Month: August 2005

To: Christine Parks
RARC
From: [REDACTED]
RE: Protocol G00146
Date: July 1, 2003

[REDACTED] and [REDACTED] cross-compared the protocols (see below) and records obtained from all possible sources (e.g., colony records, laboratory note books, check sheets) and compiled a list of discrepancies between approved protocols and actual records. The apparent and potential violations are summarized below. The period of this investigation is from March 2000 to present. The tabulated information in detail is available upon request.

Protocol approval date: 3/13/00 with final amendment on 4/19/00
Major amendment approval date: 10/15/01
Minor amendment date: 05/20/02
Renewal approval date: 04/14/03

1. Apparent Violations

• Bret left animals during the push-pull-perfusion (PPP) experiment for lunch 4 times. The protocol states that animals will be attended continuously. One animal died in the chair while Bret was at lunch.
• In 24 PPP experiments in 11 animals, 4 different drug challenges were given. The 3/13/00 protocol did not contain this, but in the 10/15/01 protocol the maximum number of drug challenges was added to be three.
• Five drugs (the ATP sensitive potassium channel blockers, tolbutamide and glybenclamide; the purinergic receptor blockers, PPADS and suramin; and the ATP hydrolysor, apyrase) that had not been stated in the 10/15/01 protocol were examined with PPP experiments.
• In 15 PPP experiments ATP doses exceeded the dose range stated in the protocols.
• In 2 animals more than 12 PPP experiments were conducted (1 animal with 13 times; 1 animal with 15 times). The 3/13/00 protocol did not contain this, but in the 10/15/01 protocol the maximum number of PPP was added to 12.
• One c-section resulting in a 4th major surgery (the 3/13/00 protocol stated that the maximum number of major surgeries was 3. This confusion occurred because the protocol stated that “the animals used for the project 1 (puberty-project) with PPP experiment can be used for breeding females in project 2, in which 3 c-sections were allowed”.

2. Inadvertent Violations

• Five animals received reheadcap surgeries. This procedure was not described in the 3/13/00 protocol, but it was added in 10/15/01 protocol.
• In 15 animals blood draws were conducted on project 2, in which no blood draw was described. In projects 1 and 4 blood drawings are described.
• In 12 animals more than 4 ml of bloods were drawn in one week. The protocol stated that taking more than 4 ml/week of bloods requires CBC. (See also related problems in No.3).
• Forty-two animals received higher doses (up to 20 mg/kg) of ketamine. The protocol stated that ketamine dose will be 10-15 mg/kg.
• Antibiotics were given to 18 animals after PPP experiments. In most cases a staff veterinarian approved the treatment, but consent was not in writing. In fact, Carol Emerson suggested antibiotics after PPP experiments on a regular basis.
• Prophylactic antibiotics were given before and after surgeries, such as cranial pedestal implantation as well as cranial pedestal repair and removal, in 59 animals. Staff veterinarians knew of this practice, but we failed to describe it in the protocol.

3. Errors due to Reproductive Services for Breeding in Our Animals

• In 7 animals Reproductive Services took blood samples up to 14 ml in a week under our protocol.
• Reproductive Services conducted ultrasounds in 8 animals under our protocol. Ultrasound examination was not described in the protocol.

4. Record Errors

   r94070     6/15/01           Remark by a veterinary assistant says "in chair".
                                However, this animal did not have cranial pedestal at
                                this time and there is no chairing record. So, there is no
                                way that she was in chair.
   r96130     7/10/00-7/14/00   Record says she was in chair after cranial pedestal
                                removal. This is not possible.
   r96112     8/8/00            The animal should be 96119. Record has been corrected.
   r99046     6/12/01           The animal should be 97046. Record has been corrected.
   r98003     6/12/01           The animal should be 98033. Record has been corrected.
   r98040     7/10/01           The animal should be 98049. Record has been corrected.
   r84108     10/3/00           This monkey does not belong to this protocol, because it
                                is a male. To take blood Reproductive Services assigned to
                                our protocol.
   rhaa56     10/3/00           This monkey does not belong to this protocol, because it
                                is a male. To take blood Reproductive Services assigned to
                                our protocol.
   r87100     12/8/00           This monkey does not belong to this protocol, because it
                                is a male. To take blood Reproductive Services assigned
                                to our protocol.
   rhaq36     4/30/01           Cranial pedestal removal surgery was stated as major
                                surgery.
   r93061     3/13/01           Cranial pedestal removal surgery was stated as major
                                surgery.
   rh1935     10/8/01-10/11/01  Chairing is not stated in colony record.
   rh2116     05/14/01          Record states "out of chair on 5/14". But it should be 5/4,
                                because there is no way that she was in chair for 13 days.
   rh2118     04/25/01          PPP experiment was conducted on 4/26/01. The date of
                                the out chair should be 4/26/01.
   r93058     12/10/02          PPP experiment was conducted on 12/11/02. The date of
                                the out of chair should be 12/11/02.
   r96082     11/27/00-11/29/00 Chairing is not stated in colony record.
   r98033     1/6/03-1/8/03     Chairing is not stated in colony record.
   r99031     2/18/02 & 2/19/01 Two records of cannulation. 2/19/01 is correct, based on
                                chairing record.
   r99031     03/12/02          Cannulated three weeks after last time by accident.
                                However no PPP experiment was conducted.
   r99077     09/10/01          Record says that pedestal repair and cannula implantation.
                                Only cranial pedestal repair surgery was conducted.
   r01050     10/14/02          There is no record saying that ketamine was
                                injected.
   rhYO3      05/12/01          Cannulation date should be corrected to 14th, based on
                                the chairing record and the PPP experiment, which was
                                conducted on the 17th.

The University of Wisconsin Madison

To: Tim Mulcahy
Chair, All Campus ACUC

From: [REDACTED]
RARC

RE: Dr. Terasawa and Protocol G00146

Date: July 10, 2003

Enclosed please find my report of the review of the clinic histories of Dr. [REDACTED] animals on protocol G146 for the last three years. Also enclosed is a memo from Dr. [REDACTED] reporting the results of her own investigation of laboratory notebooks and clinical records.

As you can see, there have been a variety of deviations from her approved protocols over this period of time. There have also been more negative outcomes than expected for the animals on the push pull perfusion studies, especially for aged animals. I understand that the All Campus ACUC will decide whether she can continue to do animal research here at the university, and may allow the Graduate School ACUC to lift her suspension and approve her most recent protocol at their discretion. If this is the case, I submit the following ideas to prevent future reoccurrences of these types of problems.

First, the [REDACTED] veterinary staff should review the clinical records of all of her current animals on a regular basis and report to the Graduate School ACUC any events of concern (once a month or once every two months.) Second, someone should review her current laboratory notebooks and report to the ACUC as above (perhaps [REDACTED] from the [REDACTED]. Third, a letter should be crafted to Dr. [REDACTED] explaining to her that further serious violations will result in loss of ability to perform animal research at the university. Last, Dr. [REDACTED] should reply in writing that she understands and accepts these conditions.

I believe a period of one year of close observation should be sufficient to assure compliance and understanding by Dr. [REDACTED] and her staff.

The University of Wisconsin Madison

Graduate School Animal Care Committee

May 12, 2003

Present: Bolton, Evans, Fechner, McCentee (n.v.), Sandgren, Schultz-Darken, Welter and Zhang

Absent:

Abbott

Guests: Dr. Kemnitz, Amanda Crumbaugh, Dr. Parks

Approval of April 14, 2003 Minutes

Sandgren/Schultz-Darken moved for approval pending minor corrections. Vote was unanimous.

Compliance Issues

Recently, two USDA investigators visited RARC and the Primate Center.

During this investigation the investigators learned that monitoring was not provided continuously for chaired animals as described in protocol [REDACTED]. During a 2-5 minute absence by a technician, an animal in the chair died. The fact that the animal died during the experimenter’s absence was not provided to the Graduate ACUC at the time of the animal’s death. It is clear to the committee that the lack of continuous monitoring constitutes a protocol violation.

[REDACTED] noted that the USDA investigators also raised a concern about the length of time needed between chairing episodes. The PI verbally reported to the investigators that she waits four weeks between chairing sessions, but the investigators found records from summer 2002 where only three weeks of rest was given between sessions. The length of rest time between sessions was not explicitly stated in the protocol. [REDACTED] will investigate this inconsistency.

Dr. Nancy Schultz-Darken noted that many of the concerns of the USDA investigators regarding this protocol highlight the necessity that the descriptions of the procedures be very clear, especially given the nature of the experiments. The AAALAC site visitors voiced many of the same concerns in March 2000.

In light of new information related to this protocol, it seems that the committee is not confident that the procedures are being followed as detailed in the approved protocol. Additionally, it seems that there are inadequacies in the protocol as it currently stands that could impact the animals’ health.

Dr. Sandgren identified two issues for the ACUC to address:

1 – The lack of continuous monitoring (the protocol violation); and
2- Increase the familiarity of the committee with the exact nature of [REDACTED] experiments.

It seems that critical information regarding this experiment was never made known to the committee. The committee discussed a response letter from [REDACTED] regarding the break from continuous monitoring. (See attached letter dated 05/07/03). [REDACTED] letter states that she will revise the protocol to re-emphasize that substitute lab staff will cover for any time when researchers take breaks so that continuous attendance is ensured. The committee accepted this proposal provided that the substitute must have visual contact with the restrained animals.

Welter/Schultz-Darken moved to suspend [REDACTED] and have the ACUC send a letter to [REDACTED] to included the committee’s acceptance of her plan to include substitute monitors and contingencies under which protocol reinstatement could occur. (See attached letter dated May 13, 2003.) Voted was unanimous with Su-Chun Zhang abstaining.

In the course of studying documentation regarding the incident with protocol [REDACTED] the USDA investigators also inquired about [REDACTED] surgeries and asked to see the intraoperative records. It appeared that these records were not immediately accessible to the investigators. This was of high concern to the investigators.

Documentation of Monitoring During Surgeries

A concern was raised by the USDA investigators regarding the lack of consistent documentation of monitoring during surgeries. Dr. Sandgren distributed a draft policy for surgical monitoring and record keeping. The committee read the draft and made suggestions for clarifications and additions.

There do not seem to be specific requirements described in AWAR of the type of intrasurgical monitoring documentation. Dr. Parks is consulting with USDA and other agencies to get more information. “Standards of Veterinary Care” have been cited as the best guideline for surgical monitoring documentation, which is what Dr. Sandgren’s proposed policy is loosely modeled upon.

Dr. Kemnitz left the meeting at this time.

Dr. Parks reminded the committee that the committee could adopt a minimum policy and then require more stringent monitoring documentation for invasive procedures described in particular protocols. Attending vets and PIs can also choose to upgrade the monitoring documentation.