Industry experts told AgencyIQ that ongoing clinical trials, as well as trials that were set to begin enrollment, could be hit hard by ripple effects from the novel coronavirus outbreak. Both industry and the FDA are quickly trying to determine how to adapt trials, protect patients, and save the clinical data needed to support future regulatory decision-making.

Executive IQ Brief

• How things work now: The initiation of clinical testing involves meeting many regulatory requirements generally meant to safeguard the safety of patients and ensure that research is conducted ethically. Conducting clinical research is a long and complex endeavor. For large-scale clinical development projects, companies may spend hundreds of millions of dollars on testing a product. Some drug products may be tested in just dozens of patients (such as a trial for a rare disease), but others may be tested in many thousands of patients.
• What’s new: But as the US begins to grapple with an outbreak of a novel coronavirus, SARS-CoV-2, life sciences companies may soon begin to find it extremely difficult to conduct clinical trials according to existing protocols and plans. The challenges facing life sciences companies are immense. Clinical data could be corrupted by patients getting sick with COVID. Supplies and drugs needed to run clinical trial sites and provide essential patients care may be interrupted by shortages or other disruptions to the supply chain. Trial recruitment could be affected if people are socially isolated, quarantined, sick or otherwise afraid to travel to medical facilities. A patient may not be able to access a clinical trial site due to decreases in public transportation, or because their caregiver is sick. Trial sites may cancel certain procedures or restrict access in a bid to make available as many medical staff and beds as possible, especially if a trial is held at an academic medical center. New guidance published this week by the FDA on how sponsors can adapt may help, but many questions remain unanswered.
• Impact: The full effects of COVID-19 on clinical trials may not be felt for months. At best, clinical trials are likely to be delayed. At worst, some could be cancelled due to significant concerns about the health of patients. For some trial types, there are only bad options: Between protecting patients from COVID-19 and ensuring those patients maintain access to potentially life-saving therapies. The FDA may make broader use of post-marketing trials to collect data if it believes that some future applications are tainted by COVID-19 concerns.

Regulatory Background

Before a new drug or a new indication for an old drug can be approved, the product must undergo clinical testing in humans. Those trials typically involve three main phases:

• Phase 1, in which a drug’s safety is tested in a small number of healthy volunteers, which helps to establish acceptable dosing levels for the drug. Some trials may also use unhealthy volunteers, such as trials for oncology drugs;
• Phase 2, in which a drug’s safety is first tested in a greater number of trial participants (Phase 2a) before the efficacy of a drug is first assessed (Phase 2b); and
• Phase 3, in which a drug’s safety and efficacy is typically established in a large, statistically significant number of patients. For many drugs, this phase may include two trials, which are also referred to as “pivotal” clinical trials.

A drug may also be subject to Phase 4 trials, which take place after a drug is approved. Phase 4 trials are generally intended to assess the long-term safety effects of a product, confirm its benefit, or identify specific issues with a drug that might not have been evident during a trial with a small number of patients.

In order to initiate clinical testing, companies need to meet many regulatory requirements generally intended to safeguard the safety of patients and ensure that research is conducted ethically.

Those protections include:

• Obtaining informed consent from trial participants ensuring that they know the risks of the trial;
• Having research reviewed and overseen by an Institutional Review Board (IRB);
• Submission of an Investigational New Drug (IND) application to the FDA before beginning a trial, which the FDA reviews to ensure that trial participants are protected;
• Written procedures outlining how the trial will be conducted.

Conducting clinical research is a long and complex endeavor. For large-scale clinical development projects, companies may spend hundreds of millions of dollars on testing a product. Some drug products may be tested in just dozens of patients (such as a trial for a rare disease), but others may be tested in many thousands of patients.

According to an AgencyIQ analysis of all new molecular entities approved by the FDA’s Center for Drug Evaluation and Research (CDER) between 2015 and 2019, the median number of patients enrolled in trials used to approve a drug ranged between 1,100 patients and 2,300 patients.

The way in which patients are assessed in trials in important to its operation. In particular, patients enrolled in a trial are expected to meet established criteria for enrollment eligibility. For example, the trial may not seek to enroll anyone with another serious health condition, a person who is already taking another drug, or persons without specific characteristics (like a specific genetic biomarker).

While these “exclusion criteria” can sometimes seem punitive, they are also helpful in ensuring that the trial is able to focus on controlling for the variables identified to demonstrate that a drug is safe and effective for use.

Regulatory Context

As the US begins to grapple with an outbreak of a novel coronavirus, SARS-CoV-2, life sciences companies may soon begin to find it extremely difficult to conduct clinical trials according to existing protocols and plans.

The challenges facing life sciences companies are immense.

Supplies needed to run clinical trial sites and provide essential patient care may be interrupted by shortages or other disruptions to the supply chain. Supplies of the investigational drug product could be interrupted, as many are made in special facilities and require advanced logistics networks for distribution. Trial recruitment could be affected if potential participants are instructed to isolate themselves socially, or become quarantined, sick or otherwise unable or afraid to travel to medical facilities. A patient may not be able to access a clinical trial site due to decreases in public transportation, or because their caregiver is sick.

For companies with ongoing trials, there are major risks as well. The health of trial participants and clinical staff could be at heightened risk, especially for patients who are already immunocompromised—such as those undergoing treatment for cancer. Trial sites may cancel certain procedures or restrict access to try to increase the availability of medical staff and resources to respond to the outbreak, especially if a trial is held at an academic medical center.

And then there’s the clinical data.

A concern for companies is the possibility that COVID-19 could disrupt the collection of their clinical data, infect their patients and otherwise make it difficult for them to prove to regulators that their drug is (or isn’t) safe or effective for use.

“How do you maintain the integrity of that trial? There might be criteria at the outset of that trial that enrollees have no underlying health conditions,” said Jeff Allen, President and CEO of the advocacy group Friends of Cancer Research (FOCR). “Would it disrupt the trial results in the long run? That consideration might not be relevant this week, but it’s likely to be in the coming weeks.”

That prospect is a frightening one for companies who may have already spent several years and tens (if not hundreds) of millions of dollars investing in the collection of clinical data to support a marketing application to the FDA. COVID-19 could well represent a setback, or even the destruction, of those efforts.

“For the ongoing trials we’re working on, we’re spending a lot of time each day looking at—patient by patient, study by study, visit by visit—what is required at that visit, and what are we doing to make that happen,” said Ken Somberg, Chief Medical Officer at TrialSpark, in an interview with AgencyIQ. “Patient safety is priority number one, but study integrity is priority number two.”

While some things can be done remotely, Somberg said, like reporting health updates or adverse events, many trials require in-person testing and interactions. And those in-person interactions may prove especially vexing for some types of patients, especially those with cancer or other serious diseases. Medical professionals are likely to be among those at highest risk of exposure to COVID-19, and even if trial patients are isolated within a particular part of a medical facility, there are still some places where patients overlap.

“In some facilities, there may be some degree of shared hospital corridors or equipment like X-Rays or CT scans that may not be able to be done in complete isolation,” said FOCR’s Jeff Allen. “If it’s a large hospital, maybe they can cordon off a wing or floor to try to maintain as much separation as possible. But in some facilities, that may not be easily done, especially as the volume of COVID-related patients are increasing.”

Even if medical facilities can keep their clinical trial area separate from their COVID-19 treatment areas, they won’t be able to keep the virus away from their patients.

“Unfortunately, the demographic in which COVID infections are most severe are also those that have a higher propensity for cancer,” said Allen. “Both are affecting people over the age of 65 disproportionately.”

Impacts on research

Already, some research organizations are feeling the impacts of COVID-19. Among the most apparent impacts are for companies that had intended to initiate clinical trials in the coming weeks to months.

“Regular healthcare is still going on. But many of the new trials in the pipeline just aren’t going to get started up right now,” said Somberg. “There are two reasons for that,” Somberg added. “The traditional logistics of how a trial starts up has a lot of face-to-face aspects to it. Investigator kick-off meetings. Monitors visiting a site for what are called pre-study qualification visits to make sure they have a suitable place to lock the medication, they have the right equipment and the like. In this current environment, the idea of starting up a study in that fashion just isn’t going to fly in terms of people moving around.”

One major exception to this could be in cases where a trial includes treatment that is integral to a patient’s care, Somberg said, such as for cancer patients who might require access to potentially life-saving treatment.

“But otherwise, I think a large number of trials aren’t going to get started up in the short term,” Somberg added.

Paul Ivsin, Vice President of Data and Analytics at Continuum Clinical, a global clinical trial recruitment company, said he had not yet seen a drop-off in patient interest in enrolling in trials, but that clinical trials staff and site sponsors were trying to evaluate whether they could remain open, and under what circumstances.

“We have not heard any major pharma pull back in trial operations. What’s interesting from our side—from recruiting patients into new studies—patient interest hasn’t dropped considerably. I was expecting that to be a leading indicator,” Invsin told AgencyIQ, noting that patients often have to travel to trial sites and receive care from medical professionals with whom they may not be familiar.

“The bailout rates of patients as they go through pre-enrolled have increased 10 to 20 percent, but they’re not dramatic,” Ivsin said. “Their condition isn’t going away. It’s not like the virus [COVID-19] is going to cure their underlying condition. And if the disease has gotten to the point where you’re actively considering enrolling in a clinical trial,” you might still feel compelled to enroll regardless of fears about infection, Ivsin added.

Even if trials are up and running, it could be difficult for some to maintain sufficient supplies to keep running, said Ryan Hohman, Vice President of Public Affairs at FOCR. “While the cancer centers generally have their own stockpiles of medical equipment, those attached to academic hospitals may be asked to pivot some of their supplies over to the emergency side of things. I think in the short term, you’re going to see decisions having to be made between cancer centers and their larger academic medical center parent organizations.”

Ivsin agreed, noting that trial sites are shifting resources, personnel and equipment—especially at academic medical centers where many clinical trials take place.

Facing complications, some sponsors and trial sites may face a difficult choice: Do they remain open and continue a study if it puts their patients or their staff at risk?

“We’ve already had one project that is on hold and we know the hold order was given by the sponsor about a day after some sites shut themselves down” as the result of COVID-19, Ivsin said. “That was in a particularly vulnerable patient population. That pattern is something I’m really looking for: Are site concerns leading to a critical mass where the sponsor or [contract research organization] CRO has no choice but to halt or pause the study?”

“I don’t think studies can survive a significant shutdown of the sites, and that appears to be where we’re headed,” Ivsin added.

TrialSpark’s Somberg agreed, telling AgencyIQ that he thought it was “inevitable” that certain trial sites close down for a period of time.

Future clinical trials work may also face challenges, as pre-clinical work has also largely ground to a halt at many academic institutions.

“Research lab operations have been cut back substantially, and students, postdocs, technicians, and faculty are only to come in for maintenance of priority equipment, cell lines, etc,” wrote Natalie Eddington, Dean of the University of Maryland’s School of Pharmacy, which works with the FDA as a Center of Excellence in Regulatory Science and Innovation (CERSI), in an email to staff this week shared with AgencyIQ.

What’s New

In light of these concerns, on March 19, 2020 the FDA released a guidance document detailing how companies can modify the operations of their trials to accommodate ongoing concerns related to COVID-19.

FDA recognizes that the COVID-19 pandemic may impact the conduct of clinical trials of medical products. Challenges may arise, for example, from quarantines, site closures, travel limitations, interruptions to the supply chain for the investigational product, or other considerations if site personnel or trial subjects become infected with COVID-19. These challenges may lead to difficulties in meeting protocol-specified procedures, including administering or using the investigational product or adhering to protocol-mandated visits and laboratory/diagnostic testing. FDA recognizes that protocol modifications may be required, and that there may be unavoidable protocol deviations due to COVID-19 illness and/or COVID-19 control measures.

The guidance recommends that sponsors prioritize patient safety and “modify study conduct accordingly.” That may include pausing recruitment efforts, modifying how patients are monitored (i.e., remote instead of in-person), or stopping the trial. “In all cases, it is critical that trial participants are kept informed of changes to the study and monitoring plans that could impact them,” the FDA explained.

Those changes would still require consultation with an Institutional Review Board, but the exact timing of that consultation may differ depending on the rationale behind a change. The guidance document explains that typically any trial modification requires the IRB to be notified before the change, but “urgent or emergent changes” to “minimize or eliminate immediate hazards or to protect the life and well-being of research participants” may permit immediate changes to a trial’s protocol. In such cases, must be reported to both the IRB and the FDA soon after.

One critical concern is the accuracy, reliability and usefulness of collected data. The FDA’s guidance indicates that it plans to be flexible about COVID-related data issues.

With respect to efficacy assessments, FDA recommends consultation with the appropriate review division regarding protocol modifications for the collection of efficacy endpoints, such as use of virtual assessments, delays in assessments, and alternative collection of research-specific specimens, if feasible. For individual instances where efficacy endpoints are not collected, the reasons for failing to obtain the efficacy assessment should be documented (e.g., identifying the specific limitation imposed by COVID-19 leading to the inability to perform the protocol-specified assessment).

The FDA said that for any trial affected by COVID-19, trial sponsors should inform regulators of contingency measures used to manage disruptions to the study, list all participants affected on a per-site basis, describe how an enrollee’s participation in a trial was affected by COVID-19, and analyze and discuss the impacts of those deviations on collected data.

Sponsors are also advised to consider the use of central or remote trial monitoring to maintain oversight of any trials where on-site monitoring is no longer feasible. Sponsors, investigators and IRBs are also advised to establish and implement policies to protect trial participants and “manage study conduct during possible disruption of the study.”

Already, the government is following its own advice. This week the National Institutes of Health released guidance on how studies should enact protective measures, including limiting study visits, conducting virtual study visits, and enacting flexible laboratory testing.

What’s Next

The full effects of COVID-19 on clinical trials may not be felt for months.

At best, clinical trials are likely to be delayed. At worst, some could be cancelled due to significant concerns about the health of patients. For some trial types, there are only bad options: Between protecting patients from COVID-19 and ensuring those patients maintain access to potentially life-saving therapies.

From a regulatory perspective, how the FDA responds to trial difficulties will be critical. The data it receives for drugs in the next several years may be tainted by concerns about COVID-19, including patients who experienced complications, suddenly dropped out or were noncompliant with trial protocols. Some of these justifications may be valid, while other companies could use COVID-19 as an excuse to obfuscate data indicating a drug’s poor performance or that it is unsafe for use.

To mitigate these effects, the FDA may heavily lean on Phase 4 trials in the years ahead, including Post-market Requirements (PMRs) and Post-market Commitments (PMCs). Under the FDA Amendments Act of 2007, the FDA has the authority under Section 505(o) of the Federal Food, Drug and Cosmetic Act to require companies to conduct studies to:

• to assess a known serious risk related to the use of the drug;
• to assess signals of serious risk related to the use of the drug; and
• to identify an unexpected serious risk when available data indicates the potential for a serious risk.

In addition to study requirements, the FDA may also ask that companies commit in writing to conducting postmarketing studies. However, these commitments are not required. These typically include studies related to clinical efficacy, clinical pharmacology, nonclinical toxicology, chemistry, or manufacturing, among other topics.

If the FDA has lingering questions about the efficacy or safety of certain drugs, they may require or recommend these studies to confirm a drug’s benefit to patients. However, research has shown that many companies do not complete these studies as required or recommended, and even when completed may not conclusively answer lingering questions.

Those flexibilities could help the FDA to be more lenient in accepting some clinical data in support of drugs, but it remains to be seen what the limits of those flexibilities look like, or what the true damage to clinical data could look like.
 

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