A Blog by Jonathan Low


Jan 24, 2022

How Smarter Covid Vaccine Clinical Trials Now Improve Other Diseases' Research

During the height of the Covid crisis, scientists responded to the urgency of the situation by using observational studies of real world experience in order to speed the development of vaccines and antigen treatments rather than relying on slower and much more expensive randomized controlled clinical trials. 

Now those methods are being applied to research into heart disease, Alzheimer's and other ailments. JL

Matthew Herper reports in Stat:

Scientists are beginning to accelerate how clinical trials are done and make them cheaper, aiming to build on what researchers learned studying treatments against Covid-19 to test medicines for heart disease, cancer, depression, Alzheimer’s, and other common ailments. Observational studies or databases, in which researchers follow large numbers of people to tease out benefits and risks of medical treatments are considered weaker than randomized controlled trials (but which) are difficult to run and the expense has gone up dramatically. “If trials continue to cost $1 billion or $2 billion each, we’re not going to get many new treatments for common diseases.”

Agroup of scientists who did more than perhaps any other to test new treatments for Covid, including establishing that the steroid dexamethasone can save lives, is now turning its focus to the rest of medicine.

The first step, announced today: a partnership with the Paris-based drug giant, Sanofi.

Sanofi will give the U.K. non-profit Protas $6.8 million to begin its work to accelerate how clinical trials are done and make them far cheaper. It aims to build on what the researchers learned studying treatments against Covid-19 to test medicines for heart disease, cancer, depression, Alzheimer’s, and other common ailments.

“One’s got to really think about how one can get better evidence at lower cost in order to get a better impact on public health,” said Sir Martin Landray, the CEO of Protas and a professor of medicine and epidemiology at Oxford University. “And that’s the motive.”

Landray is known for helping lead an effort that did more to find medicines to treat Covid than perhaps any other. The study he co-led, RECOVERY, used a network of U.K. hospitals to determine if a series of potential treatments helped hospitalized Covid patients. The study showed that hydroxychloroquine, convalescent plasma, and the HIV drugs lopinivir and ritonavir were ineffective for these patients. But it found that dexamethasone, the monoclonal antibody cocktail REGN-Cov, and the rheumatoid arthritis drug Actemra all helped hospitalized Covid patients survive.

This was all the more impressive given how many other efforts to definitively test potential Covid medicines failed because studies were too small or disorganized, and because they simply took too long to get off the ground. RECOVERY delivered results before a large clinical test of hydroxychloroquine being planned by the Swiss drug giant Novartis could even get off the ground. What’s more, it was far less expensive than research studies usually are.

It’s not unusual for pharmaceutical companies to spend hundreds of millions or even billions of dollars to conduct a single clinical trial. The RECOVERY effort, Landry said, cost under $10 million.

Now, he told STAT in an interview, it is time to apply the lessons from that effort to other medicines.

“If trials continue to cost $1 billion or $2 billion each, we’re not going to get many new treatments for common diseases,” said Landray. “And that’s not good value for patients and is not good value for those who pay for their care or deliver their care.”

In a statement, Dietmar Berger, Sanofi’s chief medical officer, said the company is “excited” to work with Protas.

“With this collaboration we are taking a bold step to significantly reduce the cost of some of our clinical trials, focusing on what matters the most for patients, doctors, regulators and payers,” Berger said.

The idea behind Protas predated the pandemic. In February 2020, Landray co-wrote a piece in the New England Journal of Medicine that decried the “real-world evidence” that many pharmaceutical companies increasingly were relying on as a “myth,” while praising randomization, the hallmark of the most rigorous medical studies, as “magic.”

“Real-world evidence” is often used as another word for what are traditionally called observational studies or databases, in which researchers follow large numbers of people in order to try to tease out the benefits and risks of medical treatments. But they are considered weaker than studies known as randomized controlled trials — in which patients are randomly assigned to receive either a new treatment or the best possible care that is otherwise available.

These trials work because picking patients essentially by a coin flip not only gives an answer that takes into account what researchers know might influence a result, but what they don’t. It’s been the standard in medicine since shortly after World War II, when U.K. researchers proved that streptomycin, an antibiotic, was effective as a treatment for tuberculosis. Traditionally, the U.S. Food and Drug Administration has considered two randomized controlled trials as the best evidence that a medicine is effective.

But randomized trials have a problem: they’re difficult to run well and are costly. And the expense has gone up dramatically over the past few decades.

For instance, studies on heart drugs have routinely approached or passed the billion-dollar mark. In the early 2000s, Pfizer said it was spending close to that amount to study a drug aimed at boosting good cholesterol. (In a massive disappointment for the company, that medicine increased the death rate in a large clinical trial.) More recently, two new cholesterol drugs called PCSK9 inhibitors, one from Amgen and the other from Regeneron and Sanofi, ran up huge bills for drug companies and then ended up generating little in the way of sales.

This means, Landray said, that pharmaceutical research heads trying to decide what products to develop look at medicines for heart disease or Alzheimer’s and see not only a low chance of success, but an incredibly expensive roadblock close to the end of the process. What’s more, medicines for rare diseases, including subsets of cancers, can often be done in much smaller, less expensive studies. But because those medicines command high prices, they can be just as lucrative.

This, in turn, creates a situation where drug companies, instead of trying to study medicines in as many people as possible, attempt to limit their studies to the group they think is most likely to show a benefit.

Landray quips that it’s as if the message from the companies funding studies is often: “Dear statistician, can you provide a mathematical justification for us limiting the scale of this study?”

But there is one potential solution: what’s known as a large simple trial. Part of the reason that clinical trials are so expensive is that they are often conducted by companies known as clinical research organizations that charge per patient. Another is that more and more processes, such as extra bloodwork and measurements and follow-up visits, are added. This yields more information, but also drives up the cost.

Landry is a proponent of a different strategy: stripping out as many of the costs and processes as possible in order to make the trial easier to run. For instance, a study attempting to understand whether prescribing people a drug decreases their chance of dying only needs to be sure it finds out if they die. In this extreme case, lots of other data collection can be skipped. By making running the trial simpler for the doctors and nurses on the front lines, it becomes easier to recruit patients in hospitals where top academics rarely go, meaning that data is collected from a more diverse population – geographically, socioeconomically, and in terms of race and ethnicity.

This is the approach that was tested in RECOVERY. It was not the first time the simple approach was used. Eric Topol and Robert Califf, who is currently being considered as the next head of the FDA, used this strategy in a study of a clot-busting drug a quarter of a century ago. And Landry and his colleagues have used the approach in studies of heart drugs, including a Merck reformulation of the B vitamin niacin. At the time, niacin was commonly used as a heart drug and Merck thought its version would be less likely to cause facial flushing. Instead, Landry and his colleagues found, the medicine did little good but increased patients’ risk of serious bleeding and infection. A similar strategy reduced the costs of testing Novartis’ new cholesterol drug, Leqvio, which is currently being rolled out by the National Health Service in a program that will aim to monitor its efficacy.

The desire to replicate that model is what led to the creation of Protas as a nonprofit. (The world, Landray said, did not need another for-profit clinical trials company.) But there is still a long way to go. The money from Sanofi is only a drop in the bucket in terms of what pharmaceutical firms will spend. Landray will need more big partners. And he says he will spend the next few years just building up the infrastructure the non-profit will need.

But it’s a start.


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