Category: Oxford

• March 25, 2021 (Thursday): AstraZeneca announced results of the primary analysis of data from the Phase 3 clinical trial evaluating the Company’s COVID-19 vaccine candidate, AZD1222, being conducted in the United States, Peru, and Chile. A brief summary of the design of this study can be found in Table 1 on this website and the full study protocol can be found here.
  
  The primary efficacy analysis included data from 32,449 study participants. The study counted cases of laboratory-confirmed symptomatic COVID-19 that were diagnosed at least 15 days after participants received the second dose of the vaccine. A total of 190 cases were observed. The Company reported that the vaccine was 76% effective in preventing symptomatic COVID-19. The Company also reported that the vaccine was 100% effective in preventing severe COVID-19/hospitalization. A total of 8 cases of severe COVID-19 were observed – all among participants who received the placebo vaccine. No safety concerns were identified. These findings are quite similar to those reported on March 22, 2021.
  
  The Company noted that 14 additional cases of possible/probable COVID-19 have been identified among study participants. These cases are currently being reviewed by experts to determine if they meet the criteria for “laboratory-confirmed, symptomatic COVID-19”. The experts reviewing these cases do not which participants received the AZD1222 vaccine. After the status of these 14 cases is resolved, the estimate of vaccine efficacy could increase or decrease a few percentage points.
  
  AstraZeneca is likely to submit the full results of their primary analyses to the US Food and Drug Administration (FDA) as part of a request for an Emergency Use Authorization (EUA) for the AZD1222 vaccine within the next two weeks. The full report submitted to the FDA, as well as a report prepared by the FDA after reanalyzing study data, is likely to be made available to the public in late April.
  
• March 23, 2021 (Tuesday):  The National Institutes of Allergy and Infectious Diseases (NIAID) made the following announcement: “Late Monday, the Data and Safety Monitoring Board (DSMB) notified NIAID, BARDA, and AstraZeneca that it was concerned by information released by AstraZeneca on initial data from its COVID-19 vaccine clinical trial. The DSMB expressed concern that AstraZeneca may have included outdated information from that trial, which may have provided an incomplete view of the efficacy data. We urge the company to work with the DSMB to review the efficacy data and ensure the most accurate, up-to-date efficacy data be made public as quickly as possible. Authorization and guidelines for use of the vaccine in the United States will be determined by the Food and Drug Administration and Centers for Disease Control and Prevention after thorough review of the data by independent advisory committees.”
  
  In clinical trials, a DSMB is an independent panel of experts responsible for ensuring the quality of study design and implementation, as well as the safety of study participants. All of the COVID-19 vaccine clinical trials funded by the US government use the same DSMB. This DSMB has access to all of the data being collected. The DSMB can quickly stop a study if a study participant experiences an adverse event, determine whether the participant received the experimental vaccine or the placebo vaccine, and communicate with health care providers treating the participant to determine if the adverse event was likely to be vaccine related. DSMBs help to minimize bias when interpreting study results because DSMB members receive no funding from the vaccine manufacturers.Dr. Anthony Fauci appeared on Good Morning America today and briefly explained the background behind the NIH announcement. Although Fauci stated that information in the AstraZeneca press release on Monday, March 22^nd. might not be completely accurate, he continues to believe data for the vaccine look quite good. He also emphasized that the US Food and Drug Administration (FDA) carefully reviews all study data before issuing an Emergency Use Authorization for a vaccine. This serves as a reminder that many safeguards are in place in the US to prevent the authorization of vaccines that have not been shown to be safe and effective.

•  March 23, 2021 (Tuesday): In response to the NIAID announcement described above, AstraZeneca announced that the interim findings reported on Monday, March 22^nd. were based on data collected before February 17, 2021. The Company stated that they are now working on the primary analyses and intend to announce the results from those analyses within the next two days. The Company also stated that findings from the primary analyses appear to be consistent with the interim analyses reported on March 22^nd., but that the primary analyses have not yet been finalized.The timing of the announcement yesterday (Monday, March 22, 2021) is perplexing. According to the study protocol, the Company planned to perform the first interim analyses when 75 cases of symptomatic COVID-19 had occurred. They planned to perform the final analyses when 150 cases had occurred. This is similar to the study design used by Pfizer/BioNTech, Moderna, and Janssen (Johnson & Johnson). However, these other companies released findings from their interim analyses within days of when they reached the number of cases needed. It is not clear why AstraZeneca took over a month. In addition, the interim analyses included 141 cases of symptomatic COVID-19, nearly the number required for the primary analyses. Given that the Company is in the midst of finalizing the primary analyses, one has to wonder why they issued the press release yesterday based on interim findings.

• March 22, 2021 (Monday): AstraZeneca announced interim findings from a Phase 3 trial investigating the Company’s vaccine candidate, AZD1222. This study was conducted in the United States and involved over 30,000 participants. Two-thirds of the people in the study received two doses of the AZD1222 vaccine, administered 4 weeks apart. The remaining participants received two doses of a placebo vaccine. About 20% of the people in the study were age 65 years or older.The announcement stated that 141 cases of symptomatic COVID-19 had occurred among study participants. However, the announcement did not state how many of these cases were among those who received the AZD1222 vaccine. Instead, the announcement simply states that the vaccine was 79% effective in preventing symptomatic COVID-19. No participants who received the AZD1222 vaccine were hospitalized or developed severe COVID-19. However, the announcement does not indicate whether anyone who received the placebo vaccine developed severe disease or were hospitalized. This makes it difficult to interpret the Company’s claim of 100% efficacy in preventing severe disease/hospitalization. (A CNN report issued on Tuesday, March 23^rd. indicated that during a media briefing Dr. Anthony Fauci said that five cases of severe disease/hospitalization were reported in the placebo group.)
  
  The Company reported that no safety concerns had been identified. They looked at the risk of thrombotic events (blood clots) in detail and found no evidence that the AZD1222 vaccine increases the risk of thrombotic events among 21,583 participants who had received at least one dose of the vaccine. However, it is not clear why this safety information was presented for 21,583 participants, whereas efficacy analyses were based on more than 30,000 participants.
  
  The announcement stated that the Company is continuing to analyze the data and plans to submit results of the forthcoming primary analyses to the US Food and Drug Administration (FDA) as part of a request for an Emergency Use Authorization for the AZD1222 vaccine in the next few weeks.
• March 11-19, 2021: On March 11^th., the Danish Medicines Agency launched an investigation of the AstraZeneca vaccine (AZD1222) after reports of thromboembolic events (blood clots) in some people who had received the vaccine. As a precaution, the Agency placed a hold on use of the vaccine in Denmark until the investigation was completed. Over the next few days, several other countries followed suit and the European Medicines Agency (EMA) launched an investigation. On March 18^th., EMA issued a statement reporting the conclusions from its preliminary review. EMA’s safety committee reviewed instances of blood clots reported as of March 16^th. By that date, over 20 million people in the United Kingdom and the European Economic Area had received the vaccine. A total of 469 thromboembolic events have been reported after vaccination. (This includes thromboembolic events observed in clinical trials.) This number is lower than what would be expected based on how often people in the general public experience thromboembolic events. Therefore, the Committee concluded that the AstraZeneca vaccine does not increase the overall risk of blood clots. However, some uncommon types of blood clots were observed. Specifically, 7 cases of blood clots in multiple blood vessels (disseminated intravascular coagulation, DIC) and 18 cases of clots in the vessels draining blood from the brain (CVST) have been reported.  Most of these occurred in women under 55. These rates are higher than what would be expected in this age group. The Committee concluded that although the benefits of the vaccine continue to outweigh the risks, patients should be informed about the “remote” possibility (about 1 in a million) of developing DIC or CVST following vaccination. Product information for patients and health care providers is being updated to include more information about this possible risk. The following information for patients is taken directly from the EMA statement:
  

  COVID-19 Vaccine AstraZeneca is not associated with an increased overall risk of blood clotting disorders. There have been very rare cases of unusual blood clots accompanied by low levels of blood platelets (components that help blood to clot) after vaccination. The reported cases were almost all in women under 55. Because COVID-19 can be so serious and is so widespread, the benefits of the vaccine in preventing it outweigh the risks of side effects. However, if you get any of the following after receiving the COVID-19 Vaccine AstraZeneca: breathlessness, pain in the chest or stomach, swelling or coldness in a leg,1 severe or worsening headache or blurred vision after vaccination, persistent bleeding, multiple small bruises, reddish or purplish spots, or blood blisters under the skin, please seek prompt medical assistance and mention your recent vaccination.

  The World Health Organization (WHO) also conducted a thorough review of thromboembolic events following vaccination with the AstraZeneca vaccine. They issued a statement on March 19^th. that concurred with the EMA report, emphasizing that while it is not known whether the vaccine caused the rare cases of DIC and CVST, close monitoring of this possible risk is needed.

  Since these reports were issued, most countries have lifted the holds they put in place on using the AstraZeneca vaccine.

• January 5, 2021: The Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom published the full Public Assessment Report for the AstraZeneca vaccine candidate, AZD1222. It can be accessed here.
  
• December 30, 2020: The Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom granted temporary approval for the AstraZeneca vaccine candidate, AZD1222, to be used in the UK. The conditions for the approval are available here. The Information for Healthcare Professionals sheet contains information from the interim analyses reported on November 23, 2020. To the best of our knowledge, findings from the final efficacy analyses are not yet available.
  
• November 30, 2020: Since AstraZeneca released the findings from the first interim analysis for its COVID-19 vaccine candidate, AZD1222, on November 23^rd, it has been reported that the most promising finding announced by the company (90% efficacy among people who received a half dose of the vaccine, followed by a full dose one month later) occurred by mistake. No one in the study was supposed to receive a half dose of the vaccine before the full dose. A company spokesperson quoted by Reuters said that all participants were supposed to receive two full doses of the vaccine. However, that does not match the information the company provided in ClinicalTrials.Gov. According to ClinicalTrials.Gov, the study being conducted in the United Kingdom was designed to test: (1) a single full dose of the vaccine; (2) a single full dose of the vaccine, followed by a half dose “booster” 4-6 weeks later; (3) two full doses of the vaccine, separated by a 4-6 week period; and (4) a single half dose vaccine for children age 5-12. The study being conducted in Brazil was designed to test: (1) a single full dose of the vaccine and (2) two full doses of the vaccine, separated by a 4-12 week period.In addition, after the company released its interim findings, it was discovered that only participants who were 55 years old or younger had received the half dose vaccine. So, we have no way to know if the vaccine would have been equally effective in older adults, who are most likely to develop severe COVID-19.Astra-Zeneca did not initially disclose the dosing mistake, contending that it didn’t matter whether the dosing change was done on purpose or not. However, it does matter!Scientific studies are designed to test specific hypotheses. These hypotheses must be stated at the start of the study, before any data are collected. If the scientists discover other interesting things when they are conducting the study, they use these discoveries to develop new hypotheses and design new studies to test them. That is simply how the scientific process works. For this reason, the 90% efficacy reported for people who received the half dose vaccine should be viewed with skepticism.Notably, AstraZeneca has not published the full protocols for the studies being conducted in the United Kingdom or Brazil. Hopefully, they will make these available to the public soon. It would also be helpful to see the interim findings broken down by: (1) country (United Kingdom/Brazil), (2) age groups identified in the ClinicalTrials.Gov records for these studies, and (3) each dosing regimen examined.Despite these concerns, the interim analyses suggest that the 2 full dose regimen of AZD1222 may reduce the risk of developing symptomatic COVID-19 by 62%. This is better than the minimal threshold of 50% efficacy recommended by the Food and Drug Administration (FDA). Although this level of efficacy is lower than the vaccines developed by Pfizer and Moderna, the AstraZeneca vaccine can be stored at normal refrigerator temperatures (36-46° F) for at least six months and is less expensive to manufacture than the Pfizer and Moderna vaccines. Therefore, the AstraZeneca vaccine still has the potential to play a significant role in bringing the COVID-19 pandemic under control.
• November 23, 2020: AstraZeneca announced results from an interim analysis of its COVID-19 vaccine candidate, AZD1222. The analysis included data from studies being conducted in the United Kingdom and Brazil. A total of 131 COVID-19 cases were included in the interim analysis. The company reported findings from two different dosing regimens. Among participants who received a half-dose of the vaccine, followed by a full dose one month later, vaccine efficacy was 90%. Among participants who received a full dose of the vaccine followed by a full dose one month later, vaccine efficacy was 62%. These findings are difficult to interpret because data from two countries were combined and different dosage regimens are being tested in these countries. It would be helpful to have the efficacy estimates reported separately for each country. In addition, in both countries, the studies are also evaluating the efficacy of a single dose regimen. No data concerning the effectiveness of the single dose regimen were reported.  
• November 5, 2020: First results from Phase 3 trials for the AstraZeneca Oxford COVID-19 vaccine, AZD1222, are expected in the fourth quarter of 2020. (Note: This link opens to a slide presentation in pdf format. Information about AZD1222 appears on Slides 25 and 31.)
• October 23, 2020: Clinical trials for the AstraZeneca Oxford COVID-19 vaccine candidate, AZD1222, resumed in the United States after the Food and Drug Administration (FDA) completed review of all safety data from trials being conducted around the world and determined that it was safe to resume the trial.
• October 2, 2020: A Phase I/II clinical trial for the AstraZeneca Oxford COVID-19 vaccine candidate, AZD1222, resumed in Japan, with approval of the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Trials had previously been resumed in the United Kingdom, Brazil, South Africa, and India.
• September 12, 2020: Clinical trials for the AstraZeneca Oxford coronavirus vaccine candidate, AZD1222, resumed in the United Kingdom after the Medicines Health Regulatory Authority (MHRA) determined that it was safe to do so.
• September 9, 2020: A participant in a clinical trial for the AstraZeneca Oxford COVID-19 vaccine candidate, AZD1222, developed an unexplained illness. The illness was identified as part of standard procedures used in all clinical trials to ensure the safety of study participants. Immediately after the illness was identified, the developers voluntarily paused all clinical trials of the vaccine being conducted around the world. In an interview with NBC News, Dr. Francis Collins, Director of the National Institutes of Health, identified the illness as transverse myelitis and explained that the illness may not have been caused by the vaccine. In large clinical trials, illnesses often happen by chance. This pause in the study will allow data safety committees and regulatory agencies like the FDA an opportunity to review data from the trials to determine if it is safe to continue enrolling participants.
• August 31, 2020: Enrollment began in the US Phase 3 trial for the AstraZeneca Oxford COVID-19 vaccine candidate, AZD1222.  Phase 3 trials of AZD1222 had begun previously in the UK, Brazil and South Africa.

Around the World

• October 1, 2020: The European Medicines Agency (EMA) announced that it had started a “rolling review” of data from studies involving AstraZeneca’s vaccine candidate, AZD1222. The EMA is the equivalent of the Food and Drug Administration in the United States. According to the EMA announcement, “A rolling review is one of the regulatory tools that EMA uses to speed up the assessment of a promising medicine or vaccine during a public health emergency. Normally, all data on a medicine’s effectiveness, safety and quality and all required documents must be submitted at the start of the evaluation in a formal application for marketing authorisation. In the case of a rolling review, EMA’s human medicines committee (CHMP) reviews data as they become available from ongoing studies, before a formal application is submitted. Once the CHMP decides that sufficient data are available, the formal application should be submitted by the company. By reviewing the data as they become available, the CHMP can reach its opinion sooner on whether or not the medicine or vaccine should be authorised.”