Update: On 18 October 2021, South Africa’s medicines regulator the South African Health Products Regulatory Authority (Sahpra) announced that the Sputnik V vaccine does not pass the country’s safety tests. The regulator declined to approve Sputnik V for emergency use in the country.
- South Africa’s regulatory body has yet to approve Russia’s Sputnik V COVID vaccine because it is still awaiting additional information on the jab.
- So far the vaccine hasn’t gained approval from any reputable regulatory bodies, like the European Medicine Agency, due to similar hold-ups with the data.
- The emergence and dominance of variants like Delta also adds to the factors that need to be assessed when selecting another vaccine for our national roll-out.
Do you feel weird about Russia’s Sputnik vaccine? You’re not alone, and the reason for it goes beyond geopolitics.
Whatever your views are about the country, Russia has disregarded many of the norms put in place to bolster public trust in medicines.
For one, the country registered the Sputnik V COVID vaccine for emergency use and rolled it out to its citizens before the trials to test its safety and efficacy were complete.
When information about the trial was finally released, researchers of Russia’s Gamaleya Institute, which produced the Sputnik vaccine, were zip-lipped about how they designed the study; the quality and integrity of their reporting on the research in The Lancet was questioned too.
In this article, part three of our Sputnik Series, we look at all the ingredients that go into regulating medicines, why the Sputnik jab doesn’t pass muster just yet and how good regulators can improve the public’s trust in vaccines.
Where is Sputnik in SA’s approval pipeline?
The Sputnik V vaccine is currently under rolling review for emergency approval by the South African Health Products Regulatory Authority (Sahpra). The regulatory body began evaluating the jab after receiving an application on 24 February.
The urgency of the pandemic has changed Sahpra’s review process slightly.
Firstly, all COVID applications are earmarked for priority review. This means they move to the top of the pile and are dealt with urgently. In a July statement, Sahpra said a COVID vaccine could be registered in under three months provided there was enough data on the jab available.
Secondly, Sahpra is considering applications on a rolling basis. This is the process through which Sputnik opted to submit their application. The idea is that rather than reviewing all the information on a jab all at once, the regulatory body can assess individual pieces of data as they become available.
But Sahpra notes this rolling review process doesn’t provide a shortcut for applicants in terms of the information the body requires to make decisions about the safety and efficacy of vaccines. So although rolling reviews are used to expedite the route to approval, it doesn’t sacrifice the requirements for the jab — Sahpra can therefore not complete its rolling review of the product until all the necessary data has been supplied.
Third, Sahpra can speed up the process of approving a COVID vaccine by using something called a reliance mechanism. This involves different regulatory authorities working together to share information.
Because regulators are receiving documentation for COVID vaccines at different times, some bodies are able to complete their reviews before Sahpra has even received an application for the jab. In such cases, Sahpra can then ask the regulatory authority that has already reviewed the vaccine to share their evaluation and documents so the local review can rely on that data and expedite the local approval process.
Sahpra has a list of trustworthy regulatory bodies that can be relied on in these circumstances, including the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA). Although it’s not a regulatory authority, Sahpra will also consider World Health Organisation (WHO) prequalification documents.
Prequalification is a safety process the WHO uses to vet medicines to make sure that manufacturers produce good quality medicines in line with international safety standards.
WATCH: A dummy’s guide to COVID vaccine approvals
But none of the “partner” authorities on Sahpra’s list of reliable regulators have granted the Sputnik jab approval yet and only one such regulator, the EMA, has received an application from Sputnik for authorisation.
As of 2 July, the WHO said the assessment of the Sputnik jab was on hold as they awaited additional data on the jab (including both non-clinical and clinical data along with manufacturing information).
Non-clinical data involves testing medicines in a lab or on animals and clinical data is obtained when medicines are tested on people.
Sahpra’s own progress with review cannot be shared in detail because of a nondisclosure agreement surrounding the application, but Sahpra CEO Boitumelo Semete-Makokotlela confirmed the regulatory body is awaiting additional information from the company for review.
What does it mean to review a vaccine?
Manufacturers who want their medicine to be used in a country must first submit a whole lot of paperwork to that nation’s medicines regulator to get it registered and approved.
This information is usually far more detailed than the data researchers provide to medical journals for peer review.
A medical journal article might be somewhere in that pile of paper, but it’s just the cherry on top of the masses of raw trial data and analysis that companies must also supply to regulators, explains Marc Blockman, a professor of clinical pharmacology at the University of Cape Town.
Bhekisisa has outlined some of the shortcomings of peer review in part two of our Sputnik series. When it comes to putting a medicine on the market, those shortfalls are combated by regulatory processes.
Medical journals publish articles to stay in business, Blockman says. “Just because it’s published, that doesn’t mean it’s clinically useful.”
You’ve got to do a critical appraisal of [the trial]. That means looking at absolutely everything.”
And that’s exactly what regulators do. But what does “absolutely everything” entail?
Prospective medicines must clear a high bar of evidence to be authorised for use. Reviewers will be looking at, for instance, how well the randomisation of the volunteers in a trial was done, as well as other factors in the study design that may impact how trustworthy the results are in the end.
Randomisation is an important part of clinical research that helps make sure the study participants are not selected in a biased way and that they represent the general population. Randomisation also helps to eliminate external factors, which scientists call confounding variables, which could potentially influence study results.
Says Blockman: “If [the study is not of a high quality], you can burn it, you can use it for a braai. Even if it’s been published in the New England Journal of Medicine.”
He cautions people sometimes confuse the approval of a medicine with how it’s used in the real world.
Regulators are looking at the available data, and then decide whether it’s safe and effective to use. They can also limit the use of the medicine to certain populations based on the information that’s submitted.
For example, if there’s limited information about how well the vaccines work in people aged 60 and older, regulators may still approve it with the condition that more data be provided as soon as possible. Or, at least, that manufacturers provide data on how well the vaccine works in people on anticoagulants (blood thinners) or blood pressure medication (since elderly people often have health conditions that require these treatments). In the case of SARS-CoV-2, the virus which causes COVID-19, regulatory bodies can also require manufacturers to provide data that proves that a vaccine is effective against the dominant variant of the virus in the country.
All that said, whether a medicine should then be included in treatment policies and bought for the public is outside the regulators’ mandate.
Blockman concludes: “Even if the Sahpra approves the Sputnik vaccine, we don’t know that the health department will buy it.”
How Sahpra’s processes compare with international regulators
Large regulators such as the FDA in the United States have huge teams of statisticians and other experts who reanalyse the data companies submit for review.
But Sahpra doesn’t have that same capacity.
The local regulator instead uses consultants who have years of experience in vaccine science development. “They’ll be able to look at the data [as well as analyses submitted by companies] and know what to look for without having to redo the analysis in most cases,” Blockman says.
Blockman says the FDA’s data mining is valuable and contributes to public safety information. But, he argues, “[For Sahpra] to redo absolutely everything would be time consuming and unnecessary. What you really need are experienced people who can see from their thorough review whether the data is reasonable and robust.”
Besides, he explains, COVID may be a new disease, but the way vaccines operate in the body is not. Nor is the kind of data you need to know how well it works.
What do other regulatory bodies have to say about Sputnik?
Several scientists have raised concerns about the quality and availability of the data underlying the Sputnik trials, but the study’s investigators have denied insinuations that they’re not transparent enough about the jab’s data.
In a letter in The Lancet an international group of scientists have, for instance, criticised Sputnik’s researchers, arguing that the reporting on the trial was “substandard”. This includes unexplained changes in the data provided by the researchers and a change in what was being measured in the study.
But Gamaleya Institute researchers have cited Sputnik’s approval in multiple countries as confirmation of their “full transparency and compliance with regulatory requirements”.
Not all regulatory authorities are, however, equally stringent in their assessment of applications. That’s why Sahpra has a list of trusted bodies upon whom they can rely.
Sputnik V has been approved for use in over 69 countries, including, amongst others Brazil, Egypt, India, Mexico, Nigeria, Namibia, Ghana, Angola, Morocco, Pakistan, Seychelles, Turkey and the United Arab Emirates. None of these countries appear on the WHO’s list of stringent medicines regulators.
The EMA began a rolling review of Sputnik V on 4 March after the European company, R-Pharm Germany GmbH, applied for authorisation. In a statement, the EMA said the “review will continue until enough evidence is available for formal marketing authorisation application”.
But some European countries, such as Hungary and Slovakia, have granted the Sputnik jab emergency authorisation through their own regulatory bodies, as opposed to waiting for a decision from the EMA. In Slovakia, however, this decision wasn’t received well and the country’s prime minister had to resign as a result of it.
The European Union has three different approaches to regulatory approval: centralised, de-centralised and mutual recognition. Centralised approval is when a company submits an application to the EMA for authorisation, which once approved applies to all European countries.
In the latter two (de-centralised and mutual recognition), countries can review approval applications through their own regulatory bodies. But, the EMA says that “the use of the centrally authorised procedure is compulsory for most innovative medicines, including medicines for rare diseases”.
COVID-19 vaccines are classified as innovative medicines, according to an EMA circular.
On 14 July, Reuters reported that the EMA was unlikely to approve the vaccine any time soon due to outstanding data. This included shortcomings around manufacturing and clinical information, particularly around side-effects from the jab.
Brazil’s medicine regulator, ANVISA, initially rejected Sputnik’s application for emergency use citing concerns about the jab’s data. They then reversed their decision two months later in June and Brazil became the 67th country to approve the vaccine for use.
But this approval did come with a few caveats, as the regulator noted that although additional documentation had been submitted, there were still gaps in the information on the vaccine.
Sputnik’s manufacturer must comply with 22 rules set out by ANVISA in order for the jab to be accepted by the country.
- Only importing vaccines from manufacturing facilities that have been inspected by ANVISA;
- A quality analysis of all vaccine batches that proves the virus in the vaccine is inactivated and cannot replicate;
- All serious side-effects must be reported to ANVISA within 24 hours.
Currently, Brazil is only importing enough Sputnik doses to cover roughly 1% of the population. Adopting a similar approach to South Africa’s Sisonke study, which aimed to gather more data on how the Johnson & Johnson (J&J) jab performed locally, the country will use data from these doses to continue to monitor and assess the vaccine’s safety and effectiveness.
What do we know about the quality of the Sputnik vaccine?
Regulatory approval involves more than assessing the clinical data on a vaccine; although regulators serve an important role in checking if the jab is safe and effective, they also have to ensure that the actual product is of good quality.
Sahpra mandates that all medications coming into South Africa have to be tested. This is to ensure that no substandard or fake medications slip into the country.
Part of the delays in the WHO’s assessment for granting Sputnik emergency approval is because of issues picked up during inspections of the manufacturing plants.
The WHO inspected five clinical trial sites (done along with the EMA) and four manufacturing plants as of 24 June — one of the plants inspected did not meet “good manufacturing practices”.
Good manufacturing practices speak to the quality of the product being produced and ensure that medicines are “consistently produced and controlled” so that the product is not being compromised.
The summary report from the WHO lists six concerns about the plant, mostly related to potential contamination of the product and a lack of control measures to prevent contamination at various stages of the manufacturing process.
Contamination can happen when the vaccine’s composition or ingredients are compromised during manufacturing. For instance, while you’re growing the vector, in the case of Sputnik, the adenovirus can possibly be contaminated with another virus. Or as was seen with a manufacturing plant in the US, where there was cross-contamination between the J&J and the AstraZeneca vaccines, both of which use two different types of adenovirus vectors.
The remaining three facilities are still being assessed, but the WHO says “they have not raised similar concerns” so far.
In April, Slovakia also flagged issues around the Sputnik vaccine’s quality about a month after the country received its first batch of doses. The Slovakian drug regulator, SUKL (The State Institute for Drug Control, or SIDC, in English) issued a statement saying: “Batches of (Sputnik V) vaccine used in preclinical tests and clinical studies published in The Lancet journal do not have the same characteristics and properties as batches of vaccine imported to Slovakia.”
The regulator went on to say: “It is only its name that links it to the Sputnik V vaccines used in about 40 countries around the world.”
But Sputnik’s manufacturer denied the allegations and issued a response on Twitter accusing the Slovakian regulator of launching a “disinformation campaign against #Sputnik V” and violating the country’s contract with the company. Moreover, it labelled the SUKL’s concerns as “fake news” and “an act of sabotage”.
Sputnik producers also claimed that the doses the regulator was referring to had been sent to an uncertified laboratory for testing and pointed out that “all Sputnik V batches are of the same quality and undergo rigorous quality control at the Gamaleya Institute… and the quality… has been confirmed by regulators in 59 countries”.
The contract published by the Slovakian health ministry outlines that Sputnik’s manufacturer will send through the specifications of the doses when they are ready to ship. The contract, however, doesn’t require Sputnik to detail the contents of vials sent to a country, but does allow for Slovakia to test the delivered jabs and return them if they do not meet the required standards.
What are local considerations?
Although South Africa’s vaccine roll-out has been slowly ramping up, it has not been without its setbacks and demand has decreased over the past three weeks, according to the health department.
In mid-July, vaccination sites in Gauteng and KwaZulu-Natal had to press pause because of civil unrest and violence in areas. Before that, a contamination issue at an American factory for the J&J jab caused a delay in the supplies slated for South Africa.
Although plans have been put in place to rectify such mishaps at the manufacturing stage and sufficient supplies to vaccinate South Africa’s 40-million adults have been ordered, such hold-ups highlight the uncertainty surrounding vaccine supplies within a constrained environment.
Barry Schoub, chair of the ministerial advisory committee (MAC) on COVID vaccines, explains that even though there is “currently an ample flow of vaccines in the pipeline… we do obviously need to have consideration for a third vaccine”.
This is because “hiccups” can occur, Schoub says. The issue with the J&J supply was unanticipated but it could just as easily have happened with Pfizer stocks — or any other vaccine for that matter.
That’s why Schoub says: “We do need to have a third vaccine strategy and this is why we have to keep looking at other vaccines.”
But, similar to the request of the EMA, SA’s MAC on COVID vaccines in April said that additional data from Sputnik’s manufacturer was needed. This included information on the safety of the jab in older people and more detail on how severity of disease was defined in the trial.
There’s something about what’s inside the Sputnik vaccine that may also give local authorities pause.
Richard Lessells is an infectious diseases expert at the KwaZulu-Natal Research Innovation and Sequencing Platform (Krisp).
He says the two-dose vaccine uses two different types of adenoviruses, which is a type of virus that causes common colds. This adenovirus acts as a carrier (vector), or trojan horse, which sneaks an unharmful form of a different virus into your body. This type of vaccine is known as a viral vector.
In the case of Sputnik, people receive two shots, 21 days apart. The first jab uses adenovirus 26 and the second adenovirus 5 as the vector.
Scientists are concerned that the use of the ad-5 virus strain in particular can increase the risk of people getting infected with HIV, based on evidence gathered in previous HIV vaccine trials. Now that this same vector is being used once more for Sputnik’s COVID jab, this could make vaccinated people more likely to acquire HIV, especially in a country like South Africa which already has a high prevalence of this virus.
Lessells says: “The concern is for the HIV-negative population that might receive [the Sputnik jab] and whether the vaccine could increase people’s risk of contracting HIV.”
The higher the proportion of people with HIV in a country, the higher likelihood that the HIV-negative population could get infected.
Given that about 15% of South Africans live with HIV, Sahpra and the health department ideally want data to show whether the jab is safe to use for the local population.
On the other hand, the adenovirus type-26 vector which is used in the first Sputnik V dose has been shown to be safe in studies using adenovirus type-26 for HIV vaccines.
But the Gamaleya Institute has now also introduced a version of the Sputnik vaccine, which uses one dose only. The one-dose jab is called Sputnik Light and consists of just the first dose of the Sputnik V jab, which uses adenovirus type-26 as a vector.
The one-dose vaccine is just under 80% effective, according to a Gamaleya press release.
The authors write: “Sputnik Light is compatible with standard vaccine storage and logistics requirements, while also being affordable with a price of less than $10. The single-dose regimen allows for immunisation of a larger number of people in a shorter time frame, furthering the fight against the pandemic during the acute phase.”
Saphra has not received a submission to review Sputnik Light, says the regulator’s chief executive officer Boitumelo Semete-Makokotlela.
What about the variants?
It’s unusual for countries’ regulators to demand that medications be studied in their own populations, Blockman says, especially in cases where the medicine is shown to be effective in very large and diverse populations.
South Africa has been fortunate that a few of the COVID vaccine trials, such as AstraZeneca, J&J and Novavax, included arms which were conducted locally.
When it comes to procuring a vaccine for South Africa, we need to consider the variants which are driving the country’s epidemic.
Schoub says what’s causing the “hold up” in terms of assessing vaccines such as Sputnik is the lack of data about how it performs against variants of the SARS-CoV-2 virus circulating in South Africa.
With the Delta now dominant in the country, there are lingering questions about what this new form of the virus could mean for the Sputnik jab.
The Sputnik team has made claims about their vaccine’s efficacy against Delta, but there isn’t sufficient data available to support their assertions.
On 22 June, the director of the Gamaleya Institute Alexander Gintsburg said on Twitter that Sputnik V could “protect from all variants of COVID known today, starting from the UK variant to the so-called Delta variant, first detected in India”.
A week later, Denis Logunov, who developed the vaccine, said: “Sputnik V efficacy against [the] Delta variant is above 90% as Sputnik V shows [a] smaller decline in efficacy against Delta than any other vaccine that published efficacy results on [the] Delta variant.”
However, in a paper published in Vaccines on 12 July, researchers pointed out that the Sputnik jab had not yet been “extensively studied” to see how it would perform against variants.
The scientists tested blood samples from people who had been vaccinated with Sputnik V and found that people’s immune response dropped 2.5-fold when they were infected with the Delta variant.
Sahpra has received some data on how well Sputnik V performs against the Delta variant, Semete-Makokotlela says, but the vaccine is still undergoing rolling review with Sahpra but all details about the data provided by the Gamaleya Institute and the review is subject to a non-disclosure agreement. This kind of confidentiality commitment between companies and regulators is, however, not unusual. International regulators sometimes have agreements to share non-public information with each other. The FDA and EMA have brokered such a deal as have the EMA and ANVISA.