With clinical trials facing challenges from COVID, the FDA offers additional clarity

Clinical trial sponsors are likely to face tough decisions in the coming months on whether to continue their investigations and how to maintain the integrity of their data. In a recent webinar, the FDA’s drug review center outlined best practices for companies to respond to COVID’s effects on their trials, but also stated that the agency would only be “flexible where appropriate” when considering this evidence.

 

By Laura DiAngelo, MPH 

 

Executive IQ Brief

  • How Things Work Now: In general, clinical trials are tightly controlled, with research teams required to adhere to FDA-reviewed and IRB-approved Clinical Protocols operating under an approved investigational new drug (IND) application. Protocols define how the trial is to be run and operated, including how the researchers intend to interact with participants, how measurements will be taken, and the tools that will be used. Any deviation from the approved protocol needs to be either documented or re-reviewed by the FDA.

  • What’s New: During the COVID-19 public health emergency (PHE), clinical trials sponsors are facing unprecedented disruptions. With the safety of participants and research staff at increased risk from the pandemic, the need for unexpected protocol adjustments and deviations have become widespread. The FDA issued guidance on March 18, updated in April, on how industry and institutional review boards (IRBs) should consider adjusting their trials as unforeseen circumstances such as quarantines, site closures, supply chain interruptions, or participant or staff infections become common. A recent webinar also tried to clarify the agency’s thinking on best practices.

  • Impact: While the FDA may offer flexibility for trial changes, the real test for that flexibility will only come when FDA review staff are considering whether to approve the product. It’s likely that data submitted under new drug applications and biologics license applications will be tainted by COVID-19 for years to come. Establishing the extent and meaning of COVID’s effects will be a difficult task for companies and regulators alike and could result in the FDA leveraging postmarketing data and requirements to monitor safety and efficacy.

Regulatory Background

During the COVID-19 public health emergency (PHE), clinical trials sponsors are facing unprecedented disruptions. With the safety of participants and research staff at increased risk from the pandemic, the need for unexpected protocol adjustments and deviations have become widespread. The FDA issued guidance on March 18 (updated in April) on how industry and institutional review boards (IRBs) should consider adjusting their trials as unforeseen circumstances such as quarantines, site closures, supply chain interruptions, or participant or staff infections become common.


In general, clinical trials are tightly controlled, with research teams required to adhere to FDA-reviewed and IRB-approved Clinical Protocols operating under an approved investigational new drug (IND) application. Protocols define how the trial is to be run and operated, including how the researchers intend to interact with participants, how measurements will be taken, and the tools that will be used. The protocol is intended to ensure that the variable being researched—the drug or therapy—is the one causing a potential effect, rather than external factors such as methodology changes. Statistical validity is near paramount to the FDA when considering evidence for approval but remains second to participant safety.


Any deviation from the approved protocol, such as a missed visit, is required to be documented by the sponsor in order to maintain compliance with good clinical practice (GCP) requirements and submitted to the FDA in clinical study reports. For global changes to study conduct, such as a permanent change in the measurement tool used to monitor participants, the sponsor must submit a protocol amendment to an IRB for review.


Regulatory Context

The outbreak of COVID-19 has resulted in widespread, unplanned deviations from clinical trial protocols.


[Read AgencyIQ’s analysis, “Clinical trials could be hard hit by COVID-19, forcing some to adapt or close down” here.]


The FDA’s March guidance document explained to clinical trial sponsors how it will consider unplanned deviations to studies resulting from COVID-19. The agency stated that external challenges, such as a city-wide quarantine, clinical research site closures, travel limitations for staff and participants, the investigational product’s supply chain, or staff/participant infections could all be confounding factors in the administration of a clinical trial.


However, the agency did not at the time provide a clear explanation of exactly how public health control measures should be applied to protocol modifications. Rather, the guidance explained the modifications “will vary depending on many factors,” such as the disease being studied and the area in which a trial is taking place. Although the FDA encouraged sponsors to engage as early as possible with their IRBs on any updates to the protocol, the agency also wrote that any updates to the protocol that would alter the statistical analysis plan would also require early engagement with the agency’s review center, as would any changes that are related to efficacy endpoints.


This left sponsors with significant questions, including when a series of deviations should be documented versus when the submission of a protocol amendment should be considered.

 

What’s New

In a webinar on April 30, representatives from FDA’s CDER Office of Medical Policy Initiatives worked to answer some of those questions from industry.


Ongoing Trials

The agency is urging clinical trial sponsors with ongoing trials to take every precaution available to ensure the safety of trial participants and staff, including the use of technologies that can facilitate remote data collection. A significant part of these risk-based considerations will be based on how a product is given to the patient. For example, a self-administered therapy may be inherently safer than one administrated by infusion, requiring a second person in the room.


Remote monitoring does raise a series of questions related to verifying data for remote site audits. While investigators are required to monitor progress, there isn’t a specific, required regulatory outline as to how monitoring should be conducted. The FDA stated that if on-site monitoring isn’t possible, sponsors should optimize remote monitoring to maintain oversight, but only if technically feasible. Agency representatives pointed to a separate guidance on risk-based monitoring, which remains in effect, that outlines the essential activities to ensure safety and data reliability.


If sponsors can set up remote viewing portals for study documents and source documents, including remote access to electronic health records (EHRs), this could facilitate remote monitoring. Additionally, investigators could upload certified copies of records to a secure database or cloud-based repository. These practices would raise another set of operational questions, however, including how to control for the remote monitoring of data in repositories for studies that are blinded (or partially blinded), as well as the limits of a participant’s original informed consent agreement.


Several investigators participating in the webinar asked the FDA whether COVID-19 screenings for participants would need to be reported as a protocol amendment, which the FDA stated would depend on the intent of the screening. For example, if the screening was part of regular health care that happened to be performed as part of a trial visit, it would not need to be submitted under an amendment. However, if a sponsor wants to use the data in its research, this would require a submission.


Additionally, sponsors questioned how a case of COVID should be reported as part of their study. Under the regulation, said FDA, it must be recorded as an adverse event (AE), “whether or not considered drug related.” If the intervention is thought to have an effect on the coronavirus, that will require additional documentation.


A key issue for clinical trial sponsors is ensuring the validity of their data and maintaining the integrity of their trial. While the FDA stated that it will be “flexible where appropriate” in accepting trial data that may not have been as tightly-controlled as usual, it does encourage exhaustive documentation of any missing data, including COVID-19-related context, and consulting with reviewers as early as possible before making changes to the data management or Statistical Analysis Plan (SAP). Any trial with a prespecified analysis will need to document how investigators plan to handle COVID-19 deviations before locking the database.


The FDA also sought to clarify when a sponsor should submit protocol amendments. While deviations are typically reported as part of clinical study reports to the FDA, protocol amendments must be approved. Notably, if the sponsor determines that the risk represents an “immediate hazard,” these may be implemented before approval by an IRB or the FDA, although the sponsor is required to report on the alteration afterwards. In general, though, the FDA maintains that protocol deviations should be submitted as reports, global changes should be reported as an amendment. Because the study may need to change significantly—and rapidly, the agency will allow consolidated protocol modifications that include several changes in a single amendment. All amendments should be flagged by the sponsor as relating to COVID-19.

 

Initiating New Trials

Agency representatives said that although the “vast majority” of staff are teleworking, the agency is committed to accepting non-COVID-related trials at this time.


However, they did have some words of caution for health volunteer trials, in which interventions are tested on non-ill people. According to the webinar, the benefit/risk balance of exposing these volunteers not only to the intervention but also, potentially, to the dangers of exposure to clinical research staff would be considered during the PHE.

 

What’s Next

Going forward, it will be important to watch how the FDA considers the types of evidence that are collected during 2020, including the flexibilities granted and the types of changes that the FDA doesn’t accept. Currently, it’s not clear that the FDA has clear guidelines on what will and won’t be acceptable for evidence generated this year, but only that sponsors should document as meticulously as possible and take a risk-based approach to trial design and continuation.


Overall, the question of whether continue or halt an ongoing trial will remain a case-by-case issue. While the FDA has laid out a set of guiding principles, the risk-profile of the disease, drug’s administration, the technological capabilities available, geographic area, and other external factors will need to be considered.


A key focus of the FDA’s webinar was the assurance that reviewers will remain “flexible where appropriate” when considering data collected during the pandemic. However, the definition of what changes are “appropriate,” and the limits of the flexibility, are likely to be defined by the agency in the coming years.


While the FDA may offer flexibility for trial changes, the real test for that flexibility will only come when FDA review staff are considering whether to approve the product. It’s likely that data submitted under new drug applications and biologics license applications will be tainted by COVID-19 for years to come. Establishing the extent and meaning of COVID’s effects will be a difficult task for companies and regulators alike and could result in the FDA leveraging postmarketing data and requirements to monitor safety and efficacy.


To contact the author of this analysis, please email Laura DiAngelo.
To contact the editor of this analysis, please email Alec Gaffney.

 

Key Documents and Dates

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