PARIS, July 13 (Reuters) – Developers of the Russian coronavirus vaccine Sputnik V have repeatedly failed to provide data that regulators see as standard requirements of the drug approval process, according to five people familiar with European efforts to evaluate the drug, providing new insight into the country’s struggle to gain foreign acceptance for its product.

Reuters reported last month that the European Medicines Agency’s (EMA) review of the drug’s safety and efficacy was delayed because the June 10 deadline for submitting clinical trial data for the drug. vaccine had not been adhered to, according to one of those people, who is close to the agency and another person familiar with the case. The EMA is the European Union’s watchdog for medicines.

The snags go beyond that single deadline, the person close to the agency said. As of early June, the EMA had received virtually no manufacturing data and the clinical data the agency received was incomplete, the person said.

Separately, an assessment of Sputnik V by a French delegation of scientists ahead of the EMA review found that vaccine developers were unable to prove that the so-called master cell bank, the building block initial vaccine, complied with specific European regulations. on preventing disease contamination, according to four people familiar with the delegation’s findings.

The EMA, which launched its formal review of the Russian vaccine in March, was previously scheduled to decide in May or June whether or not to approve the drug for use in the EU.

The person close to the EMA said that notable missing clinical information during the EMA review included case report forms that record any side effects people experience after receiving the jab in the trials. It is standard practice for developers to submit such forms, the person added. It was also not clear how scientists working on the vaccine tracked the results of people given a placebo, the person said.

The Watchdog rates these data gaps on a scale from “critical” – most serious – to “major” to “minor”. The person said nothing had hit the critical threshold, “but there are several ‘majors’,” indicating issues that can be fixed but require a lot of work. The person added that they did not expect the exam to be completed until the summer.

Several people who have interacted with the Russian Gamaleya Institute, which developed Sputnik V and oversaw clinical trials, attribute the repeated failure to provide certain information to lack of experience in dealing with foreign regulators. “They are not used to working with a regulatory agency like the EMA,” said the person close to the agency, referring to scientists at Gamaleya.

Gamaleya is supervised by the Russian Ministry of Health. Neither Gamaleya nor the ministry responded to questions for this report. The Kremlin declined to comment.

Sputnik V is marketed abroad by the Russian sovereign wealth fund, called the Russian Direct Investment Fund (RDIF).

RDIF said the Reuters reports contained “false and inaccurate statements” based on anonymous sources trying to harm Sputnik V as part of a disinformation campaign. The RDIF suggested that the vaccine could be attacked by the “Western pharmaceutical lobby”, without providing evidence of such a campaign.

RDIF added that the vaccine is registered in more than 60 countries and that studies in places like Argentina, Mexico and Hungary that already use the vaccine show it to be safe and effective. He said there had been “no serious adverse events reported”.

On the conclusions of the French delegation, the RDIF declared that “the Sputnik V cell bank fully complies with all the requirements of the EMA”.

The RDIF said it was working closely with the EMA, whose inspectors visited the production facilities of Sputnik V. “Based on the inspections already completed, we have not received any major critical comments and none of the issues raised did not cast doubt on the safety and effectiveness of the vaccine, ”said RDIF.

One of those familiar with European efforts to evaluate the drug said she had no reason to doubt that Sputnik was a safe and effective vaccine. A study by international scientists published in The Lancet in February found that Sputnik was over 90% effective.

The Amsterdam-headquartered EMA declined to comment on the details of the review while it is underway. The agency said it applies the same standards to all applicants and to authorize a COVID-19 vaccine, the EMA requires “detailed information on its safety, efficacy and quality.”

The delay could allow rival vaccine makers to capture key markets. The stumble is one of many for the developers of Sputnik V in the treatment of some overseas drug watchdogs reviewing the vaccine, which identified a lack of data, insufficient documentation of methodology, and non- adherence to what they consider to be standard protocol.

Brazilian regulators initially rejected imports of Sputnik V after technical staff highlighted “inherent risks”, citing a lack of data to ensure its safety, quality and effectiveness. The Slovak drug agency said it did not have sufficient data from Moscow before the government finally gave a limited green light for the vaccine. Hungary has given emergency approval for the jab despite what several people familiar with the process said were concerns expressed by some specialists working on the Hungarian Medicines Regulatory Authority’s review regarding insufficient documentation .

Brazilian regulator Anvisa last month gave conditional approval for imports of Sputnik V. The conditions imposed “aim to fill information gaps in the process and ensure minimum conditions for vaccine safety and quality.” , Anvisa told Reuters. He added that Sputnik V has not been distributed to people in Brazil.

The Hungarian regulator, when approving Sputnik V in January, publicly acknowledged that there can be conflicting opinions during a licensing process and received reassuring answers to its questions regarding the vaccine. The Slovak government said this month it has sold most of its Sputnik V to Russia, citing low interest.

CELL CULTURE

Sputnik V takes its name from the Soviet-era satellite that started the space race, in a nod to the project’s geopolitical importance to Russian President Vladimir Putin. EMA approval would give legitimacy to the vaccine, which initially faced skepticism from some Western scientists and politicians, and speed up its availability in Europe.

Moscow’s efforts to secure EU approval encountered obstacles before submitting its application.

In November 2020, the French government dispatched a team of scientists to Moscow to help Paris decide whether to use Sputnik V and manufacture the drug on French soil, if approved by the EMA.

The four people familiar with the delegation’s findings said documents reviewed by scientists showed fetal bovine serum had been used in the culture to nourish the master cell bank and the developers had not documented the origin. serum.

Fetal bovine serum is widely used worldwide for vaccine development. But since the outbreak of mad cow disease in the 1980s, regulators in Europe and North America have required vaccine developers to document that it is a safe source.

One of four people familiar with the work of the delegation is French scientist Cecil Czerkinsky, a member of an international advisory board set up by RDIF and who was separately briefed on the delegation’s concerns regarding the master cell bank. . The French team felt “frustrated” by the responses they received when they asked vaccine developers about the problem, Czerkinsky told Reuters.

The French delegation informally shared their findings – including their questions regarding the master cell – with the EMA, one of the people said.

RDIF told Reuters that the Gamaleya Institute “has never used” non-traceable bovine serum “for the preparation of cell banks.” He added that the Sputnik V cell bank has been independently verified not to contain prions – proteins associated with conditions such as mad cow disease. RDIF did not identify who performed the independent verification.

The EMA announced in early March that it was launching a “continuous review” of Sputnik V, a faster process that checks data as it lands. But the drug’s developers did not submit the first data until a month later, delaying the process in the early stages, a French government official briefed on the matter said.

The French Ministries of Health and Research, which sponsored the delegation to Moscow, did not respond to a request for comment on the delegation’s findings.

BRAZILIAN ATTENTION

Brazilian regulator Anvisa’s rejection in April of Sputnik V’s imports kicked off a difficult public exchange with RDIF, which threatened to sue the Brazilian agency for defamation.

A crucial issue for Anvisa is related to adenovirus, the virus that causes colds and which is used in Sputnik V to carry information around the body that triggers an immune response. Anvisa has publicly stated that there is a risk that the adenovirus in Sputnik V could replicate, potentially causing a negative reaction in recipients. Anvisa’s head of drugs and biologics called the possibility a “serious” defect. The Russians said there was no evidence of aftershocks and that Anvisa had misinterpreted the documentation.

Sergio Rezende, a former science minister advising governors of Brazilian states looking to import the Russian vaccine, said that during talks with Gamaleya, the Russians seemed unfamiliar with the expectations of Brazilian regulators. Rezende told Reuters he urged the Russians to rework their candidacy, which they initially resisted but ultimately did.

Anvisa told Reuters that its requirements “are aligned with the regulations of other benchmark agencies around the world.”

Regarding the possibility of adenovirus recurrence, Anvisa said studies and materials provided by Gamaleya indicated “the occurrence of adenovirus replication” and lacked adequate assessment of the relationship between this and vaccine safety. Anvisa added that the conditions it imposed included demonstrating the absence of replication in all batches sent to Brazil.

RDIF, in its responses to Reuters, said Gamaleya “confirmed that no replicable adenoviruses (RCA) were ever found in any of the Sputnik V vaccine lots that were produced.”

Reporting by Michel Rose in Paris, Polina Ivanova in Moscow and Emilio Parodi in Rome; Additional reporting by Matthias Blamont in Paris, Lisandra Paraguassu in Brasilia, Stephen Eisenhammer in Sao Paulo and Marton Dunai in Budapest; Written by Christian Lowe; Editing by Cassell Bryan-Low

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