Florence Library of FDA Remote Monitoring Guidance
Florence Library of FDA Remote Monitoring Guidance
Within the last few years, the FDA has released guidance on remote site monitoring and responses to questions on conducting site monitoring visits particularly after the onset of COVID-19.
Due to the recent abrupt shifts in how Clinical Trials are conducted, there has been an increased need for answers pertaining to remote monitoring.
In response, we have summarized the below FDA guidances and GCP Email inquiries and responses. The questions stem mainly from two FDA guidance documents:
So where does Florence fit?
As it is our mission at Florence to simplify clinical trial document and project management while creating a purpose-built platform for remote monitoring and collaboration. We also aim to provide sites and sponsors with an easier way to access, understand, and apply the FDA’s guidance to eRegulatory, eSource, and eTMF.
Currently the FDA’s published material is challenging to navigate and access. So to save you time and headache, we have created a library of those GCP inquiries regarding remote site monitoring processes.
Inside this library live the original questions, the FDA’s responses, and our summary of those exchanges.
What is Included in the Florence Library of FDA Remote Monitoring Guidance?
- Centralized Monitoring Summary
- Communication with Study Site Staff Summary
- Review of Site’s Processes Procedures and Records Summary
- Informed Consent
- Site’s Records
- Source Data Verification and Corroboration
- Full Account of FDA Responses to Questions Regarding Remote Monitoring
- Initiating Virtual Clinical Trial Visits
- Can a sponsor initiate virtual clinical trial visits for monitoring patients without contacting FDA if there is an assessment by the sponsor and investigator that these visits are necessary for the safety of the trial participant and it will not impact data integrity?
- Expectations for Clinical Trials Delays During COVID-19
- Considering that there likely will be delays to on-site monitoring of clinical trials during the COVID-19 public health emergency, what are FDA’s expectations in such circumstances?
- Factors to Consider for Clinical Trial Protocol Adjustments during COVID-19
- What factors should sponsors consider when deciding whether to change their clinical trial protocol during the COVID-19 public health emergency to include remote clinical outcome assessments?
- Remotely Performing Site Monitoring Visit and Source Document Review During COVID-19
- I am a study monitor and am unable to conduct on-site monitoring visits due to the COVID-19 public health emergency. May I remotely perform the site monitoring visit? What recommendations does FDA have for how I can remotely perform source document review?
- Remote Video Conferencing with Participants
- We are instituting trial participant visits remotely through video conferencing. Are there recommendations regarding best practices?
- Electronic Signatures on Clinical Trial Records During COVID-19
- What considerations apply to the electronic systems used to generate electronic signatures on clinical trial records, including informed consent documents, during the COVID-19 public health emergency?
- Initiating Virtual Clinical Trial Visits
Centralized Monitoring
Centralized monitoring is a remote evaluation carried out by sponsor personnel or representatives (e.g., clinical monitors, data management personnel, or statisticians) at a location other than the sites at which the clinical investigation is being conducted.
Centralized monitoring processes can provide many of the capabilities of on-site monitoring as well as additional capabilities. The FDA has adjusted their guidance to encourage greater use of centralized monitoring practices and less emphasis on on-site monitoring.
The types of monitoring activities and the extent to which centralized monitoring practices can be employed depend on various factors, including:
- Sponsor’s use of electronic systems
- Sponsor’s access to subjects’ electronic records, if applicable
- Timeliness of data entry
- Communication tools available to the sponsor and study site.
These factors may vary by study and by site.
Sponsors who plan to employ centralized monitoring processes should ensure that the processes and expectations for site record keeping, data entry, and reporting are well-defined and ensure timely access to clinical trial data and supporting documentation. If sponsors intend to rely heavily on centralized monitoring practices, the monitoring plan should identify when one or more on-site monitoring visits will take place.
Centralized monitoring techniques should be used to supplement or reduce the frequency and length of on-site monitoring. Traditional on-site monitoring techniques may be replaced with remote monitoring activities or centralized monitoring processes, if applicable.
Examples include:
- Monitoring data quality through routine review of submitted data to identify and follow-up on queries, e.g. missing data, inconsistent data, data outliers, and potential protocol deviations. Queries may be indicative of systemic or significant errors in data collection and reporting at a site.
- Conducting statistical analyses to identify data trends not easily detected by on-site monitoring, such as:
- Standard checks of range, consistency, and completeness of data
- Checks for unusual distribution of data within and between study sites, such as too little variance
- Analyzing site characteristics, performance metrics (e.g., high screen failure or withdrawal rates, high frequency of eligibility violations, delays in reporting data), and clinical data to identify trial sites with characteristics correlated with poor performance or noncompliance.
- Verifying critical source data remotely, as described in the monitoring plan, in cases where such source data is accessible, or where CRF data is located
- Completing administrative and regulatory tasks. Such tasks include:
- Verifying continuous institutional review board (IRB) approval by reviewing electronic IRB correspondence, if available
- Performing portions of investigational product accountability to: (1) assess whether the subject was administered or dispensed the assigned product (2) evaluate consistency between investigational product receipt, use, and disposition records
- Verifying whether previously requested CRF corrections were made.
Centralized techniques, including routine review and analysis of submitted data, may be used to identify significant concerns with non-critical data that may not have otherwise been investigated. An example would be identifying the need for clarification of a protocol procedure or indications of data fabrication recognized from monitoring source document verification.
Target on-site monitoring by identifying higher risk clinical sites through the activities described above. A higher risk clinical site may be one that has data anomalies, a higher frequency of errors, protocol violations, or dropouts relative to other participating sites. These data findings, whether related to critical or non-critical data, may warrant more intensive monitoring and consideration of an on-site visit.
Communication with Study Site Staff
Communication between the monitor and the study site staff is an essential component of monitoring. Various modes of communication could be considered for specific study time points and activities (e.g., teleconferences/videoconferences; study initiation; training of new site staff).
Review of Site’s Processes, Procedures, and Records
Informed Consent:
Verification of subjects’ informed consent is a critical activity that should be monitored (see section IV.A). The traditional approach of this verification included monitors verifying the original wet-ink signature on the consent form for each subject at the site(s). Alternatives to the traditional approach can be more effective in identifying inadequacies in the consent process and thus more efficient.
For example:
- The study site electronically sends the signed page(s) of consent forms via fax or email to the monitor, or the monitor performs remote comparison of dates of study procedures and documentation of informed consent on CRFs.
- An internet portal that enables the site staff to upload signed consent forms and enables access by designated monitors is a tool that can be considered. Use of electronic informed consent may also facilitate sponsor oversight of human subject protection.
Sponsors must attend to privacy and confidentiality concerns when considering techniques for monitoring informed consent remotely so it is critical to select compliant solutions.
Site’s Record:
A large portion of source documents are electronic and may be available to the sponsor remotely such as laboratory and radiology reports or source documents submitted by the CI for other purposes (e.g. documenting serious adverse events or adjudicated events). Consistent with ICH E6 and ISO 14155:2011, original observations can be entered directly into the eCRF or transmitted to the eCRF from various locations, devices, or instruments.
The FDA recognizes that sponsors may not have remote access to all electronic health records. Particularly records maintained by hospitals, universities, and other institutions because of data privacy, security concerns, and/or technological challenges.
As discussed in this guidance, a variety of centralized monitoring techniques can be used to replace, supplement, or target on-site monitoring activities. The majority of these techniques can be performed regardless of the extent of use of electronic records in the study. These techniques include site checks for completeness of data, frequency of protocol violations, and screen failure rates.
For example, the majority of these techniques can be performed using CRF data collected either using electronic data capture systems or entered into a database from a paper CRF collected by the sponsor.
A recent publication discusses statistical techniques for identifying various types of data errors. The statistical techniques described in this guidance may not be routinely used by all sponsors and may not be appropriate for every trial, but they are included in this guidance as examples of monitoring techniques that may be considered by sponsors.
Additional monitoring techniques, such as routine review of data as they are submitted, are possible for studies that use electronic CRFs. Although not a monitoring technique, another method of ensuring data quality routinely implemented in eCRFs is the use of electronic prompts in the eCRF. This method minimizes errors and omissions at the time of data entry, particularly if data are entered directly into the eCRF.
Source Data Verification and Corroboration:
The sponsor should consider the quantity and types of source data that need to be verified against CRFs or corroborated against other records during the sponsor’s identification of critical data and processes, risk assessment, or both. For example, review of medical record to corroborate a subject’s response of “no hospitalizations” since the previous visit on a CRF.
Also to note, a description of the quantity and types of source records should be included to verify or corroborate in the monitoring plan. Source records that provide the most meaningful information about a subject’s participation and the CI’s conduct and oversight should also be considered.
For example, for a particular study, there may be minimal benefit in comparing 100% of the source data for each subject to the CRFs for each study visit. Rather, it may be sufficient to compare the most critical data points for a sample of subjects and study visits as an indicator of data accuracy. Similarly, for a particular study, all concomitant medications, body temperature, and body weight are required by the protocol, to be collected, documented, and transcribed to a CRF. However, they may not be identified by the sponsor as critical data, because a small error rate in those variables would not affect the outcome of the trial.
FDA Responses to Questions Regarding Remote Monitoring
From the 2020 FDA’s Guidance for Industry, Investigators, and Institutional Review Boards: FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency.