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Dialogue on Deviations. Office for the Protection of Research Subjects (OPRS) February 23, 2006. Dialogue on Deviations/Violations/Exceptions. What are our policies Examples of deviations/violations/exceptions that come through OPRS
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Dialogue on Deviations Office for the Protection of Research Subjects (OPRS) February 23, 2006
Dialogue on Deviations/Violations/Exceptions • What are our policies • Examples of deviations/violations/exceptions that come through OPRS • Goal: raise awareness of how many deviations come through each month representing changes from what is set forth in the protocol.
Participants • Jeff Clark • Glenn Siegmann • Caroline Harvey • Dee Maloof • Karen Schulte • Paul Goebel
OPRS: Who we are… • Director, Michele Russell-Einhorn • Deputy Director, Amanda Hammond
OPRS: Who we are… • Systems Administration Team • Pre-Review Team • Post-Activation Team • On-Line/Communications Team
OPRS: Institutions we work with… • DF/HCC Member Institutions: • Beth Israel Deaconess Medical Center • Brigham and Women’s Hospital • Children’s Hospital Boston • Dana-Farber Cancer Institute • Harvard Medical School • Harvard School of Public Health • Massachusetts General Hospital • Affiliated Institutions
OPRS Statistics • November 1-30, 2005 • 31 new protocols received • 111 continuing reviews • 289 amendments • 50 internal adverse events • 160 deviation reports • 300+ IND safety reprots TOTAL = 900+ action items
OPRS Statistics • Deviations filed in January: 195 • Amendments filed in January: 226 • In many cases, deviations should be followed up by amendments.
Goal • While we want to do the best job we can do so that clinical research with human subjects can go forward as safely as possible… • We also have a goal of never receiving one of these letters…
DFCI Guidance on Deviations / Violations and Exceptions • Guide to Human Research Activities • DFCI IRB Manual • Standard Operating Procedures • THESE WILL ALL BE REVISED THIS YEAR
Guide to Human Research Activities • Protocol Deviations • Protocol deviations are changes in the IRB-approved protocol procedures that have the approval of the trial sponsor and the IRB prior to initiation. • All protocol deviations must be submitted to the OPRS on the DFCI IRB Protocol Deviation Form. • Upon receipt, an IRB representative will determine whether the report warrants full review by the IRB or whether it may be noted to the study file. • The PI and contact person are sent a confirmation of receipt, which notes that there will be no further communication unless requests are made by the IRB for further information or changes to the protocol/consent.
Guide to Human Research Activities (cont.) • Protocol Exceptions • Protocol exceptions apply to cases in which a single subject will be entered into a trial even though the subject does not meet the eligibility criteria. • An exception to the IRB-approved entry criteria requires the prior approval of the IRB Chair or Designee (a physician member of the IRB).
Guide to Human Research Activities (cont.) • Requests should be made on the DFCI IRB Protocol Exception Request Form. The report should include: • An explanation of why this protocol is the best choice for this individual • A description of the criteria that make this person ineligible to enroll in this trial • Documentation of approval by the trail sponsor (if there is one) to provide an exception • Protocol exceptions are sent to the IRB Chair/Designee for review upon receipt. Once any conditions for approval are met, the PI, contact person, IRB Chair, pharmacy, nursing, QACT, and MGH representatives are notified via email that the IRB is aware of and has no issue with the proposed exception.
DFCI IRB Manual • Protocol deviations, exceptions and violations requiring full review will include the appropriate forms and any supplemental materials. • All committee members will receive all materials. • These reports are generally reviewed by Panel C. • Panel C does not typically designate reviewers for these types of reports.
DFCI IRB Manual • Protocol Deviations: • Occasionally a request to change a protocol criterion will be made to the IRB chairs. This request is not an amendment to a protocol but a single request to deviate from the protocol as written to accommodate a potential study subject or a subject who is already enrolled in the protocol.
DFCI IRB Manual • Protocol Deviations (cont.): • In these cases, the following will process will take place: 1. The investigator or designated study team member submits a request to deviate from the protocol. This may be done via email, attaching the deviation request form, submitting a completed paper form, and submitting the request through the web based submission process. These requests are processed per the ORPS SOPs. 2. This deviation is referred directly to the IRB chairs/VCs for review and consultation.
DFCI IRB Manual (cont.) • The chairs/VC first determine whether or not either one of them has a conflict of interest with the protocol. If one or both do, they designate reviewers from among experienced IRB members. This will be done on an ad hoc basis. • The chairs/VCs consider the request, its impact on subject safety and make a determination. • The chairs will instruct any follow up or expectations related to this request. The Director/AD is responsible for providing feedback and information to the investigator and study team. • These are recoded in Rex as expedited reviewed and are captured in the expedited review report.
DFCI SOPs:OPRS SOP: Unexpected Events (11/2003) • Definition: • Unexpected Events are unanticipated protocol-related events that may or may not pose additional risks to subjects or others and can include: • DEVIATIONS: Changes in the IRB approved protocol procedures that have the approval of the study sponsor prior to initiation
DFCI SOPs:OPRS SOP: Unexpected Events (11/2003) • Definition of Unexpected Events (cont.): • EXCEPTIONS: Cases in which a single subject will be entered into an IRB approved trial even though this subject does not meet the eligibility criteria. An exception to the IRB-approved entry criteria requires the prior approval of the IRB Chair or designee (a physician member of the IRB) • VIOLATIONS: Accidental or unintentional changes to the IRB approved protocol procedures. This includes changes necessary in order to eliminate apparent immediate hazards to the subject, made without time for prior review by the IRB or approval from the study sponsor.
DFCI SOPs:OPRS SOP: Unexpected Events (11/2003) • Reporting Policy • Any variation from procedures specified within the protocol that (i) results in actual or potential harm to the subject, (ii) alters the potential for study benefit or (iii) has the potential to occur again, must be reported to the IRB within 7 days. The Protocol Violation/Deviation/Exception Report Form should be used.
DFCI SOPs:OPRS SOP: Unexpected Events (11/2003) • IRB Review of Unexpected Events • The committee does not ‘approve’ unexpected events that have already occurred, but determines whether or not the appropriate actions have been taken by the investigator and study team and if follow up is required. When appropriate, the IRB will approve a revision to the study made as a result of such event or may approve an investigator’s proposed corrective action plan. • The IRB will determine whether prospective events are appropriate or not (e.g. deviations and exceptions), based on the risks and potential benefits of the proposed action.
DFCI SOPs:OPRS SOP: Unexpected Events (11/2003) • Violations • VIOLATION REPORT REQUIREMENTS AND REVIEW PROCESSES REQUIRED ELEMENTS OF A VIOLATION REPORT TO THE IRB: 1. Completed DFCI IRB- Protocol Violation Report form. 2. Documentation from the study sponsor (when applicable).
DFCI SOPs:OPRS SOP: Unexpected Events (11/2003) • Violations • REVIEW PROCESS FOR VIOLATIONS: • The PI and contact person are sent an email confirmation of receipt by the OPRS Receptionist, which notes that there will be no further communication unless/until requests are made by the IRB for further information or changes to the protocol/consent. • The ORPS Director/Assistant Director, acting as a voting IRB member, reviews report and determines whether it requires the attention of the full committee or may be ‘noted’ to the file after expedited review (no further action is required). • The SAE/IRB Coordinator enters the information into Rex and either schedules the report for review at an IRB (Panel C) meeting or notes it to the file if no further action is required per expedited review. For those requiring no further action, the original is placed in the protocol’s IRB file and an email is sent to the investigator (PI) and study contact person notifying them of the IRB’s finding.
DFCI SOPs:OPRS SOP: Unexpected Events (11/2003) • Violations • VIOLATIONS SENT FOR FULL IRB REVIEW: • The SAE/IRB Coordinator makes a copy of the report, all supporting correspondence and relevant protocol documents (section of the protocol that has been violated as per the front page of the violation form) for the committee to review. • This material is passed off to the Packet Coordinator for inclusion in the meeting packet. • The SAE/IRB Coordinator retains the original report until after review.
DFCI SOPs:OPRS SOP: Unexpected Events (11/2003) • Review Process for Deviations: • The OPRS Director/Assistant Director, acting as a voting, nonscientist IRB member, reviews report and determines whether it requires the attention of the IRB Chair (or designated medical reviewer) or may undergo review by the OPRS Director/Asst. Director. • Deviations found acceptable by the OPRS Director/Asst. Director are forwarded to the SAE/IRB Coordinator to enter into Rex and notify the PI and contact person. [Requests falling under this category include such changes to protocol procedures that are unavoidable (e.g. subject to be on vacation and miss clinic appointment) and do not pose additional risk to the subject.] • Those requests that require the IRB Chair (or designee) are sent immediately to the IRB Chair (or designee) via email by the OPRS Director/Asst Director. Any changes required are communicated to the PI and contact person via email. • Once any conditions for approval are met, the PI and contact person are notified via email that the IRB is aware of and has no issues with the proposed deviation.
DFCI SOPs: NewDF/HCC SOPs for Clinical Research DANA-FARBER / HARVARD CANCER CENTER STANDARD OPERATING PROCEDURES FOR CLINICAL RESEARCH TITLE: Reporting Unexpected Events (Deviations/Exceptions/Violations) to the DFCI IRB for Approved Protocols SOP #: PM-407 Page: 1 of 1 Applicable Regulations & Guidelines: 45 CFR 46.103(b)(4)(iii) and 21 CFR 56.108(a)(4) Other References: DFCI IRB Protocol Deviation/Violation/Exception Request, The Guide to Human Research Activities Responsible Personnel: DF/HCC Principal Investigators (PI) or study staff designee, Office for the Protection of Research Subjects (OPRS)
DFCI SOPs: NewDF/HCC SOPs for Clinical Research Policy Statement: PIs are responsible for submitting the appropriate form to the IRB in the event that a deviation, violation, or exception occurs. Procedure: 1) Please see The Guide to Human Research Activities posted on the CTEO website: http://www.dfhcc.harvard.edu/clinical-research-support/clinical-trials-education-office-cteo/ 2) A deviation/violation/exception does not need to be reported when it is a minor deviation in scheduling due to a state or federal holiday, inclement weather or circumstances beyond the control of a subject or investigator. Any deviation that is not reported for one of these reasons must be noted in the subject’s medical and research record. Note: This does NOT include conflicts with a subject’s work schedule or planned vacation. 3) Any deviation/violation/exception that might affect the potential risk or benefit to subjects in any way or have any impact on the integrity of the science (e.g. conclusions that can be drawn from the study) must be reported to the DFCI IRB. Original Approval Date: CLINPOC 2/03 Revision Dates: CLINPOC 5/26/05, 1/23/06
Deviations • Subject did not complete questionnaires • Subject did not being treatment within the 14 day period set in the protocol • Some pages of the consent form signed by the subject were missing • Subject did not get this cycle 3 day 1 because he had an important meeting at work
Deviations • Staff failed to obtain pre-treatment urine specimens • Subject wanted to hold off on chemotherapy scheduled for Monday because he wanted to go on vacation • Infusion nurse gave the bevacizumab prior the gemcitabine in contradition to what is required in the protocol
Deviations • Because of neutropenia, subject was to be dose reduced from 750 mg/m2 to 600 mg/ms for cycle 2. When the subject returned to the clinic, he was not dose reduced but given the 750 mg/m2.
Deviations • Protocol does not require prophylaxis during conditioning. Subject received prophylasis at the same time as conditioning.
Deviations • Study treatment identifies acceptable ranges of 0-15 minutes for vital signs, prior to pharmacokenitics being drawn. Vital signs were taken after pharmacokenitics were drawn.
Deviations • The subject was originally scheduled for a nephrectomy on day 16 of the pre-nephrectomy treatment period. Due to extraordinary and unusual circumstances at the Brigham, all operative procedures after 12:00 p.m. were cancelled due to a lack of bed space in the hospital.
Deviations • The nephrectomy has been reschedule for the earliest available date one week beyond the 28 day pre-operative treatment period. A deviation is requested to accommodate this change in the scheduled nephrectomy. In addition to scheduling difficulties, the change in schedule has also affect the study drug supply. The subject has run out of study drug/placebo. After discussing with
Deviations • The sponsor, it has been determined the best possible procedure would be to unblind the subject in order to continue to study drug/placebo before the operation.
Deviations • Research blood samples drawn on day 2 instead of day 3 • Physical and bloodwork done one day late • CT scan delayed because of the holiday • Day 7 of treatment postponed for 3 days because subject will be out of town • Labs were not drawn as per protocol
Violations • due to human error, the ECG was not scheduled for his Day 15 visit • subject was given a reduced dose due to his decrease in weight, but continued to • take higher dose for 6 days • subject returned to clinic on 03/09 after 4 cycles of Xeloda, subject came in with evidence of PPE which she did not report because she did not want to hold treatment
Violations • UA was ordered in IDX for the subject's appt but it was never done • samples were hemolyzed and no serum chemistry or electrolyte tests could be performed • subject did not receive all the tests as per protocol at the end of study • subject missed one dose of IFN-alpha because her mail service pharmacy was unable to deliver the drug on day needed
Violations • subject did not complete the C-626 & C-419 questionnaires at baseline • subject inadvertently forgot to do the 24 hour urine collection • subject did not recieve continuous 5FU pump due to mechanical error • subject was administered commercial Filgrastim instead of Amgen study supply
Violations • Subject did not have required platelet count of 150,000 to be eligible for trial, but started on protocol. The subject was not registered with QACT prior to beginning protocol therapy. • Subject refused further sigmoidoscopies • Evaluations not performed according to schedule • BMS-247550 was administered over a 2-hour period instead of a 3-hour period
