Bharat Biotech (BB) founder and chairman Dr Krishna Ella, on Monday, said that the approval for BB’s Covaxin was being dragged into a political controversy and that it was within the rules laid down by the government in 2019 regulation.
BB will still be required to present Phase III data—expected between March and October. Whether the drug regulator accepts trial data that hasn’t been reviewed isn’t clear.
The grant of accelerated approval by the drug regulator to two vaccines, Covishield and Covaxin, has sparked a debate over grant of approval without Phase III efficacy data. Bharat Biotech (BB) founder and chairman Dr Krishna Ella, on Monday, said that the approval for BB’s Covaxin was being dragged into a political controversy and that it was within the rules laid down by the government in 2019 regulation. He also claimed that other drug regulators had granted emergency use authorisation without Phase III data. Against the backdrop, Ishaan Gera and Sarthak Ray examine the claims and counterclaims.
What do Indian rules say about emergency use authorisation (EUA)?
The New Drugs and Clinical Trials Rules, 2019, term this ‘accelerated approval’ under the provision titled ‘Requirements and guidelines for permission to import or manufacture of new drug for sale or to undertake clinical trial’. Accelerated approval will be based on data from clinical trials where a surrogate endpoint(s) shall be considered rather than using standard outcome measures such as survival or disease progression, which are reasonably likely to predict clinical benefit, or a clinical endpoint.
The provision also states that “if the remarkable efficacy is observed with a defined dose in the Phase II clinical trial of investigational new drug … it may be considered for grant of marketing approval by the Central Licencing Authority…” In such cases, additional post licensure studies may be required to be conducted after approval to further verify and describe the clinical benefits, as per the protocol approved by the Central Licencing Authority. While Ella claimed that Phase II trial data for Covaxin has been submitted to peer-reviewed journals for publication, he stated that these submissions are yet to be accepted for publication. BB will still be required to present Phase III data—expected between March and October. Whether the drug regulator accepts trial data that hasn’t been reviewed isn’t clear.
What are the surrogate endpoints that can be considered in the present scenario for giving approval? How exactly are these proxies for what the conventional primary end-points of Phase 3 clinical trials are? Dr K Srinath Reddy of the Public Health Foundation of India says, “You are looking at two different things in a trial, apart from safety: immunogenicity and clinical efficacy. It is likely that immunogenicity will translate into clinical efficacy, but till clinical efficacy is shown, you cannot be 100% certain. Most vaccines require a trial. But if a virus has high lethality but is not infecting many people, you may not get a large sample size, so you have to use surrogate endpoints. In this case, however, there has been no shortage of cases. In fact, if more centres had been engaged across India in July-August (for Covaxin), then we would have likely got better data.” Dr Ella had talked of key elements of adaptive immune system as being the surrogate endpoints for approval for Covaxin.
What are the rules for EUA in the UK and the US?
In the US, the Food and Drug Administration brought out a guidance document that says preliminary data of at least two months after the completion of full vaccination regimen be submitted along with Phase I and Phase II data for EUA approval, apart from stating that “issuance of an EUA would require a determination by FDA that the vaccine’s benefits outweigh its risks based on data from at least one well-designed Phase 3 clinical trial that demonstrates the vaccine’s safety and efficacy in a clear and compelling manner.” The rules also require the companies to submit data on local and systemic solicited adverse reactions, enrolment of at least 30,000 participants and sufficient cases of severe Covid-19 infection (a total of five or more in the placebo group) to draw up proper benefit-risk profile. In the UK, while the rules are not as comprehensive, they do indicate requirement of safety and efficacy data.
Have countries granted approval without Phase III data?
While Dr Ella talked of China, Russia and the UAE as countries that have granted EUA without Phase III data, neither the US nor the UK have done this. In the US, Moderna’s application for EUA was made on November 30, after the company released primary efficacy results. A Moderna release talked of a 94.1% efficacy against Covid-19. It also stated that “Phase 3 COVE Study has exceeded 2 months of median follow-up post vaccination as required by the US FDA for Emergency Use Authorization.” Similarly, Pfizer, in its release dated November 20, stated that as the company had demonstrated a vaccine efficacy rate of 95% in Phase III trial, and was applying for EUA. The US FDA granted approval to Pfizer on December 11, followed by an approval to Moderna on December 18.
In the case of the UK, while the Medicines and Healthcare products Regulatory Agency has been conducting a rolling review of vaccines—observing them from the development stage—it only considered Pfizer for approval to Pfizer BioNTech vaccine after submission of primary efficacy data. Similarly, approval to AstraZeneca came on December 30, after the company filed detailed data of over 11,000 participants to show clinical efficiency and immunogenicity. The AstraZeneca data showed 90% efficacy for one trial group and 62% for another.
Why hasn’t AstraZeneca received an approval in the US?
The US FDA only gave approval to AstraZeneca to restart its trial in October. As the FDA requires the company to enrol 30,000 participants, it shall only consider their data once that threshold has been passed. As per NYT, AstraZeneca executives said last month that they would only receive federal authorisation once they get results from the US trial. The company is conducting a study in India for a smaller sample, of 1,600 participants.
What are the platforms underlying the Pfizer, Moderna, Bharat Biotech and Oxford/AstraZeneca vaccines?
Pfizer and Moderna: Both are mRNA vaccines. The mRNA vaccines, which transfer genetic information from the nucleus to the cytoplasm (part of the cell in which all organelles, including the nucleus are present), have found use in vaccination recently. In an mRNA vaccine, an mRNA stand carrying instructions for the synthesis for a certain protein—in the case of the SARS CoV-2 vaccines, this is the spike protein that is present on the surface of the viral particle—is introduced to the vaccine recipient’s body as an intramuscular injection.
The mRNA is encapsulated in a lipid nanoparticle (LNP) for greater stability. Once the mRNA reaches the cytoplasm of the immune cells, the cells’ protein synthesis process use it to make the spike protein, which are then displayed on the immune cells’ surface. The mRNA is degraded by the cell’s mechanism after the protein has been synthesised. These cells then trigger both cell-mediated and humoral immune response in the body, making antibodies and likely even memory immune cells, mimicking natural infection.
The advantage this platform has over other vaccines that use the live attenuated virus or inactivated virus or viral vectors is that this a non-infectious, non-integrating platform—that is, it won’t cause infection (this is not to say live attenuated virus-based vaccines will cause infections or even carry a significant risk) and has a very little potential of insertional mutagenesis (effecting any change in the recipient’s genetic code). Also, it will induce a highly specific immune response.
On the flipside, there have been reports of severe allergic reactions in a handful of recipients of the Pfizer vaccines and in one recipient of the Moderna vaccine. While the role of vaccine-ingredients other than the viral mRNA is suspected, this is still to be established through research. Moderna lists mRNA vaccine candidates against Zika and cytomegalovirus, for which early-phase human trials are ongoing. These will expand the literature on the risks and benefits of the mRNA platform. Dr Reddy says that the vaccine-mRNA integrating into the recipient’s genetic code in some manner—some quarters have red-flagged the possibility of this as a concern—is highly unlikely.
Bharat Biotech: This is an inactivated-virus (killed virus) vaccine, in which SARS CoV-2 generated from a batch of the virus isolated at the National Institute of Virology have been inactivated—permanently rendered incapable of replication—with treatment with beta-propiolactone, which bonded to the virus’s genetic material and disabled their replication. However, the inactivated (killed) viruses in the vaccine still exhibit the spike protein. Upon injection along with an adjuvant (in this case, alum) which catalyses immune response, the antigen-presenting cells (a clutch of immune cells) engulf the inactivated virus and present the spike protein on their surface, triggering both humoral and cell-mediated immune response.
Like mRNA vaccines, this is a non-infectious vaccine. Also, the platform has been tested over the decades for safety, across pathogens. However, there is a chance that an inactivated vaccine will yield an antibody response in which not all antibodies target the spike protein—the most crucial element of SARS CoV-2 clinical infection.
Oxford-AstraZeneca/Covishield (SII): This is a viral-vector vaccine, which use a different virus (in this case, chimpanzee adenovirus) as a vector (carrier) for a piece of the pathogen’s (SARS CoV-2’s) genetic material that codes for the antigen protein (spike protein). Upon injection, it mimics natural infection by causing the cells to produce spike protein, which in turn trigger the immune response.
The big advantage is, of course, non-infective nature of the vaccine as also the fact that it triggers both T-cell and antibody generation. However, prior exposure to the virus in case of a viral vector vaccine triggers its own immune response, reducing vaccine potency. While it is still to be established if this was the reason, in the case of the Oxford/AstraZeneca vaccine trial, the ‘two full dose’ regime reported a lower efficacy figure than the ‘half and one full’ dose regime.