Transcript Warning! Warning! Warning! Letters

Warning! Warning! Warning! Letters
Learning Tools
(for Investigators and
others)
“Public” Learning Tools
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Warning Letters
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By Erich Jensen
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Project Manager
Center for the
Advancement of Clinical
Research [CACR]
Determination Letters
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By Judy Nowack
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Associate Vice President
Office of the Vice
President of Research
[OVPR]
Presentation Outline
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FDA Warning Letters
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Process
Location
Case Studies
OHRP Determination Letters
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Process
Location
Case Studies
FDA Warning Letters
Process
Location
Cases
“Read the SMALL PRINT of the 1572”
[Investigator Commitments: Box 9]
I agree…to make those records available for inspection
“Read the SMALL PRINT of the 1572”
[Investigator Commitments: Box 9]
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upervise
S _______
M ______
aintain ______
Records
dhere to _______
Protocol
A _____
earn __________
Investigator’s ________
Brochure
L ____
L et FDA Inspect
Re
ort _______
Adverse Events
__P__
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R etain Records
nform _______
Subjects
I _____
otify _I R
N ____
_ B
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rain ______
Staff
T ____
The Essential
GCP
Document
“FDA Inspector Cometh” Process
FDA Office
Site Location
1. Select Site
4. Arrive (482)
2. Contact Site
5. Review Records
3. Schedule Site
6. Interview Staff
9. Write Report (EIR)
7. Present Findings
10. Classify Inspection
8. Depart (483)
Step 10. FDA classifies Inspection
• When evaluation is completed, FDA classifies
inspection and sends a letter to site
Classification
NAI (No Action Indicated)
VAI (Voluntary Action
Indicated)
OAI (Official Action
Indicated)
Type of Letter
Notice of no significant
deviations
Informational
Warning
FDA Warning Letters (WL)
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A post FDA inspection document
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An informal advisory to a firm communicating FDA's
position on a matter but does not commit FDA to
taking enforcement action
http://www.fda.gov/oc/gcp/clinenforce.html
Warning Letter Case: “1572”
Academic Investigator:
Dr. Yu
[U of C, San Diego]
WL (17 Apr 02): Yu, MD, PhD
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“You failed to obtain a signed investigator
statement, Form FDA 1572.”
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from all investigators prior to permitting them to
begin participation in the investigation.”
“You failed to provide a complete list of the
sub-investigators.”
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who assisted you in the conduct of the
investigation.”
Warning Letter Case:
“S upervise” and “T rain Staff”
Academic Investigator:
Dr. Bear
[Virginia Commonwealth
University]
1572 Commitments: Box 9
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upervise
S _______
M ______
aintain ______
Records
dhere to _______
Protocol
A _____
earn Investigator’s
L ____
__________ Brochure
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L et FDA Inspect
Re
ort _______
Adverse Events
__P__
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R etain Records
nform _______
Subjects
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otify _I R
N ____
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rain Staff
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WL (27 Sep 02): Bear, MD, PhD
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How many times are the following “people
issues” mentioned?
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“Not qualified,” “inexperienced,” “unauthorized”
Need to “retrain,” “monitor,” “supervise”
http://www.fda.gov/foi/warning_letters/g3537d.
htm
WL (27 Sep 02): Bear, MD, PhD
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S upervise
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“It is your responsibility to
monitor all personnel…”
“There are several examples
of…reports that were not
signed or dated by you or a
subinvestigator responsible to
you.”
“…please explain how you will
supervise study staff to
ensure…”
“Your response is therefore
inadequate to explain how a
different person was granted
the authority to…”
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T rain staff
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“…individuals who have
prepared study drugs have
not been registered
pharmacists qualified by
training and experience…”
“…visits were conducted by
personnel not medically
qualified to evaluate the
subject’ disease status,…”
“…attributes these errors to
the “initial inexperience” of
the person who…”
WL (27 Sep 02): Bear, MD, PhD
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“These errors reflect a pattern of insufficient
training and experience that may impact the
safety and welfare of subjects, and the ability
to determine the safety and efficacy of the
study drug.”
Good Clinical Practice (GCP)
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A standard for the design, conduct, performance,
monitoring, auditing, recording, analyses, and reporting
of clinical trials that provides assurance that
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the Data and Reported Results are Credible,
and Accurate, = the safety and efficacy of the study drug
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and that
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the Rights, Integrity, and Confidentiality of Trial
Subjects are Protected.
= the safety and welfare of subjects
Warning Letter Cases:
SMALL PRINT Issues
Academic Investigators
 Dr Mitchell Creinin
 Dr Michael Gruber
 Dr Alkis Togias
Academic Investigator Cases
Investigator
School
FDA Inspectors
Mitchell
Creinin
University of
Pittsburgh School of
Medicine
New York University
Medical Center
Center for Devices
and Radiologic
Health [CDER]
Center for Biologics
Evaluation and
Research [CBER]
John Hopkins
Asthma & Allergy
Center
Center for Drug
Evaluation and
Research [CDRH]
Michael
Gruber
Alkis
Togias
What are the 1572 issues in
each case?
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S upervise
M aintain Records
A dhere to Protocol
L earn Investigator’s Brochure
L et FDA Inspect
Re P ort Adverse Events
R etain Records
I nform Subjects
N otify IRB
T rain Staff
The Essential
GCP
Document
Mitchell Creinin: Pittsburgh [Device]
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Inform Subject
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Notify IRB
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“…log forms were not completed…in specific dates.”
Report Adverse Events
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“…failed to submit the sponsor’s model consent form … to the
Magee-Womens Hospital IRB…”
Adhere to Protocol
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“…informed consent document…does not identify foreseeable
risks…”
“irritation or discomfort…was not recorded on …case report forms.”
Maintain Records
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“You did not maintain complete records related to each…case
history.”
Michael Gruber: NYU [Biologics]
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Maintain Records
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Retain Records
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“…failed to retain investigational records.”
Adhere to Protocol
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“…failed to prepare and maintain…accurate case histories…”
AND “…lack of source data…”
“…there were many deviations from the protocol
requirements…”
Supervise
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“…nurse practitioner was not listed on the Form FDA-1572 as
subinvestigator,…”
Alkis Togias: John Hopkins [Drug]
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Significant Issues
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“… an investigation into the death of a healthy
volunteer…”
“You failed to submit an IND…”
Alkis Togias: John Hopkins [Drug]
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Learn Investigator’s Brochure
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Notify IRB
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“You changed the dosing conditions set forth in the protocol…”
Inform Subjects
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“…you failed to promptly report…unanticipated problems…”
Adhere to Protocol
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“You failed to notify and obtain IRB approval…”
Report Adverse Events
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“…you also failed to submit supporting data…”
“…the following essential elements…were not included…”
Maintain AND Retain Records
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“You failed to systematically record..” “No records were available…”
FDA Restricted List
[http://www.fda.gov/ora/compliance_ref/bimo/restlist.htm]
Name Address
Center Type
Action
Date
Comments
ALKIS TOGIAS, MD
BALTIMORE, MD
CDER
02-JUN2003
For 3 years; restrictions in
part, "...will not serve as
principal clinical investigator
for more than one FDA
regulated clinical study per
year..."
R
More info: Dr Togias: John Hopkins
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John Hopkins University: www.jhu.edu
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JH Medicine Press Releases
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The Gazette On-Line
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http://www.hopkinsmedicine.org/hmn/
JH Public Health Magazine
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http://www.jhu.edu/~gazette/
Hopkins Medical News
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http://www.hopkinsmedicine.org/Press_releases/archive.html
http://www.jhsph.edu/Magazine/toc.html
Keyword search: “Ellen Roche” “OHRP”
More info: Dr Togias: John Hopkins
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Office of Human Research Protection
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Compliance Oversight
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OHRP Compliance Activities: Determination Letters
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Jul 19, 2001 (Suspends Multiple Project Assurance)
– Jul 23, 2001 (Reinstates Multiple Project Assurance)
– Oct 03, 2001 (First Monthly Report)
– Aug 23, 2002 (Follow-up Site Inspection and Restriction
Removal)
OHRP Determination Letters
Process
Location
Cases
Office for Human Research
Protections (OHRP)
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Administratively located in the Office of the
Assistant Secretary of HHS
Implements 45 CFR 46 (Subparts A, B, C, D)
Interprets the Common Rule
Relationship of OHRP to UM
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Federal Wide Assurance (FWA)
UM would be subject to Federal regulation even
without FWA
FWA allows multiple submissions under one
University certification
FWA grants OHRP special compliance authority
OHRP looks at the Institution
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OHRP holds the institution responsible for the
conduct of its agents, but does not take direct
action against those individual investigators who
are conducting research under the university’s
auspices
In this regard, it differs from FDA
OHRP Compliance Procedures
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OHRP evaluates all written allegations or
indications of noncompliance with HHS regulations
from any source.
OHRP initiates a compliance oversight evaluation
by writing to the “Institutional Official”
At UM, the Institutional Official is Fawwaz Ulaby,
the Vice President for Research
Contents of a letter from OHRP
initiating a compliance action
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Description of the apparent or alleged noncompliance
with reference to 45 CFR 46.
Except in rare instances in which there is a need to act
immediately, OHRP allows the institution to conduct an
investigation and report the results.
Request for ALL institutional documents associated
with a protocol.
Request for an institutional response within 30 or 60
days.
Request for a “corrective action plan” if the institutional
finds noncompliance anywhere in the study.
After Receiving a University Response
OHRP evaluates report
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May ask for more information
May conduct site visit
May make non-compliance determinations
May require specific actions or institutional
development of a “corrective action plan”
OHRP compliance close-out letters
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Are posted to the web, whether non-compliance
found or not.
(http://ohrp.osophs.dhhs.gov/compovr.htm)
Communications TO OHPR are available under
FedFOIA, but only the communications FROM
OHRP are posted
Letters may include “reminders” to institutions of
interpretations OHRP has previously made
Case 1: JHU (Dr. Rolley E. Johnson)
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Clean bill of health - but still damaging because
the posting of a letter implies wrongdoing
Notice that complaint is not specified
(Notice the list of cc’s - almost as long as the letter
itself)
Case 2: TJU and Willis Eye Hospital
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Ultimate determination after several communications
No federal funding source
Non-compliance not itemized in this one
Letter emphasizes corrective action for this research
and for the entire research compliance program
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Contacting all subjects of this research
Campus-wide audit of research that might not have undergone
review
Education plan
Policies and Procedures, more support for IRB
Suspension and re-review of 268 protocols
Case 3: Mass General Hospital
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Non-compliance issues specified in particular
research study AND on the part of the IRB
Funded by HHS
Acknowledgment of Corrective Action already
taken regarding
“Additional guidance” provided
Case 4: JHU (Lead paint abatement)
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Findings of IRB non-compliance
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Improper use of expedited review
Improper approval of informed consent document
Inadequate expertise on the IRB
OHRP acknowledges corrective actions.
Reminder: Dr Togias: John Hopkins
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Office of Human Research Protection
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Compliance Oversight
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OHRP Compliance Activities: Determination Letters
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Jul 19, 2001 (Suspends Multiple Project Assurance)
– Jul 23, 2001 (Reinstates Multiple Project Assurance)
– Oct 03, 2001 (First Monthly Report)
– Aug 23, 2002 (Follow-up Site Inspection and Restriction
Removal)
Summary: Determination Letters
Not always determinations of non-compliance.
Of interest in terms of current OHRP interpretations - recognizing that you are getting only one side of
the story
Actions/corrective actions taken by the institutions;
although the institution may require actions by the
investigator.