21 CFR Part 11—Electronic Records; Electronic Signatures

Central to any decision should be ensuring that the safety of clinical trial participants can be maintained. Sponsors, in consultation with clinical investigators and Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs), should assess whether the protection of a participant’s safety, welfare, and rights is best served by continuing a study participant in the trial as per the protocol or by discontinuing the administration or use of the investigational product or even participation in the trial. Such decisions will depend on specific circumstances, including the nature of the investigational product, the ability to conduct appropriate safety monitoring, the potential impact on the investigational product supply chain, and the nature of the disease under study in the trial. As part of this assessment, sponsors should carefully consider the following aspects of clinical trial conduct when deciding how or whether to proceed with a clinical trial:

• Assessing whether the limitations imposed by the COVID-19 public health emergency on protocol implementation pose new safety risks to trial participants, and whether it is feasible to mitigate these risks by amending study processes and/or procedures.

• Assessing the continued availability of the clinical investigator/sub-investigators to provide oversight of the trial and properly assess and manage safety issues that may emerge.

• Assessing whether there will be sufficient clinical trial support staff given the evolving COVID-19 situation and its impact on staff Are there appropriately trained staff that could be available to handle the expected tasks? Is there adequate equipment and materials for clinical trial support staff?

• Assessing whether clinical investigator sites will remain open to trial participants for required in-person assessments or whether the clinical investigator has the ability to provide required in-person assessments at an acceptable alternate location(s), or whether such protocol-specified, in-person assessments can instead be conducted virtually.

• Assessing the continued availability of clinical trial supplies and continued operations of vendors, especially related to supply of the investigational product and/or to clinical trial supplies that are essential to maintaining appropriate safety monitoring or other key trial This should include consideration of product stability (shelf life) if the treatment schedule is revised, or if the clinical site is unable to properly store the product for the needed duration.

• Assessing the continued availability of, and support for, information technology systems and any other technological tools that are needed to support the Are current contingency plans adequate for the types of disruptions that might be anticipated? What other plans can be put in place to minimize any potential disruptions?

• Assessing whether there will be continued operations of, and adequate communications with, IRB/IEC and Data Monitoring Committee (DMC) staff, if applicable, to support trial needs.

• Assessing whether it is feasible to conduct the trial in light of any COVID-19 public health measures implemented by Federal and State authorities to control the virus.

Involvement of a study’s DMC, if one has been established, can provide support for the assessments discussed above.  Since a primary responsibility of the DMC is assuring the safety of participating trial participants, the DMC’s assessment of the impact of modifications of trial conduct due to COVID-19 on patient safety is important to consider.

The risks and benefits of continuing a trial are likely different than a decision to initiate a trial (other than trials intended to evaluate investigational treatments or vaccines for COVID-19). Given the evolving situation, with likely increasing impacts on investigators, staff, and supply chains, sponsors should carefully consider the ability to effectively mitigate risks such that patient safety and trial integrity are assured.  In addition, it is important to consider whether initiation of the trial could interfere with public health measures implemented by Federal and State authorities to control the virus.

There may be circumstances in which an investigational product (either a drug, biological product, or medical device) appears to be providing benefit to the trial participant. A sponsor deciding whether to continue administering or using such a product during the COVID-19 public health emergency should carefully consider context-dependent issues, including whether a trial participant appears to be benefitting from treatment with the investigational product, whether there are reasonable alternative treatments, the seriousness of the disease or condition being treated, and the risks involved in switching to an alternative treatment if necessary. FDA recognizes that in some circumstances it may be necessary (e.g., based on lack of product supply or inability to administer or ensure the safe use of the investigational product) to discontinue investigational product administration in a trial. If there are individual trial participants for whom discontinuing the investigational product might present a substantial risk (e.g., trial participants perceived by the investigator as having a clinical benefit from the investigational product), the sponsor should consider amending the protocol, after discussion with the relevant review division, to limit investigational product use to those patients with apparent benefit and discontinue investigational product use to other participants. In all cases, if a trial participant is discontinued from an investigational therapy, it is important that there be appropriate management after discontinuation.

For IND studies, the sponsor should submit a formal amendment to its IND, with the following information added to the cover letter in the subject line:

PROTOCOL AMENDMENT – COVID-19

TITLE OF PROTOCOL

Sponsors should summarize the major changes made to the protocol related to COVID-19 in the cover letter and should include a tracked changes version of the protocol to facilitate review. As with other protocol amendments, sponsors may implement protocol amendments due to COVID- 19 upon submission to FDA if approved by the IRB.  Sponsors seeking FDA input prior to implementation should indicate that in the cover letter.

For IDE studies, the sponsor should submit a supplement to its existing IDE, with the following information added to the cover letter in the subject line:

CHANGE IN PROTOCOL SUPPLEMENT – COVID-19 or
NOTICE OF IDE CHANGE – COVID-19, as applicable 

TITLE OF PROTOCOL

The submission to the IDE should contain a tracked changes version of the protocol to facilitate review.

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.⁵   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.

As noted in the main body of this guidance, it is important to capture specific information for individual participants that explains the basis for missing protocol-specified information that includes the relationship to COVID-19 (e.g., from missed study visits or study discontinuations due to COVID-19).  This information, summarized in the clinical study report, will be helpful to the sponsor and FDA.  If it is not possible to capture this information in the case report form(s), sponsors may develop processes that enable systematic capture of these data across the sites in a manner that enables the appropriate analysis when the data are submitted to FDA. Sponsors may also develop processes to capture site-level status, site-level or vendor-level protocol deviations, and process deviations.

If there is concern about risk of exposure to COVID-19, home delivery of investigational product that would not raise any new safety risks may be implemented to protect patients from coming to clinical trial sites. In all cases, requirements under FDA regulations for maintaining required investigational product storage conditions and investigational product accountability remain; these requirements must be addressed and documented.⁶  If the protocol indicates pharmacy dispensing for self-administration at home, and this is changed to direct-to-patient shipments, then a protocol amendment would be required to permit home delivery of investigational product.⁷  If the extent of home delivery is limited to certain participants and not the entire population described in the protocol, documenting the change in the mechanisms of distribution of investigational product administration through protocol deviations may also be acceptable. If the change in the mechanisms of investigational product distribution is then included in a protocol amendment, such a change may be part of a “cumulative” amendment that includes a number of changes that accrue, rather than an urgent protocol change.⁸

FDA regulations outline sponsor and investigator responsibilities for storage conditions and accountability of investigational drug products, including disposition of unused investigational products (IPs).⁹   Under 21 CFR 312.59, the sponsor shall assure the return of all unused supplies of the investigational drug from each individual investigator.  The regulation further provides that the sponsor may authorize alternative disposition of unused supplies of the investigational drug provided this alternative does not expose humans to risks from the drug. The procedure for disposition is generally considered part of the investigational plan and is normally described in the study protocol as a study-specific plan for handling the IPs. In most protocols, such plans involve the participant bringing the unused IP to the clinical trial site and then the investigator returning the unused IP to the sponsor or its designee. During the COVID- 19 public health emergency, if appropriate, a pre-paid shipping package can be used for the participant to return IP back to a central location where it can be accounted for and disposed of per the protocol, but this approach is not the only way to satisfy the regulatory requirements for disposition of unused IP. Regardless of the chosen disposition method, sponsors and investigators must maintain adequate records regarding the disposition of the IP.¹⁰

Sponsors may consider adopting alternative procedures for disposition of IP that permit sponsors and investigators to fulfill their requirements for maintaining adequate records of IP disposition (including documenting dates, quantity, and use by particpants), provided such procedures do not expose humans to risks from the IP.¹¹   For example, it may be possible to provide the participants with a way to dispose of IP at their home (such as with a drug disposal pouch) and document such disposal through photo or video that can be transmitted to the investigator or sponsor.  FDA does not endorse a particular approach, but the risks involved (e.g., environmental considerations) with specific IPs should be considered when selecting a method for disposal. FDA has provided a consumer update Where and How to Dispose of Unused Medicines¹²that provides recommendations to consumers about how to safely dispose of unused FDA-approved medication at home. Sponsors can consider whether any of those recommended methods of disposition are appropriate for approved drugs being studied for a new use in a clinical investigation.  As noted in the consumer update, FDA only recommends flushing medications that are on the FDA flush list, which currently does not include unapproved IP.

Investigators proposing alternative disposition methods must obtain authorization of those methods from the sponsor of the trial.¹³   Additional restrictions may apply to IPs subject to the Controlled Substances Act.¹⁴

Sponsors should consider the safety risk to trial participants who would miss an investigational product infusion because of the inability to come to the clinical trial site. If a sponsor is considering providing alternative arrangements for administration of the investigational product (e.g., home nursing or alternative sites by trained but non-study personnel), the sponsor is expected to perform a risk assessment that considers the nature of the investigational product and the potential risks to both the trial participants and the health care providers responsible for administering the product at the alternative site. This risk assessment should include assessment of risk mitigation strategies.  Based on this risk assessment, sponsors should consider whether consulting the appropriate FDA review divisions regarding plans for alternative arrangements for administration of investigational products that are usually administered in a health care setting is warranted.

Consulting FDA is strongly advised for complex investigational products (e.g., cellular therapy and gene therapy products), where potentially altered storage and handling conditions could adversely affect product stability.  In all cases, applicable requirements for maintaining required investigational product storage conditions (prior and after reconstitution), investigational product reconstitution specifications per the Investigator’s Brochure, and investigational product accountability remain and must be addressed and documented. Storage conditions and investigational product accountability should be considered if the protocol is amended to permit alternative site infusions.  Defining circumstances when discontinuing investigational product administration, while continuing study participation, albeit with potentially delayed assessments, may be an appropriate option when suitable alternative arrangements cannot be made.

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.

FDA regulations generally require that the informed consent of a trial participant (in this case, a hospitalized patient) be documented by the use of a written consent document that typically includes the elements of informed consent, as described in 21 CFR 50.25, and that has been approved by the IRB and signed and dated by the trial participant or their legally authorized representative at the time of consent (21 CFR 50.27(a)). When feasible, we recommend a traditional method of obtaining and documenting informed consent using a signed paper copy of the consent form, or use of electronic informed consent.^{15  16  17}   If neither of these approaches are possible, the following procedures would be considered to satisfy FDA’s informed consent documentation requirement.¹⁸

Method 1: A photograph of the signed informed consent document can be transmitted to the trial staff

1.  An unsigned consent form is provided to the patient by a person who has entered the room.
2. The investigator/designee arranges a telephone call or video conference call with the patient (and, if desired and feasible, additional individuals requested by the patient (e.g., next of kin)).

3. To ensure that patients are approached in a consistent fashion, a standard process should be used that will accomplish the following:

• • Identification of who is on the call.

• • Review of the informed consent document with the patient by the investigator/designee and response to any questions the patient may have.

• • Verbal confirmation by the patient that their questions have been answered, that they would like to participate in the trial, and that they have signed and dated the informed consent document that is in their possession.

4. The patient (or an individual in the room) takes a photograph of the signed informed consent document and sends it to the investigator/designee.

5. A trial team member enters the photograph into the trial records along with an attestation that states how that photograph was obtained and that it is a photograph of the informed consent document signed by the patient.

Method 2: A witness can attest to the signature, but a photograph of the signed informed consent document cannot be transmitted

1.  An unsigned consent form is provided to the patient by a person who has entered the room.
2. The investigator/designee arranges a three-way telephone call or video conference call with the patient, a witness who is not otherwise connected with the clinical investigation, and, if desired and feasible, additional individuals requested by the patient (e.g., next of kin). Alternatively, in lieu of using a witness, a recording of the conversation can be made.¹⁹

3. To ensure that patients are approached in a consistent fashion, a standard process should be used that will accomplish the following:

• • Identification of who is on the call.

• • Review of the informed consent document with the patient by the investigator/designee and response to any questions the patient may have.

• • Verbal confirmation by the patient that their questions have been answered, that they would like to participate in the trial, and that they have signed and dated the informed consent document that is in their possession.

4. When using a witness, documentation in the trial records includes: (1) a signed and dated attestation by the witness who participated on the call that the patient confirmed their agreement to participate in the trial and signed the informed consent document; and (2) a signed and dated attestation by the investigator/designee stating why the informed consent document signed by the patient was not retained (e.g., due to potential contamination of the document by infectious material).

When using a recording in lieu of a witness, documentation in the trial records includes: (1) the recording of the conference call; and (2) a signed and dated attestation by the investigator/designee who participated on the call stating why the informed consent document signed by the patient was not retained (e.g., due to potential contamination of the document by infectious material).

When either Method 1 or 2 is used to document informed consent, the resulting documentation should be: (1) collected and archived, as either original paper copies or appropriately certified electronic copies (e.g., using a validated process for scanning paper copies),²⁰ and (2) retained according to applicable FDA record retention requirements as part of the trial record.²¹

If the patient is unable to provide informed consent and there is a legally authorized representative, investigators must obtain written consent from the patient’s legally authorized representative in accordance with 21 CFR 50.27(a).

Investigators may also need to obtain informed consent from a potential trial participant or their legally authorized representative when these individuals are unable to travel to the site where the investigator is located due to COVID-19 illness or travel restrictions. When investigators do not have electronic informed consent (eIC) capabilities,²² methods of obtaining informed consent other than a face-to-face consent interview may still be acceptable if those methods allow for an adequate exchange of information and documentation, and a method to ensure that the signer of the consent form is the person who plans to enroll as a participant in the clinical investigation or is the legally authorized representative of the trial participant. For example, the consent form may be sent to the trial participant or their legally authorized representative by facsimile or email, and the consent interview may then be conducted by telephone when the trial participant or their legally authorized representative can read the consent form during the discussion.  After the consent discussion, the trial participant or their legally authorized representative can sign and date the consent form.

Options for returning the document to the clinical investigator may include facsimile, a photographic image sent through electronic means, scanning the consent form and returning it through a secure email account, or posting it to a secure Internet address, especially if there are concerns about having the participant mail a potentially contaminated consent document. Alternatively, the trial participant may bring the signed and dated consent form to his/her next visit to the clinical site, if restrictions on traveling to the clinical trial site are alleviated or mail it to the clinical investigator.  The case history for each trial participant must document that informed consent was obtained prior to participation in the trial.²³   In addition, the person signing the consent form must receive a copy of the consent form.²⁴   Although FDA regulations do not require the trial participant’s copy to be a signed copy, FDA recommends that a copy of the signed consent form be provided.

The trial participant or their legally authorized representative must sign and date the informed consent form before the investigator may conduct any study-related procedures involving the participant.²⁵  Where it is not feasible for investigators to receive the signed consent form prior to beginning study-related procedures, the investigators should have the prospective trial participant or legally authorized representative confirm verbally during the consent interview that the participant or legally authorized representative has signed and dated the form. In addition, the overseeing IRB must review and approve the planned informed consent process.²⁶

Where a prospective trial participant (or legally authorized representative) is unable to print the informed consent document provided electronically by the investigator/designee, an electronic signature process is not available, and the prospective trial participant must meet time-sensitive eligibility criteria, the investigator may consider using the following alternative process to satisfy FDA requirements for obtaining and documenting informed consent:

1. The investigator/designee provides the prospective participant (or legally authorized representative) with an electronic version of the informed consent document.
2. The investigator/designee arranges a telephone call or video conference call with the prospective participant (or legally authorized representative), the investigator/designee, a witness who is not otherwise connected with the clinical investigation and, if desired and feasible, additional participants requested by the prospective participant (e.g., next of kin). Alternatively, in lieu of using a witness, a recording of the conversation can be made.²⁷
3. To ensure that the prospective participant (or legally authorized representative) is approached in a consistent fashion, a standard process should be used that will accomplish the following:

a. Identification of who is on the call.

b.  Review of the informed consent document with the prospective participant (or legally authorized representative) by the investigator/designee and response to any questions the prospective participant (or legally authorized representative) may have.

c. Verbal confirmation by the prospective participant (or legally authorized representative) that their questions have been answered and that they would like to participate in the trial.

4. Verbal confirmation by the participant (or legally authorized representative) that they signed and dated a blank piece of paper with a written statement that they voluntarily agree to participate in the protocol, noting both the Protocol ‘NUMBER’ and brief protocol title.

5. After signing and dating the newly created document, the trial participant (or legally authorized representative) sends a photograph of the signed and dated statement by facsimile, text message, or email to the investigator/designee; OR returns the document to the investigator by mail at a later date, or at a future study visit that might occur in person.

6. When using a witness, documentation in the trial records includes a signed and dated attestation by the witness who participated on the call that the patient confirmed their agreement to participate in the trial and signed the document referenced above.

7. When using a recording in lieu of using a witness, documentation in the trial records includes the recording of the conference call.

8. After the signed and dated document is received by trial staff, it should be appended to a copy of the consent document that was reviewed with the trial participant (or their legally authorized representative) and retained in the trial records as would normally be done for a signed informed consent Additionally, a note in the trial records should be made explaining the circumstances of why informed consent was obtained through an alternative method.  The case history for each trial participant must document that informed consent was obtained prior to participation in the trial.²⁸

This alternative approach must be reviewed and approved by the IRB overseeing the trial as required under FDA regulations.²⁹

Some clinical outcome assessments (COAs)³⁰ 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),³¹ 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 this 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 to conduct assessments (e.g., both telephone and video in the same trial) 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.³²

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).

FDA regulations require sponsors to monitor the conduct and progress of their clinical investigations.³³  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 COVID-19 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 on-site 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 critical source 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 copies³⁴ of source records to a sponsor-controlled electronic system or other cloud-based repository that contains appropriate security 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.³⁵

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.

Commercial sponsors may qualify for a short-term waiver from the eCTD requirements under section 745A of the FD&C Act in unique and rare circumstances and for a limited duration. During the COVID-19 public health emergency, rare circumstances may arise in which a sponsor cannot meet eCTD requirements (e.g., if the current COVID-19 public health emergency has impacted computer operations).  Companies experiencing technical difficulties with transmission of their electronic submissions to FDA should consult FDA’s electronic submission staff (contact information provided below) for technical assistance, rather than submitting a waiver request, as described in Section III.E of FDA’s guidance for industry Providing Regulatory Submissions in Electronic Format—Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (February 2020, Revision 7):

FDA may grant temporary waivers of the requirement for eCTD submission if one or more of the following events or circumstances exist:

• • Extraordinary events or circumstances occur that are beyond the control of the submitter that justify a waiver, including but not limited to, natural disasters that impact computer operations.

• • An unplanned long-term Internet disruption or other unplanned event occurs that would preclude the sponsor from submitting in eCTD format (e.g., malware attacks).

• • The sponsor intends to request a withdrawal of an application that has not yet converted to eCTD format. 

• • The sponsor submitted a request for withdrawal and has not yet received FDA’s acknowledgement of the withdrawal. ³⁶

The guidance also states:

The sponsor or applicant’s request to waive the eCTD electronic format requirement must include all of the following as supporting documentation to justify the waiver:

(a) A description of the circumstances or event–including the anticipated duration of the circumstance or event–giving rise to the need for a waiver

(b) The requested duration of the waiver

(c) A description of the proposed alternative submission format the sponsor or applicant will be using for the duration of the waiver

The request should reference all products that are to be covered by the waiver. The waiver request should be clearly titled “WAIVER REQUEST–eCTD REQUIREMENTS” in bold capital letters at the top of the first page of the submission.³⁷

Waiver requests for new drug applications (NDAs), biologics license applications (BLAs), abbreviated new drug applications (ANDAs), drug master files (DMFs), and commercial INDs may be sent to FDA electronic submission staff via email to CDER (esub@fda.hhs.gov) or CBER (esubprep@cber.fda.gov).  If a waiver is granted, FDA intends to provide information in the response letter on how to transmit the submission.  FDA intends to encourage sponsors and applicants to send submissions electronically in an alternative electronic format (e.g., PDF files following the eCTD structure).

Specific circumstances for a given clinical trial would affect the feasibility and appropriateness of shipping investigational products (IP) to locations other than clinical trial sites as specified under an IND, as well as administering the IP.  If the IPs being evaluated in the trial are administered by infusion, then it would be important that any alternative infusion center have appropriately trained personnel and oversight by physicians with sufficient experience regarding the class of products involved to assure trial participant safety comparable to administration at a trial site.

For the purposes of this guidance, local health care providers (HCPs) who are administering drugs in a manner that does not differ from their normal clinical practices would not be considered sub-investigators and need not be listed on Form FDA 1572.³⁸   FDA recommends that these HCPs be listed in site records, such as a log of activities delegated by the investigator. Any changes to a trial protocol to permit an HCP to administer the investigational drug generally must be reviewed and approved by an IRB.³⁹

The above paragraph described administration of the investigational product by local HCPs who are practicing medicine within their scope of practice. In contrast, if a sponsor will be asking local HCPs to perform study-specific research procedures or assessments that represent a direct and significant contribution to the clinical data for the study (e.g., assessing drug response for a patient or performing a procedure unique to the study and not part of routine medical care), these HCPs would be considered sub-investigators and should be listed on Form FDA 1572.

IP may be shipped from a central distribution site directly to an HCP, provided that such shipping is done under the supervision of the investigator using procedures that assure accountability and product quality (i.e., that storage conditions, as defined in the protocol, for the IP were maintained during shipping, and the drug packaging was intact upon receipt).

If the HCP administering the IP is not considered a sub-investigator, the investigator should ensure that they can obtain records regarding administration of the IP by requesting that the trial participants provide consent to allow access to medical records from their local HCPs involving trial-related data such as measuring vital signs, and results of evaluations of any symptoms or signs occurring with the infusion. Communicating the intent to request such records from the HCP in advance may facilitate this process.

Consulting the appropriate FDA review division(s) on plans for alternative administration is also recommended as per Q9 above.

If the product(s) under investigation in a clinical trial is FDA-approved, and the study does not require blinding, then local sourcing of the product(s) would be acceptable to FDA (e.g., by having the local physician write a prescription for the product instead of shipping the product directly to the patient). FDA does not consider a trial participant’s commercial procurement of the study drug when unable to secure it from the trial site during the COVID-19 public health emergency to be a sponsor charging for an investigational drug under an IND per FDA regulations at 21 CFR 312.8.  FDA also would not object if the sponsor reimburses the patient for any costs incurred by commercially purchasing the product or for charges related to an infusion.

Per FDA regulations at 21 CFR 312.6, the immediate package of an investigational new drug intended for human use must bear a label with the statement “Caution: New Drug—Limited by Federal (or United States) law to investigational use.” FDA recognizes that a commercially obtained product will not have this statement on its container. In the setting of the COVID-19 public health emergency, where alternative arrangements are being made to provide an investigational agent to a participant who is unable to come to the trial site, FDA intends to exercise flexibility without sponsors needing to seek a waiver under 21 CFR 312.10 of the investigational labeling requirements under 21 CFR 312.6.

As stated in our guidance for industry Best Practices for Communication Between IND Sponsors and FDA During Drug Development (December 2017),⁴⁰ review division regulatory project managers (RPMs) are the primary point of contact for communications between a sponsor and FDA. Both FDA and sponsors use various communication methods to focus discussions to exchange information and resolve issues efficiently. For example, telephone communication between a sponsor and FDA RPM may be more effective for time-sensitive matters.  FDA staff try to respond to sponsor questions promptly, while balancing FDA public health priorities and other work obligations. Note that to ensure participant safety, responses to safety-related inquiries will be prioritized over other inquiries. More generally, FDA understands that many questions that will arise regarding changes in trial conduct due to COVID-19 will need to be addressed expeditiously. RPMs will work with sponsors to determine the best path forward to answer their questions for certain changes in an expedited manner.

To discuss urgent issues related to IDEs managed in CDRH, sponsors should contact the lead reviewer.  For IDEs managed in CBER, sponsors should contact the RPM. For FDA feedback on a proposed future IDE study, or regarding modifications to ongoing studies that are not urgent (such as a statistical analysis plan to address missing data), a Pre-Submission is recommended. For additional information on Pre-Submissions, please refer to FDA’s guidance for industry Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program (May 2019).⁴¹

For general questions regarding FDA policy on clinical trial conduct during the COVID-19 public health emergency, sponsors should contact Clinicaltrialconduct-COVID19@fda.hhs.gov.

*⁴²  Given that trial participants may not be able to come to the investigational site for protocol- specified visits at which laboratory tests or imaging would be conducted, sponsors should evaluate whether it is feasible to use alternative laboratories or imaging centers. The suitability of such alternative arrangements may vary depending on whether the protocol-specified procedures are related to eligibility criteria, safety evaluations, or endpoint assessments.

In general, if trial participants cannot access a clinical trial site, alternative sites may be used for laboratory tests or imaging assessments that focus on the safety of trial participants when such tests and assessments are routinely performed in those settings (e.g., routine chemistries, blood counts, chest radiographs).⁴³

However, if the results of laboratory tests or imaging assessments are the basis for formal hypothesis testing, including primary or secondary efficacy endpoints and some safety endpoints, sponsors should consult with the relevant FDA review division. For example, disparities in laboratory measurements or imaging protocols will introduce increased variability and thus can affect type I and type II error rates.

When baseline tests are necessary to characterize the eligible study population, potential variation in test performance or precision related to use of an alternative laboratory or imaging center may also warrant discussion with the FDA review division.  For example, an inclusion criterion based on a commonly available, routine test performed as a safety screen (e.g., renal function on a metabolic panel) might be amenable to alternative laboratory collection with minimal impact on study results.  Using an alternative laboratory for tests related to other eligibility factors could be more likely to affect study integrity (e.g., laboratory tests to identify a tumor biomarker required for inclusion, genetic test to identify a marker that is a critical inclusion criterion).  It may be important for such assessments to be standardized at a single site or at most a few sites.  Based on the nature of laboratory tests conducted for the purpose of protocol assessments, the alternative laboratory conducting such tests for investigational purposes will likely be subject to certification and other requirements under the Clinical Laboratory Improvement Amendments (CLIA).⁴⁴   Alternative laboratory and imaging centers may also be subject to additional laws governing their operations.

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.⁴⁵

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.

The information in this guidance applies to all clinical trials, including those postmarketing clinical trials that FDA requires an applicant⁴⁶ to conduct⁴⁷ for drugs and biological products. Many of the considerations outlined in this guidance may also be relevant to postmarket device studies.⁴⁸

Applicants who are required to complete postmarketing clinical trials for drugs or biological products follow a timetable that includes due dates for completing certain milestones in the trial. FDA encourages applicants to inform FDA as soon as possible if they experience COVID-19- related delays that may affect the applicant’s ability to meet the applicable interim,⁴⁹ trial completion, and/or final report submission milestone(s). These applicants should propose feasible revised milestones for interim, trial completion, and/or final report submission milestone(s).⁵⁰

For post-market device studies, the approved post-approval study protocol or post-market surveillance plan generally includes due dates for completing certain study milestones. Due dates for certain milestones may also be listed expressly in the order requiring the postmarket study.  Applicants required to complete such studies should similarly inform FDA as soon as possible of COVID-19-related delays that may affect the applicant’s ability to meet those milestones and propose feasible revised milestones.

Applicants with PMRs or required postmarket device studies should also provide an explanation to FDA of how COVID-19 impacts the ability to meet the original milestones. FDA will evaluate the facts and circumstances of the explanation provided, as well as the conduct of the applicant, in determining whether the applicant is in compliance with the applicable authority requiring the postmarketing trial or postmarket device study after the milestone has been missed.

Additional considerations for drug and biological product PMRs include:

• PMRs Under Section 505(o)(3) of the FD&C Act. FDA will continue to make “good cause” determinations on a case-by-case basis for all missed milestones, including those where the applicant asserts that its failure to meet a PMR interim, trial completion, and/or final report submission milestone(s) is related to the current public health emergency.

• Deferred Pediatric Study PMRs Under the Pediatric Research Equity Act (PREA).⁵¹ If circumstances involving COVID-19 have affected an applicant’s ability to complete a PREA PMR, applicants may request a deferral extension for the final report submission   If an applicant has not obtained a deferral extension and fails to submit required PREA studies by the final report submission date listed in the PREA PMR, FDA is required to issue a non- compliance letter to the applicant.⁵²

• PMRs Under Accelerated Approval. For confirmatory trials, if an applicant misses an interim, trial completion, and/or final report submission milestone, FDA will review the applicant’s explanation for the delay, as well as assess the trial’s progress prior to the current public health emergency, before determining whether or not the applicant has been compliant with its milestone obligations.
• Annual Status Reports of PMRs.  Applicants must continue to follow the annual reporting requirements for PMRs⁵³ and should document in their annual status report the COVID-19-related reason(s) for missing interim, trial completion, and/or final report submission milestone(s), and any steps taken to address COVID-19-related factors.

Reports of serious adverse events (SAE) that occur in clinical practice with the use of an approved drug or biological product, whether or not the use is included in the labeling for that product, must be reported in accordance with the applicable post-marketing reporting requirements under FDA regulations at 21 CFR 314.80 and 600.80. Reports of SAEs for approved vaccines are submitted to the Vaccine Adverse Events Reporting System (VAERS), while reports of SAEs for other approved drugs and biological products are submitted to the FDA Adverse Event Reporting System (FAERS).⁵⁴

Serious adverse events that occur during a clinical trial under an IND for an approved drug or biological product being investigated for a new use to treat COVID-19 must be reported as an IND safety report per FDA regulations at 21 CFR 312.32 if they are unexpected and the sponsor determines that there is a reasonable possibly that the drug caused the SAE.

Regardless of whether an SAE occurs in the course of clinical practice or during a clinical trial, and regardless of where it is first reported, an NDA or BLA holder who is also the sponsor of an IND investigating the same drug for COVID-19 is responsible for monitoring the safety of its drug and evaluating all accumulating safety data.⁵⁵   If accumulating safety data, including use in clinical practice, indicates a new serious risk associated with the drug, an IND safety report will need to be filed to the IND, and updates will likely need to be made to the investigator brochure and/or the informed consent document.⁵⁶   For more information, see FDA’s guidance for industry and investigators Safety Reporting Requirements for INDs and BA/BE Studies (December 2012).⁵⁷

Under FDA regulations at 21 CFR 312.32, a sponsor must report to FDA any serious adverse event (SAE) that is both unexpected and for which there is a reasonable possibility that the drug caused the serious adverse event, i.e., there is evidence to suggest a causal relationship between the drug and the adverse event.

Given the community spread of infection during the COVID-19 public health emergency, trial participants in a clinical trial may be diagnosed with COVID-19 and experience SAEs associated with the disease that are not causally related to the investigational drug. However, it also is possible that an investigational drug might be causally related to a SAE associated with COVID- 19 by making trial participants in the trial more susceptible to complications from COVID-19. Establishing this potential causal relationship likely requires more than a single or even a few cases.  To determine whether a reasonably possible causal relationship exists between an investigational drug and an SAE in a randomized controlled trial, FDA recommends a comparison between the rate of observed SAEs among COVID-19 infected trial participants in the investigational drug arm to COVID-19 infected trial participants in the control arm. Given that such analyses entail examination of unblinded data, such assessments should be done only by a data monitoring committee that routinely reviews unblinded data or by a specially constituted safety committee that is appropriately “firewalled” and independent from those conducting the trial and performing other study analyses. If the latter, such a committee should review safety data only, not efficacy data.  If the trial is not randomized, in some circumstances it may be warranted to determine whether there is an excess of SAEs in trial participants diagnosed with COVID-19 by comparing the rate of such events to an external similar population diagnosed with COVID-19, recognizing that the reported rates of SAEs and mortality in patients with COVID-19 have varied widely.  In comparing the rate in the trial to the published literature, sponsors should consider reports in patients with similar comorbidities and levels of care. If the difference in SAEs across treatment arms or compared to an external population suggests a causal relationship between the investigational product and the SAEs in trial participants diagnosed with COVID-19, this finding must be submitted to FDA as an IND safety report in accordance with 21 CFR 312.32.

FDA had provided additional information about aggregate safety assessment and reporting for INDs in the guidance for industry and investigators, Safety Reporting Requirements for INDs and BA/BE Studies (December 2012),⁵⁸ and has proposed recommendations in the draft guidance for industry Safety Assessment for IND Safety Reporting (December 2015).⁵⁹

Where an IND safety report is required to be submitted to FDA under 21 CFR 312.32, the investigator must also send that IND safety report to the IRB.⁶⁰  The IRB may have additional reporting requirements regarding COVID-19 during the clinical trial.

No, it is not acceptable for an investigator to review only certain IND safety reports. Under 21 CFR 312.60, investigators are responsible for protecting the safety of trial participants in a clinical investigation. IND safety reports must be sent by the sponsor to FDA and all participating investigators⁶¹ when the sponsor determines that a serious adverse event is unexpected and there is a reasonable possibility that the drug caused the serious adverse event, i.e., there is evidence to suggest a causal relationship between the drug and the adverse event.⁶² Reviewing IND safety reports is essential for protecting the safety of trial participants because a serious and unexpected adverse event represents a new potential risk associated with the investigational product. FDA considers the review of all IND safety reports critical to fulfilling investigators’ responsibility to protect the safety of trial participants in a clinical investigation.⁶³

In addition, investigators are required under 21 CFR 312.66 to report all “unanticipated problems involving risk to human subjects or others” to the IRB.  FDA considers a serious and unexpected adverse event that meets the criteria for sponsor reporting to FDA and all investigators in an IND safety report under 21 CFR 312.32, and would generally consider a serious adverse event that meets the criteria for safety reporting for an IND-exempt bioavailability/bioequivalence study under 21 CFR 320.31(d)(3), to be an “unanticipated [problem] involving risk to human subjects or others” that therefore must be reported to the IRB by the investigator.^{64 65}

For more information about safety reporting, see FDA’s guidances Safety Reporting Requirements for INDs and BA/BE Studies (December 2012)⁶⁶ and Adverse Event Reporting to IRBs—Improving Human Subject Protection (January 2009).⁶⁷

Electronic systems⁶⁸ used to generate electronic signatures⁶⁹ 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.^{70 71}

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. When such 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)⁷² 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).⁷³

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., handwritten⁷⁴ 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 Q11 and Q12 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.⁷⁵

When a medical product is being used under an EUA, it is an authorized (though not an approved or cleared) medical product for use in clinical care that has met the statutory criteria under section 564 of the FD&C Act.  The product is not being studied under an IND or IDE when used pursuant to an EUA, and FDA therefore does not consider receipt under an EUA as receipt of an investigational product.⁷⁶   In contrast, when the same product is used in a clinical investigation under an IND or IDE, the product’s safety and/or effectiveness is being studied for investigational uses, and FDA would consider receipt in this situation to be receipt of an investigational product.

As always in the design of a clinical investigation, there may be valid scientific reasons to have an exclusion (and even a discontinuation) criterion for a medical product—a monoclonal antibody or vaccine, for example—whether that product was used under an EUA or not. These scientific reasons may include risks to an individual if they enroll or continue to participate in a clinical trial after receiving (or having received) the excluded product, or the potential impact of the use of the excluded product on trial objectives, such as confounding the determination of effectiveness of the product under investigation.

FDA regulations require sponsors to monitor the conduct and progress of their clinical investigations.⁷⁷  These regulations are not specific about how sponsors must conduct such monitoring and are therefore compatible with a range of approaches that may vary depending on multiple factors.  FDA’s guidance for industry Oversight of Clinical Investigations – A Risk- Based Approach to Monitoring (August 2013) clarifies that sponsors can use a variety of approaches to fulfill their responsibilities for monitoring clinical investigations; the guidance also describes monitoring activities that reflect modern, risk-based approaches, including remote monitoring when appropriate.

The decision as to whether remote monitoring conducted for a given site or clinical investigation was adequate or should be followed up with additional on-site monitoring visits should be based on the sponsor’s ongoing risk assessment.  The sponsor may determine that on-site follow-up of remote monitoring activities is appropriate based on a risk assessment (e.g., sites with certain data anomalies or a higher frequency of errors, important protocol violations, or dropouts relative to other sites).  As with on-site monitoring, remote monitoring should be focused on critical data and processes for human subject protection and trial integrity, such as the site’s conduct of key study procedures and documentation related to important efficacy endpoints and safety assessments.