Warning Warning Warning Letters

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Warning! Warning! Warning! Letters

• Learning Tools
• (for Investigators and others)

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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

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Presentation Outline

• FDA Warning Letters
• Process
• Location
• Case Studies
• OHRP Determination Letters
• Process
• Location
• Case Studies

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FDA Warning Letters

• Process
• Location
• Cases

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Read the SMALL PRINT of the 1572 Investigator
Commitments Box 9
I agreeto make those records available for
inspection
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Read the SMALL PRINT of the 1572 Investigator
Commitments Box 9
upervise

• S _______
• M ______ ______
• A _____ to _______
• L ____ __________ ________
• L et FDA Inspect
• __P__ _______ _______
• R etain Records
• I _____ _______
• N ____ _ _ _
• T ____ ______

aintain Records
dhere Protocol
earn Investigators Brochure
Re ort Adverse Events
nform Subjects
otify I R B
rain Staff
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FDA Inspector Cometh Process
FDA Office
Site Location
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Step 10. FDA classifies Inspection

• When evaluation is completed, FDA classifies
  inspection and sends a letter to site

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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

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Warning Letter Case 1572

• Academic Investigator
• Dr. Yu
• U of C, San Diego

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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.

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Warning Letter Case S upervise and T rain
Staff

• Academic Investigator
• Dr. Bear
• Virginia Commonwealth University

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1572 Commitments Box 9
upervise

• S _______
• M ______ ______
• A _____ to _______
• L ____ __________ ________
• L et FDA Inspect
• __P__ _______ _______
• R etain Records
• I _____ _______
• N ____ _ _ _
• T ____ ______

aintain Records
dhere Protocol
earn Investigators Brochure
Re ort Adverse Events
nform Subjects
otify I R B
rain Staff
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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

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WL (27 Sep 02) Bear, MD, PhD

• S upervise
• It is your responsibility to monitor all
  personnel
• There are several examples ofreports 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

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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.

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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
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Warning Letter CasesSMALL PRINT Issues

• Academic Investigators
• Dr Mitchell Creinin
• Dr Michael Gruber
• Dr Alkis Togias

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Academic Investigator Cases
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What are the 1572 issues in each case?

• S upervise
• M aintain Records
• A dhere to Protocol
• L earn Investigators Brochure
• L et FDA Inspect
• Re P ort Adverse Events
• R etain Records
• I nform Subjects
• N otify IRB
• T rain Staff

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Mitchell Creinin Pittsburgh Device

• Inform Subject
• informed consent documentdoes not identify
  foreseeable risks
• Notify IRB
• failed to submit the sponsors model consent
  form to the Magee-Womens Hospital IRB
• Adhere to Protocol
• log forms were not completedin specific
  dates.
• Report Adverse Events
• irritation or discomfortwas not recorded on
  case report forms.
• Maintain Records
• You did not maintain complete records related to
  eachcase history.

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Michael Gruber NYU Biologics

• Maintain Records
• failed to prepare and maintainaccurate 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,

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Alkis Togias John Hopkins Drug

• Significant Issues
• an investigation into the death of a healthy
  volunteer
• You failed to submit an IND

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Alkis Togias John Hopkins Drug

• Learn Investigators 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 reportunanticipated
  problems
• Adhere to Protocol
• You changed the dosing conditions set forth in
  the protocol
• Inform Subjects
• the following essential elementswere not
  included
• Maintain AND Retain Records
• You failed to systematically record.. No
  records were available

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FDA Restricted Listhttp//www.fda.gov/ora/compli
ance_ref/bimo/restlist.htm
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More info Dr Togias John Hopkins

• John Hopkins University www.jhu.edu
• JH Medicine Press Releases
• http//www.hopkinsmedicine.org/Press_releases/arch
  ive.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

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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)

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OHRP Determination Letters

• Process
• Location
• Cases

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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

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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

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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 universitys
  auspices
• In this regard, it differs from FDA

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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

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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.

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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

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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

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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 ccs - almost as long as the
  letter itself)

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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

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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

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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.

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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)

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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.