The developers of Russia's Sputnik V coronavirus vaccine have repeatedly failed to provide data that regulators deem to be standard requirements of the drug approval process, according to five people with knowledge of European efforts to assess the drug, providing new insight into the country's struggle to win foreign acceptance of its product.
Reuters reported last month that the European Medicines Agency (EMA)'s review of the drug's safety and efficacy was delayed because a June 10 deadline to submit data on the vaccine's clinical trials was missed, according to one of those people, who is close to the agency, and another person familiar with the matter. The EMA is the European Union's medicines watchdog.
The hitches go beyond that one deadline, the person close to the agency said. As of early June, the EMA had received hardly any manufacturing data, and the clinical data the agency had received was incomplete, the person said.
Separately, an assessment of Sputnik V by a French delegation of scientists in advance of the EMA review found that the vaccine developers were unable to document that the so-called master cell bank, the initial building block of the vaccine, complied with specific EU regulation on preventing disease contamination, according to four people with knowledge of the delegation's findings.
The EMA, which launched its formal review of the Russian vaccine in March, had previously been expected to decide in May or June whether to approve use of the drug in the EU.
The person close to the EMA said notable missing clinical information during the EMA review included case report forms that record any adverse effects people experienced after receiving the jab in trials. It is standard practice for developers to submit such forms, this person added. It was also not clear how the scientists working on the vaccine tracked the outcomes of people given a placebo, the person said.
The watchdog rates such data shortcomings on a scale that goes from "critical" - the most serious - to "major" to "minor." The person said nothing had met the critical threshold, "but there are several 'majors,'" indicating issues that can be remedied but require much work. The person added they didn't expect the review to be completed until after the summer.
Several people who have interacted with Russia's Gamaleya Institute, which developed Sputnik V and oversaw the clinical trials, attribute the repeated failure to provide some information to lack of experience in dealing with overseas regulators. "They are not used to working with a regulatory agency like the EMA," the person close to the agency said, referring to Gamaleya's scientists.
Gamaleya is supervised by Russia's health ministry. Neither Gamaleya nor the ministry responded to questions for this report. The Kremlin declined to comment.
Sputnik V is marketed overseas by Russia's sovereign wealth fund, called the Russian Direct Investment Fund (RDIF).
RDIF said Reuters' reporting contained "false and inaccurate statements" based on anonymous sources who are attempting to harm Sputnik V as part of a disinformation campaign. RDIF suggested the vaccine could be under attack by the "Western pharmaceutical lobby," without offering evidence of such a campaign.
RDIF added that the vaccine is registered in more than 60 countries and that studies from places including Argentina, Mexico and Hungary that are already using the vaccine show it is safe and effective. It said there had been "no reported serious adverse events."
On the French delegation's findings, RDIF said "the Sputnik V cell bank is fully compliant with all EMA requirements."
RDIF said it is working closely with the EMA, whose inspectors have visited Sputnik V production facilities. "From the inspections already completed we've received no major critical comments and none of the issues raised doubted the safety and efficacy of the vaccine," said RDIF.
One of the people with knowledge of European efforts to assess the drug said they had no reason to doubt that Sputnik is a safe and effective vaccine. A study by international scientists published in the Lancet in February found Sputnik to be more than 90% effective.
The EMA, which is headquartered in Amsterdam, declined to comment on details of the review while it is ongoing. The agency said it applies the same standards to all applicants and to authorise a COVID-19 vaccine the EMA requires "detailed information on its safety, efficacy and quality."
The delay could allow rival vaccine makers to sew up key markets. The stumble is one of several for the developers of Sputnik V in dealing with some overseas drugs watchdogs reviewing the vaccine, who have identified a lack of data, insufficient documentation of methodology and non-compliance with what they view as standard protocol.
Brazilian regulators initially rejected imports of Sputnik V after technical staff highlighted "inherent risks," citing a lack of data guaranteeing its safety, quality and effectiveness. Slovakia's drug agency said it had insufficient data from Moscow before the government ultimately gave a limited go-ahead for the vaccine. Hungary gave emergency approval for the jab despite what several people with knowledge of the process said were concerns raised by some specialists working on the review at Hungary's drug regulator about insufficient documentation.
Brazilian regulator Anvisa last month gave conditional approval for imports of Sputnik V. The conditions imposed "seek to overcome the information gaps in the process and ensure minimum conditions of vaccine safety and quality," Anvisa told Reuters. It added that Sputnik V has not been distributed to people in Brazil.
Hungary's regulator, at the time it approved Sputnik V in January, publicly acknowledged that there can be conflicting opinions during an authorization process and that it had received reassuring answers to its questions regarding the vaccine. The Slovakian government this month said it sold most of its Sputnik V back to Russia, citing low interest.
Sputnik V is named after the Soviet-era satellite that triggered the space race, in a nod to the project's geopolitical importance for Russian President Vladimir Putin. EMA approval would lend legitimacy to the vaccine, which initially faced scepticism by some Western scientists and politicians, and speed up its availability in Europe.
Moscow's efforts to obtain EU approval hit obstacles before it submitted its application.
In November 2020, the French government dispatched a team of scientists to Moscow to help Paris decide if it should use Sputnik V and manufacture the drug on French soil, in the event of EMA approval.
The four people with knowledge of the delegation's findings said that the paperwork the scientists reviewed showed that fetal bovine serum had been used in the culture to nurture the master cell bank and that the developers hadn't documented the serum's origin.
After this story was published, RDIF in a statement said that assertion was "false," without going into specifics.
Fetal bovine serum is commonly used around the world in vaccine development. But since the outbreak of mad cow disease in the 1980s, European and North American regulators have required that vaccine developers document it is from a safe source.
One of the four people familiar with the delegation's work 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 about the master cell bank. The French team felt "frustration" with the answers they received when they asked the vaccine developers about the issue, Czerkinsky told Reuters.
Czerkinsky, after this story was published, said in an email that since he last spoke to Reuters in May it had been "scientifically refuted" that the Sputnik vaccine had a potential problem with the master cell and fetal bovine serum. He did not respond to a follow up question from Reuters asking who had refuted this.
He also said in the post-publication email that "the harmlessness of the Sputnik vaccine is also difficult to dispute after it was administered to the population at large in a number of countries."
RDIF told Reuters the Gamaleya Institute "never used 'non-traceable bovine serum' for cell bank preparation." It added that the Sputnik V cell bank has been independently verified not to contain prions - the proteins associated with conditions like mad cow disease. RDIF didn't identify who conducted the independent verification.
The EMA in early March announced the launch of a "rolling 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 at the earliest stages, said an official in the French government briefed on the matter.
France's ministries for health and research, which sponsored the delegation to Moscow, did not respond to a request for comment on the delegation's findings.
Brazilian regulator Anvisa's rejection in April of Sputnik V imports kicked off a testy public exchange with RDIF, which threatened to sue the Brazilian agency for defamation.
A crucial issue for Anvisa related to the adenovirus, the virus that causes the common cold and which is used in Sputnik V to carry into the body information that triggers an immune response. Anvisa publicly said there was a risk the adenovirus in Sputnik V could replicate, potentially causing a negative reaction in recipients. Anvisa's manager for medicines and biological products called this possibility a "serious" defect. The Russians said there was no evidence of replication and Anvisa had misinterpreted the documentation.
Sergio Rezende, a former science minister advising Brazilian state governors who are looking to import the Russian vaccine, said that in discussions with Gamaleya, the Russians appeared unfamiliar with the expectations of Brazilian regulators. Rezende told Reuters he urged the Russians to rework their application, which they initially resisted but ultimately did.
Anvisa told Reuters its requirements "are aligned with the regulations of other agencies of reference around the world."
On the possibility of the adenovirus reproducing, Anvisa said studies and documents supplied by Gamaleya indicated the "occurrence of replicating adenoviruses" and lacked adequate assessment of the relationship between that and the vaccine's 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 "has confirmed that no replication-competent adenoviruses (RCA) were ever found in any of the Sputnik V vaccine batches that have been produced."
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