Representative photo: analuisa gamboa/Unsplash
Mumbai: Since the start of the COVID-19 pandemic last year, researchers around the world have evaluated scores of drugs and therapeutic techniques for the disease. Even according to the Clinical Trial Registry of India (CTRI), researchers in the country are testing everything from inhaled camphor and ajwain to Viagra.
This may be desperation, given the brutality of India’s second COVID-19 outbreak. It is also worthwhile in more ways than one to repurpose existing drugs to treat COVID-19.
However, in most cases, a substantial profit motive isn’t too far away. Together with India’s opaque drug regulation apparatus and its propensity to approve substances on little to no evidence – especially during the pandemic itself – these clinical trials warrant a closer look.
However, the Union health ministry’s clinical guidance document to manage COVID-19 – prepared by experts at the All Institute of Medical Sciences and the Indian Council of Medical Research (ICMR) – doesn’t feature favipiravir, itolizumab, Virafin or 2-DG. Why – especially since the regulator that approved these drugs is also under the health ministry?
Thymosin alpha 1
Mumbai-based Gufic Bioscience wanted the national drug regulator to waive clinical trials for Thymosin alpha 1, an immunomodulator that it makes. In a meeting on August 5, 2020, the Subject Expert Committee (SEC), a group of independent experts that advises the regulator, rejected its proposal and asked it to conduct phase clinical 3 trials.
The phase 3 trials for Thymosin alpha 1 began enrolling 120 people with moderate to severe COVID-19 on October 12, 2020. According to the company’s CTRI entry, the trial should have ended in 28 days (by November 10). But Gufic hasn’t issued or released any press release, preprint paper, published paper or any other update on the trial’s results. An email to the company asking about the results hadn’t been answered at the time of publishing.
Mylan and NSRT
Mylan, one of the world’s largest generic drug-makers, sought approval for daclatasvir dihydrochloride, a combination drug used to treat hepatitis C, based on some small studies conducted in Iran. The SEC rejected their request for trial waiver and asked that they conduct phase 3 trials.
Then, in a meeting on September 14, 2020, the SEC said it wasn’t convinced with Mylan’s plans for phase 3 trials and asked the company to conduct phase 2 trials instead.
But before the drug regulator had approved the phase 2 trial, Mylan submitted another request to approve a combination of their two hepatitis C drugs along with nitazoxanide, an antiparasitic agent. The SEC rejected this on October 22, 2020 – and asked Mylan to add more government hospitals in its phase 2 trial as well as to appoint a data safety and monitoring board (DSMB), a group of independent experts, to monitor the trial. The results are expected soon.
Similarly, Gujarat-based Navin Saxena Research and Technology (NSRT) submitted a repurposing request for eflornithine, an antiparasitic drug used mostly in Africa to treat sleeping sickness. The NSRT’s request specified the use of eflornithine in a dose that thus far has never been approved for use in humans (similar to concerns over another antiparasitic agent in the news, ivermectin).
Inosine Pranobex was developed in the 1970s (although some records suggest it could be older). Since then, researchers have tried to use it with many diseases, including serious ones like HIV/AIDS and amyotrophic lateral sclerosis (of the ‘ice bucket challenge’ fame).
To date, the US FDA hasn’t approved it for any disease.
In fact, one FDA official had said that Inosine Pranobex was ‘a drug in search of a disease’, according to a 2003 interview.
The drug also failed a recent phase 4 clinical trial – in which researchers and officials monitor the drug’s performance in real-life scenarios. Here researchers from the Czech Republic and Slovakia tested it against respiratory infections caused by the influenza and parainfluenza viruses, the respiratory syncytial virus and an unspecified adenovirus.
(The paper’s conclusion says the drug is safe to use – based on the secondary endpoint; the study failed on the primary endpoint. As the results say: “‘The difference in time to resolution of all influenza-like symptoms between treatment groups was not statistically significant.”)
On July 10, 2020, the SEC declined Themis Medicare’s application for India’s drug regulator to approve Inosine Pranobex against nine diseases, including COVID-19. Themis applied for approval again on November 6, 2020, after a ‘proof of concept” phase 2 trial – but the SEC rejected it again for “inadequate evidence”.
Themis is currently conducting a phase 3 trial for Inosine Pranobex in COVID-19 patients across India.
Pharmaceutical companies often outsource trial-related operations to contract research organisations (CROs).
Parexel is one of the world’s largest CROs. It represented JS016 (etesevimab), a monoclonal antibody against SARS-CoV-2 that Eli Lilly and a Junshi Bioscience, Chinese firm, had developed together, at an SEC meeting. While signing off on its approval for phase 2 trials, the SEC said Parexel should remove one of the principal investigators in the trial as they were a plastic surgeon.
This is a major oversight. JS016 is to be administered intravenously and comes with a not insubstantial risk of causing serious adverse events like severe allergic reactions. Principal investigators are clinicians who are responsible for an entire site in a trial, including providing care for patients who have developed serious, even life-threatening, side-effects. Therefore, they need to be properly qualified.
At a November 2020 meeting with the SEC, Eli Lilly also asked for clinical trials for bamlanivimab, another antibody, to be waived. Before this meeting, bamlanivimab had failed in Eli Lilly’s trials as well as in another conducted by the US government. Yet Eli Lilly had wanted bamlanivimab to be approved in India. The SEC rejected the idea.
Currently, the FDA has granted emergency approval to bamlanivimab and JS016 (etesevimab) used together. The combo is approved for use only with people who have moderate COVID-19 and who don’t require oxygen or hospitalisation. The FDA approval also notes that there is a chance the combination treatment may fail because new virus variants may resist their effects.
Parexel, the CRO, also approached the regulator on behalf of drug-makers with a proposal to conduct phase 3 clinical trials for an antibiotic called carrimycin, for COVID-19 patients. Other than China, where the Shenyang Tonglian Group developed it, carrimycin hasn’t been approved anywhere else in the world. India’s SEC also rejected Parexel’s request and noted that the data from the phase 1 and 2 trials for this drug were inadequate.
Similarly, Parexel presented a proposal to conduct phase 2/3 trials for vilobelimab, a monoclonal antibody that the FDA hadn’t approved for any disease yet. The SEC rejected the request because the drug failed a phase 2 trial vis-à-vis COVID-19. Parexel resubmitted the request a month later, only to be rejected again.
Poorly designed trials
Many COVID-19-related clinical trials have several methodological flaws.
A common one is for a non-blinded trial to have a subjective endpoint. That is, the trial’s success is measured by a doctor’s evaluation of a patient’s improvement on a 1-10 scale (subjective endpoint), and the people administering the trial know who is receiving the treatment and who the placebo (non-blinded).
To make up for having a subjective endpoint, it is important that researchers blind the trial. But if the trial both has a subjective endpoint and is non-blinded, a significant conflict of interest arises: the doctor, who is typically paid by the pharma company that makes the drug under study, knows which patient got the drug when evaluating them on the 1-10 scale.
The FDA recommends that in COVID-related trials, researchers “should make every effort to incorporate blinding into their trials” and “in trials where blinding is impractical, FDA strongly recommends an objective endpoint (e.g. all-cause mortality).”
However, several clinical trials in India use subjective parameters and are not blinded – and the Drug Controller General of India condones this failure by approving drugs that have been ‘examined’ in such trials. Recent examples include Zydus Cadila’s Virafin and Dr Reddy and DRDO’s 2-DG.
There are more in the pipeline. Trials for Virchow Biotech’s hyperimmunoglobulin, Intas Pharmaceutical’s hyperimmunoglobulin, BerGenBio’s bemcentinib, NSRT’s eflornithine, Sun Pharmaceutical’s aqueous extract of Cocculus hirsutus, Glenmark’s umifenovir and Novartis’s DFV890 all use the same trial design.
Anant Bhan, an expert of bioethics and health policy, told The Wire Science that such trials end up providing substandard evidence.
“Unfortunately the regulator is not discouraging such studies, and is instead providing approval based on such study designs. This leads to situations where there are drugs available, and these drugs being used by physicians, being sought by patients and their families in the absence of high-quality evidence on their efficacy and/or safety,” he said.
Murali Neelakantan, principal lawyer at amicus and former global general counsel for Cipla and Glenmark, said, “Given the sad state of drug regulations in India, it is predictable that Indian pharma companies will game the system to get drugs approved based on poor clinical trials.”
According to him, these companies have “easy access to the market”, and when they market their products as being ‘unique’, “there is a huge upside to doing shoddy trials and getting approvals.”
This situation is unlike the one in the economically developed world – “where there is a huge risk of product liability litigation,” he added. “Indian drug companies benefit from the tardiness of the drug regulator and the Indian legal system.”
Many trials are also out of step with evidence emerging from large international trials. For example, on March 5, 2021, researchers from the UK’s major RECOVERY trial announced that colchicine is not effective against COVID-19. Their trial had 2,363 participants. But according to CTRI, Laxai Life Science registered a trial for colchicine on April 6, 2021 – a month later. This trial is also unblinded and uses subjective endpoints.
Behind an opaque window
Repurposing a drug for a new disease is a common and accepted practice in the drug industry. “It’s not unusual to find new uses for known drugs,” Neelakantan said. “There is even a separate regulatory pathway for it in the US, commonly known as 505(b)(2).”
However, repurposing drugs – especially through flawed clinical trials – during a debilitating pandemic ought to spell some differences in our approach and thinking.
“While repurposing drugs could be useful for COVID-19, there could be harm too, or no benefits,” according to Bhan. “The only way to know is to conduct well-designed studies – and the experience in the last many months has shown us that it is possible to run such studies in short periods of time.”
Trials with small cohorts and flawed methods yield inconclusive results – and betray the trust of patients who participate in them. And when the regulator approves these products, it shares some of the blame as well.
Regulators in the US and Europe have shared guidance documents for the pharmaceutical industry that detail the design and protocols a good drug trial should have. The Central Drug Standards Control Organisation (CDSCO) released a similar document for vaccines on September 21, 2020, but nothing for drugs, which continues to remain the wild west of dodgy trials.
In 2020 and after, the SEC has rejected applications for trial waiver and approval for Swati Spentose’s pentosan polysulfate, Eris Lifesciences’ recombinant human thrombopoietin, Micro Labs’ hydroxychloroquine-based nasal spray, Macleod Pharma’s chewable favipiravir tablets and Bharat Parenterals’ oral favipiravir suspension. The body also declined Dr Reddy’s proposal to approve an arthritis drug called olokizumab.
This said, the SEC’s decisions aren’t beyond question either. It has provided sensible recommendations to the drug regulator in some cases but not others. We don’t know the rationale behind these choices because the committee’s workings aren’t in the public domain.
The CDSCO releases the minutes of most SEC meetings on its website but these are usually only just a few lines long. There is no way for experts and doctors to know what evidence the SEC evaluated or how they interpreted whatever details pharma firms provided. We also don’t know if any member of the SEC dissented with their recommendations and, if so, what their objections were. A 2019 audit of 317 SEC meetings concluded: “There is considerable heterogeneity in the minutes with almost no insight into the process of decision-making.”
At the other extreme: the US FDA live-streamed the expert committee’s approval meeting for the Pfizer-BioNTech vaccine; it lasted nine hours. The Drug Controller General of India released seven sentences summarising the Indian SEC’s meeting ahead of Covaxin’s approval.
The SEC reviews the details of a clinical trial before it begins. In COVID-related meetings, its recommendations for trials have been haphazard. For example, it recommended blinding the phase 3 trials for Thymosin alpha 1, Inosine Pranobex and Glutathione – but allowed similar trials for 2-DG, Virafin and favipiravir to proceed unblinded.
The Wire Science also found that the CDSCO hasn’t uploaded the minutes of four SEC meetings (128th, 136th, 145th and 152nd meetings). The minutes for SEC meetings in May haven’t been published yet either. This is against the CDSCO’s and ICMR’s own 2017 guidelines, which say SEC meeting minutes should be released within three days.
“Restricting information denies the people the transparency they deserve and need to be able to be vigilant against arbitrariness by the drug regulator,” Neelakantan said. “It would have helped everyone if full details of the data considered by and the discussions of the SEC were available, in the same way the FDA did for vaccines.”
Doing so, according to him, would have reassured “scientists, doctors and all people about the drugs and vaccines approved”.