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Quality Improvement Program (QIP) for
Human Research Protections
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Contact:
Judi Kuhl, Judi.Kuhl@uky.edu
859-257-9764
The Office of Research Integrity (ORI) and the University of Kentucky (UK) Institutional Review Board (IRB) developed a Quality Improvement Program (QIP) to strengthen human research protections at UK and demonstrate UK’s commitment to continuous improvement in compliance. Identifying the strengths and weaknesses of protection efforts is essential to maintaining a quality program and enables the ORI and the IRB to continue UK’s tradition of excellence.
Implementation of the QIP at UK serves to evaluate human research protections at varying levels, increase awareness of existing processes, operating procedures, educational programs, and acquire information necessary for enhancing protections. The QIP provides a means to assess UK’s level of compliance with federal, state, and institutional regulations, and Good Clinical Practice (GCP) guidelines, which is a key element in meeting the highest standards for human subject protections.
Components of the program focus on educating the University’s researchers on the mechanisms by which human subjects are protected. It also allows researchers, ORI staff, and IRB members the opportunity to improve human research protections performance. The QIP can provide useful information to identify educational/training initiatives for researchers, their staff, ORI staff, and IRB members.
The QIP consists of three main components which examine the entire research process and may focus on the researcher, the IRB’s review process, and/or the IRB records maintained by ORI.
Directed on-site reviews are conducted by the ORI QIP Coordinator and are initiated upon request by the Institutional Review Board (IRB), the Vice President for Research, or ORI Director, due to unusual circumstances, significant risks to subjects, routine failure of an investigator to comply with federal and/or institutional requirements, allegations or concerns about the conduct of the study brought to the IRB’s attention, or any case requiring further scrutiny as deemed appropriate by the IRB. The ORI QIP Coordinator may be accompanied by a representative of the IRB. A comparison of the IRB’s records maintained by ORI with the investigator’s research records may also be conducted to determine accuracy and consistency and to verify that no material changes were made to the protocol prior to IRB approval. The findings of the directed review are shared with the Principal Investigator (PI) and his/her research staff and reported to the IRB to make a determination about whether further action is necessary. If in reviewing the results of a directed review, the IRB determines that the exposed deficiencies warrant suspension or termination of the research, the IRB develops a plan for follow-up, which may entail, but is not limited to, another QI review, or monitoring of the informed consent process. If ORI conducts a directed Quality Improvement Review (QIR) on a protocol that falls under the purview of a unit with which ORI has written and approved joint standard operating procedures (e.g., IBC, MCC, VAMC), the appropriate unit representative is given a copy of the final QIR report.
PI Self-Assessment Reviews are voluntarily performed by the PI or his/her research staff. However, a PI may also be prompted by direct invitation at the discretion of the IRB, Vice President for Research, or ORI Director to perform a self-assessment review. The ORI provides a web-based self-assessment form (also available electronically, or in paper copy) to be completed by the PI and/or research staff. The PI self-assessment tool includes questions and information pertaining to federal regulations governing human research protections, local IRB policies and procedures, and International Conference on Harmonisation (ICH) GCP guidelines. The UK Self Assessment form is located at https://www.research.uky.edu/cfdocs/ORI/IRB_QA/. The results from a PI self-assessment review can be submitted to a secure database, after which time, the ORI can return suggested corrective actions to the PI for areas in need of improvement. The IRB will not be notified of results from a PI self-assessment review unless the results of the review reveal significant deficiencies in protection of human subjects in research, or the IRB directed a PI to complete the self-assessment. Reports can be generated by the ORI using the data collected from submitted self-assessment forms and may enable identification of educational initiatives for researchers. These reports are run on an as-needed basis and analyzed accordingly by the QIP Coordinator. Administrative assessment reviews are conducted by the ORI QIP Coordinator and are initiated at the discretion of the Director of ORI, and/or the Vice President for Research. A thorough examination of the IRB records may be conducted for improvement of management or to evaluate the procedures applied and/or issues addressed by the Office of Research Integrity staff and the IRB for protection of human subjects in research. An example of evaluating IRB procedures would be the use of the Consent/Assent Form Checklist [PDF located at http://www.research.uky.edu/ori/QIP/O1-QI-Consent_Checklist.pdf]. IRB member performance evaluations are periodically conducted to verify qualifications. The results of an administrative assessment are shared with the ORI Director. The results may impact current practices and may require additional educational activities for ORI staff, IRB members, or investigators/study personnel.In addition to the above described administrative assessment reviews is the Program Assessment for Accreditation, a significant component in support of maintaining AAHRPP accreditation. This assessment focuses on maintenance of applicable documentation representing current policy and procedures; utilization of the AAHRPP Self-Evaluation Instrument; and evaluation of current HRPP practices to ensure appropriate fulfillment of accreditation standards.
Educational programs/announcements are developed for investigators, their research staff, ORI staff, and IRB members based on the results of the QIP Reviews. If/when findings from QIP reviews are reported to the IRB, the IRB makes a determination whether to report the findings to FDA, OHRP, the study sponsor, the UK Institutional Official, or other internal departmental faculty/staff.
UK maintains standard operating procedures (SOPs) for each one of the QIP components. See Directed On-site Review; PI Self-assessment Review; and Administrative Assessment Review SOPs for details.
Quality Improvement Review Findings - Reporting Requirements
UNDER CONSTRUCTION/DRAFT
Are the QI Review findings reportable to the IRB?
One of the goals of the Quality Improvement Program is to educate researchers on the mechanisms by which human subjects are protected. In keeping with this intent, results of routine Quality Improvement Reviews (QIR) and Principal Investigator (PI) Self-Assessment reviews are not shared with the Institutional Review Board (IRB) unless significant or serious deficiencies in human subject protections are found. If findings from a QIR are reported to the IRB, the IRB makes a determination whether to report the findings to the UK Institutional Official, other internal departmental faculty/staff, and/or to external agencies as described in the "Mandated Reporting to External Agencies SOP".
The following guideline is used by the QIP Coordinator and/or the Director of ORI to determine whether findings need to be reported to the IRB after a routine, or PI Self-Assessment review has been conducted.
Reportable to the IRB
Significant or Serious Deficiencies in Human Research Protections (including, but not limited to):
- A major protocol violation (for more information and details, see Protocol Violations section on the IRB Review Types web page [HTML] and/or the Protocol Violation Review SOP [PDF])
- Unanticipated problem involving risk to subject or others which has not been previously reported to the IRB (for definitions, see the Policy on Prompt Reporting for Unanticipated/Anticipated Problems/Events [PDF]);
- Serious or continuing noncompliance (for definitions, see Noncompliance SOP [WORD][PDF])
Not necessarily reportable to the IRB
Minor Deficiencies in Human Research Protections (might include, but is not limited to):
- Administrative/management errors which do not impact subject safety, do not substantially alter risks to subjects, or do not affect data integrity
It is standard operating procedure to report results from a Directed QIR to the IRB.
Please note: These logs may not suit your protocol precisely, however, they may serve as a guide to get you started. Also, be mindful of HIPAA and when it might apply to data collected in pre-screen and enrollment logs.
(alphabetical order)
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"Food" For Thought
Click on the topic to go to a more detailed description of citations for:
- failing to obtain proper informed consent;
- failing to maintain accurate, complete, and current case histories;
- failing to conduct the investigation according to the signed agreement, the investigational plan, and applicable FDA regulations;
- failing to appropriately maintain investigational records
- conducting an unapproved device trial while serving as a sponsor-investigator
To view other FDA Warning Letters and Responses, visit: http://www.fda.gov/foi/warning.htm
1. Failure to Obtain Proper Informed Consent:
Excerpts from FDA Warning Letter dated:
October 7, 2005
The FDA cited an investigator for failure to obtain proper informed consent. The following violations were observed:
#1 Failure to obtain proper informed consent for 3 of 5 study subjects. [21 CFR 50.20, 812.100, and 812.140(a)(3)(i)]
Investigators are responsible for ensuring that informed consent is obtained and that records of informed consent are kept in accordance with FDA regulations 21 CFR 50.20, 812.100, and 812.140 (a)(3)(1). This includes obtaining signed new consent documents for subjects when the IRB approves changes in the protocol and accompanying consent document that alter the study procedures or may otherwise affect the subject's willingness to participate . Clinical investigators must include in each subject's case history documents evidencing that informed consent was obtained.
You failed to obtain subject signatures on the September 16, 2004, IRB-approved version of the informed consent document for 3 of 5 subjects. That updated informed consent document provides new information including:
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addition of follow-up diagnostic procedures at the 24 month visit:
- Rutherford Classification.
- Resting A.BI's, and
- Index extremity X-Ray
- changes in the statement, "You will not be charged for any non-routine costs associated with the study. These costs will be covered by the sponsor ." The new statement, "You or your insurance company will be charged for the [redacted]. Some insurance providers will not pay for the cost of the [redacted]."
- clarification of the statement, "The [redacted] is not FDA approved for placement in the but it is FDA approved for use in the study ."
The new statement " The [redacted] is investigational, which means that it is not approved by the U.S. Food and Drug Administration (FDA) for placement in the [redacted] and - updated contact information for Dr. _______.
In your response, you indicate that these three subjects were contacted by your study coordinator but declined to sign the new consent . You further indicate that they did not participate in the additional follow-up for which the new consent form attempted to solicit consent. However, there is no documentation of the subjects being contacted or withdrawn from the investigation in the case histories reviewed. Under the circumstances you describe, the subject files should have documentation of the efforts made to obtain consent, the subjects' refusals, and your subsequent steps to ensure that they were terminated from the study."
2. Failure to maintain accurate, complete, and current case histories:
Excerpts from FDA Warning Letter dated:
October 7, 2005
The FDA cited an investigator for failure to maintain accurate, complete, and current case histories. The following violations were observed:
#2 Failure to maintain accurate, complete, and current case histories. [21 CFR 812.140(a)(3)]
You failed to maintain complete, current, and accurate case history files regarding study activities required by the study protocol . Examples of this failure include, but are not limited to the following:
1) The nine month follow-up case report form (CRF) to [redacted] indicated the subject was contacted by phone, however the results of Ankle-Bracliial Index (ABI) (requiring the subject be physically present) were recorded on the CRF.
In your response you state the subject had the follow-up testing performed but did not return for the outpatient visit and then withdrew from the study. You indicate that a narrative portion of the study records documented this situation. The CRF examined by the investigator for the nine month visit notes the subject was contacted only by phone. The results documented on that CRF could not be performed by phone contact. There is no source documentation that the subject actually had the tests performed. The narrative form you provided with your 483 response to support your explanation is dated September 17, 2004, nearly one year after the subject's scheduled 9-month visit and reported withdrawal from the study. These records were therefore not complete and current.
[redacted] baseline's history record indicates that the subject was "on Coumadin" however, the discharge CRF does not list Coumadin as a medication the subject is taking. There is confusion in the documentation as to whether the subject was or was not on Coumadin. In addition, the nine month follow-up visit CRF is missing values for blood pressure (B/P) in the left arm, left ankle systolic pressure, and left ABI. In your response you state, the subject stopped his Coumadin 10 days prior to the procedure and restarted 2 days after, however, there was no source documentation noting this. The protocol requires subjects on Coumadin to have International Normalized Ratio (INR) performed. There is no documentation that INR's were performed on this subject, either in the immediate post-operative period or at his nine-month follow up visit. In addition, regulations require an investigator to notify the sponsor and the reviewing IRB of any deviation from the: investigational plan to protect the life or physical well-being of a subject or of deviations that impact the scientific soundness of the investigation. See 21 CFR 812.150(a)(4). Failure to obtain these laboratory tests is a protocol deviation and would require notification of the sponsor and IRB, but there is no documentation of such notification . In addition, you did not address missing information in the case history and CRF. Specifically, values for nine month follow-up of left arm B/P, left ankle systolic pressure, and left ABI.
Your response is inadequate; it does not describe how you are going to ensure complete, accurate, and current documentation of clinical trial data. Documentation of all protocol related elements is a critical component to conducting clinical trials including, medications taken, diagnostic procedures. adverse events, and communications with the subjects. Please provide copies of policies and procedures, with expected completion dates that are being developed and implemented to ensure proper documentation of protocol related elements and the maintenance of complete, accurate, and current case histories.
3. Failure to conduct the investigation according to the signed agreement, the investigational plan, and applicable FDA regulations:
Excerpts from FDA Warning Letter dated:
October 7, 2005
The FDA cited an investigator for failure to conduct the investigation according to the signed agreement, the investigational plan, and applicable FDA regulations. The following violations were observed:
#3 Failure to conduct the investigation according to the signed agreement, the investigational plan, and applicable FDA regulations. [21 CFR 812.100 and 21 CFR 812.110(b)]
In accordance to 21 CFR 812.100 and 812.110(b), clinical investigators are required to ensure that investigations are conducted according to the signed agreement, the investigational plan, and applicable FDA regulations, as well as any conditions of approval imposed by the IRB or FDA. In addition, federal regulations require that clinical investigators obtain prior approval from the sponsor before implementing any deviations from the investigational plan, except for deviations to protect the life or physical well being of a subject in an emergency. (21 CFR 812.150(a)(4)). If these changes or deviations affect the scientific soundness of the plan or the rights, safety, or welfare of the subjects, FDA and IRB approval are also required. (21 CFR 812.150(a)(4), 812.35(a)).
Our investigation revealed several deviations from the signed agreement and investigational plan, including but not limited to the following:
1) Under the protocol in effect at the time, inclusion criteria #3 states, "Patient requires treatment of a [redacted]. However, [redacted] had [redacted] treated during the index procedure.
In your response you state that at the time of treatment of this subject, the protocol did not list treatment of both [redacted] during the index procedure as an exclusion criteria. You do not disagree that the inclusion criteria at the time referred to treatment of a [redacted]. You state that you discussed enrollment of this subject with the sponsor and were given allowance to treat [redacted] as per standard of care and [redacted] as per the protocol. However, there is no documentation of this sponsor approval prior to enrolling this subject. You attached a letter from the sponsor dated January 28, 2003, clarifying treatment of additional [redacted] and stating they must be treated 24 hours prior to or after the index procedure, apparently to support your view that at the time of your enrollment and treatment of this subject, it was ambiguous as to whether or not subjects having more than [redacted] in need of treatment were to be excluded. You do not appear to rely on this letter as granting permission for the procedures done with regard to the subject in question, nor could you, as your subject was treated six weeks prior to the date of the letter, and you treated both lesions at the same time, not 24 hours apart, as mandated in the sponsor's protocol clarification.
Treating this subject was a protocol deviation. There is inadequate documentation of notification of the sponsor and IRB of these deviations from the investigational plan.
Please provide copies of policies, procedures, and training with expected completion dates, which are being developed and implemented to ensure deviations from the investigational plan are reported in accordance with the FDA regulations and your IRB's policy.
2) The investigational plan requires anticipated and unanticipated adverse events and complications to be recorded on the Adverse/Serious Adverse Event CRF and reported to the local IRB and coordinating center. In addition, reporting of serious adverse events occurring in the study are to be reported within 24 hours of the investigator's knowledge to the coordinating center for the principal study investigator to review. However, you did not report serious adverse events in accordance with these requirements. For example, [redacted] complained of pain in the right leg during a non-scheduled study visit on 1/31/2005. In February, the subject was seen 'by Sub-Investigator [redacted], at which time he documented clotting of the superficial femoral artery, "probably in the area of the stent." The adverse event CRF was not completed until the FDA inspection on 6/28/2005. Please note, the adverse event CRF is missing the date of the event. Furthermore, there is no documentation of the event being reported to the IRB or sponsor.
In your response you note this event was inadvertently not documented on the CRF or reported to the sponsor and IRB due to the study staff attempting to contact the subject to set up the 24 month follow-up visit. In accordance with the protocol, this event should have been reported to sponsor and IRB within 24 hours of you becoming aware of this event. Your response is incomplete ; it does not include a plan to ensure proper reporting of serious adverse events. Please provide copies of policies and procedures with expected completion dates, that are being developed and implemented to ensure reporting of serious adverse device effects are in accordance with the investigational plan and IRB policy.
4. Failure to appropriately maintain investigational records:
Excerpts from FDA Warning Letter dated:
October 7, 2005
The FDA cited an investigator for failure to appropriately maintain investigational records. The following violations were observed:
#4 Failure to maintain investigational records for a period of two years after the latter of the date on which the: investigation is terminated or completed or the date the records are no longer needed to support a PMA [21 CFR 812.140(d)]
You failed to maintain records of Duplex Flow Scans and Index Extremity X-Rays or Fluoroscopy for two years after the study completion. Examples of records not available for all subjects enrolled in trial the are the following:
1) Duplex Flow Scans at discharge, 9 months, 24 months, and non-scheduled visits:
and
2) Index Extremity X-Rays or Fluoroscopy at baseline, 9 month, and 24 month.
In your response you state the records of the Duplex Flow Scans and the Index Extremity X-Rays for all subjects were not retained by the hospital. The originals were sent to the [redacted],and the original X-Rays were forwarded to the [redacted]. You also note you have contacted the labs to obtain the originals and will retain them with the study binders for at least two years . Your response is incomplete. Although you have requested the aforementioned records, you do not indicate what policies and procedures, with expected completion dates, are being developed and implemented to ensure proper maintenance of study-related source records in the future.
The above-described deviations are not intended to be an all-inclusive list of deficiencies that may exist in this clinical study. It is your responsibility as a clinical investigator to assure adherence to each requirement of the Act and all applicable federal regulations. Within 15 working days after receiving this letter please provide written documentation of the additional, specific steps you have taken or will take to correct these violations and prevent the recurrence of similar violations in current and future studies. Any submitted corrective action plan must include projected completion dates for each action to be accomplished. Failure to respond to this letter and take appropriate corrective action could result in the FDA taking regulatory action without further notice to you. In addition, FDA could initiate disqualification proceedings in accordance with 21 CFR 812.119. Send your response to: Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Division of Bioresearch Monitoring, Special Investigations Branch, HFZ 311, 9200 Corporate Road, Rockville, Maryland 20850, Attention : Doreen Kezer, Chief, Special Investigations Branch.
5. Conducting an unapproved device trial while serving as a sponsor-investigator:
April 3, 2007
According to a warning letter from the FDA (summary follows):
A physician who started an investigator-initiated trial of a significant-risk implanted device failed to get FDA approval before starting the study and did not get signed agreements for himself and the other physicians working as subinvestigators.
Thomas Davis of the Cardiology Division of St. John Hospital and Medical Center acted as both sponsor and clinical investigator in a study of a significant-risk device but failed to submit an investigational device exemption (IDE) application to the FDA, according to the warning letter, which was based on an inspection conducted Nov. 20 to Dec. 12, 2006. In all, five different devices were implanted into 68 subjects without approval.
Davis told the FDA he was not aware that an IDE was required for an FDA-approved device to be used off-label, that there was no risk assessment from the institutional review board and that he was not aware that he met the definition of a sponsor-investigator. However, the letter said, “As a sponsor, you are required to obtain a new IDE if a device that is approved for one indication is intended to be used in a clinical study for a new indication.”
The warning letter can be accessed at: http://www.fda.gov/foi/warning_letters/b6324d.htm
FDA/HHS Quality Assurance Efforts
Click on the topic to get more details:
- Number of Device Warning Letters Increases During First Half of FY 2004, Quality System Issues Predominate
- FDA Extends Enforcement Efforts Against Clinical Sites
- HHS OIG Audit Disallows $1 Million in Costs, Cites Inexperienced PIs
1. "Number of Device Warning Letters Increases During First Half of FY 2004, Quality System Issues Predominate"
If you are conducting a device study, don't assume your subjects are safe if you are meeting all conditions for approval. Consider the impact on protections to the human subjects you recruit if any of the following issues pertain to the medical device company with which you are working.
- charges of reporting and approval failures with regard to informed consent and occurrences of serious adverse events related to the devices' use
- companies allegedly failed to comply with good manufacturing practice (GMP) standards in the quality system regulations
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firms did not properly conduct or prepare for quality audits of their medical device manufacturing processes (i.e., failures to establish adequate written procedures for quality audits and failures to conduct the required audits adequately).
Summary of significant FDA citations pertaining to human subject protections by Judi Kuhl, from:
FDA Enforcement Manual, Food & Drug Series
August 2004, Vol. 13, No. 6
"Number of Device Warning Letters Increases During First Half of FY 2004, Quality System Issues Predominate"
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2. "FDA Extends Enforcement Efforts Against Clinical Sites"
Among the citations described in FDA's Warning Letters are:
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Conflict of Interest between the trial sponsor and trial administrators;
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poor adverse event reporting;
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enrollment of subjects that did not meet inclusion/exclusion criteria;
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lack of proper informed consent procedures;
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failure to re-consent when necessary;
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failure to maintain records of subjects' case histories and exposure to devices;
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inadequate training and monitoring of the principal trial investigator;
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and, objectionable conditions at the study site.
Summary by Judi Kuhl from:
Clinical Trials Advisor
August 12, 2004, Vol. 9, No. 15
"FDA Extends Enforcement Efforts Against Clinical Sites"
3. HHS OIG Audit Disallows $1 Million in Costs, Cites Inexperienced PIs
"The Department of Health and Human Services' (DHHS) Office of the Inspector General (OIG) has recommended that the University of Southern California (USC) repay $1 million that it received to run an HIV intervention program." Based on the OIG's inspection, it was determined that USC's human research protections program failed in the following areas:
- meeting the initial goals of the project
- involvement of unapproved research involving human subjects
- conflicts of interest were not appropriately handled
- unallowable costs were claimed
In this case, the failures noted by OIG's audit stem from an inexperienced subcontractor and inexperienced Principal Investigator.
Summary by Judi Kuhl from:
Report on Research Compliance newsletter
August 2004, Vol. 1, No. 6
Access article archives and other practical tools at www.ReportonResearchCompliance.com
FDA Inspection - Preparation Resources
Check out FDA's resources to help you prepare:
- Guidances and Information Sheets on Good Clinical Practice in FDA-Regulated Clinical Trials [HTML]
- FDA Inspections of Clinical Investigators: Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors [PDF]
- International Conference on Harmonisation (ICH) E6: Good Clinical Practice: Consolidated Guidance [PDF]
OHRP Inspection - Preparation Resources
Review OHRP's resources so you know what to expect: