Warning! Warning! Warning! Letters

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					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]

        upervise
     S _______
    M ______ ______
        aintain Records
    A _____ to _______
        dhere     Protocol
       earn Investigator’s Brochure
     L ____ __________ ________
    L et FDA Inspect

   __P__ Adverse _______
    Re ort _______ Events
                                       The Essential
     R etain Records                  GCP
       nform Subjects
      I _____ _______                  Document

        otify I _ _
      N ____ _ R B
        rain Staff
      T ____ ______
            “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             Type of Letter
NAI (No Action Indicated)   Notice of no significant
                                  deviations
  VAI (Voluntary Action          Informational
        Indicated)
   OAI (Official Action            Warning
        Indicated)
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
P          upervise
         S _______
e       M ______ ______
            aintain Records
o       A _____ to _______
            dhere    Protocol
p         earn __________ ________
         L ____ Investigator’s Brochure
l       L et FDA Inspect
e
I
       __P__ Adverse _______
        Re ort _______ Events
s
s        R etain Records
u          nform Subjects
          I _____ _______
e           otify I _ _
          N ____ _ R B
s           rain ______
          T ____ Staff
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                              T rain staff
    –   “It is your responsibility to        –   “…individuals who have
        monitor all personnel…”                  prepared study drugs have
    –   “There are several examples              not been registered
        of…reports that were not                 pharmacists qualified by
        signed or dated by you or a
                                                 training and experience…”
        subinvestigator responsible to
        you.”                                –   “…visits were conducted by
    –   “…please explain how you will            personnel not medically
        supervise study staff to                 qualified to evaluate the
        ensure…”                                 subject’ disease status,…”
    –   “Your response is therefore          –   “…attributes these errors to
        inadequate to explain how a              the “initial inexperience” of
        different person was granted             the person who…”
        the authority to…”
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, = the safety and efficacy of the study drug
   and that
   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     University of          Center for Devices
  Creinin      Pittsburgh School of   and Radiologic
               Medicine               Health [CDER]
  Michael      New York University    Center for Biologics
  Gruber       Medical Center         Evaluation and
                                      Research [CBER]
   Alkis       John Hopkins           Center for Drug
  Togias       Asthma & Allergy       Evaluation and
               Center                 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
                                       The Essential
     R etain Records                  GCP
      I nform Subjects                Document

     N otify IRB
     T rain Staff
    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    Comments
                                 Date


ALKIS TOGIAS, MD   CDER   R      02-JUN-   For 3 years; restrictions in
BALTIMORE, MD                    2003      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.