Report on investigation of Allegations of Noncompliance withthe Public Health Service Policy on Humane Care and Use of Laboratory Animals _at the Unversity of Texas Medical Branch Office of Laboratory Animal Welfare March 24,2017Office of taboratory Animal Welfare Reporton Investigation of Allegations of Noncomplance with the Public Health Service Policy on Humane Care and Use of Laboratory Animals atthe University of Texas Medical Branch Preface “The Ofice of Laboratory Animal Welfare (OLAW) herein presents evaluation under provisions ofthe Public Health Service (PHS) Polcy on Humane Care and Use of Laboratory Animal (Policy), of specific -animalrelated activities conducted atthe University of Texas Medical Branch (UTMB). Based onthe results of an aut conducted by the National Institute of Allergy and Infectious Diseases (WAIO},an internal investigation, and a targeted joint site vst by OLAW, NIAID, and the US. Department of Agriculture (USDA), OLAW determined that specific animal activities were not being ‘conducted in accordance with the PHS Polly. Under the Heath Research Extension Act of 1985, (Public aw 99158), OLAW notified UTMB thatthe conditions of animal car, treatment, and use didnot meet applicable guidelines and that the institution must take corrective actions. Subsequently UTMB took “approgriate actions, Following review OLAW accepted UTMB's efforts and found the institution to be In ‘ullconpliance with the PHS Policy. LOLAW forwarded this report to UTMB on 2/7/17 and requested te institution to identify any errors of, ‘fact. Te 2/17/17 esponse indicated that inthe discussion of Exhibit #22, the 11/23/15 OLAW letter, ‘the text should have referenced “tall nipping” rather than “toe clipping.” Aso, UTMB suggested which information inthe report should be redacted for privacy reasons. OLAW made the correction and informed UTMB thatthe responsibilty for document redaction rested withthe NIH Freedom of Information Act offical and thatthe suggestions would be forwarded tothe appropriate personnel,Report on Investigation of Allegations of Noncompliance with the Public Health Service Policy on Humane Care and Use of Laboratory Animals at the University of Texas Medical Branch Background “This eportis the result of an investigation of allegations of noncompliance with the Public Health Service (P15) Plioyon Humane Care and Use ef Laboratory Animale (Policy) agnnst the Unversity of “Texas Medical Branch (UTMB). A complaint was submitted tothe Office of Laboratory Animal Welfare (014W) bythe organization Stop Animal Exploitation Now (SAEN) on August 29, 2015 stating that, according toa site vst report prepared by the National Institut fr Allergy an infectious Diseases {WAI}, nonhuman primates infected with Marburg ius were nat being euthanized ata humane ‘endpoint but were allowed to de overnight. Furthermore, SAEN state that a source connected to LUTMBallege thatthe sit vist eport had been withheld from the Attending Veterinarian (AV) and the Institutional Animal Care and Use Committe (IACUC) thus preventing them from performing an investgation. Algo, SAEN alleged thatthe biecontainment veterinarian had not been informing the |ACUCabout primate deaths and the AV had recently been terminated, SAEN stated thatthe concerns ‘violated UTMB's Animal Welfare Assurance (Assurance) nd that folowing OLAW’s investigation the Assurance should be revoked. LoLAWobtained a copy of the Januaty 26-29, 2015 audit report which evaluated @ NIAID study involving Inflectity and lethality of Marburg virus in nonhuman primates following intramuscular challenge. The site vitor found that primates died during the night and thatthe numberof animal observations did not increase although the clinical signs indicated a decline in health. The report indicated that in addition to the obvious serious animal welfare issues, crucial biomarker data were los, impacting the study. CLAW authority i derived from the Health Research Extension Act (Public Law 99-158) which Is implemented through the PHS Policy, applicable to PHS conducted or supported research research “trang, and biological testing activites invalving ive vertebrate animals. The Health Research Extension Act provides a reasonable opportunity for institutions to take corrective ation when conditons of animal care, treatment or use de not meet applicable guidelines, Institutions that conduct HS-supported research are required to have acurcent OLAW-approved Assurance. The Assurance isa document that verfies that PHS-supported research with Ive vertebrate animals sin accordance with ‘the provisions of the PHS Policy. OLAW is authorized to restrictor withdraw approval ofan institution's Assurance if that institution fails to corcec dented deficiencies ‘his OFce evaluated the allegations conducted a joint site vis involving OLAW, NIAID, and the US. Deparment of Agriculture (USDA, and presented a series of questions to UTMB for investigation bythe Institutional Animal Care and Use Committee IACUC)LAW investigation: (On August 25, 2015 OLAW sutmitted a letter to the UTMS institutional Official tating that according to the SAEN allegation: ‘The NIAID aust contained information that constituted noncompliance with the PHS Polly in that nonhuman prime:es were not being euthanized upon reaching the established humane end point. ‘The report was withheld from the Attending Veterinarian (AV) and the IACUC. ‘The veterinarian inthe biocontainment area was not informing the IACUC about primate deaths ‘The AV submitted alt of complaints for CUC investigation and itis not clear an investigation occurred. ‘OLAW submitted the additions following questions: asthe IACUC addrested the complaints submitted by the AV? \Were the established sbservation periods fllowed, including increased observations based on clinical signs: if not, how has ths been corrected? \Were the veterinarians promptly notified about clinical concerns such as depression, inappetance, or petechal rashes? = Was the IACUC aware af the problems with Inadequate animal observations? |s staff aware that aninal concerns are to be reported promptly tothe veterinary staff and is this being done? ~ Are procedures in place to ensure thatthe biocontainment veterinarian is informed about ‘environmental control problems in animal rooms suchas high humidity? \Why was OLAW not notified about the serious animal welfare iesues identified by the NIAID ste vistors? In September, 2015 OLAW submitted a formal request forthe NIAID report, UTMB response, andthe [AID review of the UTMB response. OLAW determined that a oit site vst with NIAID and USDA was necessary. The requested materials were provided and 2 joint site visit was planned, (On September 6, 2015 information was provided to OLAW by the former AV who expressed concerns about the primate studies (on September 30, 2015 UTMBrepresentatives met with NIAID to discus the primate studies. A reverse site visit summary was produced, On October 8, 2015 USDA staff produced a memo outlining an interview with a former UTMB vetecnary staff member. (On October 27, 2015 OLAW sent aletter to UTMS indicating that a jlnt site visi would be conducted on "November 17, 2015 with representatives fom OLAW, USDA Animal and Plant Health Inspection Service (APHIS)/Animal Care, USDA APIS Investigative and Enforcement Services, and NIAID. OLAW requested to meet with key personnel imolved inthe primate studies, to review records and to see the facies involved.‘On October 28, 2015 UTM provided a response to OLAW's August 25,2015 intial inquiry 2s follows: ‘The UTMB IACUC concluded that there was no noncompliance with the NIAIO audit report but verified that eight primates onthe study ded overnight ~The AV and ACUC were informed about the aut report. = Mortality was expected in the study andthe biocontainment veterinarian was required to notify the IACUC of adverse events. ‘The former AV's complaints were reviewed by the IACUC and were not found to have a negative animal welfire outcome, ‘The extabisied animal observations were followed as outlined in the protocol Four primates were euthanized upon reaching the humane endpoints. No other animals exhibited clinical signs that required notification of the veterinarian, ‘The IACUC considered the animal observation schedules to be appropriate, ‘An institutional policy was in pace regarding prompt reporting of animal concerns and stft was trained on it ‘Te biocontanment veterinaran was notied that humidity levels in the animals rooms were outside the normal range. Failty procedures were modified to provide documentation of future temperature/humidty deviations and the AV's actions. UTI had nat notified OLAW about the serious animal welfare isues identified by the NIAID site visitors because UTMB had not agreed with the assessment. The IACUC had re-evaluated the criteria on the Marburg study including observation frequency, items onthe humane scoring sheets, euthanasia criteria, and assessment of pai and stress. (On Novernber 3, 2015 OLAW conducted a search ofall active NIH grants with an animal component ‘made to UIME and incorporated a copy ofthe results in the cae fle (On November 4, 2035 OLAW responded to UTMB's October 23,2015 letter and acknowledged the information provides but indicated that the Office was “extremely conceened withthe functioning of the UTMB animal ave and use program and with the ability ofthe IACUC to appropriately cary out its functions as outlined in the PHS Policy and described in the Assurance.” The reasons for this concern were explained as follows ‘The NIAID ste vst team was constituted by knowledgeable subject matter experts who voiced fave animal welfare concerns. = AUSDA interview with a former UTMB employee produced a statement that losafty Level3 and 4 roomshousing species other than primates were not properly broken down and sanitized between stuties; veterinary rounds in biocontainment were not done frequently enough to provide adequate animal care; there was insufficient communication between the AV and biocontaiament veterinarian; the backup veterinarian was not notified when the AV was off site; and single housing of primates was not adequately justified = Testimony flom the former AV indicated thatthe Marburg study was expected to have humane’ intervention and not progress to death as an endpoint, yet 75% ofthe primates were found dead. This outcome had not been reported to the AV and IACUC, ‘The IACUC was unaware ofthe primate deaths until release ofthe aut report; emote _monitoring cf primates in the biocontainment suite was not routinely performed.‘OLAW informed UTMB that under the provisions ofthe Heath Research Extension Act of 1985, Public {aw 99-158, thatthe institution was not meeting applicable guidelines outined inthe PHS Policy and commitments made in the Assurance and that UTM must ake corrective action, Ifcorrections were rot made, the Assurance would be withdrawn and PHS grants for animal activities would be withheld. COLAW indicated that during the upcoming site vist and subsequent communications the folowing must be adresse: Development and adherence to humane endpoints [Agjustment of frequency of animal observations in elation to clinical signs Prompt reporting of enimal concerns Strong justification for single housing of primates Robust ACUC oversight of al containment activities ‘Appropriate chain of command and oversight of projects conducted in containment Timely communication between clinical veterinarians and the AV “On November 10,2015, OLAW sent a mem to UTMB requesting the following documents be made _aallable fr review by the sit vistors All relevortanimal/ctinial record forthe primates on the Marburg study [IIIACUC “ecords relevant tothe study animals including protocols, minutes, concerns ‘The most recent AAALAC site visit report ‘The two most recent USDA inspection reports ‘The two most recent semiannual program review and faclty Inspection reports Relevant biosafety SOPs, specifically addressing the BSLA and after hour procedures Biosafety inspection records ‘anyother document relevant tothe study animals and conduct of the study, including also Department of Defense studies of this type ‘©n November 16,2015 UTMB responded to OLAW's November 4, 2015 letter and state that = highly qualified AV wit significant biocontainment experience was hired on September 3, 2015. = Communication had been enhanced among the IACUC, 10, Animal Resources staff, AV, and biocontalement veterinarian, Nonhuman primate studies will be thoroughly reviewed to establish appropriate endpoint ertera. The policy for reporting adverse or unexpected coutcomeshad been revised. The IACUC will review USDA Category € studies more rigorously In esponte to IAIO's aut and response, it was agreed that animal observations willbe conductec more frequently and endpoint criteria wil be caefuly established. = TheIACUC had not approved the Marburg virus study to allow death as an endpoint and that the primates should have been euthanized prior to death. Animals nearing 2 critical stage in isease progression wl be monitored more frequently. UTMB is committed to humane animal care and se.Rodent rooms used for ASSL.3 studies do not require complete decontamination between studies because the animals are in individually ventilated cages. Veterinary technicians are conducting dil documented rounds ofall animal areas, There is daly conversation between ‘the AV and biocontainment veterinarian. One of the justifications fr single housing a primate Is to prevent cress contamination by an infectious agent. The |CUC wil thorough review requests for sngle housing primates. ‘The adverse event reporting policy had been amended to improve reporting of unexpected ‘mortality. The former AV had not raised concerns about the monkey deaths, monitoring frequency, or scoring ritera, The bivewnl vi had filed to report the monkey deaths because he didnot know this was a reportable event. The previous AV was terminated for documentad performance concerns. UTMB has a non-etalition policy and staff has been trained on it.The 10 has no oversight responsibilities forthe biocontainment laboratory. “The camera system did not provide visualization ofthe primates onthe Marburg study due visual obstructions (On November 17,2035 a site visit was conducted by representatives from OLAW, USDA, and NIAID. The requested records wer reviewed, key Individuals were interviewed, and the BSL4 area was examined from the outside and via cameras. Following the November 7, 2015 site vist and cecept ofthe November 16, 2015 UTMB letter, OLAW Senta letter on Noverber 19, 2015 thanking the 0 for arranging te vs, acknowledging the Information provided, and asking the institution to address the folowing 1) Veterinary access to animals in the 8SL4biocontainment area must be avaiable at al times ‘when necessary. Arrangements must be made to access animals in the SLA 24 hours per day, seven ‘days per week for emergency care as wells for research related purposes 2), More veterinarians and veterinary technicians are tobe “suit rained” to enter the BSLA 3) Post-approval monitoring must be conducted inthe BSL '4) Provide formation on how the IACUC isrefining humane endpoints and enhancing the detals onthe scoring sheets. Include information on the Frequency of observations a it links to cnical signs of deteriorating health, 12). Provide information on enhanced taining of aff that identify clinica signe in animal and ‘conduct endpoint scoring to ensure minimal variability among observers. 6). Provide information on how documentation can be enhanced inthe BSLA. 7), Provide an update on how animal records inthe BSLAcan be enhanced. 48), Provide information onthe establishment of SOPs and preplaced countermeasures for BSLA aceidentalexposures toa varety of agents. Include information on health providers and ‘reatmentmodaites. 9). Provide acopy of the revised policy fr reporting adverse and unexpected events 10} Explain how the loop vl be closed regarding resolution of a complaint submitted to the hotline.21) Eure that Category €stdles have extremely robust scientific justification for withholding analgesia, Ensure that pallatve care must be given if consistent with the aims ofthe stu. 12) Ensure thatthe IACUC attendance rosters inthe minutes and that committe deliberations ‘onprotocol review are adequate and included, 13) Emure thatthe protocol form eit sufficient information from the Principal Investigator {Pl to allow the IACUC t appropriately evaluat the proposal 11) Eneure that the IACUC solits animal welfare clarifiation from the Pl, not ust scientific )_ 4/30/45 NIAIO response to UTMB response [10) 8/28/35 UTM request for an extension to provide a response to the 6/25/15 leer, and OLAW's reply fx) 9/6/15 letter to OLAW from former UTMB Attending Veterinarian 12) 9/30/15 UTM reverse sit vist summary with NIAID staff 13) 10/8/15 USDA memo regarding former UTMB employee review 14) 10/27/25 eter from OLAW to UTMB announcing the 11/17/15 site iit 15) 10/28/15 leter from UTMB responding to OLAW's 10/25/15 submission of allegations 16) 11/3/15 search of active UTM grants [17) 11/4/45 eter from OLAW to UTMIB responding tothe 10/28/35 eter 18) 11/10/15 emails between OLAW and UTMB regarding the 11/37/25 ste vs See exhibit 20 site vist agenda19) 13/16/15 letter from UTM responding to 13/4/15 OLAW letter 20) 12/17/15 OLAW/USDA/NIAD site vist agenda; UTMB povies| fa) 11/19/15 letter from OLAW to UTMB addressing findings ofthe site vist and acknowledging content of the 11/16/25 eter f2) 11/23/15 email rom OLAW responding to SAEN's 11/21/15 emall comments and submission of another allegation of noncompliance at UTMB involving mice 23) 12/18/15 letter from UTM providing answers to OLAW’s questions and outlining an enhanced reporting schedule 24) 12/22/15 letter from OLAW to UTMB accepting corrective ations 25) 2/3/16 letter from UTM regarding noncompliance allegatons involving mice 26) 2/3/16-3/28/16 emails between OLAW and NIAID regarding USDA actions and plans fora plot study 27) 2/22/16 record of cal fom UTMS regarding personnel changes [2 4729/46 letter from UTM to OLAW providing corrective actions for OSL8 and also adaressing allegations regarding mice 29) 5/4/16 letter from OLAW to UTMB acknowledging corrective actions fr BSLA and also audressing the allegations regarding mice 20) 7/27/46 letter fram UTM providing an update on correct ations 131) 7/29/16 leter from OLAW to UTMB accepting the corrective actions 432) 11/22/16 memo from NIAID providing a media report regading USDA fine for UTM. 33) 1/6/17 letter rom UTM providing information on the final corrective action 34) 2/7/17 final letter from OLAW to UTM accepting the finalcorrective action, dosing the Investigation, and requesting 2 review fr errors of fact 35) 2/37/47 leter fom UTMB pointing out one eror and suggesting redactions | [36) 2/22/37 letter from OLAW thanking UTM for reviewing the draft report