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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Zosa, Noli R., M.D. 6/16/09

   

hhsbluebirdDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
  Rockville, MD 20857

 


WARNING LETTER


CERTIFIED MAIL
RETURN RECEIPT REQUESTED


Ref: 09-HFD-45-06-02

 

Noli R. Zosa, M.D. 
12444 East Washington Boulevard
Whittier, California 90602


Dear Dr. Zosa:


Between October 2, 2008 and October 7, 2008, Ms. Sonya Karsik and Mr. Brian Putz,
representing the Food and Drug Administration (FDA), conducted an investigation and
met with you to review your conduct of a clinical investigation (Protocol #433 entitled
“A Study to Evaluate the Clinical and Microbial Efficacy of 0.6% ISV-403 Compared to
Vehicle in the Treatment of Bacterial Conjunctivitis”) of the investigational drug
besifloxacin hydrochloride ophthalmic suspension (ISV-403), performed for Bausch &
Lomb Incorporated.


This inspection is a part of the FDA's Bioresearch Monitoring Program, which includes
inspections designed to evaluate the conduct of research and to ensure that the rights,
safety, and welfare of the human subjects of those studies have been protected.


From our review of the establishment inspection report and the documents submitted with
that report, we conclude that you did not adhere to the applicable statutory requirements
and FDA regulations governing the conduct of clinical investigations. We are aware that
at the conclusion of the inspection, Ms. Karsik and Mr. Putz presented and discussed with
you Form FDA 483, Inspectional Observations. We wish to emphasize the following:


1. You failed to conduct the study or ensure the study was conducted according to
the signed investigator statement and investigational plan [21 CFR 312.60].


Specifically, 3 of 4 subjects you enrolled failed to meet enrollment criteria.


a. The protocol inclusion criteria required subjects to “have a clinical diagnosis of
acute bacterial conjunctivitis and exhibit purulent conjunctival discharge (crusty
or sticky eyelids) and redness in at least one eye. A minimum score of 1 should be present for discharge and a minimum score of 1 for bulbar conjunctival
injection”.


FDA’s investigation found that Subjects 0154 and 0155 were enrolled and
received the initial dose of investigational drug despite having the ocular
discharge rating of “0 = Absent” for both eyes as documented for both subjects in
the Clinical Assessment portion of the electronic case report form (eCRF).
Specifically,


i) For Subject 0154, the Visit 1-Day 1 portion of the eCRF, documented that the
subject was diagnosed with “Pterygium nasal”. There is no documentation
that this subject had bacterial conjunctivitis as specified by the protocol.
ii) For Subject 0155, the eCRF, pg 36 documented that the subject did not meet
enrollment criteria and the Audit Trail Report generated on February 11,
2008, documented that the subject was diagnosed with “Episcleritis,” one of
the exclusion criteria in the protocol.


b. The protocol exclusion criteria excluded “subjects with suspected viral or allergic
conjunctivitis (i.e, severe itching or acute follicular conjunctivitis), or any other
disease conditions that could interfere with the efficacy and safety evaluations of
the study medication.” Our investigation found that both Subjects 0154 and 0155
had the above exclusion criteria marked as “Yes” on the “Exclusion Criteria
section of the eCRF.


Your explanation provided during the inspection is unacceptable. You stated that
your “system for screening potential study subjects was to see the subject initially,
conduct partial screening, administer the initial dose of study drug, dispense
study medication for home use to the subject, and then send the subject to be seen
by the ophthalmologist within a day or so of the Day 1 Visit to complete the
screening process.” We note that pages 12 and 15 of the protocol specifically
state, “the first Day 1 dose of study medication will be administered in the office
after the initial eye exam and conjunctival culture.”


c. The protocol required subjects to be at least one year of age. The eCRF
documented that Subject 0156 was only 10 months of age at the time of
enrollment. Our investigation found that Subject 0156 was enrolled despite not
meeting the age requirement.


When you signed the Statement of Investigator, Form FDA 1572, you agreed to
the responsibilities of a clinical investigator that included ensuring that the study
is conducted according to the investigational plan and the signed Investigator
Statement, to protect the safety, rights or welfare of the subjects and to comply
with all the obligations of a clinical investigator and all other pertinent
requirements in 21 CFR 312. We remind you that as a clinical investigator, you
retain responsibility for the conduct of the study.


2. You failed to prepare and maintain adequate and accurate case histories that
record all observations and other data pertinent to the investigation on each
individual administered the investigational drug [21 CFR 312.62(b)].


Protocol #433 stated the following:


Clinical data will be entered into electronic Case Report Forms (eCRFs). Data on
eCRFs must correspond to and be supported by source documentation maintained at
the investigational site, unless the site makes direct data entry for which no other
original or source documentation is maintained. In such cases, the site should
document which eCRFs are subject to direct data entry and should have in place
procedures to obtain and retain copies of the information submitted by direct data
entry.


FDA’s investigation found that there was no source documentation at your site to
corroborate data entered into the eCRF for any of the enrolled subjects, nor did we
find documentation regarding which eCRFs were subject to direct data entry, or
which procedures were in place to obtain and retain copies of information submitted
by direct data entry. The following items, for example, were not found in subjects’
files: ophthalmologist assessment reports, visual acuity assessment reports,
laboratory reports, subjects’ medical charts, bacterial and viral culture laboratory
reports for all culture samples collected, and subject’s worksheets documenting daily
administration of study drug. Therefore, we are unable to verify the accuracy of the
data submitted to the sponsor.


3. You failed to maintain documentation of informed consent in accordance with
21 CFR 50 [21 CFR 50.27(a)]


Specifically, 21 CFR 50.27(a) states that except as provided in 21 CFR 56.109(c),
informed consent shall be documented by the use of a written consent form approved
by the IRB and signed and dated by the subject or the subjects’ legally authorized
representative at the time of consent.


FDA’s investigation found that for all four subjects enrolled, you did not document
informed consent by the use of a written consent form approved by the IRB and
signed and dated by the subject or the subject’s legally authorized representative at
the time of consent. The only documentation available at the site to document
informed consent was the date recorded in the Informed Consent Section of the
eCRFs for all four subjects. During the inspection, you stated that you were unable to
locate these records due to the relocation of your office.


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 Tejashri Purohit-Sheth, M.D., at 301-796-3402;
FAX 301-847-8748. Your written response and any pertinent documentation should be
addressed to:


Tejashri Purohit-Sheth, M.D.
Branch Chief
Good Clinical Practice Branch II
Division of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration
Bldg 51, Room 5358
10903 New Hampshire Avenue
Silver Spring, MD 20993

 


Sincerely yours,
{See appended electronic signature page}
Leslie K. Ball, M.D.
Director
Division of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Tejashri Purohit-Sheth
6/16/2009 03:21:33 PM
Leslie Ball
6/16/2009 10:44:19 PM