Preparing for and Handling Monitoring Visits and Audits Subtitle: Why You Have to Tolerate Monitors Shari Lawler, MSN, FNP

I have no real or apparent conflicts of interest to report. Shari L. Lawler, MSN I have no real or apparent conflicts of interest to report.

Disclosure Presenter has no financial interest in anything except sheep and cattle. Good Morning! I hope everyone is as well-caffeinated as I am this morning. I’d like to thank Dr. Ron Waksman for adding Research to CRT. I work for the CRI as a Consultant CRA monitoring IIT. I’ve been a monitor for 12 years and prior to that I was a coordinator.

Key Point to Remember Effectively communicating and working with the Monitor is one of the best ways to prepare your site for an FDA Audit. If you remember nothing else I say, please remember this…effectively communicating and working with the Monitor is one of the best ways to prepare your site for an FDA audit. PIs and CRCs often dread monitoring visits which is counter-productive. View monitoring as a valuable extension of your research program. This is the person that is going to make sure you are audit

Purpose of Monitoring Visits Protection of human subjects Accuracy of data Compliance with protocol, GCP, and FDA regulations Verify that rights and well-being of subjects are protected Verify that reported data are accurate, complete, and verifiable from source documents Verify complain with approved protocol, CGP guidelines, and all applicable regulatory requirements

Administration to qualified subjects CRA Communication: Data Center Sponsor Site CRO Verify Compliance: Federal Regs Protocol GCPs IP Accountability: Storage Administration to qualified subjects Documentation of receipt, use, return Disposition of unused drug or device Source Documentation PD/AE/SAE Reporting Query Resolution Verify Accuracy: CRF/EDC

Types of Monitoring Visits Pre-Study Site Visit Site Initiation Visit Interim Monitoring Visit Close-Out Visit We’ve talked about why the monitor comes to your site, now let’s talk about when they come.

Pre-Study Site Visit Monitor will visit the site to discuss: Suitability of Investigator, Site & Staff Regulatory requirements Sponsor’s expectations Not all studies require a PSSV. These are usually conducted by the Sponsor when choosing sites that they have not worked with in the past. Be realistic when making patient population claims and enrollment projections. You don’t want to take on a study you can’t enroll in.

Site Initiation Visit Monitor will: Review protocol Review regulatory Review data submission Perform IP inventory Verify shipment of study supplies Review PD/AE/SAE/UADE reporting During the SIV the monitor will explain the study and what is required of you, the site. Take notes! This is your opportunity to ask lots of questions. The monitor will: 1) review the protocol and study requirements – be familiar with the protocol so you can ask questions. 2) review regulatory binder 3) review data handling guidelines and source documentation requirements which means access to original medical records, not shadow charts 4) perform investigational product inventory – accountability for study drug or device 5) verify receipt of study supplies, if you haven’t received lab supplies or CRF binders, etc. – let the monitor know 6) review requirements for reporting adverse events, serious adverse events or unanticipated adverse device effects

Site Initiation Visit Cont’d Discuss GCP, FDA regulations, and Sponsor requirements Discuss study staff roles & responsibilities Review CRF completion/EDC training Discuss recruitment strategies & enrollment expectations Review monitoring procedures These are the activities that the monitor will perform during the SIV. Your role as the site is to have dedicated space available for the visit, make sure study staff are present for the protocol review, pre-arrange Pharmacy visit if they are responsible for the study drug. Be familiar with the protocol so that you can ask questions at the SIV.

Preparation for IMV Clinical Research Coordinator (CRC) should arrange for: Area for monitoring Internet connection/telephone Access to medical records/EMR Time to meet with PI, Pharmacy, Regulatory Coordinator, etc. Time for addressing issues/making corrections

Preparation for IMV Cont’d Assure that documentation is available and up-to-date: Drug or device accountability log Subject screening/enrollment logs Serious adverse event reporting Protocol deviation reporting Data entry completed prior to visit Queries resolved Regulatory binder current These are the activities that the monitor will perform during the SIV. Your role as the site is to have dedicated space available for the visit, make sure study staff are present for the protocol review, pre-arrange Pharmacy visit if they are responsible for the study drug. Be familiar with the protocol so that you can ask questions at the SIV.

During the IMV PI available to discuss findings CRC available to make corrections and address action items Resolve as many outstanding action items during the visit as possible

Preparing for Audits Who What AUDIT When

Type of Audits Internal Audit Sponsor Audit Research Compliance Audit Federal Agency Audit

An FDA Audit: What the Investigator Needs to Know Notify the Sponsor, IRB, and study team of impending audit Have available: All study documents Person knowledgeable about the study A place to review records Access to a photocopier

FDA Audit: What Is Reviewed Administrative Protocol/Informed consent forms Amendments to protocol/consents Drug/device accountability records Sponsor/IRB correspondence IRB Approvals/Progress reports/AE reports 1572/Investigator Agreement

FDA Audit: What Is Reviewed Case Report Forms How data is recorded/corrected Compared to source documents Supporting Files(Source Documentation) Hospital Chart Clinic Chart Research Chart

FDA Audit: What Is Reviewed Informed Consent Forms Are all required elements included Are additional elements relevant Was it approved by the IRB Were they signed and dated by subjects Does FDA have current version

FDA Audit: What Is Inspected Interview study staff Test article storage area Data Audit Examine case report forms and compare with source documents Compare sponsor tabulations with source documents and case report forms

FDA Audit: Critical Issues Is study entry recorded? Did subject meet inclusion/exclusion criteria? Is IP administration documented? Is there study raw data? Did an IRB approve all significant stages? Did each subject provide proper informed consent prior to study entry?

FDA Audit: Critical Issues Were all screened subjects entered? Does amount of test article used coincide with number of subjects treated? Was test article properly disposed of? Was blind maintained? Was randomization scheme followed?

FDA Audit: Common Deficiencies Protocol non-adherence Failure to report concomitant therapy Inadequate and inaccurate records Failure to report adverse events Inadequate drug or device accountability IRB problems Informed consent

FDA Audit: What Goes Wrong Most commonly observed deficiencies in these areas include: Failure to follow the protocol Violation of inclusion/exclusion criteria Failure to perform required tests Failure to maintain adequate and accurate records absence of supporting source documents inaccurate or incomplete source documents

FDA Audit: Exit Interview Discuss inspection findings May issue an 483 Represents deviations from federal regulations for clinical investigators Verbal response to 483

Tips for A Successful Study: Understand Responsibilities Read the following before you sign-on ICH GCP Consolidated Guideline FDA GCP Regulations FDA Information Sheets for IRB’s and Clinical Investigators: http://www.fda.gov/oc/oha/irb/toc.html 21 CFR Part 312 / 21 CRF Part 812 http://www.access.gpo.gov/nara/cfr/index.html

Tips for a Successful Study: Enhancing Protocol Adherence Fully understand protocol limits and the importance of strict compliance Is there latitude with concomitant therapy? Is it ok to skip procedures that are not medically necessary (lab tests, PEs, biopsies)? Which protocol procedures can be performed by non-physician study support staff?

Tips for a Successful Study: Enhancing Record Quality Clearly understand what records are to be maintained and how they should be completed Original source data for critical study endpoints Use your site’s indigenous record-keeping system to the maximum extent possible, discuss this with the sponsor up front

Tips for a Successful Study: Enhancing Record Quality All records should meet the ALCOA test: Attributable Legible Contemporaneous Original Accurate

Tips for a Successful Study: Enhancing Record Quality Minimize the need for transcription Don’t throw anything away especially originals Expect the worst FDA will be inspecting the records

Tips for A Successful Study: Communicate With the IRB Protocol changes Continuing review With sponsor and monitors Openly address problems With regulatory authorities Understand expectations Honor reporting obligations