The Epilepsy Pathway Innovation in Africa (EPInA) short messaging service (SMS) randomized control trial (RCT) was designed to examine the effect of SMS reminders on adherence to anti-seizure medication (ASM) among people living with epilepsy in Nairobi. The intervention involved sending automated text, graphic or audio messages to the mobile phones of persons with epilepsy (PWE) or their caregivers. As a behavioral intervention, the trial focused on enhancing medication adherence without involving any investigational drugs.
The study was a partially blinded, randomized, controlled trial with two arms: treatment and control. Participants in the treatment arm received SMS reminders tailored to their medication schedules. In contrast, participants in the control arm received SMS messages about general health behaviors, such as sleeping under a mosquito net or handwashing, with no reminders related to medication adherence. Each participant was followed for one year, with three specific follow-up points: Month 3, Month 6, and Month 12. To ensure quality and compliance with relevant study procedures, monitoring was conducted continuously—from before the study’s initiation, throughout its duration, and up to close-out monitoring.
Monitoring the SMS trial involved a clinical trial monitor visiting the site to have conversations with the study team to ensure that all activities conducted during the trial were in line with the study protocol, standard operating procedures, good clinical practice (GCP), and regulatory requirements. Monitoring confirms that (i) the rights and well-being of human subjects are protected; (ii) the reported trial data are accurate, complete, and verifiable from the source documents; and (iii) the trial follows the current study protocol, good clinical practice, and regulatory requirements.
Moreover, proper implementation of monitoring strategies informs the detection of potential risks, which may include data quality and ethical considerations, plan mitigation strategies, and error correction procedures.
The EPInA SMS trial conducted the site initiation visit in February 2023, the first routine monitoring visit in March 2023, and the second routine monitoring visit in November 2023, and we plan to conduct a close-out monitoring visit after the end of the trial (completing participant follow-ups).
The processes and approaches of clinical trial monitoring have several steps, beginning with a site initiation visit.
The site initiation visit is the first step in the clinical trial monitoring process. These visits ensure that the study site is prepared to implement the protocol, confirming the availability and readiness of site facilities and that study personnel have the necessary skills and training. All essential study documents and approvals must be in place at this stage. Documents such as curriculum vitae (CV) for key personnel, certifications (following training of key personnel on research ethics and good clinical practice), and data protection agreements are assessed. Usually, these documents are filed in a site investigator master file.
The assessment of the readiness of the study facilities entails a check of the structural elements relevant for the study procedures. Essential equipment is inspected to ensure it is functional and ready to use. Moreover, for a trial with a biospecimen collection component, it is crucial to ensure enough laboratory space, equipment, and consumables for effective processing, as well as transportation and storage processes. The understanding of the study protocol, standard operating procedures, consenting process, documentation, maintenance of the site investigator master file, and documentation requirements by the key personnel is also assessed.
At the end of the site initiation visit, emerging issues and pertinent observations are discussed between the monitor and the project staff, including the principal investigator, where minor and significant recommendations are communicated. Recommendations need to be addressed before the study site is ‘initiated.’ Initiation means that the study has been allowed to proceed.
Routine monitoring visits follow after the site has been initiated and the trial is in progress. The number of routine visits depends on the duration of the trial, but each visit should take place quarterly or at most every four months. The main aim of the routine monitoring visit is to confirm, among other things, that the study participants’ welfare and rights are protected and that the study protocol is conducted per the standard operating procedures and good clinical practice. Further, these visits ensure adequate reporting of participant safety and study endpoints. During these visits, the monitors review all screening and enrollment logs to ensure completeness and that all participants involved in the trial met the inclusion criteria. Monitors also review documentation around the informed consent process to ensure no participant was involved in the study against their will. Follow-up logs are also assessed to ascertain the participants who returned for follow-up, those who were lost to follow-up, and the reasons for dropping out of the trial.
Randomization logs are records used to document how participants are allocated to different study groups. These are also assessed to ensure that the randomization of study participants to the different trial arms (treatment and placebo) is adhered to. Monitors review the randomization report generated by the trial data manager. Monitors also review the capacity of the lab and lab staff to handle, process, and store samples by checking the logs to ensure that all the procedures are conducted according to the laboratory’s standard operating procedures. Some level of access is provided to the monitors to access the de-identified data to assess critical processes and data for completeness, accuracy, and integrity.
A debriefing meeting between the study monitors and the study team follows each routine monitoring visit. The meeting discusses the monitoring visit’s outcomes, emerging issues, and recommendations. Minor, major, and critical issues are identified, root causes are dissected, and solutions to ensure compliance are explored and deployed.
The study monitors generate monitoring reports which are shared and approved by study reviewers. The monitoring report for each visit is shared with the study team.
Close-out monitoring is conducted after the trial implementation is completed. In some situations, it is done just before the implementation is completed. Close-out monitoring ensures that all trial activities have been completed according to the protocol’s schedule and procedures.
Specific areas for concern during the close-out monitoring include reviewing the report on adverse events and serious adverse events. Moreover, discussions on investigational product accountability and handling post-study closure are conducted to ensure clarity. Further discussions are had on the retention of all the study documents. Laboratory storage for future analysis and the regulatory obligation of the study closure are also discussed during the close-out monitoring.
After this close-out monitoring visit, any notifications to relevant bodies about the study closure are initiated, including a report to the ethics review board. The monitors then officially declare the study site closed, and a closeout report is issued.
Based on the site initiation, routine and close-out monitoring from the SMS trial, we can draw several lessons relevant to implementing a successful clinical trial.
- Importance of timely and complete documentation
The regular and thorough monitoring visits ensured that important documentation—such as consent forms, necessary approvals for the study, subject information, laboratory documents, information about the study staff, and all monitoring reports—was accurate, complete, and properly stored in the physical and electronic Investigative Site Master files.
Monitoring visits prioritized participant safety by ensuring compliance with informed consent, GCP methods, documentation, trial SOPs, study protocol, research ethics, and prompt adverse event reporting.
- Up-to-date and quality data
Monitoring visits highlighted the importance of precise, comprehensive, and verified data. This ensured that there were no data mistakes, information gaps, or disparities that could compromise the integrity and results of the study.
- Identification of risks and mitigation measures
Regular monitoring during the EPInA SMS trial implementation enabled us to identify and mitigate risks early. Each identified risk was evaluated based on the likelihood of occurrence, its impact on participant safety and trial integrity, and the threshold for such errors. Timely implementation of mitigation strategies helped minimize potential hazards that could have compromised the safety and quality of the study.
- Adherence to study protocol and good clinical practice
Monitoring the clinical trial ensured that the study was conducted in compliance with the approved study protocol and good clinical practice. Any changes to the study protocol or failure to adhere to GCP could negatively impact the validity of the findings. Therefore, monitoring ensured that any deviations were promptly addressed and that GCP guidelines were followed. This further promoted the reliability and accuracy of the data.
- Training and support of study staff
The trial monitors shared their knowledge during monitoring visits, which allowed the site personnel and project staff to receive training on GCP rules and protocol requirements. As a result, the trial’s conduct and data quality improved, likely due to the ongoing and intentional training provided to the study staff.
In conclusion, monitoring trials is essential in ensuring the safety, integrity, and reliability of research findings. This includes reviewing trial procedures, data collection, and protocol adherence to identify and address potential problems. By providing oversight, training, and adhering to regulatory standards, the safety of study participants is ensured, and risks are managed to achieve the high quality and integrity of the study.