NIH IRB Guidelines for protocol deviations during COVID-19 outbreak

Dear Intramural Research Program,

Due to the evolving situation with COVID-19 infections, we understand that there may be increasing challenges with research participants coming to the Clinical Center or other study sites to complete study visits. The following guidelines address the IRB expectations with regard to deviating from the protocol and reporting to the NIH IRB.  Please note, if the NIH IRB is not the IRB of Record for your study, you must follow the direction of the IRB of Record as well as the NIH reporting requirements.

The regulations allow for investigators to modify the protocol without prospective IRB approval when necessary to prevent an immediate apparent harm to the subject.  Typically, when this occurs the event must be reported to the IRB via a Reportable Event Form (REF) within 7 days of the deviation.  Given the potential need for this to occur on a much larger than usual scale, not all planned deviations will need to be reported to the IRB in an expedited time frame.  Only those deviations which meet the definition of a major deviation will require reporting, specifically those that have the potential to negatively impact the rights, welfare or safety of the subject, or to substantially negatively impact the scientific integrity or validity of the study (see policy 801, Reporting Research Events).

If a subject cannot complete a protocol specified study visit or intervention, the Principal Investigator (PI) should assess the impact of the missed visit on the safety of the subject and the scientific validity of the trial.  If in the PI’s determination, neither of these are meaningfully impacted by the deviation, these do not need to be reported to the IRB in an expedited manner.  The event should be included in the summary of events reported at the time of continuing review (CR).

If in the opinion of the PI, the missed visit or intervention poses a risk to the safety of the subject, the investigator should develop a plan to minimize the impact of the deviation.  For example, if the subject is scheduled to return to the study site for safety lab work, the investigator may arrange for labs to be drawn either at a location closer to the patient’s home, such as a commercial lab or physician’s office. Similarly, if a subject requires a scan to determine if a study treatment can continue, then this might be arranged to happen at a local site and the results be transmitted to the study team for review and decision making.

In the above examples, if there is sufficient time to obtain prospective IRB approval, the investigator should submit a “single patient planned deviation” request form via NIH iRIS. If there is insufficient time to get prospective IRB approval and the change is necessary to assure the safety of the subject, the investigator may implement the change without prospective IRB approval and then must report the deviation via a REF form within 7 days.

The situation becomes more complicated if it is necessary for a study intervention, such as administration of an investigational drug, to occur at a non-research site.  It is acceptable under HHS regulations for a non-study site to administer a study intervention if all of the following conditions are met (see OHRP engagement guidance).

1. Institutions (including private practices) not initially selected as a research site whose employees or agents administer the study interventions being tested or evaluated under the protocol limited to a one-time or short-term basis (e.g., an oncologist at the institution administers chemotherapy to a research subject as part of a clinical trial because the subject unexpectedly goes out of town, or is unexpectedly hospitalized), are NOT engaged provided that ALL of the following conditions also are met:
   
   1. an investigator from an institution engaged in the research (e.g. the NIH) determines that it would be in the subject’s best interest to receive the study interventions being tested or evaluated under the protocol;
   2. the institution’s (e.g. the private practice) employees or agents do not enroll subjects or obtain the informed consent of any subject for participation in the research;
   3. investigators from the institution engaged in the research (e.g. the NIH) retain responsibility for:
      1. overseeing protocol-related activities;
      2. ensuring the study interventions are administered in accordance with the IRB-approved protocol; and
      3. ensuring appropriate arrangements are made for reporting protocol-related data to investigators at the engaged institution, including the reporting of safety monitoring data and adverse events as required under the IRB-approved protocol; AND
   4. an IRB designated on the engaged institution’s FWA is informed that study interventions being tested or evaluated under the protocol have been administered at an institution NOT selected as a research site.

Note, it is essential that the study principal investigator be in close contact with the staff at the outside institution in order to fulfil the responsibilities outlined in c.i-c.iii above.

If study drugs are to be shipped or otherwise provided to non-study team members for administration to subjects, the study team will need to develop a plan for providing the investigational drug to the responsible physician.  All FDA regulations around drug accountability still apply.  The PI may contact the Office of Research Support and Compliance and the Investigational Pharmacy with any questions on how to ship/supply the drug.  Contact Gini Guptill at Virginia.guptill@nih.gov (ORSC) or Esther Jeon (Pharmacy)

Investigators should also be aware that there may be significant costs associated with study subjects receiving interventions at non-study sites.  We would advise you to work with your IC leadership to determine what those costs will be and if there is any available mechanism to defray the costs to participants.  Subjects should be informed if they will incur any additional cost.

Example scenarios

A healthy volunteer is enrolled in a study that requires a visit to the Clinical Center or other study site for completion of questionnaires, blood work and an MRI scan.  The subject cannot travel to the Clinical Center/study site due to travel restrictions.  What should the study team do?

As the study subject is a healthy volunteer, missing study interventions does not adversely affect their health or safety.  The loss of a single subject has no impact on scientific validity. The study team should determine that this is a minor deviation that is reported in summary format at the time of CR.  If several subjects miss visits and this impacts scientific validity, the investigator should adjust their protocol appropriately and, if necessary, submit an amendment to the IRB.

Several subjects enrolled in a long-term observational study of the natural history of a disease are unable to come for their scheduled assessments.  What should the study team do?

As this is an observational study only with no therapeutic interventions, there is no impact on safety or welfare of the subjects.  The investigator should determine the impact on the scientific validity of the study.  If it is determined not to meaningfully impact scientific validity, this may be reported at the time of CR.  If the investigator determines that the scientific validity is impacted, the investigator should assess whether changes to the study need to be made to allow for valid conclusions to be drawn (i.e., add additional visits, increase enrollment) and submit such changes as an amendment to the IRB.  In addition, a reportable event form should be submitted to the IRB.

A subject is enrolled in an interventional trial that requires IV administration of an investigational drug and subsequent monitoring of safety labs.  The subject is unable to return to the Clinical Center for the intervention due to travel restrictions.  What should the study team do?

The study team should confirm that travel to the NIH is not feasible, and if at all possible, the subject should receive the investigational agent and subsequent monitoring and care at the study site.  If in fact this cannot occur, the study team should determine if there is a local institution that is suitably qualified to administer the intervention and monitor the safety of the subject.  The PI must identify a responsible physician at the site that is willing to perform these tasks.  This person should receive training by the PI on the protocol and explicit direction on what they will be required to do.  This may be conducted remotely by phone or Webex. The PI should provide a copy of the protocol to the responsible physician, along with any other information and documentation needed to ensure the safe administration of the study intervention.  If assessment of safety labs or other research data are needed, these data must be transmitted to the study PI in a timely fashion, and the study PI remains responsible for assessing the data.  Suitable arrangements that comply with all FDA requirements for providing the study drug to the responsible physician will need to established.

Please refer to OHSRP letter “non study site instructions”emailed to all investigators on 3/12/2020 and posted here.

A subject is enrolled in an oncology study.  They are taking an oral investigational drug at home but are scheduled to come to the Clinical Center for a follow up PET/CT scan.  The results of this scan will be used to determine if the subject remains on the investigational drug.  The subject cannot travel to the Clinical Center. What should the study team do?

The study team should determine if the scan can be done at a site closer to the subject’s home.  If so, the study team should arrange for the scan to be done there and the results transmitted to the team for interpretation.  If this can be arranged, this deviation is unlikely to affect the safety/welfare of the participant so may be reported at the time of CR.  If it is determined that this scan cannot be done, yet it is felt by the study team to be important for the safety and/or welfare of the participant, the study team should decide what course (i.e. continue drug…not continue drug.. ) is in the best interest of the subject and act accordingly.  This should be reported to the IRB on a reportable event form as a major deviation.

We realize there are many possible permutations to these scenarios.  Hopefully, this will provide you with some assistance in how to deal with them.  As always, the safety and welfare of our research subjects is paramount, and investigators and study teams should take whatever steps are necessary to ensure this.

Please do not hesitate to contact us with questions.  We ask that you direct your questions to the NIH IRB email inbox at IRB@od.nih.gov.  This email inbox is monitored daily and will assure that your questions are routed to the correct individual in a timely manner. For questions related to drug shipment or FDA requirements, please contact Gini Guptill at ORSC Virginia.guptill@nih.gov or Esther Jeon jihyunesther@nih.gov at Pharmacy.

Thank you.

Jonathan Green and the OHSRP team.