Theradex Audit 2013: Findings & Corrective Action
Overview Discuss Findings and CAP for: Informed Consent Content IRB Informed Consent Eligibility Treatment Serious Adverse Events Response General Data Quality Summary Q & A
Informed Consent Content Findings: Description of the extent of confidentiality of records NCIs access to medical records has not been disclosed, albeit, access to government agencies is disclosed. Response: We acknowledge this oversight. We were able to locate the reference to NCI access in our Institutional HIPAA form, but understand that that is required to be included in the ICF. Description of risks or discomforts The frequency of fatigue has been listed in the greater than 20% category instead of less than 20% category. In addition, decreased lymphocyte count is missing. Response: The UWCCC consent form risk language appears to be exactly the same as listed in the NCI-approved consent form template provided by the lead site for the 04/01/2013 protocol version (model consent form is being sent as supporting documentation). The lead site was contacted and made aware of these deficiencies noted during the audit. The lead site agreed that the consent version that the UWCCC is utilizing is correct, with fatigue in the greater than 20% category (not the less than 20% category) and not listing decreased lymphocyte count in the risk section.
Informed Consent Content Description of risks and discomforts. The frequency of anemia has been listed in the less than 20% category instead of greater than 20% category. In addition, increased LDH is missing. Response: In Protocol Addendum #4 and the accompanying model consent form, the risk anemia or decrease in a red blood cell protein (hemoglobin) that carries oxygen in the body was reworded to lack of enough red blood cells (anemia) in the likely category. Likewise, the CAEPR in that version of the protocol (v2.1) showed that hemoglobin was reworded to anemia and was listed in the Likely (>20%) category. Following this, in Protocol Addendum #6, the CAEPR in that version of the protocol (v2.2) showed that anemia was moved from the Likely (>20%) category to the Less Likely ( 20%) category; however, the accompanying model consent form did not reflect this change. Because of the change in the CAEPR, our local consent form was revised to move the risk of anemia from the likely category to the less likely category. LDH was not listed in the model consent form provided by the sponsor (model consent form is being sent as supporting documentation). Additionally, the only place where increased lactate dehydrogenase is listed is in CAEPR (v2.3) under the section where the relationship to the study drug is still undetermined.
Informed Consent Content Corrective Action Plan All UWCCC regulatory staff has been made aware of the deficiencies noted regarding ICC. Training in this regard emphasizes the importance of contacting the sponsor if there are noted discrepancies between the model consent form and the CAEPR to ensure that subjects are provided with the most current and accurate risk information. Informed consent forms are double-checked against the model consent forms prior to submission to the IRB to ensure that all risk information is accurate. Additionally, all regulatory research staff have been re-educated regarding the requirement to list the NCI in the privacy/confidentiality section of the ICF in order to legitimately allow the NCI to access these records. As a consequence of the audit findings, all consent forms for NCI sponsored trials are being reviewed and updated as necessary to ensure that NCI is listed in the privacy/confidentiality section.
IRB Finding: Amendment approvals occurring outside of the 90 day window. 12 instances over 2 protocols (from 2010, back when paper system) 1 instance in particular due to waiting/batching and then slow turnaround on part of research group Corrective Action: Since the time of the majority of these IRB deviations, the UWCCC and HS-IRB have developed streamlined processes in which to ensure protocol amendments are approved within 90 days. The IRB s transition to an electronic submission system in November 2010 greatly reduced turnaround times for amendments, although it did take over a year for all studies to be integrated into the system. The new electronic system requires regulatory staff to submit amendments within 45 days of receipt and inform the IRB of the date for the 90 day deadline. Additionally, the IRB meets every week to discuss deadlines and re-prioritizes applications based on these deadlines. All regulatory staff members have been trained on these processes and were re-educated regarding them as a result of this audit.
Informed Consent Findings: Consent form not signed and dated by subject Response: We acknowledge that the research coordinator did not ensure that the research participant dated their signature on the Informed Consent Form. A Note-to-File, dated 10/17/10, is in the research chart documenting the consenting process as well as the date the subject signed the informed consent form. The coordinator who conducted this informed consent process is no longer employed at the UWCCC. Re-consent tissue collection ICF not signed and dated by subject Response: We acknowledge that the research coordinator did not ensure that the research participant completed the signature and date page of the sample collection consent form upon re-consenting. A Note-to-File, dated 02/11/11, is in the research chart documenting the consenting process as well as the date the subject signed the informed consent form. Again, this was the same coordinator as in the above deficiency and she is no longer employed at the UWCCC.
Informed Consent Corrective Action Plan: All UWCCC research coordinators have been thoroughly re-educated on the importance of ensuring all components of the Informed Consent Process are followed, not the least of which is to ensure that the research subject sign and date the Informed Consent Form to demonstrate their consent and willingness to participate in a study. Our training instructs that this it is essential to ensure the individual sign and date all required pages each time they are consented to a study, either initially or if there is a need for reconsenting.
Eligibility 0 major deficiencies!
Eligibility- What does this mean? It means that in the last three years, research groups are working to ensure: Eligibility criteria are thoroughly reviewed and the proper labs, procedures, reports are obtained Eligibility checklist are being properly signed and dated by physician PRIOR to subject being registered Tests are being re-done if existing results fall outside the protocol specified window
Treatment Findings: Cycle 1 orders were not signed by the investigator in the space meant for signatures, albeit, each page was initialed by the investigator. In addition, the cycle 1 order had some blank spaces that were not completed. Response: We acknowledge that the investigator did not sign the cycle 1 orders on page 3 where indicated, although, as noted by the auditor, the investigator did initial every page. 3 instances of Treatment doses incorrectly administered, calculated or documented where study drug was infused over the protocol specified duration Response: Acknowledged. The oncology clinic nurse did not follow the protocol treatment orders that were provided. Discrepancy between pill count and patient diary ( patient reported 100% complinace, pill count showed otherwise)
Treatment Corrective Action Plan: We continue to work with the Oncology Clinic Manager to educate and train the oncology clinic nurse staff on the importance of following the specific treatment orders described in the protocol. Treatment orders are routinely provided to clinic staff to ensure adherence to protocol requirements. In addition, research staff members communicate directly with the nurse in clinic on patients treatment days to reinforce treatment plans/procedures and assessments that needs to be performed that day. Training and education regarding this important aspect of clinical research is ongoing, and the results of this audit are utilized as teaching tools. As with other aspects of our clinical research training initiatives, we conduct case scenarios with new and continuing research staff to test their competence in understanding the rationale for dose delays/dose reductions and the importance of documenting those decisions. Finally, we have developed and implemented the use of a Dose Reconciliation Form for documenting compliance for studies with oral treatments.
Adverse Events Findings AE requiring expedited reporting delayed (8 instances) Grade 2 laryngeal hemorrhage (10/26/11) was not reported via expedited reporting to the NCI until 01/19/12. Response: The protocol version approved at our institution at the time of the grade 2 laryngeal hemorrhage (10/26/11) was version 6/16/2011 which still included an ASAEL, therefore we did not report this event as it was expected. It was not until the next version of the protocol, version 9/22/2011 that it switched to the SPEER, which did indicate that above a grade 1 laryngeal hemorrhage would be unexpected and therefore require expedited reporting.
Adverse Events Corrective Action Plan: Across the UWCCC clinical research infrastructure, we have implemented a comprehensive training initiative for new and continuing research staff that includes instruction on the proper maintenance of adverse event logs. In our training, we teach that our institutional requirement is to create and maintain adverse event logs which require timely review and sign-off by the investigators. Our institutional Standard Operating Procedure on Adverse Event Reporting and Documentation includes step by step instruction on how to assess, grade, determine specific reporting requirements and document adverse events. The training on the timely reporting of expedited adverse events is emphasized for all research staff, from investigators to study coordinators to regulatory personnel. We will continue to concentrate training efforts in this area, specifically using these audit findings as a teaching tool.
Disease Outcome/Response Findings: Claimed Response cannot be verified or auditor disagrees with claimed response (6 instances) The Best Response has been submitted to NCI as N/A; however, a repeat CT scan done at an eight week interval demonstrated Stable Disease. The response should be changed from Stable Disease (08/16/12) to Not Evaluable since the first follow-up scan was done only 3-4 weeks from the baseline scan. A Best Response of Progressive Disease was not confirmed at 6-12 weeks as required by protocol. A bone scan was ordered for confirmation (02/27/13) but the patient, along with the physician, elected to discontinue secondary to grade 3 fatigue and visual changes. The Best Response reported should be unconfirmed Progressive Disease or Not Evaluable or patient withdrawal. The patient s Best Response has been reported as Stable Disease (03/28/13). The reported Best Response, however, needs to be changed to Partial Response as noted on 07/09/13. The patient s Best Response has been reported as Stable Disease (03/28/13). The reported Best Response, however, needs to be changed to Partial Response as noted on 07/09/13. The patient's Best Response to treatment has been reported as Stable Disease. The Best Response should be changed to Progressive Disease as the patient was taken off study due to progression determined in an unscheduled CT scan performed a month after the baseline scan. Response for all: The research staff has amended the RECIST measurement form. The response in the database already reflected that the patient was.
Disease Outcome/Response Findings: Failure to detect cancer (as in a prevention study) or failure to identify cancer progression The patient's dose was held on 11/01/12 due to a grade 2 rash which resolved on 11/14/12. The patient was instructed to reduce his AZD6244 dose from 75 mg twice daily to 50 mg twice daily. The patient, however, was noted to have disease progression per CT scans obtained on 11/19/12. The patient kept taking the AZD6244 until 11/29/12. Response: Scan was obtained at local physician s clinic on 11/19/12. The patient s next appointment with their study physician was on 11/29/12. The scans were reviewed at that visit and PD was determined. Patient came off study at that time. Corrective Action Plan: As a corrective action for this category, we are developing specific Standard Operating Procedures (SOP)that address Response Evaluations and the expectations for timely review and measurement via RECIST as well as ensuring physician verification of the stated response. In addition to developing specific SOPs, we are conducting training sessions focusing on timely Response Determination to ensure patients are not receiving ineffective treatment. Our training efforts in this area are ongoing, specifically using these audit findings as a teaching tool.
General Data Quality Findings: Only 1 Major deficiency noted in this category! Labs drawn at screening were not repeated on cycle 1 day 1 as required by the protocol. The auditor located a Note-to-File stating that it was not the protocol chair s intent to have the labs repeated. The auditor was not able to verify if the site obtained an approval from the IRB for this deviation. Weekly serum chemistries were not located during cycle 1. CBC s were not located in cycle 1 for weeks 3 and 4. In addition only INR, and not Prothrombin Time, was obtained in cycle 1. Response: : We acknowledge these deficiencies. Please note that our IRB would not require reporting of the deficiency regarding C1D1 labs not being drawn, as they require three such episodes before reporting to them. The study coordinator responsible for these deficiencies is no longer employed by the UWCCC Corrective Action Plan: Through a comprehensive training initiative for new and continuing research staff that we have developed over the last several years, we have instituted mandatory educational and training sessions that focus on the importance of protocol adherence. A significant portion of the curriculum is devoted to hands on exercises that require individuals to identify what and when specified lab tests, diagnostic procedures, etc. must be obtained per protocol. Additionally, individuals are trained on appropriate study documentation. Our Source Documentation Standard Operating Procedure outlines the specific requirements for maintaining thorough and accurate subject records in order to provide evidence of protocol adherence, ensuring subject safety, and allow confirmation of proper study conduction. We will continue to concentrate training efforts in this area, specifically using these audit findings as a teaching tool.
Summary Important to understand that we send in this report as a single institution, and therefore we need to ensure that we address these issues across the institution, not just within a single research group. UWCCC SOPs are being developed on many of these specific areas Response Assessment and Documentation Training has improved performance across the institution Keep up the good work!
Hello Kitty says: Know and follow your protocol!