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Department of Health
and Human Services Public Health Service
Food and Drug Administration
Center for Biologics Evaluation
and Research
1401 Rockville Pike
Rockville, MD 20852-1448
Notice of Opportunity for HearingMay 21, 2002
By Certified
Mail - 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 information indicating that you
repeatedly or deliberately violated federal regulations in your capacity as
investigator in clinical trials with unlicensed biological and investigational
new drugs, specifically, [redacted]. The violations provide the basis for the
withdrawal of your eligibility as a clinical investigator to receive
investigational new drugs.
By letter dated June 21, 2001, the Center for
Biologics Evaluation and Research (CBER) informed you of the specific matters
complained of and offered you an opportunity to respond to them in writing or at
an informal conference pursuant to 312.70(a) of Title 21 of the Code of Federal
Regulations (CFR). The letter also gave you the option of entering into a
consent agreement with the agency, thereby terminating any administrative
proceeding. You chose to respond at an informal conference conducted on August
24, 2001. The informal conference was transcribed, and a copy of the transcript
was provided to your counsel. You provided written exhibits to supplement your
presentation. CBER has considered your explanations and concluded that they are
unacceptable because they fail to adequately address the violations set forth
below. Accordingly, you are being offered an opportunity for a regulatory
hearing pursuant to 21 CFR Part 16; on the question of whether you are entitled
to receive investigational new drugs.
A listing of specific violations
follows. 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 investigator is 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's care; and for the
control of drugs under investigation.
On [redacted] 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 a clinical investigator in
the use of unlicensed biological drugs and investigational new drugs for the
following reasons:
A. You enrolled several subjects who were not
eligible for the study; see item (2) below.
B. You failed to obtain
proper institution Review Board (IRB) approval of protocol modifications; see
items 2(A) and 3, below.
C. You failed to perform the study procedures
required by the protocol to monitor the effects of the study drug in subjects;
see item 2(B), below.
D. You failed to abide, by the safety provisions
required in the protocol; see item 2(C), below.
E. You permitted
subjects to self-administer the investigational [redacted] without your
supervision and without IRB approval; see items 3(D) and 4, below.
F.
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].
- Subjects who failed to meet the eligibility criteria were allowed to
participate in the clinical trial.
Subject
Subject Entry
Status
Protocol Requirement
[redacted]
Age ³ 75 years old
[redacted]
[redacted]
2 weeks past previous therapy
Age ³ 75
years old Corticosteroids within past week
[redacted]
[redacted]
Hemoglobin = 8.0 g/dl Karnofsky performance of 60%
[redacted]
[redacted]
Interferon within last 4 weeks
[redacted]
[redacted]
Antibiotic treatment of Infection
[redacted]
[redacted]
Corticosteroids within past week
[redacted]
[redacted]
Recent treatment with other therapies
[redacted]
[redacted]
Recent treatment with other
therapies
[redacted]
[redacted]
Stage IIA melanoma
History of multiple myeloma
[redacted]
[redacted]
Corticosteroids within past week
[redacted]
[redacted]
History of prostate cancer with bone metastases
[redacted]
[redacted]
Stage I melonoma
[redacted]
[redacted]
Stage I melonoma
[redacted]
I. During
the informal conference you confirmed that subjects [redacted] and [redacted],
and therefore did not meet the age [redacted] to participate in the trial. You
stated, "We submitted the protocol amendment and got their verbal approval and
then had the official written approval after that, but waited until they said we
could begin [redacted] those patients. Even if true, your explanation would be
insufficient, as undocumented "verbal approval" from an individual IRB member is
insufficient to justify deviation from your approved protocol.
On the
contrary, you failed to withhold the [redacted] until you received proper IRB
approval of the protocol amendment to delete the upper age limit of 74. Subjects
[redacted] received the first [redacted] of the [redacted], however, the
handwritten notation by Dr. Plunket (IRB Chair) reading "Full Approved" is dated
[redacted].
Likewise, your [redacted] letter to Dr. Obiri at CBER
misleadingly implies that you had not yet enrolled and [redacted] subjects who
were beyond your protocol's initial age restriction. It states, "We would like
to delete the upper age limit, as several patients qualifying for treatment in
all respects other than being less than 75 years of age have requested
treatment." In fact, by that time, you already had subjects [redacted] in the
trial and had given them [redacted] of the investigational product. The
documentation further states that IRB approval of the waiver forms themselves
were "reviewed and approved effective [redacted] over a year after the initial
[redacted] of subjects.
II. The protocol excludes subjects who were
taking corticosteroids, yet you enrolled subjects [redacted], into the study.
During the informal conference, you stated that "steroids are immunosuppressant
to some extent" and that the use of steroids "might block & blind your
ability to detect an immune response to the [redacted]. You explained that you
enrolled the subjects into the study because you were able to collect safety
data.
We do not agree with your explanation. One of the objectives of
this study is to establish the [redacted] ability to elicit an immune response
in subjects with advanced melanoma. The enrollment of these subjects was
inappropriate because you were aware that these, immunosuppressed subject would
likely not be able to produce an immune response to the [redacted] when that was
one of the purposes of the study. Although you the that you intended to obtain
safety data firm these subjects, you were not justified in enrolling these
ineligible subjects because you exposed them to the unknown risks of an
investigational [redacted] without the expectation of benefit.
III.
Subject [redacted] failed to meet several eligibility criteria (see table
above). During the informal conference, you indicated that subject [redacted]
had receive blood transfusion and that the subject's hemoglobin had risen to 8.0
g/dl at the time of the subject's enrollment, and that the Kamofsky score
increased to 70% after the blood transfusion.
In fact, according to the
documents, you provided during the informal conference, on the date of the first
[redacted] of the investigational [redacted], subject [redacted] had a
hemoglobin of 8.0 g/dl, and a Kamofsky score of 60%. Therefore, subject
[redacted] should have been excluded from the study because the subject failed
to meet these protocol eligibility requirements [redacted].
You further
explained that you submitted a protocol amendment on [redacted] to allow
subjects with a Kamofsky score of at least 50% to participate in the study. We
do not accept this explanation in relation to subject [redacted] because you
submitted the protocol amendment to the IRB after the subject died on
[redacted]. You submitted the Eligibility Criteria Waiver to the IRB for review
and approval on [redacted], eleven months after the first [redacted].
IV. During the informal conference, you stated that the protocol should
have been amended to remove the criterion excluding patients who had an active
infection requiring antibiotics within the past week. However, because you
failed to amend the protocol, subject [redacted] should have been excluded from
the study.
V. Subjects [redacted] should have been excluded from the
study because they had received treatment for their cancers within the past four
weeks (see table above),yet you enrolled the subjects anyway.
During the
informal conference; you stated, "the issue again is all of those treatments are
immunosuppressive to some extent (chemotherapy, radiation therapy, and surgery).
So, it may weaken efficacy data, but I did not think it would effect the
collection of safety data...."
We do not accept your explanation because
you were aware that immunosuppressed subjects would likely not be able to
produce an immune response to the [redacted]. I when that was one of the
purposes of the study. Although you suggest that you intended to obtain safety
data from these subjects, you were not justified in enrolling these ineligible
subjects because you exposed them to the unknown risks of an investigational
[redacted] without the expectation of a benefit.
VI. Subject [redacted]
had a history of multiple myeloma and stage IIA melanoma at the time of
enrollment. At the informal conference, you explained that you amended the
protocol to include. However, you submitted the proposed protocol amendment to
the IRB on, [redacted], after the subject received the first. You did not submit
an 'Eligibility Criteria Waiver" form to the IRB until six months later; on
[redacted]. During the informal conference, you stated, that this subject was
immunosuppressed because of [redacted] when that was one of the purposes of the
study. Indeed, the presence of other cancers was an exclusion criterion and this
subject should have been excluded. As you acknowledged, she "had no business
being in the clinical trial."
VII. During the informal conference, you
acknowledged that subject [redacted] a had a history of prostate cancer with
bone metastases at the time of enrollment [redacted] but was exposed to the
unknown risks of an investigational without the expectation of a benefit.
VIII. Subjects [redacted] had [redacted], yet you enrolled them in the
study. During the informal conference, you expressly acknowledged that it was
inappropriate to have included them in this study.
B. You failed to
perform the-study procedure required by the protocol. For example:
- You failed to evaluate subjects' immune response to the [redacted] by
delayed type hypersensivity (DTH). The following table shows that DTH testing
was not reported on the following weeks:
Subject #
Week(s)#
[redacted]
92
[redacted]
20
[redacted]
5, 20, 56
During the informal conference, you
confirmed that the DTH testing was not done for the last two or three doses for
subject [redacted] and at week 20 for subject [redacted].
In regards to
subject [redacted] documents that you provided during the informal conference do
not document that DTH testing was assessed on weeks 5 (6/23/98), 20 (10/22/98),
and 56 (6/29/99) at 48 or 72 hours after administration of the [redacted].
During the informal conference, you explained that documentation of DTH
reactions "is hit or miss."
Further, the protocol requited two people to
evaluate each DTH response before it is recorded to control bias in assessing
the immune response to the [redacted]. During the informal conference, you
acknowledged that the third nurse coordinator probably did not have two people
involved to evaluate each DTH response. In addition, in your response letter
dated January 25, 2001, to the Form FDA 483, Inspectional Observations, you
explain that "two people did not always evaluate each DTH response."
ii.
There is no documentation that you performed all laboratory tests and clinical
procedures at the intervals required by the protocol. There are no records
documenting that hematology and chemistry blood tests were performed for
subjects [redacted] at week 4. During the informal conference, you acknowledged
that some laboratory tests were not conducted at week 4.
C. You did not
follow the protocol requirement to discontinue the investigational [redacted]
for several subjects with documented progression of disease. The protocol
amendment dated 1/30/97 states, "If a patient's disease should progress as
defined by [redacted] criteria future [redacted] will be halted, and the patient
will be referred for appropriate multidisciplinary [redacted]". Several subjects
met [redacted] criteria of disease progression, but they were not discontinued
from the [redacted]. Examples include the following:
i. Subject
[redacted] was enrolled in the study on [redacted] with [redacted] as documented
in the medical records in [redacted] yet you continued to administer the
[redacted] in violation of the protocol. Subject [redacted] received the first
[redacted] and continued to receive [redacted] an additional two years.
ii. In a letter dated [redacted] to the subject [redacted] physician,
you acknowledge that subject [redacted] had a "recurrence or progression of
disease." The outpatient history/physical record documents recurrent nodules on
the right pelvis and para aortic. Subject [redacted] was administered four doses
of [redacted] after this date, before ending on [redacted].
During the
informal conference, you described that you obtained IRB and FDA permission to
continue additional doses of the investigational [redacted] following debulking
surgery. In fact, you had already administered four additional doses of
[redacted] before you submitted the request to the IRB and the FDA, according to
the document you provided FDA during the informal conference.
iii. The
medical records for subject [redacted] document recurrence or progression of
disease, but you continued to administer the [redacted]. For example, a Progress
Note dated [redacted] documents that the subject had [redacted] and now with
definite recurrence in the lymph nodes of the neck.
We do not accept the
explanation presented during the informal conference. You stated that time of
the study, patients whose disease had progressed "should be stopped at that
point" and discontinued from the study. You further explained that you later
thought that 'because of the nature of immunotherapy" you could continue to
administer the [redacted] for additional periods.
Although you
eventually requested FDA approval to treat subjects with progressive or
recurrent disease, in a letter to FDA dated [redacted] you did not have
permission to deviate from this protocol requirement at the time that subjects
[redacted] were enrolled in the study. Indeed, you acknowledged at the informal
conference that "it was in the protocol and we deviated from the protocol. We
shouldn't have."
D. Several subjects received concurrent radiotherapy,
chemotherapy, immunotherapy, or other treatment in violation of the protocol
which specifically excludes such concurrent treatment. Examples include the
following:
i. Subject [redacted] was administered interferon and
chemotherapy concurrently with the investigational [redacted].
ii.
Subject [redacted] was administered the [redacted] concurrently with interferon
treatment: The [redacted] Summary Sheet" dated [redacted] reports "... unable to
determine if the side effects related to [redacted] received double dose of
interferon the same day [redacted].
iii. Subject [redacted] was
administered the [redacted] from [redacted]. During that period, the subject
received several courses of chemotherapy and radiotherapy.
iv. The
[redacted] Summary Sheet" dated [redacted] documents that subject [redacted]
completed seven weeks of radiation therapy.
v. Study records document
additional subjects as receiving concurrent therapy.
Subject
Treatment
Reason
Date started
[redacted]
Radiotherapy
Prostate cancer
[redacted]
[redacted]
Radiotherapy
Prostate cancer
[redacted]
[redacted]
Intron/Interferon
Melanoma
[redacted]
[redacted]
Intron/Interferon
Multiple
myeloma
[redacted]
[redacted]
Chemotherapy
Melanoma
[redacted]
[redacted]
Intron/Interferon
Melanoma
[redacted]
We note that subjects [redacted] and
[redacted] were administered concurrent therapies for treatment of other cancers
that should have excluded these subjects from the study.
During the
informal conference, you acknowledged that you were aware of these concurrent
therapies, yet continued to administer the investigational [redacted] in
violation of this protocol requirement. You stated, the issue again is all of
those treatments are immunosuppressive to some extent (chemotherapy, radiation
therapy, and surgery). So, it may weaken efficacy data, but I did not think 6
would effect the collection of safety data...."
The continued
administration of investigational [redacted] to these subjects was inappropriate
because immunosuppressed subjects would likely not be able to produce an immune
response to the [redacted]. Although you state that you intended to obtain
safety data from these subjects, the protocol prohibited further administration
of the [redacted] to these subjects. The continued administration of the
[redacted] to these subjects exposed them to unknown risks without the
expectation of a benefit.
E. The protocol required the primary series of
eight [redacted] each week for eight weeks, and then a [redacted] every
[redacted] months (weeks 20, 32, 44, 56, 68, 80, 92, and 104) for 2 years, for a
total of 16 [redacted]. You did not follow the protocol-mandated [redacted]
schedule for several subjects.
i. You administered an additional
[redacted] to subject [redacted] on week 45 [redacted] without IRB approval see
item 3B. At the informal conference you provided documentation that on
[redacted] the IRB approved additional [redacted]
ii. You administered
extra doses of [redacted] to subject [redacted] at weeks 26 [redacted], 27
[redacted], 28 [redacted], and 29 [redacted] without IRB approval; see item 3B.
At the informal conference, you stated that you asked for IRB approval
for these additional [redacted. According to the documentation you provided at
the informal conference, you did not receive IRB approval until [redacted] after
you had already administered the extra [redacted]. You did not even submit the
request to the IRB until [redacted], after you had administered extra and
unscheduled [redacted] of the [redacted. Contrary to your response at the
informal conference, you did not have IRB permission for these [redacted]. In
addition, you did not have permission from FDA until [redacted] see item 3B,
below.
F. Vital signs were not obtained 30 minutes after [redacted] of
the [redacted] for subjects [redacted] (on week 5), and [redacted] (on weeks 8),
and [redacted] 3, 4, 5, and 7). During the informal conference, you did not
provide documentation to verify whether subjects [redacted] had the vital signs
measured following the [redacted]. The protocol states, "Patients wilt 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.
During the informal
conference, you acknowledged that vital signs were not always obtained 30 after
[redacted] for several subjects. In addition, your response letter dated
[redacted] to the Form FDA 483, Inspectional Observations, states, "...this
protocol condition was not strictly enforced following later [redacted]."
3. You failed to obtain IRB approval prior to implementing protocol
amendments or changes in the research activity. [21 CFR 312.66].
A. You
failed to obtain prior IRB approval to waive the entry criteria for several
subjects. On [redacted], you submitted Eligibility Criteria Waiver" request
forms to the IRB Chair requesting approval to permit the enrollment for ten
ineligible subjects [redacted] and [redacted]. However, you had already
administered the investigational [redacted] to the subjects during the period of
[redacted] to [redacted] well before the IRB Chair granted the protocol waivers
on [redacted]. Three of these subjects were dead by the time you submitted the
waiver requests to the IRB. The, following table shows that subjects were
administered the study [redacted] several months to one year before the waivers
were granted.
[redacted]
The IRB did hot
approve all of these Eligibility Criteria Waivers until [redacted] specifically
and expressly noting that "these were review and approved effective [redacted] "
further evidencing the impropriety of enrolling and [redacted] the subjects
before that date. Additionally, after [redacted] you continued enrolling
ineligible subjects without obtaining prior IRB approval. You submitted
additional waivers to the IRB for review and approval after the subjects were
enrolled in the study, as documented in the following table:
[redacted]
*The IRB approved the waiver for subjects
[redacted], respectively.
During the informal conference you stated,
"Those [waivers] were supposed to be sent to the IRB for approval, as the
protocol says. She did not understand that at first." You further indicated that
eleven of those waivers were all filed at once when you discovered the study
nurse had not been filing them. Although site personnel may have been delegated
the responsibility for submission of the waivers, the clinical investigator
retains responsibility for ensuring that the waivers were appropriately
submitted to the IRB for review and approval.
The original protocol
approved by the IRB states that exclusion criteria could be waived by the
"Sponsor-investigator on a case-by-case-basis after the author of the protocol,
you after approval" from the IRB. As the author of the protocol, you
established this protocol requirement, but failed to abide by it, explaining
instead that in some cases, you obtained verbal acquiescence from a single IRB
member. This neither satisfies the protocol, nor does it permit the IRB to
adequately assure the protection of subjects or prospective subjects.
During the informal conference, you stated, "for the most part we had
verbal approval" of the waivers, acknowledging that you lacked approval in
certain cases. Not only is verbal approval insufficient, but approval sought
after the fact for an action already taken is meaningless. There is also no
contemporary evidence to document that you obtained prior verbal IRB approval of
your waiver request, even if such a procedure were permissible. Indeed, the fact
that the IRB subsequently issued written approvals for the waivers tends to
prove that you circumvented the proper IRB review process; it shows that you
submitted the waiver requests after you had already enrolled the subjects and
initiated [redacted] despite the fact that the IRB had a procedure for formal,
written waiver approval, which you did not utilize.
B. In a letter to
the IRB dated [redacted] you requested permission to "...give two of our
[redacted] protocol patients [subject [redacted] four additional [redacted]. You
made a similar request to FDA in a letter dated [redacted]. However, the
[redacted] visit Tracking Log" for subject [redacted] documents that the subject
received four (4) additional weekly [redacted] on [redacted], (week 26),
[redacted]; (week 27), [redacted] (week 28), [redacted] (Week 29) without IRB
approval (see also item 2(E)(ii), above). You also administered an additional
[redacted] to subject [redacted] an week 45 [redacted] without IRB approval (see
also item 2(E)(i), above).
You failed to withhold the additional
[redacted] until the IRB had reviewed and approved your request. The IRB Chair
gave qualified approval of the additional [redacted] on [redacted]. An
"Administrative Note" dated [redacted] from the IRB Chair to Dr. McGee,
indicates that the IRB reviewed and approved your request effective [redacted]
with the understanding that this procedure has been given approval from the FDA.
However, FDA approved the additional [redacted] on [redacted]. Therefore, at the
time of the IRB action on your request, you did not have FDA permission for the
additional [redacted] and therefore, failed to follow the IRB Instructions.
C. On [redacted], you submitted a protocol amendment to the IRB to
delete the upper age limit of 74 years., You failed to wait for full IRB
approval before you implemented the protocol amendment and, on [redacted], you
administered the first [redacted]. The IRB Chair approved the protocol amendment
or [redacted] after the [redacted] had occurred. See item 2Ai, above.
D.
You permitted subjects to self-administer the [redacted] without IRB approval.
On [redacted] you informed FDA of the death of subject [redacted] on study; and
described that the subject "was instructed on study drug self-administration"
from [redacted], through [redacted]. In addition, the inspection revealed that
subject [redacted] was given two doses of [redacted] for self-administration in
[redacted]. However, it was not until [redacted] that the IRB tentatively
approved the self-administration of the [redacted] and GM-CSF contingent upon
requested changes. The IRB Chair approved this protocol amendment on [redacted].
Your response letter to the Form FDA 483 states that you sought IRB
approval to permit subjects to self-administer the [redacted]. However, the IRB
approval for this protocol amendment was obtained more than two (2) years after
subjects [redacted] started self-administration of the [redacted], and eight (8)
months after subject [redacted] death.
During the informal conference,
you acknowledged that you did not have prior IRB approval for
self-administration.
4. You failed to control the Investigational drug
[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.
- During the inspection, FDA was informed that the study [redacted] 155 and
#156 were sent to subject [redacted]. The subject's wife reportedly
administered the [redacted].
- The inspection documented that you supplied/shipped the investigational
drug to subject [redacted] located in [redacted]. The subject
self-administered the [redacted] without your supervision or the supervision
of a sub-investigator.
- You supplied the investigational drug to subject [redacted]. The Progress
Notes dated [redacted] document that the subject's primary care physician
"will administer the [redacted].
During the informal conference,
you stated, "that is an activity that in retrospect was a wrong thing to do,
something that I would not do now."
Pursuant to 21 CFR 16.22 and
312.70(a), you are hereby notified of your opportunity for a regulatory hearing
before FDA to determine whether you should be disqualified from receiving
investigational drugs. The matters to be considered at the hearing are set forth
in paragraphs 1 through 4, above,. Under FDA regulations, you have the right to
be advised and represented by counsel at all times. Any regulatory hearing on
this matter will be governed by the regulations in Title 21 of the Code of
Federal Regulations, Part 16, and the FDA's guidelines on electronic media
coverage of public administrative proceedings, 21 CFR 10, Subpart C. Copies of
those regulations are enclosed .
Your written request for a hearing must
be postmarked; if mailed, or received, if faxed, (with the original to follow by
mail) within ten (10) working days of receipt of this letter. Please address the
letter to:Dr. James F. McCormack, Coordinator
Bioresearch Monitoring
Program
Division of Compliance Policy (HFC-230)
Food and Drug
Administration
5600 Fishers Lane
Rockville, Maryland 20857
Telephone
(301) 827-0425
Facsimile (301) 827-0482
If no response to this letter
is received by that time, you will be deemed to have waived your right to a
regulatory hearing, and a decision in this matter will be made based on the
facts available to the agency.
A request for a hearing may not rest upon
mere allegations or denials but must present specific facts showing that there
is a genuine and substantial issue of fact that warrants a hearing. Pursuant to
21 CFR 16.26, a request for a hearing may be denied, in whole or in part, if the
Commissioner or his delegate determines that no genuine and substantial issue of
fact has been raised by the material submitted. A hearing will not be granted on
issues of policy or law. Written notice of a determination of summary judgment
will be provided, explaining the reasons for denial of the heating.
If
you wish to respond but do not desire a hearing, you should contact Dr.
McCormack within the time period specified above and send a written response
containing your reply. The letter should state that you waive your right to a
hearing and that you want a decision on the, matter to be based on your written
response and other information available to the agency.
The agency's
offer to enter into a consent agreement remains open. Entering into a consent
agreement would terminate the administrative procedures, but would not preclude
the possibility of a corollary judicial proceeding. You were sent a draft
consent agreement enclosed with FDA's letter to you dated June 21, 200l. If you
would like to choose this option, please contact Dr. McCormack.
No final
decision by FDA has been made at this time on your eligibility to continue to
use investigational drugs. Moreover, there will be no prejudgment of this matter
if you decline to enter into a consent agreement and decide instead either to
request a regulatory hearing or to request that the decision be based on
information currently available to the agency.
Please inform Dr.
McCormack within ten (10) working days whether you wish to request a hearing or
to have this matter resolved by consent agreement or based on the information
available to the agency.
Sincerely yours,
/s/
Dennis E.
Baker
Associate Commissioner for Regulatory Affairs
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