Hi, Elizabeth here, and welcome!
In this post I will be discussing the infamous monitoring visit reports, also known as MVRs, or trip reports. I know this does not sound like the most exciting topic, but it is extremely important as it is a huge part of the CRA career.
So, are you with me? You can do this, LOL!
Again, not the most interesting topic, but hang in there.
There will be many good tips to help you with monitoring visit report completion.
So, for those of you that don't know, let's start with the guidelines. Per ICH/GCPs, the monitor should submit a written report to the sponsor after each trial site visit or trial related communication.
The guidelines also state what each report should include, and I'm going to just summarize this part….It should include a summary of what the monitor reviewed, any significant findings, facts, deviations, deficiencies, and actions taken or to be taken. So, because of this, when you work for a company, there should be SOPs, Standard Operating Procedures regarding each type of monitoring visit. It will include the purpose of each type of visit, the tasks performed at each, as well as templates attached (usually monitoring visit report template for that particular type of visit, confirmation letter, and follow-up letter). In this post, we're going to focus solely on the trip report, so I'll make sure to stay on track regarding that 😉
As monitoring reports contain so much detail, the reviewer can get a clear picture of what is going on at a site without even being there. That's how much detail there is! A third party can read it and know exactly what's going on, and this is especially important in the case of an audit. QA auditors and FDA auditors should get a clear picture as well.
Depending on the type of visit will determine the content of the report and the procedures that are performed at each. In this post, I'm going to reference a Routine Monitoring Visit, or RMV, as this is going to be the type of report that you will complete the most. This report will contain tons of detail, for example - documentation of everything reviewed including consent forms, HIPAAs that were reviewed, source document review, source document verification, query resolution, review of the Investigator Site File (aka Regulatory Binder), lab samples, and study drug review/accountability.
So, let's stop here for a minute. I just loaded you up with a long list of what a CRA is going to assess. I wanted to stop here and make a point regarding detail. When you document what was reviewed, I want you to be specific. For example….the FIRST thing that you review for any subject is going to be the consent form and the HIPAA. If you do not have a signed ICF and a signed HIPAA, then you must stop there. You cannot go any further without a signed ICF and a signed HIPAA. This is a whole other topic…but, in your report when you're documenting which consents/HIPAAs were reviewed, in addition to that subject number, you want to also include the version reviewed.
There may be multiple versions of the consent form in your study. So, it is very important that you document in addition to the subject number, what version you reviewed. Then, of course, you would document if there were any issues observed. Same thing with source document review and source document verification……..when you document what was reviewed, be specific. Again, in addition to documenting the subject number, you want to also note the visits that you reviewed. If there are any pending queries for the site to resolve, list the visit numbers in addition to the subject number.
The contents of the Investigator Site File, aka the Regulatory Binder, will also contain tons of documentation which includes multiple versions. So, for example, regarding the protocol……there may be an original protocol, and then an amendment 1, 2, and 3. The Investigator Brochure, there could be a version 1, version 2, version 3. I already mentioned the consent form could have multiple versions as well. Sometimes if the study goes on for years, there will be multiple versions of the medical licenses for a doctor as the initial one provided will have an expiration date, and then a renewed license provided. There may also be numerous versions of CVs, GCP training documentation, 1572s, etc. Believe me, the binder grows, and grows, and grows as you are on a study leading to multiple binders!!
The important thing here is when you are documenting Regulatory Binder review, you want to be extremely specific. For example, when reviewing the ISF, you notice a Protocol Signature Page or PSP is missing. Remember, be specific and include the version number (was it the PSP of the original protocol or one of the amendments?). Be specific, not only for the reviewer to get a clear picture, but also for a monitor that may be taking over your site. The new CRA can have a clear picture knowing exactly what was reviewed and where to jump in. I have definitely taken over many sites, and a detailed report makes things a whole lot easier!!!
Many companies use CTMS where the Action Items generated in the trip report will appear on the follow-up letter. The follow-up letter is sent to the site after the visit, and this includes what action items the site needs to resolve. It is important that the site know the specifics as well. They need to know, as a reminder for them, what version they need to provide. So it's very important, again, to be specific.
Same thing with lab samples. You would not just list the subject number. Be specific. What visit was this? For which lab sample? Was it a PK sample? Was it a urinalysis? Be detailed. Lastly, the same thing with IP accountability, Investigational Product accountability.......What subject, what visit? Or if it was an issue with a drug shipment, where the IP was not documented on the accountability log, be sure to include which shipment (date or shipment#).
Other things that a CRA is going to assess, and document in the trip report, includes if the site is compliant with the protocol, compliant with ICH/GCP regulations, if a site is entering data in a timely manner, and if answering queries in a timely manner. Typically, the timelines for entering the data and query turnaround time is per the CRF completion guidelines.
Additionally, a CRA will assess and document if the site staff is performing study procedures that they've been delegated appropriately by the PI to perform. If so, were they on the delegation log to do that task? Are they qualified to perform it? Have they been appropriately trained?
The CRA will also assess and document if there is proper PI oversight (is the PI involved, are they overseeing the trial, are they overseeing the study staff appropriately?). The CRA will also document who was present at the visit (will document everyone that was present, and also if he/she met with the PI and what was discussed). LOTS of detail. Since we are on the subject of detail, I want to jump to the importance of being detailed when documenting an issue observed.
A CRA should not just document the issue and that’s it, end of story. It's important that the issue is documented, but also the resolution and what measures were taken in order to prevent it from happening again. In addition, the CRA should indicate if it requires reporting to the IRB (Institutional Review Board). Let’s look at an example…..
A CRA observes that the consenter did not sign Subject 001’s ICF. Let’s pretend in this case it is ICF version 2.0. Remember earlier I mentioned version number, subject number, and if any visits are involved, note the visit. In this case, I would document that, upon review of Subject 001’s version 2.0 consent form, it was observed that the consenter did not sign and date when consenting the subject…..so great, wonderful, this includes which subject, what the version was, and what the issue was. It does not include; however, the corrective and preventative actions.
Okay, first of all, what's required to correct it? To correct the issue, the consenter definitely needs to sign and date the consent form, and remember that when they're signing, it should always be with the current date….Even though this should be Research 101, I'm not kidding….. I've actually had people ask, now what day do you want me to sign with? And I'm thinking, OMG, it's always today's date!! Always sign with the current date, never backdate. Just a side reminder, to always make sure that anyone signing, even though it's later, should sign with the current date and note it as a Late Entry.
Okay, so in this example, you've got the consenter signing as a Late Entry with the current date. Now, when a reviewer looks at this consent form, the subject will have one signature date, and then the consenter has their signature date. There are different dates between the subject and the consenter on the ICF. There needs to be some sort of explanation that documents the issue in the source. In my experience, if I were to see this (the two different dates), the first place I would look is the consent process documented in the source in order to see if this was addressed. Definitely would be the first place I would look.
In the initial documentation of the consent process, it should be included that the subject received a copy of the signed consent. As the consenter, in this example, added their signature since the subject received the initial copy, I would advise the site to give the subject an updated copy, and then to document that in the source once completed.
Lastly (wow, this is a long example LOL), I would request the site to confirm if the issue requires reporting to their IRB. Now each IRB is different in regard to what they require reported. Typically, most central IRBs that I’ve had experience with, require issues reported that affect subject safety or data integrity. It used to be, way back in the day, where every protocol deviation was reported, but now, they may not be as concerned about a one-day out of window visit, for example. Like I mentioned though, anything affecting subject safety or data integrity, they definitely want to know about. As each IRB is different and has their own process, I usually document a blanket statement in my trip report….."that the site was advised to submit this to the IRB per their reporting guidelines", and then I would confirm this with the site (if it was reportable or not per their IRB). Once confirmed with the site, I would also request them to document if reportable or not, in order to close the loop. If yes, I also would verify the documentation where submitted to the IRB.
Now that the issue has been corrected, how will it be prevented from happening again? Usually this is through reeducation or retraining of the site. In this case, you will want to retrain the person obtaining consent regarding the consent process. Also remind them to ensure completeness of the ICF during the consent process; confirming the ICF is complete and accurate at that time. After retraining regarding the consent process, make sure to document that retraining.
So, this is how I would document the issue in my report….Upon review of Subject 001’s version 2.0 consent form, it was observed that the consenter did not sign and date when consenting the subject. Dr. Smith was advised to sign/date the consent form with the current date, give an updated copy to the subject, and document in the source as a Late Entry. The site was advised to submit this issue to the IRB per their reporting guidelines. Dr. Smith was re-educated regarding the consent process, the training documented, and filed in the Regulatory Binder. A copy of the training documentation was retrieved for the study TMF as well.
And there you go 😊 It includes the issue, the correction, and how to prevent it from happening again. Whatever could not be confirmed by completion of the visit would be listed as an open Action Item in the report. Usually the part regarding submitting to the IRB, and giving an updated copy to the subject were listed as follow-up. These were separated into two Action Items.
So, these are just some examples of what can be documented in an RMV trip report. I will go into way more detail in my upcoming course, which will also include more tips regarding completion as well.
Some general tips include grammar, spelling, the importance of proofreading, and reports should be written in third person. Also, you want to ensure consistency!!
In some report templates, there were questions that could conflict based on the wording….it might ask in one section, was the site compliant with the protocol and study procedures? Somebody may answer 'no', and then list/document what the issues were….Then in another section, it will ask if there were any protocol deviations noted and then it’s answered 'no'…..I was like, okay, read it carefully, because if over here they're not compliant with the protocol, then where it asks if there were any protocol deviations in the next section you'd expect to see 'yes' answered.
Conflicting answers could also occur in the Investigator Site File section. It may ask if the ISF was reviewed and if it was complete and accurate. It would be answered 'yes' by the CRA, and then later in the comments note there was a missing document. Same thing in the IP section, if any issues with study drug answered 'no', but then you see an open Action Item regarding a study drug issue. Take the time to ensure that the report is consistent and all flows together.
That's another huge thing that you will see in monitoring…..consistency. If there is another place that the same thing can be found or reported, you want to make sure it matches and is consistent, whether it be different reports or different places in the source. For example, with study drug, if I'm reviewing the source and IVRS reports, I need to confirm this data is consistent with what is documented on the accountability log, the actual inventory, and the pill count. Everything needs to be consistent!
I wanted to throw that little side tip out there, but for the sake of time, I did want to jump and mention again how important, timely trip reports are. In my experience, in addition to training compliance, this was a HUGE metric and that's why I wanted to touch on this again. You may remember me mentioning in the time management post, where I touched on the importance of on-time trip reports and report turnaround time. Sometimes they use the acronym MVR TAT for Monitoring Visit Report, Turnaround Time. So, remember, like I've mentioned, primary obligations as a monitor are subject safety and data integrity; therefore, it's important that all observations, issues, any resolution, re-education, and anything escalated is properly documented. And again, as a CRO, Contract Research Organization, included in our contract is time and budget, and we're contracted with the sponsor. Part of that contract is submission of trip reports; therefore, we want to be compliant and meet our contractual obligations. That is another important reason.
Lastly, in the GCP R2 addendum, it notes that reports of onsite or centralized monitoring should be provided in a timely manner for review and follow-up. The results of monitoring activities should be documented in sufficient detail to allow verification of compliance with the monitoring plan. Remember that CMP, the Clinical Monitoring Plan, you're going to hear about this a lot!
Like I mentioned, most companies are going to track that draft submission date and the finalization date. So, these due dates are going to depend on your company SOPs, your Standard Operating Procedures (and if you are going to follow the CRO SOPs or the sponsors – will be specified in the CMP). It depends on whose SOPs you are following, and what is in there regarding due dates - But the take home message is being on time. Set reminders, whatever works for you!
For me, it was definitely reminders!! I would set reminders in Outlook, in addition to reminders on my phone. I set a reminder when my draft was due, and also set a reminder after my draft was submitted. Why would I do that? Because even though it was out of my hands and with the reviewer, it was still my responsibility. If late, it would still reflect on me. Wait, what!? It’s with the reviewer, if it was late, wouldn’t it fall on them? Unfortunately, no. We have the responsibility to ensure our reports are finalized on-time as well.
The most current timelines I experienced as a CRA were draft reports due by business day 7 and finalized by business day 14. I would set a reminder when it was getting close for my draft due, after submitted I would set a reminder to go off within 2 days. I did this in order to give the reviewer time to review it, but also for me to have time to make any required revisions/clarifications. If you do not receive your report back from the reviewer in a timely manner, contact them. I would just shoot over an email, “Hi Jill 😊 Wanted to see if there were any revisions needed on Dr. Smith’s 02Apr2020 RMV Report in order to finalize on-time. Thanks so much!!”. Usually I would get a response thanking me for the reminder. You would never want your report to slip through the cracks. Once I made any revisions/updates, I would add another reminder to ensure I received confirmation of finalization by Day 14. It is a process, for sure!! So, even though you've submitted it to them and you're waiting on them to review it, you need to track it and stay on top of it. You do not want it to slip through the cracks. I do not want you to get dinged if a report is late. During every part of that turnaround time process stay on top of it.
Also, it is better to be proactive than reactive. Keep your leads and management up to date. They shouldn’t have to come to you for an update. For example, if I was working on a report, and it was Day 7 when a draft was due, and I knew it would take me until 7pm to finish, I would send an email to my Lead CRA and Line Manager in order to let them know it was coming, and would still be on-time.
Oh my goodness, time is just flying, and I could go on and on. There is so much more for me to talk about. Tips for successful trip report completion, I'll definitely review this in detail during my upcoming course.
Thank you so much!! I pray you guys are safe out there. Let's work together to flatten the curve, and stop the spread of the Coronavirus and COVID-19.
Again, please stay safe!