India’s drug regulator has failed the pandemic stress test. The U.S. should take notice

The Covid-19 pandemic has served as a stress test for drug regulators across the world. India’s has failed.

Amid the desperate scrambles for therapeutics and vaccines to stem the havoc caused by the pandemic, drug regulators have had to resist tremendous political pressure to approve unproven therapies. Rick Bright, the former head of the Biomedical Advanced Research and Development Authority (BARDA), the federal agency that helps secure the U.S. from chemical, biological, radiological, nuclear, and emerging infectious disease threats, left his position, alleging in his whistleblower complaint that he faced political pressure to allow the distribution of hydroxychloroquine, an unproven drug for treating Covid-19 that had been championed by President Trump.

It is no different in countries like India, which have traditionally supplied vaccines to many low-income countries. With its capacity to manufacture 3 billion vaccine doses a year, India is key to ensuring that the global population receives effective vaccines in a timely manner.

An important agenda item for the incoming Biden administration is reestablishing America’s credibility in multilateral initiatives and access to affordable vaccines led by the World Health Organization. Given that much of the manufacturing of vaccines intended for low-income countries will most probably be in India, and supported by the United States Agency for International Development, it is incumbent on the new administration to make a clear-eyed assessment of the capability and the function of the drug regulator in India and other countries where these vaccines will be made.

The Indian regulator is the Central Drugs Standard Control Organization (CDSCO), which is headed by the Drug Controller General of India (DCGI), a post currently held by Dr. V.G. Somani. The organization has been embroiled in a series of controversies over the approval of new drugs being actively pushed by Indian pharmaceutical companies during this pandemic and in the conduct of clinical studies for Covid-19 vaccines.

I’ll begin with the approvals of two “new” drugs — itolizumab and favipiravir — for treating Covid-19 patients. Indian regulations define new drugs as those that have not previously been used to treat specific indications in the country.

The itolizumab approval

Itolizumab (Alzumab) is an anti-CD6 monoclonal antibody that was originally developed by Biocon, one of India’s largest pharmaceutical companies, to treat psoriasis. The company was hopeful that the drug could be repurposed to treat the cytokine storm that can occur in severe cases of Covid-19.

But instead of testing this hypothesis in a well-designed clinical trial, the drug was tested on a small cohort of 30 patients. On the basis of data generated from this poorly designed study, CDSCO granted the company an emergency use authorization (EUA) so itolizumab could be used treat cytokine release syndrome in patients with moderate-to-severe Covid-19 and acute respiratory distress syndrome on the recommendation of a “subject expert committee.” The approval was granted subject to the company conducting a Phase 4 study, which involves post-marketing surveillance. In effect, CDSCO waived a typical, rigorously designed Phase 3 clinical trial, like those had been carried out in the U.S. and Europe to evaluate the efficacy of remdesivir and dexamethasone.

The CDSCO’s actions soon came under withering criticism for a number of reasons including a poorly designed trial, lack of rigor, lack of transparency about the membership of the subject expert committee, and confusion about the provision in Indian law that allowed for emergency use authorization.

The National Taskforce of the Government of India that was set up to determine treatment protocols for Covid-19 declined to include itolizumab in the national treatment protocol, exposing how even government bodies had little faith in the regulatory process that was used to approve the drug for treating Covid-19 patients.

When questioned about the legal basis on which the approval was granted, Sundar Ramanan, the head of Biocon’s regulatory affairs who answered on behalf of the Indian drug regulator, falsely claimed that the EUA was granted under a specific section of India’s Drugs & Cosmetics Act, which can be used by the government during epidemics.

This was simply not true. Drug approval under Section 26B requires publication of the government’s decision in the Gazette of India, the country’s equivalent of the U.S.’ Federal Register, yet the Gazette of India had published no such information about Section 26B being invoked for approval of Biocon’s drug.

In response to an RTI query (the Indian equivalent of the Freedom of Information Act in the U.S.) that a colleague of mine had filed, CDCSO denied that the approval for adding the treatment of Covid-19 to itolizumab’s indications had been granted under the provisions of Section 26B, but that it had had been granted emergency use authorization.

It’s reasonable to ask why the company would intentionally mislead people and, more importantly, why India’s drug regulator let this misinformation stand without a rebuttal. It also turned out that the New Drugs and Clinical Trial Rules of 2019 (more on that later) which govern the approval of new drugs in India, actually had no provisions allowing the government to grant EUAs.

In a recent press conference, director Somani apparently conceded that there is no provision for granting an EUA under Indian law, and that his office in fact granted an accelerated approval for it. Under Indian law, accelerated approval can be granted when a new drug demonstrates “significant” or “remarkable” advantages in terms of efficacy — none of which have been shown for itolizumab.

Despite the confusion surrounding itolizumab and its non-inclusion in the national treatment protocol, Biocon has reportedly seen a sevenfold increase in its sales in October. Of interest, Biocon’s U.S. partner, Equillium, which had announced in July that it intended to conduct Phase 3 trials for itolizumab, announced on Nov. 25 it would not conduct trials for this indication, meaning that the company had abandoned any plans to seek a FDA approval for the drug.

The favipiravir approval

The second dodgy approval granted during this pandemic by the CDSCO is for favipiravir (sold as FabiFlu in India), an antiretroviral drug developed by Japan’s Fujifilm Group to treat influenza that it licensed to Mumbai-based Glenmark Pharmaceuticals.

In June 2020, director Somani, on behalf of CDSCO, granted Glenmark “emergency use” approval to market favipiravir as a treatment for mild and moderate cases of Covid-19. Experts have raised serious questions about the efficacy of this drug in treating patients with Covid-19. A review of the literature on favipiravir in June by a trio of Indian researchers concluded that there was no convincing evidence for the efficacy of the drug in treating Covid-19. At the time, there were serious questions being raised about the medical basis of the approval granted to Glenmark, since the DCGI was simply not disclosing any information that Glenmark had provided upon which the CDSCO based its approval.

Glenmark recently announced the results of a Phase 3 trial it conducted in India on the efficacy of favipiravir for Covid-19. It claimed the drug was more effective than the standard of care for treating mild and moderate cases of Covid-19. Critics have questioned the company’s claim, asking why the trial was open label and why the outcome regarding the primary endpoint, which was viral clearance, was not statistically significant. The company has been accused of cherry picking from the trial’s secondary endpoints to launch a media campaign claiming the drug is effective for treating Covid-19.

Controversy notwithstanding, the company has made significant profits from the sale of favipiravir, because several Indian states have included the drug in their treatment protocols. The Municipal Corporation of Bombay alone has reportedly bought 2.7 million tablets of FabiFlu.

The fiasco of vaccine trials

In addition to being a global capital for makers of generic drugs, India is also home to some of the largest vaccine manufacturers in the world. Several clinical trials are underway there to test the efficacy of both domestic and internationally developed vaccines. Prominent among these are two trials: one by the Serum Institute of India, which is testing the Oxford-Astra Zeneca vaccine; the other by Bharat Biotech, which is testing the company’s vaccine candidate. Both trials have run into a storm of bad publicity because of missteps by the companies and by the drug regulator tasked with oversight of these clinical trials.

One patient enrolled in the study sponsored by Serum Institute of India reported a serious adverse event in October 2020: The patient could not recognize his family for a few days, and was diagnosed with acute encephalopathy. This information was not immediately disclosed, and wasn’t reported widely until a few weeks later after the volunteer decided to sue the institute for heavy damages, claiming that the vaccine was the cause of his neurological disorder.

The company’s response? It announced its decision to countersue the patient for five times the sum, claiming defamation by the volunteer since the institutional ethics committee, the data safety monitoring board, and the regulator had concluded that there was no link between the vaccine and the serious adverse event suffered by the volunteer.

None of this inspires confidence in the development process or the efficacy of the vaccines. In the U.K. and the U.S., clinical trials for Covid-19 vaccines were temporary halted as soon as volunteers reported serious adverse events and remained halted until there as an investigation and the data and safety monitoring board gave its approval to proceed. Both the companies and the regulators informed the public about these events in a relatively transparent manner. In India, we never heard about the severe adverse event until news of the legal threat spilled into the media.

A similar “irregularity” occurred in a Phase 1 trial of the Bharat Biotech vaccine, in which a participant developed viral pneumonitis in August 2020. The company did not report this information, which came to light only after it was leaked to the Economic Times in November. The DCGI did not deem it necessary to either inform the public or halt the trials until a transparent investigation had been conducted into whether the pneumonitis was, or was not, causally related to the use of the vaccine candidate.

A second fiasco with the Bharat Biotech vaccine candidate took place when a minister in a state government was diagnosed with Covid-19 after enrolling himself in the trial with great fanfare. His participation in the study was highly publicized and while it is not clear which arm of the study he was randomized to, claims were made by the sponsor that he did not receive the vaccine candidate. The damage to public confidence has very most likely been already done.

As in the U.S., vaccine makers in India and the drug regulator are under serious political pressure to get vaccines to the market. A recent visit by Narendra Modi, India’s prime minister, to all the major vaccine manufacturers in the country was highly publicized and has only increased the pressure on the drug regulator and clinical trial sponsors to succeed.

A decade of regulatory failures

These regulatory failures did not emerge with the Covid-19 pandemic. They reflect more than a decade of such failures in India.

In the past decade, the CDSCO has been the subject of two parliamentary investigations and one sweeping injunction by the Indian Supreme Court. In 2012, the Parliamentary Standing Committee on Health and Family Welfare exposed shocking lapses in how four new drugs that had never been authorized in better regulated markets like those in Europe or the United States received approval in India.

A subsequent inquiry report into the manner of these approvals was made public, earlier this year, only after a long battle under India’s Right to Information Act forced the government to publish the report after claiming for years that the report was not traceable.

No action was taken against the officers within the CDSCO found to be responsible for approving these questionable drugs.

The second parliamentary report, in 2013, focused on irregularities in the conduct of clinical trials for the HPV vaccine in India. That report exposed serious ethical lapses in the informed consent process because of a poor regulatory framework for overseeing clinical trials in India. Later that same year, the Indian Supreme Court passed a sweeping temporary injunction restraining the government from providing permission to conduct future clinical studies until it could reform the regulatory process.

These two reports and the order of the Indian Supreme Court have led to half-baked reforms culminating in the 2019 New Drug and Clinical Trial Rules, which were passed via executive fiat rather than legislative action. Within a year of the creation of this new regulatory regime, it has become clear that changing laws will have no effect until the people who are meant to police it have the necessary training and political will to enforce the law.

The pandemic has severely constrained the U.S. FDA from inspecting overseas manufacturing facilities that supply the U.S. market with drugs and vaccines. In fact, Sen. Elizabeth Warren has recently written to the FDA commissioner voicing her concerns about the quality of the drug supply chain.

The agency has given a waiver to vaccine manufacturers in order to meet the demand for vaccines as soon as they are approved for large-scale immunization across the U.S. But given the track record of the CDSCO to enforce quality standards, it is myopic to extend these waivers to manufacturing facilities located overseas that fall under the purview of a dysfunctional drug regulator.

Dinesh Thakur, the former director and global head of research information and portfolio management at Ranbaxy Laboratories, was the whistleblower in the Ranbaxy case and is a key source in “Bottle of Lies” by Katherine Eban. He is now a public health activist focused on improving the quality of affordable medicines.