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November 16, 2015

Axel Wolff, MS, DVM Director, Division of Compliance Oversight Office of Laboratory Animal welfare Rockledge 1, Suite 360 6705 Rockledge Drive, MSC 7982 Bethesda, Maryland 20892-7982

Re: Animal Welfare Assurance #A3314-01 (OLAW Case lG)

Dear Dr. Wolff,

Research Services Office of the Assoc. VP

301 University Blvd. Galveston, TX 77555-0156

0409.266.9400 F 409.266.9470 E sponsoredresearch@utmb.edu

W http://research.utmb.edu

UTMB is in receipt of your letter dated November 4, 2015, in which you state that the Office of Laboratory Animal Welfare (OLAW) is "extremely concerned with the functioning of the UTMB animal care and use program and with the ability of the IACUC to appropriately carry out its functions as outlined in the PHS Policy and described in the Assurance". In response, we are confident that UTMB has made and continues to make the necessary enhancements to its structure, communication, and practices related to the institution's animal care and use program and the science that supports the use of animals in research, particularly in biocontainment areas. The following are several notable programmatic improvements.

A. Hiring a Highly-Qualified Animal Resource Center (ARC) Director.

Following the dismissal of the former attending veterinarian (A V) on June 9, 2015, UTMB recruited an A V with significant biocontainment experience, a documented history of collegiality, and the ability to manage and work well with others. On September 1,2015, UTMB hired Douglas L. Brining, DVM, DACLAM, as Executive Director of the ARC and AV. Dr. Brining served as Branch Chief and A V at the NllI Rocky Mountain Veterinary Branch in Montana and brings to UTMB a wealth of experience in the oversight of high-level biocontainment facilities, including ABSL-3 and ABSL-4. Since coming to the institution from the University of Colorado-Boulder, Dr. Brining has taken ownership of improving communication with the biocontainment veterinarian and strengthening ARC practices. This written response, as well as verbal discussions that will take place during the November 17,2015, visit will detail some of Dr. Brining's initial communication advancements as well as programmatic enhancements that have already been made.

B. Increased Communication and Programmatic Enhancements.

UTMB continues to address the need for improved communication between the ARC, IACUC, 10, investigators, research community, and others involved in the institution's animal care and use program. On many levels, ~uch communication has already improved as evidenced by increased collaboration between the A V and biocontainment veterinarian, which has, in tum,

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bolstered information sharing to the IACUC. Furthermore, the A V and biocontainment veterinarian plan to conduct town hall assemblies and attend departmental meetings to discuss many of the programmatic enhancements documented in this written response with the UTMB research community. Such enhancements, coupled with other improvements at the institutional and IACUC levels, will only strengthen UTMB's animal use program. For example, for studies involving non-human primates, we will conduct a complete and thorough review process to examine endpoint criteria and observation frequency prior to the commencement of currently­approved studies in biocontainment. As part of that process, and to foster increased awareness, the IACUC members have and will continue to discuss adverse outcome re:porting requirements and pertinent scoring criteria. To this end, the IACUC amended its Reporting Adverse or Unexpected Outcome policy to clarify what must be reported to the committee as an adverse or unexpected outcome. Moreover, the IACUC has initiated a more rigorous protocol review process and greater discussion involving Category E studies. This written response, as well as verbal discussions that will take place during the November 17,2015, visit 'will provide additional detail regarding these programmatic and institutional enhancements.

c. UTMB's Partnership with NIAID to Address Increased Observations.

On May 1, 2015, the National Institute of Allergy and Infectious Diseases (NIAID) provided a reply to UTMB's institutional response regarding NIAID's audit of the non-GLP STDY-13-0005-TG, Infectivity and Lethality of Marburg Virus Angola in Non-Human Primates Following Intramuscular Challenge. The NIAID reply resolved most of the non-animal welfare issues. However, both parties remained committed to making improvements, on ago-forward basis, to modify observation frequencies and endpoint criteria evaluation. Furthermore, the welfare of these non-human primates is vital to support the integrity of the data generated by the study. In support of that commitment, a contingent of UTMB officials traveled to NIAID's offices on September 29, 2015, to discuss, among other items, the need to balance sufficient observation of non-human primates involved in high-level biocontainment projects while maintaining the health and safety of humans who enter such areas. At the end of that productive meeting, NIAID officials requested that UTMB prepare a proposal for NIAID's consideration with respect to increased observations of non-human primates and other alternatives that may be applied to all future Category E studies as required by study design. Additional information pertaining to the UTMB-NIAID meeting will be presented during the November 17, 2015, visit.

Your letter includes a number of detailed concerns on page two (2), which have been broken down into the following sub-parts as outlined in your document. Below, we provide our responses to each concern and outline areas for improvement where applicable.

D. Paragraph One

1. lVumerous primates were allowed to proceed to death as an endpoint.

UTMB acknowledges that death was not to be the endpoint of the non-human primates involved in this specific study. It is important to note that it was not UTMB's intent to allow the animals to proceed to death as an endpoint. The IACUC has begun efforts to re-examine the use of clinical scoring sheets and related criteria, as well as reviewing practices related to the scoring of animals used in high-level biocontainment studies. Additional discussion regarding this issue will occur during the November 17, 2015, visit.

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2. UTMB itself indicated that eight animals died overnight but that it was determined that no additional observations were required as the conditions deteriorated.

UTMB acknowledges that eight (8) animals died overnight. However, these non­human primates did not reach the required scoring of five (5), which would have warranted increased monitoring, much less the scoring of nine (9), which would have warranted euthanasia, per the approved protocol. UTMB acknowledges this to be an area for improvement. The IACUC and the institution are undertaking efforts to address the feasibility of increased observation frequencies and the evaluation of endpoint criteria, as needed, for high-level biocontainment studies while, at the same time, working to ensure the health and safety of human workers involved.

3. The categorical denial by UTMB of the NIAID findings and OLA W's concerns seem to indicate a complete misunderstanding of UTMB's responsibilities regarding animal welfare.

UTMB takes seriously its responsibility with respect to research studies involving the use of all animals. The IACUC investigated and thoroughly examined concerns regarding possible noncompliance with the approved IACUC protocol, finding that the study met protocol criteria. Certainly, improvements have been and will continue to be made with respect to animal welfare, such as addressing increased observations, a more rigorous IACUC protocol review process for Category E studies, and policy enhancements. UTMB is dedicated to making such improvements, as evidenced by the hiring of the current A V with biocontainment and regulatory expertise, as well as working with federal agencies and other sponsors to address issues that arise. In our letter to NIAID officials dated March 13, 2015, UTMB objected to certain language used in the audit report. As we stated in the letter, UTMB and the IACUC are equally committed to providing the appropriate care and treatment to all of its animals involved in all research studies.

E. Paragraph Two

1. A statement provided by a USDA Veterinary Medical Officer indicated that an interview of a former employee found that ABSL-3 rooms housing species other than nonhuman primates are not properly broken down and sanitized between studies.

The following responses have been provided by UTMB' s Operations Manager for the husbandry functions in the Galveston National Lab:

Rodents: due to animals being housed in individually ventilated cages, we do not decontaminate the entire room between each study. The rooms operate with similar agents and on a rotating study basis, so each room is infrequently completely vacant. We perform our monthly duties in the rooms per SOP, and these cleaning duties are recorded on the husbandry sheet. These duties include disinfecting the walls and ceilings, trash bin, and food bin; changing the rack pre-filters; and cleaning the hoses and nozzles. When a room is completely vacant, we will decontaminate with vaporized hydrogen peroxide (VHP) or paraformaldehyde cycle to be prepared to house any agent in the room. We keep the VHP (ABSL-3) printouts and documentation of biologic indicator (Bn clearance for each run. Those documents are not filed by any certain project but we can reference them by date if needed. The ABSL-4 (paraformaldehyde) cycle documentation is kept by the biocontainmentlEHS team.

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FerretslRabbits: they are usually housed in a room by themselves, per study, so we will clean the ventilated caging and decontaminate the room between studies. If they happen to be housed in a room with other studies we will only clean and remove the ventilated unit and clean the room monthly, like we do for the rodents.

2. Veterinary rounds in biocontainment are not done frequently enough to provide adequate care to the animals and that only monthly rounds are usual~v conducted and documented in the logs.

Veterinary rounds (by certified veterinary technicians and certified animal technicians) are performed daily at UTMB, including holidays and weekends. Round results and health concerns are reported to the veterinarians as they arise, and evaluations are made by the veterinarian when needed. The entry record logs for these areas will be available for review upon request at the November 17,2015, meeting.

3. Rounds in other areas are performed much more frequently.

See response to E.2., above.

4. There was insufficient communication between the AV and biocontainment veterinarian.

UTMB's current A V and biocontainment veterinarian have made focused efforts to address the communication deficiencies that were commonplace during the tenure of the previous AV. Dr. Brining has taken the approach of becoming fully invested in the workings of the biocontainment suite, as well as making a concerted effort to communicate daily with the biocontainment veterinarian on any programmatic issues involving the institution's animal care program.

5. The backup veterinarian was not notified when the AV was off site.

Communications between the A V and biocontainment veterinarian have improved greatly since the hiring of Dr. Brining and are functioning openly and smoothly. Additional questions or concerns pertaining to such communication may be addressed during the November 17, 2015, visit.

6. Single housing of primates is not adequately justified.

The IACUC requires scientific justifications for single housing of all social species and justifications are provided to and reviewed by the IACUC for these projects. Non­human primates have been, and will continue to be, socially housed at lJTMB. The current rationales for single housing primates include the risk for cross infection (data concerns) and safety concerns for the laboratory and animal care staff. Moving forward, the IACUC will continue to evaluate the justifications and scientific merit of singly housing primates on a case-by-case basis to ensure that they are adequately justified for each study design.

7. Approximately 75% of the primates on the study actually were allowed to proceed to death as an endpoint.

See response to D.1., above.

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F. Paragraph Three

1. Testimony from the former AV indicated that the protocol for the Marburg study stated that death was not to be the endpoint and humane interVention was to occur prior to death.

See response to D.l., above.

2. He also confirms that 75% of the animals werefound dead.

See response to D.l., above.

3. Because euthanasia was the expected outcome the dead animals were an adverse outcome and should have been reported to the AV and the lACUC.

UTMB acknowledges that the deaths of the non-human primates should have been reported to the IACUC. As previously mentioned, the IACUC has amended its Reporting Adverse or Unexpected Outcome policy to clarify what must be reported to the committee as an adverse or unexpected outcome which has been communicated to investigators and research staff campus-wide. Additionally, the IACUC has and will continue to proactively discuss adverse outcome reporting requirements and pertinent scoring criteria; will initiate a more rigorous protocol review process; and will engage in greater discussion involving Category E studies.

4. [The A V] was never informed about any monkey deaths and feels that the monitoring frequency should have been increased and the scoring criteria enhanced.

UTMB does not have sufficient information to conclusively state whether the former A V was informed of non-human primate deaths. At the time the protocol was initially reviewed and approved by the IACUC, the former A V did not express any concerns regarding the monitoring and scoring criteria stated in the original protocol. After implementation of the protocol, the former A V had numerous opportunities in which to voice any concern he may have had regarding monitoring frequencies and scoring criteria. Not only did the former AV serve as a member of the IACUC, but he had a standing agenda item at each meeting to deliver an ARC Director's Report to raise issues. The former A V could also have engaged in discussions with investigators and research staff, veterinary staff, institutional officials, and others to voice concerns. UTMB has no evidence at the institutional or IACUC levels that the former A V raised such concerns prior to his notice of termin~ltion.

5. The biocontainment veterinarian never reported any monkey deaths or unexpected outcomes during rounds.

UTMB's biocontainment veterinarian reported numerous unexpected outcomes during rounds, particularly those requiring notification to the IACUC per policy. However, at the time, the deaths of the non-human primates involved in the particular study were not reported due to the then interpretation ofIACUC's Reporting Adverse or Unexpected Outcome policy. Since that time, the IACUC has clarified its policy regarding what must be reported to the committee as an adverse or unexpected outcome. Further, as previously mentioned, the IACUC will proactively discuss, in-depth, adverse

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outcome reporting requirements and pertinent scoring criteria; will initiate a more rigorous protocol review process; and will engage in greater discussion involving Category E studies.

6. The A Valleges reprisal and termination of position for attempting to talk to the Vice Provost regarding animal welfare concerns.

The previous A V was terminated for documented performance concerns. UTMB maintains and enforces a Non-Retaliation Policy (mOp 3.2.9) that encourages employees to report any activity that appears to violate applicable laws and regulations, policies, andlor procedures. Further, this policy provides a specific pathway for an employee to follow if he or she believes they are the subject of retaliation. Additionally, the former A V could have utilized UTMB' s Hotline to report, anonymously if chosen, any such concerns. Most importantly, and as previously mentioned, the former A V had multiple formal avenues in which to express animal welfare concerns, namely (a) at convened IACUC meetings; (b) to the Chair of the IACUC; (c) to institutional officials; or (d) to any ARC and GNL staff. UTMB has no evidence that the former A V voiced such concerns prior to his notice of termination, either at the institutional or IACUC levels. Documentation in support of this paragraph can be provided at the November 17, 2015, visit.

7. The A V alleges a conflict of interest on behalf of the 10 in that she oversees the biocontainment studies and therefore is overseeing herself.

In September 2012, my institutional role at UTMB was Assistant Vice President of Sponsored Programs and Pre-Award Management. In this capacity, I had the responsibility for executing all research-related agreements and served as the Administrative Official for contracts. On June 1,2013, I was promoted to the position of Associate Vice President for Research Administration, initially reporting to the Provost until a Chief Research Officer was hired. At that time, I assumed institutional responsibility for the administrative oversight of the IACUC office and ARC. Consequently, I currently only execute agreements in the absence of the current Director who assumed the responsibilities of serving as the Administrative Official. In my current institutional role and in my capacity as the 10 I do not have, and have never had, input or oversight with the conduct of studies performed in the Galveston National Laboratory. Further, as the 10, I do not oversee the functioning of the IACUC in any capacity.

G. Paragraph Four

1. The lA cue was unaware of the monkey deaths until the audit report was released.

See response to F.3., above.

2. Remote monitoring of animals in the suite using cameras was not routinely performed.

In this particular case, the use of cameras to monitor the non-human primates was not feasible due to plastic sheeting and other visual obstructions. Additional clarification may be provided by the biocontainment veterinarian at the November 17, 2015, visit.

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3. Staff reported a hostile work environment was created by the biocontainment veterinarian.

UTMB thoroughly investigates all allegations of noncompliance with our Institutional Handbook of Operating Procedures policies and UTMB' s Standards of Conduct Guide, which enforce applicable federal and state laws. UTMB is currently investigating various allegations within the ARC but did not substantiate any instances of UTMB's biocontainment veterinarian creating a hostile work environment.

UTMB recognizes and acknowledges the mutual goal of OLAW, USDA, NIAID, and other federal agencies-to make animal welfare a priority-while, at the same time, providing scientifically valid and reproducible results in studies involving life-threatening diseases. Our institutional leadership, as well as its faculty and staff engaged in the care and use of animals in research, are committed to maintaining high ethical -standards; adhering to federal, state, and local laws; and maintaining institutional policies and procedures that ensure that animal research being conducted on campus is done in a responsible and ethical manner. We look forward to a productive and collaborative meeting on November 17,2015.

~~~ Toni D' Agostino Associate Vice-President for Research Administration Institutional Official University of Texas Medical Branch 301 University Boulevard Galveston, Texas 77555-0156

cc: Robert Gibbens, DVM, Western Sector Director, USDA-APHIS-AC William Dowling, PhD, Program Officer, Office ofBioDefense, Research Resources and Translational Research, NIAID

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