Close-Out Visits

I've done about 10 close-out visits in the last few months so it feels like a good time to write a short article explaining what the objectives of these visits are and how a typical close-out visit (COV) is conducted.

A COV will occur once subjects are no longer being dosed, all the data have been collected (there are no more outstanding AEs/SAEs & all outstanding Queries/data clarification forms have been resolved appropriately), the database is locked and ready for statistical analysis, and the study conduct has ended. At this point, the site's contributions are over so the monitor returns for one final visit to shut down the site. The whole concept behind a close-out visit is to ensure that everything is neat and tidy at the study site and that the documentation is well organized and will remain intact and be accessible in the future as needed for regulatory reasons. A sponsor or the FDA should be able to return to the place of study conduct years later and re-create exactly what occurred at all points during the trial by reviewing the regulatory documentation, subject and source documentation, full medical charts, and any other applicable study records. Documentation is everything in our industry and we are always saying, "if it isn't documented it didn't happen." If thorough and accurate records are not maintained, the PI cannot prove that the study was conducted in accordance with the protocol and all applicable regulations and that subject safety was adequately monitored throughout the conduct of the trial.

Site Supplies and Drug Return

We are using tamper evident tape to
box up investigational product for return.
If the tape is lifted it leaves behind an
artifact to show it has been tampered with.

One of your major objectives at the COV will be to assist the site in dealing with any unneeded study materials or supplies. With permission from the sponsor, some of these activities can even take place before the close-out visit as you remotely supervise. The close-out duties will likely include disposing of or retrieving all unused lab or study supplies such as patient handouts, electronic diaries, etc. In most cases, you will have the site generate a file note or similar documentation so there is a record indicating that study supplies were disposed of or moved off-site. 9 times out of 10, the Investigational Product (unused and the used packaging) will need to be inventoried, accounted for in drug logs, and then shipped to a depot or destruction facility. Sometimes the drug will be destroyed on site by a pharmacist or according to the site's SOP but this is really the decision of the sponsor. If you are lucky, you were able to pack up and ship back drug routinely throughout conduct otherwise you will have to deal with it all at the end.


Essential Documents
You will have the PI sign off on any tracking logs that were used during the study. The original will be placed in the site's Regulatory binder but you will retrieve a copy for the Trial Master File. You will ensure that a Subject Identity List was completed and will be kept that lists the contact information for all treated subjects (you will not take a copy of this document as it has private information and stays at the site only). Documents you will take copies of include: Site Visit Log, Subject Screening AND Enrollment Log, Delegation of Authority Log, Proof of Drug Receipt, Subject Specific Investigational Product (IP) Accountability Logs, Copies of temperature/freezer logs, Site Initiation Statement, Training Documentation, Overall Site IP Log, Protocol/Amendment Signature Pages, Any updated 1572s, medical licenses, or CVs, Site communications to the IRB/IEC (ethic committee), and the IRB Final Status Document. Obviously in a study with many safety reports, a long line of routine monitoring visits, multiple site hand-offs/transitions between several different monitors, or a slew of important correspondence, checking that the essential documents binder(s) is in perfect order can be a time-consuming task.

Subject Records
Although you will have already verified this throughout conduct, the close-out visit is your last opportunity to be absolutely sure that the appropriate version of signed and dated Informed Consent Forms are on file for every subject. You will also check that all source is complete (all lab reports and ECGs have been signed and dated with Clinical Significance assessed by the PI/Sub-I) and that all AEs/SAEs have been signed off by the PI/Sub-I and that they were followed to resolution as specified by the protocol. Finally, check that all significant Protocol Deviations (study procedures not conducted according to protocol, enrollment of inappropriate subjects, dosing errors, consenting errors, unblinding, subjects developing withdrawal criteria yet continuing in study, etc.) have been properly recorded and the sponsor/IRB has been notified as appropriate.

PI Responsibilities
Discuss with the PI his/her responsibilities including: query/data collection following the close-out visit, essential document retention, publication rights, and the necessity to update the Financial Disclosure statement if there are changes in their financial interest for up to one year following completion of the study. Finally, explain to the PI the potential for regulatory agency inspection and the requirement that the site notify the CRO/sponsor immediately if contacted for an audit/inspection.

Assuming you have done a thorough job in monitoring throughout conduct, the COV should be a relatively short-visit. Meeting with the PI to discuss their regulatory responsibilities post trial conduct and obtaining required signatures usually takes less than 20 minutes assuming they are an experienced investigator and are already familiar with the GCP schpeel. Drug return often takes several hours but you can prepare most drug return documents in advance of the visit by using sponsor or IVRS reports and usually save a considerable amount of time on-site. You should have been reviewing the regulatory binder at every visit throughout conduct so it should really be in order at this point and stuffed to the brim - I usually budget no more than an hour to ensuring that the binder is complete.

After you complete the close-out visit, you will write a report to the sponsor to let them know that all of the objectives were completed and a follow-up letter to the site thanking them for their participation and informing them that there are no further pending action items. Any new regulatory documentation you copied while on site will need to be forwarded to the Trial Master File so that the sponsor's documentation is a true mirror of what is on site.

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

• Introduction to Monitoring December 2007
• Meeting with the PI August 2011
• Routine Monitoring Visits March 2008

Who's running this study?

I just received an interesting article from a colleague:
http://www.tampabay.com/news/business/article463686.ece
The article discusses a clinical research unit in Florida where the PI oversight isn't exactly verifiable. This is always an issue for us as monitors, especially when the Dr. practices from one location and the study is conducted in another. I apply extra scrutiny in this case to ensure everything is in order and that the data isn't "too perfect" (do the subjects even exist? qualify? are they being followed properly as per protocol?, etc.)

As a monitor, I always like to have the sponsor pin down (before conduct begins) exactly which actions can be delegated (lab draws, EKG, etc) and which actions must be reserved for the PI or medically licensed personnel. In many studies, the assessment of Inclusion/Exclusion Criteria, Physical Exams, Dose escalations/de-escalations, and Lab/safety reviews are responsibilities that must be reserved for the physician. It is best if this is written in a statement on the Delegation of Authority Log but I take what I can get and always include this as a topic at site selection and initiation visits.

I always prefer to work with sites where the PI is highly involved but as monitors we don't always get that choice and the quality of the data can suffer. However, I recently worked with a site that enrolled almost 30 subjects in one month. They were the highest enroller and the numbers shocked everyone -- I immediately suspected that the PI may not have been very involved in the conduct due to the volume and time commitment that would require. The site had been initiated at the IM so by the time I had my first visit, they had enrolled over 10 subjects in this 7 week study. I conducted 4 routine monitoring visits over the 2 months and even brought co-monitors with me to handle the volume and "sniff out the deficiencies". At each visit the PI was available and very informed about his subjects and was constantly asking me to go back to the sponsor for clarifications on the protocol and to discuss changes he witnessed in his patient's lab values. My instincts were good but the reality is this PI was also very good and very involved in the oversight and conduct of the trial so I had nothing to worry about after all. The site was organized, fast at CRF entry/query resolution, and thorough. I would work with the site again in a heartbeat. That just goes to show that you don't always have to compromise quality when you have quantity.

On the other hand, I had a few other high enrollers in this study where PI oversight would have gone a long way to improving conduct. So the takeaway here is be especially wary when the PI is MIA and you have an over-zealous coordinators who always reassures you that "it's fine" ,"I'm handling it", "oh really, I didn't realize the protocol meant it that way..." and other red flag statements. Make sure the PI is available to meet with you at every visit. If you have had 2 visits in a row where the PI isn't around, escalate it to your lead CRA or the sponsor or refer to your SOPs. When an investigator signs a 1572, that is a legal contract that they agree to personally oversee the conduct of the trial. If you aren't satisfied that this is happening, document it in your report and follow-up via phone or meet with the PI to discuss your concerns. It is an uncomfortable conversation but that is one of your responsibilities as a monitor. I know from experience that this conversation is easier to have in the beginning rather than at the last visit before data lock, or when it is time to sign off on the casebook, or even after a (gulp) sponsor or FDA audit.

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

Tips for Frequent Travelers

So I have already written to you about travel safety, and now I am going to write about some travel perks; mainly hotel points and airline miles. It is to your benefit when traveling for business to accrue some rewards for yourself. First you will want to obtain and read a copy of your company's travel policy so you know where they can flex and where you will need to flex. For example, my company requires me to book through their travel agent and we have preferred hotels and a preferred rental car company. I must pay for everything with my corporate Amex and then be reimbursed (so other loyalty Credit Cards are not an option) but I can (and do) add Membership Rewards to my Amex account for $75 a year and collect membership rewards points for every dollar of my employer's money I spend on travel to and from sites.

I spend a lot of time on airplanes and
collecting reward miles is a real perk
that I can use to obtain discounted or free
 leisure travel.

In regards to airfares, it is wide open so I can research and communicate to the travel agent which fares I want provided they are within the travel policy guidelines. In this way, I can maximize my reward points and choose to focus my reward accruing efforts on a preferred airline/chain so I can rack up miles/status/points for leisure travel. Be careful of diversifying too much or you will only achieve a low level of status/rewards in many programs whereas it is typically better to have a lot of status/rewards in just a few programs. This is less flexible but in general, you will see greater returns when you focus your efforts.

I was first going to attempt to download all the tidbits I have learned over the years but then decided a list of my favorite web links would be much more effective.


Find the Lowest Airfares

• ita software - Click on the graphic in the lower left called 'Search Fares using QPX'. Be exact with your entry as this system can't really 'guess' at what you want. When your results come up use the third toggle button at the top to 'choose flights (graphical)' Now you can sort and stack and filter or just choose one segment at a time. I love this site! The only airline I have found not listed so far is SW so I just check them separately.

• Kayak.com - Another price aggregator as above.

• FareCast.com - Will the fare be cheaper if you wait until next week to book it? This site tells you!

• Yapta.com - Tag a fare and book it once it is cheaper. If the fare does drop after you already booked (assuming you booked directly through the sirline website) you might be entitled to a refund or future credit thanks to the low fare guarantee).

• Many airlines will give you bonus miles for booking through their site. I can't do this because we are required to use the agency but this is especially powerful when you own and book with their co-branded credit cards. Something to look into...

Booking Hotels

• tripadvisor.com - great reviews and rankings of so many properties

• PointMaven.com - hotel bonuses!
  

• Again, pick one or two chains and accrue status so you get upgraded rooms and executive lounge access, free breakfast, bonuses, etc. Plus, once you are at the higher tiers you typically accrue points faster. This chart is helpful for comparing the different loyalty programs - thanks Starwood Preferred Guest program!

• One more tip here, once you get high level status in one program call competing programs and ask them to 'status match' or to allow you to 'challenge' the high tiers of their loyalty programs. These promotions are usually offered in the first half of the year. Airlines will status match, too -- never hurts to ask, anyway!

Misc

• seatguru.com - Make informed decisions when choosing your seat - make sure your seat fully reclines and that it doesn't have a blocked view of the TV or limited space.
  

• seatcounter.com - How many seats are left in each class of service on a plane. Helpful when you are hoping for operational or status based upgrades to a higher class cabin or if you are looking to get bumped (sometimes you can plan to miss a flight because you will be compensated with a free roundtrip US ticket or a discount voucher for future travel).

• MileMaven.com - Airline bonuses and promotions.

• flyerguide.com/wiki - An ever-changing Wiki that has aggregated information about traveling and loyalty programs. Companion website to flyertalk, see below.

• flyertalk.com - This is an online forum with lots of frequent travelers who share their tips. I subscribe to posts and threads and I get these emailed to me weekly. I download my email to a local client so I can browse through them in digest format while on my frequent flights. I have learned so much here and love this free site.

Tools for Tracking Points and Miles

• Here is an application you can download to have a desktop view of all your mileage/points programs: http://www.usatoday.deskport.biz/

• I prefer a web-based program so I can recommend the following: http://www.mileagemanager.com/ (this site is free to try for 30 days and then $14.95 annually. It has rewards summaries but also lets you know which accounts are about to expire, and my favorite part is the 'Elite status summary' which tells you what you need to earn to get to the next Elite level in any given program.)
  

• http://moneycenter.yodlee.com/ (this site is free and will also manage your personal finances and help you set budget goals or you can just add your reward programs and have it manage those exclusively. Of note, your bank might already subscribe to this service for you as some major financial institutions like Bank of America, Fidelity, and Wachovia do... Check here)
  
  

Shoot me an email or leave me a comment if something important is missing from this post or you have more questions about this topic that I can answer. I would also love to hear your tips and success stories so feel free to leave those comments as well!
Read more about What to Pack in this post.

Clinical Fraud Hearing Held Today

I received an email from my old boss today alerting me to an interesting webinar. I am posting it for other people's benefit. She states "The webcast below is a hearing to explore fraud at a clinical site for a study conducted by Sanofi-Aventis. The hearing took place this morning. Interestingly, the CRO and the CRA who monitored the site are among the witnesses..."

from the webinar site:
"Ketek Clinical Study Fraud: What Did Aventis Know?
The House Energy and Commerce committee’s subcommittee on oversight and investigations will hold a hearing at 11 a.m. EST to explore what Sanofi-Aventis knew about the problems with clinical trials for its Ketek antibiotic. Last February, the FDA withdrew approval for two of three uses for the drug, and issued a Black Box warning for use in treating community-acquired pneumonia, which was issued in the wake of numerous Ketek patients suffering 93 adverse events, including 12 deaths.

Among the witnesses will be Chuck Grassley, the US Senator from Iowa, and Ann Marie Cisneros served as a clinical research associate for PPDI, a contract research organization that conducts clinical trials on behalf of drug sponsors. Last February, Cisneros appeared at a hearing held by the same committee focusing on the FDA’s failure to ensure safe prescription drugs. Cisneros testified that Aventis knew of fraudulent clinical trial data involving Ketek, but that the company chose to ignore it."

Go here to watch an archived webcast

Feel free to comment on this post or shoot me an email if you have any thoughts or additional questions.