Questions around the shot mount as it faces scrutiny from Europe’s medicines watchdog.
May 12, 2021 5:00 pm
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The vaccine, developed by the state-backed Gamaleya Institute, was first used in Europe in Serbia and Hungary
| Alexis Lloret/Getty Images |
For a while, the Sputnik V coronavirus vaccine seemed unstoppable. But Russia’s hottest export may still fall short of what should have been its crowning achievement: the EU regulator's seal of approval.
Sputnik’s latest problems started when it ran into a surprise roadblock — rejection by the Brazilian regulatory authority, Anvisa, on April 28. It flagged issues around the quality, safety and efficacy of the vaccine. In addition, its inspectors were barred from entering certain facilities.
But Brazil wasn't the first drugs regulator to raise concerns. In Europe, the Czech medicines agency was also unable to approve the adenovirus vaccine, and Slovakia’s regulator also said it had concerns, though the country has decided to go ahead with the rollout anyway.
Whether the European Medicines Agency will also have a bone to pick with Sputnik remains to be seen. POLITICO spoke to its former executive director, Guido Rasi, who made it clear that the Brazilian regulator's objections shouldn't be taken lightly.
"It's a very mature authority," said Rasi, who described Anvisa as "very, very well-prepared." Anvisa has steadily worked to implement the standards upheld by the EMA and the U.S. Food and Drug Administration, he noted.
For its part, the EMA has revealed few details of its Sputnik assessment. A rolling review began in March, but the agency hasn't yet received the full clinical trial data package. Inspections of vaccine clinical trial and manufacturing sites are ongoing.
It's unclear whether the same quality issues detected in Brazil will crop up in Europe, since different sites will be inspected. But Rasi stressed he's sure that if any quality defects are found, "the EMA would reply the same [way]."
"Quality is as important as benefits," he said. "No compromise on that."
The first cracks
The vaccine, developed by the state-backed Gamaleya Institute, was first used in Europe in Serbia and Hungary. Then, the Czech Republic and Slovakia signaled their interest. But it was when Austria announced a deal, along with statements from German policymakers about starting talks, that Sputnik really found its stride.
Meanwhile, outside of Europe, the Russian vaccine was collecting a string of victories in countries all over the world — with Argentina, Turkey and India approving the vaccine and inking deals.
But things started to take a turn in April, when the Slovak drugs regulator ŠÚKL concluded that Sputnik doses delivered to the country didn’t match with those supplied elsewhere. It also said the Russians failed to provide sufficient data on the jab. (That was just the latest twist in the country's tumultuous debate over the jab, which saw the previous government collapse in March amid fallout from then-Prime Minister Igor Matovič's unilateral order of 2 million doses without his coalition partner's green light.)
"Batches of vaccine used in pre-clinical tests and clinical studies published in the Lancet [medical journal] do not have the same characteristics and properties as batches of vaccine imported to Slovakia," ŠÚKL wrote in its opinion.
This inspired a furious rejoinder from the Sputnik team via Twitter, where it fumed that the regulator hadn't tested the vaccine in a laboratory with the correct regulatory clearance, and that it had launched a "disinformation campaign" directed against the shot.
All of this wasn't enough to stop Slovakia’s health minister from essentially green-lighting the vaccine last week, after side-stepping its regulator and asking Hungary to perform the necessary checks. The minister, Vladimir Lengvarsky, said the rollout would probably start in June.
Meanwhile, in the neighboring Czech Republic, the country’s medicines regulator — also called ŠÚKL — said on April 29 it didn’t have enough data to decide whether to approve the drug.
"We received so little material that we could not say if we would recommend its use or not," said Irena Storová, the head of ŠÚKL, in an interview with Radiožurnál. "It was only a fraction of the documentation that is submitted by default for the registration or assessment of a drug or medicine."
Anvisa, for its part, said that its decision to reject the vaccine was based on "flaws in product development in all stages of clinical studies … [and] an absence or insufficiency of quality control, safety and efficacy data."
At issue is how the vaccine uses a mild cold virus — an adenovirus — to enter human cells to deliver instructions to make a tiny part of the coronavirus. These instructions prime the immune system to attack the coronavirus once it infects the body. This viral vector should be modified to prevent replication — essentially to preclude infecting people with the adenovirus.
Anvisa has warned, however, that the development of the adenovirus used in Sputnik might allow it to still continue replicating in the body. This could mean infecting people with a common cold. While such an infection may be mild for some people, it could cause serious illness in others, "especially in people with low immunity and respiratory problems," Anvisa said.
Zoltán Kis, a research associate at the Future Vaccines Hub at Imperial College London, points out such an effect is highly unusual. He explains that the replication gene is typically deleted “when you create a vaccine for the first time — the prototype of the vaccine.” Developers then hand over this unique vaccine “seed” to the manufacturers, with the replication gene already deleted, and the manufacturers scale up production of this product.
According to the Brazilian regulator, the international standard — which, like Europe, it follows — is for zero replicating viral vectors in vaccines. However, the Sputnik developers have set their own threshold for the presence of replicating virus, Anvisa said.
It also flagged "inadequate" studies by the Sputnik team, including in the analysis of "impurities and contaminating virus during the manufacturing process."
This problem relates to byproducts from making the vaccine, Kis said. To make adenovirus vaccines, first cells are grown in which the adenovirus replicates. These cells are fed nutrients until they die, releasing proteins, lipids and other organic components. These all need to be taken out until levels are low enough for regulators, to reduce the risk of side effects like allergic reactions.
For its part, the Russian Direct Investment Fund, the Russian sovereign wealth fund in charge of promoting the shot abroad, has claimed that Anvisa's decision is politically motivated. In its response, it said that the regulator's statements "have no scientific basis," and it denied the presence of any replicating virus.
Separately, in an interview with Indian media channel NDTV, RDIF chief Kirill Dmitriev said that the Brazilian regulator was still "open to reconsider Sputnik."
Data troubles
Independent of the regulators, some scientists have also raised further questions about the clinical trial results backing the shot. They point to suspicious patterns in the reported results, which those scientists say look too uniform to be the result of chance.
While the publication in February of the Phase 3 data in the prestigious Lancet was undeniably a coup for the Sputnik team, these skeptical scientists have been leading the charge in an equally well-known publication: the British Medical Journal.
In a peer-reviewed essay in the BMJ, Christoffer van Tulleken, honorary associate professor of infection and immunity at University College London, summarized the recent criticism of the Lancet paper. He noted, for example, the questions flagged by scientists around data patterns as well the lack of transparency.
The Lancet is effectively acting as a cheerleader for the Russian shot while allowing obvious errors through its peer-review process, he wrote, giving it a pass before top drug assessment agencies had a chance to look at it, and clearing the path for approval for regulators from countries with less experience in vaccine assessments.
"If Sputnik is not authorized [by the EMA], much more serious questions will surface about the avoidable harm driven by overconfidence in journal peer review and the more far reaching damage to the public’s fragile confidence in other vaccines that are truly safe and effective," he warned.
In response to a request for comment from POLITICO, a spokesperson for The Lancet said that the research had been "independently peer-reviewed by international experts on COVID-19 and vaccines, including a statistical reviewer."
That article follows a non-peer-reviewed letter in the BMJ sent by another group of scientists. Among them is Vasily Vlassov, an epidemiologist and public health expert at Moscow’s Higher School of Economics, and vice president of the Russian Society for Evidence-Based Medicine. Some of his criticisms have also recently been published in a separate letter to the BMJ.
Vlassov said he was worried by a lack of safety data for around 30 percent of the participants in the Lancet trial — information that's still missing despite the "massive vaccination campaign" underway in Russia.
The Russian scientist said he believes the vaccine is generally “quite safe,” in line with the other jabs. But even a “very low complication rate” had been obscured to ensure favorable comparisons with Western vaccines, Vlassov added.
Another signatory is Florian Naudet, a professor of therapeutics at the University of Rennes 1. He said that when the Sputnik team released Phase 1 and Phase 2 clinical trial data, his interest was piqued by a curious uniformity in the results. Requests to the Sputnik team for data were met with silence.
The publication of the Phase 3 clinical trial results in the Lancet prompted the April letter to the BMJ. Here Naudet joined other skeptical scientists, including Enrico Bucci, an adjunct professor of biology at Temple University in Pennsylvania, who runs a research integrity company and had already publicly criticized the Lancet results.
Previously, the Sputnik research team had attributed the lack of variability to the small sample size. That’s why Naudet said it was “surprising” that the much larger sample size from Phase 3 exhibited the same lack of variations.
Naudet pointed to one table in particular, in which the vaccine’s efficacy was broken down by age group. Again and again, the efficacy data came out within a narrow band between 90 and 92 percent. It's an unusual finding, given that by chance one could expect more variability in the different age groups, with results falling anywhere between 70 percent to the high 90 percent range, he explained.
The chances of getting such a uniform distribution randomly are slim, concluded the researchers who wrote to the BMJ.
"[It's] important to say [that] we cannot affirm that there is a problem," said Naudet. "But we can say that it's suspect enough to warrant an inspection of the database."
On Wednesday, the group of scientists published a letter in the Lancet, collecting their concerns around transparency, clinical trial design, and what they described as peculiar patterns in some of the data. The Lancet also published a response to the letter from the authors of the Sputnik study. They maintained that the clinical trial “fully complies” with regulatory standards, and that uniformity in some of the data just confirms that the vaccine’s effectiveness “does not differ between age groups.”
Some concerns over the data are shared, at least in part, by Rasi, who said he wasn’t impressed by the standards of the published data. "Those data ... are far from being sufficient for any regulatory purpose," he said.
He thinks it’s entirely likely that the Sputnik team will submit more complete data to the EMA that could help put doubts to bed. But he also cautioned, “I'm certain it's not coming very soon.”
Sputnik's boosters
Not everyone is so critical.
Leeza Osipenko, senior lecturer in practice in the department of health policy at the London School of Economics, said the vaccine has her backing. The academic led the U.K.’s National Institute for Health and Care Excellence (NICE) scientific advice between 2014 and 2018.
She has taken the Russian shot herself and was recently tested for her immune response, "which showed very high antibodies."
"Same results for everyone I know — not just my immediate friends and family," she added. "Sputnik is an excellent vaccine and no serious side effects have been associated with its administration."
She points to a "very negative anti-Russian climate in the world, which is damaging the rollout," citing the vaccine's difficulties in the Czech Republic — where a diplomatic incident has thrown relationships with Russia into disarray — as a case in point.
But Osipenko agreed that the Lancet article had elements that left it open to criticism, and notes its publication was rushed. "It is also disappointing that Russia has not shared raw data when requested," she added.
However, the academic didn’t think the data had been spun: "If inconsistencies are found, it is due to carelessness and lack of time," she said.
Jonathan Cushing, who heads Transparency International’s health team, takes a balanced view on the issue of data-sharing, noting that a reluctance to be fully transparent isn’t something limited to Sputnik.
However, once a vaccine becomes a tool of the state, as is the case with Sputnik, the stakes become higher, he argues: "You’re adding another dimension. If it's political prestige, the pressure is going to be much greater."
Still, if there are any inconsistencies in the data, EU citizens can rest assured that the EMA will find them, said Rasi.
EMA inspectors have already visited clinical trial sites in Russia "to ensure that the ethical standards have been complied with, and that the data reported in the clinical study reports can be verified," said Fergus Sweeney, head of clinical studies and manufacturing at the EMA, during a press briefing Wednesday. Inspections of the manufacturing facilities that would produce for the EU are ongoing, he added.
The EMA is "gathering more information that are filling in all the gaps in the dossier," added Marco Cavaleri, head of vaccines strategy at the EMA. The regulator should be able to "better define what could be the timetable for a potential approval" in the coming weeks, he added.
"[The regulators] have a great deal of experience," Rasi said. He recalled one French EMA inspector who took just a glance at one company’s data at their lab before declaring they are "all fake" and walking out.
"Their experience is huge," Rasi said, "so if they're not convinced, they will not make a [positive] decision."
https://www.politico.eu/article/russia-sputnik-coronavirus-covid-19-vaccine-hot-steak/
