Deitz, Robert, M.D.

Department of Health and Human Services	Public Health Service Food and Drug Administration
	Silver Spring, MD 20993

WARNING LETTER

CERTIFIED MAIL

RETURN RECEIPT REQUESTED

4/01/2010

Ref: 10-HFD-45-03-03

Robert Deitz, M.D. 

2001 Union Street

Suite 625

San Francisco, CA 94123

Dear Dr. Deitz:

Between May 19 and 28, 2009, Aneel K. Sandhu, representing the Food and Drug Administration (FDA), conducted an investigation and met with you to review your conduct of a clinical investigation [Protocol (b)(4) entitled “(b)(4)”] of the investigational drug (b)(4), performed for (b)(4)

This inspection is a part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of research and to ensure that the rights, safety, and welfare of the human subjects of the study 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 and the protection of human subjects. We are aware that at the conclusion of the inspection, Aneel K. Sandhu presented and discussed with you Form FDA 483, Inspectional Observations. We wish to emphasize the following:

1. You failed to maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation [21 CFR 312.62(b)].

Discrepancies in records were found in all six subjects enrolled in Protocol (b)(4), raising significant questions about the reliability of data at your site.

a. For Subject 34002, the following deficiencies were noted:

i. On January 20, 2005, this subject was enrolled in the study and was administered the study drug. You submitted a protocol deviation/violation report to the Institutional Review Board (IRB) on May 2, 2005 stating that this subject was enrolled without having signed an Informed Consent Form (ICF). The subject’s records contained two copies of the ICF. One was signed on May 10, 2005, and another copy was an altered version which reflected a signature date of January 10, 2005. You stated in your affidavit obtained by the field investigator during the FDA inspection that you believe that the ICF with a signature date of January 10, 2005 is an altered document. You stated that you did not alter the document and that you do not know who altered it.

ii. The electronic Case Report Form (eCRF) for the Baseline Visit states that the subject signed the ICF on January 20, 2005. However, according to the Baseline Visit worksheet, the ICF was signed on September 18, 2003. The subject’s records did not contain an ICF dated September 18, 2003 or January 20, 2005. In addition, as stated above under 1(a)(i), the subject’s records contained two copies of the ICF, one copy was signed on May 10, 2005 and the other was altered to indicate it was signed on January 10, 2005. Thus, it appears that the subject signed the ICF on May 10, 2005, which was not accurately recorded in the Baseline Visit eCFR or worksheet.

iii. The eCRF for the 12-Month Visit states that pre-bronchodilator spirometry was conducted on January 17, 2005 and that post-bronchodilator spirometry was conducted on January 17, 2006. However, the 12-Month Visit worksheet states that both of these spirometries were conducted on July 17, 2006. We note that your office manager stated during the inspection that this worksheet was mistakenly documented as the 24-month visit, but was in fact the 12-Month Visit worksheet.

iv. Pages 1 through 5 were missing from the ICFs dated May 10, 2005 and January 10, 2005.

b. For Subject 60060, the following deficiency was noted: The February 9, 2006 30-Month Visit worksheet contains a check mark in the box labeled “Yes” for the question, “Has the patient had any of the following during the past 6 months?” These four choices follow the question: non-serious malignancy, serious malignancy, serious asthma exacerbation, and other serious adverse event. The same page of the worksheet indicates that if the answer to this question is “yes,” an adverse event (AE) worksheet packet is to be completed for each AE. However, no completed AE worksheet packet was in the subject’s records.

c. For Subject 34004, the following deficiencies were noted:

i. The AE section of the 6-Month Visit worksheet contained conflicting information about whether the subject suffered an AE or not. On one page, it states that the patient did not have a non-serious malignancy, serious malignancy, serious asthma exacerbation, or other serious adverse event. However, on another page, in response to the question “What type of adverse event was this?” the “non-serious malignancy” box is checked.

ii. Pages 1 through 8 were missing from the ICF.

d. For Subject 60667, the 12-Month Visit worksheet did not document the subject’s response regarding whether an adverse event had been experienced in the previous six months.

e. For Subject 62694, the following deficiencies were noted:

i. The eCRF for the 12-Month Visit states that spirometry was conducted on June 26, 2007. However, the 12-Month Visit worksheet states that the spirometry was conducted on July 26, 2007.

ii. Page 9 was missing from the ICF.

2. You failed to obtain informed consent in accordance with the provisions of 21 CFR part 50 [21 CFR 312.60].

a. Subject 34002 was enrolled in the study before you obtained the subject’s legally effective informed consent, in violation of 21 CFR 50.20. As explained above under 1(a)(i), on January 20, 2005, Subject 34002 was enrolled in the study and was administered the study drug. You submitted a protocol deviation/violation report to the IRB on May 2, 2005 stating that this subject was enrolled without having signed an informed consent form. The subject’s records contained two copies of the informed consent form. One was signed on May 10, 2005, and another copy was an altered version which reflected a signature date of January 10, 2005. You stated in your affidavit obtained by the field investigator during the FDA inspection that you believe that the ICF with a signature date of January 10, 2005 is an altered document. You stated that you did not alter the document and that you do not know who altered it. Thus, available documentation indicates that you did not obtain the subject’s informed consent until May 10, 2005, months after the subject was enrolled in the study.

b. For three subjects, you failed to document informed consent by the use of a written consent form approved by the IRB, as required by 21 CFR 50.27. Specifically, ICFs, signed by the following subjects on the indicated dates, were sample ICFs, which were not approved by the IRB:

a. Subject 34002, signed on February 7, 2007

b. Subject 34004, signed on May 29, 2006

c. Subject 60060, signed on October 12, 2006

3. You failed to promptly report to the IRB all changes in the research activity [21 CFR 312.66].

The following Protocol Amendments were not submitted to the IRB for review and approval:

a. Amendment A3 dated October 15, 2007, which contained additional information regarding expert oncology review of all malignancy adverse events.

b. Amendment A4 dated April 14, 2008, which increased the frequency of physical examination, review of systems, review of laboratory results, and review of radiologic findings from only at screening and baseline to every 6 months.

4. You failed to ensure that the investigation was conducted according to the signed investigator statement and the investigational plan [21 CFR 312.60].

a. The protocol specified that clinical examinations were to be performed by the investigator (you), and you signed the Form FDA 1572, Investigator Statement, indicating that you were the investigator and that there were no sub-investigators. However, the clinical examinations for the following visits were performed by (b)(4), M.D:

i. 12-Month Visit for Subject 62694

ii. 18-Month Visit for Subject 34004

iii. 30-Month Visit for Subject 34004

iv. 18-Month Visit for Subject 60667

v. 12-Month Visit for Subject 60060

b. The protocol specified that subjects who miss any visit were to be contacted by telephone. There is no documentation that you attempted to contact Subject 60667 after the subject missed the 6-Month visit.

c. The protocol specified that spirometry was to be performed at the baseline visit. You did not perform spirometry at the baseline visit for the following subjects:

i. Subject 34002: Baseline visit on January 20, 2005; spirometry on August 23, 2003

ii. Subject 34004: Baseline visit on May 12, 2005; spirometry on July 21, 2005

iii. Subject 60060: Baseline visit on August 8, 2005; spirometry on June 24, 2004

5. You failed to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects [21 CFR 312.62(a)].

You did not maintain records of study drug disposition for Subjects 62694 and 34004.

6. You failed to retain records required to be maintained under 21 CFR part 312 until 2 years after the investigation was discontinued and FDA was notified [21 CFR 312.62(c)].

By a letter dated June 13, 2008, the sponsor notified you that your participation in Protocol (b)(4) was terminated, thereby discontinuing your investigation. The sponsor also notified FDA, by a letter dated June 13, 2008, that your participation in Protocol (b)(4) was terminated. Between May 19 and 28, 2009, Aneel K. Sandhu, representing the Food and Drug Administration (FDA), conducted an investigation and met with you to review your conduct of Protocol (b)(4). At the time of the inspection, which was less than 2 years after your investigation was discontinued and FDA was notified, there were no eCRFs in the records for Subjects 60060, 34004, and 34003. Available documentation indicates that you failed to retain eCRFs for Subjects 60060, 34004, and 34003 for the required period of 2 years after the investigation was discontinued and FDA was notified.

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 on-going 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 Culllity, 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 Branch I

Division of Scientific Investigations

Office of Compliance

Center for Drug Evaluation and Research

Food and Drug Administration

Bldg 51, Room 5354

10903 New Hampshire Avenue

Silver Spring, MD 20993

Sincerely yours,

/S/

Leslie K. Ball, M.D.

Director

Division of Scientific Investigations

Office of Compliance

Center for Drug Evaluation and Research

-