Routine Monitoring Visits

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Pre-Study Visits and Site Initiation Visits

Posted onJanuary 7, 2008byThe Lead CRAininitiation visit,PSVwith20 Comments

Depending on the company you work for and the Standard Operating Procedures (SOPs), youmay be required to complete an in-person Pre-Study Visit (PSV) before an investigator isinitiated to join a clinical trial. In some cases, you may even be able to perform this via

telephone, web-conference, or it might be waived altogether (say, for example, an investigator

your firm has collaborated with in the past 18 mos or so).

The objectives of a pre-study visit are to review the adequacy of the site, the training and

experience of the study staff, the access to the right patient population, and the sites interest inthe study. If the site isnt motivated or if they are already participating in studies that would

compete for the patient pool, they may not be a good recruiter. It is expensive to start up a site,

monitor them, and supply them with all the study materials and training. Ideally, you would only

open sites that would perform well but in reality, there are always dud sites in every study(Read my related post onSelecting Qualified Investigators). This is typically a 2-4 hour visit.

After your visit, you will likely need to complete a report template or assessment and send a

follow-up letter to thank the site for hosting you and inform them whether or not they have beenchosen to participate in the study.

At an Investigator Meeting there may be

presentations and break out sessions

to answer questions and train study

staff with the skills required to properly

execute the protocol.

The initiation of a site can sometimes occur at an Investigator Meeting (IM) where all the

potential investigators are brought together in (a typically quite fancy) hotel or other conference

arena to receive group training on the new study. More often, however, this will actually takeplaceon-site. This is usually a 4-8 hour visit and you may be accompanied by a Project Leader,

Medical Monitor, or even Data Management personnel just depending on the desire of the

sponsor. Before your visit, you will coordinate a convenient time for the study site and confirm
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your visit with a letter informing them when you will arrive and what the objectives of the visit

will be. It is important to physically be at the site so, as a monitor, you can visit the labs,

pharmacies, and other areas where the research will be conducted to ensure they are adequate.For example, both labs and pharmacies should have restricted access and the site should know

where it will store the Investigational Medicine/Product (IP) and this location should be locked.

If the site will be storing blood or tissue samples, you will inspect their freezers and ensure thatthey maintain adequate temperature logs and have standardized sample handling protocols andtraining.

During your initiation visit you will probably spend a great deal of time training or reviewing the

study protocol design and answering questions from the site personnel. You will also want the

Principal Investigator (PI) to be available for specific parts of your presentation. Specifically,

you will need to discuss the Investigators Responsibilities as related to the regulations to ensurethere is agreement and understanding (The investigator may choose to delegate some of his/her

responsibilities but ultimately, they will be responsible for all actions and conduct of the study.

Specific study related activities can only be delegated to those who posses adequate training and

experiencea secretary cannot perform a Physical Exam, etc.); You will explain publicationpolicies and documentation responsibilities; You will inform the PI that you will need timely

access to subjects records and the acceptable time frame for completing patient data case reportforms (CRFs) and answering queries regarding the data). Document everything that is discussedso you can add it to your report and if there are any questions that are unresolved at the end of

your visit, you can include resolution for those in your follow-up letter after the visit.

Email me if you have more specific questions. Now that our study is underway, next time I will

discuss how and why we completeroutine monitoring visits throughout the study conduct period.

Routine Monitoring Visits

Posted onMarch 16, 2008byThe Lead CRAinchecklist,CRF,essential documents,ICF,

informed consent,IP,template,TMF,trial master filewith12 Comments

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 theyare 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
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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 trialconduct for ICH/GCP compliance.

When planning your monitoring visitsit is helpful to have a reasonable expectation

of how think the medical records and sourcedocuments will be. Know in advance how much

you will need to review so you budget enoughtime to successfully complete your objectives.

Your agenda from visit to visit may vary slightly based on the length of the study and how manytimes you plan to visit, the amount of time you spend to plan at the site for this particular visit,

the sites progress to date (if a site has yet to enroll any subjects you surely wont have any CRFs

to review or pull), and where you are at with the general monitoring plan (for example, drugaccountability 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 typicallylast 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 havent been there before!). More often than not, your study lead will provide you witha 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 wasadequately informed and consented to the study before any study procedures were

completed (I recommend checking lab draw times and ECG timesif required at the

screening visitagainst the consent time to be extra sure that the consent was the firststudy 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 andin 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 (eachpage 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
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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 subjects medical chart until consent has beenproperly obtained.

2. Check for Serious Adverse Events (SAEs): Per the guidelines, an SAE is any untowardevent that results in death, prolonged or new hospitalization (longer than 24hrs),significant disability, or congenital anomaly (birth defect). If the event has not beenreported, 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 verifythat subjects were sign at the right times and the right procedures were conducted as perthe 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 subjects data to complete the safety and efficacyanalysis 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 regulationswhite-out is not OK),

attributable (who wrote it? Is it initialed and dated), contemporaneous (was it written atthe 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 ofthe 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 staffhave left. Can the site manage with current staff? Has the site or the lab moved? Confirmthat there are adequate study supplies

8. Study-Specific Monitoring Tasks: Depending on the protocol, you may need to performadditional 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 everyvisit 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 everythingaccurately and completely in your follow-up letter.


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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 companys SOPs. Always report significant compliance issues to your management, thesponsor, IRB, and QA as appropriate. Remember that you must document everything because of

the adage, if it isnt documented, it didnt happen. Please contact me if I can elaborate on

anything or if you think Ive left something important out.

Close-Out Visits

Posted onJuly 9, 2008byThe Lead CRAinMonitoringwith4 Comments

Ive done about 10 close-out visits in the last few months so it feels like a good time to write ashort 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 sites 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 ensurethat 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 exactlywhat occurred at all points during the trial by reviewing the regulatory documentation, subjectand source documentation, full medical charts, and any other applicable study records.

Documentation is everything in our industry and we are always saying, if it isnt documented it

didnt happen. If thorough and accurate records are not maintained, the PI cannot prove that thestudy was conducted in accordance with the protocol and all applicable regulations and that

subject safety was adequately monitored throughout the conduct of the trial.
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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 unneededstudy materials or supplies. With permission from the sponsor, some of these activities can eventake 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 siteby a pharmacist or according to the sites SOP butthis 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 DocumentsYou will have the PI sign off on any tracking logs that were used during the study. The original

will be placed in the sites Regulatory binder but you will retrieve a copy for the Trial MasterFile. 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 DrugReceipt, 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, Sitecommunications 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
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correspondence, checking that the essential documents binder(s) is in perfect order can be a time-

consuming task.

Subject RecordsAlthough 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 InformedConsent 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 werefollowed 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 asappropriate.

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 yearfollowing 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 arean 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 byusing sponsor or IVRS reports and usually save a considerable amount of time on-site. Youshould 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 brimI 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 theirparticipation 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 sponsors documentation is a true mirror of what is on site.

Monitoring Visit Follow-Up Letters


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Posted onJune 5, 2013byThe Lead CRAinessential documents,regulatory binder,SMF,templatewith

4 Comments

Youll send a confirmation letter (or email if your SOPs allows it) prior to everymonitoringvisit,be it a pre-study qualification visit, asite initiation visit,routine monitoring visit,close-outvisit,etc. Then youll need to document your visit findings in amonitoring report. Finally, you

will send the principal investigator a follow-up letter summarizing the visit and discussing any

critical findings or action items.

Create Your Monitoring Visit Follow-Up Letter

As a rule, I try to keep the follow-up letter to no more than two pages. It is best practice to havethe letter completed, reviewed, and sent within 7 days of the visit. I write the letter to the

Principal Investigator (PI) but Cc in the coordinator and trial TMF and/or the regulatory person,my Lead CRA or Project Manager, etc. as appropriate per my SOP.

your Lead CRA or the Sponsor may want

to approve the letter or provide a study-specific

template so check with your Lead before you send it

I dedicate the first sentence to listing the personnel who were present at the visit and thanking thestudy staff for their time and attention during the visit. Be sure to include the dates of the visit as

the letter will be filed in the Site Master File and the dates should match the Monitoring Visit

sign-in log dates. This is a good point to discuss any staff changes or recommended re-training.
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Next I typically document the progress of study enrollment and then proceed to summarize the

status of the Site Master File review, source data verification, and Case Report Form completion.

A Summary, Not a Novel

I break up the content where possible by using in-text tables or bulleted lists to note thefollowing items as appropriate per the trial monitoring plan and SOP:

Informed Consent tracking details Summary of patients/Case Report Forms reviewed Site Master File or Source Documentation deficiencies/inconsistencies or Safety Findings Protocol Deviations or Critical Findings (and appropriate recommended corrective actions as

discussed with my regulatory contact, PM, or Lead CRA)

Supply Issues: lab kits,Investigational Medicinal Product,source documents, etc. Action Items: resolved since last visit, new pending and wherever possible

No Surprises

My most important tip for follow-up letters is, no surprises. During your time on-site youshould be meeting with the PI and discussing the status and progress of the visit. You should be

summarizing your findings and discussing any issues so they can assist you to resolve everything

while you are on-site. If there are deviations or safety issues that need to be reported to the IRB,you can remind the Investigator of their responsibility to do so. You can also provide re-training

on the protocol or study procedures during your meeting on-site.

The Follow-Up letter should be

a recap of your discussion, not a news flash.

In regards to action items, it is best practice to resolve everything before you leave the site to theextent possible. I have extended monitoring visits to an additional day with approval from my

Lead when there were items I would be able to complete with an extra half a day or so rather

than leave pending.

If you are unable to meet with the PI during the visit, document this in your follow up letter and

include a reminder that you are available by phone to speak with the PI.
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Follow-Up Letter Template

Im not planning to post a template. Please dont email me for a template as you can easily makeyour own using the guidance from this post that is study-specific for your trials needs.

The Memo to File or Note to File (NTF) isOverused

Posted onNovember 18, 2011byThe Lead CRAinTMFwith2 Comments

A Note to File is not always the best way to capture Information

These memos are often sloppy, contradictory, confusing, or alarming (I once monitored at a site

where the PI had written the following memo Although employees and family members of Dr.

XXXX and this facility were enrolled in the trial XXXX, they were in no way unduly influencedor coerced to participate. Ummm, wow, this was part of the study record and you cant retract it

under any circumstances). Memos to File have to be reviewed and reconciled between the Site

Master File and the TMF. Frankly, there are better ways to capture the information i.e. traininglogs, protocol deviation forms, monitoring reports, etc. so why do many monitors insist that the

site generate a million NTF? I actually ask my coordinators to take it easy on the memos and to

avoid writing them unless absolutely necessary or at least after serious consideration.

Is a Note to File even Necessary?

Some Memos to File are global correspondence from the sponsor or CRO and are necessary toaddress operational issue or questions (expanded specimen shipping instructions, imaging vendor

holiday operation hours, clarification on processes, tracking, substitution of lab kits, etc.) theseare beyond the scope of my discussion here.
http://clinopstoolkit.com/2011/11/the-memo-to-file-or-note-to-file-ntf-is-overused.htmlhttp://clinopstoolkit.com/2011/11/the-memo-to-file-or-note-to-file-ntf-is-overused.htmlhttp://clinopstoolkit.com/2011/11/the-memo-to-file-or-note-to-file-ntf-is-overused.htmlhttp://clinopstoolkit.com/author/theleadcrahttp://clinopstoolkit.com/author/theleadcrahttp://clinopstoolkit.com/author/theleadcrahttp://clinopstoolkit.com/category/tmfhttp://clinopstoolkit.com/category/tmfhttp://clinopstoolkit.com/category/tmfhttp://clinopstoolkit.com/2011/11/the-memo-to-file-or-note-to-file-ntf-is-overused.html#commentshttp://clinopstoolkit.com/2011/11/the-memo-to-file-or-note-to-file-ntf-is-overused.html#commentshttp://clinopstoolkit.com/2011/11/the-memo-to-file-or-note-to-file-ntf-is-overused.html#commentshttp://clinopstoolkit.com/2011/11/the-memo-to-file-or-note-to-file-ntf-is-overused.html#commentshttp://clinopstoolkit.com/category/tmfhttp://clinopstoolkit.com/author/theleadcrahttp://clinopstoolkit.com/2011/11/the-memo-to-file-or-note-to-file-ntf-is-overused.html


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Your Thoughts?

I am assuming this will be a controversial topic because monitors tend to be very passionate

about whether these notes are a hindrance or a help; please leave a comment with your thoughts.There is no regulatory requirement to produce Memos to File but I think in some cases sponsors

and sites can benefit from them at timesthey are, however, more powerful when used inmoderation. Oh, and if you produce a NTF please sign and date it, accurately.