The initial discourse around COVID 19 focused on testing, critiques of containment measures, projections of the number of infections during the ‘peak’ of the epidemic, and consequently preparedness of the health system to respond to the same. In India, the epidemic has accelerated in recent weeks and the health system is feeling the pressure of the rising number of infections. So there is a consequent urgent focus on treatment options and scrutinizing preliminary results from clinical trials of potential drugs that could be used. There is also a frantic race for the development of a vaccine against COVID-19 with several stakeholders from governments, private foundations, academic institutions, international bodies, pharmaceutical companies collaborating together in what is seen as ‘an unprecedented’ manner.
Global collaboration and the race for treatments and vaccines for COVID 19
On 24th April 2020, the WHO launched the ACCESS TO COVID-19 TOOLS (ACT) ACCELERATOR which is an effort at “A Global Collaboration to Accelerate the Development, Production and Equitable Access to New COVID-19 diagnostics, therapeutics and vaccines”. This collaborative effort includes BMGF, CEPI, Gavi, Global Fund, UNITAID, Wellcome Trust among others, and has committed itself to “equitable global access to innovative tools for COVID-19 for all”.
As of June 12, 2020, there were almost 2,100 trials testing drugs and vaccines targeting COVID-19. Of these, over 231 were still in the first phase, 1029 in Phase II, 580 in Phase III, and 225 trials in Phase IV of clinical trials.
Among the prominent clinical trials currently underway is the Solidarity Trial launched by the World Health Organization and its partners. The Solidarity Trial will compare four treatment options against standard of care, to assess their relative effectiveness against COVID-19. By enrolling patients in multiple countries, the Solidarity Trial aims to rapidly discover whether any of the drugs slow disease progression or improve survival. Other drugs are planned to be added based on emerging evidence.
The ‘Recovery Trial’ is one of the biggest trials presently to look for therapeutic options against COVID-19. It started with testing six potential drugs — Lopinavir-Ritonavir (commonly used second-line drugs to treat HIV), Low-dose Dexamethasone, Hydroxychloroquine (this arm is now stopped), Azithromycin (a commonly used antibiotic), Tocilizumab (an anti-inflammatory treatment is given by injection) and Convalescent plasma (collected from donors who have recovered from COVID and contains antibodies against the Coronavirus). The trial has recruited over 11,500 patients in over 175 NHS (National Health Service) hospitals in the UK. The trial is supported by a grant to the University of Oxford from UK Research and Innovation/National Institute for Health Research (NIHR) and by core funding provided by NIHR Oxford Biomedical Research Centre, Wellcome, the Bill and Melinda Gates Foundation, the Department for International Development, Health Data Research UK, the Medical Research Council’s Population Health Research Unit, and NIHR Clinical Trials Unit Support Funding.
The third prominent clinical trial is by the National Institute of Allergy and Infectious Diseases (NIAID) which has initiated a randomized, controlled clinical trial to evaluate the safety and efficacy of the antiviral drug Remdesivir in hospitalized adults diagnosed with COVID-19. It will take place in up to 75 locations globally. Presently 39 sites are participating in the trial.
The latest ‘breakthrough’ drug: Dexamethasone
In the past week, there have been several announcements related to drugs and vaccines. First came the news of Dexamethasone, a steroid that reduces inflammation and used to treat Rheumatoid arthritis, Lupus, and certain kinds of tumors. The Recovery trial found that Dexamethasone significantly reduced mortality risk by one-third in ventilated patients and by one-fifth in patients receiving only oxygen. Based on these results, the trial concluded that one death would be prevented by the treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone.
This drug works by dampening down the body’s immune system. Coronavirus infection triggers inflammation as the body tries to fight it off. Sometimes the immune system goes into overdrive which could be fatal. The very reaction designed to attack infection ends up attacking the body’s own cells. Dexamethasone calms this effect. It is being considered as a major breakthrough in the treatment of COVID 19 and has been recommended to be standard of care for patients on a ventilator or on oxygen. These findings were found to be so significant that Dexamethasone’s arm in the Recovery trial has been stopped. It is important to note that Dexamethasone is suitable only for people who are already in the hospital and receiving oxygen or mechanical ventilation. Soon researchers made another announcement that Dexamethasone could actually harm patients with mild illness. And that it could have different effects at different stages of the illness. Experts say- In the initial stages of the illness when the immune system is fighting off the virus, using an anti-inflammatory drug which suppresses the immune system would definitely be harmful.
Dexamethasone should not be used as a preventive or in patients with mild illness. In the later stage of the illness when the immune system goes into overdrive it causes a ‘cytokine storm’. Cytokines are molecules that are released by the immune cells to recruit more cells into the fight against the pathogen. But there are times when the immune system does not stop as it would under normal circumstances. And causes damage to lungs, kidney, liver leading to death. Therefore using an anti-inflammatory drug at a later stage during the second phase of the illness seem to help reduce the risk of death. However, we need to consider this as work in progress and keep a close watch on further developments.
But there are doubts about whether or not it will be useful in India because steroids have been used for the moderate to severely ill Covid-19 patients from the first revised guidelines published on March 31. The latest Indian guidelines released on June 13 also recommend Methylprednisolone for three days in moderate illness and five-seven days for severe illness. But soon Indian government authorized the use of Dexamethasone to treat patients with moderate and severe symptoms and has since then put up a revised protocol for the clinical management of COVID 19.
Saga of Hydroxychloroquine
Findings related to COVID 19 treatment and prevention are presently being received very cautiously given that public trust in ‘evidence’ has suffered a setback after the hydroxychloroquine episode.
Controversy surrounded Hydroxychloroquine, an anti-malarial drug, from the time it was found to have some in vitro effect (tested outside a living organism) on the virus. However, this finding was weak and required a lot more robust testing. Poor evidence notwithstanding, Donald Trump declared on TV that hydroxychloroquine was a ‘game-changer’ and that he was considering taking it himself even though he had tested negative for the virus.
This immediately raised a red flag in the scientific community. Researchers from the National University Singapore had already advised: “caution”, “prudence” and “rigour” in the development of new treatment. Similarly, when India declared the use of Hydroxychloroquine as prophylaxis for high-risk health care workers and asymptomatic contacts of confirmed cases, researchers from Mahatma Gandhi Institute of Medical Sciences writing in the Lancet, questioned the government’s decision to allow extensive use of the drug even in the absence of any evidence of its effectiveness. They pointed out that there was no peer-reviewed publication that evaluated the drug for exposure prophylaxis of SARS-CoV-2 infection.
The New England Journal of Medicine was very critical of the US Food and Drug Administration for succumbing to political pressure and issuing an Emergency Use Authorization (EUA) to Hydroxychloroquine on March 28. The article charged that FDA’s actions posed ‘fundamental threats to the U.S. drug-evaluation process’. Privileging speed at the cost of good science was against the principles of evidence-based medicine and warned that such actions would seriously compromise public trust in the drug-review process.
Hydroxychloroquine use took on political overtones in Brazil to such an extent that those supporting its use resorted to death threats against the principal investigator of a chloroquine clinical trial which involved 21 research institutions in Brazil, Spain, and Mozambique. The study found that Chloroquine when used in high doses, is not safe. This trial did not use Hydroxychloroquine, the so-called safer version of Chloroquine. Micheal Coudrey, an American political activist with 256700 Twitter followers referred to the study as “a left-wing funded study that intentionally administered extremely high doses and used a less-safe version of the drug hydroxychloroquine, then used this as a pretense to indicate that chloroquine was ineffective and dangerous”. Soon after, Brazilian president’s son Eduardo Bolsonaro (who has 2 million Twitter followers) called it “a fake study aimed at demonizing the drug”. In another tweet, he claimed that the study’s authors were affiliated to the part that is funded by former Brazilian President Luiz Inácio Lula da Silva and asked for an investigation. Soon after, Lacerda started to receive death threats through social media and had to request police protection.
A twist in the tale: The Lancet fiasco
Justifiably the scientific community was very disturbed by how political forces were holding them to ransom. But the worst was yet to come. No one could have imagined that the NEJM’s warning to drug regulators about jeopardizing public trust would apply to its own fraternity of scientific journals.
May 22, 2020 issue of the Lancet carried a paper that claimed to have analyzed 96000 patient records from 671 hospitals from a global database which had been taken from a Chicago- based data analytics company called Surgisphere. The dataset also included about 15,000 patients treated with Hydroxychloroquine either with or without an antibiotic. The paper reported that hydroxychloroquine when used for the treatment of COVID-19 was ‘associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias “.
These were explosive findings. Scientists who had been clamoring against the use of Hydroxychloroquine felt vindicated. They could now cite these findings to advocate against the use of the drug. The buzz created led the scientific community to scrutinize the paper more closely. Curiously enough, the research and academic community had not heard of the availability of such large database which the lancet authors claimed to have used. They also found it strange that not even one healthcare facility was named or acknowledged in the study though the authors claimed to have drawn data from 671 hospitals. Slowly, data discrepancies also began to emerge. Researchers from the University of California questioned how the authors could claim to have captured data from over 60,000 hospitalizations in about 550 hospitals in the US by April 13th while actually 6,000 hospitals across the US contributed to these numbers around the same date. Similarly, a researcher from the University of Pittsburgh and an investigation by Guardian Australia found that there had been only 67 deaths from Covid-19 by April 21 while the Lancet authors claimed that there had been 73 deaths. When no satisfactory answers were forthcoming from the authors or Surgisphere, Lancet editors asked for an independent third-party peer- review of the database. But Surgisphere refused to transfer the full dataset, client contracts, or the full ISO audit report citing confidentiality contracts. Following this response, the authors requested that the paper be retracted.
It soon turned out that Surgisphere was owned by one of the co-authors of the paper Sapan Desai. Soon, investigations by The Guardian and others found that Surgishpere was a fraud. A search of publicly available material found that several Surgisphere’s employees had little or no data or scientific background. An employee listed as a science editor appears to be a science fiction author and fantasy artist. Another employee listed as a marketing executive in an adult model and events hostess, who also acts in videos for organizations. Additionally, it was found that Sapan Desai himself had been named in three malpractice suits.
To trust or not to trust
The Lancet episode shook the research community across the globe. It was beyond comprehension that a journal of the stature of Lancet could succumb to the pressure to beat the race and actually bypass the peer review process and publish an article that had used fraud data. The pressure to announce spectacular, headline-grabbing, ‘ground-breaking ‘ discoveries seemed to have spared no one.
From the time the COVID 19 epidemic burst upon the world, information about the virus, how it came to be transmitted to humans, the natural history of the disease, options for treatment and prevention and other details have not only been changing rapidly but have been dogged by conspiracy theories, fake news, and plain superstitions. In such a scenario, long-established scientific journals had been the only mainstay of reliable information for patients, medical practitioners, and the general public. After the Lancet fiasco however it seems as though this last bastion of trust has also been seriously compromised. Recently the Recovery Trial announced that it found no clinical benefit from the use of hydroxychloroquine in hospitalized patients with COVID-19 and there had been no significant reduction in mortality. The Hydroxychloroquine episode seems to have drawn to a close until another study or Trial came by on another day to raise some more questions.
Blithe approvals and announcements continue despite serious flaws and concerns
Despite this trail of mess in the past weeks, optimistic announcements of approvals of drugs for treating COVID 19 have continued blithely. During the past week in India, Glenmark announced that it had obtained clearance for its drug Favipiravir under the brand name FabiFlu, for the treatment of patients with mild to moderate COVID-19 at a price of about Rs 103 per tablet. Glenmark received the manufacturing and marketing approval under the Accelerated Approval Process from the Drugs Controller General of India (DCGI). The company has reported that its own in-house research and development team developed the Active Pharmaceutical Ingredients (API) and the formulation for FabiFlu. Glenmark said a randomized multi-center study was done in India enrolling 150 patients to test the drug’s efficacy and safety in mild to moderate Covid-19. The study’s details are yet to be published in a peer-reviewed paper. Glenmark claims that Favipiravir has shown clinical improvement of up to 88 percent in mild to moderate COVID-19 cases and has led to a rapid reduction in viral load within four days and provides faster symptomatic improvement. The approval’s restricted use entails responsible medication usage where every patient should sign an informed consent before treatment initiation. Favipiravir is an oral antiviral approved for the treatment of influenza in Japan since 2014. It selectively inhibits RNA polymerase, a process necessary for viral replication.
Serious questions have been raised since the approval of Favipiravir, where the study was conducted by an in-house trial with a small sample. Public health experts and activists have demanded answers from the Drugs Controller General of India (DCGI) as to the basis on which Flavipiravir was approved pointing out the secrecy surrounding its approval and several flaws in the study itself. First of all, the question of why does a ‘mild’ case need any intervention at all because of mild cases of COVID 19 clear up on its own. This casts doubts on the very premise of the study. Secondly, they point out that available scientific evidence is not strong enough to warrant approval. Thirdly, the study conducted was not a Randomized Control Trial (RCT) which is a gold standard in research related to new drugs. Fourthly, they highlight the secrecy surrounding its approval where the DCGI has not made public the minutes of the meeting of the Subject Expert Committee (SEC) which is set up by the DCGI to review all drugs that come up for approval. There is no information about the composition of the SEC or the results submitted by Glenmark based on which the DCGI/ SEC gave their approval. Further, these findings have not been published in a peer-reviewed journal. Similar concerns have been raised by the All India Drug Action Network (ADIAN) about lack of transparency in regulatory approval mechanisms that pose a serious threat to patient safety and demanding that the Central Drugs Standard Control Organization (CDSCO) make public all of the following: names of SEC members along with minutes of the SEC meeting, the evidence submitted by Glenmark, the basis on which the SEC/ CDSCO approved the drug, the restrictions for its marketing, clinical trial data and so on.
These are serious concerns that point to the DCGI which has approved the drug against available scientific evidence and by that is equally party to the violation of a fundamental principle of research ethics “Do no harm” and of willfully exposing patients to unnecessary harm.
Close on the heels of the announcement by Glenmark came the announcement by Cipla that it had received a voluntary non-exclusive license to manufacture and market a generic version of Remdesivir from Gilead Sciences Inc. Remdesivir is the only USFDA approved Emergency Use Authorisation (EUA) treatment for adult and pediatric patients hospitalised with suspected or laboratory-confirmed COVID-19 infection. Cipla said it has been granted regulatory approval by the Drug Controller General of India (DCGI) for restricted emergency use in the country as part of the accelerated approval process. The NIAID Trial found that Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. Remdesivir received EUA from USA FDA based on the preliminary analysis which included 1,063 hospitalized patients with advanced COVID-19 and lung involvement, showing that patients who received Remdesivir had a 31% faster time to recovery than those who received placebo (P< 0.001). Specifically, the median time to recovery was 11 days in patients treated with Remdesivir compared with 15 days in those who received a placebo.
NIAID trial of Remdesivir has also been beset by similar accusations against the US government for pushing approval of drugs for political gain rather than based on robust scientific evidence. For instance, it has pointed out that a combination of three drugs was found to reduce viral shedding and hospital in 5 days and therefore is more effective than Remdesivir which took 11 days. But these triple-drug regimen has not received any attention that it deserves. The reason is being attributed to the fact that all the three drugs in the regimen are out of patent which means that no company stands to profit. In contrast, Gilead obtained ‘orphan drug status’ for Remdesivir in the US which gave it exclusive rights to market and sell the drug for a period of 7 years. But after public outcry, Gilead backtracked and asked the US government to rescind the status. Gilead has been accused even earlier of ‘price gouging’ for Hepatitis C and HIV drugs, which many activists say was one of the main reasons for their inability to control the epidemic. Activists have also pointed out the conflict of interest in Remdesivir. A person who served as head of Federal Affairs in Gilead from 2011 to 2017 is presently a member of the White House Coronavirus task force.
A word of caution
The narrative of drugs and treatment of COVID 19 illness seems to be beset by fraud and lies where political considerations and commercial interests seem to have taken precedence over robust scientific evidence and ethical conduct by all actors concerned. This is a terrifying situation, that too during a pandemic of such magnitude. The way forward needs people’s movements, ethical researchers and experts, civil society organizations and citizens to be ever- vigilant, cautious, closely read the fine print and not be swept away by the flood of ‘breakthrough findings’ and hasty approvals through opaque processes.
The author is a convener of Karnataka Janarogya Chaluvali ( Campaign for healthcare Karnataka) and a Health Activist. She also holds a Ph.D. in Public Health from NIMHANS.