Sharon Appelman-Eszczuk, BScN, RN, CCRP
Faculty of Medicine and Dentistry
University of Alberta
Cathy Laferriere, BSc
Abstract: Good communication is the key to successful collaboration between clinical research site staff and the monitor, facilitating recruitment and ensuring compliance with Health Canada regulations. This article provides an overview of the monitor’s expectations of the site staff and the site staff’s expectations of the monitor. Tools to aid the site staff and the monitor in working together are provided. Scenarios describe possible issues that arise in monitor-site staff relationships and illustrate ways to resolve situations where the site staff and the monitor do not see eye to eye.
Standard Operating Procedures
Health Canada requires clinical research sites to have standard operating procedures (SOPs) in place for essential processes: informed consent, delegation of duties, investigational product accountability, and adverse event reporting. While Health Canada states that this is not necessary if the protocol explicitly describes these processes, protocols never do this. Thus, sites must always have SOPs to describe their essential processes, which the monitor will review.
Evidence of satisfactory training of site staff involved in the essential processes must be documented, and the documentation must cover initial and ongoing training. Over the course of a study, the SOPs may be updated, especially if the study lasts for years. When the SOPs are updated, the site staff members who are involved in the study must be informed of the update and read the revised SOPs. They must acknowledge in writing that they have read the revised SOPs, and they must date the acknowledgement. Both the monitor and Health Canada will look for this type of documentation.
An SOP is written instructions documenting a routine or common activity followed by clinical research site staff. SOPs should be concise, easy-to-read, and provide step-by-step instructions. They should be short and simple. Including too much information makes it more difficult for site staff to follow SOPs. The SOPs must be available to monitors and auditors.
Table 1 provides an overview of the three SOPs required by Health Canada: informed consent, adverse event reporting, and investigational product accountability. Clinical research sites must also have an SOP on delegation of duties. Under informed consent, Health Canada requires a procedure to explain how the site obtains and maintains the consent of subjects to participate in clinical trials. Obtaining consent is one procedure, and maintaining consent is another procedure. A very short clinical trial, such as 12 weeks, usually only requires initial consent. If the subject comes to study visits and complies with study requirements, this is evidence of maintaining consent in a short study.
For longer studies, such as a study at the University of Alberta that is scheduled to last eight years, it is necessary to prove that the clinical research site has a procedure in place for maintaining consent. Longer studies are very likely to have protocol changes and updated safety information, which require an updated informed consent form. The process for maintaining consent must cover the way in which new information is provided to subjects and the way in which this is documented.
When a protocol at the University of Alberta is amended after all of the subjects are enrolled in a study, the clinical research site does not redo the entire informed consent form. Institutional policies require what is called a “consent addendum,” in which subjects receive the new or changed information. The subject receives the new information and has access to the previous informed consent forms and addendums. This is how the University of Alberta maintains the subjects’ consent to participate in a study.
Health Canada requires a procedure for reporting adverse events and drug reactions, including who reported the event/reaction, what occurred, and when it occurred. Information for reports is taken from the interview with the subject and is recorded on the source document. The SOP must cover all of this, and everyone on the study team must follow this SOP. The adverse events procedure must also indicate who is responsible for assessing the relationship between the study medication and the event and the severity of the event. Assessing causality is usually done by the investigator and can rarely be delegated.
Drug accountability can be difficult. Some clinical research sites use a pharmacy for investigational products while others do not. Some sites use a pharmacy for part of drug accountability and handle part of it themselves. For example, if the drug can be kept at room temperature, the site will store it, but if the drug has to be mixed or prepared, the pharmacy will handle this. Drug accountability includes determining who will receive the drug, maintaining documentation of receipt, registering the drug in the electronic system, following the storage requirements, and communication with the sponsor. The drug destruction procedure must also be included in the SOP. Some sponsors allow the drug to be destroyed on site. If this is the case, it must be documented in writing for each protocol. The SOP must document who will be responsible for each task related to drug accountability.
It is rare for an investigator to handle all study tasks alone. Thus, an SOP on delegation of duties by the investigator to members of the study team is also necessary. This SOP should not be overly specific because it must work across many different protocols. It should include a comprehensive delegation of duties log. Clinical research sites can create their own delegation of duties log, use a log provided by the contract research organization, or combine the two logs. The delegation of duties log is quite important and will guide the monitor’s work.
Delegation of duties is an ongoing process. For longer studies, the duties delegated at the site initiation visit are likely to change. Individuals come and go, and their responsibilities may change. The log must be updated.
SOPs take time to develop and require revisions. Starting with these four basic SOPs is recommended. Templates are available to guide development of SOPs. The templates, however, are only guides, as no two sites are the same. A clinical research site’s SOPs must demonstrate the procedures that are actually used at the site.
Often, monitors who visit the University of Alberta only ask whether the clinical research site has SOPs; they do not need to see them. If, however, during a monitoring visit, a monitor sees something odd, the monitor might ask to see the relevant SOP. When Health Canada conducts an audit, the auditor will want the see the clinical research site’s SOPs.
The monitor must ensure that the clinical research site has an SOP on training documentation. If the site is audited, the monitor’s name will be listed. The monitor must train site staff members and instruct them on writing an SOP for training documentation, highlighting the importance of this SOP. If the site does not develop a training documentation SOP, the monitor must note in reports that the site has been instructed to do so.
Health Canada Training Requirements
Health Canada requires training documentation on International Conference on Harmonisation Good Clinical Practice for the investigator, sub-investigator, and study coordinator. Investigators often feel that they receive the necessary training by attending the investigators’ meeting. This, however, is not sufficient. Good Clinical Practice training is necessary every two years.
Study staff members must also have documented training on the Health Canada Food and Drug Acts and Regulations (Part C, Division 5: Drugs for Clinical Trials Involving Human Subjects). The delegation log must document that the right task has been delegated to the right person who has been appropriately trained.
Documentation of study training by site staff is the most likely type of documentation to be forgotten. If the monitor trains site staff on the initial protocol, this is easily documented. Training, and documentation of training, when the protocol is amended, however, is more difficult. While the study coordinator is capable of providing training on protocol amendments, the investigator should do this, as the investigator is responsible for everything.
What Clinical Research Site Staff Should Expect From the Monitor
The demands on clinical research staff members, whether they are new to the field or experienced, are increasing and sometimes seem overwhelming. Starting with the basics and building from there, with refinements as necessary, makes the work easier. It is important to continually learn.
Appelman-Eszczuk’s clinical research site at the University of Alberta conducts about 22 clinical trials at one time, with a team of 14 staff members. The team includes study coordinators, administrative support, a student, and a finance person. The site uses its relationships with industry and contract research organizations to move forward projects that both monitors and site staff have committed to completing.
In order to make the relationship with monitors work, clinical research sites should have certain expectations of the monitor (Table 2). The monitor or the sponsor’s representative must be well-versed on the protocol and the protocol requirements so that the site staff members will know up front what will happen during the study. The monitor must also know about the disease and indication that are being studied.
Knowledge about the applications of the vendors that will be used in the study is also important. The monitor should know which vendors are providing services such as case report forms, central laboratory services, and interactive voice response systems, as well as how to use these applications.
Clinical research sites rely on monitors to keep them informed of what is happening with the protocol. The monitors have regular meetings on each protocol. They should be providing the site with feedback about issues discussed that are relevant to the site’s conduct of the study.
Accessibility is necessary. Clinical research sites need a monitor who will return phone calls and answer emails. If the monitor is not available, the person listed as the back-up must be available.
The monitor must be well-prepared, organized, and use the clinical research site’s time wisely. This includes arriving and leaving on time. If the monitor is flying in the morning of the monitoring visit, the monitor should let the study coordinator know this so that the study coordinator can do other work until the monitor arrives.
Being organized and focused on the clinical research site is also important. The monitor should not spend hours on a teleconference for another project while at the site. Appelman-Eszczuk’s clinical research site at the University of Alberta schedules specific times for the study coordinator and other site staff to meet with the monitor; the monitor should conduct these meetings as scheduled.
The monitor should respect the clinical research site’s policies and be adaptable to the study coordinator’s schedule. Most of the time, issues related to the site’s policies are misunderstandings that can be easily cleared up by asking questions. Appelman-Eszczuk is always willing to explain the rationale for any of the site’s actions or policies. She also only schedules monitoring visits when the study coordinator is available.
Being part of the project team and a genuine advocate for the clinical research site is important. The monitor should not be someone who just comes in with a checklist and leaves after completing it, followed by sending a letter that has no concrete basis for any findings. The monitor should understand what is happening at the site and represent the site to the project team. This includes sharing the site’s concerns and successes with the project team.
What the Monitor Should Expect from the Site Staff
The monitor should also have certain expectations of clinical research site staff (Table 3). Site staff should understand and follow the protocol. The protocol exists to ensure the safety of subjects, which must always come first. The monitor must also ensure that the site is following the protocol in order to develop high-quality data. In order for the data from all sites to be comparable, they must be high quality.
Site staff should provide clear, complete documentation and have the source documents available for each subject. Clear, complete documentation means providing all of the documentation that is required as per the protocol. It is preferable for all of the documentation to be in the same place. Site staff should not duplicate data. Training documents must also be available.
The person who is doing the data entry must follow the e-case report form (eCRF) completion guidelines. If, for example, the sponsor expects specific data to be entered within three working days of the visit, this should be done. It is acceptable, however, if the site cannot do this until the fourth day. Waiting a month to enter the data is not acceptable.
With electronic case report forms, the monitor can review the forms remotely. If there is an error, the monitor will contact the study coordinator to resolve the problem, which could simply be a typo. The study coordinator should answer a query in a timely manner. If values are out of the acceptable range, the query will be generated immediately. The monitor will also generate queries during monitoring visits. Queries that are pending for a day or so are acceptable; however, not responding for 30 days is unacceptable. The monitor will discuss this with the study coordinator to determine whether there is a good reason that queries are still pending (e.g., the study coordinator was on vacation or there was an issue with the database) or the study coordinator simply did not check and respond to them. In some cases, the study coordinator did not know how to answer the query and forgot to ask the monitor for guidance.
Communication between site staff and the monitor is encouraged. Laferriere would rather have study coordinators who call her twice a day with questions about queries than those who simply do not answer the queries. Site staff members should work as a team with their monitor, who is not a police officer going to the site to tell staff members that they did not do their jobs. It is important to discuss issues and ensure that there are no misunderstandings. The monitor should adapt to the site’s schedule. For example, perhaps the study coordinator needs to start at 10:00 a.m. or leave at 4:00 p.m. to pick up children. To prevent misunderstandings, the monitor should ask the study coordinator about his/her expectations of the monitor.
Scenarios of Interactions between Sites Staff and Monitors
The following scenarios illustrate collaboration between the clinical research site and the monitor. In the first scenario, a four-hour site initiation visit has gone wrong. The monitor doing the site initiation visit was the most available monitor; however, she will not be the site’s monitor for the study.
The monitor was not familiar with the protocol or the vendors that are being used in the study. She read the protocol while traveling to the clinical research site and told the site staff this upon arrival.
A site initiation visit involves bringing together the investigators, study coordinators, laboratory and pharmacy staff, and anyone else who will be working on the study. It is disappointing to have a monitor who knows little about the study and is not well prepared for the site initiation visit.
Tips for avoiding this type of situation include asking key questions when scheduling the site initiation visit, such as whether the monitor has been trained on the protocol. Site staff members should get details about this, such as the number of other clinical research sites that have already been trained by the monitor. If a site is the first to be trained, the visit is likely to take longer due to the first-time training for the monitor. Site staff should also ask whether the monitor is familiar with the vendors that will be used and ask questions about those vendors.
It is recommended to request the monitor who will be assigned to the clinical research site to conduct the site initiation. The site may have to wait a week or two for its monitor to be available; however, it is worth it. Site staff should ask who will be accountable for follow-up to the site initiation visit, such as responding to unresolved questions. Site staff should document whether the monitor who led the site initiation visit or someone else will do this.
The site study team should then be prepared for the site initiation visit based on the information generated by asking questions. Appelman-Eszczuk’s clinical research site at the University of Alberta will select a date and a time that works for the primary team members on the protocol. It is not always possible to have 100% of the team at the site initiation visit; however, the investigator, primary study coordinator, and representatives of the laboratory and the pharmacy will be available. They should be given the protocol in advance and informed about the visit. The time for the visit can be altered to ensure that the designated monitor conducts the visit. A physician who allocates an hour for the visit will not be impressed if the monitor does not have the necessary knowledge about the study. Site staff should also document what was covered during the visit and the required follow-up.
In the second scenario, the investigator is not available to meet with the monitor, who must meet with the investigator face-to-face at least at every other monitoring visit. Tips for this situation include trying to schedule and confirm an appointment in advance before the next monitoring visit. The meeting only takes 10 minutes unless there are problems with the study. The monitor may need to change the date of the monitoring visit in order to meet with the investigator.
If the monitor is unable to schedule a meeting with the investigator, the monitor can schedule a telephone discussion to inform the investigator of any issues with the study. This can prevent future deviations. The monitor can also send the investigator a detailed email and ask the investigator to acknowledge receipt of the email and respond to any issues.
Finally, the monitor should document any findings in the follow-up letter to the clinical research site. Since the monitor was unable to meet with the investigator, the monitor will document all of the findings in the letter as well as the necessary steps to resolve the findings. If the site is audited, the monitor will be asked how often he/she met with the investigator and whether the investigator was aware of what was happening with the study.
The third scenario covers remote or in-house monitoring, which is becoming increasingly common. Sometimes the in-house monitor is requesting information about a monitoring visit within hours after the monitor has left the site. The monitor may request the blinded source to be scanned or faxed to him/her to validate the electronic data capture. Even if a serious adverse event was submitted to the electronic data capture system with full supporting documentation, safety teams may still request additional information.
Tips for handling remote monitoring include asking whether remote monitoring will be involved before committing to conduct the study. Site staff should ask detailed questions, such as what type of source documentation verification will be done (e.g., 100% or 80%, or whether only random source data verification and review of informed consent forms will be done). Questions should also cover who will do the monitoring and when and where they will do it. Clinical research site staff should ask directly about remote monitoring and document the response. The appropriate site resources must be allocated to support requests from the sponsor and the vendors.
Investigator Oversight of the Study
Lack of investigator oversight of a study is a common finding in audits and inspections. Both monitors and site staff should be monitoring investigator oversight of the study. Evidence of this is necessary and will be required in the event of an audit by Health Canada. Sponsors and contract research organizations also want to see evidence of this.
Ways to document investigator oversight of a study include dated source notes showing that the investigator has reviewed that the subject met the inclusion/exclusion criteria. The date of the source notes must be before the subject was randomized into the study. Progress notes written or dictated by the investigator provide evidence of his/her involvement in study conduct and subjects’ visits.
Laboratory results must also be signed and dated by the investigator. If the results are out of the range, the investigator must assess whether this is significant. The monitor will look for the date, which should be within a week of receiving the test results.
The investigator, or at least another physician, must assess the causality and severity of adverse events in writing. Clinical research sites that use an adverse event log can have the investigator initial and date the assessment of each adverse event there. Adverse events must be assessed in a timely manner.
The key to successful collaboration between clinical research site staff and the monitor is great communication, starting from the beginning of the study. Site staff members must get to know their monitors (on-site and in-house). Although site staff members are very busy, a brief site visit or telephone call can save a great deal of confusion and questions. Monitors must get to know site staff and the experience of the site staff. For example, when the monitor arrives at the site, the monitor should take a few minutes to greet the study coordinator and other site staff members and ask how they are doing. Knowing a site’s experience gives a monitor faith in the site’s ability to conduct the study, which will be demonstrated during on-site monitoring.
Issues should be sorted out in a positive manner, and a team approach combined with flexibility is necessary. It is natural for people to become defensive, and clinical research site staff and monitors all have tight schedules. Resolving issues in a positive manner leads to great relationships. When site staff and the monitor work together as a team, this leads to a mutual commitment to the study. Site staff and the monitor should do what they say they will do within the specified timeframe. Flexibility may require, for example, a site to deviate from its SOPs to comply with the study’s requirements.
Clinical research site staff and the monitor should be advocates for each other. Site staff should let the monitor’s manager, other members of the study teams, and the investigator know that the monitor is doing a great job. Investigators often hear about problems, but they rarely hear about what is going well, such as having a great monitor. Monitors should be advocates for their sites.