US phase 3 results enable FDA review of the Oxford/AstraZeneca vaccine

1 April 2021. Related: COVID-19: vaccine research, COVID-19.

Simon Collins, HIV i-Base

After an unexpected series of announcements the Oxford/AstraZeneca vaccine looks ready for FDA regulatory review in the US, almost three months after approval in the UK.

This study provides an important data set with constant and consistent dosing. Earlier phase 3 studies had used half dosing and extended dosing periods in UK participants, although this did not prevent approval in the UK and EU.

First, on 22 March 2021, US NIH and AstraZeneca both issued press releases reported 79% efficacy against symptomatic COVID-19. This was from a planned interim analysis from a phase 3 study that was run in the US and South America. [1, 2]

However, this prompted a letter from the NIH Data and Safety Monitoring Board (DSMB) for the study suggesting efficacy rates of 69% and 74%. A second NIH press release reported that the DSMB claimed AstraZeneca had selected inappropriately positive results. [3] The company responded with a short statement that the interim results were planned but the full results would be available within two days. [4]

Then on 25 March, the updated results based on the full data set reported 76% efficacy (95%CI: 68% to 82%) against symptomatic COVID-19. [5]

Other results from the full analysis included 100% efficacy against severe and critical disease and hospitalisation (0 vs 8 cases in active vs placebo) and 85% efficacy (CI: 58% to 95%) against symptomatic COVID-19 in participants aged 65 and older.

These results included an additional 49 cases – now totaling 190 from almost 32,500 participants (randomised 2:1 for active:placebo). They are all broadly consistent with the interim analysis published a couple of days earlier.

Symptomatic cases were reported two weeks after the second vaccination, with doses given four weeks apart.

Baseline characteristics included 60% having higher risk health complications (diabetes, obesity etc). Approximately 80% were white and 8% African American and 4% Native American.

The vaccine was well tolerated, with no safety concerns, including for blood clots.

comment

The most important outcome is that this vaccine will now be submitted to the US FDA.

However, no-one has commented on the four-week dosing schedule in the US study. The earlier UK study that separated doses by 12 weeks reported this longer schedule as a factor for 90% efficacy. Indeed, this data was used to support the 10-12 week schedule currently used in the UK.

The motivation for the highly unusual action by the DSMB is not clear, but it hasn’t been helpful. To publicly question study results and then be so far out with their own prediction is particularly questionable.

As this group should know the data most closely, they should now explain the urgency for them to have undermined confidence in this vaccine. They should also explain how their own efficacy assertions were so wrong.

References

1. NIH press release. Investigational AstraZeneca vaccine prevents COVID-19. (22 March 2021).
   https://www.nih.gov/news-events/news-releases/investigational-astrazeneca-vaccine-prevents-covid-19
2. AstraZeneca press release. AZD1222 US Phase III trial met primary efficacy endpoint in preventing COVID-19 at interim analysis. (22 March 2021).
   https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/astrazeneca-us-vaccine-trial-met-primary-endpoint.html
3. NIH second statement. NIAID Statement on AstraZeneca Vaccine (23 March 2021)
   https://www.nih.gov/news-events/news-releases/niaid-statement-astrazeneca-vaccine
4. AstraZeneca press release. Update following statement by NIAID on AZD1222 US Phase III trial data. (23 March 2021).
   https://www.astrazeneca.com/media-centre/press-releases/2021/update-following-statement-by-niaid-on-azd1222-us-phase-iii-trial-data.html
5. AstraZeneca press release. AZD1222 US Phase III primary analysis confirms safety and efficacy. (25 March 2021).
   https://www.astrazeneca.com/media-centre/press-releases/2021/azd1222-us-phase-iii-primary-analysis-confirms-safety-and-efficacy.html

This report was first published on 25 March 2021.