FDA Warning Letter to McGee

Return Receipt Requested

J. Michael McGee, M.D.
1145 South Utica, Suite 253
Tulsa, Oklahoma 74104

Dear Dr. McGee:

The Food and Drug Administration(FDA) has investigated allegations that you failed to fulfill the responsibilities of a clinical investigator for a study utilizing an unlicensed biological investigational new drug, in violation of FDA regulations governing investigational new drugs. Between July 17 and August 4, 2000, Mr. Joel Martinez and Mr. David Beltran, investigators from the FDA Dallas District office, met with representatives of the University of Oklahoma and clinical study personnel to inspectthe records relating to the use of the investigational. At your option, you chose not to participate in the inspection. This inspection was conducted as part of the FDA's Bioresearch Monitoring Program, which includes inspections designed to review the conduct of research involving investigational products. The inspection focused on the study protocoltitled,FDA has reviewed your written response, dated January 25, 2001, to the Form FDA List of Inspectional Observations that was presented to the representatives at the end of the inspection. Our comments regarding your explanations follow below. This letter addresses your responsibilities as the clinical investigator of the research with an investigation. Until August 15, 2000, you were also the sponsor of the research. Your activities as the sponsor of the research discussed in a separate letter. We believe that you have repeatedly or deliberately violated regulations governing the proper conduct of clinical studies involving investigational new drugs as published under Title 21, Code of Federal Ratio (CFR), Part 312. These regulations are available. at www.access.gpo.gov/nara/cfr/index.html.

This letter provides you with written notice of the matters under complaint and initiates an administrative proceeding, described below, to determine whether you should be disqualified from receiving investigational articles as set forth under 21 CFR~312.70. A listing of the violations follows. The applicable provisions of the CFR are cited for each violation.

1. You failed to fulfill the general responsibilities of investigators.
[21 CFR ~ 312.60]. An investigatoris responsible for ensuring that an investigation is conducted according
to the signed investigator statement, the investigational plan, and applicable regulations;for protecting the rights,
safety, and welfare of subjects under the investigator' care; and for thecontrol of drugs under investigation.
On[ 1 you signed the Form FDA 1572, 'Statement of Investigator,'in which you agreed to conduct the study
in accordance with the protocol and applicable regulations. Our investigation revealed that you did not fulfill your
obligations as the clinical investigator in the use of investigational new drugs for the following reasons:

A. You failed to adequately protect the safety and welfare of subjects .

  1. You enrolled several subjects who were not eligible for the study see item 2(A), below.
  2. You failed to conduct the appropriate tests to ensure that only eligible subjects were entered into
    the study; see item 2(B), below.
  3. You failed to obtain proper Institutional Review Board (IRB) approval of protocolmodifications;see
    items 2(A) and 3, below.
  4. You failed to perform the study procedures required by the protocol to monitor the effects of the study drug in subjects;
    see item 2(C), below.
  5. You failed to abide by the safety provisions required in the protocol; see item 2(D), below.
  6. You pe~itted subjects to self-administer the investigational without your supervision and without IRB approval;
    see [ items 3 D) and 4, below.

B. You failed to control the investigational drug; see item 4, below.

2. You failed to ensure that an investigation is conducted according to the investigational plan (protocol).
[21 CFR ~ 312.60].
A. Subjects who failed to meet the eligibilit ycriteria were allowed to participate in the clinical trial.
The protocol included a provision that selection criteria may be waived by the sponsor-investigator if approved by the
Institutional Review Board on a case-by-case basis.' However, for several subjects, you failed to obtain advanced IRB approval
to waive the entry criteria; see item 3(A), below. You submitted an 'EligibilityCriteria Waived request form subject to
the lR~ on 2/13/98, eleven months after you initiated and nine months after the subject's death. In fact, subjects- were
dead by the time you submitted an 'Eligibility Criteria Waivef' request form to the IRB for these subjects. You administered
the investigational product to numerous subjects even though they should have been excluded.Your response letter explains that
'the protocoldid not always reflect the rapidly evolving understanding of the path ophysiology of melanoma.' If the protocol requires
revision based on new information or because there should be a change in procedure, amendments should be submitted to the FDA
and to the IRB for review and approval. Further, your response explains that you submitted 'EligibilityCriteria Waivefl request forms
to the IRB when you 'became aware' of the requirement to do so. We do not accept your explanation because, as the author of the
protocol you established these requirements.

B. YOU failed to conduct the appropriate tests to ensure that only eligible subjects were entered into the study.

  1. You did not perform into the study. ~ P as an exclusion criterion.
  2. You did not perform screening tests for~ ~The protocol excluded subjects known to be positive.

Your response letter indicates that the consistent procedure was to ask patients whether they were positive and that testing for has not
required by the protocol. We reject your explanation. Your protocol specifically excluded subjects who were because these conditions
would place study subjects at additional risk. Rather than conduct the laboratory tests to confirm that the subjects were eligible for the
study, you relied on patient-completed history forms administered just before consenting. This is not appropriate because subjects might
not (1) know that they have the condition, and or (2) be willing to disclose the correct information because they want to participate
in the research regardless of the attendant risks.

C. You failed to perform the study procedures required by the protocol. For example:

  1. You failed to evaluate subjects imune response to the by testing at weeks required in sesion 2 of the protocol. Ther is no testing reported
    at weeks for subjects and The protocol also requires two people to evaluate each response before it is recorded to control bias in assessing
    the immune response to the [ ] The inspection revealed that this protocol requirement was not followed. Your response letter does not dispute
    this observation and explains that any response was to be recorded by the Nurse Coordina or in he patient's record, although this did not
    always happen,' and that two people did not always evaluate each response.'

  2. There is no documentation that you performed all laboratory tests and clinical procedures at the intefvals required by the protocol.
    Examples include, but are not limited to, the following:
    1. There are no records documenting that hematology and chemistry blood tests were performed for subjects.
    2. There are no records documenting that subjects were tested.

Your response letter agrees, 'Some laboratory tests may not have been conducted according to the schedule outlined in the protocol....'

D. You did not follow the protocol requirement to discontinue the investigation or several subjects
with documented progression of disease. The protocolamendment dated 1/30/97 states, 'If a patient's
disease should progressas defined criteria, future will be halted ....' Several subjects criteria of disease
progression, but they were not discontinued from the Examples include, but-are not limited to,
the following:

  1. Subjects enrolled in the study on 6/16/97 with Stage III melanoma, and progressed to Stage IV melanoma. The medical
    records document further disease progression in August 1998, yet you continued to administer the[ ]in violation of the protocol.
    Subjects received the first [ ]on 6/18/97 and continued to receive until 6/19/99, an additional two years.
  2. In a letter dated 12/16/97, to the subject's physician, you acknowledge that subject had a 'recurrence or progression of disease.'
    The outpatient history/physical record for subject, document recurrent nodules on the right pelvis and para aortic. Subject * was
    administered four doses after this date, before ending on 2/19/98.
  3. The medical records for subjects recurrence or progression of disease, but you continued to administer the[ ].

Your response letter states, 'Dr. McGee informed FDA of his intention to continue to treat two patients with disease progression
on February 19, 1998, and received IRB approval for this practice on February 20, 1998.' Your representation of the interaction
with FDA is incorrect. Your specific request to FDA was to administer additional [] higher dose for subject because the subject
might have seen immuno supressed due to radiotherapy and 'had not shown an immunolical response.' Your request included
administration of additional [] or subject because the subject was immuno supressed due to major tumor debulking surge. Furthermore,
your request did not specify your intention to treat all subjects with disease progression. You did not formally request FDA approval
to treat subjects with progressive or recurrent disease until one year later, in a letter to FDA dated January 22, 1999.

E. Several subjects received concurrent radiotherapy, chemotherapy, immunotherapy, or other treatment in violation
of the protocol, which specifically excludes such concurrent treatment. Examples include, but are not limited to, the following:

  1. Subject was administered concurrent interferon, and chemotherapy.
  2. Subject was administered the[ ] currently with interfer on treatment. The summary Sheer dated 9/23/98 reports'. ..unable to
    determine if the side effects related to[]received double dose of Interfer on the same day (9/21 /98).. ..'
  3. As administered the[ ] frorn December 1997 until August 1999. During that period, the subject received several
    courses of chemotherapy and radiotherapy.
  4. The Summary Sheet dated 4/7/00 documents that subject completed seven weeks of radiation therapy.
  5. Study records document additional subjects as receiving concurrent therapy.

Your response does not dispute this observation. Your response letter states, 'Initially,Dr. McGee obtained Eligibility Criteria
Waivers for patients who received adjuvant therapy during times prescribed by the protocol' and includes copies of the 'Eligibility
Criteria Waivers' for subjects, and received concurrent therapy. However, the IRB hair granted the waivers after you enrolled
these subjects and administered the investigation to them. Waivers were to be prospectively secured.

F. The protocol required the primary services. YOU did not follow the protocol-mandate schedule for several subjects.

  1. You administered additional at weeks 45 & 2 18/98),46 (2/23/98),47 (3/2/98), and 48 (3/1 0/98) for subject see item 3B.
  2. You administered extra doses of [] to subjects at weeks 26 (1/29/98), 27 (2/5/98), 28 (2/10/98), and 29 (2/19/98); see item 36.
  3. You administered extra doses of [] to subject at weeks 47 (4/20/99),50 (5/11/99), and 54 (6/17/99).
  4. Subject was administered the [] at week 35 instead of week[].

Your response does not dispute this observation, and states, 'The [] were given as close to the schedule in the protocol as
practicable, although deviations occasionally occurred.' We view that the additional or these subjects represent unscheduled and extra[].

G. Vital signs were not obtained 30 minutes after. The protocol states that "Patients will be required to remain in the
physician's office for 30 minutes afterward. The vital signs will be checked again.' The purpose of measuring the subject's
vital signs was to monitor for any potential allergic reaction.

Your response does not dispute this observation, and states, '.. this protocol condition was not strictly enforced following later[].

3. You failed to obtain IRB approval prior to implementing protocol amendments or changes in the research activity. [21 CFR ~ 312.66].

A. On 2/13/98, you submitted 'EligibilityCriteria Waiver' request forms to the IRB Chair requesting a removal
permit the enrollment for eleven . . *'However, you had administered the investigational of each subject during the period of 2/10/97 to 8/1 1/97, well before the (RB Chair granted the protocol waivers on 2/23/98. Four of these subjects were dead by the time you submitted the waiver requests to the IRB.

Your response letter does not dispute this observation, and states, '.. .an Eligibility Criteria Waiver was to have been completed and submitted to the IRB for approval. For the first several patients, this did not occur.' Your response further states, '. ..The IRB approved all of these Eligibility Criteria Waivers on February 23, 1998. In all of the cases after that point, Dr. McGee promptly informed the IRB of these exceptions.. .' This statement is incorrect. After February 23, 1998, you continued enrolling ineligible subjects without obtaining prior IRB approval.

B. In a letter to the IRB dated 2/ 1/98, you requested permission to give two of our protocal patients. Documents that the subject
received four (4) on 1/29/98 (week 26), 2/5/98 (week 27), 2/1 0/98 (week ;8), and-2/l 9/98 (week 29) without IRB approval (see also item 2( F)(ii), above). You also administered additional subject weeks 45 (2/18/98),46 (2/23/98),47 (3/ 98), and 48 (3/10/98) without IRB approval
(see also item 2(F)(i), above). At the time of your request, you had already administered four additional weeks subject one additional to subject you failed to withhold the additional until the IRB had 'reviewed and approved your request. The IRB Chair approved the additional on February 20,1998.

C. On 2/10/97, you submitted a protocol amendment to the IRB to delete the upper age limit of years. You failed to wait for IRB
approval before you implemented the protoco amendment the first to (both subjects older than years). The lRB Chair approved the protocol amendment on 2/14 7, after the[ ] had occurred.

D. You permitted subjects to self-administer the without IRB approval. On April 9, 1999, you inform the FDA of the death of subject
on study, and described that the subject 'was instructed on study drug self-administration' from July 2, 1997, through January 27, 1999.
In addition, the inspection revealed that subject as given two doses for self-administrationin May 1997. However, on
November 11 , 1999, the IRB tentatively approved the self-administration of the upon requested changes. The IRB Chair
approved this protocol amendment on December 11,1999. Your response letter describes that you sought IRB approval to permit
subjects to self-administer[] in November 1999. However, the IRB approval for this protocal later, after subjects [] and eight
8 months after subject.

4. You failed to control the investigational drug. [21 CFR ~ 312.61].

You failed to administer the investigational drug only to subjects under your supervision or under the supervision of a sub-investigator responsible to you.

A. During the inspection, FDA was informed that the study ;#155 and #156 were sent to subject. The subject's wife, who is a
registered nurse, reportedly administered the[].

B. The inspection documented that you suppIied/shipped the investigational drug to subject located in California. The
subject self-administered the []without your supervision or the supervision of a sub-investigator.

C. You supplied the investigational drug to subject Tennessee. The Progress Notes dated 4/27/99 document that
the subject's primary care physician will administer the[] FDA was informed that the subject was allowed to store the study drug at
the subject's home in a refrigerator.

5. You failed to maintain adequate records of the disposition of the investigational drug. [21 CFR ~ 312.62(a)].

There are discrepancies between records regarding the status of subject. The "Lisit Tracking Log'does not document whether subject
was administered[]. However, the 1999 'Annual Progress Report'to the IRB documents that subject has enrolled on 12/98, received four []
and was misdiagnosed with Melanoma versus Paget's disease.

This letter is not intended to bean all-inclusive list of deficiencies with your clinical studies of an investigational new drug. On the basis
of the above listed violations, FDA asserts that you have repeatedly or deliberately failed to comply with the cited regulations, and it
proposes that you be disqualified as a clinical investigator. You may reply to the above stated issues, includingany explanation of
why you believe you should remain eligible to use investigational drugs and not be disqualified as a clinical investigator, in a wrtten response
or at an informal conference in my office. This procedure is provided for by regulation21 CFR ~ 312.70(a).

Within fifteen (15) days of receipt of this letter, write me to arrange a conference time or to indicate your intent to respond in writing.
Your written response must be forwarded within thirty (30) days of receipt of this letter. Your reply should be sent to:

Steven A. Masiello, Director
Office of Compliance and Biologics Quality (HFM-600)
Center for Biologics Evaluation and Research Food and Drug Administration
1401 Rockville Pike Rockville, Maryland 20852-1448

Should you request an informal conference, we ask that you provide us with a full and complete explanation of the above listed violations. You should bring with you all pertinent documents, and you may be accompanied by a representative. Although the conference is informal, a transcriptof the conference will be prepared. If you choose to proceed in this manner, we plan to hold such a conference within 30 days of your request.

At any time during this administrative process, you may enter into a consent agreement with FDA regarding your future use of investigational products. Such an agreement would terminate this disqualification proceeding. Enclosed you will find a proposed agreement.

The Center will carefully consider any oral or written response. If your explanation is accepted by the Center, the disqualificationprocess will be terminated. If your written or oral responses to our allegations are unsatisfactory, or we cannot come to terms on a consent agreement, or you do not respond to this notice, you will be offered the opportunity to request a regulatory hearing before FDA, pursuant to 21 CFR Part 16 (available at the Internet address identified on page 1 of this letter) and 21 CFR ~ 312.70. Such a hearing will determine whether or not you will remain entitled to receive investigational products. You should be aware that neither entry into a consent agreement nor pursuit of a hearing precludes the possibilityof a corollary judicial proceeding or administrative remedy concerning these violations.

Steven A. Masiello
Director Office of Compliance and Biologics
Quality Center for BiologicsEvaluation and Research