AstraZeneca’s COVID-19 vaccine candidate, AZD1222—also known as the “Oxford vaccine” or ChAdOx1 nCoV-19—was purportedly under consideration by at least some factions within the U.S. executive branch to contribute to a potential “October Surprise;” in fact, the vaccine was under consideration for an expedited approval process, prior to the forthcoming U.S. presidential election. Why? According to a report from the Financial Times, it is because of what was deemed positive results from a relatively small UK study. TrialSite wrote that the Phase 3 AstraZeneca study was designed for an unprecedentedly fast conclusion. But by September 6, what now appears to be at least two safety events associated with the clinical trial contributed to a temporary hold on the study. By September 12, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) deemed the study safe to resume and India followed suite, as reported on September 16, when India’s DCGI gave Serum Institute of India (SII) the greenlight to resume the study with some caveats. In the meantime, in what has become a politicized process all the way around, the sponsor’s lack of sufficient transparency hasn’t contributed to an expedited FDA review and approval to resume the study. The FDA is taking its time to diligently, methodically and holistically analyze the safety incidents to better understand what and how the neurological illnesses associated with the study occurred; thereafter, the agency undoubtedly assesses the risk of proceeding with the study. Why the FDA is taking more time and effort than their counterparts in England or India is not certain but this U.S. agency represents the “gold standard” of regulatory authority.
A Special Vaccine?
From the start, the “Oxford” vaccine (AZD1222), known as ChAdOx1 nCoV-19, demonstrated promise. This candidate vaccine was developed from a derivation of a common cold virus (ChAdOx1), a weakened form known as an adenovirus that triggers infections in chimpanzees, but yet genetically modified so as it’s compatible in humans.
White House Plans with AZD1222?
It was AZD1222 that was the subject of material chatter association with an expedited process leading to an emergency use authorization (EUA). TrialSite reported that the Financial Times (FT) shared that that the members within the U.S. administration identified AZD1222 as a candidate for expedited review, to “bypass normal regulatory standards to fast-track” the experimental AZD1222 for use in America ahead of the November 3, 2020 election.
Four FT journalists penned that White House chief of staff Mark Meadows and Treasury secretary Steven Mnuchin informed top Democrats of administration consideration of the AZD1222 fast-track trajectory, “….according to one person briefed on a July 30 meeting the paid held with Nancy Pelosi.” Apparently, the two representing the White House suggested that emergency use authorization “possibly be assigned to the AstraZeneca vaccine.” The rationale for an EUA would have been positive data arising out of a relatively small UK study.
Study Design Anomaly?
In fact, an actual anomaly in study design called out by TrialSite, supported such a proposition, that AZD1222 could possibly be associated with an EUA before year end.
With a estimated start date of August 17 followed by an estimated primary completion date of December 2, 2020, the bulk of this study involving up to 30,000 participants spanned just 3.5 month in duration—a strikingly unprecedented condensed timeline. By comparison, the average duration for the rest of the COVID-19 vaccine Phase 3 clinical trials is about 15 months.
Now with this ongoing delay, consideration for AZD1222 before the end of the year is nearly impossible at this point as the FDA still hasn’t opted to resume the study.
On September 6, the standard review process triggered a voluntary pause to all Phase 3 clinical trials investigating the “Oxford vaccine” known as AZD1222. A standard process, this allowed for a review of safety data by independent committees and international regulators. By September 12, AstraZeneca issued a press release declaring, among other things, that the UK drug regulatory MHRA concluded that the vaccine trials are safe to resume.
As TrialSite reported on September 23, India had also resumed while the FDA still looked into the problems associated with what was now purported to be two safety incidents associated with the trial. Although, India’s Central Drug Standard Control Organization (CDSCO) known as Drug Controller General India (DCGI) required additional caveats moving forward (additional monitoring for safety, etc.).
The White House, which sought aggressive progress with vaccines receiving Operation Warp Speed funding (AstraZeneca has received over $1b), now undoubtedly frets as two major regulatory authorities have reviewed the same medical safety data and concluded that the study is safe to proceed. Yet the FDA has opted to slow down and further analyze the safety data associated with the two participants in the AZD1222 Phase 3 trial.
Honesty is the Best Policy
Senior Medical Correspondent for CNN, Elizabeth Cohen, raised some fundamental questions about the British-originated vaccine in a September 25 piece. The CNN journalist reminds the reader first and foremost that since the trial’s temporary pause, regulators still haven’t identified whether the neurological-based illnesses were associated with the Oxford vaccine or not.
Differing accounts or stories here raise concern for all those who care about transparency and patient safety. Ms. Cohen suggests that the British pharmaceutical sponsor offers differing accounts of the ill study participants. The CNN correspondent first identified that AstraZeneca’s explanation of the first sick volunteer was that they fell to “an undiagnosed case of multiple sclerosis.” Yet, according to the University of Oxford website (again the actual makers of the vaccine):
“In the current trial we have undertaken safety reviews when volunteers in the trials of ChAdOx1 nCoV-19 developed unexplained neurological symptoms including changed sensation or limb weaknesses, and have paused the study while a safety review took place.”
Additionally, the company reports that the second volunteer experienced “an unexplained illness,” however Ms. Cohen and CNN dug up an internal company document dated September 10 that was in fact distributed to study investigators on September 11.
In this artifact, AstraZeneca disclosed that a previously healthy 37-year-old female became ill with “transverse myelitis” upon the second dosing of the Oxford vaccine candidate. She was hospitalized on September 5. Yet apparently, AstraZeneca doesn’t want to publicly disclose this fact, saying instead via a spokesperson that they “cannot disclose medical information,” reports Cohen.
Transparency is King
CNN Cohen spoke with Yale School of Medicine professor Dr. Harlan Krumholz, who told the media, “Those are very different statements” referring to the accounts declared by AstraZeneca and those posted on the Oxford website. An accurate, clear and uniform response is required for true transparency, suggests Krumholz. The Yale physician continued, “Their information should be consistent, and when its not consistent, that raises questions.”
TrialSite reminds that any vaccine development effort involving a novel disease will most certainly include some twists and turns, including safety incidents. That the study was put on hold in the bigger scheme of things is a healthy process, indicating that the regulatory process is working: patient safety is of highest concern.
However, with AstraZeneca’s acceptance of over $1 billion in U.S. public funds (Biomedical Advanced Development Authority–BARDA) for the clinical development and at risk manufacturing of AZD1222, a good case can be made that transparency is necessary and due to the public.