As the Covid-19 pandemic spread around the world two years ago, one of India’s leading biotech corporations was rushing to expand a very important vaccine from the Indian government. The plan designed through Bharat Biotech was, in part, a major effort to create a local product that can improve the lot of India’s pharmaceutical industry.
However, a STAT review of documents detailing steps taken toward government approval found that regulators were approving the vaccine, called Covaxin, despite discrepancies in the number of clinical trial participants. In addition, questionable adjustments have been made to testing protocols, which are established procedures for testing a vaccine or drug to speed up the approval process.
For example, the number of other people enrolled in the Phase 1 trial differed from what was later published in a medical journal. Significant adjustments were also made to the Phase 2 testing protocol, while immunogenicity knowledge from the previous Phase 1 was not yet available.
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In addition, the Phase 3 protocol was approved while Phase 2 was still ongoing and the final vaccine candidate was decided without Phase 2 data, according to protocol documents and minutes of meetings held through an expert committee reporting to India’s Central Drug Standards Control Organization (CDSCO). ), the national regulator guilty of approving medicines. It was the firm that legalized the vaccine for emergency use in January 2021, two months before the effects of Phase 3 were known.
As a result, experts in public fitness and clinical trial design have expressed fears that Bharat Biotech’s vaccine has been hastily approved. Quality medical products succeed in patients.
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“My challenge is that the public and medical network conforming to the truth where the regulator is undermined when the regulator and the (expert committee) seem to settle for ‘inadequate information’ on which to base their decisions, or lack clarity in their minutes. as to why it was rational. They seem to be under pressure and this is a very worrying scenario,” said John Jacob, a professor of network fitness at Christian Medical College in Vellore, India, who reviewed the documents.
There are cases that allow such changes in the protocol, such as continuous adaptive trials, that mix other stages and allow changes in the design of a trial while the study is ongoing. But first the parameters of possible changes must be explained. in a protocol, which has not happened with the approval process for Covaxin, and no clinical justification for adjustments has been proposed.
For their part, Bharat Biotech executives pointed out some mistakes, but maintained that their decisions reflected the demanding operating situations amid the pandemic. They also argued that they faced “political” pressures to get a vaccine out of the lab door as temporarily as possible, yet denied taking shortcuts. And they insisted that measures taken to speed up the trial had been proven in talks with regulators.
“In an old sense of product development, we would do everything the right way: let’s play through the rules of the game and all the rules of the game would be followed. But here’s a scenario the world didn’t foresee. “Krishna Mohan, director of Bharat Biotech, told us: “. . . Don’t think there was a challenge with the veracity of the data. Yes, it was an approach, but it was dictated by the nature of the pandemic.
Covakin’s marketing effort is a convergence of several key concerns.
Bharat Biotech’s vaccine was being developed at a time when features were needed to combat the pandemic. The World Health Organization thought the vaccine was desirable because, unlike the Moderna and Pfizer/BioNTech mRNA vaccines, the Covaxin vaccine does not require much low-temperature storage, which facilitated its deployment in low- and middle-income countries.
In addition, the Indian government relied on a locally manufactured vaccine to meet national fitness requirements, which is why the Medical Research Council of India, a government agency, collaborated with Bharat Biotech to expand Covaxin. This had the added advantage of polishing the symbol of the domestic pharmaceutical industry, which has been criticized by foreign regulators.
But the Indian government, which collects a 5% royalty on sales and has given the company a $200 million production subsidy, has also been accused of lax policing. the U. S. Food and Drug Administrationafter inspections of production services controlled by the large number of drugmakers founded in the country. In doing so, the FDA has made Indian regulators appear negligent.
“The Indian government denies the quality crisis facing the pharmaceutical industry,” said Dinesh Thakur, a whistleblower who revealed that Ranbaxy Labs, now owned by Sun Pharmaceutical, had falsified verification data and manufactured drugs that met protection standards. The company pleaded guilty to felony charges in the U. S. The U. S. government paid $500 million to settle fines and civil lawsuits.
“As far as (the government) is concerned, it needs to see India’s pharmaceutical industry grow, at the expense of public health. It will not establish or enforce any regulations that threaten the expansion of. . . the industry,” said Thakur, whose base awarded grants to an Indian online journalist who was recently attacked via Bharat Biotech with a court order for articles about his shooting.
From the beginning, a lack of transparency surrounded the vaccine effort.
For months, documents on the agreement between the Indian Council of Medical Research and Bharat Biotech, as well as phase 1/2 and phase 3 protocols have not been made public. And in Phase 1, the company identified a serious adverse event in a patient. , which we then decided was not similar to the injection. But disclosure only came after the episode leaked through the media.
This is not in line with informed consent requirements, according to Malini Aisola and Siddhartha Das, civil society activists who specialize in public health issues and investigated Covaxin’s approval process, which included questions about irregularities in initial trials. They also worked with All India Drug Action. Red to convince CDSCO to finally release the minutes of expert committee meetings at which covid-19 vaccines were reviewed.
“The protocols were not in the public domain while the trials were taking place, and the trials were moving at breakneck speed with no data based on the granting of approvals,” Aisola said, adding that handling the adverse occasion also set a bad tone for research and sharing data with the public. This is not just a purely clinical issue. It is about the role of the government and its partner, who more than satisfied cooperated, because he also benefited.
More controversy erupted last spring. The Brazilian government raised considerations about the manufacture of Bharat Biotech. Then the WHO, which indexed the vaccine for emergency use in November 2021, suspended the materials after an inspection of the services revealed unspecified problems. This resolution meant that UN procurement agencies, such as UNICEF, would no longer send the injection to other countries. A WHO spokesman declined to provide an update on the results.
For now, it’s unclear whether the disruptions recently revealed with the clinical trial will raise even more questions about the Indian government’s willingness to oversee it. CDSCO and India’s Drug Comptroller General, which oversees CDSCO, did not respond to emails seeking comment on adjustments to Covakin’s testing protocols and upcoming government approval.
Looking at the documents, there is a transparent difference in the number of registrants. Reporting Phase 1/2 data, the protocol implies that 402 participants won the first dose and 394 gained the current dose. But the effects published in the Lancet Infectious Diseases in January 2021 mean that another 375 people gained a first dose and 368 gained a momentary dose. (See Figure 1 on page 640. )
Mohan declared the error. However, he explained that the company ran into problems quickly because a large number of jobs had to be done remotely, making it difficult to communicate between three other groups of employees who managed clinical operations, data and interactions with regulators. This made it difficult to communicate with trial participants.
These communication gaps meant that the medical journal was not updated, claiming that the Comptroller General of Medicines of India had been informed of the other number of participants. “Maybe we’ve leaked it,” he said. It wasn’t intentional. ” It was because of those multiple groups working. . . It wasn’t so much a breach. . . The concept was, “Let’s get the knowledge out. “
“In retrospect, maybe there have been other channels of communication,” he continued. “We were focused on the production part, the protection of people, the ethics in the management of the subjects. . . Our purpose was in another state of mind. . . . (It was) a domain that caught our attention and maybe next time one of the caveats is that we know we need to be careful.
One expert said the other numbers are worth pointing out, but they probably wouldn’t have been harmful. “About the results? Probably not,” said Reshma Ramachandran, who leads the collaboration for regulatory rigor, integrity and transparency at Yale School of Medicine.
However, the company dosed a larger number of subjects than reported in the medical journal, Aisola explained, who cautioned that this raises questions about the integrity of the trial data.
The cases surrounding adjustments to control protocols are also unclear.
For example, in September 2020, the CDSCO Expert Committee approved amendments to the Phase 2 protocol, adding the abandonment of the placebo group, with two vaccine candidates compared instead. Changes were also made to the dosing period and age of the participants. Explanation of why given to accelerate phase 2 testing, according to the documents. The protocol published in Lancet Infectious Diseases.
In addition, the Expert Committee legalized that the trial continue on the basis of animal studies, as the immunogenicity knowledge of the Phase 1 trial had not been evaluated and was not in a position to present it (see meeting minutes here and here). This kind of knowledge is vital because it shows the extent to which a vaccine produces an immune reaction to a virus.
Explaining those changes, Bharat Biotech’s Mohan argued that “speed dictates (our actions) and as knowledge arrives, we feel (more) comfortable. . . There was a lot of dialogue, extensive debates. . . They (the regulators) have been quite us. . . They had similar questions: Why are you converting your protocol, your strategy?
“All of this has been debated day after day. We did what we did, with the transparent goal of getting it right,” he continued. “There was no doubt about the size of the cutting patterns. . . There were no spontaneous or random thoughts. . . It was debated for a long time considering the ultimate goal of getting a vaccine on time and not taking shortcuts.
Under the circumstances, it would be moderate to make the case, according to Yale’s Ramachandran. “There’s a higher fortune rate with phase 1 studies because they’re often small and meant to look only at protection and dose,” he said. “If there was no obvious protection on trial occasions, which would have stopped the trial at the time it was occurring, then you can also assume that the drug is safe before moving into phase 2. “
But he called the decision to abandon the arm “problematic. “For what? Such a resolution would possibly be feasible in a scenario where a vaccine is already an established product and has been shown to be effective. In this scenario, it would be unethical to have one arm instead of a comparison group, Ramachandran explained. But that was not the case in September 2020.
“Since phase 2 is meant to examine efficacy in addition to side effects, an arm is needed to demonstrate whether, thanks to the vaccine, the number one end results were achieved or if it was by chance. Without an arm for this phase, I would have no evidence of relative effectiveness compared to patients who don’t have access to anything at all,” he told us.
In addition, such knowledge is needed to monitor adjustments in population immunity due to immediate exposure to the virus. “Without this knowledge, any assessment would be biased by asymptomatic infection of (participants),” John said. “Not transparent from the point of view The documents presented that there was a moderate justification for cutting the length of the pattern or abandoning the arm altogether. “
Even more concerning, they said, is the resolution to approve the Phase 3 protocol, adding the vaccine candidate variety, while the Phase 2 trial is underway and effects are not yet known. Phase 2 is a protective and effective checkpoint for Phase 3 participants and is therefore a vital means of examining the hazards to those participants.
In other words, this is the point in the procedure where regulators would have to decide whether a larger Phase 3 trial would be beneficial, but the information from Phase 2 is needed to make that decision. Without the information, it is difficult to design a Phase 3 trial. , which is used to assess efficacy, ensure the evidence can be extrapolated to the general population and capture long-term side effects, Ramachandran said.
However, minutes of an October 5, 2020, meeting of the topic expert committee imply that the organization sought the candidate vaccine to decide on the basis of phase 2 protection and immunogenicity data, although the data had not been submitted through the company.
Another puzzle considers the main points provided in the protocols of the Phase 3 study.
A third edition of the Phase 3 protocol, dated October 2020, indicated that the vaccine candidate was decided based on animal studies and knowledge of Phase 1 interim studies (see page 15 for formula selection). However, a fourth edition of the protocol, dated March 2021, which after enrollment in Phase 3, stated that the candidate also decided to rely on the knowledge of immunogenicity and protection of Phase 2. (See page 15. ) The protocol was approved and recruitment was carried out.
“It gave the impression that the overall course of vaccine progression was being followed based on knowledge as you moved from one phase of the trial to the next,” Aisola said. “They strategically updated the protocol to replace the facts. “
However, Bharat Biotech’s Mohan argued that the company felt confident moving to Phase 3 as it did, given the effects of animal testing, and that the decision to set the dosage was “extremely debated”. He denied that shortcuts had been taken and that there was “a lot of refusal from regulators” to justify the company’s decisions.
“There is a continuum of verification results, a continuum of decision-making and a continuum of achieving final results. As we accumulated knowledge and gained confidence, we seemed to be on the right track. So we didn’t wait for phase 2. . . We said, “Let’s start with phase 3. We can continue to investigate, but we would be late. “
“They criticized us for being backward and there was tension in the country. . . Some of them were politicians and some of them were scientists. . . I think the resolution to move forward is quite rigorous.
However, discrepancies and protocol adjustments led John of Christian Medical College to recommend that it merit review. “The apparent inconsistencies in the publications in relation to their submissions are deeply troubling and should be thoroughly examined,” he wrote.
When asked if the editors of the Lancet Infectious Diseases would investigate the published findings, a spokesperson wrote to say that “we are in contact with the authors and will provide additional updates as needed. “
He added that the Lancet publishing organization “sets incredibly high standards for publication, and we are committed to making sure our editorial processes meet our criteria of excellence. All original study articles published in the Lancet journals are subject to independent external peer review and adhere to Practice recommendations for excellence in publishing based on recommendations made through the International Committee of Medical Journal Editors and adhere to the rules of the Publication Ethics Committee.
Meanwhile, the episode confirms persistent considerations about the Indian government’s oversight of medical product development, according to Aisola. Goals.
“We know that government has been an integral component of the overall process. The vaccine came from a government lab and was only presented to Bharat Biotech to expand it,” he told us. “Subsequently, the government supervised it and directed it to the point where it was deployed with Phase 3 that did not end at that time.
“It’s about taking shortcuts and pushing for an Indian vaccine. . . We now have a regulatory formula that is deeply committed for the future. They did things that are not in the rule book and it has the norm. And that’s the maximum damage. “
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