Foreign rare advance announcement of the new crown vaccine trial program for a glimpse.

Author . . . On September 6th, a serious adverse event occurred in a phase II/III clinical trial (NCT04400838, COV002) in the UK, triggering the suspension of the vaccine's global Phase III trial.
, however, AstraZeneta and Oxford University, as developers of vaccines, did not disclose information in a timely manner.
AstraZeneta issued a statement on its website the next day after several US media outlets disclosed the suspension of the AZD1222 Global Phase III trial on September 8, but did not disclose the specifics of the serious adverse events.
12 September, the AZD1222 was approved by the MHRA, the UK's drug regulator, to resume Phase III trials, but has not yet been resumed in other countries.
incident caused a stir abroad, leading to the whole society's trust crisis in pharmaceutical companies.
are calling on new crown vaccine developers to be more transparent about their information, including the disclosure of Phase III trials.
public pressure, Moderna first announced the Phase III trial (NCT04470427) of the vaccine candidate mRNA-1273 on September 17.
Pfizer followed suit on the 17th to announce the candidate vaccine BNT162b2 I/II/III trial (NCT04368728) program.
AstraZeneta announced the U.S. Phase III trial (NCT04516746) of the vaccine candidate AZD1222 on September 20.
The essence of the clinical trial program is a blueprint for clinical trials, detailing how to select the participants in the trial (entry criteria), how to conduct the trial (blind method, grouping, control, etc.), how to use the experimental drug (frequency, dose, sequentia/simultaneous, etc.), how to decide as early as possible whether to continue the trial (in-period analysis, statistical analysis method), and how to determine efficacy and safety (end point, adverse events), etc.
the trial is usually kept strictly confidential between the end of the clinical trial.
the three leading candidates for the new crown vaccine have been publicly tested, a rare move aimed primarily at dispeling public doubts.
growing public concern that the safety and versus effectiveness of the vaccine have been approved for sale without adequate validation, under pressure from U.S. President Donald Trump to provide a new crown vaccine before Election Day (November 3).
's three trials compared to modelna, Pfizer and AstraZeneta clinical trials recruited healthy subjects, randomly divided into two groups, receiving candidate new crown vaccines and placebos, then returning to real-world life, conducting regular follow-up follow-up, and conducting in-phase analysis when a certain number of cases (events) of new coronavirus infections were conducted to determine as early as possible whether the vaccine's effectiveness met the requirements and whether clinical trials were necessary to continue.
Chart 1. Comparison of three clinical trial scenarios: Company Announcement, China Health Industry Capital Research Center, FDA requirement that the new crown vaccine be at least 50% effective, which is the minimum requirement for obtaining emergency use permits (EUAs) rather than the normal requirement for vaccine efficiency.
AstraZeneta's performance target line is set at 0.5, while Moderna and Pfizer have an effect target of 0.6, with a potentially lower clinical trial success rate.
the three trials were all new coronavirus infections, which are determined by symptoms and new coronavirus nucleic acid RT-PCR tests, according to the U.S. Centers for Disease Control and Prevention (CDC).
Chart 2. New Coronavirus Infection Determination Criteria As prescribed by the CDC Source: CDC, China Health Industry Capital Research Center, and three clinical trial programs have selected slightly different primary endpoints based on the CDC's New Coronavirus New Infection Determination Criteria.
Chart 3. The main endpoint sources for the three clinical trials: company announcement, mid-term analysis of the three trial options of the Zhongkang Industrial Capital Research Center, and in Modelna's Phase III clinical trial, the treatment group injected two candidate vaccines, mRNA-1273, on the first and 29th days, respectively.
to determine the effectiveness of the vaccine, Moderna's Phase III trial counted cases of new coronavirus infection only 2 weeks after the second injection.
when the total number of new coronavirus infections in the treatment and control groups reaches 151, it is sufficient to determine whether the vaccine candidate is 60% effective.
an in-period analysis was conducted at 35 per cent and 70 per cent of the total target cases (151) when the total number of infections in the treatment group plus control group was reached.
in-phase analysis is to detect reliable evidence of vaccine effectiveness (vaccineefficacy, VE) of more than 30% early.
In Moderna's statistical analysis, the O'Brien-Fleming consumption function is used to calculate the effect boundary and guarantees that the one-sided false positive error rate for in-period analysis and primary analysis (when the target number of cases is observed) is no higher than 0.025, compared to the hypothesis H0:HR≥0.7 (equivalent to ratio risk VE≤0.3).
Chart 4. The effect boundary sources of each analysis of the Moderna pilot scheme: Company announcement, in-period analysis 1 in the table above of the China Health Industry Capital Research Center means that when the cumulative number of cases reaches 53, if the vaccine effect (VE) ≥0.741, then the trial can be stopped, based on the available evidence to apply to the FDA for emergency use permit (EUA);
, if VE≥0.565 can stop the test and submit it to THEA, if VE≥
when the cumulative number of cases reaches 151, if the VE-lt;0.495, it means that the trial fails.
Modelna's trial program allows trials to be stopped as early as possible in a relatively small number of cases, which can lead to exaggerated awareness of vaccine efficacy and neglect of safety issues.
if millions of people are vaccinated in the future, safety problems could become very serious.
For the Pfizer/BioNTech phase II/III trial of vaccine BNT162b2, the number of patients in the treatment and control groups was equal, with one injection each on the first and 22nd days, followed by observations of new coronavirus infections 7 days after the second injection.
Pfizer's pilot program consists of four in-phase analyses conducted by a non-blind statistical team when the cumulative number of cases reaches 32, 62, 92 and 120.
Pocock consumption function for the phase II/III trial of BNT162b2.
analysis of each period, the calculated success criteria guarantee that the probability of Class I errors is no higher than 2.5%.
Chart 5. In-period analysis of the Pfizer pilot program Source: Company Announcement, China Health Industrial Capital Research Center compared to Moderna, Pfizer's pilot program is more aggressive, set up up to 4 in-period analysis, in the cumulative number of cases at least 32, if the vaccine effect VE point, that is (placebo group number of cases - number of vaccine group cases) / placebo group number of cases ≥76.9%, can be submitted to the FDA emergency permit application.
this condition is not met, the trial continues and the same is said for subsequent in-period analysis.
approval of EUA in a smaller cumulative case, although there is a risk of safety, it is unethical to allow some subjects to continue receiving a placebo while the trial has shown that the vaccine is effective enough.
AstraZeneta's trial program is completely different from the previous two, with only one in-phase analysis set up in 75 cumulative cases to pre-stop clinical trials of the candidate vaccine AZD1222 and submit emergency approvals to the FDA.
addition, AstraZeneta's pilot scheme uses the Lan-DeMets consumption function to calculate the level of α.
for the trial group, the vaccine group and the placebo group had a ratio of 2:1, with one dose injected on the first and 29th days, respectively, to observe and count new coronary infections from the first day.
the results of the three pilot schemes are set up mid-term analysis, and after the mid-term analysis are likely to apply for emergency use permits.
how long it takes to reach the number of cases analyzed in the in-period depends on the prevalence trajectory of the outbreak and how likely the test participants are to be exposed to the virus.
, of course, it is also likely that, as AstraZeneta did, the trial could be suspended due to serious adverse events caused by the participants, causing the trial to lag behind.
Zaks, Moderna's chief medical officer, and Mr. Bancel, the CEO, said in a media interview that the first mid-term analysis was unlikely to take place before November.
Zaks said it was theoretically possible that the candidate vaccine mRNA-1273 would be effective enough through the first in-phase analysis, but the probability might not be high.
Pfizer said it would only share information about the analysis if it decided to stop the trial, either the candidate vaccine BNT162b2 was very effective or ineffective.
, Pfizer CEO Albert Bourla has repeatedly assured people that the results will be tested in October.
AstraZeneta's CEO Pascal Soriot believes the vaccine candidate, AZD1222, will be approved by the end of 2020.
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