Charles J. Coté, M.D.
Massachusetts General Hospital
Department of Anesthesia and Critical Care
55 Fruit Street
Boston, MA 02114
 

Dear Dr.  Coté:

Between April 14 and 30, 2008, Ms. M. Patricia Murphy and Ms. Michelle M. Noe,
representing the Food and Drug Administration (FDA), conducted an investigation and
met with you to review your conduct of the following clinical investigations of the
investigational drug Zemuron® (rocuronium bromide), performed for Organon:

•  Protocol [redacted] entitled, “An open-label, randomized, phase IIIB, multicenter trial to evaluate the pharmacodynamic parameters of intubation bolus, and bolus and infusion maintenance doses of Zemuron® in pediatric and adolescent subjects” and
•  Protocol [redacted] entitled, “A randomized, assessor-blind, dose-ranging, phase IIIB, multicenter trial comparing the intubating conditions and time course of block of three different intubating doses (0.45 mg/kg, 0.6 mg/kg and 1.0 mg/kg) of Zemuron® in pediatric and adolescent subjects under general anesthesia.”

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 May 22, 2008 written response to the Form FDA 483, Inspectional
Observations, 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.  Murphy and
Ms.  Noe presented and discussed with you Form FDA 483, Inspectional Observations.
We wish to emphasize the following:

1.  You failed to conduct the studies according to the signed investigator statement
[21 CFR 312.60]. 

When you signed the investigator statements (Form FDA 1572) for the above-
referenced clinical investigations, you agreed to take on the responsibilities of a
clinical investigator.  You specifically agreed to personally conduct, or supervise those
aspects of the study you did not personally conduct, and to ensure that all associates,
colleagues, and employees assisting in the conduct of the study were informed about
their obligations. 

a.  You failed to adequately supervise individuals to whom you delegated study tasks.  The FDA inspection revealed that your supervision of personnel to whom you delegated study tasks was not adequate to ensure that the clinical trials were conducted according to the signed investigator statement and applicable regulations.  Your failure to provide adequate oversight resulted in inadequate informed consent documentation and inadequate and inaccurate records as outlined in items 2 and 3 below.  In your May 22, 2008 response to the Form FDA 483, you stated that although you were personally involved in the study, you did not ensure that the delegated staff were fully trained, and you did not verify their performance as documented in the case report forms (CRFs).  We acknowledge your assurance that corrective actions have been taken to assure  more rigorous documentation. 

b.  Regarding protocol [redacted], you did not list the names of all subinvestigators who would be assisting in the conduct of the investigation, as required by the Statement of Investigator, Form FDA 1572.  The FDA regulations specified that in the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team.  "Subinvestigator" includes any  other individual member of that team [21 CFR 312.3(b)].  During the inspection,  you told the FDA investigator that the protocol-required blinded assessments were  done by residents present in the operating room on the day of surgery.  By  performing these significant study activities, the residents should have been listed on the Form FDA 1572 as subinvestigators.  We acknowledge your assurance that in the future, the individuals who are involved in research-related assessments will be included on a Form FDA 1572. 

2.  You failed to obtain legally effective informed consent [21 CFR part 50 and 21
CFR 312.60]. 

Except as provided in 21 CFR 50.23 and 21 CFR 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.  The information that is given to the subject or the representative shall
be in language understandable to the subject or the representative [21 CFR 50.20]. 
Informed consent must be documented by the use of a written consent form approved
by the institutional review board (IRB) and signed and dated by the subject or the
subject's legally authorized representative at the time of consent [21 CFR 50.27(a)]. 
You also failed to obtain proper assent as determined to be appropriate by the IRB
[21 CFR § 50.55]. 

a.  Fabricated signatures of the subject's legally authorized representative were found
on the consent forms for subjects 114403 and 114601, who were enrolled in
protocol [redacted], and subject 124402, who was enrolled in protocol [redacted].  We
note that you discovered the fabricated signatures through your own internal
audit, and that you sent letters dated September 10, 2007 to the parents of subjects
114403 and 114601, and a letter dated December 11, 2007 to the representatives
of subject 124402, requesting that the informed consent documents be signed
again.  In addition, you promptly reported the findings to the IRB.  In your May
22, 2008 response to the Form FDA 483, you stated that you asked the study
coordinator to ensure that copies of the original, signed consent forms were
placed in the subjects' medical records, according to institutional policy, but you
did not confirm this action.  You stated that had this occurred, you would have
been able to retrieve a copy of the original consent forms.  You stated that it is
presumed that your former research nurse (study coordinator) apparently falsified
the signatures after she lost the original, signed consent forms.  You also stated
that you reported these findings to the Board of Registration in Nursing.  As the
clinical investigator, you are responsible for oversight of study activities
delegated to study staff. 

In your written response you also stated that you took immediate action to contact
the families that had consent forms with apparently false signatures.  You stated
that you was able to reach two out of three and they sent confirmatory signed
statement that they had allowed their child to participate in a research project
prior to study procedure.  You stated that the third family had vacated their
apartment and you were not able to contact them.  You stated that documentation
by the CRO exists to confirm that you did in fact obtain consent from all subject
parents prior to participation in the study on a valid consent form.  We do not find
your response to this observation adequate as it does not include documentation to
support your statements. 

b.  Regarding protocol [redacted], page 5 of the informed consent document asks "Do
you agree to allow your child to have blood samples taken?" followed by a space
for the subject or subject's legally authorized representative to respond by
checking "YES" or "NO" and initial.  However, pharmacokinetic samples were
collected from subjects without obtaining informed consent for blood sampling. 
Examples include, but are not limited to, subjects 114403 and 114503.  We note
that you sent a letter dated December 11, 2007 to the IRB informing the IRB that
these subjects did not consent to blood draw.  In your May 22, 2008 response to
the Form FDA 483, you stated that you will ensure that you are aware of any
options sections included in the body of the consent form.  However, you did not
state how you will ensure that proper consent is obtained. 

c.  Regarding protocol [redacted], the IRB requires that subjects who are 7-13 years old
sign a Research Assent form.  Subject 124501 was seven years old at the time of
consent, but did not sign a Research Assent form prior to being enrolled in the
study.  We note that you sent the subject’s representative a letter dated December
11, 2007 requesting that the subject sign and date a Research Assent form. 
Therefore, you failed to obtain proper assent as determined to be appropriate by
the IRB [21 CFR § 50.55]. 

d.  According to the study records, representatives for subjects 114302 and 114504
were non-English speaking.  The subjects’ representatives signed informed
consent documents written in English rather than a language understandable to the
representatives.  The subjects’ representatives were not provided with either a
translated consent document or a "short form" translated consent document.  We
note that the names of the translators were written on the signed consent
documents.  In your response to the Form FDA 483, you acknowledged that you
failed to provide translated consent documents to these subjects, but stated that
you would train your staff on this requirement so it would not happen in the
future.  We acknowledge your assurance that corrective actions will be taken to
ensure that this finding is not repeated in any future studies. 

e.  Informed consent documents were dated by study personnel rather than the
legally authorized representative for subjects 114302, 114401, and 114504
enrolled in protocol [redacted], and subject 124601 enrolled in protocol [redacted].  In
your May 22, 2008 response to the Form FDA 483, you acknowledged that it was
your routine practice to insert the date yourself, prior to the parents’ signatures, in
order to simplify the process.  You stated that you now know that subjects and
parents must date the consent forms themselves.  We acknowledge your assurance
that corrective actions have been taken to ensure that this finding is not repeated
in any future studies. 

3.  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)]. 

Examples include, but are not limited to, the following:

a.  Regarding protocol [redacted] the primary efficacy parameter was the total dose
from administration of intubating dose to reappearance of T3 after the last
maintenance bolus dose of Zemuron®, or discontinuation of Zemuron® infusion. 
The duration of drug administrations used to calculate the total dose (mg) does
not correspond to the time interval of drug administration recorded on the Train-
of Four Watch (TOF-Watch) source document for the following subjects:

b.  Regarding protocol [redacted], the "Infusion Rate (mL/min)" was not recorded for
the 10 subjects who were randomized and received the infusion maintenance dose
for protocol [redacted].  In your May 22, 2008 response to the Form FDA 483, you
acknowledged you recorded the dose in mcg/kg/min that was obtained from the
computer generated TOF-Watch and did not appropriately calculate the infusion
rate in ml/min. 

c.  The study records indicate that informed consent for subject 114403 enrolled in
protocol [redacted] was obtained on June 2, 2006, and informed consent for subject
124402 enrolled in protocol was obtained on November 30, 2006.  Each
of these informed consent documents contains a signature similar to yours entered
on the line above the statement “Study Doctor or Person Obtaining Consent.”
During the inspection, you stated that the signatures on these documents were not
yours.  In your May 22, 2008 response to the Form FDA 483, you stated that the
signatures on these documents were fabricated.

d.  Regarding protocol [redacted] the "Concentration of Zemuron® Infusion (mg/mL)"
on the source document for the administration of (infusion) maintenance dose was
recorded as "1:1" or "0.5:1" for subjects 114201, 114406, 114505, 114602,
114603 and 114607.  Based on this documentation, the actual drug concentration
is uncertain.  In addition, the concentration on the source document does not
match the concentration reported on the CRF for subject 114501.  In your
response to the FDA Form 483, you stated that your research nurse recorded these
doses.  You also stated that, in the future, you will ensure that staff delegated to
document specific information, such as dilutions, are adequately trained on how
to do so. 

We acknowledge your assurance that corrective actions have been taken to ensure
that the findings in item 3 are not repeated in any future studies. 

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 or will be taking 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,

Leslie K. Ball, M.D.
Director
Division of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research