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.
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