AstraZeneca and Johnson & Johnson (J&J) said they will resume Phase III trials of their COVID-19 vaccine candidates, at the recommendation of safety boards overseeing the studies that found no evidence the vaccines caused the patient illnesses that touched off pauses in recruitment.
AstraZeneca confirmed Friday that the FDA had authorized a re-start of the company’s up-to-30,000-patient Phase III trial of AZD1222 (NCT04516746), which the company is co-developing with the University of Oxford and a spinout company. AstraZeneca paused global patient recruitment in the trial last month, sparked by a “potentially unexplained illness” involving a participant from the U.K.
“The FDA reviewed all safety data from trials globally and concluded it was safe to resume the trial,” AstraZeneca stated, after The Wall Street Journal first reported the resumption.
The FDA held up resumption of the trial for more than a month while it investigated the patient illness. U.S. Secretary of Health and Human Services (HHS) Alex Azar II told CNBC on September 23 that the trial would remain on hold in the United States pending “answers to important questions” over the vaccine’s safety for patients—details of which have not been disclosed by the agency.
Likewise, AstraZeneca has not disclosed specifics on the patient illness that led to the enrollment pause. The New York Times reported that the adverse event was a diagnosis of transverse myelitis, citing an unnamed source. Testifying on September 9 before the U.S. Senate Committee on Health, Education, Labor & Pensions on Wednesday, NIH Director Francis S. Collins, MD, PhD, appeared to confirm that report when he described the reason for the trial pause as a “spinal cord problem.”
The FDA’s action followed the resumption of the trial in the U.K., Japan, South Africa—and Brazil, where the health agency Anvisa on Wednesday reported the death of a patient who volunteered to take the vaccine.
The patient—a Brazilian national but otherwise unidentified—is believed to have been in the control group given a meningitis shot and not among patients dosed with AZD1222, after an unnamed source told Reuters that the Brazilian portion of the trial would have been suspended had the death been linked to the vaccine.
The Federal University of Sao Paulo said an independent review committee had also recommended the trial continue.
“The restart of clinical trials across the world is great news as it allows us to continue our efforts to develop this vaccine to help defeat this terrible pandemic,” AstraZeneca CEO Pascal Soriot said.
AZD1222 is based on an adenovirus vaccine vector and the COVID-19 spike protein. After vaccination, the surface spike protein of the coronavirus is produced, which primes the immune system to attack the coronavirus if it later infects the body.
Both AZD1222 and J&J’s COVID-19 vaccine candidate JNJ-78436735 are among 19 “Front Runner” leading candidates among the more than 300 COVID-19 therapeutics under study in GEN’s updated and just-launched “COVID-19 Drug & Vaccine Candidate Tracker.”
Potential billions from Washington
Both vaccine candidates have potentially billions of dollars invested in them by Washington through “Operation Warp Speed,” the program through which President Donald Trump’s administration has committed the nation to delivering 300 million vaccine doses protecting against SARS-CoV-2 by January 2021.
Federal agencies have committed up to nearly $1.5 billion toward supporting JNJ-78436735, from development through licensure—an award of more than $456.2 million in February from the Biomedical Advanced Research and Development Authority (BARDA), followed August 5 by approximately $1 billion from HHS and the U.S. Department of Defense (DoD) to support a manufacturing demonstration project including the ability to deliver vaccine doses to government-designated locations nationwide.
BARDA has also committed up to $1.2 billion toward the development, production, and delivery of AZD1222 via Operation Warp Speed. In addition to co-funding the U.S. Phase III trial, BARDA also agreed to fund another trial designed to evaluate the vaccine in children. AstraZeneca has agreed to furnish BARDA with 300 million doses of the vaccine.
Also on Friday, J&J said it was preparing to resume the U.S. portion of the 60,000-participant ENSEMBLE study (NCT04505722) assessing its COVID-19 vaccine candidate JNJ-78436735 (Ad26.COV2.S).
J&J temporarily paused the ENSEMBLE trial on October 12—as well as all other clinical trials of the vaccine candidate sponsored by J&J’s Janssen Pharmaceutical Cos.—citing a patient’s “unexplained illness.” According to The Washington Post, which cited two unnamed sources, a male volunteer in his twenties had a cerebral hemorrhage and transverse sinus venous thrombosis following a stroke.
J&J said the trial’s independent Data Safety Monitoring Board (DSMB) recommended that the company resume recruitment of patients after it found no evidence that the vaccine led to the “serious medical event” experienced by the patient.
“Based on the information gathered to date and the input of independent experts, the company has found no evidence that the vaccine candidate caused the event,” J&J said in a statement. At Johnson & Johnson, there is no greater priority than the health and safety of the people we serve every day around the world. Our primary goal is to ensure the safety, well-being, and privacy of the participants and all those involved in our trials.”
Talking with overseas regulators
The company has offered no details about the participant’s illness, but did say it is in talks with regulators outside the United States to resume the trial. J&J has said it aims to enroll participants in Argentina, Brazil, Chile, Colombia, Mexico, Peru, and South Africa, in addition to the United States.
The ENSEMBLE trial will resume enrolling volunteers at up to nearly 215 clinical research sites in the United States and worldwide.
ENSEMBLE is a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the safety and efficacy of a single vaccine dose versus placebo in up to 60,000 adults ages 18 years old and older, including what J&J said would be “significant” representation from participants over age 60. The trial will include participants both with and without comorbidities associated with an increased risk for progression to severe COVID-19.
In addition to the ENSEMBLE trial, J&J’s pause also extends to at least three other clinical trials of JNJ-78436735 that were reported to be recruiting patients according to ClinicalTrials.gov:
- A Phase II study (NCT04535453) evaluating humoral immune responses of three dose levels of the J&J vaccine administered intramuscularly (IM) as a two-dose schedule (56 days apart) and as a single vaccination; and testing both compressed and expanded two-dose schedules of the vaccine 28 and 84 days apart, in up to 550 participants.
- A Phase I/II study (NCT04436276) assessing the safety, reactogenicity, and immunogenicity of the J&J vaccine candidate at two dose levels, administered IM as a single-dose or two-dose schedule, with a single booster vaccination administered in one cohort, in up to 1,045 participants in groups of adults ages 18–55 and ages 65 and older.
- A Phase I study (NCT04509947) evaluating the safety and reactogenicity of the J&J vaccine candidate IM at two-dose levels, and as a two-dose schedule in up to 250 healthy participants in groups of adults ages 20–55 and ages 65 and older.