Summers, Timothy, MD 2/24/10
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WARNING
LETTER
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Ref:
10-HFD-45-01-02
Timothy Summers,
5000 Highway 39
Meridian
Dear Dr. Summers:
Between March 25 and 27, 2009, Ms.
Barbara Wright, 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) Inc.
This inspection is a part of the
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 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 and the protection
of human subjects. We are aware that at the conclusion of the inspection, Ms.
Wright presented and discussed with you Form FDA 483, Inspectional
Observations. You have not provided a written response to the Form 483. By
letter of April 27, 2009, Alliance Health Center (AHC) responded to the Form
483, recognizing that the facility and you failed to adequately address certain
protocols. ACH also indicated that you were no longer conducting clinical
research at the AHC facility. We wish to emphasize the following:
1. You failed to conduct the studies
or ensure they were conducted according to the signed investigator statement
and the investigational plan, and to protect the rights, safety, and welfare of
subjects under the investigator's care [21 CFR 312.60].
a.
Eligibility criteria are designed specifically for each clinical investigation
by the sponsor to optimize the interpretability of the data to the disease
process under study and to minimize foreseeable harm of enrolled subjects due
to co-morbidities and possible interactions with concomitant medications. Three
of the six subjects randomized in this clinical investigation did not meet
eligibility criteria of having Bipolar I Disorder and as such were placed at
risk of injury from participation in the study. Specifically:
i. The
protocol eligibility criteria state that a “subject must have a primary diagnosis
of Bipolar I Disorder … as defined by the DSM-IV criteria and confirmed by the
[Kiddie-Schedule for Affective Disorders and Schizophrenia (K-SADS)].” Subject
1001 was screened and randomized to the study without a primary diagnosis of
Bipolar I disorder confirmed by a fully-completed K-SADS assessment. In
particular, the K-SADS assessment for Subject 1001 did not contain the
indicated Depressive Disorders and the Mania supplements.
ii.
The protocol eligibility criteria state that a subject must have a Young Mania
Rating Scale (YMRS) score greater than or equal to 17 at the screening and
baseline visits. Subjects 1009 and 1010 were each randomized to the study with
a YMRS score of 8 at baseline.
b. The
protocol states that the first dose of the study medication is taken at the
baseline visit after completion of baseline visit procedures to confirm subject
eligibility and to perform post-dosing pharmacokinetic (PK) sampling. Subject
1010 was dosed on December 8, 2006, three days prior to the baseline visit on
December 11, 2006 and as such did not have eligibility confirmed and did not
have PK sampling performed.
c. The
protocol requires that efficacy be assessed using the YMRS, the Children’s
Global Assessment Scale (CGAS), and Clinical Global Impression (CGI) scale at
each visit. The CGI assessment was not performed at the Week 1 study visit for
Subject 1010.
d. You
failed to follow protocols related to the enrollment of wards of the state. The
Institutional Review Board (IRB) “Initial Review Submission Form”
Enrollment
of subjects who do not meet eligibility criteria, and not performing
study-related procedures jeopardize subject safety and welfare and compromise
interpretation and validity of the investigational endpoints.
2. 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)].
During
the inspection, the study records (including study templates and assessment
tools) were observed to be unbound and appeared to lack a system of controls,
with entries posted to the wrong visit form and multiple versions completed for
the same visit. Subject records contained missing pages, numerous unexplained
corrections and conflicting information. Few progress notes were observed
Violations included, but were not limited to, the following:
a. The
protocol eligibility criteria state that a subject must have a YMRS score
greater than or equal to 17 at the screening and baseline visits. Study records
for Subject 1006 contained two sets of original records with different scoring
for the YMRS assessments reportedly obtained during the October 31, 2006 study
visit. One of the copies of the YMRS for Subject 1006 dated October 31, 2006
has a score of 11 and the other copy has a score of 23. You provided no
explanation for the discrepancies in these records.
b. The
K-SADS-Present and Lifetime Version is a multi-part diagnostic interview instrument
that consists of a screening interview and five additional diagnostic
supplements. The additional diagnostic supplements may be indicated based upon
scores obtained as determined by the answers given by the subject during the
screening interview. The KSADS-PL for Subjects 1001, 1004 and 1006 were missing
every other page and/or the required supplements.
c. The
records for Subject 1004 contained numerous errors in subject number, protocol
number, and date or identity of study visit. For example:
i. Numerous
records reflect that subject number 1002 was used instead of the correct
subject number 1004.
ii.
Forms marked “Screening Visit,” “Week 1 Visit,” and “Week 4 Visit” all are
dated October 31, 2006.
iii.
There are two forms marked “Week 1 Visit” documenting the Children’s Depression
Rating Scale Revised (CDRS-R) evaluation with two different dates, October 31,
2006 and November 8, 2006.
iv.
You utilized a form from another study entitled “ Study” to document testing
completed on this subject for this study.
Failing
to maintain adequate and accurate case histories compromises the interpretation
of and the validity of the clinical investigational endpoints.
3. You
failed to obtain informed consent of each subject in accordance with the
provisions of 21 CFR Part 50 [21 CFR 312.60].
Except
as provided in 21 CFR 50.23 and 50.24, no investigator may involve a human
being as a subject in research unless the investigator has obtained the
legally-effective informed consent of the subject or the subject's legally authorized
representative [21 CFR 50.20].
As an
investigator, it is your responsibility to obtain informed consent in
accordance with 21 CFR Part 50. Except as provided in 21 CFR 56.109(c),
informed consent shall be documented by the use of a written consent form
approved by the IRB and signed and dated by the subject or the subject's
legally authorized representative at the time of consent. A copy shall be given
to the person signing the form [21 CFR 50.27(a)].
You
failed to obtain legally-effective informed consent from Subject 1001 to whom
you prescribed the investigational new drug, (b)(4). Specifically, the
informed consent form for Subject 1001 in Protocol (b)(4) was signed
only by a parent and not by a representative of the Mississippi State Department
of Human Services. At the time of the clinical investigation, the child was in
the legal custody of the Mississippi State Department of Human Services and
thus only the Mississippi State Department of Human Services could serve as the
child’s legally-authorized representative and grant permission for the child to
participate in the clinical investigation.
Failing
to obtain adequate informed consent jeopardizes the safety and welfare of
enrolled subjects by denying them an opportunity to assess the risks and
benefits of their participation in the clinical investigation.
4. You
failed to promptly report to the IRB all changes in the research activity and
you made changes in the research without IRB approval [21 CFR 312.66].
FDA
regulations require that the clinical investigator shall assure that he will
promptly report to the IRB all changes in the research activity and all
unanticipated problems involving risk to human subjects or others, and that he
or she will not make any changes in the research with IRB approval, except
where necessary to eliminate apparent immediate hazards to human subjects [21
CFR 312.66].
You
violated this requirement by administering the investigational new drug (b)(4),
to Subject 1010 without obtaining IRB approval of the modified informed consent
document. Specifically, the IRB-approved version of the informed consent
document for Protocol (b)(4) was altered by hand to state that the
subject would not receive payment for participation in accordance with the
schedule listed on the form unless treated as an outpatient, and this altered
form was signed by the parent of Subject 1010.
Failure
to promptly report changes in the research activity to the IRB and making
changes in the research without IRB approval compromises the safety and welfare
of subjects enrolled in the clinical investigation.
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 Lewin, 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 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,
{See appended electronic signature
page}
Leslie K. Ball, M.D.
Director
Division of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
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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
02/04/2010