A view of CMC Vellore. Source: YouTube.
Bengaluru: Since India reported its first COVID-19 case a year ago, the evidence for treatments of this viral illness have undergone a sea-change. In the early days of the pandemic, observational studies and small trials from across the world pointed to potential roles for hydroxychloroquine, convalescent plasma and tocilizumab.
The Indian drug regulator was also quick – soon found to have been too quick – to approve two drugs tested in Indian trials, favipiravir and itolizumab, even though these trials didn’t really demonstrate these drugs’ efficacies.
But in the fog of the pandemic, as death tolls rose and few treatment alternatives showed up, doctors began to prescribe these experimental therapies widely. Even India’s Ministry of Health and Family Welfare endorsed the use of hydroxychloroquine, plasma therapy and tocilizumab – while several state governments, including those of Maharashtra and Karnataka, endorsed favipiravir and itolizumab. Proponents of evidence-based medicines criticised these official endorsements which, arguably, drove up the indiscriminate use of these drugs.
Critics have advanced several arguments against the widespread use of unproven drugs outside of clinical trials in a pandemic. For one, some of these drugs could harm patients. Investigators in Maharashtra’s PLATINA trial for convalescent plasma reportedly stopped the trial early because more patients in the plasma arm were developing blood clots or dying. Meanwhile, other drugs could burn a hole in the patient’s pocket. A 200 mg vial of tocilizumab, for example, costs up to Rs 20,000.
Could doctors have taken a more measured approach to experimental drugs in the anxious atmosphere of a pandemic? Some medical institutions did, and indeed still do so – reviewing evidence frequently and intensively, and eschewing the routine use of drugs that don’t have strong evidence to support them.
One such was the Christian Medical College (CMC), Vellore, whose treatment guidelines didn’t recommend drugs such as tocilizumab and favipiravir until now, unless they could be administered in clinical trials. As a centre for several clinical trials, including the WHO’s SOLIDARITY trial and the Indian Council of Medical Research’s PLACID trial for convalescent plasma, CMC Vellore was able to offer such a choice to patients.
(Update: The results of the RECOVERY trial, a randomised trial of over 4,000 patients, were published in a preprint last night, and showed tocilizumab cut mortality compared to standard of care in the severely ill. This evidence may be strong enough to change practice in favour of tocilizumab.)
In an interview with The Wire Science, Priscilla Rupali, an infectious disease specialist who heads CMC Vellore’s guideline development team, and Joy Mammen, a pathologist and a specialist in transfusion medicine, talked about the challenges of developing treatment guidelines during a pandemic, when evidence is shifting rapidly.
Excerpts follow. The questions are in bold and the reporter’s notes are in square brackets.
Could you talk about why you felt the need to develop your own guidelines for the treatment of COVID-19 in the first place? Why did CMC Vellore not choose to follow, for instance, the WHO’s fairly extensive COVID-19 treatment guidelines instead?
Priscilla Rupali: One reason we thought it important to develop guidelines for COVID-19 was that it was a new disease, and there was nothing known about appropriate treatments. There was widespread panic and anxiety among both patients and staff alike. We deal with nearly 9,500 patients on an outpatient basis, have more than 2,300 inpatients and 10,000 employees at any given time.
So for a new disease, it is important to standardise treatment guidelines. And while the WHO interim guidelines first came out on May 27, India saw its first case in January 2020, and our hospital saw its first case in March. That means that following WHO’s guidelines wasn’t an option for us. Hospitals like ours had to set up their own guidelines.
Who is on CMC Vellore’s guideline-development team? What does the process of developing guidelines look like?
Priscilla Rupali: The guideline-development team needs to be led by a subject expert. In this case, because COVID-19 is an infectious-disease, the team was led by an infectious-disease expert. Further, internal-medicine specialists formed a large part of the group. Then we had content experts, like specialists in anticoagulation, haematology, pulmonary medicine and virology.
We used to meet twice a week. Within those three days, we would review all new literature, and dissect it to see how we could adapt the findings to our hospital. It was a very intensive exercise in the beginning, because we were floundering at that point in time, and we wanted to make use of every opportunity. We had a large group of people who were sifting through evidence and deciding which studies were relevant and which were not.
How big was the group that developed the guidelines?
Priscilla Rupali: It was pretty big – about 40-45 people at any given time. The moment somebody presented some new information to the group, they automatically joined the group.
With 40-45 group members, surely there would have been disagreements about how evidence should be interpreted? How were these differences resolved?
Priscilla Rupali: Being an academic body made up of senior clinicians and academic professionals, there were bound to be disagreements. But I think that is a healthy thing, because you can’t expect such experts to believe one thing over another. And we are not an expert-opinion based body; we are an evidence-based body.
Yet, despite the disagreements, we almost always came to a consensus about what we would adopt at a minimum. For example, initially, the decision of whether to adopt anticoagulation [drugs that prevent blood clots from forming] or not was a very important one for us. And we reviewed the evidence for a minimum of 10 meetings, before we came to some kind of a conclusion as to what we could adopt as a minimum guideline.
Today, we use prophylactic anticoagulation for all patients. In severe or critically ill patients, we go up to intermediate-dose anticoagulation. For those who have evidence of thrombotic disease [in which patients have a high risk of developing blood clots], we adopt therapeutic [high-dose] anticoagulation.
Joy Mammen: The thing about SARS-CoV-2 was that there was no certainty, and we didn’t have any experience with this organism in the past. If it was an organism that had caused an outbreak earlier, and we had some knowledge of it, we would have had some science to go on.
And many forms of information were reaching people – not only in the scientific world but also among laypersons, who have access to many different opinions. These opinions are bound to affect people’s thinking. When so much information and opinion is all over the news, how do you make a wise and a just decision?
There was always disagreement, but we usually managed to come to a consensus. But this consensus was not hidebound. It wasn’t as if we told doctors: we have decided this, and you have to follow this. There is space for the clinician to look at an individual patient and decide.
CMC Vellore also conducted clinical audits to map how well doctors adhered to treatment guidelines. How do such audits work? What do you do when doctors deviate from guidelines?
Priscilla Rupali: Clinical audits are not meant to be punitive; they’re meant to refine treatment. For example, some individuals believed in remdesivir firmly when it first came out. And there were some individuals who were not for it, because until today, there is no convincing evidence that it reduces mortality.
But there is some evidence that remdesivir decreases progression to severe disease. So, given the uncertainty about whether it actually works, it made sense for us to look at our patient data, apart from peer-reviewed literature. So far, we have seen more than 11,000 COVID-19 patients. And so, we have a large enough patient sample to be able to study whether remdesivir is useful or not.
We had a data team that would regularly sift through information from these patients, and monitor clinically significant outcomes and lab parameters. And we were able to pick up, through clinical audits, that remdesivir worked in a particular population.
Today, we recommend remdesivir in patients on oxygen but not in those who are mechanically ventilated.
While CMC Vellore has treated thousands of COVID-19 patients, observational data from these patients cannot be prioritised over randomised controlled trials (RCTs). So what do you do when your observational data is at odds with RCTs?
Priscilla Rupali: There is no question that RCT evidence has to be prioritised over any retrospective clinical audit or adaptive design. We have to ensure that we keep to a minimum standard prescribed by an RCT. But RCT evidence has to be interpreted in the light of our clinical experience.
Joy Mammen: The practice of evaluating evidence is a good thing. It is our daily bread and butter. But once too often there is an individual patient who is sitting in front of the doctor with personal variables that need to be accounted for. The doctor needs to narrow down the big statistics from RCTs to the individual they are dealing with. Here, guidelines sometimes help, but sometimes have to be modified for that patient’s benefit and for that situation.
Could you describe a situation in which evidence-based guidelines are modified for the patient’s benefit? Can a doctor ever make a decision that contradicts RCT-evidence-based guidelines?
Joy Mammen: I don’t think any treatment should contradict the evidence-based guidelines. What I’m saying is: there is scope within clinical judgment to adapt the guidelines for that particular patient.
Priscilla Rupali: An example would be – suppose you have a patient with persistent fever that has gone on for beyond eight days. He’s not requiring oxygen, and you are wondering why the fever hasn’t come down. In that case, you would wonder whether there is inflammation going on. You do a CT scan, and you find that he has a mild pneumonia and his inflammatory parameters are gradually going up.
Such a patient still doesn’t fulfil the criteria for steroids [The RECOVERY trial found that COVID-19 patients who received corticosteroids when they didn’t yet need oxygen were more likely to die compared to oxygenated patients on corticosteroids. Based on this, the WHO Organisation issued a “conditional recommendation” not to use this class of drugs in the former group. A ‘conditional’ recommendation is based on evidence of poorer quality, compared to a ‘strong’ recommendation].
But a doctor could argue that they are not going to wait until the patient needs oxygen. Maybe they need to start them on some therapy now.
The clinical decisions for every patient are not dichotomous: it’s not just a ‘yes’ or a ‘no’. A lot of these decisions lie on a continuum. If you decide something on day one of the patient’s admission, you may decide differently on day ten, depending on how the patient’s condition has evolved.
Joy Mammen: Sometimes people assume that if there is a written treatment guideline, it has to be followed to the letter. But treatment protocols have to be responsive. You have to monitor the patient, look at the evidence, look at the lab results, and modulate the treatment for that particular patient. The patient is not a statistic. You use statistics to guide their treatment.
Some hospitals, such as the Mahatma Gandhi Institute of Medical Sciences in Sevagram, Maharashtra, have made an explicit decision to stay away from certain drugs that have very little evidence supporting their use. These include hydroxychloroquine, plasma and tocilizumab. Their reasoning is that because they are a rural hospital whose patients are often not wealthy, it is not fair to make the patients pay for drugs with unknown efficacy. Have you taken any such decisions to explicitly prohibit certain unproven drugs?
Priscilla Rupali: For us, a drug would be a hard-no only if there is definitive evidence of harm. Everything else has to be studied in the context of a clinical trial.
Hydroxychloroquine is not recommended anywhere in your guidelines. But if your guidelines don’t prohibit its use either, does that mean doctors at CMC Vellore could still prescribe hydroxychloroquine for COVID-19?[Multiple clinical trials have shown that hydroxychloroquine does not benefit patients at any stage of disease, whether mild, moderate or severe. Recently, the WHO issued a strong recommendation against the use of hydroxychloroquine regardless of disease severity].
Priscilla Rupali: Yes, but remember, the guideline-development body is made up of experts. So I don’t think somebody would disagree completely with them. That’s the power of an academic group which has world-renowned experts from all fields.
It’s very difficult for one person on the floor to be obstinate and say no, I am definitely going to give hydroxychloroquine. It’s not like it will never happen, but I would say it would be extremely unusual for somebody to completely disregard evidence-based guidelines.
Joy Mammen: Yes, I think that such a situation would be an outlier, because there is also an accountability system. Normally, a single individual is not making all treatment decisions for a patient. There are several discussions with the consultant on the floor, and discussions with consultants outside. It is not an isolated situation where one doctor sees a patient and nobody else gets to know what was happening. That’s the advantage of being treated by a team.
CMC Vellore has decided not to store favipiravir in the hospital pharmacies to prevent abuse. Isn’t that an explicit prohibition?
Priscilla Rupali: Favipiravir is an oral drug, and so it has potential for great abuse. It is easily obtainable over the counter. If you look at the evidence very closely, it’s not convincing at all. The first trial for favipiravir was published in an engineering journal, and it showed that the drug increased viral clearance and brought the fever down. But if you look at the data very closely, only 25% of the trial participants actually had fever to begin with. So who are we treating with favipiravir? We are treating mild cases who would have gotten better anyway. We were not convinced of its efficacy to use it up front.
In a more recent clinical trial, patients given favipiravir showed faster viral clearance with some clinical improvement. But the trial numbers were small, and only mild or moderate patients were included. At this point there is still equipoise [uncertainty whether the treatment works].
But can doctors at CMC Vellore still prescribe favipiravir if they want? Glenmark, which received regulatory approval to sell favipiravir for COVID-19, has marketed the drug heavily. So patients may hear of the drug from other channels and demand it.
Priscilla Rupali: Anybody is free to do anything in India because most drugs are available over the counter here. Can a doctor prescribe favipiravir or can the patient get the drug from outside? Of course they can. But will they do it? Hopefully not, because they would have read our guidelines.
At times, we have had patients who have actually taken favipiravir before coming to us and developing breathlessness. But we are hoping that with adequate education, knowledge and evidence-based guidelines, people would be more willing to listen to evidence.
Does that mean that favipiravir will never be useful? No – we are only saying that, right now, it needs to be studied in the context of a clinical trial.
You say that you prioritise enrolment in clinical trials for drugs when the evidence is weak or inconclusive. But are there enough, well-designed clinical trials going on at CMC Vellore, such that patients actually have an option to access experimental drugs via clinical trials?
Priscilla Rupali: We did have a couple of clinical trials ongoing as part of WHO’s SOLIDARITY [trial]. But none of those trials were for favipiravir. There is no major clinical trial with favipiravir as an arm today, because nobody is really convinced it works.
What do your guidelines say about plasma therapy?
Priscilla Rupali: Our guidelines say – use it only in the context of a clinical trial.
Joy Mammen: In the early days of COVID-19, we were merely translating our experience with plasma therapy in Ebola and other diseases to COVID-19. We didn’t have any other treatments, and so, convalescent plasma was a possibility then. We understand the science of it: the convalescent person has antibodies to the SARS-CoV-2 virus, which can possibly help the ill patient.
But one of the fundamental principles of treatment is that if you are able identify the element which is causing the improvement – antibodies in the case of plasma – you should isolate it. This is because, traditionally, giving plasma is considered a very risky practice. In the teaching slides that we use for our postgraduates and residents, we ask them not to transfuse the patient unless they are really going to save a life. Don’t do it without a valid reason.
Regardless of how well you screen the plasma donor, there is always a residual risk of infection in transfusing a patient. We are not doing pharmaceutical processing on the plasma and inactivating pathogens before transfusing. We are only screening for pathogens with highly sensitive tests.
Secondly, many variables come into play while collecting plasma and administering it to a patient. The availability of antibodies inside that plasma differs from person to person. There is also evidence that people with mild infections really do not produce high levels of antibodies.
Also, at what stage should the recipient get the plasma? The PLACID trial [an RCT for convalescent plasma therapy, in which CMC Vellore was a site] was designed for worsening patients, when oxygen saturation dropped. But when we looked at the overall data and the results, we found no benefit.
Since then, new data published from Argentina and Spain has revealed that giving convalescent plasma with high antibody titres early in the disease to elderly hospitalised patients may indeed be beneficial. However, there are practical considerations here that may preclude plasma’s widespread use in early-stage patients.
Going forward, the Drug Controller General of India (DCGI) has permitted some drug-manufacturing companies to take the convalescent plasma, isolate the immunoglobulin-G [the type of antibody thought to be beneficial to the patient] from it, and then lyophilise [freeze dry] it. They also inactivate pathogens through procedures like pasteurisation. This improves the safety, because you know that you are getting the specific entity that has treatment value. I see this to be a good way forward for reaping the benefits of convalescent plasma.
What is the practice at CMC Vellore for interleukin-6 inhibitors [drugs that inhibit an inflammatory molecule called interleukin-6, high levels of which are thought to worsen outcomes in COVID-19 patients] like tocilizumab and itolizumab? These drugs have been widely administered to patients in the inflammatory phase of COVID-19.
Priscilla Rupali: We haven’t used tocilizumab. If you look at the evidence from the Roche-funded COVACTA and other trials, they only show that it decreases time to discharge. Mortality and clinical symptoms did not improve by the addition of tocilizumab. So does it justify giving something that costs Rs 40,000 to a patient who is already struggling to pay their intensive care bills? It doesn’t.
And besides, we don’t really have convincing evidence that blocking just interleukin-6 is useful. There are probably other pathogenic mechanisms we are unaware of in COVID-19. So blocking just one pathway may not be enough? The reason why steroids have been so useful compared to tocilizumab is because they are so non-specific, and reduce inflammation overall, instead of targeting just one molecule. There’s not enough evidence to say that just targeting interleukin will make a dramatic change to the patient’s condition.
However, the situation is dynamic and constantly evolving. In the recent EMPACTA trial, interleukin-6 inhibitors prevented a select group of critically ill patients from progressing to mechanical ventilation or severe disease. The results of the REMAP-CAP trial, published as a preprint, but not yet peer-reviewed, seem to suggest that there may be a mortality benefit in some patients.
At the moment, we haven’t changed our guidelines, but it may be something to consider in the future.
How often should a hospital review evidence during a pandemic? The health ministry and various state governments have been slow, not updating for months at a time.
Joy Mammen: I do not know whether there is an ideal frequency. But it is challenging for anyone to review the fast-evolving evidence during a pandemic, even for an institution like ours. It was only possible for us because there was cooperation, an acceptance of responsibilities and a division of labour. It may be harder for state governments and the central government, who have to coordinate across multiple institutions and districts.
Now that we are seeing very little COVID-19 in the state, we plan to evolve our informal process of synthesising evidence into something formal. So we have begun a project to develop guidelines using the GRADE methodology [a method in which each type of evidence is rated for quality, with RCTs being rated the highest]. We hope that these guidelines, which we will publish, will be applicable across most low- and middle-income countries, and will answer most treatment questions with a firm scientific backing.
The reporting for this article was supported by a grant from the Thakur Family Foundation. The foundation did not exercise any editorial control over the contents of the article.
Priyanka Pulla is a science writer.