REBECA Practice: Clinical Research Associate

As the sponsor's designated representative, you are responsible for ensuring that the protocol is followed and for reporting any deviations from the protocol to the sponsor. Therefore, it is essential that you have a thorough understanding of the protocol.

ACTION: read the Trial Synopsis of the Study Protocol (page 6) and familiarize yourself with the protocol before the training.

NOTE: In real life, you will be supported in this task. The sponsor will provide you with training to facilitate you understand the protocol and address any questions you may have. This is such an important task to assure quality that it is mandatory and is tracked. Auditors and inspectors from regulatory bodies can request CRA training records.

Your CTL has involved you in the preselection of specific sites for the clinical trial. Before accepting a site as feasible for participation in a clinical trial, many aspects need to be checked, including country selection based on population criteria, legislative requirements, and more. CRAs do not typically play a vital role in this process. However, CRAs are included in the pre-selection of specific sites because, in many cases, they have previous experinece with the sites and have gained field knowledge of their practices and conditions.

You have the contact information for St. James Hospital and have already checked their interest in participating in the study. You have sent them short surveys to assess their access to the study's target population, the availability of in-house trained staff for the trial, the capability of their laboratories, and more. In general, you are evaluating criteria to assess the overall capacity of the institution to conduct the study and to ensure that the data produced will be comparable with other participating sites.
One of the criteria you need to check is the availability of facilities at the site needed for conducting the trial. To perform this task, you need to know which facilities are required for the trial. This information can be derived from the diagnostic requirements and tests that the study's patients will undergo according to the protocol. All these tests are described in detail in the Study Evaluation Table (or visit plan table) of the protocol.

ACTION:make a list of the facilities that are needed for this study according to the test and diagnoses that appears in the protocol synopsis in the Treatment Study Visit (page 10 of the protocol document) and check on the website of St. James hospital, if they have these facilities.

NOTE: You will need to report all this information into the corresponding pre-selection report Many sources of information, not only collected by you, but also from records of the institution, of the sponsor knowledge about the site, and self-disclosure data from questionnaires administered to the site, etc., will fill up documentation to allow the sponsor to select a site. It is the sponsor’s prerogative to make that decision.

In the first pre-selection phase, St. James Hospital has been selected. Then, the initiation process begins. This is a complex process that lasts for months until the site is activated and can start recruiting participants and conduct the trial. It is not a linear process, but one where many parallel actions take place. In general, the process of documentation review takes place early on to ensure suitability and later approval by regulatory agencies. At the same time, training and preparation of the team, verification of equipment and supplies, and data management setup also take place. As CRAs, you play a key role in the initiation process of selected sites assigned to you. You need to ensure that all required documentation is gathered according to the section “Documentation required to initiate trial” stated in the protocol (Page 67)

ACTION: check if all the research team  has handled to a valid Good Clinical Practice (GCP) certificate  and indicate in the site initiation report form if one is missing.

NOTE: this is a very lengthy process and clinical research sites frequently struggle a lot with the required paperwork. Management studies show that this process is key to motivating the whole team to work for the study and prioritize it. Your supporting role is crucial here.

Before activating a site and during the initiation  visit, you need to meet with the investigators and make sure they understand the protocol. This is of utmost importance to assure the safety of the patients and ensure the data quality and integrity. For this reason, you need to introduce first the scientific aspect of the study to the investigators in a meeting.

NOTE: the investigators are the Principal Investigator (PI) and the sub-investigators. The PI is usually a head of a unit in a department, the sub-investigators are other physicians designated by the PI.

Important points of the scientific aspects of a trial that need to be effectively communicated in this meeting are:

•      Main purpose of the study? What phase is it? And the rationale behind of this study, ie the main hypothesis.
•      What variables are going to be measured to test the hypothesis (Entry and Secondary points)
•      What is the target population for the study (trial population)? Criteria of inclusion and exclusion.
•      Explain the pathology and comorbidities.
•      Overview of the study design.
•     To remember the investigation team that not procedures of the study can be performed before the patient agrees to participate in the trial by the sign of the Informed Consent Form (ICF).

ACTION: Read the scientific aspects of the protocol (found in the trail synopsis and in the background information-page 22 of the document) and prepare a presentation covering the important points stated below.

NOTE: In this meeting, you will be assisted by an sponsor’s expert of their Medical Department , so any technical (clinical) questions that investigators may have can be answered by them. You are not a physician, so you can only provide an overview of the diseases and certain comorbidities, but you are not responsible to answer clinical questions.

TIP FROM THE EXPERT: Investigators are all physicians, and their research tasks are compromised by their clinical obligations; their time is very limited. Throughout the project, your role with them will be to ensure they oversee the conduct of the study according to the protocol, regulation and GCP, while also making things easy for them.

You have already trained the research team, now you need to train the rest of the staff involved in the trial. Research nurses need practical training on aspects of the protocol such as administering the drug if applicable, sampling the patients per the visit schedule outlined in the protocol. Pharmacy staff require training in drug management and dispensation as they will be handling the drug to the patient and/or study coordinator. Investigators, Study Coordinator and data entry person need training on the data management system, eCRF (electronic Case Report Form), interface, and procedures. All training sessions must be documented in the training log, which should be attached to the required documentation, signed, and dated by all the trainees and the trainer.

ACTION: Review the training log and indicate in the summary visit form if all staff has received the training.

NOTE:  Throughout the entire life of the clinical trial, you will need to check this training log. Staff turnover in hospitals is high and it's essential to ensure that all staff involved in the trial have received appropriate study training to participate in the trial.

very time CRAs visit a site, they issue a monitoring report of the visit to the sponsor and send a follow-up letter to the site with the main outcome of the visit. In this letter, CRAs describe the visit actions and findings, and include any items requiring follow-up. It is crucial to provide adequate details and supporting information. In cases where any site action is required, a brief rationale needs to be provided. This may include references to the protocol, GCP guidelines, etc.

ACTION: write a site initiation visit follow up letter using this sample, informing about the trainings and clearly stating the missing attendance of one of the pharmacy staff in the training log, and the missing CGP training certificate form one of the investigators. Request specific site/staff action.

TIP FROM THE EXPERT: All follow-up letters should have a positive tone to foster a constructive relationship, especially in the first visit letter, as it is the first time you meet the staff. After all, both parties - the sponsor and the site - want the study to be successful and compliant with applicable regulations. Putting oneself in the other's shoes helps maintaining this collaborative positive attitude.

Finally, all the documentation has been gathered, regulatory agencies have given their approval, the contract between the sponsor and site has been signed, all staff has been trained, and supplies have been sent and properly stored. You have communicated all this to the sponsor, and now the sponsor is about to activate the site by sending the ready-to-enroll letter. The site can now start recruiting the first patients.
You have reviewed the monitoring plan, your roadmap to monitor your assigned sites. According to your monitoring plan, for all newly recruited participants, inclusion and exclusion criteria need to be monitored, among other things. To conduct an efficient visit, you need to communicate your intentions to the site so they can arrange their agendas and have the necessary documentation ready for your visit.

ACTION:Review the monitoring plan (the items you should monitor are highlighted) and write a site visit letter to formally communicate the site your visit and monitoring expectations. (You can use this template)

According to the monitoring plan, every time a new participant is recruited, you need to check if the inclusion and exclusion criteria are met and informed consent is signed by the patient.

ACTION:Review the clinical history of the new recruited participant and check if the inclusion and exclusion criteria are met.

TIP FROM THE EXPERT: Ensure that the informed consent is obtained before drug administration, and the consent process is documented accordingly on medical records (patient had time to make question and to think about his/her participation in the study? Was trial explained to the patient by an investigator? Patient received a signed copy of the informed consent?). This is indeed one of the inclusion criteria.

During the visit, as planned, you checked the clinical records of participant 5 and found that she had a relapse of the disease a month ago. You verified that this adverse event was appropriately reported in the clinical history (following ALCOA principle), was properly transcribed into the CRF, and the following treatments were applied according to the protocol. After treatment, the participant was properly informed and decided to continue with the trial, and the next doses were provided. All procedures were performed in compliance with the protocol. However, the RMI scan was performed a month after the completion of steroid treatment, and the re-signed informed consent has not been added to the archive. This is a deviation from the protocol.

ACTION: Fill the Sample Protocol Deviation Log, and write a note to the file. Find in the protocol the reasons to support this note (page 58).

NOTE: A note to the file is a memorandum, usually filed in the regulatory binder, that explains an issue and/or a deviation of protocol. Like a follow-up visit letter, this communication document includes a brief summary of the issue/deviation, a rational for it, an action plan to ensure resolution of the issue, and an evidence that proofs the action is completed and effective. Moreover, it may also include an action plan to prevent issue recurrence upon implementation. In this case, you decided to train the investigators and the study coordinator on the correct documentation of this specific unreported adverse event.

After a clinical trial is complete at site level (all patients finished their treatment and follow up period), you should prepare several additional documents. You generally provide an accountability log to the authorities that tracks drug products to show drug accountability dispensation and returns (if any) per participant. It also helps you track the drug product stock and any imbalances at the end of the study, as well as any unused drug that must be disposed of or destroyed per sponsor’s instructions. You also must provide an Investigational Product Destruction report that describes and ensures that the site Pharmacy and indirectly yourself as CRA, have properly handled any leftover products. Because you are an experienced CRA, you have been monitoring the product accountability and product destruction during your previous monitoring visits, so much of the work has already been done.

To finish, you need to prepare the close-out report, but another CRA will do it because your company has reassigned you to another site.