The research community is understandably concerned about the impact of COVID-19 on ongoing clinical trials. To help share guidance and best practices, Advarra has assembled the following summary based on the questions we’ve received via our Ask Advarra form. We will update this summary with new information as it becomes available, so be sure to check back often. If you want to be alerted whenever we add new topics, sign up here for email notifications.

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Note: This information reflects the IRB policies at Advarra. IRB policies vary; check with your reviewing IRB to ensure you are following their requirements.

Table of Contents

General Guidance and Requirements Revised

Revised to include FDA guidance on monitoring devices, Health Canada information, and additional resources

If you are changing the conduct of the protocol permanently, please submit an amendment. This can be done in a reasonable time frame after initiating the change to eliminate immediate hazards to participant safety.

If you are changing the protocol procedures temporarily, no notice to Advarra is required unless:

  • There is an increased risk of harm to participants; or
  • The integrity of the data will be adversely impacted.

Please consider that when there is a change in the administration of a study agent or the shipping of a study agent, in most cases this will need to be reported to the IRB since in-hospital/office/clinic monitoring will not be available to participants at their homes.

FDA COVID-19 Guidance

FDA Guidance Conduct of Clinical Trials of Medical Products during the COVID-19 Pandemic key takeaways:

  • Any change implemented to manage study conduct during disruption of the study as a result of COVID-19 control measures must be documented.
  • A listing of all participants affected by the COVID-19 related study disruption must be documented. This documentation should include unique participant number identifier, investigational site, and a description of how the individual’s participation was altered.

FDA Guidance Enforcement Policy for Non-Invasive Remote Monitoring Devices Used to Support Patient Monitoring During the Coronavirus Disease-2019 (COVID-19) Public Health Emergency key takeaways:

The policy applies to the following non-invasive remote monitoring devices that measure or detect common physiological parameters and that are used to support patient monitoring during the COVID-19 public health emergency:

Device Type Classification Regulation Product Code
Clinical electronic thermometer 21 CFR 880.2910 FLL
Electrocardiograph (ECG) 21 CFR 870.2340 DPS
Cardiac monitor 21 CFR 870.2300 DRT, MWI, MSX
Electrocardiograph software for over-the-counter use 21 CFR 870.2345 QDA
Pulse Oximetry (SpO2) 21 CFR 870.2700 DQA
Non-invasive Blood Pressure (NIBP) 21 CFR 870.1130 DXN
Respiratory Rate/Breathing Frequency 21 CFR 868.2375 BZQ
Electronic Stethoscope 21 CFR 870.1875 DQD

For the duration of the public health emergency, FDA does not intend to object to modifications to the FDA-cleared indications, claims, or functionality of these devices made without prior premarket notification submission if the modification does not create an undue risk in light of the public health emergency. FDA currently believes a modification does not create such undue risk in the following scenario:

  • The device is intended for the purpose of displaying, printing, or analyzing the physiological parameter(s) measured by the device; and
  • The device is intended for the purpose of supporting or providing adjunctive recommendations to the healthcare professional or patient about prevention, diagnosis, or treatment of COVID-19 or co-existing conditions; and
  • The healthcare provider and/or patient can independently review the basis for any diagnostic or treatment recommendations.

Health Canada COVID-19 Guidance

Health Canada Notification Management of Clinical Trials During the COVID-19 Pandemic: Notice to Clinical Trial Sponsors  key takeaways:

  • Eligibility assessments should be carried out as usual.
  • If participants may be put at risk by missing a study visit, the sponsor/site should evaluate whether the participant should be discontinued from the study.
  • Sites should have a way to document deviations that occur as a result of COVID-19 control measures and report them to the sponsor and REB according to those entities’ requirements.
    • Sponsors are not required to report these deviations to Health Canada unless the deviations place participants at risk.
  • Processes may need to be changed to accommodate pandemic safety practices, such as using an electronic alternative to wet ink signatures.

Health Canada Guidance Special Access to Remdesivir key takeaways:
Health Canada’s Special Access Programme (SAP) and Gilead Sciences Canada Inc. are considering requests for Remdesivir to treat COVID-19 on a patient by patient basis. Researchers are advised to initiate the request with Gilead first. After submitting the request to Gilead, submit a Special Access Request Form to the SAP. Review the guidance page for complete instructions on submitting requests to both SAP and Gilead.

Additional Resources

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Enrollment Revised

Revised to include Health Canada information

US:

  • A halt or delay in enrollment does not have to be reported to the IRB, but it may need to be reported to the sponsor.
  • A total suspension of a non-therapeutic trial does not need to be reported to the IRB, but it should be reported to the sponsor.
  • A total suspension of a therapeutic trial should be reported to the IRB if participants are enrolled and may be at risk due to the discontinuance of study procedures. The report should include a plan for managing those risks. This suspension should also be reported to the sponsor.

Canada:

  • If recruitment or enrollment is halted, sponsors should inform Health Canada using a clinical trial application notification (CTA-N).
  • A temporary hold on recruitment/enrollment does not need to be reported to Advarra.

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Enrolling COVID-19 Positive and Presumptive Positive Research Participants: General Considerations New

  • Discussion of the risks and benefits can be done over the phone.
  • Time for questions needs to be provided and can be done over the phone.

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Changes to the IRB Approved Protocol

Protocol deviations do not need to be reported to Advarra unless they impose an increase in the risk of harm to participants or adversely affect the integrity of the data.

  • A protocol deviation is something that applies to individuals (not the study as a whole).
    • Example: If individuals are not able to travel for an in-person visit because of concerns related to COVID-19, that is a minor deviation and does not need to be reported unless it impacts the risk to the participant.
  • This is Advarra’s standard reporting requirement; other IRBs’ policies may vary.
  • For more information, see section 18.3 of the Advarra IRB Handbook for Investigators, Institutions, Sponsors, and Sponsors’ Representatives (available in the Reference Materials section of the Advarra CIRBI Platform [login required]).

Changes that impact the conduct of the study and are permanent (or for the duration of this COVID-19 situation) should be considered amendments to the IRB approved study.

  • These can be implemented as soon as possible to avoid immediate hazards to the safety of participants; and
  • Amendments can be submitted as soon as is reasonably possible given the situation and the need to attend to changes in this research and other research to avoid harm to participants.
  • The IRB needs enough information to assess the proposed change.
    • Changes can be submitted as sponsor correspondence or a note to file pending a full study amendment (revising the protocol/ICF).
  • For sponsors with multiple studies affected by the same protocol change (e.g., use of telehealth for study visits) a single letter may be submitted to Advarra as a “generic item.”

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Protocol Deviations Revised

Revised to include Health Canada information

Protocol deviations do not need to be reported to Advarra unless they impose an increase in the risk of harm to participants or adversely affect the integrity of the data.

  • A protocol deviation is something that applies to individuals (not the study as a whole).
    • Example: If individuals are not able to travel for an in-person visit because of concerns related to COVID-19, that is a minor deviation and does not need to be reported unless it impacts the risk to the participant.
  • This is Advarra’s standard reporting requirement; other IRBs’ policies may vary.
  • For more information, see section 18.3 of the Advarra IRB Handbook for Investigators, Institutions, Sponsors, and Sponsors’ Representatives (available in the Reference Materials section of the Advarra CIRBI Platform [login required]).

Canada:
If the deviations to not place participants at risk, sponsors are not required to report these deviations to Health Canada.

  • Sites should have a system in place to identify, document, assess, and report protocol deviations to the sponsor and REB.
  • Sponsors should define/identify the protocol deviations that must be reported.

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Remote Visits to Substitute for In-Office/Hospital/Clinic Visits Revised

Revised to include change in risk considerations

Remote visits via telephone, telemedicine, Skype, Facetime, or other appropriate virtual communication may be substituted for a visit to an office, hospital, or clinic without prior review by the IRB. A substitution of a remote visit would be a protocol deviation, if it does not increase harm to participants, and would not need to be reported to the Advarra IRB. If there is a harm to participants from not going to an in-office visit, the study team should take whatever steps are appropriate and necessary to mitigate that harm and report those actions, in as reasonable a time frame as possible, to the IRB.

Change in risk considerations when conducting visits at home:

  • Will the study staff be wearing personal protective equipment (PPE)?
  • What other safety protocols are needed to protect a participant from exposure when inviting study staff into their home?
  • How will the health status of the study staff going into the home be evaluated prior to entering the participant’s home?

Advarra recommends that participants be advised of the change in study visits by letter or other form of communication. Re-consent is not required, and the letter does not need to be submitted to the IRB.

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Remote Consenting New

Informed consent may be obtained by telephone. When obtaining consent by telephone, researchers must:

  • Document how the ICF was transmitted to the participant (e.g., email, fax, mail, etc.).
  • Document how the participant’s signature was obtained. For example:
    • Electronic signature
    • Scanned and emailed, faxed, or mailed back to the study team
    • Photograph of signature/signature page sent back to the study team

Note: For FDA regulated research, the participant must also date the ICF.

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Options for providing the ICF:

  • Have the ICF provided to the participant/LAR in the containment unit or quarantined space (the ICF can be discarded);
  • Provide the participant/LAR with an electronic version of the ICF via a tablet, computer, or other device;
  • Provide an audio recording of the ICF; or
  • Read the entire ICF over the phone (only do this if no other option is available).

Considerations for the informed consent process:

  • Researchers should review and discuss the ICF with the patient/LAR and answer their questions.
  • The clinical team may conduct the research consent process if it is documented that they were educated in what the research involves.
    • This helps ensure the clinical team can knowledgeably consent someone to the research.
  • If the patient/LAR agrees to participate, the ICF should be signed (unless the ICF is being read to the patient/LAR because a copy could not be taken into the patient’s space).
  • Once the participant/LAR signs the ICF, it can be uploaded to a system such as REDCap (if possible). Alternately, a picture can be taken of it and sent to the study team. The ICF can be destroyed if it can’t be taken out of the unit.
  • If it is not possible to obtain a digital image of the signed page, the study team should both document that an imaging device was not available and have a witness to the consent process.
  • The entire consent process must be documented in the study records.

Note: Under these circumstances, having a witness to the consent process would be considered a best practice.

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Revised to include clarifying example

Re-consent is not necessary unless the changes to the research are such that the original consent is no longer valid (e.g., re-consent is not necessary when changing from clinic visits to remote visits). Participants should be notified of changes to the research via a letter or other form of communication. This does not need to be reported to the IRB unless the changes increase the risk of harm to participants.

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Changes to Informed Consent: Testing for Respiratory Symptoms

If the changes involve testing for respiratory symptoms and clarification regarding cost of PCP visit and testing, they do not alter the fundamental consent to the study. No new consent to participate in the study is required. Such changes can be provided to the participants by way of a letter or other documented means of communication.

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Replaces previous section “Informed Consent: How to Capture Signatures on an ICF Virtually”

If researchers cannot obtain a participant’s signature on the ICF, there should be:

  • Documentation of the method used for communication with the participant;
  • Means by which agreement was communicated;
  • Documentation that no imaging technology was available to capture a signed consent form;
  • A witness to the process (for more than minimal risk research); and
  • A witness signature.
    • Note: For FDA regulated research the witness should also date the form.

A request for participants to not sign the ICF is not considered a waiver of documentation. This assessment relies upon the FDA information sheet Informed Consent.

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Notifying Participants of Changes to Study Visit Procedures

Advarra recommends that, instead of updating the ICF, the study team notify participants of the change in study procedure by letter or other form of communication. If remote or virtual visits are not possible, please address with participants the issues that would arise if they do not come in for their visit. For example: Would they have to be withdrawn from the study? Is a delay something that would not result in any increase of harm?

In terms of remote visits, these can be substituted without prior approval of the IRB. Temporary remote visit substitutions at a single site do not need to be reported to the IRB unless the change in procedure will increase the risk of harm to participants.

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Remote Monitoring Visits New

Replaces previous section “Remote Monitoring”

FDA recognizes that sponsors may not have remote access to electronic health records maintained by hospitals, universities, and other institutions because of data privacy and security concerns as well as technological challenges. Sponsors should consider risk-based approaches to monitoring using the study information format (i.e., electronic, paper, or combination of electronic and paper), tools, and other resources available to them.

Consider the following approach for conducting remote monitoring visits:

  • At the site, establish the use of a HIPAA compliant tool (e.g. Dropbox Business, EPIC restricted access account, etc.) to provide access to source materials.
  • Add the source materials and provide the monitor specific access to only the source materials needed.
  • Notify the monitor when the materials are ready for review.
  • Establish a limited time frame for when the materials will be available.
  • Promptly remove the monitor’s access at the end of that time frame, and delete source materials if appropriate.

Example Workflow

Remote monitoring visit example workflow for Coronavirus Guidelines
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317372/

Canada:

  • If you need to make a change to incorporate remote monitoring as a result of COVID-19, this does not need to be submitted to Advarra for approval.
  • If needed, critical activities should be prioritized to ensure participant safety.
  • Any changes to the monitoring program should be documented.
  • Remote/electronic monitoring may need to take the place of wet ink signature.

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Changes Relating to the Study Agent Revised

Revised to include Health Canada information

US:
If participants are not able to come to the site for drug dispensation, drugs may be shipped to participants provided that:

  • It does not increase the risk of harm (e.g., it would not increase the risk of harm if participants are taking drugs orally, but if drugs are normally injected by staff at the study site it would increase the risk to ship the drug directly to the participant for self-administration);
  • FDA and sponsor drug accountability requirements, state law, and pharmacy requirements allow for shipment (e.g., sponsors should be consulted about shipping investigational products); and
  • Any changes to the protocol to allow drug shipment should be documented in writing (letter amendment is sufficient) and submitted to the IRB.
  • FOR CTEP trials only: where there are oral investigational agents, the Pharmaceutical Management Branch is altering its standard operating procedures for the next 90-day period to allow the dispensing pharmacy to ship oral investigational agents directly to patients.

Canada:
Shipping drugs from sites directly to participants is acceptable, provided that:

  • The drugs that will be shipped are drugs that the participant could take on their own (e.g., the study drug doesn’t have to be administered in a hospital/clinic setting or have any special conditions for handling);
  • The sponsor maintains complete and accurate records concerning the shipment, receipt, disposition, return, and destruction of the study drug;
  • The study drug is administered in accordance with applicable regulations and GCP; and
  • Study drugs are transported, handled, and stored in a manner that mitigates the risk of exposure to temperatures outside labelled storage conditions.
  • For more information, see Management of Clinical Trials during the Covid-19 Pandemic: Notice to Clinical Trial Sponsors.

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HIPAA Compliance and Telemedicine

Telemedicine is an acceptable option where it can adequately replace an in-person physical examination.

For the purpose of HIPAA, the HHS Notification of Enforcement Discretion for telehealth remote communications during the COVID-19 nationwide public health emergency waives penalties for noncompliance with HIPAA. OCR will exercise its enforcement discretion and will not impose penalties for noncompliance with the regulatory requirements under the HIPAA Rules against covered healthcare providers in connection with the good faith provision of telehealth during the COVID-19 nationwide public health emergency. This notification is effective immediately.

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HIPAA Compliance and Telemedicine Application Vendors New

The OCR guidance Notification of Enforcement Discretion for Telehealth Remote Communications During the COVID-19 Nationwide Public Health Emergency identifies the following popular video chat applications that may be used to help provide telehealth visits during the COVID-19 public health emergency:

  • Apple FaceTime
  • Facebook Messenger video chat
  • Google Hangouts video
  • Skype

Providers are encouraged to notify patients that these third-party applications potentially introduce privacy risks. Providers should enable all available encryption and privacy modes when using such applications.

The following applications should not be used in the provision of telehealth by covered healthcare providers:

  • Facebook Live
  • Twitch
  • TikTok
  • Similar video communication applications that are public facing

Vendors that represent that they provide HIPAA compliant video communication products and that they will enter into a HIPAA business associate agreement (BAA) include:

  • Skype for Business
  • Updox
  • VSee
  • Zoom for Healthcare
  • Doxy.me
  • Google G Suite Hangouts Meet

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HIPAA Compliance and Covered Entities

OCR has published the bulletin HIPAA Privacy and Novel Coronavirus advising covered entities of further flexibilities available to them as well as obligations that remain in effect under HIPAA as they respond to crises or emergencies.

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Package Handling

Per the WHO, it is safe to handle a package from China or any other place where the virus has been reported. The likelihood of an infected person contaminating commercial goods is low, and the risk of catching the virus that causes COVID-19 from a package that has been moved, traveled, and exposed to different conditions and temperatures is also low.

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New Research Protocols: COVID-19 Impact on the Conduct of Research

  • Ensure that you have adequate study staff and resources before you begin conducting the study.
  • Consider delaying enrollment if your study procedures may be impacted by the pandemic, or submit a protocol modification to the IRB to change the procedures.
  • Note that screening questions relating to COVID-19 are not considered research questions unless you will be collecting data on COVID-19.

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IRB Notification of Study Hold/Suspension or Termination Revised

Revised to include Health Canada information

Advarra requires IRB notification of a study hold/suspension or termination imposed by the institution, sponsor/CRO, investigator, other reviewing IRB, other government agency, or other party. Advarra is waiving this requirement for 120 days (through July 30, 2020) during the COVID-19 pandemic, except where the institutional suspension or termination relates to noncompliance by an investigator or identification of safety issues impacting study participants.

Measures should be in place to ensure that research participants are properly informed of any suspensions/termination and that any procedures needed for participant follow-up are in place.

Canada:
Sponsors who pause study recruitment or temporarily halt a trial should notify Health Canada using a clinical trial application notification (CTA-N).

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