IRB Integrity

I am starting to monitor a new study at 4 Academic Institutions. The Academic Institution Review Boards (IRB) have a reputation for being very stringent and the IRB process can be quite lengthy (not to mention the contracts process and everything else related to start-up). It has been interesting to contrast the reporting and documentation requirements required for these study sites versus other studies I have worked on that used a central IRB. For example, some IRBs don't even want the IND Safety Alert letters submitted to them unless the cause of the Serious Adverse Event is at least possibly related to Study Drug, some IRBs have approved new versions of the ICF and yet only require consenting newly enrolled subjects on the updated version but no re-consenting of currently enrolled subjects, some IRBs don't even want to be informed of the Protocol Deviations unless they directly impacted subject safety or the integrity of the study, etc.

In any case, I came across a media piece about ethics committees this week on Anderson Cooper and found it provocative so I am posting the link for you. These Academic IRBs may be difficult to navigate but at least they aren't fly-by-night operations like the ones shown here. Click here to see the video.

14-Apr-2009: Just a quick update that Coast IRB has been shut down. Here is a link to the Denver news article a friend sent me. Click here to read the story!

Close-Out Visits this Quarter

I've been performing close-out visits for a variety of studies lately and I am ramping up on a new study. Sorry I haven't been able to post sooner, but in this economy I am happy to have a great job that is keeping me busy with such interesting and varied assignments.

I have been closing other people's sites on studies I didn't even work on so one of my more time-consuming responsibilities has been a full regulatory binder review. Typically for sites I manage over time, I know what is in the binder and can verify that the documentation contents at the study site match the contents at the sponsor's Trial Master File (TMF) exactly (since I work for a large organized CRO we also have a fantastic suite of applications and reports to help us with this reconciliation process). The reports and previous monitoring reports help me identify what documents need to be updated and I email the list to the coordinator several weeks before the visit. Since I need to retrieve a copy of any updated documents for the TMF I just ask the coordinator to slip a second copy for me in a folder or email me an electronic version and this has dramatically reduced the time I would spend taking apart their binder and hovering over the copy machine. Some sponsors want the site to keep originals of all study logs and some sponsors want the site to keep copies so they get the original. Some sponsors consider a signed CV to be good for 2 years whereas some require annual updates. Some sponsors want an updated 1572 and/or Financial Disclosure Forms at the end of the study and some sponsors don't ask for this at all. There are few hard and fast rules for documentation (aside from the ICH/GCP guidelines in section ICH E6, Section 8.4) so I have to understand the study specific requirements in advance of the visit (these are communicated in team meetings and documented in the study monitoring plan) to know which documents to retrieve.

Another area that has required a lot of time and attention is the return of the Investigational Product (IP). To assist me with the drug return I have requested reports from the inventory management system several weeks in advance of the visit and submitted them to the pharmacist or Study Coordinator. I ask them to organize the medication numerically by lot/kit # into used and unused lots and to check that all drug receipt and dispensing forms are accurate and complete and that the quantities match the CRFs. I follow-up over the next several days via phone or email and ensure they have completed the task. Typically they print the inventory reports and highlight them or make comments when there is a discrepancy. I always have them fax me any notes and copies of all the drug logs so I can review them. I can prepare the bulk of all my drug return documentation before I even arrive at this site and that saves a lot of time during the visit.

The last item that has been a real time-synch is reviewing the safety binder to ensure that every safety alert was acknowledged by the Principal Investigator (PI), submitted to the Institutional Review Board (IRB), acknowledged by the IRB, and that all that documentation is filed in the binder and submitted to the TMF. Luckily, I have been able to do work prior to the visit to help this task go as smoothly as possible (one study I closed out had over 5000 safety alerts so that could easily have been several days work whereas another study only had 42 and I knocked out the review task in about an hour). As you know, this review of safety letters should have been occurring all through conduct and regular monitoring visit but unfortunately, when it is not your site, you're really forced to re-review every bit of documentation unless the previous monitoring report(s) can confirm the documentation is current. For each site I closed I sent a safety letter tracker. It was just an excel spreadsheet where each alert was listed by date in the order in which it was sent to the site with a brief description that included the event #, event name, event onset date, patient initials, and a column specifying whether the event was an intial report or follow-up report. Finally, I added three blank columns to the end of the spreadsheet with the titles 'Date Ack. by PI' , 'Sent to IRB Y/N', 'Date of IRB Ack.' In each case, I required the study staff to complete the tracker and email it back to me prior to the visit. By using this technique we easily discovered missing documentation in advance fo the visit. I was able to forward blank copies to the site to prepare before the visit and we had time to obtain sign-offs and do the necessary IRB submissions. It was helpful to be sure pending safety letters didn't delay official notification to the IRB of study closure.

In summation, close-out visits at my own sites go pretty quickly and are fairly routine whereas there is a lot more work involved with closing out someone else's sites. To make the visits easier I worked with the site staff several weeks before the visit to address the documentation gaps in the regulatory binder, review all the IP documentation, and to ensure that all safety letters had been properly acknowledged by both the PI and the IRB. By thoroughly preparing in these 3 time-consuming areas, I had plenty of time while on site to accomplish all of my close-out responsibilities (click here to learn more about COVs in my blog post from last year). One other huge plus is that I knew what to expect once I arrived on the site, had developed a rapport with the staff, had prepared organized checklists, and then I left the sites with minor or no pending action items whatsoever. This all contributed to being able to easily and quickly finalize my close-out visit reports. I hope my experience helps you better prepare when you are asked to close-out someone else's site (or even your own). Do your homework before the visit and it should go like clockwork.

Routine Monitoring Visits

Routine or Interim Monitoring visits are basically any visit that occurs after the site is initiated and up until the site is closed out. As monitors, we visit our sites periodically to ensure that they are compliant with all the regulations, subject safety is being adequately followed, data is being captured in a timely and reliable manner, the Investigational Product is being handled as per protocol and relevant regulations/guidelines, there are no significant deviations from the planned study protocol, all important study documentation is being generated and stored properly, and that the research site is adequately supplied in regards to lab kits and other pertinent study materials. The ultimate purpose of our job is to protect subject safety by monitoring the trial conduct for ICH/GCP compliance.

When planning your monitoring visits
it is helpful to have a reasonable expectation
of how think the medical records and source
documents will be. Know in advance how much
you will need to review so you budget enough
time to successfully complete your objectives.

Your agenda from visit to visit may vary slightly based on the length of the study and how many times you plan to visit, the amount of time you spend to plan at the site for this particular visit, the site's progress to date (if a site has yet to enroll any subjects you surely won't have any CRFs to review or pull), and where you are at with the general monitoring plan (for example, drug accountability may be done all along or just at close-out).

Prior to your visit you will contact the site to set up a suitable time for your visit. Visits typically last a day or two. Ideally, the PI would be available to meet with you during the visit. You will send a confirmation letter to the site once a date is set (be sure to confirm the address before you go if you haven't been there before!). More often than not, your study lead will provide you with a monitoring visit checklist or at the very least, a monitoring report template so you will know exactly what tasks you are expected to perform on-site and what topics to cover. Here are some of the specific tasks that are routinely performed at these visits:

1. Informed Consent Form (ICF) review: You are ensuring that every subject was adequately informed and consented to the study before any study procedures were completed (I recommend checking lab draw times and ECG times - if required at the screening visit - against the consent time to be extra sure that the consent was the first study procedure to occur). There are other state specific regulations you will need to know and monitor for. For example, in some states subjects must be 19 to participate and in California every subject must sign the 'CA Bill of Rights' document, etc. Sometimes there are multiple versions of a consent due to a change in the facility address or the details of the protocol. Ensure that all subjects signed on an IRB approved version (each page will be stamped in the upper right hand corner and the version date will be printed on each page). Proper consenting of subjects is critical to ensure the security and privacy of health data and that subjects are adequately informed of the study procedures, risks and, benefits. If the consent is not signed or properly completed inform the Study Coordinator and do not review this subject's medical chart until consent has been properly obtained.
2. Check for Serious Adverse Events (SAEs): Per the guidelines, an SAE is any untoward event that results in death, prolonged or new hospitalization (longer than 24hrs), significant disability, or congenital anomaly (birth defect). If the event has not been reported, assist the Study Coordinator in doing so and inform the sponsor immediately.
3. Review Protocol Compliance: In your chart and source document review, you can verify that subjects were sign at the right times and the right procedures were conducted as per the protocol. You will have study-specific procedures for reporting deviations. Deviations of a serious nature may be reported in an expedited manner and may need to go to the IRB (dosing errors, unblinding of study treatment, subject enrolled that did not satisfy entry criteria, etc.)
4. Compare source documents to Case Report Forms: You are checking that the data in the chart matches the Case Report Forms (which will be later entered into the clinical database and combined with other subject's data to complete the safety and efficacy analysis for the Investigational Product). Determine whether or not CRFS being completed in a timely manner. You also want to verify that the source is complete, neat (all corrections must be compliant with the regulations - white-out is not OK), attributable (who wrote it? Is it initialed and dated), contemporaneous (was it written at the time the procedure was completed?), valid (is the data collected even possible?), etc. Sometimes you will be asked to pull the case report forms and send them in to data management and other times they will stay at the site until the end of the study.
5. Review Investigational Product (IP): The study protocol will explain how the IP is to be stored, dispensed, and returned. Verify that all of this occurred properly by reviewing temperature logs, storage facilities, administration records, IVRS entries/reports for subject-specific IP accountability, and speaking to the relevant personnel.
6. Regulatory Binder / Essential Documents Review: Determine if any forms need to be updated or pulled for the Trial Master File (TMF). The TMF is meant to be an exact replica of all the documentation at the site. Specific information regarding the contents of the essential documents binder are covered in section 8 of the guidelines.
7. Confirm Site Adequacy / Site Status: Determine if there are new staff at the site or if staff have left. Can the site manage with current staff? Has the site or the lab moved? Confirm that there are adequate study supplies
8. Study-Specific Monitoring Tasks: Depending on the protocol, you may need to perform additional tasks such as shipping materials back to headquarters (for example lab specimens, xrays, etc.), calibrating or reviewing calibrations of equipment, site training, checking eDiary compliance, etc.
9. Review Ongoing or Pending Issues from Previous Visits: At some point during every visit work with the staff to resolve any items identified at previous visits as ongoing issues. Indicate in your report once these are resolved.
10. Review of findings with the site: Whether or not you find issues during your visit, keep the site staff posted on your progress and how things are going. Especially, if the Principal Investigator is not available during the visit, be sure to summarize everything accurately and completely in your follow-up letter.

Try to schedule your next (or next several) visits before you leave the site. After the visit, write your report and send the follow-up letter within a week or per your monitoring plan and refer to your company's SOPs. Always report significant compliance issues to your management, the sponsor, IRB, and QA as appropriate. Remember that you must document everything because of the adage, "if it isn't documented, it didn't happen". Please contact me if I can elaborate on anything or if you think I've left something important out.

You may also like...from The Lead CRA archives:

• Introduction to Monitoring December 2007
• Meeting with the PI August 2011
• Close-Out Visits July 2008