Warning! Warning! Warning! Letters Learning Tools (for Investigators and others)
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Transcript of Warning! Warning! Warning! Letters Learning Tools (for Investigators and others)
Warning! Warning! Warning! Letters
Learning Tools
(for Investigators and others)
“Public” Learning Tools
Warning Letters– By Erich Jensen
Project Manager Center for the
Advancement of Clinical Research [CACR]
Determination Letters– By Judy Nowack
Associate Vice President Office of the Vice
President of Research [OVPR]
Presentation Outline
FDA Warning Letters– Process– Location– Case Studies
OHRP Determination Letters– 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]
S _______ M ______ ______ A _____ to _______ L ____ __________ ________ L et FDA Inspect
__P__ _______ _______ R etain Records I _____ _______ N ____ _ _ _ T ____ ______
upervise
aintain Recordsdhere Protocolearn Investigator’s Brochure
Re ort Adverse Events
nform Subjects
otify I R Brain Staff
The Essential GCP Document
1. Select Site
2. Contact Site
3. Schedule Site
4. Arrive (482)
5. Review Records
6. Interview Staff
7. Present Findings
8. Depart (483)
9. Write Report (EIR)
10. Classify Inspection
FDA Office Site Location
“FDA Inspector Cometh” Process
Step 10. FDA classifies Inspection
• When evaluation is completed, FDA classifies inspection and sends a letter to site
Classification Type of Letter
NAI (No Action Indicated) Notice of no significant deviations
VAI (Voluntary Action Indicated)
Informational
OAI (Official Action Indicated)
Warning
FDA Warning Letters (WL)
A post FDA inspection document– 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
“You failed to obtain a signed investigator statement, Form FDA 1572.”– from all investigators prior to permitting them to
begin participation in the investigation.”
“You failed to provide a complete list of the sub-investigators.” – 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
S _______ M ______ ______ A _____ to _______ L ____ __________ ________ L et FDA Inspect
__P__ _______ _______ R etain Records I _____ _______ N ____ _ _ _ T ____ ______
upervise
aintain Recordsdhere Protocolearn Investigator’s Brochure
Re ort Adverse Events
nform Subjects
otify I R Brain Staff
PeopleIssues
WL (27 Sep 02): Bear, MD, PhD
How many times are the following “people issues” mentioned?– “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
S upervise– “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…”
T rain staff– “…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
“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)
A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that
the Data and Reported Results are Credible, and Accurate,
and that
the Rights, Integrity, and Confidentiality of Trial Subjects are Protected.
= the safety and efficacy of the study drug
= 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
Center for Devices and Radiologic Health [CDER]
Michael
Gruber
New York University Medical Center
Center for Biologics Evaluation and Research [CBER]
Alkis
Togias
John Hopkins Asthma & Allergy Center
Center for Drug Evaluation and Research [CDRH]
What are the 1572 issues in each case?
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]
Inform Subject– “…informed consent document…does not identify foreseeable risks…”
Notify IRB– “…failed to submit the sponsor’s model consent form … to the Magee-
Womens Hospital IRB…” Adhere to Protocol
– “…log forms were not completed…in specific dates.” Report Adverse Events
– “irritation or discomfort…was not recorded on …case report forms.” Maintain Records
– “You did not maintain complete records related to each…case history.”
Michael Gruber: NYU [Biologics]
Maintain Records– “…failed to prepare and maintain…accurate case histories…”
AND “…lack of source data…” Retain Records
– “…failed to retain investigational records.” Adhere to Protocol
– “…there were many deviations from the protocol requirements…”
Supervise– “…nurse practitioner was not listed on the Form FDA-1572 as
subinvestigator,…”
Alkis Togias: John Hopkins [Drug]
Significant Issues– “… an investigation into the death of a healthy
volunteer…”– “You failed to submit an IND…”
Alkis Togias: John Hopkins [Drug]
Learn Investigator’s Brochure– “…you also failed to submit supporting data…”
Notify IRB– “You failed to notify and obtain IRB approval…”
Report Adverse Events– “…you failed to promptly report…unanticipated problems…”
Adhere to Protocol– “You changed the dosing conditions set forth in the protocol…”
Inform Subjects– “…the following essential elements…were not included…”
Maintain AND Retain Records– “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 R 02-JUN-2003
For 3 years; restrictions in part, "...will not serve as principal clinical investigator for more than one FDA regulated clinical study per year..."
More info: Dr Togias: John Hopkins
John Hopkins University: www.jhu.edu – JH Medicine Press Releases
http://www.hopkinsmedicine.org/Press_releases/archive.html
– The Gazette On-Line http://www.jhu.edu/~gazette/
– Hopkins Medical News http://www.hopkinsmedicine.org/hmn/
– JH Public Health Magazine http://www.jhsph.edu/Magazine/toc.html
Keyword search: “Ellen Roche” “OHRP”
More info: Dr Togias: John Hopkins
Office of Human Research Protection– Compliance Oversight
OHRP Compliance Activities: Determination Letters– 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)
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
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
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
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
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– 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
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)
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
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– 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
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)
Findings of IRB non-compliance– 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
Office of Human Research Protection– Compliance Oversight
OHRP Compliance Activities: Determination Letters– 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.