Coronavirus treatment: chaotic drug search lacks centralized strategy

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One of the most important milestones in the US’s return to normal is the development of effective treatments to combat covid-19. But a Washington Post review of the massive effort revealed a disorganized and dispersed approach that has so far echoed the rest of the US response to the virus. 24-hour researchers describe the lack of a centralized national strategy, overlapping efforts, a range of small-scale trials that will not lead to definitive answers, and no standards on how to prioritize efforts, data to collect or how to share to get answers faster.

“It’s a cacophony; it is not an orchestra. There is no conductor, “said Derek Angus, director of the department of critical medicine at the University of Pittsburgh medical school, who is leading a covid-19 trial that will test multiple therapies. “My heart hurts in the complete chaos of the answer. “

The global establishment of biomedical research could be one of the most powerful assets of the campaign against the new virus, with experts from around the world – and in particular the scientific and medical power of the United States – in a rare alignment in their focus on a single enemy. Large trials intended to be final have been launched. But with more than 500 human clinical trials worldwide, lack of coordination puts the world at risk of ending up with a series of inconclusive and contradictory studies and little idea of ​​which interventions work for the next wave of disease. .

Francis Collins, director of the National Institutes of Health, the country’s largest biomedical research agency, acknowledged the frustrations of researchers and doctors, but said in an interview on Wednesday that he had worked behind the scenes to launch a public partnership- unprecedented private to address the problems. He said the framework involves major pharmaceutical companies such as Pfizer and Johnson & Johnson, national and international government agencies, including the European Medicines Agency, and university research centers.

Collins said month-long talks have been kept secret to ensure adherence to an approach that may require sacrifices of personal recognition, scientific credit and profit – a centralized decision, for example, not to proceed to a company’s drug tests to move faster over a competitor.

“I think we have the leverage to lead this whole complicated ecosystem,” he said. “When you look at some of the things that happen sporadically, it is unlikely that we will learn what to do with these little disconnected trials. It is about replacing that with a consistent, evidence-based approach. … I want to know what works, and I want to have an answer by June or July. “

Agency officials said more details would be released in the coming days.

Anthony S. Fauci, director of the National Institute of Allergies and Infectious Diseases (NIAID), said in an email on Tuesday that the Collins-led partnership was “the functional equivalent of a national strategy”.

While Collins was working on this strategy, hospitals, pharmaceutical companies, government labs and individual physicians were inundating the system with proposals for drugs and other interventions to test the virus – an outpouring that reveals just how the research enterprise remains compartmentalized and fragmented. For example, 26 separate US trials are listed for the antimalarial drug hydroxychloroquine, all with different designs. Some people use the medication as a preventative, others as a treatment. Some use it alone, some with other medicines or vitamins, and some do not have a comparison group to say if the medicine is responsible for the result. This will make it more difficult to determine whether, or under what circumstances, the medicine can work.

Collins said a task force is tackling this problem by sifting through a hundred possible Covid-19 treatments to decide which six to eight drugs are most promising to move forward in large trials ladder. These will be deployed in large clinical trial networks.

The new federal effort is motivated in part by what happened in China. Clifford Lane, deputy director of clinical research and special projects at NIAID, was behind the epidemic in February as part of an international delegation to help the world learn from the Chinese experience. He was troubled by the lack of a strategic plan to prioritize and accelerate the most promising treatments, leading to a patchwork of inconclusive results.

“We need to have a broader strategy than every university, every institute and – to be blunt – every country” working on their own research efforts, said Lane in an interview.

At the heart of the problem is the fundamental question of whether a drug really works. Typically, drugs and medical procedures are first tested in small clinical trials that establish safety before the most promising are channeled into larger trials, in an iterative process spanning several years. These trials, which usually randomly assign patients to receive either a drug or a placebo, prove that drugs, vaccines and medical procedures are effective and safe. But with the urgency of the coronavirus threat, deadlines have been tight, doctors are experimenting uncontrollably because they are administering regular care, and the typical research model is too slow.

Prioritize research

David Boulware, a doctor and infectious disease scientist at the University of Minnesota, has received at least 50 emails from companies and researchers with treatments they want to test. The urgency to find something – anything – for patients who have nothing but supportive care has led researchers to withdraw everything from the market: a mixture of promising existing drugs, basic treatments stem cells and new compounds designed specifically against covid-19.

The energy is remarkable, but it must be channeled. Clinical trials, whether it’s an HIV drug or a brand new drug, compete for many of the same patients. If there are too many trials in a hospital, none of them can enroll enough patients to get clear results. If there are too many similar small trials running in parallel, their results individually may not be conclusive and the data may have so many differences that it cannot be aggregated.

“There are all kinds of people who want to try anything, because people are desperate,” said Boulware.

He and others who were unaware of Collins’ plans argue that national leadership – be it advice on how to prioritize trials, a central effort coordinating body or a mechanism to act as a matchmaker between institutions working on similar ideas – could help channel the pervasive scientific desire to make a bigger and faster impact.

Large-scale efforts are already underway: the World Health Organization has organized a massive trial in 90 countries of four promising therapies. The National Institutes of Health is testing the antiviral drug remdesivir in more than 50 institutions and launched a large trial for an antimalarial drug last week. A $ 50 million effort at the Duke Clinical Research Institute will test hydroxychloroquine in 15,000 healthcare workers and create a registry that can be used to speed up future trials, like a vaccine.

“People shouldn’t be fatalistic that we will have little evidence for things that work,” said Collins. “I hope we have three to four [treatments] by summer. ”

But as the federal effort has largely taken place in secret, individual institutions have rushed to set up panels of experts to assess trials that make sense to move forward. At the University of Pennsylvania, a multi-week-old committee assigns priority marks to trials based on criteria such as their ability to compete with existing efforts and how to recruit all the patients necessary to achieve a result. A task force at Duke University is doing a similar review.

“There are a lot of things boiling. It would seem that a sensible thing to do would be to line up everyone around the same tests, not one test for each context and not to let each institution do its own thing and at the end of the day, everyone has give it a try… and we don’t know what to think about it, ”said Steven Joffe, bioethicist at the University of Pennsylvania. “Let’s get to an answer. “

Many of the proposed trials overlap – using the same drug, such as hydroxychloroquine, an anti-malaria treatment that has been touted by President Trump, his lawyer Rudolph W. Giuliani, and conservative talk show host Laura Ingraham.

Boulware is halfway through one of these hydroxychloroquine trials, which examine whether the drug is effective in preventing disease or treating people with mild cases. Those who participate will receive the drug or vitamin in the mail.

He said he was motivated by his experience working on Ebola, when by the time a well-designed trial was operational, the epidemic was dying. He continued his trial on hydroxychloroquine for weeks before hearing – last Friday – the National Institutes of Health having refused to fund it. He found international collaborators by chance and on social media when some Canadian researchers emailed him asking if he would share his trial design with them. He ended up connecting Canadians to each other and is now working to overcome the complex legal requirements for sharing data.

But now his trial is potentially in competition with a bunch of others who are also testing hydroxychloroquine across the country – and enrollment has slowed in recent days.

Risks of inconclusive evidence in the age of social media

Small trials and even anecdotal reports of treatments that appear to have worked in small groups of patients are already shared, sowing both hope and confusion over the evidence.

A study published Friday in the New England Journal of Medicine reported that 53 people took Remdesivir, an Ebola drug Trump rented, and many families tried to access it outside of the trials. However, the results were impossible to interpret because some of these patients may have improved on their own and there was no comparison group of patients who did not receive the drug. Hydroxychloroquine, the cheap and readily available antimalarial drug, has also been widely used in patients despite the only evidence suggesting that it might work.

As new small-scale studies are designed, the risks of inconclusive but suggestive results increase – and, paradoxically, they could make it more difficult to conduct well-designed clinical trials that determine whether a treatment works. Well-designed clinical trials require that patients be ready to be randomly assigned to receive treatment – or a placebo.

Emma Meagher, director of clinical research at the Perelman School of Medicine at the University of Pennsylvania, said that her institution’s study on the malaria drug in critically ill patients does not have a comparison group receiving a placebo because the media around the drug made it the standard of care despite the lack of evidence. Each meeting, she said, begins with a discussion of how to prevent the next experimental therapy from becoming like hydroxychloroquine.

In some ways, designing research studies when clinicians have an imperative to provide their patients with the best possible care is inherently delicate. Outside of leading research hospitals, patients may not have access to trials, so clinicians have little choice but to give them drugs equivalent to an uncontrolled experience. The Infectious Diseases Society of America released guidelines last week that clinicians should only give investigational drugs in trials, but fewer rural safety nets and hospitals have access to them.

“Do we really want to have [some] people try new and different things and the rest of you sit and wait? Asked Benjamin Linas, a doctor specializing in infectious diseases, who oversees clinical trial protocols at Boston Medical Center.

Wasted time

Many researchers have said they hope a national strategy will help unify and accelerate research, but lament the time already wasted. The United States did not have an active pandemic clinical trial network, but existing clinical trial networks, such as those used to test HIV treatments, are being reoriented . Collins said he has never seen research progress faster, but in a pandemic that can still feel slow.

“We have imperfect networks. I mean there are, but they have never been tested that way, “said Adrian Hernandez, vice-dean of clinical research at Duke University School of Medicine. “Having a common infrastructure that can do rapid cycle testing – it would be beneficial. “

Collins said he started partnering with private companies, research institutes and other agencies in mid-March. If he had started earlier, he said, the urgency of the situation may not have been clear to the groups he had to convince to work together. He disagrees that much time has been lost and noted that efforts have been able to build on an existing framework for drug pursuit with the collaboration of the industry called Accelerating Medicines Partnership.

Partnerships that used to take a year and a half to put in place were established in a week, he said.

“I think it’s a world record for all that stuff; it might have been difficult to get full unanimous agreement on what is clearly unprecedented – for a willingness to give up control, “said Collins.

As with other areas of pandemic planning, many hope that the United States will learn from this lesson that it needs a preparedness plan not only to allocate essential supplies and step up testing, but also to plan research.

“The problem is that we must remember to invest in preparedness, at times when we are not affected by a pandemic or an epidemic,” said Barbara Bierer, director of regulatory foundations, ethics and program Harvard Clinical and Translational Science. Center. “And it’s hard to reallocate or commit resources to something that doesn’t immediately appear on the horizon. “

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