Lack of clarity, rigour raise doubts over Covid-19 vaccine trials: Experts

The problem is that traditionally there has been poor scrutiny of clinical trials in India where often the emphasis is on cutting costs, said Arun Bhatt, former president of the ISCR

Jammi Nagaraj Rao, a UK-based public health physician and epidemiologist, has scanned through approximately 477 COVID-19 trials registered on India’s Clinical Trials Registry. Around 192 of these were observational studies, not multi-phase randomised clinical trials. And at least 53 were for traditional Indian remedies and homoeopathy.

“Many are badly designed and unlikely to set the world alight. Some are downright mischievous,” said Rao. He also advised special caution with the vaccine trials India is conducting: “With drug trials, a repurposed drug is being given to someone already ill. In vaccine trials, an entirely new formulation will be given to un-infected volunteers. Trials have to be done very safely robustly.”

Clinical trials in India for drugs to treat COVID-19 lack the rigour needed to make them trustworthy, medical researchers told IndiaSpend. Ideally these trials should be randomised and controlled, as per the World Health Organization. But current Indian trials have a small number of participants and are characterised by poor and biased study design, experts said. These trials also do not follow the globally accepted good practice of being published in peer-reviewed research journals, for the scrutiny of the scientific fraternity.

To date, no drug or vaccine has been found to be effective in curing or preventing the SARS-CoV-2 virus that has affected over 2.8 million Indians and caused more than 53,000 deaths in India till August 20. Indian pharma companies have been racing to repurpose old drugs or offer alternative therapies to treat the disease, while regulators have been hurrying to approve them by waiving accepted research norms. This haste is producing questionable results, experts like Rao fear.

“Whether it’s an electric toaster or a paracetamol tablet, we depend on the reliability and integrity of public regulators to protect us from poor practice. Patients with serious illnesses have little choice but to rely on professionals and regulators to maintain the highest standards in clinical research, so that the drugs they take are both safe and effective,” said Rao.

With clinical trials bypassing accepted norms of research, do doctors and patients have enough data to take the right decision on drugs investigated in Indian clinical trials?

“At our hospital, we strongly believe in evidence-based medicine. So we are not prescribing drugs for COVID-19 which everyone is buzzing about -- like tocilizumab, hydroxychloroquine or favipiravir. I would not take these drugs myself. We need to see robust evidence,” said S.P. Kalantri, director and professor of medicine at the Mahatma Gandhi Institute of Medical Sciences, Maharashtra.

The fact that most of these drugs have been repurposed and reinvestigated does not mean that they can have discounted clinical trial standards, said Kalantri. “With a repurposed drug, at best we know the side-effects. But other than that we have no information about its efficacy for a new condition like COVID-19. Hence we still need high-powered clinical trials,” he said.

Small trial sizes

Consider the sample size as one metric to assess Indian clinical trials for COVID-19:

• There were 30 participants in the phase 2 trial for Biocon’s drug formulation itolizumab (normally used to treat psoriasis). The drug regulator then waived the mandatory phase 3 trial altogether. Soon after, the government-appointed National Task Force for COVID-19 asked the company to provide more evidence on this drug.
• There were 100 participants for Patanjali’s trial for Coronil, a herbal concoction claimed as a “cure” for COVID-19. After the company began to advertise its claims, the government asked it to stop until its research could be further validated.
• The phase 3 trial of Glenmark’s favipiravir, an antiviral drug, had 150 patients, whereas phase three trials are generally much larger. The company was given an accelerated authorisation by India’s drug controller, based on data privately submitted to the drug regulator. Soon after, the company was pulled up by the same regulator for making false claims about its use and overpricing.

Contrast these trials with the sample sizes of some of the most prominent trials abroad for drugs to tackle COVID-19 -- the RECOVERY trial in the UK and the SOLIDARITY trial led by the World Health Organization (WHO), for instance. Since March, the RECOVERY trial has enrolled 12,240 participants at 176 active sites to study six types of potential treatments for COVID-19. The WHO’s SOLIDARITY trial was spread across 21 countries with nearly 5,500 patient participants, as of July 1, 2020.

The RECOVERY trial in the United Kingdom is a useful model for conducting a large, robust trial quickly and transparently. For example, the dexamethasone arm had 6,425 participants, and the hydroxychloroquine arm had 4,674. The studies on both these drugs have been completed; they concluded that dexamethasone reduced death in patients with severe respiratory complications, and that hydroxychloroquine had no benefit in patients hospitalised with COVID-19.

RECOVERY was designed in such a way that recruiting large numbers was made a priority. Every COVID-19 patient in the UK is invited to participate, according to its website, and 13% of all hospital admissions had agreed to take part. To obtain “strong evidence”, the trial would require “large numbers” of 2,000 participants per arm, the website said. This thrust has meant that the UK has been able to have such a large trial, despite having a much smaller population and lower COVID-19 count than India.

No presence in top research journals

In the research fraternity, it is considered a good practice to publish the results of a clinical trial. But none of the Indian companies that declared their formulations as effective in dealing with COVID-19 -- Biocon, Glenmark or Patanjali -- have published their research in known peer-reviewed journals, in the weeks since they announced their findings. Instead, details of the trials are being communicated through press releases and press conferences.

“In just a few months after the virus was discovered, trials like RECOVERY, SOLIDARITY, and by scientists at the National Institutes of Health and in Wuhan, managed to publish their trial data, and in prestigious medical journals. This greatly influenced COVID treatments. By contrast, Indian scientists haven’t put out good studies for scrutiny in the pandemic-- this is a case of missed opportunity.,” said Kalantri.

All through the pandemic, a large amount of scientific literature has been published by scientists around the world, either in the form of pre-prints (versions published before peer review) or as peer-reviewed papers (examples here, here and here). The data is being scrutinised by researchers around the world, with their papers upheld or debunked, and even retracted.

The British Medical Journal (BMJ) has been maintaining a regularly updated database with a review of the current evidence for COVID-19 treatment, drawing from the published works of researchers around the world. It is updated as and when trial information is published.

But there is no Indian research that has made it into this meta-analysis (an analysis combining the results of multiple scientific studies). One of the researchers working on this database told IndiaSpend that the reason for this is that the analysis "looks at pre-print and published trials and there were not any from India".

Transparency issues flagged

India’s public health community has been alert to the problems in Indian clinical research even before the COVID-19 pandemic.

“We should have had clinical trials during this pandemic that we could be proud of, which showed the world the way forward. In a country of 1.3 billion people and over 500 medical colleges, we should be able to complete trials and generate our own clinical data,” said Kalantri.

The problem is that traditionally there has been poor scrutiny of clinical trials in India where often the emphasis is on cutting costs, said Arun Bhatt, former president of the Indian Society for Clinical Research.

“We have always had small trials in India, with the Indian drug regulator not often asking that a trial applicant get more participants. So obviously, for a pharma company, any extra patient in a trial is an extra cost for them. And if no one is asking them to get more patients in, why should they?” said Bhatt.

On August 5, 2020, 12 health professionals and civil society activists wrote to the Union health ministry asking for more transparency in clinical trials and drug regulation in India. They asked that the clinical trial registry also upload the minutes of the ethics committee deliberations on the granting of permission to clinical trials. They also pointed out that the registry does not ask for investigators to publish information about primary data sets, which could possibly allow pharmaceutical companies to cherry-pick data. File notings and the rationale for approval/rejection of drugs should be made public, they said.

The Indian Society for Clinical Research wrote in March to the Indian government with specific advice on how best to conduct clinical trials during the pandemic. In their note, they also sent links to best practices in other countries.

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