions, this applies to you as well.
OLAW and USDA have NOT changed their position on what constitutes a significant change. What has changed is the introduction of two new processes administrative handling of SOME (but not all) significant changes to be initiated without Full-Committee Review or Designated Member Review. In both of these processes, the IACUC MUST have written policies that address the specific significant changes to animal activities.
These new processes ARE optional – you do NOT have to change the way you currently review and approve significant changes or modifications or amendments to protocols using FCR or DMR but you may want to! Also note that the veterinarian has always been expected to provide clinical care and this has not changed.
OLAW and USDA have designated specific significant changes that MUST be reviewed and approved by either FCR or DMR. No “ands, ifs or buts”. IACUCs cannot deviate from this requirement.
OLAW and USDA have also designated other specific significant changes that CAN be administratively handled by using an IACUC-established mechanism of “veterinary verification and consultation” if and when there is an IACUC-policy that addresses the specific significant change. In these cases, FCR or DMR is NOT required to incorporate the change in the protocol and to initiate the significant change.
In addition, OLAW and USDA also allow requests for increases in animal numbers to be administratively handled using an IACUC-established mechanism for doing so according to an IACUC-policy describing allowable increases. In these cases, FCR, DMR, veterinary verification and consultation are NOT required. Individuals designated by the IACUC can give the nod to permit increases in animal numbers as long as the request is in keeping with the IACUCs policy on allowable increases and is handled in accord with the process that the IACUC has established.
So what we have here are two new methods, both administrative in nature, for permitting the initiation of some significant changes. Both are contingent on the existence of IACUC-policies that address specific significant changes

5. Also Permitted Other allowed activities:
Minor changes MAY be administrative handled by institutional personnel who support the IACUC without IACUC approval, policies, consultation, or notification.
Use of fewer animals than approved by the IACUC does NOT require administrative handling, IACUC approval, policies, consultation, or notification.
OLAW and USDA also go on to clarify that other specific changes can be administratively handled without any IACUC-involvement or IACUC-notification.
In addition, the Guidance addresses minor changes that can be administratively entered into a protocol without an IACUC-policy, or consultations or notifications.
Finally, OLAW and USDA point out that the use of fewer numbers of animals requires no action at all.

6. Review
IACUCs now have 3 methods for handling significant changes to previously approved animal activities:
Classic handling of specified or all significant changes: FCR or DMR by IACUC.
Administrative handling of procedures performed on animals through veterinary verification and consultation (VVC) by IACUC-designated veterinarian.
Administrative handling of increases in animal numbers.
In summary, we now have three possible methods for allowing a PI to go forward with a significant modification. With the exception of some very specific significant modifications that must be approved by either FCR or DMR, other significant modifications may now be implemented using administrative handling approaches2 and 3 depending upon the nature of the modification.

7. 1: Classic Significant changes that can ONLY be approved by FCR or DMR
from nonsurvival to survival surgery;
resulting in greater pain, distress, or degree of invasiveness;
If USDA regulated, literature review is required
in housing and or use of animals in a location that is not part of the animal program overseen by the IACUC;
in species;
in study objectives;
in Principal Investigator (PI); and
that impact personnel safety.
The IACUC MAY choose to require review of other significant changes by FCR or DMR.
These are the significant changes that MUST be reviewed and approved prior to initiation by the classic approach of FCR and DMR. While IACUCs may add other significant changes to this particular list if it feels that FCR or DMR should be performed, IACUCs cannot remove or modify these specific changes.
For these specific significant changes, the PI must submit an amendment which must be reviewed and approved by either FCR or DMR before the change can be initiated..

8. 1. OLAW USDA Expectations
Some significant changes require FCR or DMR and may NOT be approved by VVC or administrative handling.
The IACUC may not develop and approve policies regarding administrative changes to these activities.
So what are the expectations should you decide to adopt the VVC approach?
You must have IACUC policies in place that clearly address specific significant changes that are eligible for the VVC approach (list 2).
So what are policies?
Policies in the context of OLAW’s guidance are defined as guidance documents, SOPs and formularies that address animal activities.
These policies CANNOT address significant changes that OLAW and USDA has designated for FCR and DMR only review and approval. (List 1)
IACUC policies must be reviewed according to a mechanism established by the IACUC and no less than every 3 years.
Methods for reviewing and approving IACUC policies may be by FCR or DMR; by polling IACUC members; or by some other mechanism which makes policies available for IACUC member review and input.
Regardless of the mechanism you establish for reviewing and approving policies, ALL IACUC members are expected to be familiar with these

9. 2: Veterinary Verification and Consult (VVC)
Some significant changes may be administratively handled according to IACUC-approved policies with verification by and in consultation with an IACUC-authorized veterinarian:
anesthesia, analgesia, sedation, or experimental substances;
euthanasia to any AVMA approved method including those approved with conditions as long as the conditions are met,
not permitted to have a policy that allows change to a euthanasia method that is not approved in AVMA Guidelines;
duration, frequency, type, or number of procedures performed on an animal.
So here is what’s new. This is the first of two new administrative approaches for handling significant modifications not listed in the previous slide. We are calling it the Veterinary Verification and Consultation (VVC) Approach.
These significant changes may be administratively handled according to IACUC-approved policies with verification by and in consultation with an IACUC-authorized veterinarian
anesthesia, analgesia, sedation, or experimental substances;
euthanasia to any AVMA approved method including those approved with conditions (as long as the conditions are met)
duration, frequency, type, or number of procedures performed on an animal

10. 2. Advantages of VVC
Permits research team to immediately apply some significant changes to all animals under the protocol.
Avoids delays associated with writing and submitting an amendment for IACUC review and approval and reduces the risk of compromising an ongoing research activity.
Reduces regulatory burden.
So what are the advantages of having IACUC-policies that address significant changes and using the VVC approach?
The VVC approach
Can avoid common delays associated with submitting an amendment and awaiting IACUC-review and approval
Can permit the initiation of some significant changes in an expeditious manner for all animals under the protocol not just one that may require an immediate veterinary intervention for example
Will likely improve the overall efficiency of some animal research activities
Will likely reduce the risk of compromising an on-going research activity waiting for IACUC-approval of a critical change
And reduce not only regulatory burden.

11. 2. OLAW USDA Expectations of VVC
IACUC policies (guidance documents, SOPs and formularies) that address significant changes must be written, reviewed, and approved before they are implemented.
IACUC policies must be reviewed and approved by consensus at least every 3 years by methods that include:
FCR or DMR;
polling by telephone calls or ; or
posting policies in an electronic format for IACUC member review.
IACUC members are expected to understand and be familiar with their policies.
So what are the expectations should you decide to adopt the VVC approach?
You must have IACUC policies in place that clearly address specific significant changes that are eligible for the VVC approach (list 2).
So what are policies?
Policies in the context of OLAW’s guidance are defined as guidance documents, SOPs and formularies that address animal activities.
These policies CANNOT address significant changes that OLAW and USDA has designated for FCR and DMR only review and approval. (List 1)
IACUC policies must be reviewed according to a mechanism established by the IACUC and no less than every 3 years.
Methods for reviewing and approving IACUC policies may be by FCR or DMR which would be considered best practice; by polling IACUC members; or by some other mechanism which makes policies available for IACUC member review and input.
Regardless of the mechanism you establish for reviewing and approving policies, ALL IACUC members are expected to be familiar with these

12. 2. IACUC Responsibilities of VVC
Designate: The IACUC must authorize veterinarian(s) to administratively handle significant changes by VVC.
Vet must understand IACUC policies and have lab animal training or experience.
Does not have to be AV or IACUC member.
May be identified by title, role, or name.
Document and record: IACUC must establish a mechanism for documenting significant changes handled by VVC.
So what is this verification and consultation approach?
First things first: The IACUC must clearly designate what veterinarians are authorized to verify and consult. The authorized veterinarian is not limited to the AV. In fact in some cases, other veterinarians may be equally as suitable or even more suitable than the AV by virtue of their familiarity with the IACUC policy, species and the specific research.
The veterinarian serves several roles in this VVC process:
The vet verifies that the significant change is addressed and permitted in a corresponding IACUC policy.
The vet determines if the requested change is appropriate for the species under the given circumstance.
The vet may recommend modifications to the requested change, ones that are also covered under policy and deemed more appropriate for the animal and/or the science
The vet is authorized to disallow the administrative handling of the change and ask the PI to submit an amendment describing the change to the IACUC for review and approval.
Deferring to the IACUC may be necessary
if the change is not permitted under a policy
if there are concerns that the change may not be appropriate for the particular circumstance
If it cannot be ascertained that personnel are trained and qualified to perform the change
As well as other reasons
members are expected to be familiar with these
Remember once again, policies that are eligible for handling using the VVC approach cannot include significant changes that result in
nonsurvival to survival surgery;
greater pain, distress, or degree of invasiveness;
housing and or use of animals in a location that is not part of the animal program overseen by the IACUC;
in species;
in study objectives;
in Principal Investigator (PI); and
that impact personnel safety.
If the requested significant modification involves any of those items presented under the Classic Approach, the change must be sent to FCR or DMR.
And you are not off the hook for documentation of significant changes that have been handled by the VVC approach.
However, it is up to the IACUC how it chooses to document this process and the incorporation of significant changes.
In addition, these significant changes must make their way into the protocol or the protocol file. This documentation is important for many reasons including, but not necessarily limited to, ensuring the PI has been allowed to implement the significant change and is not deviating from the approved protocol, and to permit the IACUC to review the change at least annually during continuing review if the activity involves a USDA-regulated species.

13. 2. Vet Responsibilities of VVC
Verify:
Certify that an IACUC policy covers the requested significant change.
Determine if the change is appropriate for the specific circumstances.
Consult: Recommend modifications if appropriate and within the scope of the policy.
Defer: Refer the significant change for FCR or DMR by the IACUC, if indicated.
So what is this verification and consultation approach?
First things first: The IACUC must clearly designate what veterinarians are authorized to verify and consult. The authorized veterinarian is not limited to the AV. In fact in some cases, other veterinarians may be equally as suitable or even more suitable than the AV by virtue of their familiarity with the IACUC policy, species and the specific research.
The veterinarian serves several roles in this VVC process:
The vet verifies that the significant change is addressed and permitted in a corresponding IACUC policy.
The vet determines if the requested change is appropriate for the species under the given circumstance.
The vet may recommend modifications to the requested change, ones that are also covered under policy and deemed more appropriate for the animal and/or the science
The vet is authorized to disallow the administrative handling of the change and ask the PI to submit an amendment describing the change to the IACUC for review and approval.
Deferring to the IACUC may be necessary
if the change is not permitted under a policy
if there are concerns that the change may not be appropriate for the particular circumstance
If it cannot be ascertained that personnel are trained and qualified to perform the change
As well as other reasons
members are expected to be familiar with these
Remember once again, policies that are eligible for handling using the VVC approach cannot include significant changes that result in
nonsurvival to survival surgery;
greater pain, distress, or degree of invasiveness;
housing and or use of animals in a location that is not part of the animal program overseen by the IACUC;
in species;
in study objectives;
in Principal Investigator (PI); and
that impact personnel safety.
If the requested significant modification involves any of those items presented under the Classic Approach, the change must be sent to FCR or DMR.

14. 2. IACUC Policy Does Not Apply
What if a significant change is requested, but not covered under an IACUC policy?
The PI sends an amendment to the IACUC for review and approval.
IACUC modifies an existing policy to include the requested change according to the IACUC-established mechanisms for making modifications to IACUC policies.
IACUC develops a new policy that addresses the requested change, according to the IACUC established mechanisms for developing, reviewing, and approving IACUC policies.
So what if a change is not currently covered under an IACUC policy?
You have 3 options.
Option #1: “Classic Approach” - The PI may have to send an amendment to the IACUC for review and approval
Option #2: You may be able to modify an existing policy to include the requested change according to the IACUC-established mechanisms for making modifications to IACUC policies.
Option #3: Or you may decide to implement a new policy that addresses the requested change,  according to the IACUC established mechanisms for developing, reviewing and approving IACUC policies
If you find yourself the position of having to modify an existing policy or develop a new policy, the IACUC should follow its procedures for doing so. And remember, all IACUC members are expected to be familiar with these policies. Neither can take place without involving the IACUC in some manner.
housing and or use of animals in a location that is not part of the animal program overseen by the IACUC;
in species;
in study objectives;
in Principal Investigator (PI); and
that impact personnel safety.
If the requested significant modification involves any of those items presented under the Classic Approach, the change must be sent to FCR or DMR.

15. 3. Administrative Handling of Animal Numbers Increase
An increase in previously approved animal numbers may be handled administratively according to an existing IACUC reviewed and approved policy WITHOUT additional consultation or IACUC-notification
So what if a change is not currently covered under an IACUC policy?
You have 3 options.
Option #1: “Classic Approach” - The PI may have to send an amendment to the IACUC for review and approval
Option #2: You may be able to modify an existing policy to include the requested change according to the IACUC-established mechanisms for making modifications to IACUC policies.
Option #3: Or you may decide to implement a new policy that addresses the requested change,  according to the IACUC established mechanisms for developing, reviewing and approving IACUC policies
If you find yourself the position of having to modify an existing policy or develop a new policy, the IACUC should follow its procedures for doing so. And remember, all IACUC members are expected to be familiar with these policies. Neither can take place without involving the IACUC in some manner.
housing and or use of animals in a location that is not part of the animal program overseen by the IACUC;
in species;
in study objectives;
in Principal Investigator (PI); and
that impact personnel safety.
If the requested significant modification involves any of those items presented under the Classic Approach, the change must be sent to FCR or DMR.

16. 3. Expectations of Administrative Handling of Animal Numbers Increase
IACUC must have a policy that describes increases in animals numbers that can be handled administratively, permitted changes (e.g., percentage, range, or number), and who may approve the change (e.g., IACUC administrator).
IACUC policy may be written broadly for all species or may be written specifically by species (e.g., rodents,  dogs, NHPs).
The original rationale for the numbers of animals should continue to support the increase in number, range or percent being requested. If not, a revised rationale is required .
While this process delivers the same advantages as the VVC process, there are some important expectations worth mentioning.
The process must once again be based on IACUC-policy that delineates what increases in animals numbers, if any, can be handled administratively and under what circumstances.
The policy probably should describe or identify those who are authorized to administer this process.
The IACUC policy on animal numbers can be written broadly for all species or more specifically for each species or somewhere in between.
Some IACUCs may limit increases in animal numbers to a maximum percent increase or a relative number or even a range. For example, IACUC may allow 20% increases in rodents, increases in rabbits of 5 – 10 animals; and no increase for nonhuman primates unless approved through FCR or DMR or handled via the VVC administrative method.
But here is an important catch: Both PHS Policy and USDA regulations require proposals and significant changes include a rationale for the appropriateness of animal numbers. While PHS Policy does not explicitly apply these requirements to significant changes, PHS Policy sets forth the expectation that research activities will be conducted in accord with the Animal Welfare Act.
Regardless of the mechanism for allowing increases in animals based on IACUC-Policy, it behooves whoever is designated responsible for administering this process to ensure that the originally approved rationale for the animal number continues to apply to the increases being requested. If not, a revised rationale for the appropriateness of animal numbers should probably be requested. Perhaps your IACUC-Policy will require the PI include an explanation or rationale for why the additional animals are needed as a way to manage this concern. And certainly, if the request is based on the need to replace animals that have experienced unexpected morbidity or mortality, the IACUC Policy may include language that in such circumstances the request for for additional animals be deferred to the IACUC.
The bottom line here is that the IACUC-policy on animals numbers should be developed with considerable thought and attention to all the possible scenarios. And this is probably the approach to take with all of these IACUC-policies that address significant changes that can be handled administratively.

17. 4. Administrative Changes
Administrative changes may be managed without IACUC-approved policies, consultations, or notifications:
correction of typographical errors;
correction of grammar;
contact information updates; and
change in personnel, other than the PI
(An administrative review must be conducted to ensure that all such personnel are appropriately identified, adequately trained and qualified, enrolled in occupational health and safety programs, and meet other criteria as required by the IACUC.)
Now to address some other specific changes that may be handled purely administratively. These changes are
correction of typographical errors;
correction of grammar;
contact information updates; and
change in personnel, other than the PI
None of these items necessitate IACUC-approved polices, veterinary verification and consultation, or even IACUC notifications.

18. 5. Administrative Change
The use of fewer animals than approved may be handled without IACUC policy, approval, notification, consultation, or administrative handling.
Lastly, the Guidance sets forth that use of fewer animals than originally approved for use does not constitute a change that requires any action.
However, IACUCs may want to ensure that investigators understand that whether they are using fewer total animals or fewer animals within their experimental groups that they must do so without compromise to validity of the data.

19. Questions?