Holland, James A., M.D. Notice of Opportunity for Hearing (NOOH) 8/14/07

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DEPARTMENT OF HEALTH &. HUMAN SERVICES'
AUG 1 ~ 2001
Public Health Service
Food and Drug Administration
Rockville MD 20857
NOTICE OF OPPORTUNITY FOR HEARING (NOOH).
CERTIFffiD MAIL
RETURN W;;CEIPT REOUESTED
James A. Holland, M.D.
116 Mimosa Drive
The Lewis Hall Singletary Oncology Center
Thomasville, Georgia 31792
Dear Dr. Holland:
The Center for Drug Evaluation and Research (the Center) ofthe Food and Dmg Administration
(FDA) has infonnation indicating that you repeatedly or deliberately failed to comply with the
requirements of21 CPR Part 312 in your capacity as an investigator in clinical trials with
multiple investigational new drugs. The Center also has infonnation indicating that you
repeatedly or deliberately submitted false information to FDA or the sponsor in required reports.
These violations provide the basis for withdrawal ofyour eligibility as a clinical investigator to
receive investigational new drugs.
The Center's findings !U'e based on infonnation obtained during FDA inspection ofthe following
.' clinical studies for which.you were the investigator ofrecord: . .
1. Protocol "Open Label, Multi-National, Multi-Center Study of l in
Combination with Cisplatin and 5-FlourouracU (5-FU) in Subjects with Metastatic or Locally
Recurrent Gastric or Gastroesophageal Cancer Previously Untreated with Chemotherapy."
This study ofthe investigational dmg was perfonned for'-----'
2.
3. Protocol "An Open-Label, Randomized, Multicenter, Multi-Phase IIIlII
Study 01 in Combination with Cisplatin (CDDP) or in Combination
with 5-FUand CDDP (Cisplatin) Compared to the Combination ofCDDP and 5-FU in
Patients with Metastatic or Locally Recurrent Gastric Cancer Previo~ly Untreated with
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.Chemotherapy for Advanced Disease." This study of the investigational drug I was
performed for--------------------------'
4. Protocol "A Multicenter, Multinational Randomized Phase III Study of
Docetaxel Plus Versus Vinorelbine Plus Cisplatin in Chemotherapy-NaIve
Patients with Unresectable Locally Advance and/or Recurrent (Stage IIIB) or Metastatic
(Stage IV) Non-Small Cell Lung Cancer." This study of the investigational drug Docetaxel
was performed for Aventis Phannaceuticals, Inc. .
5. Protocol "Multicenter Phase II Trial of Weekly Taxotere® and!!'-"."--_......
) in Patients with Advanced Non-Small Cell Lung Cancer." This study of the
'.--~ investigational drug Taxotere® was performed for Aventis Pharmaceuticals, Inc. (Rhone-
Poulenc Rorer Research and Development).
6. Protocol "A Multicenter Phase III Randomized Trial Comparing Docetaxel
Administered Either Weekly or Every Three Weeks, in Combination with Prednisone vs.
Mitoxantrone in Combination with Prednisone for Metastatic Hormone Refractory Prostate
Cancer." This study of the investigational drug Docetaxel was performed for Avenns
Pharmaceuticals, Inc. (Rhone-Poulenc Rorer Research and Development).
7. Protocol ~'Clinical Protocol for a Randomized, Double-Blind, Placebo-
Controlled Parallel Group Comparison ofthe Analgesic Activity 01
",="-~~~~~----'
20 mg BID Versus 75 mg BID in Patients withC~onic Cancer Pain." This study
of the investigational drug was performed for _
8. Protocol "APhase III, Multicenter, Randomized Active-Controlled Clinical Trial
to Evaluate the Efficacy and Safety ofRhuMAb VEGF (BEVACIZUMAB) in Combination
with Standard Chemotherapy in Subjects with Metastatic Colorectal Cancer." This study of
the investigational drug Bevacizumab was performed for Genentech, Inc.
9.. Protocol "A Phase II, Multicenter, Double-Blind, Randomized, Active-
Controlled Clinical Trial to Evaluate the Efficacy and Safety ofrhuMabVEGF, A
Recombinant Humanized Monoclonal Antibody to Vascular Endothelial Growth Factor, In
Combination with 5-FU and Leucovorin Chemotherapy in Subjects with Metastatic
Colorectal Cancer Who Are Not Optimal Candidates for First Line CPT-II." This study of
. the investigational drug Bevacizumab was performed for Genentech, Inc.
10. Protocol "Phase III Randomized, Double-Blind Study 01 vs. Placebo
in Low Grade Superficial Bladder Cancer." This study ofthe investigational drug
_________---1 was performed forl....- ,
11. Protocol "A Randomized, Open-Label, Stratified, Parallel-Design,
Controlled Study of"--__..... for the Treatment of Patients with Stage IIIB or Stage IV
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Non-SmaIl-Cell Lung Cancer in Conjunction with Chemotherapy." This study of the
investigational drug Injection was performed for "--- ~ ____
FDA conducted an inspection between November 14, 2002 and January 03, 2003. After the
inspection, and pursuant to section 312.70(a) of Title 21 ofthe Code ofFederal Regulations [21
CFR 3l2.70(a)], the Center informed you; by letter titled "Notice ofInitiation of Disqualification
Proceedings and Opportunity to Explain" (NIDPOE) dated September 22, 2004, ofthe specific
matters complained of and offered you an opportunity to respond in writing or at an informal
conference. The NIDPOE also offered you the option of entering into a consent agreement with
FDA, thereby terminating this disqualification proceeding against you. In response to the
NIDPOE, your representative, Ms. Gloria H. Arthur, Esq., submitted written correspondence
dated October 26,2004. This written correspondence provided responses to allegations made in
the NIDPOE and requested an "evidentiary hearing."
In accordance with 21 CFR 312.70(a), we have provided you with ample opportunityto meet
with the Director of the Djvision ofScientific Investigations, for an informal conference. On
your behalf, Ms. Arthur delayed scheduling an informal conference on several occasions,
asserting that you did not have access to any records anq needed time to obtain them. Once an
informal conference was scheduled, she requested its postponement, asserting continued
difficulties in obtaining any records. We agreed to reschedule the conference and to help you
obtain records if needed. However, neither you nor Ms. Arthur has responded ·to our proposals.
The Center has concluded that you have now received adequate opportunity for an informal
conference. Further, the Center has determined that your failure to respond to our proposals
constitutes a waiver ofthe opportunity to have such a conference.
On April 24, 2007, you pled guilty to violating Title 21, United States Code, Section 331(e).
Specifically, you admitted to wrongfully and unlawfully failing to establish and maintain
adequate and accurate case histories for individuals enrolled in three ofthe studies discussed·
more fully below (Protocol , Protocol and Protocol_
). As the plea agreement states, you had "the responsibility, authority, and duty to ensure that
adequate and accurate case histories were maintained and [to] promptly detect and correct
inadequate and inaccurate case histories, but wrongfully and unlawfully failed to do so, including
by failing to review or check the accuracy of ... case histories and reports of laboratory analysis,
electrocardiograms, ejections fraction testing, radiology reports, surgical rep'orts, and operative
and progress notes." The plea agreement notes one example in particular, of documents falsely
stating and representing the results ofblo~d chemistry analysis so as to purport th~t an individual
met the inclusion criteria for Protocol , when, in fact, the individual was
ineligible due to impaired kidney and liver function. As detailed more fully below (see item
2(a», the administration of the study drug to this individual may have contributed to his death.
In light ofyour plea and after reviewing all other available information, the Center has concluded
that your written explanations are unacceptable to address the violations set forth below.
Accordingly, you are being offered an opportunity for a regulatory hearing pursu~t to 21 CFR
parts 16 and 312, to determine whether you are entitled to receive investigational new drugs.
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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 21 CFR part 16 and FDA's guidelines on
electronic media coverage of administrative proceedings, 21 CFR part 10, subpart C. Enclosed
you will [rod copies of these regulations. A listing of the specific violations follows. These are
matters that will be considered at the regulatory hearing. Applicable provisions ofthe CFR are
cited for each violation.
1) You failed to personally conduct or supervise the clinical investigations [21 eFR
312.60].
When you signed the investigator statement (Form FDA 1572) for each ofthe abovereferenced
clinical investigations, you agreed to take on the responsibilities ofa clinical
. investigator at your site. Your general responsibilities (21 CFR 312.60) include ensuring that
the investigation is conducted according to the signed investigator statement, the
investigational plan, and applicable regulations; protecting the rights, safety and welfare of
subjects under your care; and ensuring control of drugs under investigation. You specifically
agreed to personally conduct the clinical studies or to supervise those aspects ofthe studies .
that you did not personally conduct. While you may delegate certain study tasks to
individuals qualified to perform them, as clinical investigator you may not delegate your
general responsibilities. Our investigation indicates that your supervision ofpersonnel to
whom you delegated study tasks was not adequate to ensure that the clinical trials were
conducted according to the signed investigator statement, the investigational plan, and
applicable regulations, and in a manner that protected the rights, safety, and welfare of
human subjects.
a. You'delegated certain tasks to individuals not qualified to perform such tasks.
You delegated the performance ofprotocol-specified clinical evaluations (e.g., physical
examinations and [mal determination of subject eligibility) to Paul Kornak,.a study
coordinator. For example, Mr. Kornak determined eligibility and performed the
qualifying physical examination on subject. (2553) who was not eligible for the study
and who died while enrolled in protocol (see violation 2a). Mr. Karnak
was not a licensed physician.
You delegated to , another study coordinator, responsibility for
determining subject eligibility. She also was not medically qualified to perform these
duties without adequate supervision. We believe you never questioned her regarding
subject eligibility nor did you request patient files from her so that you could perform an
independent evaluation ofsubject eligibility. Further, we believe that when she presented
case report fonns (CRFs) for your review, you would just sign, without review, the last
page or pages of the CRF that required your signature. Because you failed to provide
adequate supervision, Ms. independently determined subject eligibility. .
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In the written response dated October 26, 2004, your representative claimed that Mr.
Kornak was hired as a member ofthe research team by Dr. Hrushesky, whom you were
brought in to replace, and that you were not involved in the original decision to hire Mr.
Kornak. You further claimed that the administration knew that Mr. Kornak had lost his
medical license long before you became affiliated with the Albany VAMC. Your
response is inadequate. The salient issue is whether Mr. Kornak possessed the
qualifications to perform the tasks he did. Available documentation indicates that Mr.
Kornak was not hired as a physician and was not qualified to perform medical
evaluations and assessments. With respect to Ms. , you claimed that you
"never" at any time delegated to her responsibility for determining subject eligibility or
'required her to independently determine any clinical aspects of a patient's eligibility.
YoUr response is inadequate. As discussed above, we believe you failed to provide
adequate supervision, and, as a consequence Ms. , the studycoordinator,
independently determined subject eligibility.
b. You failed to adequately supervise individuals to whom you delegated study tasks.
Despite numerous indications ofproblems with the conduct ofstudies for which you
were responsible, you did not provide adequate supervision or institute actions to correct
problems.
For example, the sponsor ofprotocol , , al.erted you that there were
serious data integrity concerns about this study, and made multiple efforts over several
months to resolve data discrepancy issues. We understand that questioned the
eligibility ofpatient. (0402) based on concerns arising from Mr. Kornak's alteration,
removal, and replacement ofstudy related documents. We also understand that you were
made aware ofthese concerns by in December 2001, and that from then tlliough May
2002.continued to pursue resolution oftheir concerns with you.
Your explanations and responses to the problems identifiedby.indicate either a lack
ofunderstanding ofthe potential seriousness ofthe underlying p.roblems or an effort to
downplay them. In either case, your conduct did not appear to comport with your duty to
conduct or supervise Mr. Kornak in the study.
In your written response, you denied these allegations, claimed that there were not.
numerous indications ofproblems with the conduct of the studies, and claimed that
alleged data discrepancy issues were reported to VAMC's IRE andto.within 24-48
hours. Your response is inadequate. Available documentation indicates that you did not
adequately address data discrepancy issues identified by , as described above, and
that there were numerous indications ofproblems with the conduct of the studies, as
discussed below (see violations 2 through 5).
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2) You failed to protect the rights, safety and welfare of subjects under your care
(21 CFR 312.60).
a. In Protocol , you enrolled subject. (2553) in a study for
which he was clearly ineligible due to his impaired liver and renal function, and dosed
this subject with a nephrotoxic study drug that may have contributed to his death.
_ excluded subjects with impaired liver and renal function. You randomized
subject 2553 to the study despite laboratory results from 5/25/01 that indicated significant
renal and hepatic dysfunction: creatinine (1.9 mg/dL), creatinine clearance (41 ml/min),
alkaline phosphatase (378 U/L), SGOT (99 U/L), and total bilirubin (1.9 mg/dL). Had
you reviewed this subject's laboratory results, it should have been obvious to you that
this subject was ineligible.
In addition; these laboratory results were altered onthe CRF submitted to the sponsor,
making it appear that the subject was eligible for enrollment: creatinine (1.3 mg/dL),
creatinine clearance (60.3 ml/min), alkaline phosphatase (208 U/L), SOOT (39 U/L), and ,
total bilirubin (0.9 mg/dL) (also see violation 3.a).
b. In Protocol , you enrolled subject" (9715) in a study for which he
was clearly ineligible due to evidence of coronary disease. Because of the investigational
drug's mechanism ofaction and reports ofhemorrhage and thrombosis, subjects with
significant coronary disease, including serious arrhythmia requiring medication, were
excluded from the study. Subject (9715) was enrolled despite an echocardiogram
that strongly suggested ischemic cardiomyopathy, and an electrocardiogram (BCG) that
documented rapid atrial fibrillation. In fact, the cardiologist plaQ.Ded to start treating the
subject for heart failure ("begin Cardizem, aspirin and Fosinopril") and the subject was
also being treated for his arrhythmia (the CRF for concomitant medication during cycle
1-2 reported that the subject was, receiving Metoprolol).
In your written response, you denied these allegations and stated that you were unable to
respond to the specific allegations above because you do not have access to the referenced
data. In addition, you denied falsifying, altering, or manipulating patient data to enroll
ineligible subjects in any research study. Further, you claimed that when you became aware
that Mr. Kornak had falsified data, you alerted the IRB and ofthe misconduct. Your
response is inadequate. Available documentation ipdicates that these subjects were clearly
not eligible for enrollment. Yet, you allowed these ineligible subjects to participate in the
study placing them at increased risk of harm. In addition, you stated in your written response
that you were responsible for "100% of the inpatient care of Oncology patients" and "100%
responsible for the clinical studies." ,
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3) You repeatedly or deliberately submitted false information to the sponsor in a required
report [21 CFR 312.70(a)].
For at least five protocols, source documents were altered and false infonnation was recorded
on the CRF. In almost all cases, the changes made it appear thatineligible subjects were
eligible for studies, that protocol-required evaluations were done when they were not, or that
protocol-required timeframes were met when they were not.
a. Protocol required that hematology and chemistry labs be done within 8
days ofinitiation of study drug. Subject" (2352) began study drug on 2/22/01.
Source documents indicate that hematology and chemistry labs were done on 2/13/01
(minus 9 days), but the CRF indicates they were done on 2/15/01 (minus 7 days).
b. Protocol required, that a computed tomography (CT) ofthe thorax be
done 8 weeks after initiation of study drug. Subject (2551) began the study drug on
2/1/01. Source documents indicate that a CT of the thorax was done on 3/16/01 (plus 6
weeks), but the CRF indicates that the procedure was done ~n 3/29/01 (plus 8 weeks).
c. Protocol excluded subjects with creatinine> 1.75 mg/dL, creatinine
clearance 60="" ml/min,="" ast=""> 85 U/L, total bilirubin> 1.0 mgldL, and alkaline
phosphatase =:: 340 U/L. Source documents for subject. (2553) indicate that he had
multiple abnormal laboratory values that should have excluded him from enrollment in
the study: creatinine (1.9 mgldL), creatinine clearance (41 ml/min), AST (99 U/L), total
bilirubin (1.9 mgldL), and alkaline phosphatase (378 U/L). The CRF, however, indicates
that creatinine (1.3 mgldL), creatinine clearance (603 ml/min), AST (39 U/L), total
bilirubin (0.9 mgldL), and alkaline phosphatase (208 U/L), were all acceptable for
enrollment in the study..
d. Protocol required that subjects have an ECG done within the 14 day
period prior to randomization.
1) Subject. (30704) was randomized on 6/6/00. Source documents indicate that the
ECG was not done until 6/15/00 (after randomization), but the CRF indicates that the
ECG was done on 6/5/00: In addition, the following observation was deleted from the
version ofthe ECG in theCRF: "When compared with ECG of 10-June 200011:38,
premature ventricular complexes (PVCs) are no longer present."
2) Subject" (30712) was randomized on 11/8/00. Source documents indicate that ~
ECG was done on 10/5/00 (over a month before randomization), but the CRF indicates
that the ECG was done on 11/7/00.
3) Subject" (30713) was randomized on 12/19/00.' Source documents indicate that
an ECG was done on 1/11/01 (after randomization), but the CRF indicates that the ECG
was done on 12/17/00.
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4) Subject" (30716) was randomized on 4/17/01. In source documents, there is no
record of an ECG having been done around the time the subject was randomized (the
only ECG in source documents is one done on 12/27/00), but the CRF indicates that an
ECG was done on 4/16101.
5) Subject. (30718) was randomized on 7113/01. The date on a source document for
an ECG done on 6/28/96 was changed to 7/9/01. In addition, the following observations
were removed: "cannot rule out septal infarct (cited on or before 16-Sep-1994),"
"Abnormal ECG when compared with ECG of 16-Sep-1994," and "QRS duration has
increased." In addition, source documents indicate that subject (30718) had a
baseline LVEF (left ventricular ejection fraction) of 47%; however, the CRF recorded
that the LVEF was 50%.
6) Subject. (30719) was randomized on 8113/01. Source documents mdicate that an
ECG was done on 8/15101 (after randomi.zation), but the CRF indicates that an ECG was
done on 8/10/01.
7) Subject. (30720) was randomized on 9/21/01. In source documents, there is no
record of an ECG having been done around the time the subject was randomized. The
ECG in the CRF was originally dated 8/31/00 and was the ECG for another subject. The
date was changed to 9/14/01 and the subject identifier was changed.
e. Protocol required that sUbjects have hematology and chemistry labs done
within the 14 day period prior to randomization.
1) Subject (30708) was randomized on 9/21/00. Source documents indicate that
hematology and chemistry labs were done on 9112/00, but the CRF indicates that labs
were done on 9/14/00.
2) Subject. (30714) was randomized on 12/26/00. Source documents indicate that
hematology labs were done on 12/13100, but the CRF indicates that labs were done on
12/24/00. I
3) Subject" (30715) was randomized on 113/01. In source documents, there is no
record that hematology labs were done around the time ofrandomization, but the CRF
indicates that labs were done on 12126/00.
f. Protocol required that subjects have metastatic prostate adenocarcinoma
unresponsive or refractory to hormone therapy. Prior hormonal therapy had to include
luteinizing hormone-releasing hormone (LHRH) agonists, either alone or in combination
with castration or orchiectomy. If the subject was being treated with LHRH agonists at
the time ofenrollment, that therapy was to be continued. The protocol excluded subjects
with prior isotope therapy. ·Progress notes for subject" (30713) dated 9/01/01 were
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altered to make it appear that" had received LHRH agonists (the antiandrogen drug
Casodex was deleted and the LHRR agonist Zoladex inserted) and to omit the fact that
_ had prior iSQtope therapy ("iodine implantation" was deleted and "radiation
therapy" inserted). Progress notes dated 9/25/00 were also altered to omit a reference to
prior iodine therapy ("iodine seed implant" was deleted and "radiation therapy" inserted)
and to be consistent with the alteration in 9/1/01 progress notes (the LHRH agonist
"Lupron" was deleted and the LHRH agonist "Zoladex" inserted). The
inclusion/exclusion detenninations recorded in the CRF for this participant reflect
reliance on this altered infonnation.
g. Protocol required that subjects have a bone scan within the 21 day period
prior to randomization.
1) Subject" (30713) was randomized on 12/19/00. The date ofthe bone scan in
source documents was 6/20/00 (six months before randomization). In the CRF, this date
was changed to 12/6/00.
2) Subject" (30715) was randomized on 1/3/01. In source documents, there is no
indication that a bone scan was done around the'time ofrandomization, but the CRF
indicates that a bone scan was done on 12/20/00.
h. Protocol (enrolling subjects with histologically diagnosed new or
recurrent low grade superficial bladder transitional cell carcinoma) required a baseline
cystoscopy within the 4 week period prior to randomization, a Transurethral Resection of
the Bladder Tumor (TURBT) within the 12 week period prior to randomization, and a
CT scan, intravenous pyelogram (IVP) 'or retrograde pyelogram within the 12 week
period prior to randomization to rule out an upper urinary tract tumor (malignancy in the
upper urinary tract was a basis for exclusion). Subjects with clinically significant hearing
loss were excluded from the study because the study dru;...c;g"..!,==;- ...
'-:-~:---'has been associated with ototoxicity. Subject (0402) was randomized on
8/21/01. The following documentation for subject appears to have been falsified.
The inclusion/exclusion detenninations recorded in the CRF for this participant reflect
reliance on this altered infonnation:
(1) A cytoscopy and TURBT were done on subject.on 4/19/01 (more than 17
weeks before randomization). The Operative Note was altered, making it appear
that the procedures were done within the protocol-specified timeframe: the date
was changed from 4/19/01 to 7/19/01 and the following observation was inserted
in a font that is different from the remainder of the document: "Retrograde
pyelogram revealed no abnonnality ofthe upper urinary tract." The dates on two
pathology reports from specimens obtained during previous cystoscopies were
also altered. The original reports were dated 4/11/00 and 4/19/01 and the altered
versions were dated 7/11/01 and 7/19/01, respectively.
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(2) A report for a 7/12/01 "urethrocystogram retrograde S & I" was altered. The
dates and subject identifiers on another person's report were changed, making it
appear as though the report was for a study perfonned on subject
(3) A report for a 7/21/01 intravenous pyelogram was altered. The dates and subject
identifiers on another person's report were changed, making it appear as though
the report was for a study performed on subject
(4) A 7/13/01 audiology report was altered to delete observations about clinically
significant hearing loss. The following statements were deleted:
• "Patient was counseled regarding hearing aids; he is reportedly not
interested at this time."
• "Patient will consider binaural amplification."
i. Protocol required that a com lete blood count be done within the 12
week period prior to randomization. Subject (0273) was randomized on 1/25/01.
The hematology report contained in source docwnents is dated 12/18/00. Although th.e
labs were done within the protocol specified time frame, the date ofthe report in the CRF
was changed to 1/25/01.
j. Because the study drug, has been associated with
proteinuria (ranging from clinically silent, transient, trace proteinuria to nephrotic
syndrome), Protocols _ and required that subjects be tested for
protein in the urine by dipstick uri.D.alysis at screening. SubjeCts who tested positive e.
1+) were required to undergo 24 hour urine collection prior to enrollment; those with
greater than 500mg ofurinary protein/24 hours were excluded from the study. The
protocol also required that subjects be monitored for proteinuria every 2 weeks by
dipstick urinalysis. Subjects who developed new proteinuria or an exacerbation of
preexisting proteinuria were required to undergo 24 hour urine collection. Subjects with
greater than 2 g urinary protein/24 hours that did not resolve over an appropriate time
were to be discontinued from the study and considered for renal biopsy. Urine dipstick
results reported on the CRFs differed from those in source documents as follows:
(1) Source documents indicate that subject (11281) in protocol 1...-__--"
tested 1+ for urine protein at.screening, but the CRF indicates that the subject
tested negative and was not further evaluated for proteinuria (i.e., did not undergo
the required 24 hour urine collection). Source documents also indicate that the
subject was not tested for urine protein on day 14 of Cycle 2, but the CRF
indicates that the subject tested negative.
(2) Source documents indicate that subject" (11282) in protocol 1...-__--"
tested 1+ for urine protein on day 14 and day 28 ofCycles 2 and 3, but the CRF
indicates that the subject tested negative on each ofthese dates. Source
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documents also indicate that the subject tested 2+ on day 28 of Cycle 5, but the .
CRF indicates that the Cycle 5/day 28 test was not done.
(3) Source documents indicate that subject I (9711) in protocol
,~~.-......~- was not tested for urine protein at day oand day 28 of cycle 2, but the CRF
indicates that the subject tested negative and trace on day 0 and day 28 of cycle 2,
respectively.
In your written response, you denied these allegations and stated that you were unable to
respond to the specific allegations above because you do not have access to the referenced
data. Your response is considered inadequate.
4) You failed to conduct the studies or ensure they were conducted according to the
approved protocols [21 CFR 312.60]. .
a. Protocol excluded subjects with impaired liver and renal
function. You randomized subject (2553) to the study despite laboratory results that
indicated significant renal and hepatic dysfunction: creatinine (1.9 mg/dL), creatinine
clearance (41 ml/min), AST (99 U/L), total bilirubin (1.9 mg/dL), and alkaline
phosphatase (378 UIL). You subsequently dosed this subject with a nephrotoxic study
drug that may have contributed to his death (see violation 2).
b. Protocol excluded subjects with serious cardiac arrhythmia requiring
medication. Subject (9715) was enrolled despite an echocardiogram that strongly
suggested ischemic cardiomyopathy, an ECG that showed rapid atrial fibrillation, and the
qardiologist's stated intent to start treatment with Cardizem, aspirin and Fosinopril. The
CRF for concomitant medication during cycle 1-2 also reported that the subject was on
Metoprolol (see violation 2). .
c. Protocol excluded subjects with previous or recurrent malignancies
other than gastric carcinoma. Subjects (2352) and :(2555) were enrolled
despite histories of colon cancer.
d. Protocol required that ECGs be done on study subjects at the end ofthe
study. You failed to obtai]} the required end-of-study EeGs for 15 of23 subjects (30701,
30703,30706,30709,30711-30713,30715-30721, and 30723) enrolled in the study.
e. Protocol required that multiple gated acquisition-left ventricle ejection
fraction (MUGA-LVEF) evaluations be done at the end ofthe study for all subjects
enrolled. You failed to obtain the required end-of-study MUGA-LVEF for 14 of23
subjects(30701,30703,30705, 30706,30708, 30709, 30712,30713,30715,30717,
30718, and 30721-30723) emolled in the study.
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
Page 12 -- James A. Holland, M.D.
f. Protocol required clinical tumor assessments at baseline and every 3
weeks after initiation of the study drug. You failed to perform one or more of the
required tumor assessments for 8 of23 subjects (30702, 30711, 30712, 30715, 30718,
30719,30721, and 30722) enrolled in the study.
g. Protocol required bone scans at baseline, weeks 12,21,30 and at the
end-of-study. You failed to obtain one or more ofthe required bone scan assessments for
10 of23 subjects (30703, 30704, 30711-30713, and 30718-30722) enrolled.
h. Protocol excluded subjects with clinically signifi~ant hearing loss.
Subject" (0402) was randomized on 8/21/01 despite a 7/13/01 audiogram that
reported bilateral sensorineural hearing loss and recommended use of a hearing aid, and
subject complaints of tinnitus and difficulty hearing background noise.
1. Because of the risk ofproteinuria associated with the study drug, protocols "--__-J
and _ required that subjects be tested for urine protein by dipstick urinalysis at
screening and that they have a 24 hour urine collection prior.to enrollment ifurine protein
was ~ 1+.
1) Subject" (11281) was enroiled inprotocol_after testing positive (1+)
for urine protein by dipstick, but a 24 hour urine collection was not done for this subject
(see violation 3).
2) Subject" (9714) was enrolled inprotocol_after testing positive (1 +)
for urine protein by dipstick, but a 24 hour urine collection was not done for this subject.
j. Protocol required that the dose of study drug be adjusted only if a
subject's weight changed by at least 10%. The dose for subject (9711) was adjusted
despite a weight change of less than 10%.
k. Protocol required that enrolled subjects have colorectal cancer with
evidence ofmetastases. Subject" (9714) was enrolled despite having no
documented evidence ofmetaStases.
1. Protocol excluded subjects with a history of malignancy other than
non-small cell lung cancer within the preceding 5 years, except for basal cell carcinoma
ofthe skin or carcinoma in situ of the cervix. Subject (20371) was enrolled despite
a diagnosis of squamous cell carcinoma of the ear.
m. Protocol excluded subjects with mild to moderate hepatic insufficiency.
Subject. (1438) was enrolled despite evidence ofhepatic insufficiency (SGOT,
SOPT, and alkaline phosphatase were all elevated).
•
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b)
(6)
(b) (6)
(b) (6) (b) (6) (b) (6)
(b) (6)
Page 13 -- James A. Holland, M.D.
n. Protocol RP _ required that all serious adverse events during the study
period, whether or not considered to be related to study treatment, be reported to the
sponsor within 24 hours or, at the latest, on the following day.
(1) Subject. (2556) was last administered study drug on 9/17/02 and died on
'---_...... The death was not reported to the sponsor until 11/5/02.
(2) Subject. (2553)was last administered study drug on 6/5/01 and died on
The death was not reported to the sponsor until 6/14/01.
o. Protocol required that serious adverse events be reported to the sponsor
"immediately" upon discovery ofthe event, whether or not the events were unexpected or
considered to be associated with the use of the study drug. Subject. (1438) was last
administered study drug on 3/9/02 and died on . The death was not reported to the
sponsor until 7/15/02.
In your written response, you denied these allegations and stated that you were unable to
respond to toe specific allegations above because you do not have access to the referenced
data. Your response is considered inadequate.
5) You failed to lQ.aintain adequate and accurate case histories that record all observations
and other data pertinent to the investigation on each individual [21 CFR ~12.62(b)].
a. For protocol , there were different heights and weights reported in source
records for subject (30704). Due to these conflicting measurements, the subject's
body surface area was incorrectly calculated and the subject received an incorrect dose of
the study drug.
b. For protocol , you failed to complete the CRF for study drug administration
between 6/4/02-10/10/02 for subject" (11282). .
c. For protocol "-- .....,
administration for subjects
, you failed to complete the CRF for study drug
(9713),. (9714) and"(9715).
d. For protocol '---__~----J' you failed to complete the CRF for subject. (1438).
In your written response, you denied these allegations and stated that you were unable to
respond to the specific allegations above because you do not have access to the referenced
data. Your response is considered inadequate.
Your request for a hearing must be made, in writing within ten (10) business days after receipt of
this letter, and should be directed to Fredric 1. Richman, Director, Division of Compliance
Management and Operations (HFC-21 0), Office of Enforcement, ORA, FDA, 15800 Crabbs
Branch Way, Rockville, MD 20855, Telephone (240) 632-6862, FAX (240) 632-6859. Uno·
Page 14 -- James A. HoUand, M.D.
response to this letter is received by that time, you will be deemed to have waived any right to a
regulatory hearing, and a decision iIi these matters will be made based on the facts available to
FDA. No hearing will be held.
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 had been
raised by the material submitted. A hearing will not be granted on issues ofpolicy or law.
Written notice of a determination ofsummary judgment will be provided, explaining the reasons
for denial of the hearing.
Ifyou wish to respond but do not desire a hearing, you should contact Mr. Richman 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 thai you want a decision on the matter to be
based on your written response and other information available to FDA.
FDA's offer to enter into a consent agreement, attached to the NIDPOE dated September 22,
2004, remains available. Entering into a consent agreement would tenninate the disqualification
proceeding, but would not preclude the possibility of a corollary administrative or judicial
proceeding.
No final decision by FDA has been made at this time on your eligibility to continue to receive
investigational new drugs. Moreover, there will be no prejudgment of this matter ifyou 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 infonnation currently available to FDA.
Please inform Mr. Richman within ten (10) business days ofwhether you wish to request a
hearing or to have this matter resolved by consent agreement or infonnation available to FDA.
~::.A
~~£O'KGlavm
As . te Commissioner
for Regulatory Affairs