Advarra stands together with the research community during the COVID-19 crisis. We offer free resources to address the impact of COVID-19 on ongoing clinical trials and prioritize reviews of new COVID-19 studies.

This summary of guidance provided via Ask Advarra—a free resource to answer your research questions—is updated at least weekly. If you want to receive alerts about new topics when we update this page, sign up here for email notifications.

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

Topics

General Guidance for Advarra Studies

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.

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Regulatory Guidance and Other Resources Revised

Regulatory Guidance and Other resources revised to include Supplements for Approved Premarket Approval (PMA) or Humanitarian Device Exemption (HDE) Submissions During the Coronavirus Disease 2019 (COVID-19) Public Health Emergency and Enforcement Policy for Face Masks and Respirators During the Coronavirus Disease (COVID-19) Public Health Emergency

Advarra has compiled the following list of regulatory guidance documents and other resources to help you remain compliant during this challenging time. Have a question about these external resources? Ask Advarra.

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Enrollment

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

  • 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 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

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]).

 

US: Any change implemented to manage study conduct during disruption of the study as a result of COVID-19 control measures must be documented per FDA.

  • 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.

 

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

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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Transfer of Participants Between Sites

  • Transfer of participants to a closer research site: Transferring participants to another approved research site on the same protocol should not be problematic since the research has been approved at the new site. Be sure to document this transfer.
  • Transfer of participants to a research site not approved to conduct the research: IRB approval must be in place at the new site before the participant can be transferred to that site.
  • Transfer of participants to a non-research site and to non-research staff: Per CTEP guidance, this may take place provided that:
    • The non-research healthcare provider is providing intermittent/short-term care;
    • The responsible investigator believes it is in the participant’s best interest to continue study activities;
    • The activities provided by the non-research healthcare provider are conducted under the responsible investigator’s oversight in accordance with the protocol; and
    • There are assurances that processes are in place to report all required information to the responsible investigator who is responsible for ensuring that the data is entered into the data management system for the trial.
    • For more information, reference OHRP Guidance Engagement of Institutions in Human Subjects Research.

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When a copy of the fully executed ICF will be returned to the study team, 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:
    • Document that the participant signed and dated the ICF;
    • 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.

HIPPA Considerations

Disclosures to Prevent a Serious and Imminent Threat:

Health care providers may share patient information with anyone as necessary to prevent or lessen a serious and imminent threat to the health and safety of a person or the public – consistent with applicable law (such as state statutes, regulations, or case law) and the provider’s standards of ethical conduct. Thus, providers may disclose a patient’s health information to anyone who is in a position to prevent or lesson the serious and imminent threat, including family, friends, caregivers, and law enforcement without a patient’s permission. HIPAA expressly defers to the professional judgment of health professionals in making determinations about the nature and severity of the threat to health and safety. For more information, see 45 CFR 164.512(j).

Disclosures to Family, Friends, and Others Involved in an Individual’s Care and For Notification: The covered entity should get verbal permission from individuals or otherwise be able to reasonably infer that the patient does not object, when possible. If the individual is incapacitated or not available, covered entities may share information for these purposes if, in their professional judgment, doing so is in the patient’s best interest.

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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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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 ICF;
  • 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 ICF.
      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.

HIPAA Considerations

Disclosures to Prevent a Serious and Imminent Threat: Health care providers may share patient information with anyone as necessary to prevent or lessen a serious and imminent threat to the health and safety of a person or the public – consistent with applicable law (such as state statutes, regulations, or case law) and the provider’s standards of ethical conduct. Thus, providers may disclose a patient’s health information to anyone who is in a position to prevent or lesson the serious and imminent threat, including family, friends, caregivers, and law enforcement without a patient’s permission. HIPAA expressly defers to the professional judgment of health professionals in making determinations about the nature and severity of the threat to health and safety. For more information, see 45 CFR 164.512(j).

Disclosures to Family, Friends, and Others Involved in an Individual’s Care and For Notification: The covered entity should get verbal permission from individuals or otherwise be able to reasonably infer that the patient does not object, when possible. If the individual is incapacitated or not available, covered entities may share information for these purposes if, in their professional judgment, doing so is in the patient’s best interest.

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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

US:

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 pandemic. 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 also 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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Shipping Study Drugs to Subjects

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 (a letter as an 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;

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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

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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Part 11 Compliant Electronic Signature Capture

As with all systems for capturing electronic signatures, complying with 21 CFR Part 11 is in part dependent on how the software is configured and managed at the user end. For reference, here are links to information on Part 11 compliance for Adobe Sign and DocuSign:

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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

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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Non-Invasive Remote Monitoring Devices Used to Support Patient Monitoring

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.

This 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

 

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Guidance on Reopening Research

Advarra has not developed any specific guidance on site reopening, as this will be governed largely by regional reopening plans in conjunction with local regulations and institution/site-specific plans. However, we are here to help navigate the challenges with restarting and advancing research. To support research sites and institutions in their critical role in research, Advarra is offering a free eLearning module that helps sites evaluate priorities and available resources to determine a plan for restarting studies. If your institution needs help restoring your research in the wake of COVID-19, fill out the form to get started. An Advarra representative will contact you to discuss next steps based on your institutional needs.

For general information on ensuring staff and participant safety at the site, we suggest reviewing the Centers for Disease Control and Prevention (CDC) website Information for Healthcare Professionals About Coronavirus (COVID-19). CDC also offers the general guidance on community reopening Reopening Guidance for Cleaning and Disinfecting Public Spaces, Workplaces, Businesses, Schools, and Homes. While not specific to research, the American Medical Association (AMA) resource COVID-19: A Physician Practice Guide to Reopening provides information on best practices for planning when and how to reopen physician practices.

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Managing Multiple Reporting and Compliance Obligations

In addressing changes to research needed because of the COVID-19 pandemic, researchers should keep abreast of federal regulatory guidance, sponsor directives, and local organizational policies and requirements. Particularly important is adhering to local requirements at the site where the research will be performed; these requirements will consider the availability of local resources, state law restrictions, and the risk of local exposures. In cases where the requirements of a central IRB or sponsor are not as restrictive as local requirements, investigators should be sure to adhere to local standards at their own sites.

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Additional Expenses Not Covered by Site CTA/Budget

We suggest referring to NIH Guidance for NIH-Funded Clinical Trials and Human Subjects Studies Affected by COVID-19, which discusses unexpected expenses and what to do about them.

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Expanded Access Programs

We suggest reviewing the FDA Coronavirus Treatment Acceleration Program (CTAP) page, which also includes links to other FDA resources.

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