Clinical Research Monitoring 101: The Basics You Need To Understand To Become A Clinical Research Associate
If you are like most people that eventually stumble over to my blog TheClinicalTrialsGuru.com or perhaps my Youtube Channel youtube.com/DanSfera , it is likely because you are interested in learning more about the clinical research industry, as well as one of the most desirable positions in this industry, the Clinical Research Associate (CRA). This book is meant to be used as a basic overview of what I believe to be the most important topics that someone who would like to become a CRA would need to know. Reading this book will definitely not guarantee that you will land a job as a CRA or any other position in this industry for that matter. This book is a starting point, and shows you the areas that you will need to focus more of your time on long after you have read this book. We have started a CRA Academy online training school where we have had dozens of students successfully complete and get hired as CRA’s, study coordinators, Clinical Trial Assistants (CTA’s) and other such positions. Please visit TheCRAacademy.com to learn more. One of the biggest factors that will determine whether you get hired as a CRA or not is your previous clinical research experience. If you have none, my CRA Academy will get you started off with some internship experience at a clinic near you. There are also free ways for you to get your experience on your resume and I wrote an article about one of those strategies here: https://www.linkedin.com/pulse/fastest-way-get-experience-clinical-research-industry-dan-sfera?trk=mp-reader-card Please feel free to connect with me after you read this book. I am on just about every social network (search for Dan Sfera) and often use Instagram http://www.instagram.com/DanSfera to livestream my own job interviews, host question and answer sessions, and also broadcast glimpses into our CRA Academy live training webinars. I hope that this book can serve as a solid introduction into the world of being a CRA. If you ever have any questions, find me on social media or email me email@example.com . Onwards and Upwards!
SITE SELECTION VISITS
Have you ever wondered how clinical research sites are awarded studies? The process isn’t as simple as you may think. Some of the most common ways to obtain a study would be through Investigator Interest Questionnaires, automatically generated invites and referrals.
An Investigator Interest Questionnaire, otherwise known as a feasibility survey, is self-explanatory; any person from the site can manually go to the pharmaceutical company’s (sponsor) website and input their Investigator’s information to be entered into a database for selection or consideration based on the information submitted. These days web portals such as drugdev.org make this process even easier.
Additionally, automatically generated invitations can also be sent from the sponsor to the Investigator based off of therapeutic expertise and enrollment fulfillment through participation of other previously awarded studies of said sponsor. Lastly, recommendations and/or referrals depending on previous work history or agreements with affiliated sites can be a great source of obtaining studies. Clinical Research Associates (CRA’s) can and will recommend a site depending on their personal past experiences with the site; this may be due to the overall work ethic, professionalism, enrollment capabilities etc of the site. Basically, the better the past experience was with a CRA, the more likely it is for the site to be re-selected.
Once a site is prequalified by the sponsor considering all the aforementioned processes, a CDA (confidentiality disclosure agreement) will be submitted by the sponsor to the attention of the Investigator so that additional information can be securely released to the site. Upon submission of the CDA, a protocol synopsis following and a feasibility survey will be sent out to the site. Feasibility surveys contain specific inquiries for consideration in relation to the goals set forth by the sponsor for the study to be awarded to the site.
Once all of this is completed, a 1–4 hour visit will be scheduled in order for a CRA to be sent out to confirm the accuracy of the site’s capabilities to satisfy the sponsors goals. These visits have many acronyms that carry the same meaning [e.g., PSSV (pre site selection visit), SSV (site selection visit), SEV (site evaluation visit, SQV (site qualification visit)]. The CRA’s will generally be met by a coordinator and conduct most of the visit with them. Approximately 30–60 minutes is required with the Principal Investigator for the visit. During the SSV, formal introductions will be made followed by a tour of the facility. At this time, the CRA will be observing the facility’s features (e.g., calibrated equipment, adequate/appropriate equipment, proper use of equipment, adequate space, double locked storage rooms for IP/Source documents, limited access areas, site’s standard operating procedures, cleanliness and organization) as well as the overall look and “feel” of the clinic as some of the many qualifying factors used to determine site qualification.
For the site, it is important to be professional but also give the CRA a sense of comfort and assurance that the site is suitable for participation in the protocol. After the tour is completed, the remainder of the visit will be a sit down meeting to cross reference the accuracy of the projections and capabilities reported on the feasibility survey made by the site. This will also be an opportunity to further gauge Investigator and site interest in the trial.
The CRA will generate a report by updating the feasibility assessment and making note of observations to take back to the sponsor for final review. The questions asked by the CRA to the site at the SSV will be almost exactly identical to the feasibility survey questions. In addition, new questions might arise if interest is sparked by an unexpected answer. It is of utmost importance as a CRA and as a site to be fully prepared and transparent during the visit so that the site’s capabilities are not over or under emphasized as this can lead to the study not being awarded or even worse, the study being awarded only later to find out that the site was not suitable for participation for a variety of reasons but most typically due to the site not being able to meet the recruitment goals. Some of the bigger questions to be asked will be about the targeted therapeutic demographic, the “how’s and where’s” to ensure enrollment fulfillment, Investigator and Study Coordinator experience as well as responsibility and availability for the trial’s duration. Additionally, prior site audit disclosures, facility licensure and certifications, previous IRB experience in regard to study startup, projected turn-around times, and anything that needs further clarification should be addressed. At the end of the visit, the CRA will take all that was discussed, noted, and observed into consideration to weigh the pros and cons of the site and make an educated decision on whether or not the site is suitable for the trial.
Essential Documents that encompass a Sponsor or CRO’s Trial Master File that pertain to clinical research are referred to as Regulatory Documents or “Reg Docs” for short. These Regulatory documents consist of important contracts, agreements, training and delegation logs to name a few that will be filed with the Sponsor, FDA or both. In addition, the documents being covered will usually be stored in a study specific binder or binders that are provided to each research site that happens to be participating in that particular study. It is the site’s (and ultimately the PI’s) responsibility to fill out all applicable documents fully and correctly, apply real-time captured dates and signatures wherever applicable as well as filing documents in the correct sections of the provided binder in a timely manner. Clinical Research Associate’s (CRA’s) should never write on original site sources or regulatory documents unless specified on the form in question; such as a site visit log. Once the study is completed the sponsor will determine if the site will retain the original regulatory documents or copies of them for storage. The sponsor will also specify exactly how long the source and regulatory documents will be kept after the study has been completed in case an audit should arise within the timeframe specified. As a side note, the Contract Research Organization (CRO) and/or “Sponsor” will typically be much more stringent in terms of regulations than what the U.S. Food and Drug Administration (FDA) already have set in place.
Form FDA 1572 is the statement of Investigator; “No investigator may participate in an investigation until he/she provides the sponsor with a completed, signed Statement of Investigator, Form FDA 1572 (21 CFR 312.53(c)).” This form is arguably one of, if not, the most important document pertaining to regulatory and clinical research in general. It is required for any clinical research study involving investigational drugs, biologics and/or products. This is an agreement signed by the Principal Investigator (PI) providing specific information of the investigator(s) and the site to assure the sponsor that compliance with FDA regulations regarding the clinical trial will be met. The form will require Investigator(s) information (education, training, experience), site addresses, additional facility locations, Institutional Review Board (IRB) to be used and sometimes additional pages among other specifics. This form FDA 1572 can and will be updated whenever a change is applicable.
Financial Disclosure Forms (FDF’s) are to be completed by any investigators listed on the 1572. The FDF states whether or not any of the listed investigators have any financial interests in the outcome of the specified study. If there is a financial interest, the nature of those interests, arrangements and/or payments must be disclosed and any steps taken to minimize the potential for bias resulting from those interests and arrangements must be described. The maximum allowed monetary or equity investment amounts received will be specified in the FDF.
E-Signature and password confidentiality agreements are to be acknowledged and completed by the Investigator(s) because they are just as legally binding as his/her hand written signature. Password confidentiality is imperative due to the aforementioned fact. With that being said, E-Signatures are needed for various action items but most commonly to sign off on completed electronic case report forms (e-CRF’s) towards the end of the study to certify that the data entered in to the Electronic Data Capture (EDC) system is complete and accurate in comparison to the original source documents. 21 CFR Part 11 covers this topic.
Protocol Signature Pages and any Training Logs are to be acknowledged and signed by the PI as well as anyone in attendance of the protocol training or amended training (present or future) with the PI signing off to ensure they are adequately trained. By the PI signing this page, he/she is agreeing to the proper conduct of the study in accordance to the protocol as well as FDA and Good Clinical Practice (GCP) guidelines.
Note-To-Files (NTF’s) are a special tool used to elaborate on any special circumstances, discrepancies and/or situations that may not otherwise be clarified properly in a designated place. They can be used for almost anything that requires further explanation, or to provide clarification as to why something was or was not done. For example, if a deviation is performed it can be noted in detail to explain if it was intentional (maybe due to an immediate subject safety issue) or performed in error and why. NTF’s should be used when no other means are adequate enough but when in doubt, extra documentation through NTF’s will not hurt and will only help to aid in clarification. I always tell my study coordinators that “NTF’s are your best friends.”
The Confidentiality Disclosure Agreement (CDA) is one of the first forms completed by the Investigator or site. This agreement is meant to protect and ensure the security of any trial related material or information such as the Investigator Brochure (IB) or protocol that is disclosed to the site. The CDA legally binds the entire site to secrecy in regards to all aspects of the protocol and any other associated intellectual property of the Sponsor.
The Delegation of Duties Log, more commonly known as the Delegation Log or the Site responsibility log, delegation of responsibilities, delegation of tasks, delegation of authorities, etc. This log will do as titled, it specifies which duties are delegated to whom at the site and the tasks listed must be appropriate to the individuals’ education, training and/or experience. All personnel performing any study specific tasks must be listed with the PI signing off on all delegated roles. The PI will also sign off on any dates that any given personnel stop performing tasks at the site and/or seize participation as an investigator for that trial. Delegation logs require information such as: name, role(s), start/end date(s), signatures, initials and tasks assigned.
Institutional Review Board (IRB) correspondence lastly, but also equally important as any of the documentation listed above, is filed and treated with utmost importance as all of this correspondence will typically refer to the protection and safety of study subjects. The IRB will also ensure the site is able to conduct the given study safely, ethically, and in accordance to the FDA and GCP guidelines. There are two types of IRB’s: Central and Local; most independent sites will work with central IRB’s since local IRB’s are usually tied to sites associated with Hospitals and Universities. IRB’s will determine whether or not the site is fit safely and ethically conduct the given study based on all the available information provided such as how many studies are under the PI at the present time, and the qualifications of the PI and/or site and personnel. The IRB’s main concern lies with the safety of subjects regarding the PI’s oversight/involvement and sites capabilities.
This wraps up a brief overview of regulatory documents in clinical research. In our CRA Academy, we cover these and other topics in much greater detail, and ensure that students have a firm grasp of these fundamental principles of clinical research.
A Clinical Research Associate (CRA) is a liaison between the site and sponsor, dedicated to focusing on the needs of both to be able to give feedback and provide suggestions while maintaining Good Clinical Practices (GCP’s). As a CRA, it is imperative that before anything occurs, a great working relationship is created with the site in order to eliminate any fear of communication and become more efficient as well as productive. This will encourage the site to ask questions and verify certain statements that the protocol or sponsor may be ambiguous about, therefore, eliminating any unnecessary errors and/or deviations and keeping surprises during Interim Monitoring Visits (IMV’s) to a minimum. Establishing this kind of relationship will prevent resistance and help to nurture the success of the site, the CRA, and ultimately the goals of the Sponsor. With that being stated, source documents can be discussed.
A Source document is to be considered any data, document, or record created and/or collected as the first point of data entry during the course of a clinical trial. One of the main objectives of a CRA is to provide quality assurance to the sponsor, this requires the ability to thoroughly verify the Source Documents of a trial during an IMV or sometimes via Remote Monitoring Visit (RMV). In order to be adequately accomplished, there are five principles known as ALCOA: Attributable, Legible, Contemporaneous, Original, and Accurate (ALCOA) for the proper verification of source documents to ensure data integrity, validity, and subject safety among other aspects.
Attributable, is the first principle of ALCOA pertaining to who is responsible and for which data point collections. The Delegation of Duties Log, will do as titled, it specifies which duties are delegated to who and the tasks listed must be appropriate to the individuals’ education, training and/or experience. All personnel performing any study specific tasks must be listed with the PI signing off on all delegated roles. The PI will also sign off on any dates that any given personnel stop performing tasks at the site and/or seize participation as an investigator for that trial. Delegation logs require information such as: name, role(s), start/end date(s), signatures, initials and tasks assigned. A CRA will utilize this log as a tool when performing verification of data.
The second principle is Legibility, this is extremely important because if data is unreadable, then it is useless and raises concern as to what data point is being overlooked or unchecked. When a mistake is made or something is not legible, it should be corrected by striking it through with one line, re-writing it, then noting the correction with initial and date. This should be performed in real time immediately after the error or during discovery of an error. Using whiteout or blinding an error is not an acceptable form of correction and should be avoided in order to maintain transparency. If this is found, typically it will not be malicious but as a CRA, it would be wise to train and/or educate a site of the aforementioned so that the errors are not misinterpreted.
Contemporaneous is the third principle and demonstrates that collected data should be existing, occurring, or originating during the same time. Data can only be assumed credible, if it is recorded and documented at the time of which a measurement or action is taken. All of the sources for a given subject must correspond, creating a story that should flow and make sense raising no doubt or leaving unanswered questions. If data is not collected in this way, there may be bigger concerns to be wary of, such as fraud, and ultimately would lead one to suspect that the integrity of the data may have been compromised.
The fourth principle of ALCOA is Original. Any item on which a data point is collected, no matter what was used to record the data, is now the original source document and should be included in the subject source as the source for that data point. It is not recommended to collect data on random items, a site should have standard operating procedures detailing exactly how data is to be recorded, but these things may occur. It is important that original data is not transcribed to another source document in order to prevent errors being created during the transcription due to misinterpretation. Action by the CRA should be taken so that the site is aware of avoiding capturing data in this way, and that it is secured along with the corresponding sources.
Accuracy, is the fifth and final principle and typically requires discretion and data trending by the CRA if alarming inconsistencies are discovered. All aspects of the data should be taken into account while investigating inconsistencies, such as use of different pieces of equipment or procedures/assessments performed by different personnel. At this point, asking whoever performed the task is usually the best option as it will give the CRA insight on details of how the inconsistency may have occurred.
Subject Identifiers consist of information uniquely relative to the subject such as the following: Initials, date of birth, and subject number. Each subject’S initials should be consistent throughout the trial beginning with the initialing of each page of the ICF (Informed consent form). Date of birth and subject numbers will also be unique to the subject especially when being registered into any electronic system or database in conjunction with the trial. Subject numbers will have a variety of formats and may also include the site number specific to the particular site.
Medical records, if applicable, should be released by the subject via a medical records release form. These records are wanted by sponsors for most trials but the reality is that they cannot always be obtained; with this in mind, sponsors (and Good Clinical Practice) have required that for most trials as long as three separately documented attempts have been made to gather a subject’s medical records, that is sufficient enough. Although this may not be true for all trials which require medical records as part of the inclusion criteria due to specific diagnostic information that is needed for subject randomization. Some acceptable forms of these attempts include but are not limited to fax confirmations and documentation of telephone calls made. This process is to be completed by the site within the screening visit window.
Most sponsors provide compensation for the completion of visits within a trial to the subject. The sponsor or CRO may require proof of payment to the subject.
Adverse event logs are specific to each subject and are to begin once the ICF has been signed. The log is a sequential running log with adverse events to be numbered as they occur if they are to occur. Each row will be specific to one AE (Adverse Event) and contain sections requiring further detailed information for that AE. The information required will consist of the medical term, start and stop dates, severity, causality, action taken, and end results to name some. This log will require PI initials and must be signed off by the PI once the subject has been successfully completed or withdrawn.
Concomitant medication logs (con med logs), much like AE logs will begin at the moment of ICF signing but will record any medications or supplements being taken at least 30 days prior to screening until the end of the trial. This log is to be completed to the site’s best ability until further information is collected from released medical records. This log will require detailed information pertaining to the medication such as: the name, start and stop dates, route, regimen, indication, and dosage. As a side note, further clarification may be needed by the subject in some cases where medications are being prescribed to the subject before the dates of diagnosis which would require the medications. This log must remain current and capture any starting as well as ending medications. The PI must sign off on this log once the subject has been successfully completed or withdrawn as well, or once the study has been closed out at the site.
Interactive Voice/Web Response Systems, more commonly referred to as IVRS or IWRS. These systems can be accessed either via web and/or telephone and are used mainly for IP (Investigational Product) and recording subject visits. For IP, this system is used to dispense, reconcile, adjust dosages, auto-reorder IP, and record unscheduled visits to name a few functions which some may or may not be utilized by all of the IWRS/IVRS systems. The systems will project future visit dates once a visit is recorded and will also notify the site via email if a subject is to fall out of their visit window. Recorded activity confirmations will be provided and are to be printed out and filed within the subject source.
Inclusion/Exclusion criteria is required to be appropriately met (inclusion criteria) or not met (exclusion criteria) by the subject before randomization and again on the day of randomization. These criteria are specific to the trial and implemented to ensure the subject is qualified to safely randomize. If at any time the criteria are no longer met, then the subject is to be withdrawn from the trial with the sponsor as well as the IRB being notified.
Progress notes are an essential part of trial visits and are to be detailed starting when the subject enters the site. Progress notes should be clear and tell a story reflecting on everything that happened regarding the subject’s visit. Any procedures, processes and if any questions were asked should all be noted in the notes at the end of the subject source. This is an easy way to remember how or why certain things happened much like note-to-files except for the subject source folder instead of the regulatory binder. Reading through the progress notes should eliminate any confusion or questions that are raised within the subject visit source.
INTERIM MONITORING VISITS
Interim Monitoring Visits (IMV’s), also referred to as Routine Monitoring Visits (RMV’S), are the most common type of Monitoring Visit that a site will have. These Visits will occur every 4–6 weeks on average and will typically be conducted by a regionally based CRA (in most cases) assigned to multiple participating sites in the greater geographic area. It is possible that a project manager will assign any given CRA to sites where long travels may be necessary. A dynamic monitoring plan for each site will be established by the CRO before a trial begins based on the projected activity as well as risk profile of the site by using three different monitoring strategies and tools known as: Traditional, Remote, and Risk Based Monitoring which will be explained in detail regarding the advantages and disadvantages of each.
First, Traditional Monitoring is the most commonly used strategy and has been widely utilized for decades. It is where a CRA will simply visit a site every 4–6 weeks based on enrollment activity and perform 100% SDV (Source Data Verification) while picking up where he/she left off from the previous monitoring visit. Each site visit will be conducted using the same processes by the CRA, the only variable being the frequency of visits which will be determined based on enrollment activity. As expected, a site with greater enrollment activity will be visited more often while sites with low activity will have more time in between each monitoring visit. After SDV is performed, the CRA will then look through the documents in the regulatory binder to confirm that they are there and hold up to ALCOA standards with whatever time may be left over for the visit. Some of the disadvantages to this strategy are that to perform 100% SDV, there may be little to no time left over for proactive activities such as going through the regulatory documents and conducting other essential parts of the visit such as further protocol training, in depth meetings with the PI, helping with recruitment strategies and/or providing the necessary tools for a site to be more successful.
With the Introduction and help of Remote Monitoring Visits, a CRA can now view sources and complete SDV via virtual workspaces instead of having to perform this function on site, leaving much more time for the activities that are typically overshadowed by SDV in the Traditional Strategy of Monitoring. Remote Monitoring is not to be confused as a standalone strategy, it is a tool to be used in conjunction with Risk Based and/or Traditional Monitoring based on the given sites’ risk profile.
Traditional Monitoring is a form of Monitoring that the research industry has begun to move away from since 2013 when the FDA issued guidance regarding Risk Based Monitoring. Risk Based Monitoring is exactly what it sounds like; each site will have a specified “risk profile” assigned which will then in turn be used by sponsors and CRO’s to establish the attributes of a site and determine where the risks lie. One of the benefits of this strategy will be the ability to more easily detect fraud using algorithms and big data technology while amassing these large amounts of real time data electronically as is beginning to become a preferred method of monitoring. The purpose of Risk Based and Remote Monitoring Visits are not to eliminate the physical visits of Traditional Monitoring but instead to make the physical visits much more efficient by abolishing the time consumption of 100% on-site SDV.
Before an IMV can occur, a Confirmation Letter must be sent for the site to acknowledge and agree upon the scheduled date and time which is subject to change based on availability. The Confirmation must also provide an outline which details the activities or action items the CRA would like to perform or review and should be prepared and/or updated by the site prior to the IMV. There will always be action items; no site or process is perfect and it is the duty of the CRA to find items or processes to be updated or corrected by the site before the next IMV within a reasonable timeframe. The Confirmation Letter will also state how long the PI will be needed to discuss any and all findings whether the preferred option of in person or via teleconference. They PI should be made available for at least 5–10 minutes per IMV.
On the day of the IMV, the CRA will more than likely be met by the study coordinator followed by settling in and asking for action items and new sources (since the previous visit) to be reviewed. No one CRA will have the same process as far as review goes, monitoring style is typically based on preference and what works for them on a case by case basis. With that being said, a general list of items to be reviewed, especially by new CRA’s until their own monitoring process has been developed through experience, should be as follows but not necessarily in this order: IP Accountability, Regulatory Maintenance, Site Recruitment Plans, Electronic Data Capture Verification, Training Logs, Protocol Deviations and Reviewing any New Activities since the previous IMV.
Correspondingly, a Follow-Up Letter, which is very similar to a Confirmation Letter and equally as important, should be sent to the site to summarize the IMV and what was accomplished. Any and all new or unresolved action items and/or findings will be listed as well as updates to enrollment such as newly screened and randomized subjects. The next tentative IMV will be listed with a projected date that is subject to change. One of the more important things will be the description that notes if there was a meeting with the PI. This is important because it gives insight into PI oversight and availability as well as involvement and is something that can be frowned upon or subject to investigation by the FDA or Sponsor if it is determined that there may not be adequate oversight of the trial. All things considered, the Follow-up Letter should accurately depict the IMV.
SITE INITIATION VISITS
A Pre-Selection Visit (PSV) is to ensure pre-qualification of a site and eliminate sites that do not possess adequate qualities to conduct the trial and must occur in order to determine if additional resources should be used to perform a Site Initiation Visit (SIV).
Once the site has been selected and the trial has been awarded, a Clinical Research Associate (CRA) will be assigned to the site and a start-up packet will be sent along with any essential documents or items including but not limited to: lab kits, data collection equipment, relevant trainings, regulatory documents, and shipping items. As soon as the CRA has been selected for a site, it is their duty to introduce themselves to the lead staff [including Principal Investigator (PI)] and start to help the site with the completion of any action items. When the site is near the completion of all key elements the CRA is to communicate with someone from the site to schedule the best date and time that is accommodating for both parties but in favor of the PI. After a date has been determined, the CRA will send an SIV confirmation letter containing the details of all that will be expected of the site and performed or discussed on the day of visit. The primary objective of an SIV is to activate the site so that they can ultimately begin collecting data pertaining to the trial in the form of screening and randomizing study participants.
Before this can occur and the site can be activated, it is the responsibility of the CRA to verify that there are no pending submissions, approvals, documents, trainings or shipments essential to the success and start of the trial during the SIV. The CRA will typically be greeted by a Clinical Research Coordinator (CRC) and met by the PI shortly after. The CRA will typically be assigned to a monitoring room by the CRC to set up anything pertaining to the completion of the SIV. Most often, and even more so with newer sites or inexperienced staff members, there will be pending action items for the site to complete and it is important for the CRA to guide the site in the correct manner to achieve the completion of anything that needs to be done before that site can be activated. It is also helpful to remember that all CRA’s have different processes and preferences, the order of which is subject to change depending on what they feel is the most important to review first on a site-by-site basis.
For the duration of the SIV, staff will be trained on the protocol by the CRA. Upon completion of the training, the CRA will then tour the facility to confirm that the site has all of the requirements necessary to conduct the trial. Some of the things to be examined would be: adequate space, adequate and appropriate Investigational Product (IP) storages, calibration checks, filed documents, IRB approvals, acceptable source document storage, EDC & IRT accesses, lab kit accessibility, and enrollment projections. The responsibilities and Sponsor expectations of the staff and ultimately the PI will be explained by the CRA as well as any key dates or projections such as study milestones, which will require sites to be mindful of the Sponsor’s short term objectives, in order to streamline the projected target on track for completion.
Towards the end of the SIV, the Delegation log will be filled out and the CRA will ask if there are any questions by the site before the SIV training log is completed. Finally several other items will be documented by the CRA including when the site expects to screen their first subject, and/or if the site is still missing anything they should receive before an actual screening visit can occur. The CRA will try to circumvent any obstacles standing in the way of the site starting to screen patients. In addition, the CRA will inform the site of standard timeframes such as when upcoming monitoring visits should be conducted (typically 2 weeks after the first screening and/or randomization). When the SIV has concluded, the site should expect to receive a follow-up letter regarding the details of the SIV and any action items that the site may have pending from the visit.
CLOSE OUT VISITS
Close out Visit’s (COV’s) consist of multiple activities that are performed by a CRA to confirm that the site’s obligations to the sponsor have been met and any post study obligations are understood as well as followed through on. Closeout activities verify that study procedures, all regulatory documents and data are 100% completed, and any Investigational Product (IP) or supplies are returned or destroyed with documentation of the details pertaining to the destruction. It is especially important that the Principal Investigator (PI) is also available to sign off any documents required for the closeout to be completed.
A close out visit is typically due to the sponsor’s enrollment goal being completed or sufficient positive or negative data results that have been collected, but an unscheduled close out visit can also occur if a site does not have enough forward progress or cannot meet the projected enrollment/screening numbers of the original agreement between the sponsor and site pertaining to subjects as well as other various turnaround times.
A close out visit should ensure that all outstanding Case Report Forms (CRF’s) have been corrected, collected, organized, and filed as required. All data needs to be clean and complete with queries all being corrected and resolved as well as signed off by the Principal Investigator (PI). All serious adverse events (SAE’s) have been reported, resolved and/or followed up, as specified in the protocol. All Regulatory documents are to be complete and up to date with the originals maintained in the designated binder as agreed upon at study start up, this includes, but is not limited to: Investigators’ Curriculum Vitae(s) (CV’s), IRB approval letters, all amendments, Informed Consent Forms (ICF’s), IRB correspondence, Training logs, Delegation logs, any Drug Accountability forms (DA), and subject logs. All CRF’s and study related documents should also be kept on site for an additional two years minimum after close out so that any documents needed can be accessed before being archived off site for an extended period of time. Any provided equipment, supplies and/or materials are to be returned if specified by the sponsor and/or Clinical Research Organization (CRO).
A final report will be prepared for the Institutional Review Board (IRB) and is likely to include, but is not limited to, study conduct and outcome, safety and efficacy observations, complete disclosure of any SAE’s experienced during the course of the trial and the study close-out date. This report is to ensure that the site acknowledges that the trial has concluded and the site will be free to move on with other trials. Typically, after a close out visit, documents may be requested as to resolve any discrepancies that are found so that any loose ends can be tied up. The Principal Investigator will receive a CD-Rom or a USB flash drive with all EDC data for their records and in case there is ever an audit by a regulatory agency. It is the responsibility of the Clinical Research Associate (CRA) to send a follow up letter detailing the close out visit, listing pending action items, ensure that the IRB “closed” status has been obtained and all equipment returned as well as obtain the address of the location where trial documents will be archived after the two year on site requirement.
Miscellaneous Items and Terms That A CRA Needs To Know
What is a Protocol Deviation? A Protocol Deviation consists of a departure from the current IRB approved version of said protocol. The deviation can be major, minor and may or may not impact the safety of a study participant. Deviations occur frequently across all sites, and are unavoidable due to human error but can be minimized by using experienced staff or hosting frequent protocol training with appropriate Prncipal Investigator oversight. To come across a site without any protocol deviations would be a rarity but it is possible depending on the site’s level of expertise and the complexity of the trial. An example of a minor deviation would be something similar but not limited to the mislabeling of a collection tube such as a urinalysis. However, if this urinalysis collection tube were to be a safety endpoint, it could be a major deviation due to putting the subject’s safety at risk by not collecting and/or labeling correctly.
Another example of a major deviation would be to randomize a subject that does not meet all the appropriate Inclusion/Exclusion Criteria, since this jeopardizes the subject’s safety and protocol design in a major way. The only time a deviation can and will be considered acceptable is when it is done to protect the safety of the subject. A prime, yet common example of this would be to withhold an onsite dose administration (per protocol) to prevent the “double-dosing” of a randomized subject if they’ve returned for a corresponding visit but mistakenly took their dispensed investigational product as part of their daily routine in the morning before the visit took place. When a deviation occurs, it is possible that it could be reportable to the IRB and is up to the site to check with the IRB and report in a timely manner if applicable. A protocol deviation log is not required by all sponsors and there is no standardization of this form, however, some sponsors will require the tracking and reporting of all deviations that occur onsite by the CRA. Depending on preference or processes, deviations can also be recorded on confirmation and follow-up letters by the site’s CRA.
Queries within Electronic Data Capture systems, much like protocol deviations, are also consistently unavoidable due to human error. These queries can be due to just about anything, unless the electronic Case Report Form perfectly matches the corresponding source documents. Some other common queries could be caused by differing units of measurement of the same procedure, spelling errors, missing data and/or incompleteness and should be brought to the attention of the investigators by the CRA. In these cases, a note to file may be applicable or possible retraining of the study staff by the CRA and/or Principal Investigator.
For any personnel involved in clinical research, it is of utmost importance to become familiar with the schedule of events “cheat sheet” that can be found in every protocol; it is a great quick reference and can be resourceful since most times underneath or near the schedule of events, “subtext” can be located. This contains important and detailed information which can be easily overlooked by protocol reviewers new to clinical research. If there were ever a Cliff’s Notes for a study protocol, the Schedule of Events (or Assessments) would be it!
Investigational Product accountability is easily one of the simplest yet most stressful responsibilities of an investigator, site staff, and/or CRA since there is little to no room for error. All IP should be accounted for immediately once the site receives, dispenses, and collects returned IP. When less IP is returned to the site than expected by a subject, it is the responsibility of the Investigator to gather the details of the missing/unreturned IP and record the subject’s response in the visit notes. After IP is returned the site, expired, and/or study closeout is nearing — it is up to the CRA to account for all IP, new and returned, at every site visit. This will also help with shipping IP out for destruction whenever is it applicable.
The unblinding of a randomized subject in any case other than for the safety of the subject would be and is considered a major protocol deviation. It is the Investigator’s responsibility to promptly document and report the details pertaining to the unblinding of a subject.
No clinical trial is the same, especially when being performed across multiple sites. Whatever your role may be in clinical research, it is critical to remember that communication is key. There are answers to your questions at every turn, as well as underutilized resources which are waiting to be tapped into. From Sponsors, CRO’s, sites, CRA’s, Investigators — we are all a team and are working towards the same goals of advancing medicine and ultimately improve the livelihood of the people all around us that are living with uncontrolled conditions and/or disorders.
This is certainly a lot of information to process. I recommend you use this book as a reference guide as well as a starting point for further exploration on these topics. Simply google (or Youtube) terms or topics from this book (you may find some of my own videos) and dive deep into the information. Try to obtain some experience in the clinical research industry as an unpaid intern or commission based patient recruiter. Perhaps my CRA Academy can help get you the informational foundation as well as the practical hands on experience that employers are looking for. Whatever the case may be, don’t be a stranger, connect with me on social media and welcome to the world of clinical research! (This rabbit hole is certainly deep).
ABOUT THE AUTHOR
Dan Sfera (me) has been involved in the clinical research industry on a full time basis since 2005. I started out as a study coordinator, then eventually became (and still am) a research clinic owner. I started blogging about the industry in 2010 and have since started my own business development consulting company and CRO, a CRA Academy, and most recently, became a Senior contract CRA. I can be reached in the following ways:
My CRO: http://www.DSCScro.com
My CRA Academy: http://www.TheCRAacademy.com
Call/Text: (949) 415–6256
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