THE COVID-19 caseload continues to rise in India, with State governments, including those of Delhi and the industrial hub Maharashtra, signalling that their States are experiencing new waves of the pandemic. The mortality rate has recorded a corresponding spike, and at the moment of writing, it had crossed 1,33,000. Authorities are scrambling to find ways to contain the spread of the virus. There is little doubt that effective treatment is of the utmost urgency, but would it be all right to approve drugs before there is sufficient scientific evidence of their efficacy and before the stipulated regulatory trials have been conducted?
Critical reports on the pharmaceutical companies involved in the development of vaccines for COVID-19 have aggravated the worries surrounding the treatment and control of the disease in India. It was reported that the trial for the vaccine Covaxin was continued without a pause despite a serious adverse event. Obviously, the news of the adverse event was withheld from the public when it occurred. The established practice is to halt a trial when there is any serious adverse event. Covaxin is the much-touted Indian vaccine that Bharat Biotech International Ltd (Hyderabad) and the Indian Council of Medical Research (ICMR) are developing. The Serum Institute of India Pvt. Ltd in Pune, Maharashtra, and Cadila Healthcare Ltd in Ahmedabad, Gujarat, are the other Indian pharma majors in the vaccine race.
Even more shocking, some of the drugs the Drugs Controller General of India (DCGI) has approved for use in COVID-19 treatment also have a history of adverse events that the competent authorities have not properly investigated. It has been confirmed that during the clinical phase II trial for the drug itolizumab (alzumab)—which is manufactured and marketed by Biocon Biologics, a subsidiary of Biocon Limited, founded by Kiran Mazumdar-Shaw—at least two COVID-19 patients were taken off the trial because of severe adverse events. So says a separate presentation/report from Biocon on the trial that surfaced in the public domain in August (source: https://www.biocon.com/docs/FINAL_Biocon_Itolizumab_COVID19_Study_Summary.pdf (page/slide 4)). One of the two patients died nine days after being taken off the trial because of an infusion reaction upon initiation of the first dose, as per Biocon’s own report (referenced above). However, the data available in the public domain indicate that the drug control authorities did not take these serious adverse events into consideration when they granted approval for the drug.
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Itolizumab was originally approved for the treatment of psoriasis in 2012. On July 10, it was approved for “restricted emergency use”, and the DCGI waived the requirement for a phase III clinical trial. The anti-viral drugs favipiravir and remdesivir were approved for COVID-19 patients in June. The World Health Organisation (WHO) recently advised against the use of remdesivir for hospitalised COVID-19 patients, citing lack of evidence for positive outcomes. The DCGI, which comes under the Central Drugs Standard Control Organisation (CDSCO), gave Glenmark Pharmaceuticals Ltd an accelerated authorisation for favipiravir after a phase III trial that had only 150 patients and much before the company shared the results of the trial. Five months after the DCGI approved the drug and it had been given to thousands of patients with mild to moderate symptoms, the company released its report on the phase III trial, the results of which proved to be inconclusive. “Lack of statistical significance on the primary endpoint was confounded by limitations of the RT-PCR [reverse transcription polymerase chain reaction] assay,” stated the report while maintaining that there was significant improvement in time to clinical cure.
Need for transparency
Advocacy groups such as the All India Drug Action Network (AIDAN) have sought transparency in the regulatory processes and approvals of COVID-19 drugs and vaccines. They have repeatedly written to the CDSCO seeking clarifications about the legal provisions under which approvals for restricted emergency use have been granted and whether any condition/restriction was attached to such approvals. Malini Aisola of AIDAN told
Frontline : “What does restricted emergency use even mean? There is no such terminology in the statute or rulebook. We have asked the CDSCO to share details of the evidence on the basis of which approvals were granted. Restricted emergency use approvals for favipiravir and itolizumab, which enabled these drugs to come on market, are deeply problematic because there was insufficient data to go on. Worse, the regulator waived requirements for phase III trials, which were essential for establishing any benefit to these drugs. What do these approvals even mean in light of the decisions to keep them out of the National Clinical Management Guidelines for COVID?”
It appears thar it was against this background and by citing lack of evidence that the NITI Aayog decided against including itolizumab in the Ministry of Health and Family Welfare’s clinical management guidelines for COVID-19. Therefore, the manner in which the itolizumab clinical trial was conducted and the norms of the regulatory process were flouted created a trust deficit in the public with regards to the actions of the drug controllers operating under the Health Ministry.
Itolizumab to treat CRS
Itolizumab was approved for the treatment of cytokine release syndrome (CRS) in patients with moderate to severe acute respiratory distress syndrome (ARDS) due to COVID-19. So far there is no conclusive study on the role of CRS in COVID-19. In fact, the findings from a systematic review and meta-analysis published recently in the peer-reviewed journal
The Lancet question the role of cytokine storm in COVID-19-induced organ dysfunction. Experts have pointed out that negative results of other repurposed drugs such as tocilizumab and sarilumab in the treatment of CRS in patients suffering from ARDS caused by COVID-19 raise the possibility of itolizumab also showing a negative result. Only a large, well-blinded randomised controlled trial (RCT) can prove otherwise.
Itolizumab is a biologic that is created from a cell line. This cell line was changed. On September 21, the Central Licencing Authority granted Biocon permission for post approval (supplement) change (a copy of the letter the DCGI sent to Biocon giving its approval is available with
Frontline ) under the provisions of the New Drugs and Clinical Trial Rules, 2019, to manufacture for sale the 100mg/vial (single-use vial) itolizumab injection pharmaceutical formulation based on the new cell line. This facilitates listing of itolizumab as a new drug approved for manufacturing and marketing in India for both psoriasis and CRS in ARDS due to COVID-19.
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According to the claims Biocon made in a press conference on July 13, the DCGI’s decision to waive the phase III clinical trial and approve the drug conditionally was after a positive end result, that is, the phase II trial indicated that there was a statistically significant mortality reduction with use of the drug: allegedly 20 patients on the treatment arm (itolizumab with standard care) recovered fully, while 3 out of 10 patients on the control arm (only standard care) died. The purpose of phase II trials is to evaluate the short-term adverse effects and associated risks of a drug and to derive the optimal dosage. The only thing for the company and regulatory body to do after a positive end result of such a trial would be to assess whether or not to continue with phase III clinical trials.
There were several major contradictions between Biocon’s report
on the phase II trial on COVID-19 patients, which became available in the public domain in August, and the data and results that Biocon presented in its July 13 press conference.. These contradictory reports showed that the premise on which itolizumab was said to get approval from the DCGI for treatment of COVID-19 patients was ill-informed. It further came to light that the phase II trial was not an RCT and several patients on the treatment arm were “selected”. According to a report in
The Wire Science , the chief medical officer of Biocon himself stated that five patients on the treatment arm were selected to test the safety of the drug. Additionally, the minutes of a meeting the Subject Expert Committee of the CDSCO had, on May 28 said that it had observed two serious issues with the ongoing trial then. Biocon had got and analysed interim data, which was not part of the protocol and could heavily influence the trial to achieve desired endpoints.
During the July 13 press conference, Biocon mentioned that two patients who were on the treatment arm were removed from the trial prior to dosing and replaced, whereas the report released in August said that they had been removed because they suffered an infusion reaction shortly after initiation of dosing. The trial design and objective desired an “intention to treat” analysis, which means that patients taken off treatment arms have to be analysed as patients are allocated arms after randomisation. All patients once randomised are included in the analysis to arrive at the result. The report further stated that one of the two discontinued patients died nine days later, while the other recovered.
The number of patients with comorbidities does not tally either. While in July the company said only one patient on the control arm had a comorbidity (diabetes), the report from August showed that the control arm had two patients with diabetes, two with hypertension and one with chronic obstructive pulmonary disease (COPD). A COPD-type of comorbidity was not mentioned earlier even though patients with this comorbidity are highly vulnerable to COVID-19.
Towards the end of the press conference on July 13, a video clip was shown of a COVID-19 patient being treated with itolizumab. The trial demanded observation of a patient for 30 days. That is, the trial could not have been over before July 21. However, it was said to have been concluded on July 7, and the DCGI granted conditional approval for use of the drug on July 10. Evidently, despite being an unproven drug, itolizumab was being administered for off-label use in some hospitals.
Off-label use
When a licensed drug is used for a medical condition for which it has not been approved, it is considered off-label use. This does not require the DCGI’s permission, and any physician can prescribe a drug if he/she thinks that it can save a patient’s life. Biocon admitted that while the phase II trials were going on, 150 patients were administered this drug off-label. According to Dr Amar Jesani, editor of
Indian Journal of Medical Ethics and a medical professional with considerable clinical experience, the decision regarding off-label use is the exclusive prerogative of the doctor with the consent of the patient. “The company has no role to play in such use. Indeed, any promotion of off-label use of a drug by the company, directly or indirectly, is unethical and illegal,” he told
Frontline .
Interestingly, Biocon introduced Dr Hemant Thacker, a cardio-metabolic specialist and consulting physician, during the press conference on July 13 as one of the experts who had led the clinical studies but did not categorise him as a principal investigator of the registered clinical trial. However, at the same press conference Dr Thacker said he was approached by Biocon to conduct the clinical trial and that he recruited the first patient on May 12. He said that he had recruited 21 patients for the clinical trial and five independent ones. By any yardstick, Dr Thacker’s involvement and the trial he advanced could be deemed only as “off-label” since he was not formally registered for the clinical trial. He advocated use of the drug in ventilated patients even though the protocol of the clinical trial strictly prohibited it.
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Such off-label use on behalf of a pharma company and promotion of the efficacy of an unproven drug have the potential to confuse the treatment guidelines that hospitals and other doctors follow. It raises another serious question: Why did Biocon approach a doctor to conduct the unregistered study or off-label use when the safety of the drug was unknown and a registered trial was under way? Some doctors have openly said that itolizumab is an effective drug and also suggested use on ventilated patients even though the clinical trial protocol was just for moderate to severe patients (not those on ventilators). In contrast to Dr Thacker’s off-label use, Dr Rosemary D’Souza, a registered principal investigator of the trial, started her trial on May 18 with the first recruitment. Currently, a phase IV (post-marketing surveillance) trial of the drug on a pool of 300 patients is going on and is expected to take a few months.
On the basis of the limited phase II trial, the DCGI gave its approval for restricted emergency use of itolizumab on COVID-19 patients. Experts, including Dr Shashank Joshi, overall coordinator of the trial, then expressed reservations about the small sample size. This trial had in total four to five principal investigators. One of them expressed his reservations on some platforms but not all that indeed a large RCT was needed. But it was not against phase II. What the CDSCO did was waive phase III (large RCT). Many other experts were of the view that the current sample size was insufficient to give conclusive evidence (source:
https://www.youtube.com/watch?v=2WE_6lqDyLE&feature=youtu.be&ab_channel=RajyaSabhaTV ). They said they had not used itolizumab to treat COVID-19 patients for two reasons. First, it was not a proven treatment for COVID-19, and second, the medical practitioners were adhering to the government’s clinical management guidelines, which did not include the drug. Dr Ravi Vaswani, COVID nodal officer for clinical care at the Yenepoya Medical College, Mangaluru, told
Frontline over the phone: “The evidence for its use is unclear. The possibility of harm and its magnitude are not defined. By nature, I’m not a doctor who thinks it fashionable to prescribe new drugs. How many more reasons do you need [for not using itolizumab]?”
Frontline has not got any response from Biocon to queries sent to it repeatedly through email.
Another relevant factor about itolizumab is that it is a relatively expensive drug, priced at Rs.7,950 for a 5 ml vial of alzumab injection and Rs.32,000 for the full therapy. Biocon’s aggressive marketing, however, increased the sales volumes of itolizumab by seven times in three months. Data from the market research firm AIOCD AWACS (All Indian Origin Chemists & Distributors Ltd Advanced Working, Action & Correction System) showed that from zero sales in June, 50 units were sold in July and 350 units in August.
U.S. firm’s partnership
Equillium Inc is a United States-based biotechnology company that had previously announced a partnership with Biocon to initiate a phase III clinical trial to evaluate itolizumab in hospitalised COVID-19 patients in the U.S. It has now put these plans on hold. Bruce Steel, chief executive officer of Equillium, in a statement said: “Based on a thorough review of recent updates regarding the efficacy of new potential vaccines and other treatment options, we have made the strategic decision not to initiate our Phase-3 trial as previously planned. We are continuing to assess the rapidly evolving clinical and commercial landscape related to this pandemic and may consider other options to evaluate Itolizumab in Covid-19 patients, including government research initiatives.”
According to the WHO, all existing treatments have proven ineffective against severe COVID-19 except for corticosteroids. This includes drugs that were championed by the likes of U.S. President Donald Trump. A WHO-supported trial, the results of which were released on October 15, came to the conclusion that remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferon had little or no effect on the overall mortality, initiation of ventilation and duration of hospital stay in hospitalised patients.
Alternative ‘remedies’
A simple search on the Clinical Trials Registry of India reveals that hundreds of observational and interventionist trials are going on in various hospitals and containment zones. Alternative home remedies are being peddled as effective strategies to ward off the virus, even by Prime Minister Narendra Modi. A hospital in Gujarat is conducting trials on the preventive effects of Ayurveda and homeopathy. Plans to give hydroxychloroquine to vulnerable slum dwellers in Mumbai were shelved only after experts pointed to the risks involved and the scant evidence for its efficacy. But it continues to be given to patients elsewhere despite studies showing that the drug alone was not associated with reduced mortality in hospitalised COVID-19 patients but that the combination of hydroxychloroquine and the antibiotic azithromycin significantly increased mortality.
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The yoga guru Baba Ramdev’s Patanjali, which manufactures everything from jeans to cow urine, was advertising a herbal concoction called Coronil as a cure for COVID-19 after conducting a trial on 100 people until the government asked it to stop doing so. While herbal concoctions and Ayurveda potions may not have severe side-effects, drug-related treatments have the potential to cause harm, which must be carefully weighed before they are pushed into the market to unsuspecting patients.
The WHO has cautioned physicians and medical associations against recommending or administering unproven treatments to patients with COVID-19 or people self-medicating with them. Instead of jumping into the fray with experimental treatments, the authorities should be careful and encourage a transparent trial process, suggest health experts. The scientific community’s concerns need to be addressed in a timely manner and the standard practise of publishing the results of clinical trials in peer-reviewed publications should be followed. Internationally, there have been multiple instances of phase II and phase III clinical trials showing contrasting results. Biocon is yet to publish its trial data or get them peer reviewed.
Moreover, Biocon’s defence that critical trial stages should be skipped as there is a pandemic raging does not hold water. The WHO and its partners launched one of the largest international RCTs called Solidarity Therapeutics Trial that has enrolled almost 12,000 patients in 500 hospital sites in over 30 countries. The progress achieved by this collaborative effort and the RECOVERY trials in the United Kingdom show that large, well-blinded RCTs are possible even during a pandemic without compromising people’s lives. Even the phase II clinical trial (called PLACID) the ICMR conducted to test the efficacy of plasma therapy for COVID-19 treatment had 464 patients. Indeed, there are vital issues and questions that need to be answered before drugs are administered to patients even to effect a partial cure or control. But in India even official agencies seem to look the other way when it comes to ensuring compliance with standard regulatory processes and adherence to scientific evidence.
Siddhartha Das has a PhD in physics and is a researcher in quantum information theory. He is actively involved in pursuing his interest on the linkages between public health, science and medical ethics.