| Public Health Service Food and Drug Administration |
Silver Spring, MD 20993 |
Department of Health and Human Services
WARNING LETTER
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Ref: 11-HFD-45-09-03
Laura A. Teasley, M.D.
Loma Linda University Health Care
Faculty Medical Offices, Suite 1800
11370 Anderson Street
Loma Linda, CA 92354
Dear Dr. Teasley:
Between July 26 and August 24, 2010, Thomas R. Beilke, representing the U.S. Food and Drug Administration (FDA), conducted an investigation of your former practice. During the course of the inspection, Mr. Beilke met with you to review your conduct of a clinical investigation (Protocol (b)(4), titled "(b)(4)") performed for (b)(4). You were the investigator for this clinical investigation between March 2008 and March 2009.
This inspection is a part of FDA's Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of research and to help ensure that the rights, safety, and welfare of the human subjects of those studies have been protected.
From our review of the establishment inspection report and the documents submitted with that report, we conclude that you did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations. We wish to emphasize the following:
1. You failed to ensure that the investigation was conducted according to the signed investigator statement, in that you failed to personally conduct or supervise the clinical investigation [21 CFR 312.60].
When you signed the Statement of Investigator (Form FDA 1572) for the above-referenced clinical trial, you agreed to take on the responsibilities of a clinical investigator at your site. Your general responsibilities as a clinical investigator include ensuring that the clinical trial is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; protecting the rights, safety, and welfare of subjects under your care; and ensuring control of drugs under investigation [21 CFR 312.60]. By signing Form FDA 1572, you specifically agreed to personally conduct the clinical trial or to supervise those aspects of the trial that you did not personally conduct. While you may delegate certain study tasks to individuals qualified to perform them, as a clinical investigator you may not delegate your general responsibilities. Our investigation indicates that your supervision of personnel to whom you delegated study tasks was not adequate to ensure that Protocol (b)(4) was conducted according to the signed investigator statement, the investigational plan, and applicable regulations, and in a manner that protects the rights, safety, and welfare of human subjects.
Specifically, Protocol (b)(4) [Chapter 1, Section 1.3(F) (Examination Procedures), and Chapter 2, Section 2.3.2 (Baseline Testing Procedures)] required that fundus photographs and optical coherence tomography (OCT) scans be obtained for each enrolled eye, both to assess subject eligibility and to serve as baseline measures for the study. As the clinical investigator, you delegated the responsibility for obtaining these fundus photographs and OCT scans to the study coordinator at your clinical site.
Your affidavit states, “It is my professional opinion that the later scans [...] do not match those OCT scans taken at baseline. I also compared the [fundus photographs on the] baseline scans with the fundus photographs taken of the respective subject’s eyes approximately at baseline[,] and it appears that they do not match[,] either. Photographs that are taken of the same eye from the same subject on different dates should have retinal blood vessel patterns that match exactly.” As such, it is expected that for any given eye, fundus photographs taken separately from the OCT scans should match the fundus photographs on the OCT scans.
However, it appears that for some subjects, the fundus photographs on the baseline OCT scans do not match the fundus photographs taken separately. Thus, it appears that some study subjects’ baseline OCT scans have been substituted for other unknown patients’ OCT scans. This inconsistency was found in records for subjects including, but not limited to, the following:
a. The fundus photograph on the OCT scan of Subject 0035’s OD dated October 16, 2008, does not match the fundus photograph taken separately of Subject 0035’s OD dated October 16, 2008.
b. The fundus photograph on the OCT scan of Subject 0015’s OD dated August 13, 2008, does not match the fundus photograph taken separately of Subject 0015’s OD dated August 14, 2008.
c. The fundus photograph on the OCT scan of Subject 0015’s OS dated August 13, 2008, does not match the fundus photograph taken separately of Subject 0015’s OS dated August 14, 2008.
As a result of these discrepancies in the records, it is not possible to ascertain if these subjects were eligible for enrollment in the study.
You indicate in your August 19, 2010, affidavit that one of your responsibilities as clinical investigator was to double-check the OCT scans necessary for each subject. You also acknowledged in your August 19, 2010, affidavit that “this substitution or manipulation [of the OCT scans and fundus photographs] may have allowed them [the subjects] to have been falsely qualified for the study.” Your failure to adequately supervise the individuals to whom you delegated study tasks resulted in these discrepancies in your study records, as well as the enrollment of subjects who may not have met the eligibility criteria. Enrollment of subjects who may not meet eligibility criteria raises concerns about the extent to which subjects’ rights, safety, and welfare were protected, and about the reliability and integrity of the data captured at your site.
2. You failed to ensure that the investigation was conducted according to the investigational plan [21 CFR 312.60].
Chapter 2, Section 2.2.2 of Protocol (b)(4)(Version 5.0, dated March 24, 2008) specified an inclusion criterion of diabetic macular edema present on clinical exam and central subfield thickness on optical coherence tomography (OCT) ≥ 250 microns, within 8 days of randomization. However, the following OCT scans were taken off-center:
a. June 5, 2008, OCT scan of Subject 0003’s OS; and
b. December 4, 2008, OCT scan of Subject 0040’s OD.
These off-center readings made these two subjects appear eligible when they may not have been.
Your failure to ensure that OCT scans were obtained as specified by the protocol, which led to the enrollment of subjects who may not have met the eligibility criteria for the investigation, significantly undermines the reliability and integrity of the data captured at your site. In addition, enrollment of subjects who may not have met eligibility criteria, and failure to properly perform study-related procedures, raise concerns about the extent to which subjects’ rights, safety, and welfare were protected.
This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational drug. It is your responsibility to ensure adherence to each requirement of the law and relevant FDA regulations. You should address these deficiencies and establish procedures to ensure that any ongoing or future studies will be in compliance with FDA regulations.
Within fifteen (15) working days of your receipt of this letter, you should notify this office in writing of the actions you have taken to prevent similar violations in the future. Failure to adequately and promptly explain the violations noted above may result in regulatory action without further notice.
If you have any questions, please contact Constance Cullity, M.D., M.P.H., at 301-796-3397; FAX 301-847-8748. Your written response and any pertinent documentation should be addressed to:
Constance Cullity (formerly Lewin), M.D., M.P.H.
Branch Chief
Good Clinical Practice Enforcement Branch
Division of Good Clinical Practice Compliance
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration
Building 51, Room 5354
10903 New Hampshire Avenue
Silver Spring, MD 20993
Sincerely yours,
{See appended electronic signature page}
Leslie K. Ball, M.D.
Acting Office Director
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration
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This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.
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/s/
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LESLIE K BALL
10/14/2011
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