• 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?

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 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).

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.

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.

Answer: FDA regulations allow for changes to be made to the investigational plan or protocol without prior FDA review or approval, if the change is intended to eliminate an apparent immediate hazard or to protect the life and well-being of trial participants. Therefore, changes in protocol conduct necessary to immediately assure patient safety, such as conducting telephone or video contact visits for safety monitoring rather than on-site visits, can be immediately implemented with subsequent review by the IRB and notification to FDA. Since this reflects a protocol deviation (until the amendment is approved), documentation of the required deviations, as described above, would generally be acceptable (i.e., a document that lists each deviation, study reference ID, patient ID, and date). For example, documenting that all protocol-specified visits will be done by telephone contact rather than on-site visits, and that procedures requiring in-person visits will either not be conducted, or performed by other means (specified, as appropriate). Since the change to telephone or video contact visits would likely result in some protocol-required procedures not being conducted (e.g., vital signs, blood samples for safety laboratory studies), the sponsor must evaluate the potential impact on patient safety, and consider how to mitigate risks to patients, including the need to discontinue the investigational product.

For IDE studies, sponsors are required to report deviations implemented to address the imminent safety risk to FDA within 5 working days after learning of the deviations. We recognize that challenges related to the COVID-19 pandemic may make it difficult to meet this timeframe. Sponsors may consolidate implemented deviations when submitting 5-day reports and should update FDA as soon as possible.

Answer: FDA recognizes that monitors may not be able to access the trial sites for on-site visits in a timely manner during the COVID-19 public health emergency. Sponsors should work to find alternative approaches to maintain trial participant safety and trial data quality and integrity, such as enhanced central monitoring, telephone contact with the sites to review study procedures, trial participant status, and study progress, or remote monitoring of individual enrolled trial participants, where appropriate and feasible. FDA recognizes that delays in on-site monitoring may result in delayed identification of GCP non-compliance (including major protocol deviations) at the clinical trial site(s) (including protocol deviations not due to the impact of COVID-19). Sponsors should carefully document situations where monitors were unable to access, or had to delay monitoring of, a clinical site. Sponsors/monitors should also include in their documentation of protocol deviations or other GCP non-compliance issues identified at clinical sites whether delayed identification was due to postponed monitoring. FDA recognizes that unique situations at clinical sites will occur due to COVID-19 control measures and will consider these circumstances when evaluating inspectional observations.

Answer: Some clinical outcome assessments (COAs)24 can be conducted remotely in clinical trials during the COVID-19 public health emergency, including COAs for performance outcome (PerfO), interview based clinician-reported outcome (ClinRO), 25 patient-reported outcome (PRO), and observer reported outcome (ObsRO). During the COVID-19 public health emergency, sponsors may still be conducting in-person assessments on some trial participants, whereas remote assessments may be necessary for others to protect their safety or to respond to COVID-19-related public health measures implemented by government authorities to control the virus. When deciding whether to change their clinical trial protocols to include remote COAs, sponsors should evaluate the general and specific considerations outlined below.

General considerations regarding (1) prioritization of trial participant safety and privacy; (2) maintenance of data quality and integrity, including minimizing missing data; and (3) appropriate training for personnel and trial participants, which are discussed elsewhere in the guidance, are also common to all COAs. Other general considerations that are common to all COAs include attention to (1) the potential for increased variability in trial data; (2) the feasibility of conducting a specific type of COA remotely, depending on the context of use; (3) documentation and audit trails; and (4) availability of technology and technical support required for remote assessment. These considerations are explained in more detail below.

Increased Variability in Data: When switching from in-person to remote assessments, sponsors should perform remote assessments in a manner as similar as possible to those done in-person, while protecting trial participant safety and privacy. To the extent feasible, sponsors should ensure that the methods and conduct of remote assessments are consistent across sites, trial participants, and visits to minimize variability in the data. For example, if a sponsor decides that video is their preferred method of remote assessment in a clinical trial, then using different methods (e.g., both telephone and video in the same trial) to conduct assessments may increase variability. Maintaining consistency in assessment methods should be balanced, however, against the need to minimize missing data and the decision to use different methods should be justified in study documentation.

Feasibility of the Assessment Method within the Context of Use: Investigators should assess the feasibility of conducting a specific type of COA remotely, which will depend on corresponding trial goals and needs (e.g., ability to conduct the assessment in a way that captures all the data needed to evaluate the endpoint in the trial), given that not all assessments can provide an accurate assessment when done remotely.

Documentation and Audit Trails: Investigators should document, and sponsors should include data on related variables in the clinical trial datasets, whether an assessment was conducted in-person or remotely (including type of technology used), as well as the date of the assessment and the person who conducted the assessment. Sponsors also should ensure that remote data acquisition, transmission, and storage are secure, and that the privacy of trial participants is protected. When sponsors use electronic platforms to perform remote assessments that transmit data directly into trial records, these platforms should include automated audit trails.

Technology and Technological Support: Sponsors planning to use remote electronic assessments as part of a clinical investigation should use appropriate technology and develop procedures for provision of technology and technical support to trial participants, investigators, and/or other trial personnel to facilitate those assessments. For example, sponsors could develop a plan to accommodate trial participants who are either already enrolled in a trial or may be enrolled in a trial in the future, but who do not have access to appropriate communication technology (e.g., cell phones or internet), by providing trial participants with these services.

Specific considerations for certain COA types are explained below.

PerfO- and interview-based ClinRO-specific considerations: For these types of assessments, sponsors should consider (1) appropriateness of remote assessment for the type of clinical data to be collected; (2) special investigator training to administer the PerfO or interview-based ClinRO assessments remotely; and (3) procedures for assessing and confirming the safety of trial participants, their privacy, and appropriate setting and resources to adequately complete the assessment.

Recognizing that components of the PerfO and interview-based ClinRO assessment for some trials may specify visualization or in-person interactions with trial participants that may be difficult to replicate through remote interactions, sponsors should assess whether these components can be evaluated in an alternative way that still permits an accurate clinical assessment. When components of the assessment cannot be accomplished in a remote encounter, investigators should document, and sponsors should report in the clinical trial datasets, any aspects of the assessment they are unable to accomplish remotely. Sponsors should consider whether the information that can be collected remotely will be sufficient to reliably assess the clinical outcome and support robust conclusions for the study.

PRO- and ObsRO-specific considerations: For these types of assessments, sponsors should consider (1) potential for missing data when switching from in-person assessment to remote assessment; (2) whether switching from use of paper- or electronic-based PRO and ObsRO assessments completed independently to assessments administered verbally by another person may lead to bias of scores (e.g., if trial participants try to please the site staff by offering ratings that might not truly reflect their experience); and (3) that data collected with PROs and ObsROs through verbal administration should not be considered a substitute for required safety monitoring throughout the trial.

To minimize potential bias resulting from verbal administration of PRO and ObsRO assessments, sponsors should ensure interviewer training and use of an interview script. Sponsors may also consider using automated virtual interviewers or a trained neutral third-party interviewer to administer the assessments remotely.

The potential for missing data is also a limitation when switching from in-person to remote assessment using paper-based PRO or ObsRO assessments, if the trial participant or observer fails to complete all or part of the questionnaire within a given timeframe. To mitigate potential for missing data, sponsors should consider remote electronic capture of these assessments through technologies that can remind trial participants to complete the questionnaires and/or verbal administration at the time instructed (assuming appropriate steps are taken to minimize bias from verbal administration).

Answer: FDA regulations require sponsors to monitor the conduct and progress of their clinical investigations. The regulations are not specific about how sponsors must conduct such monitoring and are therefore compatible with a range of approaches to monitoring that may vary depending on multiple factors. Therefore, certain aspects of site monitoring visits may be done remotely if technically feasible. FDA understands that there may be deviations from the timing of on-site monitoring visits set forth in the trial monitoring plan and procedures, and that sponsors may consider ways to replace on-site monitoring visits with remote monitoring visits during the COVID19 public health emergency. Further, there may be components of an on-site monitoring visit, as outlined in the trial monitoring plan, that cannot be completed remotely.

During the COVID-19 public health emergency, traditional on-site monitoring might be difficult for reasons such as (1) sites may not be able to accommodate monitoring visits (e.g., due to staffing limitations or site closures) or (2) monitors may not be able to travel to trial sites. When planned onsite monitoring visits are not possible, the reason should be documented and available for review by the sponsor and during FDA inspections.

The sponsor should consider using a risk-based approach to prioritize sites for remote monitoring, including as many study sites as feasible (and with a frequency as close to that described in the site monitoring plan as feasible). The decision regarding which sites to prioritize for remote monitoring should be guided by centralized monitoring or other information available about site performance (e.g., frequency and severity of protocol deviations previously identified during monitoring visits or currently identified by centralized monitoring, number of randomized active trial participants, experience of site staff, known history of prior major audit or inspection findings).

Remote monitoring should be focused on review of critical study site documentation and source data. If the materials identified for review include participants’ medical records that normally would be reviewed at the site (and such a review is consistent with the trial participants’ informed consent documents) then, as discussed below, remote review of medical records may be explored with trial sites to complete source document review. When the study monitor cannot access the site to review criticalsource documents, requests for review of source documents that may include private health information should be consistent with requirements for source document validation and review as described in the current study monitoring plan or other appropriate study-specific document. When remote monitoring processes and procedures have not previously been described by the sponsor, these processes and procedures should be established (e.g., in a revised study monitoring plan or in updates to existing sponsor policies and procedures).

During remote monitoring, the study monitor should focus on trial activities that are essential to the safety of trial participants and/or data reliability. Sponsors and monitors may wish to consider one or more of the following options to facilitate remote monitoring access to clinical site records:

• If the site can provide appropriate resources and technical capabilities, consider establishing a secure remote viewing portal that would permit site staff to provide access to the site’s study documentation and/or trial participants’ source documents for the study monitor’s review. In addition, the potential for remote access to trial participants’ electronic health records may be explored with trial sites.
• Sites could upload certified copies of source records to a sponsor-controlled electronic system or other cloud-based repository that contains appropriate security controls. In the setting of a blinded or partially blinded study, if source documents contain potentially unblind information, controls to protect the study blind should be in place prior to transfer of source documents (e.g., use of an unblinded study monitor to review source documents, restricted access to folders containing copies of source documents). It is not necessary for the clinical site to have control of certified copies of source documents uploaded to such a repository; however, the clinical investigator should maintain control of the original source records.

Regarding retention of copies of source documents used for remote review, it would not be necessary to retain the certified copies of source documents used for remote review, provided the clinical investigator retains the original source documents according to FDA regulations for the retention of records.

In addition, processes and procedures should be established for the handling of source document copies that were placed in temporary storage locations for remote review and that are no longer needed after the remote monitoring has concluded.

Remote monitoring activities, including remote review of source documents, should be documented in the same level of detail as on-site monitoring activities, and any resulting actions to address issues identified from the remote source document review should be consistent with procedures and processes described in the study monitoring plan.

Answer: With the increasing use of telemedicine in clinical practice, a number of resources may be available to provide recommendations on best practices. FDA does not endorse any particular telemedicine best practices. However, from an FDA regulatory perspective, important considerations for trial visits through video conferencing include:

• The investigator or study personnel who will conduct remote visits should be trained on how to conduct real-time video conferencing visits (e.g., training on the use of telemedicine for remote clinical trial visits).
• Procedures should be put in place to maintain a trial participant’s privacy, as would be done for a clinical visit.
• Both the investigator and the trial participant should confirm their respective identities with one another before engaging in a real-time video conference visit according to an identity verification plan developed by the sponsor.

To provide the same information that would be documented during a face-to-face visit, the date of a real-time video conference visit should be documented in the trial records—and if specified in the protocol, the time of the visit. Investigators should consider asking for the trial participant’s location during a video conference visit in case a medical emergency arises during the visit.

FDA considers real-time video interactions, including telemedicine, as a live exchange of information between the trial personnel and trial participants. These interactions are not considered electronic records and therefore are not subject to 21 CFR part 11.

Answer: Electronic systems used to generate electronic signatures on clinical trial records, including informed consent documents, during the COVID-19 public health emergency must comply with the requirements outlined in FDA regulations at 21 CFR part 11 (Part 11) when applicable.

FDA is aware that there are multiple commercial off-the-shelf (COTS) software systems providing electronic signature services for clinical trial records. FDA does not certify individual electronic systems or methods to obtain Part 11 compliant electronic signatures, but COTS vendors may be able to provide sponsors and other regulated entities with information regarding whether their systems are Part 11 compliant. Whensuch information is unavailable from the vendor, and a Part 11 compliant electronic system is required, sponsors and other regulated entities must take other steps to ensure the electronic system or software in use is Part 11 compliant. For further information regarding Part 11 compliance, see FDA’s guidance for industry Part 11, Electronic Records; Electronic Signatures – Scope and Application (August 2003) and the additional recommendations proposed in the draft guidance for industry Use of Electronic Records and Electronic Signatures in Clinical Investigations under 21 CFR Part 11 – Questions and Answers (June 2017).

When an electronic system that is Part 11 compliant is not available, regulated entities must have an alternate means of obtaining required signatures (e.g., handwritten wet ink signatures executed on documents, handwritten stylus or finger-drawn signatures executed on electronic documents that are then printed or appropriately witnessed). Alternative methods for obtaining signatures on informed consent documents during the COVID-19 public health emergency are described in Q10 and Q11 of this guidance. When handwritten methods are used, the sponsor and other regulated entities should ensure that all records containing original handwritten signatures are (1) collected and archived, as either original paper copies or appropriately certified electronic copies (e.g., using a validated process for scanning paper copies), and (2) retained according to applicable FDA record retention requirements.