Lessons Learned from FDA

Warning Letters
Partners Human Research Quality Improvement Program
QUICK BITE Series
September 2, 2004

Lessons Learned from FDA
Warning Letters
What is a warning letter?
Why should you care if you are not
conducting FDA-regulated research?
What are the common violations cited by
the FDA?
How can you avoid/correct these
violations?
What is an FDA Warning
Letter?
Letter issued by the FDA, citing violations
identified during its routine or for-cause
audit of investigators/study sites. It usually
requires immediate response that includes
corrective actions from the investigator.
Sample Warning Letter
Sample Warning Letter
Why should you care if you are not
conducting FDA-regulated research?
Similar requirements
FDA requirements vs. Partners requirements
Similar violations
FDA warning letter citation vs. QI Program
onsite review common findings
You may be audited by the FDA even
though you are not conducting an FDA-
regulated study
What are the common
violations cited by the FDA?
Informed consent
Investigator responsibilities
Protocol deviations
Study records
IRB approval
Regulatory documentation
Informed Consent
Dating the consent form
FDA Citations
You did not ensure that subjects
dated their signature on the consent
form. Your study coordinator
recorded the date of signature on the
consent form for subjects.
You did not ensure that the
subjects brother dated his
signature to indicate when he
provided written consent for the
subjects study participation.
Subjects signing the informed
consent in most cases did not
complete dates. It appears that the
study coordinatorcompleted the
date.
You did not ensure that the
witness dated the signature.
Subject signed the consent
form on [redacted];
however, the witness signed
the consent on [redacted].
Informed Consent
Dating the Consent Form
How to avoid and correct
Do not date for subjects
All individuals MUST sign AND date the
consent form for themselves
If someone forgets to date the consent form,
write a signed and dated note to file explaining
how and when the subject was consented
Write a signed and dated note to file
explaining why dates are different
Informed Consent
Copies of the Consent Form
You failed to provide
study subjects with a copy
of their signed informed
consent document.
There was no documentation that
subjects who were enrolled in this
study received informed consent.
The original consent forms could
not be located for 18subjects
enrolled in the study. Copies were
available in study binders and
subject charts.
FDA Citations
Informed Consent
Copies of the Consent Form
Always give subjects a copy of
the signed and dated consent form
Document that this was done!
Always maintain the original signed and
dated consent form in the subject file
How to avoid and correct
Investigator Responsibilities
You did not personally conduct
or supervise this study.
Staff who were delegated the
authority to perform certain functions
were not adequately credentialed,
trained, or monitored.
You misrepresented your presence
at the institution by signing and
dating source documents and
consent forms on days you were, in
fact, absent from the institution.
We also note that during the inspection,
you admitted that you are conducting many
studies that you are not able to remember
all of them. This suggests that you are not
as involved as we would expect of a
principal investigator.
FDA Citations
Investigator Responsibilities
Stay involved
Give yourself credit document your involvement
Only delegate responsibilities to appropriate
individuals who are qualified and trained
Maintain documentation of training for all staff
ALL study staff must be approved by the IRB!

How to avoid and correct
Protocol Deviations
You did not conduct certain
follow up visits or document efforts
to locate missing subjects.
Numerous assessments were
not completed as required by
the protocol.
The cholesterol profile testing
was not done for subject.
Physical exam at six months was not
done for subject.
An ultrasound was not done at six
months for subject.
FDA Citations
Protocol Deviations
Report ALL protocol deviations to the IRB
according to the reporting guidelines, which can
be found at http://healthcare.partners.org/phsirb/prodevex.htm
Develop and implement an adequate corrective
action plan to avoid future deviations
Amend the protocol if necessary
How to avoid and correct
Study Records
Incomplete/Inaccurate Records
FDA Citations
There was no supporting
datato confirm information
contained in their case histories
to demonstrate their eligibility
Number of discrepancies were noted
between source documents and data
recorded on the CRFs[CRF] indicates
that a pericardial effusion was present, but
echocardiogram reportstates that no
pericardial effusion was present.
The CRF contained blank
fields.
There is no record of who
administered the study drugWithout
a record of who administered the study
drug, you cannot assure that these
injections were performed by a
member of the blinded study team.
Source data for various
assessments could not be
located.
Study Records
Incomplete/Inaccurate Records
All information entered on a CRF or data collection
sheet must be supported by source documents
A signed and dated note-to-file can be used to
explain:
How information was obtained
Who obtained information
Any discrepancies
Missing or incomplete data
How to avoid and correct
Study Records
Poor Quality
All medical records/case
reports audited had numerous
write-over corrections which
lacked dates and initials.
Entries were obscured by correction fluid.
There is no documentation
of the name or initials of the
person making entries in the
records.
Recordswere written in
pencil, and many entries
are illegible.
FDA Citations
Study Records
Poor Quality
Never obscure the initial entry
Use a single line to cross-out the incorrect
information; enter the correct information next
to it, and initial and date the change
Always use ink to enter data
Sign/initial and date ALL entries
How to avoid and correct
IRB Requirements/Approval
Your IRB requires that a written
report of the death of any research
subject be made within 5 business
daysfive or more subject deaths
have not been reported to the IRB.
Revised case report forms identifying
additional data to be collected, for
which IRB approval was not
documented, were used after initiation
of the study.
You failed to obtain IRB
approval for the media
advertisements used to recruit an
enroll subjects for the protocol.
You failed to ensure IRB approvalfor
the duration of the clinical study. Study
records document that [you performed
study procedures] after the IRB
withdrew its approval and informed you
that your appeal for continued approval
was denied.
FDA Citations
IRB Requirements/Approval
Obtain IRB approval prior to initiating study
Obtain IRB approval for any changes made
during the course of the study
Do not allow study to lapse. Submit
continuing review at least 45 days prior to
expiration
Report all adverse events to the IRB according
to Partners guidelines:
http://healthcare.partners.org/phsirb/adverse.htm
How to avoid and correct
Regulatory Documentation
The sponsor provided a log sheet, on which all
study personnel are required to provide their
signature, initials, title, responsibility for the
study, and start and stop dates. The log is
incomplete in that the start and stop dates were
not recorded for several of the study personnel.
The Form FDA-1571, dated August 22,
1996, lists Dr. [redacted] the principal
investigator for the study, as the monitor.
No record was available during the
inspection to document any monitoring by
Dr. [redacted].
FDA Citations
Regulatory Documentation
How to avoid and correct
Maintain all essential documents as required
by section 8 of the ICH GCP Guidelines
Use the QI Program Self-Assessment
checklist to ensure compliance
How can you avoid/correct
these violations?
Stay involved
Educate Staff
Delegate responsibility appropriately
DocumentDocumentDocument
Report Report Report
Utilized the QI Program services
Services Provided by the QI Program
Conduct on-site review of your study files to ensure
regulatory compliance and good clinical practice
Provide on-site consultation as you set up new studies or
monitor on-going studies Delegate responsibility
appropriately
Provide an annotated study binder to facilitate proper
documentation
Assist study sites as they prepare for upcoming audits by
FDA, NIH, or other external agencies
Assist study sites in conducting self-assessment