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Clinical trial sponsors should consider the potential for missing data and bias when deciding whether to switch from in-person to remote collection of observer-reported and patient-reported outcome assessments during the COVID-19 pandemic, the US Food and Drug Administration says.

In the latest update to its question-and-answer guidance on managing the novel coronavirus’ impact on clinical trials, the agency gives additional advice on remote collection of clinical outcome assessments and electronic collection of informed consent. It also addresses the compliance requirements for electronic systems that are used to generate electronic signatures on clinical trial records.

The 3 June revisions follow a mid-May update in which the agency discussed reporting of serious adverse events in the context of COVID-19.

ObsROs And PROs

The agency first addressed remote collection of certain types of clinical outcome assessments (COAs) in a mid-April update to the guidance, emphasizing feasibility and consistency when it comes to remote collection of performance and clinician-reported outcome assessments. (Also see "For COVID-Impacted Trials, Investigators Should Practice Remote Assessments Beforehand, US FDA Says" - Pink Sheet, 19 Apr, 2020.)

The latest revision expands on this issue and includes two more types of COAs: patient-reported outcomes (PROs) and observer-reported outcomes (ObsROs).

The agency outlines several general considerations common to all COAs:

  • Prioritization of trial participant safety and privacy;

  • Maintenance of data quality and integrity, including minimizing missing data;

  • Appropriate training for personnel and trial participants;

  • Potential for increased variability in trial data;

  • Feasibility of conducting a specific type of COA remotely, depending on context of use;

  • Documentation and audit trails; and

  • Availability of technology and technical support required for remote assessment.

For PROs and ObsROs specifically, sponsors should consider the potential for missing data when switching from in-person assessment to remote assessment. They also should weigh 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. Such bias could occur, for example, if trial participants try to please site staff by offering ratings that might not truly reflect their experience, the agency said.

In addition, data collected with PROs and ObsROs through verbal administration should not be considered a substitute for required safety monitoring throughout the trial, the guidance states.

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

 

To minimize potential bias, sponsors may want to consider using automated virtual interviewers or a trained neutral third-party interviewer to administer PRO and ObsRO assessments remotely.

 

Another limitation when switching from in-person to remote assessment using paper-based PRO or ObsRO assessments is the potential for missing data if a trial participant or observer fails to complete 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),” the guidance states.

Informed Consent Via App

The Q&A guidance recommends use of electronic means for securing informed consent when face-to-face contact with study participants is not possible or practical due to COVID-19 control measures. (Also see "For COVID-Impacted Trials, Investigators Should Practice Remote Assessments Beforehand, US FDA Says" - Pink Sheet, 19 Apr, 2020.)

The latest guidance revision reflects the availability of the FDA’s MyStudies app for use by investigators to obtain informed consent.

“The agency is providing this resource after hearing that investigators were having difficulties obtaining informed consent for clinical trials when patients were in isolation rooms in health care facilities or could not travel to outpatient clinics,” the agency said in a 29 May announcement about the app’s availability.

 

FDA has made its MyStudies app available for investigators to use in obtaining informed consent when face-to-face contact with study participants is not possible or practical.

 

The agency released the MyStudies app in 2018 to help investigators and sponsors securely gather real-time, contextual data about medication use and other health issues facing patients. The app was developed under the FDA-Catalyst program, which has served as a test-bed for real-world evidence demonstration projects. (Also see "Real-World Evidence Demo Projects From US FDA To Include New Mobile App" - Pink Sheet, 6 Nov, 2018.)

The app is now referred to as COVID MyStudies in the Apple App and Google Play stores. Investigators can use the app to send the informed consent document electronically to the patient, or his or her legally authorized representative. Once the patient or representative has signed the form, he or she will receive an electronic copy. The investigator then can access the signed consent in a secure manner and print it or transfer the file electronically.

“To facilitate free use of the app during the public health emergency, FDA intends to fund the technical assistance required to operate the COVID MyStudies App, which will be provided by the Harvard Pilgrim Healthcare Institute, as resources permit,” the guidance states.

Notably, the app complies with 21 CFR Part 11, the agency’s regulation governing electronic records and signatures.

Electronic systems used to generate electronic signatures on trial records, including informed consent documents, must satisfy Part 11 requirements, the agency said in a new Q&A added to the guidance.

The FDA does not certify individual electronic systems or methods to obtain Part 11 compliant electronic signatures, but vendors of commercial off-the-shelf software systems may be able to provide sponsors and other regulated entities with information about their systems’ compliance, the guidance states.

“When an electronic system that is Part 11 compliant is not available, regulated entities must have an alternate means of obtaining required signatures (e.g., handwritten wet ink signatures executed on documents, handwritten stylus or finger-drawn signatures executed on electronic documents that are then printed or appropriately witnessed),” the agency said.

Adverse Event Reporting

Since the guidance’s initial release in mid-March, the agency periodically has been updating the document to address commonly asked questions about study conduct during the public health emergency. (Also see "For COVID-Impacted Studies, US FDA Loosens Video Conferencing But Tightens Home Infusion Guidance" - Pink Sheet, 12 May, 2020.)

On 14 May, it added two new Q&As about adverse event reporting obligations in the context of  COVID-19.

The first question asks about reporting a serious adverse event in clinical practice with an approved drug that is being used off-label to treat COVID-19, while the drug is also being studied for a COVID-19 indication under an investigational new drug application.

Reports of serious adverse events (SAEs) that occur in clinical practice for an approved drug, whether or not the use is included in labeling, must be submitted to the agency’s adverse event reporting system, the guidance states.

SAEs occurring during a clinical trial under IND for an approved drug being investigated to treat COVID-19 must be reported as an IND safety report if they are unexpected and the sponsor determines there is a reasonable possibility the drug caused the adverse event.

 

“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.”

 

“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,” the guidance states.

“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.”

The guidance separately addresses the question of reporting obligations when a trial participant in a non-COVID study is diagnosed with COVID-19 and experiences an SAE related to the coronavirus.

It is possible that an investigational drug might be causally related to an SAE associated with COVID-19 by making subjects more susceptible to complications from the disease, the agency said. “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,” the guidance states.

Such an analysis would require an examination of unblinded data and, consequently, should be performed only by a data monitoring committee or a specially constituted safety committee that is “firewalled” and independent from those conducting the trial and performing other analyses.

“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,” the FDA said.

“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 subjects diagnosed with COVID-19, this finding must be submitted to FDA as an IND safety report.” 

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