Global regulators at odds on Phase III efficacy threshold for COVID-19 vaccines

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Regulators are aligning their guidance on COVID-19 vaccine development through the the International Coalition of Medicines Regulatory Authorities, but they have yet to agree on the criteria for vaccine efficacy.

A report released last Friday from the second COVID-19 vaccines workshop held by ICMRA detailed regulators’ guidance on the preclinical and clinical data required to start Phase III testing of COVID-19 vaccines and how those Phase III trials should be designed.

The workshop was held on June 22 and jointly convened by EMA and FDA. ICMRA includes 30 national and multi-national regulatory authorities.

On efficacy endpoints, regulators said the primary endpoint should be lab-confirmed COVID-19 of any severity, with other important endpoints being severity of disease as measured by hospitalization, mechanical ventilation and death.

They also stated that studies should be powered “to estimate vaccine efficacy as robustly as possible, generally favoring more conservative stances on the success criteria that would rule out licensure of weakly effective vaccines that could do more harm than good.”

However, according to the report summary, “A specific numeric value to be used for the lower bound and vaccine efficacy point estimate was not agreed upon at this stage.”

The lack of agreement on an efficacy threshold comes into stark contrast to FDA’s July guidance, which stated that vaccines need to show a 50% reduction in the number of positive COVID-19 cases vs. a placebo (see “Borio, Dolsten say FDA’s COVID-19 Vaccine Guidance Hits Mark”).

Therefore, while regulators called for Phase III trials to be standardized such that vaccine candidates can be compared across different trials, sponsors still don’t have certainty as to what global regulators will accept as a positive outcome in a Phase III trial.

One vaccine designed for COVID-19 -- AZD1222 (ChAdOx1 nCoV-19) from AstraZeneca plc (LSE:AZN; NYSE:AZN) -- has made it into Phase II/III testing, and at least four more are slated to enter Phase II/III or Phase III trials by this fall.

Both Moderna Inc. (NASDAQ:MRNA) and partners BioNTech SE (NASDAQ:BNTX) and Pfizer Inc. (NYSE:PFE) plan to start Phase III studies of their respective mRNA COVID-19 vaccine candidates this month. Inovio Pharmaceuticals Inc. (NASDAQ:INO) expects to start a Phase II/III trial of INO-4800 this summer. The fourth vaccine, NVX-CoV2373 from Novavax Inc. (NASDAQ:NVAX), received a $1.6 billion boost last week from Operation Warp Speed, the U.S. government’s initiative to fund and accelerate the development of vaccines and therapeutic countermeasures for COVID-19. NVX-CoV2373 will move into Phase III testing this fall (see “Novavax Gets Another Boost”).

Other guidance details

According to the report, preclinical data should include in vivo data characterizing the vaccine-induced immune response and immune markers of enhanced respiratory disease outcomes, along with functional responses such as neutralizing mAb vs. total mAb response. The group acknowledged that prior to starting a Phase III trial, it would be preferred but not necessary to have non-human primate data from a post-vaccination challenge study to determine any risk of enhanced respiratory disease, although challenge data from other animal models may provide supportive evidence.

In addition to the safety and immunogenicity of each dose level being characterized in early clinical studies, the regulators also called for data showing the vaccine-induced immune response and immune markers for potential enhanced respiratory disease across all patient populations expected to be included in a Phase III trial.

For the Phase III design itself, the regulators said they should be adequately powered with “many thousands of participants.” So far details disclosed by several of the most advanced COVID-19 vaccine programs have pointed to Phase III enrollments of about 30,000 participants.

The report added that because pre-vaccination screening is unlikely to occur in the real world setting, Phase III trials should collect safety and efficacy data for both COVID-19-naive individuals -- the priority population for the study -- and patients who have previously been infected.

Trial length should also be at least one year to allow for sufficient safety data collection, with multiple interim readouts for futility.

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