Monitoring & Auditing
What is the scope of an audit?
(same as monitoring) -Informed Consent -Eligibility Criteria -Protocol Adherence -IRB Submissions -Regulatory Documents -Drug/Device accountability -AE/SAE recording and reporting -Monitoring reports
What is the difference between external & internal audits?
-External Auditing Sources •Food & Drug Administration (FDA) For Cause vs. Routine •NIH •Study Sponsor •City of Philadelphia -Internal Auditing Sources •Office of Clinical Research (OCR) •Office of Research Integrity & Compliance
What will the monitor look at regarding drug/device accountability?
-May be Delegated to a central pharmacy (IDS). -Product Receipt -Storage conditions -Dispensing -Returns -Destruction
What is auditing?
-Point in time assessment of the effectiveness of the monitoring system and study compliance with the protocol and applicable regulations -Looks at the effectiveness of policies and processes -Any clinical research study being conducted at UPENN is subject to audit by a number of sources. An audit of a clinical research study seeks to validate the quality of the clinical study and assures that the rights & welfare of the human subjects in the study have been protected -Inspection Readiness
Who are the DSMB members?
-Relative expertise to the condition being studied -Experience in clinical trials -Serving on other DSMB's -Absence of conflict of interest (financial & intellectual) -Can't be the Principal or sub- investigators on the study -Composed of clinicians in the revenant clinical specialties -Biostatistician -Medical ethicist -Other scientists -Non-scientist (not in the study, but maybe have the disease) -Commitment to attend meetings -Chair may be appointed by Sponsor to facilitate meetings
What will the monitor look at regarding AEs and SAEs?
-Reporting and Recording are not the same •All events are recorded but not all are reported -Serious Adverse Events •Reported per the protocol •Assessed by the PI •Followed to resolution -Laboratory Assessments
What will the monitor look at regarding eligibility?
-Signed eligibility confirmation document -Supporting documents to confirm eligibility
What should happen after the monitoring visit?
-Study team should make time to review to clarify the monitors queries and questions -Ensure all queries are answered prior to the next monitoring visit. -Respond to findings in the monitoring letter.
What is a sponsor?
-The person who takes responsibility for and initiates a clinical investigation. -The Sponsor does not actually conduct the investigation unless they are a Sponsor/Investigator. -Hold the IND/IDE/CTA -Individual or an Institution: Pharmaceutical company, Governmental agency, Academic institution, Private organization
Describe the principal investigator role?
-Ultimately responsible for the local conduct of the clinical trial as outlined in the investigator statement (1572), investigational plan, protocol and applicable regulations. -Collecting, reporting and evaluating of all safety events -Communicating with the sponsor all safety information related to the IP.
What is the DSMB Charter?
-Written by Sponsor -DSMB Composition (multi-disciplinary) -Operating Procedures -Frequency of ongoing monitoring (based on risk levels and recruitment rates) -Type of data required for review by the DSMB -Plans for statistical analysis and review -Contents of report and recommendation to be issued by the DSMB -Meeting minutes, how the meetings will be held, etc.
Monitoring of a Clinical Trials is required by. . .
Federal Regulations
What does the 1572 state?
I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subjects. I agree to personally conduct or supervise the described investigation(s). I agree to inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and I will ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are met.
Who is responsible for the oversight of the research
IRB, PI, Sponsor
What is the purpose of monitoring?
To verify that: •The rights and well being of human subjects are protected •The reported trial data are accurate, complete and verifiable from source documents •The conduct of the trial is in compliance with the current approved protocol/amendment(s), with GCP and with applicable regulatory requirements. •Quality Control = Ongoing, real-time assessment of study compliance with -the applicable regulations and -the protocol •Required by Federal Regulations (21CRF 312) and GCP ( ICH E6 5.1) •Encompasses data and safety oversight
Discuss FDA 483 observations:
-483 = a Notice of Inspectional Observations -FY 2016, the FDA issued 4,528 483's -Qualifications of responsible personnel -Adverse reactions, reporting and follow up -Expiration dates of IP -An investigation not conducted in accordance with the signed statement of investigator and investigational plan (1572) -Failure to prepare or maintain adequate/ accurate case histories -Investigational drug disposition records are not adequate -ICF issues (not approved, signed, dated, used) -Failure to report to the sponsor safety events -Record retention
What is the monitoring plan?
-A description of the methods, responsibilities and requirements for monitoring the trial -Tailored to the specific human subject protection and data integrity risk of the trial. -Should include a description of monitoring approaches, requirements for communicating monitoring results, managing non-compliance issues, and methods for ensuring quality oversight -Emphasize the monitoring of critical data and processes. -Special focus on aspects of the research that are not routine clinical practice and may require additional training -Provide a brief description of the study -List the Study Objectives -Describe the anticipated rates of recruitment -Describe any training required for monitors who will be responsible for the safety oversight of the trial -Monitoring methods and approaches -Describe the scope of monitoring and communication of monitoring results -Format -Process for communication -Describe the make-up of the DSMB and when it is to meet -Identify rules for when a trial may be stopped early (statistical considerations for early stopping when trending in the direction of harm or possible lack of effect)
What is a Data Safety Monitoring Board (DSMB)
-A group of individuals with pertinent expertise that reviews on a regular basis accumulating data from one or more ongoing clinical trials -Advises the sponsor regarding the continuing safety of trial subjects and those yet to be recruited to the trial, as well as the continuing validity and scientific merit of the trial -Used in early-phase investigations and some federally funded studies -Structure and operation outlined in a charter -Permits continuation or recommends halting of the study -Appointed by the Sponsor
What is a medical monitor?
-A licensed physician with expertise in the area being studied -PI can act as the medical monitor -Reviews and interprets safety data throughout the study -Issues recommendations to maintain subject safety -Cannot be PI, can have no financial conflict, and must be appropriately trained in the protocol
What will the monitor look at regarding informed consents?
-All copies of all approved versions of the ICF -Original signed consents -Original signed re-consents -Chart documentation of informed consent process
What regulatory documents will the monitor review?
-All submissions and decisions of the IRB/EC -Protocols and Informed Consents -Investigator's Brochure -Any written information provided to subjects -Advertisements -Delegation of Authority and signature log -CV and qualifications of Investigator and Sub Investigator -Financial Disclosure -FDA form 1572 -Certificates/Accreditations and laboratory ranges -Investigational Product (IP) accountability -Monitoring letters and follow up letters -All communications between the PI and the Sponsor -Meeting minutes -Protocol training -Screening/Enrollment log -Final report to Sponsor at time of study closure.
Who appoints the monitoring roles and what are the qualifications?
-Appointed by the Sponsor -Have the scientific and/or clinical background needed to monitor the trial adequately -Be thoroughly familiar with the investigational product (IP), the protocol, written informed consent and any other written information to be provided to subjects, the sponsor's SOP's, GCP and the applicable regulation requirements. -All qualifications must be documented -Must be separate from the research - no bias.
What is a study monitor or CRA?
-Assesses compliance with protocol, federal regulations and Good Clinical Practice -Perform monitoring of individual case histories, assess adherence to the protocol, ensure the ongoing implementation of appropriate data entry and quality control procedures, and in general assess adherence to good clinical practices. -Eyes and ears of the Sponsor -Need not be qualified to diagnose or treat the disease being studied -Strong knowledge of documents related to clinical studies, medical terminology and routine medical tests and procedures
What determines the level of monitoring?
-Degree of oversight dependent on risk level, size and complexity of the study as determined by the sponsor -On site vs. remoted monitoring •Differences in scope -Extent and nature of monitoring is established by the Sponsor in a Data Safety Monitoring Plan
What will the monitor look at regarding SDV and protocol compliance?
-Documentation to support all protocol required elements -Documents must be original -For every study intervention should be documentation of completion -CRF verification
What are some common findings during monitoring?
-Enrollment criteria not met -Informed consent process incorrect -Lack of Documentation of PI Oversight -Device and drug accountability discrepancies -Inappropriate delegation of study tasks to unqualified persons -Inadequate/Lack of Resources -Failure to adequately protect study subjects/data
Why is oversight of the research important?
-Ensures Data are reliable and reproducible -Protects subjects -Protects the Investigator -Protects the Institution
What will a monitor review?
-Essential Documents -Regulatory Document -Informed Consent -Eligibility & Inclusion/Exclusion -Adverse Event and Serious Adverse Event Recording & Reporting -Drug/Device Accountability and Storage -Source Data Verification
Describe the June 200 FDA report:
A report published by the FDA's Office of Inspector General in June of 2000, reviewed 184 official actions taken by the FDA since 1994. These actions were then categorized into different types of violations. In summary, the report found of those violations reviewed: -85% were based on documentation problems, including missing data, data discrepancies, falsification of data, and poor data collection. -82% were protocol violations, including enrollment violations, failure to follow the protocol, problems with investigator agreements, and violations related to drug use -74% were reporting violations, including failure to submit to the IRB or sponsor reports, consent forms, protocols, advertisements, and adverse events. -67% were human subject protections violations, most often surrounding the use of a deficient informed consent form, not obtaining signed informed consent prior to performing a study procedure, or missing signatures or dates on the informed consent form. -44% were drug/device/biologic control violations, citing poor control of the receipt, use and disposition of investigational drugs, devices, or biologics
DSMB members should. . .
Be experienced in clinical trials, Have no conflict of interest, Contain a biostatistician
What is CAPA?
Corrective and Preventative Action -Issue -Root cause analysis -Corrective Action -Implementation -Effective date -Preventative Action -Evaluation -Establish and maintain procedures for implementing corrective and preventative action
What is the difference between Monitoring Vs. Auditing?
Monitoring ("Quality Control") = Ongoing regular assessment of study compliance with the protocol, GCP and applicable regulations (happens throughout the study) Auditing ("Quality Assurance") = Point in time assessment of the effectiveness of the monitoring system and study compliance with the protocol and applicable regulations; occurs once at beginning of study (for improvements) and once at the end
What are the different monitoring roles?
Sponsor, Study Monitor, Medical Monitor, Data Safety Monitoring Board, Principal Investigator
DSMB Should Be Considered/Used When. . .
oThe study endpoint is such that a highly favorable or unfavorable result, or even a finding of futility, at an interim analysis might ethically require termination of the study before its planned completion oThere are a priori reasons for a particular safety concern, as, for example, if the procedure for administering the treatment is particularly invasive oPrior information suggesting the possibility of serious toxicities oUse of vulnerable populations oPopulation at elevated risk of death or serious outcome oLarge multi-centered or long duration study
