Lack of data on Sputnik V vaccine delays EMA approval

(Corrects paragraph 27 of the July 13 article to clarify the number of sources. Three of the sources familiar with the delegation's findings, not four as the article indicates, said that the information showed that fetal bovine serum had been used to feed the master cell bank and that the developers had not documented the origin of the serum.One of the three sources clarified that the information was contained in documents and not four.)

by Michel Rose, PolinaIvanova and Emilio Parodi

PARIS (Reuters) - The developers of Russia's Sputnik V COVID-19 vaccine have repeatedly withheld data that European regulators consider standard requirements of the vaccine approval process. drugs, according to five sources familiar with the matter.

Reuters reported last month that the European Medicines Agency (EMA) validation of the Russian vaccine was delayed due to a lack of timely submission of clinical trial data due on June 10, according to a source close to the agency and a second familiar with the matter.

According to the source close to the EMA, the problems go beyond this single deadline. By early June, the agency had received virtually no manufacturing data and the clinical data it had was incomplete.

Furthermore, an evaluation of Sputnik V by a French delegation of scientists prior to EMA review found that the vaccine developers were unable to prove that the master cell bank, the element base of the vaccine, complied with specific European regulations on the prevention of disease contamination, according to four people with knowledge of the delegation's findings.

The EMA, which launched its official assessment of the Russian vaccine in March, would normally have decided in May or June whether or not to allow the drug to be used in the EU.

Notably missing clinical information from the EMA review included forms for reporting adverse reactions patients experienced after receiving the vaccine in trials, according to the source close to the EMA .

She added that developers are used to submitting these forms. Additionally, it was also unclear how scientists working on the vaccine tracked those who received a placebo, she added.

The watchdog assesses these shortcomings on a scale that ranges from "critical", the most serious, to "major" and then "minor". According to the source close to the EMA, nothing had reached the critical threshold, "but there are several 'major'", indicating problems that can be corrected but require a lot of work. She added that she did not expect the exam to be completed until the summer.

Several people who have had contact with the Russian Gamaleya Institute, which developed Sputnik V and oversaw clinical trials, attribute the repeated inability to provide certain information to lack of experience in dealing with regulators strangers. “They are not used to working with a regulatory agency like the EMA,” said the person close to the agency, referring to scientists from Gamaleya, an institute supervised by the Russian Ministry of Health.

Neither Gamaleya nor the ministry responded to questions. The Kremlin also declined to answer questions from Reuters.

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

RDIF said the Reuters investigation contained "false and inaccurate statements" based on unnamed sources attempting 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.

The investment fund added that the vaccine is registered in more than 60 countries and that studies in countries such as Argentina, Mexico and Hungary, which already use it, show that it is safe and effective. “No serious adverse events were reported,” he added.

Regarding the findings of the French delegation that visited Moscow, RDIF said that "the Sputnik V cell bank fully complies with all EMA requirements."

The RDIF added that it was working closely with the EMA, whose inspectors visited the Sputnik V production facilities. of the questions raised casts doubt on the safety and efficacy of the vaccine," RDIF said.

One of the sources familiar with the matter said she had no reason to doubt that Sputnik V is a safe and effective vaccine. A study conducted by international scientists and published in the international medical journal The Lancet in February concluded that Sputnik V was more than 90% effective.

The Amsterdam-headquartered EMA declined to comment on details of the ongoing assessment. The agency said it applies the same standards to all applicants and to authorize a COVID-19 vaccine it needs "detailed information about its safety, efficacy and quality".

The delay could allow competing vaccine makers to capture key markets as Sputnik V developers face several hurdles in evaluating the vaccine by some foreign drug regulators, who have noted a lack of data, insufficient documentation of methodology, and failure to follow what they consider standard protocol.

Brazilian regulators initially rejected imports of Sputnik V after technical staff noted "inherent risks", citing a lack of data guaranteeing 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 to the vaccine.

Hungary has granted emergency authorization for the vaccine, despite concerns about insufficient documentation raised by some specialists working on its evaluation at the Hungarian medicines regulator, sources familiar with folder.

Last month, Brazilian regulator Anvisa conditionally cleared Sputnik V imports. vaccine," Anvisa told Reuters. He added that Sputnik V has not yet been distributed to the Brazilian population.

When it approved Sputnik V in January, the Hungarian regulator publicly acknowledged that there could be conflicting opinions during the licensing process and that it had received reassuring answers to its questions about the vaccine . The Slovak government said this month that it had sold most of its doses of Sputnik V back to Russia, citing low interest.

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CELL CULTURE

Sputnik V is named after the Russian satellite that sparked the Soviet-era space race, and evokes the project's geopolitical significance to President Vladimir Putin. EMA approval would lend legitimacy to the vaccine, which initially met with skepticism from some Western scientists and politicians, and speed up its availability in Europe.

Moscow's efforts to secure EU approval ran into obstacles long before Russia could submit its case.

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

Three of the four sources with knowledge of the delegation's findings said that information from Gamaleya that the scientists had access to showed that fetal bovine serum had been used to feed the master cell bank and that the developers had no not documented the origin of the serum.

According to one of these three sources, this information was contained in the documents of the vaccine developer. The fourth source with knowledge of the delegation's findings said there was a problem with the compliance of the cells used in the development of the vaccine with European rules.

After this article was published, the RDIF said in a statement that the claim about the use of untraceable bovine serum was "false", without going into details.

Fetal bovine serum is commonly used around the world for vaccine development. But since the outbreak of mad cow disease in the 1980s, European and North American regulators have required vaccine developers to document serum traceability.

French scientist Cecil Czerkinsky is one of four sources familiar with the work of the French delegation in Moscow and is a member of an international advisory board set up by the RDIF. He was informed informally of the delegation's concerns regarding the master cell bank. The French team felt "frustrated" with the responses they received when they asked vaccine developers about it, the scientist told Reuters.

After the article was published, Cecil Czerkinsky said in an email that since his last conversation with Reuters in May, it had been "scientifically refuted" that the Sputnik vaccine presented a potential problem with the parent cell and the fetal bovine serum. He did not respond to a question from Reuters asking who refuted the information.

He also said in the same email that "the safety of the Sputnik vaccine is also difficult to dispute after it has been given to people in a number of countries."

The French delegation has informally shared its findings, including its questions regarding the mother cell, with the EMA, one of the sources said.

RDIF told Reuters that the Gamaleya Institute "has never used 'untraceable bovine serum' for cell bank preparation." He added that the Sputnik V cell bank has been independently checked to make sure it does not contain prions, the proteins associated with diseases like mad cow disease. The RDIF did not specify who carried out this independent verification.

In early March, the EMA announced the launch of a "rolling review" of Sputnik V, a faster process that checks data as it comes in. But the drug's developers did not submit the first data until a month later, which delayed the process in the early stages, said a French government official briefed on the matter.

The French health and research ministries, which sponsored the delegation to Moscow, did not respond to a request for comment on the delegation's findings.

BRAZILIAN CAUTION

The rejection of Sputnik V imports by Brazil's health watchdog Anvisa in April sparked a heated public exchange with RDIF, which threatened to sue the regulator for defamation.

A crucial question for Anvisa concerned adenovirus, the virus that causes colds and is used in Sputnik V to carry information in the body that triggers an immune response. Anvisa has publicly stated that there is a risk that the adenovirus present in Sputnik V will replicate, which could cause a negative reaction in recipients. Anvisa's head of drugs and biologics called the possibility a "serious" defect. Russia said there was no evidence of replication and that Anvisa misinterpreted the documentation.

Sergio Rezende, a former science minister who advises governors of Brazilian states wishing to import the Russian vaccine, said that in discussions with Gamaleya, the latter did not seem to know the expectations of Brazilian regulatory authorities. Sergio Rezende told Reuters he urged the Russians to rework their request, which they initially refused to do but eventually did.

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

Regarding the possibility of the adenovirus reproducing, Anvisa clarified that the studies and documents provided by Gamaleya indicated "the occurrence of reproducing adenovirus" and that there was no assessment of the relationship between this characteristic and the safety of the vaccine. 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 “has confirmed that no replicating adenovirus (RCA) has ever been found in any of the batches of Sputnik V vaccines that have been produced.”

Corrects paragraph 27 of the July 13 article to clarify the number of sources. Three of the sources familiar with the delegation's findings, and not four as the article indicates, said the information showed that fetal bovine serum had been used to feed the master cell bank and that the developers had no not documented the origin of the serum. One of the three sources clarified that the information was contained in documents and not four.

(Reporting Michel Rose in Paris, Polina Ivanova in Moscow and Emilio Parodi in Rome; with contributions from Matthias Blamont in Paris, Lisandra Paraguassu in Brasilia, Stephen Eisenhammer in Sao Paulo and Marton Dunai in Budapest; written by Christian Lowe; French version Kate Entringer, edited by Sophie Louet and Jean-Michel Bélot)

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