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.1Several experts3, 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,2 thus 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,1 where it says that when COVID-19 was suspected, participants were assessed with “COVID-19 diagnostic protocols, including PCR testing”. Here, we lack some crucial information, such as the clinical parameters determining suspected COVID-19, what diagnostic protocols were used, when the PCR testing was done, what specific method was used, or how many amplification cycles were used. The way cases of suspected COVID-19 were defined could have led to bias in PCR testing used to assess the number of confirmed COVID-19 cases, which is crucial for the efficacy determination.
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,1 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,1 data 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,1 the number of participants reported for the different vaccinated age cohorts do not add up to the reported total (n=338 vs n=342). With such inconsistencies, we question the accuracy of the reported data.
Clear and transparent regulatory standards exist for provision of clinical trial data, including data reported in clinical study reports that are considered sufficient for regulatory review and approvals. The reporting of the interim analysis1 in the phase 3 Sputnik V clinical trial fully complies with those standards. It is on this basis that Sputnik V has received registration in 51 countries, which confirms our full transparency and compliance with regulatory requirements.
The amendment was made to the protocol on Nov 5, 2020. The complete protocol, as amended (Section 10.4 Interim Analysis and Statistical Significance Level Applied), was submitted to The Lancet along with the rest of the documents for review.
Efficacy is assessed within 6 months after first dose (time of observation of study participants); however, the calculation of the primary outcome is based on the number of cases of COVID-19 in participants who received both doses (after second dose), as indicated in the protocol. This is consistent with the primary outcome of other studies.
weehingthong 