The Sputnik vaccine case study (Part Three): The role of regulators — why South Africa hasn’t given approval

In June, Bhekisisa started doing research that would explain how well Russia’s Sputnik V vaccine works and to gauge whether it would be suitable for use in South Africa’s Covid-19 vaccine roll-out. Soon enough, it was realised Sputnik V had flouted the rules of every part of the system that produces scientific research.

This is the third of a four-part series published by Daily Maverick. Part One reveals that Sputnik V is plagued by red flags and question marks surrounding its clinical trials and results. Part Two explains how checkpoints in the scientific system are put in place to ensure that research can be sped up in a safe way. But during the Covid pandemic, the accelerated timeline to push out research in an effort to help has exposed gaps in the process. Today’s article explores the role of the regulatory bodies and why Sputnik V is not endorsed.

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 tight-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 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 its 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. Read more here.

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.



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 it 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 affect 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. 

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. Read more here.

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, decentralised 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 (decentralised 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.

This includes:

• 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.