Health

How India Ignored Its Own Code for Use of Experimental Drugs in an Outbreak

Any experimental use of a drug during an outbreak must be accompanied by informed consent, and must be reviewed by a national ethics committee.

Bengaluru: In the last week of March, Sreenivas , a 30-year-old nurse, heard that the Mumbai government hospital where he worked was giving resident doctors a course of the anti-malarial drug hydroxychloroquine (HCQ). The hospital said it was following a one-page advisory from India’s apex medical-research agency – the Indian Council of Medical Research (ICMR) – on March 22 to administer the drug as prophylaxis for COVID-19.

By then, the number of people confirmed to have COVID-19 in India had crossed 500, and was growing fast in Mumbai.

When staff nurses heard that doctors were getting the drug, some grew anxious, Sreenivas told me on the phone. They wanted the drug, too, but the hospital didn’t have enough. Their anxiety was exacerbated by the fact that some of them worked in a COVID-19 isolation ward but didn’t have N95 masks, which can protect against airborne transmission of the novel coronavirus. Some also had other illnesses, like diabetes and hypertension, both of which are known to make a COVID-19 infection worse.

So several nurses purchased HCQ from medical stores instead of waiting for the hospital to replenish its stock, Sreenivas said. After all, ICMR had recommended the drug: that must mean HCQ works.

Ultimately, the hospital did procure enough HCQ to give staff nurses too. However, Sreenivas said, no one from the hospital’s administration said anything about the drug being experimental – that it could be useless in preventing the disease. The hospital didn’t talk about the drug’s side-effects either, from milder ones like nausea and stomach ache to severe ones like hypoglycaemia and heart-rhythm abnormalities.

HCQ also interacts with a bunch of other commonly used drugs, including insulin, azithromycin and cimetidine. Further, HCQ is to be used with care in people with eye problems, low blood sugar and many other conditions. ICMR’s advisory didn’t mention any of this, nor did the hospital.

“I know this because I googled. But some of my colleagues don’t know, or they [ignore] what they know. They were just taking the drug,” Sreenivas said.

The nurse’s experience is no different from that of thousands of healthcare workers across India, who have been told by their hospitals to take HCQ, no ifs and buts. This is mostly in line with the ICMR’s advisory, which says a doctor must prescribe the drug, but doesn’t discuss informed consent.

Informed consent means that everyone consuming the drug must do so only after fully understanding its benefits and harm.

While consent is the cornerstone of all medicine, there is a reason why it is especially germane in the case of HCQ for COVID-19. Around the world, no drug regulator has approved HCQ as a prophylactic or as treatment for COVID-19 because there is little evidence that it works in this case. The only thing that governments, including India’s, have done is provide temporary permission for off-label use. Full regulatory authorisation everywhere is conditional on robust evidence of the therapy’s efficacy becoming available.

But such temporary permissions are not a green-light for indiscriminate use. Instead, they ought to be accompanied by stringent checks and balances, such as informed consent, the approval of bioethicists and careful monitoring of the drug’s effects.

In 2016, the WHO developed guidelines for situations exactly like this, called the Monitored Emergency Use of an Unregistered or Investigational Drug (MEURI) guidelines. The ICMR followed in the WHO’s footsteps in 2017, publishing its own version of the MEURI guidelines as part of a document entitled the ‘National Ethical Guidelines for Biomedical Research in Human Participants’. The section on MEURI in India’s 2017 document clearly says that any experimental use of a drug during an outbreak must be accompanied by informed consent, and must be reviewed by a national ethics committee.

But it seems like the ICMR sidestepped its own guidelines while issuing its advisory. The advisory doesn’t even mention informed consent, an omission that has trickled down to hospitals across the country. Several doctors and health officials I spoke to said that if ICMR had issued the advisory, there must be a good reason for it, and informed consent was unnecessary.

Doctors from two of Mumbai’s government hospitals, the Gokuldas Tejpal Hospital and Sir J.J. Group of Hospitals, told me there was no process of informed consent. Rohit Deshpande, the head of general medicine at Gokuldas Tejpal Hospital, said he screened patients for comorbidities such as hypertension, which could interfere with HCQ.

But if anyone refuses the drug, he said, “I tell each and everyone to take. I am making sure they do. After all, I am prescribing it as a doctor and they are not taking it on their own.”

Jibin T.C., the president of Mumbai’s United Nursing Association, said some nurses in Mumbai’s hospitals were being asked to take the drug even if they didn’t want to. In Indore, the chief medical and health officer Pravin Jadia said 10,000 contacts of confirmed COVID-19 cases and around 3,000 healthcare workers had received the drug as prophylaxis. But when asked whether these people had been told that the drug was experimental and may not work, he said, “No. When we are giving the drug to so many people, we can’t say such things.”

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Politics versus science

A woman holds a hydroxychloroquine prescription in Seattle, Washington, US, March 31, 2020. Photo: Lindsey Wasson

The ICMR’s HCQ advisory doesn’t seem to have been reviewed by a national ethics committee either – which is another requirement under the Indian MEURI guidelines. One committee that could have reviewed the advisory was ICMR’s so-called ‘Central Ethics Committee on Human Research’. However, the last Central Ethics Committee that ICMR appointed in 2017 completed its term in 2019, and one of its members, Bhopal-based bioethicist Anant Bhan, said he is unaware of any new committee having replaced them.

Another national ethics committee, called the COVID-19 National Ethics Committee (CoNEC), is currently listed on the ICMR’s website. But it was formed on April 4, some two weeks after the ICMR issued its advisory.

When asked which national ethics committee reviewed ICMR’s decision to prescribe HCQ, Roli Mathur, the member secretary of CoNEC and the head of ICMR’s bioethics unit, suggested the MEURI guidelines wouldn’t apply to HCQ.

“The prophylactic use of HCQ has been recommended with very specific indications, and is not for use by others. This does not fall under the ambit of the ICMR National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, 2017,” she said in an email. When asked what guidelines or law HCQ was in fact governed by, she wrote, “Implementation of HCQ use is governed by the Ministry of Health and Family Welfare.”

However, Bhan and other bioethics experts disagreed, and said the case of HCQ was exactly the kind of scenario that the ICMR’s 2017 guidelines, and its MEURI section, were made for. “The ICMR is violating its own guidelines,” Amar Jesani, a Mumbai-based bioethicist who was a member of the Central Ethics Committee from 2015 to 2017, told The Wire Science.

India’s evasion of ethical protocols is particularly troubling given the global enthusiasm for HCQ was apparently driven by political motives, not scientific evidence. After a flawed clinical study from France suggested that the drug may work against COVID-19, US President Donald Trump called it a game-changer, encouraging everyone to use it.

But on March 5, the former head of the US Biomedical Advanced Research and Development Agency, Rick Bright, filed a scathing whistleblower complaint accusing Trump’s team of pushing HCQ and other drugs to help the business interests of their associates. Bright accused government officials of ousting him from his previous position because he had resisted pressure to invest in these unproven drugs. And it was on his insistence, Bright said, that the drug was eventually approved under the ’emergency use authorisation’ (EUA) protocol. EUA requires that people receive the drug only under strict clinical supervision. Further, both healthcare workers and patients receive extensive fact-sheets about the drug’s experimental nature.

The MEURI protocol would have ensured India took similar precautions against indiscriminate use – so why did ICMR skip it? It’s hard to say. One bioethicist who didn’t wish to be named said India’s decision may have been driven by political pressure from the Ministry of Health and Family Welfare. “There is a lot of pressure on scientists to do something, kuch karo,” the expert said.

Questions to the ministry on the issue went unanswered.

The HCQ case sets a crucial precedent because it’s the first of several experimental COVID-19 drugs that India will have to regulate the use of. Others include Gilead Sciences’ antiviral drug remdesivir and convalescent plasma therapy. On May 1, the US Food and Drug Administration gave remdesivir an EUA based on preliminary clinical data.

Meanwhile, the demand for plasma therapy – in which blood plasma containing antibodies against the novel coronavirus is transfused from recovered patients to those currently sick – is high in India. In April, the Max Super Specialty Hospital in New Delhi administered this therapy to a patient, even though it hadn’t been approved, attracting the criticism of even the health ministry.

“For hydroxychloroquine – at least you can argue that it is a pill that is easy to take. What is worse is if people start taking plasma therapy,” Sanjay Nagral, a gastroenterologist at the Jaslok Hospital, Mumbai, and an editor of the Indian Journal of Medical Ethics, said.

Legally speaking, any biomedical research into new drugs is regulated by the New Drugs and Clinical Trials Rules 2019. These rules specify that such research must follow the ICMR’s 2017 National Ethical Guidelines. Under the guidelines, ICMR could either have followed the MEURI protocol or prescribed the drug as part of an “academic trial”, Dhvani Mehta, a legal policy researcher at New Delhi’s Vidhi Centre for Legal Policy, said.

But whichever route ICMR had picked, it wouldn’t have been able to avoid taking informed consent and a review by an ethics committee. “Informed consent and ethics committee approval are the backbone [of all medical research],” Urmila Thatte, a clinical pharmacologist and bioethicist at the Seth GS Medical College and KEM Hospital, Mumbai, said.

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The story behind MEURI

Health workers dressed in protective suits carry a Congolese woman confirmed to have Ebola as she is admitted to a treatment centre in Butembo, 2019. Credit: Reuters/Baz Ratner

The idea of the MEURI protocol first came up during the Ebola outbreak in Western Africa in 2014. This outbreak raised several thorny questions about medical ethics. The haemorrhagic illness was killing up to 50% of those it infected, and there were no drugs proven to work against it. Only a clutch of investigational drugs existed, and some of them hadn’t even made it past human safety studies, such as ZMapp, mab411, REGN-EB3 and remdesivir. And international healthcare workers, like Doctors Without Borders, said they were reluctant to use these untested drugs given the rumours among the residents of countries like Liberia that Ebola was being spread by foreigners.

This situation flipped dramatically sometime in August 2014. The trigger was the cure of two American aid workers in Liberia, who had been flown back to the US for treatment when they contracted Ebola. Doctors administered ZMapp to them under the US’s compassionate-use laws , after which both patients recovered. This shifted sentiments in Liberia, and those who had been suspicious of untested therapies now wanted to know why they weren’t receiving the miracle drugs that the Americans did.

But giving ZMapp to thousands of affected people was going to be hard. The manufacturer only had a few courses of the drug. More importantly, giving an unproven drug to so many people without a clinical trial was (and remains) a bad idea. The recovery of the two American aid workers yielded little insights into ZMapp’s efficacy. Along with the drug, the two workers had also received top-notch supportive treatment in the US, and there was no way to tell if the drug alone, the treatment alone or both together cured them.

What if ZMapp was actually a dangerous drug, with serious adverse effects that were worse than the Ebola virus disease itself? Such adverse effects are often impossible to pinpoint without a randomised and placebo-controlled clinical trial (RCT).

The history of medicine is littered with RCTs contradicting observational data on the safety of drugs. An oft-cited example is hormone replacement therapy, which doctors thought would protect menopausal women against coronary heart disease. This perception changed in 2002 when RCTs showed that women on the treatment suffered heart disease more often. One explanation for this discrepancy – called the timing hypothesis – is that women who start hormone therapy later after menopause were more likely to suffer heart disease compared to those who started early. The reason could be that the former may already have plaque in their arteries, which oestrogen could rupture and cause blockages.

Some scientists have also raised the possibility that HCQ could eventually prove dangerous to people with COVID-19. This worry stems from the fact that even though chloroquine – a compound similar to hydroxychloroquine – is effective against chikungunya in test tubes, it seemed to worsen chikungunya when given as prophylaxis to macaques.

“I think this is a serious concern,” Art Kreig, a former practicing rheumatologist and the founder of Checkmate Pharmaceuticals, a US-based firm that studies cancer immunotherapies, said.

It’s for reasons like this that many scientists considered RCTs to be a moral obligation during the Ebola outbreak. The problem was that large-scale compassionate-use could make it harder to conduct RCTs because people would begin to believe that the drug works. If some people refused to take a placebo, as controlled trials need, or if compassionate use depleted stock, such a trial couldn’t happen. There were other obstacles in the way of Ebola clinical trials in West African countries, including violence against healthcare workers, that could disrupt any study.

Ultimately, one factor that changed people’s minds about using ZMapp on compassionate grounds in West African nations was the exceptional nature of Ebola itself. As the WHO noted in a 2014 report, the then-ongoing Ebola outbreak was historically the biggest, with a high case-fatality rate. When the disease itself was killing so many, not giving the drug became unethical – or so the thinking went.

The words of the Liberian information minister, to BBC in August of that year, best captured this sentiment. Acknowledging he knew that the drug had adverse effects, Lewis Brown said, “The alternative for not testing this is death, a certain death… This is not even the rock and the hard place for us.”

Still, the WHO insisted on clinical trials by the side. “One can’t keep doing MEURI all the time, and use the untested medicine as de facto therapy when it is not,” Jesani, who was also a member of a WHO Ethics Working Group during the Ebola outbreak, said.

So in October 2014, the working group’s members brainstormed on clinical-trial designs where no participant would be denied a possibly effective drug. One suggestion, according to Jesani, was to use a historical control, in which people getting the drug are compared to those who have been ill in the past but didn’t receive the drug.

Ultimately, in line with the WHO’s suggestions, Congolese and American researchers designed a humane trial – in which no one would be denied an experimental drug. Instead, four experimental drugs were compared with each other. And the trial protocol was such that even if it was disrupted by conflict, the researchers could resume it later. Results from the trial, which arrived in 2019, showed that mAb411 and REGN-EB3 outperformed Remdesivir and ZMapp.

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India’s take on MEURI

The WHO flag. Photo: US Mission Geneva/Flickr, CC BY 2.0

This fraught history led the WHO in 2016 to publish the guidelines for ethical clinical research during outbreaks. The agency noted that these debates were common across multiple epidemics – whether SARS, H1N1 or even drug-resistant tuberculosis. And the same global concerns led India to publish a MEURI protocol in its National Ethical Guidelines in 2017.

The Indian MEURI protocol is not as extensive as the WHO’s, however. For example, apart from requiring informed consent and an ethical review, the WHO calls for researchers to share data about the drug. Specifically, the WHO guidelines say that physicians overseeing the use of experimental drugs “have the same moral obligation to collect all scientifically relevant data on the safety and efficacy of the intervention as researchers overseeing a clinical trial.”

The Indian guidelines abbreviate this requirement thus: “Sharing data on safety and efficacy would be beneficial to reduce delay for others.”

But it doesn’t seem like ICMR has followed either the Indian or the global guidelines thus far. Even though the agency’s chief of epidemiology, Raman Gangakhedkar, said in a press conference in April that his team had monitored adverse effects among 480 healthcare workers consuming HCQ, the corresponding data hasn’t been published anywhere.

Another point of departure from the WHO’s guidelines is that the Indian protocol does not call for RCTs to test MEURI drugs. In contrast, WHO says that widespread use of experimental drugs shouldn’t delay the start of such trials, which must happen as quickly as possible.

For now, it doesn’t seem like ICMR has launched any such trial. As on May 5, the body had not registered any placebo-controlled RCTs for prophylaxis on the Clinical Trial Registry of India. And it isn’t clear if ICMR is funding anyone else conducting such research either.

Vivekanand Jha, executive director of the George Institute of Global Health, New Delhi, told The Wire Science that his team had applied for funding for an RCT from ICMR on April 15. They’re yet to hear back.

Some wise up, others don’t

Raman R. Gangakhedkar. Photo: YouTube

Since March 22, when ICMR issued its advisory, much of the enthusiasm for HCQ has died down. A few new clinical trials found the drug didn’t help sick patients much, while other studies threw up a link between treatment with the drug and heart-rhythm abnormalities among such patients.

In response, a panel of experts from the US National Institutes of Health recommended against the use of a combination of azithromycin and HCQ to treat COVID-19. And the FDA warned against the use of hydroxychloroquine or chloroquine outside clinical trials or hospitals.

But India’s advisories for both prophylaxis and treatment – which recommend the use of HCQ and azithromycin – remain unchanged. And even though Gangakhedkar said in April that several healthcare workers taking the drug had experienced side-effects like hypoglycaemia, the advisory hasn’t been updated to reflect this information. Gangakhedkar also said it was worrying that doctors and nurses had taken the drug without electrocardiograms (ECGs) first – but the advisory doesn’t recommend ECGs yet.

Some hospitals have wised up, however. For example, the Wockhardt Hospitals in South Mumbai had initially told all healthcare workers to take the drug, but is now being more cautious. Kedar Toraskar, a critical care specialist at Wockhardt, said workers are now being told that new trial data on HCQ doesn’t look promising, although they still have the option to take the drug.

The Indian government’s own enthusiasm continues unabated. In an April 28 press conference, Lav Agarwal, joint secretary to the health ministry, said those with mild symptoms of COVID-19 and wishing to be isolated at home could do so if their caretakers took HCQ as prophylaxis.

Meanwhile, in Wardha district of Maharashtra, a plan is afoot to acquire enough of the drug to give all police personnel in case the number of COVID-19 cases begins to surge, according to Nilesh M. Bramhane, a police inspector. Bramhane said he had asked the district civil surgeon about the right dose, and the civil surgeon had sent him ICMR’s guidelines in response.

“I think the tablets will arrive soon,” Bramhane said.

Priyanka Pulla is a science writer.

The reporting for this story was funded by a public health journalism grant to Priyanka Pulla from The Thakur Family Foundation.