Via Federal Express WARNING LETTER Center for Devices and Radiological Health 2098 Gaither Road Rockville. MD 20850

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1 DEPARTMENI OF HEALTH & HUMAN SERVICES Pubic Heath Service Stephen Smith IV, M.D., Chair Kaweah Deta Heath Care District Institutiona Review Committee 400 West Minera King 119 Visaia, Caifornia Dear Dr. Smith: 3c/68 24 Via Federa Express WARNING LETTER Center for Devices and Radioogica Heath 2098 Gaither Road Rockvie. MD Food and Drug Administration This Warning Letter informs you of objectionabe conditions found during a Food and Drug Administration (FDA) inspection of the Kaweah Deta Heath Care District Institutiona Review Committee (KDHCD IRC), which serves as the Institutiona Review Board (IRB) for Kaweah Deta Hospita. This etter aso requests that you impement prompt correptive actions. Ms. Marie K. Kinkade and Mr. Thomas W. Gordon, investigators from FDA s San Francisco District Office, conducted the inspection on December 2, 3,4, 5, and 10, The purpose of the inspection was to determine whether your activities and procedures as an IRB compied with Tite 21, Code of Federa Reguations (21 CFR), Part 50 - Protection of Human Subjects, Part 56 - Institutiona Review Boards, and Part Investigationa Device Exemptions. These reguations appy to certain cinica studies of products reguated by FDA. Our review of the estabishment inspection report submitted by the district office reveaed serious vioations of the above stated reguations. At the concusion of the inspection,. inspection report review are discussed beow: 1. Faiure to conduct adequate continuing review of the research. (21 CFR and %.109(f)) Pursuant to 2 1 CFR (a), IRBs are required to review a research activities covered by FDA reguations in 21 CFR Part 56. Furthermore, to hep ensure that the rights and wefare of human subjects are protected, IRBs are required to conduct continuing review of this research at intervas appropriate to the degree of risk, but not ess than once per year. (21 CFR (f)) KDHCD IRC faied to satisfy these requirements. Exampes of this faiure incude but are not imited to the foowing:

2 Page 2 - Stephen Smith IV, M.D., Chair Your IRB faied to ensure that continuing review of research was conducted on at east an annua basis. For exampe, your IRB did not conduct continuing reviews of the foowing studies: 2. Faiure to prepare, maintain, and foow adequate written standard operating procedures (SOPS) governing the functions and operations of the IRB. (21 CFR (a) & (b), and 21 CFR 56,115(a)(6))) An IRB must prepare, maintain, and foow written procedures that describe the IRB functions and operations, incuding: conducting initia and continuing review of research; ensuring that changes to approved research may not be initiated without IRB review and approva, except where necessary to eiminate apparent hazards to human subjects; ensuring prompt reporting to the IRB, appropriate institution officias, and FDA of any unanticipated probems invoving risks to human subjects or others and any instances of serious or continuing noncompiance with FDA reguations pertaining to Irks or determinations of the IRB. (21 CFR (a), (b)) Prior to December 1, 2003, your IRB acked adequate procedures for: Conducting initia and continuing review of research, Determining whether an investigation invoved a significant or non-significant risk device and which projects required review more often than annuay, Ensuring prompt reporting to your IRB of changes in research activity, and Ensuring prompt reporting to your IRB, appropriate institutiona officias, and FDA of unanticipated probems invoving risks to human subjects or others, or any instance of serious or continuing noncompiance with FDA s IRB reguations or the requirements or determinations of your IRB. On December 1,2003, the IRB approved new written SOPS which appear to incude most of the required eements described above. The new procedures are inadequate, however, in that they do not provide a method to inform cinica investigators of their responsibiity to report information to the IRB, such as providing annua reports to the IRB to aow for continuing review, obtaining IRB approva for changes in approved research prior to

3 Page 3 - Stephen Smith IV, M.D., Chair impementing (except in imited circumstances), and prompty reporting any unanticipated probems invoving risks to human subjects. 3. Faiure to propery utiize expedited review. (21 CFR (b)) The IRB may use the expedited review procedure to review minor changes in previousy approved research during the period (of one year or ess) covered by the origina approva. This process aows the review to be carried out by the IRB chairperson or by one or more experienced reviewers on the IRB. The IRB is required to adopt a method of keeping a members advised of research studies that have been approved by expedited review. (21 CFR (b)-(c)) Your IRB impropery utiized expedited review to renew study approva. On May 28,2003, over two weeks after the in view to renew th (h,, 4. Faiure to have a majority of IRIS members present when reviewing and approving research studies. (21 CFR (c)) Each IRB is responsibe for ensuring review of proposed research when a majority of the IRB members are present except when using an expedited review procedure. (21 CFR 56.1 OS(c)) You faied to satisfy this requirement on more than one occasion. An exampe of this faiure incudes your February 28, 2001 and Juy 17,2002 IRB meetings where there was not a majority of members present to review or vote on research proposas. In an effort to satisfy the majority requirement, the IRB Chair was con meeting to submit his vote of approva on the study. Since the IRE4 Chair was not present at the meeting, this did not satisfy the requirement in 2 1 CFR (c). 5. Faiure to prepare and maintain adequate documentation of IRIS activities. (21 CFR (a)(), (a)(2), (a)(4) and (a)(5)) FDA reguations require that an IRB prepare and maintain adequate documentation of their activities incuding: copies of a research proposas reviewed; approved sampe consent documents; meeting minutes in sufficient detai to show actions taken by the IRB; votes on these actions incuding how members voted; a written summary of the discussion of controverted issues and their resoution; copies of a correspondence between the IRB and the investigators; and membership rosters containing specific information. (21 CFR (a)) Exampes of your faiure to prepare and maintain adequate documentation incude, but are not imited to, the foowing:

4 Page 4 - Stephen Smith IV, M.D., Chair Your IRE! meeting minutes did not consistenty incude specific information regarding the IRB s determination of whether studies invoved significant or non-significant risk devices, the continuing review and actions taken by the IRB for each study, the frequency of review for each study, and the number of members voting for, against, and abstaining from IIW actions. For exampe, your meeting minutes for 2001,2002, and 2003 ony show the resuts of voting on approva of research studies as M/S/C (motion, seconded, carried). The IRB did not maintain a documents received from cinica investigators, such as the protocos, investigator brochures, advertising, and the approved informed consent forms. The IRB membership ist for 2003 faied to incude two members earned degrees, representative capacity, experience, and empoyment or reationship between the members and the institution. The IRB 2002 membership roster aso isted an individua as a voting member, even though-stated during the inspection that this individua was not an IRB member or aternate, and participated ony as an ad hoc substitute in the September 18,2002 and December 9,2002 IREJ meetings. Progress reports were missing from the w study fie for 1997, 1998, 1999,200O and eport on fie for th for The deviations cited above are not intended to be an a-incusive ist of deficiencies at your site. As an IRB, it is your responsibiity to ensure that your operations are conducted in accordance with appicabe FDA reguations. Within fifteen (15) working days, pease respond to this etter in writing. You shoud be aware that FDA considers the IRB s noncompiant actions to be serious vioations of

5 Page 5 - Stephen Smith IV, M.D., Chair the aw. Faiure to respond to this etter and to take prompt action to correct these vioations may resut in reguatory action without further notice, incuding initiation of procedures to disquaify the IRB. Pease address your correspondence to the U.S. Food and Drug Administration, Center for Devices and Radioogica Heath, Office of Compiance, Division of Bioresearch Monitoring, Program Enforcement Branch II (HFZ-3 12), 2098 Gaither Road, Rockvie, Maryand 20850, Attention: Linda Godfrey, Consumer Safety Officer. A copy of this etter has been sent to FDA s San Francisco District Office, 1431 Harbor Bay Parkway, Aameda, Caifornia We request that a copy of your response aso be sent to that office. If you have any questions, fee free t extension Center for Devices and Radioogica Heath

6 Page 6 - Stephen Smith IV, M.D., Chair cc: Kristina Borror, Ph.D. Office for Human Research Protections Department of Heath and Human Services The Tower Buiding 1101 Wootton Parkway, Suite 200 Rockvie, Maryand 20852