• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

  • Print
  • Share
  • E-mail

Fisheries Research Laboratory- SIU-C 02-Nov-07

Department of Health and Human Services' logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration

 

Rockville MD 20857


Certified Mail - Restricted Delivery
Return Receipt Requested

NOV 02 2007

Glendal W. Poshard, Ph.D.
President
Southern Illinois University-Carbondale
1245 Lincoln Drive, Mail code: 6801
Carbondale, Illinois 62901

WARNING LETTER

Dear Dr. Poshard,

On May 24, June 4, and June 5, 2007, representatives from the Food and Drug Administration (FDA), Chicago District Office, inspected the following nonclinical laboratory study conducted at the Fisheries Research Laboratory, Southern Illinois University - Carbondale: "The Safety of 17a-Methyltestosterone Administered in the Feed for Induction of Sex Inversion in Tilapia," Protocol SIUC-05-MT-04, INAD #011236.

This inspection was conducted as a part of FDA's Bioresearch Monitoring (BIMO) Program which includes inspections designed to verify compliance with Title 21, Code of Federal Regulations, Part 58 -- Good Laboratory Practice (GLP) Regulations [21 CFR 58]. The regulations at 21 CFR 58 apply to nonclinical laboratory studies of products regulated by FDA. 21 CFR 58 can be found on the Internet through links on FDA's web page at www.fda.gov.

At the conclusion of the inspection, FDA investigators presented and discussed the items listed on Form FDA 483, Inspectional Observations, with Anita M. Kelly, Ph.D., Study Director. We have reviewed the inspection report, along with related documents, and conclude that your facility violated FDA regulations governing the conduct of nonclinical laboratory studies. This letter provides you with written notice of these violations. The applicable provisions of 21 CFR 58 are cited for each violation.

1. The nonclinical laboratory study was not conducted in accordance with the protocol [21 CFR 58.130(a)]. For example:

• The facility failed to necropsy all fish required to be necropsied by the protocol. It is unclear whether the intent of the protocol was for all fish to undergo necropsy, or for only those fish chosen for histopathological exam to undergo necropsy. However, on May 24, 2007, the in-life study endpoint, study personnel determined that fish weighing less than 0.500 grams would not undergo necropsy. This included some of the fish chosen for histopathological exam. Therefore, under either interpretation of the protocol, the study was not conducted in accordance with the protocol with regard to the necropsy of the fish.

• The protocol indicated that the temperature of the water in the tanks should be maintained at [(b)(4)] Review of the Daily Measurements recorded in the Water Quality Record show temperature values outside of this range in several tanks on several days. For example, the Water Quality Record for Tank 9 indicates that the temperature was [(b)(4)] on April 23, 2007. The Water Quality Record for Tank 10 indicates that the temperature was [(b)(4)] on April 23, 2007. The Water Quality Record for Tank 1 indicates that the temperature was [(b)(4)] on May 8, 2007. Finally, the Water Quality Record for Tank 7 indicates that the temperature was [(b)(4)] on May 14, 2007. Thus, the study was not conducted in accordance with the protocol with regard to the water temperature of the tanks.

2. Not all data entries were dated on the date of entry and signed or initialed by the person entering the data [21 CFR 58.130(e)]. For example, some Mortality Record Sheets and Necropsy Record Sheets do not contain the signature or initials of the person responsible for recording the data.

3. The Quality Assurance Unit (QAU) failed to periodically submit to management and the study director written status reports on each study, noting any problems and the corrective actions taken [21 CFR 58.35(b)(4)].

4. The receipt and distribution of each batch of test and control articles were not documented, including the quantity and date of each batch distributed and returned [21 CFR 58.107(d)]. For example:

• The amount of test article on hand after the four week treatment period exceeded the amount initially received for two of the three test article usage records audited. Specifically:

o On March 30, 2007, the facility documented receiving [(b)(4)] batch 002. On June 4, 2007, the facility had approximately [(b)(4)] in inventory. However, the facility's records indicate that it should have had approximately [(b)(4)] in inventory.

o On March 30, 2007, the facility documented receiving [(b)(4)] batch 002. On June 4, 2007, the facility had approximately [(b)(4)] in inventory. However, the facility's records indicate that it should have had approximately [(b)(4)] on hand.

• On June 4, 2007, FDA investigators observed the weighing of the amount of [(b)(4)] particle size #1 in inventory. The weighing showed that there were [(b)(4)] of this test article in inventory. However, the test article inventory record indicated that there were [(b)(4)] in inventory.

5. All deviations from standard operating procedures (SOPs) were not authorized by the study director and documented in the raw data [21 CFR 58.81(a)]. For example:

• SOP 4.0 paragraph 2, "Duties and Responsibilities Testing Facility Management", provides, "In the event that the study director should need to be replaced due to illness, vacation or some other short-term period, a memo from the Director of the Fisheries and Illinois Aquaculture Center will be issued stating who the interim study director will be." Testing facility management failed to adhere to SOP 4.0 by failing to promptly replace the study director as necessary during the, conduct of the study. Specifically, no interim study director was appointed when the study director was on vacation. This deviation from SOP 4.0 was not authorized by the study director or documented.

• SOP 8.0 paragraph 6, "Quality Assurance Unit (QAU) Responsibilities", provides that the QAU has responsibility for "[Submitting] reports to the manager and study director noting any problems and the corrective actions taken." The QAU failed to submit any reports to the study director or to the testing facility management. This deviation from SOP 8.0 was not authorized by the study director or documented.

6. The study director failed to assure that unforeseen circumstances1 that may affect the quality and integrity of the nonclinical laboratory study were noted when they occurred and to assure that corrective action was taken and documented [21 CFR 58.33(c)]. For example:

• As previously discussed, the Water Quality Record documented instances of water temperature values outside the range specified in the protocol. No corrective action was documented with regard to these instances. Because fish are cold blooded, changes in water temperature affect the physiologic state of the fish, inducing potential stress. Stress, in turn, affects drug absorption and metabolism. Therefore, changes in environmental conditions, such as water temperature, may have significantly affected measurements and study outcomes.

• As previously discussed, necropsies were not performed in accordance with the protocol. At the in-life study endpoint, study personnel determined that fish weighing [(b)(4)] would not undergo necropsy, even though the protocol did not address the possibility of fish being too small to be necropsied. The study personnel's decision was not noted, nor was corrective action documented. Many of the fish weighed [(b)(4)], and the weights of the fish were heterogeneous at the in-life study endpoint. Thus, examination of fish [(b)(4)] may have been important to detect drug related effects on body weight as well as other potential causes of low body weight. As a result, the failure to examine fish weighing [(b)(4)] may have affected study outcomes and analysis of data.

• The study was not performed in the room described in the protocol. The study was moved from the room described in the protocol because that room became unavailable. However, the change in room was not noted when it occurred. The placement of experimental units is an important factor in eliminating bias due to random environmental effects. This is especially true in aquaculture experiments where environmental effects can significantly affect study outcomes. Because the change in room altered the placement of experimental units, this deviation from the protocol may have significantly biased the study data and affected study outcomes.

7. The study director failed to assure that all experimental data, including observations of unanticipated responses of the test system, were accurately recorded and verified [21 CFR 58.33(b)]. For example:

• According to the protocol, the study began with [(b)(4)] tanks, each containing [(b)(4)] fish, for a total of [(b)(4)] fish. The mortality data sheets document [(b)(4)] mortalities. At the conclusion of the study approximately [(b)(4)] fish were euthanized. Thus, the study data fails to account for approximately [(b)(4)] fish.

• The protocol required that the tanks be cleaned daily between 07:00 - 08:00 a.m. However, there is no documentation indicating that the tanks were cleaned daily as required by the protocol.

• The protocol indicated that the fish would be observed four times per day for measurement of feed consumption, the presence or absence of fecal material, and for changes in behavior and responses. However, there is no documentation showing the times at which the fish observations were made.

The above is not intended to be an all inclusive list of violations. As a facility conducting nonclinical laboratory studies, you are responsible for ensuring that your studies are in compliance with the law.

You should take prompt actions to establish procedures to ensure that such violations do not recur in any on-going or future studies. Failure to do so may result in regulatory actions without further notice.

You should notify this office in writing of the steps you have taken to bring your facility into compliance with the law within fifteen (15) working days of receiving this letter. Your response should include each step that has been taken or will be taken to correct the violations and prevent their recurrence. If corrective action cannot be completed within fifteen (15) working days, state the reason for the delay and the time within which the corrections will be completed. Please include copies of any available documentation demonstrating that corrections have been made.

Please direct your written response and any pertinent documentation to:

Vernon D. Toelle, Ph.D., Team Leader
BIMO and Administrative Actions Team (HFV-234)
Division of Compliance
Office of Surveillance and Compliance
Center for Veterinary Medicine
7519 Standish Place, Room 142
Rockville, MD 20855-2773

If you have any questions concerning this letter, please feel free to contact Dr. Toelle at 240-276-9238.

Sincerely yours,

/S/

Neal Bataller, M.E., D.V.M.
Director
Division of Compliance (HFV-230)
Office of Surveillance and Compliance
Center for Veterinary Medicine

cc: Fernando Manuel Trevino, Ph.D.
Southern Illinois University
Office of The Chancellor-SIUC
Mailcode: 4304
Carbondale, Illinois 62901

John Andrew Koropchak, Ph.D.
Southern Illinois University
Vice Chancellor for Research and Graduate Dean-SIUC
Mailcode: 4344
Carbondale, Illinois 62901

Christopher Carl Kohler, Ph.D.
Director
Southern Illinois University
Fisheries & IL Aquaculture Center - SIUC
Mailcode: 6511
Carbondale, Illinois 62901

___________________________________________________________

1 Protocol violations are by their nature "unforeseen." Protocols are written to cover "foreseen" possibilities. Therefore, if the protocol does not cover a particular situation, it is an "unforeseen circumstance." When such unforeseen circumstances occur, they must be recorded to ensure that those circumstances are noted when data is compiled for submission to FDA.