FDA Today | FDA's Looming Adverse Event Challenge

Hello and welcome to the first week of FDA Today. I’m your host, Alec Gaffney. I’m the Head of Research at POLITICO’s AgencyIQ. Our division analyzes FDA regulatory developments related to the life sciences industry, including pharmaceuticals, biologics, medical devices, diagnostics, dietary supplements and over-the-counter drugs. We aren’t journalists, but regulatory analysts.

Each morning (Tuesday to Friday), we’re going to walk you through one FDA regulatory development that we found interesting.

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Today, we want to focus on how the FDA keeps track of the safety of vaccines, and why the FDA is in for some serious headaches in the months to come as tens of millions of Americans start to get vaccinated.

I’d love to hear your comments, questions, ideas and suggestions as we get started. Send me an email or Tweet. - Alec Gaffney ([email protected] / @AlecGaffney)

The FDA’s looming adverse event challenge

President-elect Joe Biden has pledged to vaccinate 100 million Americans within the first 100 days of his presidency. While achieving that goal would undoubtedly be good for public health, widespread vaccination is likely to cause a few operational headaches for the FDA by making it more difficult to track and analyze potential side effects caused by – or merely associated with – the administration of the vaccines.

First, let’s quickly talk about a regulatory term you might be unfamiliar with: Pharmacovigilance.

• Pharmacovigilance refers to the monitoring of a drug or biological product’s effects after it has been approved. Currently, pharmacovigilance involves an overlapping network of monitoring methods and requirements. First, companies are required to collect, analyze and submit to the FDA reports of adverse events that they receive. If they receive a report of an event that is “serious and unexpected” (i.e., not listed on the drug’s label), they must notify the FDA within 15 days. Pharmaceutical companies must also submit regular reports summarizing both new and known adverse events.
• Data on adverse events can come from many sources. Some reports will be submitted from doctors or health care facilities. Others will be submitted by patients. Pharmaceutical companies are also required to do their own proactive monitoring, including monitoring social media, medical journals and news reports. The FDA sometimes also requires the submission of additional data as a condition of approval. For example, Pfizer is required to submit to the FDA information about all COVID-19 vaccine administration errors and cases of COVID-19 in vaccinated persons that result in hospitalization or death.
• But the FDA doesn’t just rely on companies to report adverse events. The agency maintains some of its own vigilance systems, including its Sentinel Initiative and its Biologics Effectiveness and Safety (BEST) system, to track the performance of approved drugs and biologics. It also works closely with other federal agencies and systems, notably including the CDC’s Vaccine Adverse Event Reporting System (VAERS).
• Adverse event monitoring systems generally work by tracking data about a large number of patients. For example, FDA’s Sentinel Initiative currently tracks data on 70.6 million patients, with data derived from health payers and hospital systems with which Sentinel has a partnership.

It’s sometimes difficult to determine when an adverse event has been caused by a medical treatment instead of just being associated with it.

• For example, when the FDA was reviewing Pfizer and BioNTech’s COVID-19 vaccine prior to its Emergency Use Authorization, it noted that four patients enrolled in the companies’ study had developed Bell’s palsy, a condition marked by partial (and often temporary) facial paralysis or weakness. Meanwhile, no patients had developed it in the placebo group. While a casual observer might immediately point to this as a cause for alarm, the FDA was more cautious in its analysis. “The observed frequency of reported Bell’s palsy in the vaccine group is consistent with the expected background rate in the general population, and there is no clear basis upon which to conclude a causal relationship at this time.” The regulator said it would recommend surveillance of the condition after the vaccine was authorized. ( Moderna’s study also found several instances of Bell’s palsy).
• Another example: Twelve participants in the same vaccine study experienced appendicitis, of which 8 study participants received the vaccine and four received the placebo. Here again, the FDA said that while the number of cases appeared to be numerically higher among study participants who received the vaccine, it “occurred no more frequently than expected in the given age groups” and lacked a “clear basis upon which to suspect that this imbalance represents a vaccine-related risk.”

But once tens or hundreds of millions of Americans begin to receive the vaccine, the job of assessing these adverse events will become much more difficult.

• When a significant portion of the US population receives a vaccine for COVID-19, almost every medical event they experience will become associated with that vaccine. Every headache, heart attack, diagnosis and death will now be associated with the vaccine by virtue of it having occurred after the patient was vaccinated. It will become a real-world example of the fallacy of Post hoc, ergo propter hoc, which translates to “after this, therefore because of this.”
• Of course, vaccines – like any medical product – can cause adverse events. But most medical events will not be caused by vaccines. Every day, people experience heart attacks, are diagnosed with new medical conditions, have organs fail, or die suddenly or of old age. These events happened before COVID-19, and they’ll happen long after, too. But in the minds of some people, the medical events they experience will have been caused by the vaccine. And the more media attention these events receive, the more other people may believe that their events were caused by a COVID-19 vaccine, too.
• We were reminded of the FDA’s challenges with associations after reading media reports of a doctor who died two weeks after receiving the vaccine. According to the reports, the doctor experienced idiopathic thrombocytopenic purpura (ITP), a condition in which the immune system attacks blood platelets, causing bruising and bleeding. While ITP has been associated with the administration of vaccines in rare cases, it can also be caused by many other conditions, including viral infections, immune disorders and low-grade leukemias. It may also be caused by other medication being taken.
• “The problem then becomes determining whether his tragic outcome was a coincidence or due to the vaccine,” wrote David Gorski, a surgical oncologist at the Karmanos Cancer Center and the author of the blog Science-Based Medicine, of the deceased doctor. “Unfortunately, [the] case is, at present, a single anecdote, making it impossible to demonstrate causation.”

The FDA is likely to rely on at least two approaches to assess safety.

• First, it can rely on “natural history data,” or historical data on the rate at which events are experienced in the general population. For example, FDA’s Sentinel database contains 788 million person-years of data, which can allow it to see if vaccinated persons experience adverse events at a greater rate than might be expected.
• Second, it can compare cohorts of patients on a prospective basis, including patients who were vaccinated versus those who weren’t, and patients who received a specific vaccine versus those receiving another vaccine.
• The FDA last week also had a brief comment period on a draft protocol for monitoring adverse events for COVID-19 vaccines. That protocol, run through its BEST system, is set to monitor Adverse Events of Special Interest (AESI) in several different patient groups, including pregnant women, children and older adults. However, a consistent challenge for the FDA will be “data lag” – a lag in the time between when an event happens and when the FDA is made aware of that event through its data vendors.
• Of course, tracking adverse events will become more difficult once more vaccines become available for use. Because many patients are receiving data about their vaccines using paper cards, they may easily confuse the name of the vaccine they received if they lose the card.
• Finally, FDA has already indicated its willingness to update vaccine labeling based on new or emerging data. For example, both Pfizer and Moderna’s COVID-19 vaccines now contain warnings about the potential for the vaccines to cause anaphylaxis, a severe and potentially life-threatening allergic reaction. Those warnings were added based on data seen in the UK following the authorization of Pfizer’s vaccine. The CDC’s VAERS database has received reports of at least 21 cases of anaphylaxis following 1.9 million vaccinations, or a rate of 11 cases per 11.1 million doses.

[Want to know more about the FDA’s adverse event tracking systems? AgencyIQ subscribers can read our analysis of how COVID-19 is acting as a pressure test of FDA’s Sentinel System.]

What we're thinking

Details about the ongoing negotiations for the reauthorization of the Prescription Drug User Fee Act are always hard to come by, so when FDA releases the high-level meeting minutes for the negotiation sessions, we try to pay close attention.

FDA released several new updates this week regarding those negotiations, including updates from its steering committee and a workgroup focused on facility inspections.

A few of the details that caught our eye:

• FDA and industry are deep in discussion about a proposal for Complex Innovative Designs for clinical trials (which Congress has pressed FDA on for years, including in the 21st Century Cures Act).
• FDA and industry are still trying to figure out the resources that FDA needs to improve its gene therapy program, which has had a difficult time hiring staff in recent years. Peter Marks said recently that he’s looking for a “significant increase” in gene therapy staff at the Center for Biologics Evaluation and Research.
• FDA appears to be asking for additional resources to help support its post-market adverse event tracking system, called the Sentinel Initiative. That system could be helpful for supporting Real-World Evidence, and FDA’s notes indicate that the discussion has focused on ways to expand Sentinel’s use beyond just safety monitoring.

One word of caution: The latest negotiation meeting minutes are from early November 2020, so negotiators have likely met a few more times since then.

What we're watching and reading

• This piece by BioCentury’s Steve Usdin, who reports that Janet Woodcock is expected to serve as Acting FDA Commissioner upon the resignation of Stephen Hahn later this month. Usdin also reports that former FDA Commissioner David Kessler will serve Biden as an advisor to President Joe Biden, leaving Joshua Sharfstein as the presumptive front-runner for the job of commissioner. But we hear that Sharfstein isn’t yet a lock for the position.
• This piece by the Pew Trusts calling on Congress to “authorize risk-based review of all in vitro diagnostics, including those from laboratories. Right now, the FDA regulates In Vitro Diagnostics (IVDs), but HHS recently revoked any authority it had over a type of diagnostic known as Laboratory Developed Test (LDTs), which are developed by (and used within) clinical laboratories and overseen by CMS. Some members of Congress, including Sens. Richard Burr (R-NC) and Michael Bennet (D-CO) have proposed that IVDs and LDTs be regulated under a unified, risk-based framework [Read AgencyIQ’s analysis here].
• This series of interviews by Nutritional Outlook with the top regulatory officials and leaders of key dietary supplement industry groups. Author Jennifer Grebow asked: What issues are you expecting to see in 2021? Some recurring themes: Quality, accountability, regulation of cannabidiol, and a potential modernization of the Dietary Supplement Health and Education Act (DSHEA). [AgencyIQ’s FDA Forecast 2021 has an in-depth look at why we think CBD regulation will be a key issue for FDA next year. ]
• Billionaire entrepreneur Mark Cuban’s new generic drug company, the Mark Cuban Cost Plus Drug Company, which seeks to market low-cost generics at a transparent price point: The cost of manufacturing, plus a 15 percent markup. One thing Cuban and company might want to watch out for is falling afoul of the FDA’s Office of Prescription Drug Promotion (OPDP ). While his company mentions its intent to market generic albendazole, an anti-parasitic drug marketed under the brand name Albenza, it does not accurately describe the indications for which the drug has been approved for use by the FDA and omits or oversimplifies several of its side effects. Such issues commonly result in the FDA warning companies for noncompliance with federal regulations.

Analysis available exclusively to AgencyIQ subscribers:

FDA Forecast 2021: The FDA confronts the pandemic, a new president and policy changes

What will the FDA do in 2021? AgencyIQ’s research team developed an extensive, 93-page report making our predictions about the regulatory changes that will take place in the year ahead and what they will mean for the life sciences industry. If you work in regulatory policy or government relations, this report is a must-read. (Dec. 22)

HHS quietly hires private contractor to review certain COVID-19 diagnostic submissions

A new contracting announcement from the Department of Health and Human Services (HHS) indicates that it is looking to authorize Laboratory Developed Tests (LDTs) for COVID-19 without input from the FDA. These LDTs – which are a subset of in vitro diagnostics (IVDs) – have been in regulatory limbo since August of 2020, following a policy disagreement between the FDA and HHS. (Jan. 13)

CDRH expects continued regulatory review delays for device submissions as pandemic drags on

Medical device sponsors should not expect a return to normal business at its diagnostics review division any time soon, said Tim Stenzel, director of FDA’s Office of In Vitro Diagnostics and Radiological Health (“OHT7”), today. On a “town hall” call intended to provide regular updates to developers of diagnostics, Stenzel also provided updates on the agency’s thinking about COVID-19 diagnostics and OHT7’s prioritization of submitted applications for review. (Jan. 13)

HHS wants to exempt dozens of device types from pre-market requirements

In a surprise move, the US Department of Health and Human Services this week issued a notice that it will immediately exempt seven low-risk medical devices from pre-market review requirements and is further proposing to exempt an additional 84 products. But according to AgencyIQ’s review, HHS’ proposal is challenged by several issues which may subject it to heightened scrutiny from public health officials. (Jan. 12)

Supreme Court grants FDA request to reinstate in-person dispensing requirements for mifeprisone

The Supreme Court of the United States on Tuesday ruled in favor of the FDA which had asked the court to lift an injunction that had suspended its in-person dispensing requirements for mifepristone, a drug used for medical pregnancy termination. (Jan. 13)

CTTI panel discusses the use of master protocols for COVID-19 treatments

In a virtual webinar held today by the Clinical Trials Transformative Initiative (CTTI), study investigators, clinical trial experts and former FDA officials including Commissioners Robert Califf and Mark McClellan discussed ways to increase the use of master protocols for COVID-19 treatments. (Jan. 13)

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