Punjwani, Sohail S., M.D.
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Public Health Service |
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02/04/2010
WARNING
LETTER
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Ref:
10-HFD-45-01-04
Sohail Punjwani, M.D.
Professional Clinical Research
1065 NE 125th Street, Suite 221
North Miami, Florida 33161
Dear Dr. Punjwani:
Between January 20 and February 18,
2009, Ms. Brunilda Torres and Ms. Colleen Aspinwall, representing the Food and
Drug Administration (FDA), conducted an investigation and met with you, to
review your conduct of the following clinical investigations:
Protocol
(b)(4), entitled “(b)(4),” of the investigational drug (b)(4)
performed for (b)(4).;
Protocol
(b)(4), entitled, “(b)(4)" of the investigational drug (b)(4)
performed for (b)(4).; and
Protocol
(b)(4), entitled “(b)(4)” of the investigational drug (b)(4)
performed for (b)(4)
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, the documents submitted with
that report, and your March 13, 2009 written response and its attachments, we
conclude that you did not adhere to the applicable statutory requirements and
FDA regulations governing the conduct of clinical investigations. We are aware
that at the conclusion of the inspection, Ms. Brunilda Torres and Ms. Colleen
Aspinwall presented and discussed with you Form FDA 483, Inspectional
Observations. We wish to emphasize the following:
1. You failed to conduct the studies
or ensure they were conducted according to the investigational plans, and to
protect the rights, safety and welfare of subjects [21 CFR 312.60].
a.
Section 3 of Protocols (b)(4) specified that for subjects with a body
weight less than 45 kg, the target dose of study drug was 60-80 mg/day; and for
subjects with a body weight greater than or equal to 45 kg, the target dose of
study drug was 120-160 mg/day. These protocols also specified that the dose
level of 160 mg/day was not to be achieved before Day 8 of treatment. These
study drug administration limits were not always followed.
The
study drug and matching placebo were supplied as 20-, 40-, 60-, and 80-mg
capsules, with the appearance and size slightly different among the dosage
strengths. All medications were packaged in AM (morning dosing) and PM (evening
dosing) blister cards that supplied medication for seven days plus three extra
days. Each blister card was marked with four different-colored columns labeled
with the letters A, B, C, and D to distinguish the different potencies. Each
column contained one potency (20-, 40-, 60-, and 80-mg), such that four capsule
strengths were available for each dose. Per protocol, the nursing staff and
subjects' parent(s) or guardian(s) were to select one capsule for the morning
administration and one capsule for the afternoon administration, and leave the
remaining capsules in the blister pack. Throughout the study and when dosing
modifications were necessary, subjects were to receive clear specifications
regarding which capsule was to be taken from the morning and afternoon blister
cards. When changes to the original dosage plan were necessary, unscheduled
visits were recommended so that subjects could be observed and so that changes
to the dosage plan could be fully explained to the subjects and to his or her
parent(s) or guardian(s).
Regarding
Protocol (b)(4): Six of the seven
randomized subjects received dosages in excess of protocol-specified limits:
i.
Subject 1001, age 13 at the time of enrollment, was randomized on May 9, 2006,
and discontinued on June 5, 2006, upon completion of the study. Subject 1001,
with a documented weight of 46.8 kg, was overdosed on study medication for 20
consecutive days while participating in study (b)(4).
Specifically, on May 16 and 17, 2006 (Treatment Days 8 and 9), this subject
received 180 mg/day; on May 18 and 19, 2006 (Treatment Days 10 and 11), this
subject received 240 mg/day; on May 20 and 21, 2006 (Treatment Days 12 and 13),
this subject received 320 mg/day; on May 22, 2006 (Treatment Day 14), this
subject received 400 mg/day; and from May 23 through June 4, 2006 (Treatment
Days 15 through 27), this subject received 180 mg/day. This subject experienced
sedation and dizziness during the study.
ii.
Subject 1003, age 15 at the time of enrollment, was randomized on June 1, 2006,
and discontinued on June 27, 2006, upon completion of the study. Subject 1003,
with a documented weight of 65 kg, was overdosed on study medication for 21
consecutive days while participating in study (b)(4) Specifically, on
June 7, 2006 (Treatment Day 7), this subject received 180 mg/day, in excess of
the protocol-specified maximum dose of 160 mg/day prior to Day 8 of treatment.
On June 8 and 9, 2006 (Treatment Days 8 and 9), this subject received 240
mg/day. From June 10 through 26, 2006 (Treatment Days 10 through 26), this
subject received 400 mg/day. On June 27, 2006 (Treatment Day 27), this subject
received 280 mg/day.
iii.
Subject 1004, age 16 at the time of enrollment, was randomized on June 1, 2006,
and discontinued on June 14, 2006, prior to study completion, due to lack of efficacy
and sedation. Subject 1004 received doses in excess of the maximum target dose
(160 mg/day) for 3 consecutive days while participating in Study (b)(4).
Specifically, on June 9, 2006 (Treatment Day 9), this subject received 320
mg/day. On June 10 and 11, 2006 (Treatment Days 10 and 11), this subject
received 240 mg/day. This subject experienced sedation during the study.
iv.
Subject 1005, age 15 at the time of enrollment, was randomized on June 14,
2006, and discontinued on July 18, 2006, prior to study completion, due to
noncompliance. Subject 1005 received doses in excess of the maximum target dose
(160 mg/day) for 16 consecutive days while participating in study (b)(4).
Specifically, on June 21 and 22, 2006 (Treatment Days 8 and 9), this subject
received 180 mg/day. From June 23 through 27, 2006 (Treatment Days 10 through
14), this subject received 240 mg/day. From June 28 through July 3, and July 5
through July 6, 2006 (Treatment Days 15 through 20 and Days 22 through 23),
this subject received 400 mg/day. On July 4, 2006 (Treatment Day 21), this
subject received 200 mg/day.
v.
Subject 1006, age 13 at the time of enrollment, was randomized on June 26,
2006, and discontinued on July 25, 2006, upon study completion. Subject 1006,
with a documented weight less than 45 kg, was overdosed on study medication for
a total of 7 consecutive days while participating in study (b)(4).
Specifically, from July 11 through 17, 2006 (Treatment Days 16 through 22),
this subject received 400 mg/day.
vi.
Subject 1007, age 10 at the time of enrollment, was randomized on June 27,
2006, and discontinued on July 25, 2006, upon study completion. Subject 1007,
with a documented weight of 39.5 kg, was overdosed on study medication for 13
consecutive days while participating in study (b)(4) Specifically, from
July 12 through 24, 2006 (Treatment Days 16 through 28), this subject received
120 mg/day.
Regarding
Protocol (b)(4): The only subject
randomized in this study received dosages in excess of protocol-specified
limits:
vii.
Subject 1001, an adolescent, was randomized on May 1, 2006, and discontinued on
May 23, 2006, prior to study completion, due to worsening auditory
hallucinations that apparently caused the subject to lacerate her wrists.
Subject 1001, with a documented weight of 66.5 kg, was overdosed on study
medication for 17 consecutive days while participating in study (b)(4).
Specifically, on May 5, 2006 (Treatment Day 5), this subject received 320
mg/day. From May 6 through 21, 2006 (Treatment Days 6 through 21), this subject
received 400 mg/day.
In
your March 13, 2009 response, you stated that you were first notified on July
26, 2006 by (b)(4) data management personnel that there were dosing
errors in the conduct of the studies, stemming from your mistaken assumption
that all capsules contained in the study drug blister pack were of the same 20
mg strength. Immediately upon becoming aware of this issue, you stated that you
telephoned each subject's parent or guardian to inform him or her of this
error, and inquired about any possible safety concerns or issues, of which
there were none. You stated that during these calls, you instructed the parents
and guardians to stop dispensing the currently prescribed dosage and begin the
corrected dosage amount. A follow-up letter was also sent to the parents and
guardians on August 4, 2006. You noted that the (b)(4) study monitor
conducted a targeted review with you and your research staff on the correct
dosing and dispensing of study medication on July 26, 2006. Additionally, on
July 31, 2006, your research staff attended the (b)(4)-hosted Question
and Answer (b)(4) Recruitment meeting that included training on the
dosing and dispensing for all (b)(4) research sites conducting the
above-referenced studies in which you were involved.
As part
of your corrective action plan, you made formal revisions to your Standard
Operating Procedures (SOPs). Specifically, you indicated that the Dosing and
Dispensing of Investigational Product SOP was revised to add a more detailed
inpatient and outpatient dosing process and to further specify how the clinical
investigator, or designee, should document dosing instructions in both
milligrams and tablets/capsules, as well as clearly document original dosing
schematics and any titration throughout the study. You also noted that the
Study Launch Procedures SOPs were revised to: (1) emphasize the materials
reviewed and received at the investigator meetings, (2) include the review of
the applicable Institutional Review Board (IRB) manuals for investigators, and (3)
include internal documentation of the dosing and procedures to be performed on
a mock subject from screening through study completion. Additionally, you
stated that the Quality Assurance/Quality Control (QA/QC) Program SOP was also
revised to ensure the oversight of two subjects, or 10% of the population
randomized, with ongoing review of dosing and dispensing, protocol compliance,
prior/concomitant medications, and prohibited medications.
We
acknowledge your response. However, we are concerned that the response is not
adequate to prevent future recurrence of the violation noted above. In
particular, we are concerned that you did not properly understand the study
drug packaging from the start of the study and you did not ensure that the
appropriate dose was administered throughout the study. We are aware that the
sponsor subsequently changed the packaging for the investigational product
following observations that clinical investigators were not properly dosing
subjects. Notwithstanding the packaging concerns, as clinical investigator, you
retain responsibility for ensuring that the protocol is followed, including
ensuring that the proper dose is administered to subjects.
b.
Section 5.3.3 of Protocols (b)(4) and (b)(4) specified that you
were to have developed a titration plan to increase the subject's total daily
dose of study medication from a 20 mg starting dose (at the baseline visit) to
a target dose achieved over 2 weeks, in general. In developing the titration
plan, you were to have considered the subject’s psychiatric history, current
psychiatric status, and weight. The Protocol also permitted you to modify the
plan at any time based on a subject’s clinical response and toleration. You or
a staff member were to have explained the titration plans to subjects, and to
have clearly specified which capsules the subjects were to have taken from each
AM and PM column for the first seven days of the titration plan. Furthermore,
Section 5.3.4 of Protocols (b)(4) and (b)(4) specified that you
were to have assessed subjects' compliance with study medication administration
at Week 1 and at each subsequent visit. Additionally, you were to have counted
medication returned by subjects to reconcile medication dispensed with
subjects' reported usage. There is no evidence that you developed dosing
titration plans for the subjects enrolled in these studies, or that you
assessed subjects' compliance and performed the requisite drug reconciliation
as specified in the protocols.
In
your March 13, 2009 response, you acknowledged your failure to fully document
specific dosing instructions and titration plans. You stated that you
recognized that this specific documentation was necessary in order to ensure
accurate dosing. As a corrective measure, you stated that your Dosing and Dispensing
of Investigational Product SOP will be revised to include more specific
information on how, why, and when dosing changes are documented. We acknowledge
your assurance that corrective actions will be taken. However, we note that
your response did not contain a detailed outline of procedures or processes
that would be implemented to prevent future recurrence of the violation noted
above. Specifically, we are concerned that your lack of adherence to the
protocol in developing dosing titration plans, assessing subjects' compliance,
and performing drug reconciliation led to the significant overdoses and
resultant adverse events experienced by the pediatric subjects enrolled at your
site as described above. As you noted in your response, you were first notified
on July 26, 2006 by (b)(4) data management personnel that there were
dosing errors in your conduct of these pediatric studies. It is likely that
your lack of adherence to the protocols led to your failure to recognize the
overdosing at your site, until it was discovered and brought to your attention
by the sponsor's data management unit. While there may have been concerns with
the packaging of the study drug, your failure to conduct the requisite safety
measures contributed to the unnecessary exposure of pediatric subjects to
significant overdoses, which jeopardized the subjects' rights, safety, and
welfare.
c.
Section 6.2 of Protocol (b)(4) required serum pregnancy and urine drug
screening tests to be performed at baseline. These tests were not performed for
the following subjects:
i.
Subject 1002's serum pregnancy and urine drug-screening tests were not
performed at baseline.
ii. Subject 1003's serum pregnancy and urine drug-screening tests were not
performed at baseline.
iii. Subject 1004's urine drug-screening tests were not performed at baseline.
iv. Subject 1007's urine drug-screening tests were not performed at baseline.
In
your March 13, 2009 response, you stated that Subjects 1002, 1003, 1004, and
1007 were inpatients at baseline. Given that the pregnancy and urine drug
screen tests were negative for these subjects at the time of screening, you
indicated that your research staff did not repeat the tests at baseline as they
assumed there was no opportunity for the results to change. You noted that a
Visit Checklist was created to ensure that all study-related procedures are
being conducted for each visit, and that completion of this checklist is now
standard work practice at your site. We acknowledge your response. However,
regardless of the results obtained at screening, the serum pregnancy and urine
drug tests should also have been performed at baseline as specified in the
protocol. The Visit Checklist you have instituted as standard practice at your
site to prevent any similar future occurrences is acceptable.
2. You failed to promptly report to
the Institutional Review Board (IRB) all changes in the research activity [21
CFR 312.66].
On
August 2, 2006, upon confirming study drug dosing errors, the sponsor
instructed you to cease subject enrollment at your site. On February 7, 2007,
the sponsor notified you of its decision to terminate your investigational
site's participation in the (b)(4) pediatric studies, including
Protocols (b)(4) due to good clinical practice (GCP) noncompliance
related to dosing errors and continued delays in resolution of queries and
data-clarification forms. You failed to notify the IRB of these decisions made
by the sponsor. Documentation available at your site indicates that
notification of the IRB was limited to the submission of protocol deviation
reports concerning subjects' overdosing errors. Furthermore, you failed to
notify the IRB of the sponsor's decisions in the continuing review reports and
study close-out letters.
In
your March 13, 2009 response, you stated that you assume full responsibility
for the lack of notification to the IRB. To ensure continued compliance with
IRB guidelines, you noted that formal training concerning IRBs was conducted at
your site on March 17, 2007, and the Western Institutional Review Board Guide
for Researchers Versions 1.5 and 1.6 was distributed at your site for
independent review. We acknowledge your response and find your corrective
actions acceptable.
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 Cullity (formerly 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
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
Building 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