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National Review – Beyond the Magic Bullet: Medical Progress Is Often Incremental

National Review – Beyond the Magic Bullet: Medical Progress Is Often Incremental

Life won’t completely return to normal while the novel coronavirus remains a threat to health and to life. More than 60,000 Americans have already lost their lives to this virus; while older people seem especially vulnerable, the virus has demonstrated its ability to kill people of all ages. Even as the country edges back to work and school, there’s a palpable anxiety. We don’t want to get infected, and we don’t want to infect others.


The most appealing solution would be a transformational treatment that immediately neutralized the threat. This would most likely be in the form of a vaccine, a preventive approach currently used against viral illnesses including polio, measles, mumps, rubella, hepatitis A, and hepatitis B. According to the Milken Institute, nearly 100 potential vaccines for COVID-19 are “in development,” some by big pharmaceutical houses such as Johnson & Johnson and Pfizer, others by smaller biotechs such as Moderna.


Another attractive, equally transformative solution would be a treatment that was completely curative — one that might not prevent the infection but would be able to eliminate the virus, the way an effective antibiotic can cure a bacterial infection. The singular example here are the cures several companies have developed for hepatitis C. After a relatively short period of treatment — weeks to months — the virus is gone.


Transformative therapies are what many medical researchers dream of developing, and what so many in society hope for from biomedical science, the “magic bullet” in Paul Ehrlich’s famous phrasing, borrowing from what Boston University professor Muhammad Zaman describes as an “old superstitious belief that bullets could be charmed, under the right spell, to hit a particular person” — or, in this case, a particular pathogen.


For those eagerly waiting, I have some good news and bad news.


First, the bad news: While the polio vaccine was an infinitely better treatment than the iron lung, such transformative therapies are notoriously difficult to come by, especially for most anything besides infectious diseases — and even here, there are challenges. Bacteria are increasingly resistant to antibiotics, and developing effective vaccines for viruses can be a challenge.


Now the good news: Our progress in most diseases, from pediatric cancer to diabetes to HIV, reflects not the singular impact of one curative medicine but rather the progressive improvement in treatment, iteratively, over time. Incrementalism, it turns out, may be grossly underrated.


Wednesday brought some much needed “good news,” according to White House health adviser Dr. Anthony Fauci. Data from a study of Gilead’s experimental medicine remdesivir, conducted by Fauci’s National Institute of Allergy Immunology and Infectious Disease (NIAID), showed a “clear-cut positive effect in diminishing time to recover,” Fauci told reporters. The randomized controlled study included a placebo arm.


Remdesivir, Fauci said, shortened the time to recovery by about a third. “Although a 31 percent improvement doesn’t seem like a knockout 100 percent, it is a very important proof of concept because what it has proven is that a drug can block this virus,” he said. “This is very optimistic.”

Respected Evercore analyst Umer Raffat offered this tidy summary: “Remdesivir ‘works,’ but it’s not a magic bullet.”


I’ve been following remdesivir developments with particularly keen interest (my wife leads virology at Gilead), and my sense is that Fauci and Raffat are exactly right: Remdesivir would seem to represent a significant step forward, though it is not a cure for the disease, nor an end to the pandemic.


“We have a certain heroic expectation of how medicine works,” Atul Gawande observed with characteristic eloquence in “The Heroism of Incremental Care,” a New Yorker essay in 2017. Gawande admits he “was drawn to medicine by the aura of heroism — by the chance to charge in and solve a dangerous problem.” Even so, he’s come to recognize that in the care of patients, it’s often the “incremental steps that produce sustained progress.”


This seems to hold not only for the care of individual patients but also in the evolution of treatment for a particular condition.


As pediatrician Darshak Sanghovi, author of A Map of the Child and now the chief medical officer of Optum Labs, noted in 2008, the long-term survival of children with leukemia dramatically improved between the early 1970s and the late ’90s, “skyrocketing from less than 20 percent to around 80 percent.”  Why? Because pediatric oncologists “saved lives simply by refining the use of old-school drugs,” systematically varying the doses and routes of administration. Using this approach, Sanghovi explains, doctors gradually learned what drug combination, doses, and sites of injection worked best. And they kept at it. With each small innovation, survival rates crept forward a bit — a few percent here and there every couple of years — and over decades those persistent baby steps added up to a giant leap.


Childhood cancer is hardly exceptional; Sanghovi cites other examples, including the treatment of tuberculosis and the management of heart disease.


Another example he might have pointed to: the treatment of HIV, which through a process of incremental innovation — and thanks to some new medications — has evolved from a death sentence to a difficult but somewhat tractable disease treated with complicated polypharmacy, and from there to an entirely manageable, chronic condition, often requiring just a single combination pill taken once a day. Incremental improvements led to a profound improvement in care — though still not quite a cure.


Unless or until a vaccine against COVID-19 is developed, we will likely depend on such iterative innovation — including non-pharmacological approaches such as “proning” and, potentially, the use of nebulized saline to reduce aerosolization — to progressively improve the treatment of patients. The remdesivir results reported Wednesday represent an important early step in this process.



If incremental invention — deliberate tinkering — is so useful, is there anything that can be done to accelerate this process and help the sorts of curious doctors (Harvard surgeon Judah Folkman lionizes them as “inquisitive physicians”) innovate faster or more effectively?

One interesting approach to this is the use of “real world” data: information gleaned from traditional patient–doctor encounters. The thought is that perhaps there are patterns that can be extracted from the data, characteristics of patients who seem to do better, or worse, than other similar patients. By deliberately learning from as many patients as possible, the thinking goes, health-care practitioners can deliver better outcomes.


This is very much what the U.S. Food and Drug Administration is trying to do, according to Dr. Amy Abernethy, FDA principal deputy commissioner. “Within the context of COVID-19, we’ve got this urgency to learn what we can as soon as we can,” she commented at a recent webinar sponsored by the Duke-Margolis Center for Health Policy, “and that means that we need to be learning from the patients that are receiving care right now and trying to understand how do we apply that as quickly as possible.”

Efforts to collect real-world data on COVID-19 are the core of a new initiative, the COVID-19 Evidence Accelerator, launched by Friends of Cancer Research and the Reagan-Udall Foundation, which was mandated by Congress to accelerate regulatory science. The goal, according to a note in BioCentury, is “to create ways to learn from the COVID-19 patient experience and reinvest that knowledge in ways that benefit future patients.”


Whether these systematic efforts to catalyze insight and accelerate incremental innovation will succeed is anyone’s guess. But while much of the world is mired in resignation, pessimism, and bitter partisan squabbles, these efforts to attack COVID-19 are promising, broad-based developments that should leave all of us feeling hopeful and more than a tad encouraged.…