By Fateh Cheklat & Sophie Hammer
Promoters or pharma laboratories have implemented a branched system to evaluate treatments or medical device … developed in clinical research:
- A service takes over the drafting of a protocol (project) and verification of clinical data;
- A service takes care of biometrics, that is to say, the processing and analysis of collected data;
- One or more centers propose to patients or healthy volunteers to “test” the valuable medical products or medical devices and collect data of patients included.
In each service, one or more players provide the interface with other services between which there must be continuously a documented communication.
The communication between these various services is done by three key players:
- Clinical Research Associate (CRA) on the side of clinical research (promoter),
- Data manager (DM) on the side of side biometrics (promoter)
- Clinical site coordinators (CSCs) on the side of investigation center (clinical research site).
In general, the three have in common scientific competences, but the CRA has more medical and administrative knowledge, the DM has computer knowledge and data management, and the CSC has medical and technical knowledge.
The objective of this article is to address the various tasks performed throughout the entire study by these three players, the difficulties faced by each and to specify activities where they collaborate, interact and communicate more.
So let’s start by listing the activities of each throughout the study.
I. The various tasks throughout the study
|Biometrics||Clinical Research||Investigation center|
|Study protocol (Reference)|
|Writing the « data management plan »
Preparing the CRF paper
Testing the reliability of the database
Programming coherence and attendance tests
Establishing standard error messages and expected responses…
Writing the « data validation plan »
Writing the CRF filling guide
Writing specifications in case of import of data (centralized laboratories)
Selecting the input mode
Training CRAs on the CRF
|Preparing the informed consent form and the information note to the patient
Preparing regulatory submissions to the various authorities: ANSM, CNIL, CCTIRS, CPP, Medical board… etc.
Performing the feasibility and the screening visit with the centers
Preparing and implement the study on the different participating centers.
Ensuring the delivery of CRF /sampling kits/ processing on all participating centers
Training investigators and CSCs on the CRF
|In some cases, receive the proposal for participation in the study and communicate it to the investigator,
In some cases, prepare the table and investigator fees,
Preparing the implementation within the center
Attending the implementation meeting
Listing the potentially includable patients and give the list to the investigator
Creating work tools (nurse sheet listing the acts to perform during each visit, tracking sheet of concomitant treatments, tracking sheet of the patient’s medical history, tracking sheet of adverse events…)
In some cases, prepare the prescription model for the allocation of treatments
|Checking and confirming the entry
Starting the consistency tests
Generating listings for data review
Generating “Data Clarification Form” (DCF) or manual / automatic queries and send them to the CRA
Validating data after the correction
Reconciling the clinical database and pharmacovigilance or medical device vigilance base
Coding medical terms and treatments respectively under Medra (Medical Dictionary for Regulatory Activities) and WHODRUG
Writing data management reports
Designing export data tables for analysis.
|Verifying the success of the test in each center which he is responsible:
Ensuring that the center includes patients and help the investigator to find solutions in case of difficulties
Checking the presence and compliance of the informed consent of each patient participating in the project
Checking that the data reported on the CRF are identical to that existing in the patient’s medical record.
Editing DCF manuals on site in case of any discrepancy between the CRF and the source file or in case of questions and checking the corrections made by the center
Checking if the center follows the Protocol and the regulations in force and identifying deviations to the protocol and Good Clinical Practices (GCP).
Following the resolution of identified problems and proposing solutions to the investigator
Checking the proper keeping of the investigator workbook and ensuring that all regulatory documents are present
Checking the correct allocation of treatments, patient compliance and overall accounting at the pharmacy
Making a Report to the project manager of the progress of the study and problems encountered on site.
|Participating in the inclusion of patients
Calling IVRS system (Interactive voice response) or use IWRS (Interactive Web Response System) to request the randomization of a new patient,
Calling the IVRS / IWRS to request the allocation of treatments,
Helping the investigator to report serious adverse events within 24 hours of becoming aware by the doctor.
Contact the CRO or promoter to request an un-blinding of the study in case of severe adverse events, on request of the investigator,
Organizing and managing visits and examinations of patients, coordinating the arrival of the patient in different services
Preparing blood collection kits
Sending samples to centralized laboratory
Making pharmacokinetic and pharmacodynamic manipulation (bench)
Filling the CRF
Answer to DCFs
Updating workbook investigator and ensuring that the center’s documents are current (patient list, delegation list of tasks, etc.)
Preparing the coming of the CRA for data verification
|Freezing the database once all the data has been monitored and reviewed by the DM, and all DCF resolved.
Extracting the data and sending them to the statistician l
|Making closure visit of the center
Ensuring the presence of all regulatory documents in the investigator workbook
Ensuring the destruction or return of all study treatments and biology kits
Archiving CRFs and any correspondence
|Archiving source files and any correspondence|
Interactions mean requests, exchanges, and unfortunately, sometimes misunderstandings.
II. The encountered difficulties
By the CSC
Investigating doctors often have a heavy workload and little time to be given to clinical research. The CSC must then anticipate and better prepare all necessary documents to ensure that the investigator does not forget any data.
Similarly, the hospital team is not always used to intervene on clinical trials and, often, this represents an additional workload that they do not understand the value at first. The role of the CSC is to explain the value of these additional actions and ensure that the team thinks of it in creating tools adapted to each study.
It can sometimes be frustrating for a CSC to realize that, despite his best efforts, a test has not been done or data was not recorded in the patient’s source file by the investigating doctor, so it creates data missing, which the CRA will ask him during monitoring visits. The CSC must implement actions that will prevent the situation from happening in the future: team training, modification of tools…
By the CRA
As for the CSC, the CRA may also have trouble getting an appointment with the investigating doctor due to his busy schedule. The CRA has often only a few minutes to discuss any problems encountered on site. He must, again, be well organized so as not to forget anything.
The CRA may be required to work with centers that do not include the expected number of patients. The CRA must regularly remind the center, identify challenges and provide solutions. For many reasons, it happens that the center does not give enough time to the study, the CRA must then succeed in motivating the team to ensure objectives are met.
By the DM
The DM should review all study data, not being on site, he can have difficulty to understand what the CSC meant by completing the electronic CRF, especially in open fields. Similarly, a data may seem logical to CSCs and CRAs who have access to the source data, which is not necessarily the case remotely.
The DM, CRA and CSC must work in tandem to ensure the quality of data collection because the ultimate objective is the evaluation of a product of the study that will, perhaps, help future patients.
The DM must build a CRF and a database meeting the protocol requirements and be sure to explain how to use it to the various clinical research actors (project manager, CRA, CSC, Investigator). He must also communicate with the CRA and the investigator on inconsistencies or deviations reported in the database.
The CRA must properly train investigators and their staff on the study, in every detail and emphasize the importance of data to collect. He must ensure close monitoring of the activities of the centers which he is responsible and support (training, advice, and logistics) investigators and CSCs for the proper conduct of the trial. He must detect any deviations and missing data throughout the study and retrain centers to the protocol or make a reminder of good clinical practice if necessary.
The CSC is the foundation of clinical research, he assists the investigator and the care team and ensures the smooth running of the study on site. He must anticipate the usual errors of center to prevent any protocol deviations and missing data that will have a negative impact on the data analysis.
It is up to the 3 agents to train, inform, anticipate, check, ensure, communicate, act and react in time.
For more information on professions of CRA, CSC and DM, you can see the following articles:
The whole truth about the CRA profession (https://blogdelarechercheclinique.com/toute-verite-sur-metier-darc/)
CRA, CSC, how to choose the right position? (Http://blogdelarechercheclinique.com/arc-et-tec-comment-bien-choisir-son-poste/)
Expectations of investigating doctors from CRAs and CSCs (https://blogdelarechercheclinique.com/ce-quattendent-les-medecins-investigateurs-des-arc-et-tec/)
Role and duties of a Clinical Data Manager (https://blogdelarechercheclinique.com/role-taches-dun-data-manager-clinique/)