Sputnik V phase 3 trial: Data discrepancies, substandard reports
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Restricted access to data hampers trust in research. Access to data underpinning study findings is imperative to check and confirm the findings claimed. It is even more serious if there are apparent errors and numerical inconsistencies in the statistics and results presented. Regrettably, this seems to be what is happening in the case of the Sputnik V phase 3 trial.
Several experts 3 , 4 found problematic data in the published phase 1/2 results. 2 We have made multiple independent requests for access to the raw dataset, but these were never answered. Despite publicly denying some problems, formal corrections were made to the Article, 2t hus addressing some concerns.5 Notwithstanding the previous issues and lack of transparency, the interim results from the phase 3 trial of the Sputnik V vaccine1 again raise serious concerns.
We have a serious concern regarding the availability of the data from which the investigators draw their conclusions. The investigators state that data will not be shared before the trial is completed, and then only by approval of stakeholders, including a so-called security department. Data sharing is one of the cornerstones of research integrity; it should not be conditional and should follow the FAIR principles.
The second concern pertains to the trial protocol, as already described in an open letter by the Russian Society for Evidence-Based Medicine.3 The Sputnik V investigators mention that three interim analyses were added to the study on Nov 5, 2020,1 but this change was not recorded on ClinicalTrials.gov (NCT04530396). Unfortunately, the full study protocol has not been made publicly available, so the rationale behind this change or the type I error rate adjustment, if any, is not known.
According to the ClinicalTrials.gov record NCT04530396, the primary outcome was changed on Sept 17, 2020. Initially, the primary outcome was to be assessed after the first dose, but the evaluation was postponed to after the second dose. The presented primary result (efficacy of 91·6%) is dependent on this change, but the reasons for the change have not been made public. Moreover, the latest ClinicalTrials.gov record (Jan 22, 2021) defines the primary outcome inconsistently: “Primary Outcome Measures: percentage of trial subjects…after the first dose…based on the percentage…after the second dose”.
Besides these protocol amendments, the definition of the primary outcome is unclear in the Article,
A final point of concern about the study protocol relates to the enrolment and randomisation of patients. According to the trial profile in figure 1 of the Article, 35 963 individuals were screened and 21 977 individuals were randomised. The ClinicalTrials.gov record for NCT04530396 (Jan 20, 2021) mentions that 33 758 patients were enrolled. We would expect that this last figure should be equal to either the number of participants screened or randomised. Moreover, there is no information about what caused the exclusion of 13 986 participants, as per the trial profile.
The third concern relates to the data reported and numerical results. We found the following data inconsistencies: (1) in figure 2 of the Article,
1data for the vaccinated group on day 20 refer to more individuals than at day 10, as if there was either information missing for 100 participants at day 10, or participants were enrolled after day 10 (figure 2 was formally corrected on Feb 20, 2021, but the correction statement did not state the reasons leading to such correction); and (2) in table S1 of the appendix, 1the number of participants reported for the different vaccinated age cohorts do not add up to the reported total (n=338 vs n=342).
We checked the homogeneity of vaccine efficacy across age groups (interaction tests): the p value of the Tarone-adjusted Breslow-Day test was 0·9963, and the p value of a non-asymptotic test was 0·9956, 6indicating a very low probability of observing a homogeneity this good if the actual homogeneity is perfect. By applying 18 other homogeneity tests (six in table 1, seven in table S6, six in table 2 of the Article 1), we could not find other major abnormality in the overall distribution of p values (appendix).
We also found some highly coincidental results reported in table S3 of the appendix. In particular, two upper confidence limit values for two different distributions (placebo group at baseline for unstimulated and antigen-stimulated measures) both equal 0·708. Of course, this is possible, but we call once more for access to the data from which the statistics originate for close scrutiny.
In line with our earlier concerns with the phase 1/2 results4and the substandard reporting of the phase 3 interim results,1we invite the investigators once more to make publicly available the data on which their analyses rely. Access to the protocol, its amendments, and the individual patient records is paramount, as much for clarification as for open discussion of all the issues.
We also invite the Editors of The Lancet to clarify the consequences of further denying access to the data needed for assessing the results presented, should the authors still deny it.
References
- 1.
- Logunov DY
- Dolzhikova IV
- Shcheblyakov DV
- et al.
Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia.
Lancet. 2021; 397: 671-681
- 2.
- Logunov DY
- Dolzhikova IV
- Zubkova OV
- et al.
Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomized phase 1/2 studies from Russia.
Lancet. 2020; 396: 887-897
- 3.
- Vlassov V
- Rebrova O
- Aksenov V
Commentary on the publication of preliminary results of the Sputnik-V vaccine phase 3 trial.
Date: Feb 5, 2021
Date accessed: February 18, 2021
- 4.
- Bucci E
- Andreev K
- Björkman A
- et al.
Safety and efficacy of the Russian COVID-19 vaccine: more information needed.
Lancet. 2020; 396: e53
- 5.
- Logunov DY
- Dolzhikova IV
- Tukhvatullin AI
- Shcheblyakov DV
Safety and efficacy of the Russian COVID-19 vaccine: more information needed—Authors’ reply.
Lancet. 2020; 396: e54-e55
- 6.
- Sangnawakij P
- Böhning D
- Holling H
On the exact null-distribution of a test for homogeneity of the risk ratio in meta-analysis of studies with rare events.
J Stat Comput Simul. 2021; 91: 420-434
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Dr Darko Butina
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The Lancet is an international journal which accepts research papers by the researchers from recognised research institutions. What we are witnessing now are concentrated attempts to discredited Sputnik V vaccine for purely political reasons which have nothing to do with science. The same journal has reported that Sputnik vaccine is the safest (by its mechanism of action) and most effective, The standard practices in publishing of scientific papers is the right to reply by the researchers who developed the vaccine and conducted the original trials before publishing such a damaging paper, which obviously it was not done in this case.
What the authors failed to do is to include the same detailed analysis of clinical trials of mRNA-based vaccines used in USA, Europe, UK and Canada and explain why so many side-effects and deaths are now being reported in western world and NOT in over 60 countries that use Sputnik V vaccine?
Just to remind readers about the paper published in The Lancet in February:
The Lancet: Sputnik V COVID-19 vaccine candidate appears safe and effective
• Ian Jones
• Polly Roy
Published: February 02, 2021DOI:https://doi.org/10.1016/S0140-6736(21)00191-4
Their Conclusion: “The development of the Sputnik V vaccine has been criticised for unseemly haste, corner cutting, and an absence of transparency.
But the outcome reported here is clear and the scientific principle of vaccination is demonstrated, which means another vaccine can now join the fight to reduce the incidence of COVID-19.
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Mark Tapley
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Another fake vaccine for the fake virus. The so called vaccine business is a bargain basement opportunity for easy money by the pharmaceutical crooks that are immune from all liabilities. Guaranteed profits as long as the idiots keep lining up and the criminal governments keep throwing tax money down the allopathic drain of corruption.
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Tom
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It is vitally imperative that all data must be exact as possible, all encompassing and relative to the trials when determining the usefulness and safety of any new vaccines or injections. These new injections must be tested thoroughly before blindly injecting them into any person. And that would be a first for big pharma. They want to avoid the required 5-10 years of trials and testing because they know their poisons would be voided and dismissed from consideration. They want the profits now! Gotta have those billions in profits before millions of potential customers are wiped off the face of the planet.
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Mark Tapley
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Hello Tom:
The only thing imperative is that truth about the fake virus, fake test, fake numbers and the latest blood toxin continue to be covered up as it has been since the first Rockefeller poison injection in he early staged of the vaccine scam over a hundred years ago. Thats why the Rockefeller’s founded the CDC and big Pharma in the first place and the Zionists have controlled all of the MSM since before WW1.
All of their schemes involve money up front for the insiders. Over 21,000 millionaires and billionaires were created in the U.S. just from the contrived WW1. Thats just icing on the cake. This bunch already has most of the wealth. The real goal is obtained when the plundering operation is complete. Its just a repackaged version of the same one that Zionist operative Marx (Moses Mordecai Levy) wrote about in his communist manifesto, now disguised as the Green Energy plan of Agenda 2030-21.
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Gus
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There is a very good reason why ” data will not be shared before the trial is completed, and then only by approval of stakeholders” and why they are not interested in “data sharing and following the FAIR principles”.
Level III trials cost a LOT of money, and involves collecting extremely valuable information (can’t commercialize a drug without that). It’s very rare that pharma companies share openly that data or protocols, as it’s a great way for competitors to catch up and even perhaps learn a few tricks they missed.
Only the relevant regulator gets to see that data, and only in very specific conditions & settings.
Has anyone found the protocol details and raw data for the mRNA vaccines level III trial?
I don’t think so!
Of course, one could say they have not done LIII trials (for a number of complex but valid real-world reasons – these are in progress…maybe), so you can’t get the data.
To confuse everyone, let’s obliterate the Russians who are doing LIII trials as they should!
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