Category: Medicine
A new Operation Warp Speed for better vaccines
The Biden administration is launching a $5 billion-plus program to accelerate development of new coronavirus vaccines and treatments, seeking to better protect against a still-mutating virus, as well as other coronaviruses that might threaten us in the future.
“Project Next Gen” — the long-anticipated follow-up to “Operation Warp Speed,” the Trump-era program that sped coronavirus vaccines to patients in 2020 — would take a similar approach to partnering with private-sector companies to expedite development of vaccines and therapies. Scientists, public heath experts and politicians have called for the initiative, warning that existing therapies have steadily lost their effectiveness and that new ones are needed…
Jha and others said the new effort will focus on three goals: creating long-lasting monoclonal antibodies, after an evolving virus rendered many current treatments ineffective; accelerating development of vaccines that produce mucosal immunity, which is thought to reduce transmission and infection risks; and speeding efforts to develop pan-coronavirus vaccines to guard against new SARS-CoV-2 variants, as well as other coronaviruses.
Here is the WaPo article, here is commentary from Eric Topol.
The case for nurse practitioners
Many states have recently changed their scope of practice laws and granted full practice authority to nurse practitioners, allowing them to practice without oversight from physicians. Physician groups have argued against this change, citing patient safety concerns. In this paper, we use a ratio-in-ratio approach to evaluate whether the transition to full practice authority results in harm to patients as proxied by rates of malpractice payouts and adverse action reports against nurse practitioners. We find no evidence of such harm, and instead find that physicians may benefit from the law change in terms of reduced malpractice payouts against them.
That is from a new NBER working paper by Sara Markowitz and Andrew J.D. Smith.
Peltzman Revisited
Casey Mulligan has an excellent new paper, Peltzman Revisited: Quantifying 21st-Century Opportunity Costs of Food and Drug Administration Regulation. What are the costs of delaying a new drug or a vaccine? Longer and bigger clinical trials increase safety but I’ve often made the point that the people who would have lived had a good drug been approved sooner are buried in an invisible graveyard and thus these costs are typically undercounted–the failure to see the invisible graveyard biases decisions in favor of delay. Mulligan makes a different and rarely considered point about substitution effects. If a vaccine isn’t available there are substitutes but these substitutes are themselves potentially unsafe and ineffective. But who is testing the substitures?
Many of these substitute interventions, such as remote work, closing schools, and canceling normal medical appointments, are beyond the jurisdiction of the FDA and can be utilized without any attempt to demonstrate their safety or efficacy.
If the substitutes work, the costs of delay are reduced. The FDA, for example, is right to prioritize drugs for which there are few alternative treatments. But the standards for many vaccine or drug substitutes are completely different than those used to approve a vaccine:
Closing schools to in-person learning is an important example of a prevention activity that was available, was applied to tens of millions of children in the United States, and was outside the FDA’s jurisdiction…Obviously the FDA’s effectiveness standard for vaccines differs from the effectiveness standard (if any) that school districts applied in deciding to close schools.
Where were the randomized controlled trials for closing schools, shutting the parks and beaches, and delaying medical appointments? Thus, it’s quite possible that greater safety of vaccines comes at the expense of greater time under less safe and possibly unsafe substitutes. As Mulligan concludes:
Approval delays for pandemic tests and vaccines pushed tens of millions of individuals and businesses into preventions and treatments that were both outside FDA jurisdiction and hardly safe or effective. The pandemic experience raises the question of whether, on the whole, consumers engage in more unsafe and ineffective practices than they would if FDA approval were not a prerequisite for pharmaceutical sales.
Addendum: Much else of interest in the paper including a calculation of the value of the vaccines in the hundreds of billions and trillions very much in line with work done by the AHT team, including myself ,in the AER PP (especially the appendix) and Science.
GPT-4 Does the Medical Rounds
GPT4 passed the medical licensure exam but the critics want to know how does it perform in the real world? Zak Kohane, pediatric endocrinologist, data scientist, and chair of the Harvard Chair of the Department of Biomedical Informatics at Harvard Medical School has apparently been working with GPT4 for about 6 months. He has a forthcoming book (with Peter Lee and Carey Goldberg). He writes:
“How well does the AI perform clinically? And my answer is, I’m stunned to say: Better than many doctors I’ve observed.”—Isaac Kohane MD
That’s from a review of the book by Eric Topol. Not much more information to be had in the review but if you think about it, this bit is hilarious:
I’ve thought it would be pretty darn difficult to see machines express empathy, but there are many interactions that suggest this is not only achievable but can even be used to coach clinicians to be more sensitive and empathic with their communication to patients.
Capabilities of GPT-4 on Medical Challenge Problems
Large language models (LLMs) have demonstrated remarkable capabilities in natural language understanding and generation across various domains, including medicine. We present a comprehensive evaluation of GPT-4, a state-of-the-art LLM, on medical competency examinations and benchmark datasets. GPT-4 is a general-purpose model that is not specialized for medical problems through training or engineered to solve clinical tasks. Our analysis covers two sets of official practice materials for the United States Medical Licensing Examination (USMLE), a three-step examination program used to assess clinical competency and grant licensure in the United States. We also evaluate performance on the MultiMedQA suite of benchmark datasets. Beyond measuring model performance, experiments were conducted to investigate the influence of test questions containing both text and images on model performance, probe for memorization of content during training, and study calibration of the probabilities, which is of critical importance in high-stakes applications like medicine. Our results show that GPT-4, without any specialized prompt crafting, exceeds the passing score on USMLE by over 20 points and outperforms earlier general-purpose models (GPT-3.5) as well as models specifically fine-tuned on medical knowledge (Med-PaLM, a prompt-tuned version of Flan-PaLM 540B). In addition, GPT-4 is significantly better calibrated than GPT-3.5, demonstrating a much-improved ability to predict the likelihood that its answers are correct. We also explore the behavior of the model qualitatively by presenting a case study that shows the ability of GPT-4 to explain medical reasoning, personalize explanations to students, and interactively craft new counterfactual scenarios around a medical case. Implications of the findings are discussed for potential uses of GPT-4 in medical education, assessment, and clinical practice, with appropriate attention to challenges of accuracy and safety.
Here is the full paper by Harsha Nori, Nicholas King, Scott Mayer McKinney, Dean Carignan, and Eric Horvita. Ho hum, people, ho hum!
Via Ethan Mollick.
UK to Adopt Pharmaceutical Reciprocity!
More than twenty years ago I wrote:
If the United States and, say, Great Britain had drug-approval reciprocity, then drugs approved in Britain would gain immediate approval in the United States, and drugs approved in the United States would gain immediate approval in Great Britain. Some countries such as Australia and New Zealand already take into account U.S. approvals when making their own approval decisions. The U.S. government should establish reciprocity with countries that have a proven record of approving safe drugs—including most west European countries, Canada, Japan, and Australia. Such an arrangement would reduce delay and eliminate duplication and wasted resources. By relieving itself of having to review drugs already approved in partner countries, the FDA could review and investigate NDAs more quickly and thoroughly.
Well, it’s happening! After Brexit, there were concerns that drugs would take longer to get approved in the UK because the EU was a much larger market. To address this, the UK introduced the “reliance procedure” which recognized the EU as a stringent regulator and guaranteed approval in the UK within 67 days for any drug approved in the EU. The Reliance Procedure essentially kept the UK in the pre-Brexit situation, and was supposed to be temporary. However, recognizing the logic of recognizing the EU, the UK is now saying that it will recognize other countries.
Our aim is to extend the countries whose assessments we will take account of, increasing routes to market in the UK. We will communicate who these additional regulators are and publish detailed guidance about this new framework in due course, including any transition arrangements for applications received under existing frameworks.
The UK is already participating in a mutual recognition agreement with the FDA over some cancer drugs. Therefore, it seems likely that the FDA will be among the regulatory authorities that the UK recognizes. If the UK does recognize the FDA, then we only need the FDA to recognize the UK for my scenario from more than 20 years ago to be fulfilled.
It’s thus time to revisit the Lee-Cruz bill of 2015, which proposed the Result Act (I was an influence).
Reciprocity Ensures Streamlined Use of Lifesaving Treatments Act (S. 2388), or the RESULT Act,” which would amend the Food, Drug and Cosmetic Act to allow for reciprocal approval of drugs.
Addendum: Many previous posts on FDA reciprocity.
Restrictions on state public health authorities
Conservative and libertarian forces have defanged much of the nation’s public health system through legislation and litigation as the world staggers into the fourth year of covid.
At least 30 states, nearly all led by Republican legislatures, have passed laws since 2020 that limit public health authority, according to a Washington Post analysis of laws collected by Kaiser Health News and the Associated Press as well as the Association of State and Territorial Health Officials and the Center for Public Health Law Research at Temple University.
Health officials and governors in more than half the country are now restricted from issuing mask mandates, school closures, and other protective measures or must seek permission from their state legislatures before renewing emergency orders, the analysis showed.
Here is more from the Washington Post.
On graduate student mental health (from my email)
…we often discuss mental health in terms of treatment and selection effects. While more causal inference is needed, I believe it some points are often overlooked.
Personality plays a role: Many in the field can be characterized as overachievers. This behavior can easily turn pathological if it is driven by a fear of failure or a sense that self-worth is contingent on competence. Moreover in a competitive academic environment. Exit may be psychologically very difficult if your self-worth is on the line.
Policies within graduate programs exacerbate the issue: In my program, if a student drops out, the University will not award them a master’s degree if they already have a similar degree from another university. This policy discourages students exit and may keep them in situations that are not beneficial for their mental health.
Economists tend to overrate the effectiveness of educational signals in selecting prospective grad study: Interviews are often not a part of the selection process, which I believe is a missed opportunity to assess a student’s psychological readiness for a PhD program. For many far less stressful jobs psychological testing is standard. In my experience, I only received interviews from programs that had already accepted me (meant to convince me to accept offers).
From anonymous.
Semaglutide, Ozempic, and the end of the Great Stagnation
I am no expert on this weight loss drug, but many people on both the bio side and the VC side are telling me it works. Might it, or some variant thereof, become the best-selling drug of all time?
Just think that within five years we likely will have come up with good, serious remedies to Covid, to obesity (a major, major public health problem, especially in America), to malaria, and to dengue, vaccines in the latter two cases. And that is unlikely to be the end of the list.
That is an astonishing record, and we are truly living in a golden age for biomedicine. Ozempic is further evidence that the great stagnation is over, even though the current world is not mimicking the physical dynamism of say the 1920s.
No Respect for Diversity of Opinion or Choice
David Zweig notes an important correlation:
The colleges with the most stifling atmospheres for speech also have the most aggressive Covid vaccine policies. The colleges that most welcome and protect a free exchange of ideas, in turn, have the least intrusive vaccine requirements.
Number 1 ranked [on Fire’s Free Speech Index, AT] Chicago has no vaccine mandate at all. The university merely “strongly recommends” Covid vaccination. Numbers 2, 3, 4, and 5 on the list – Kansas State, Purdue, Mississippi State, and Oklahoma State – do not require any Covid vaccination either. They do each highly encourage vaccination, though.
At the bottom, Columbia not only requires the primary series for its students, but also requires the most recent bivalent booster. Ditto for second-to-last place Penn. For the many students who received an initial booster early on, this means a requirement of four doses. Rounding out the worst five colleges for free speech, Rensselaer Polytechnic Institute, Georgetown, and Skidmore also mandate all students be boosted. Though compared to Columbia and Penn they are relatively lax, only requiring “a booster,” meaning the third shot could have been from a long while ago, and not necessarily the bivalent.
Why are the colleges with the worst limits on free speech also the worst for limiting bodily autonomy?
Columbia and its ilk had a history of liberalism which, as is well-known now, has recently morphed into a more stifling form of modern progressivism that doesn’t tolerate dissent. The political tribalism that demands in-group thinking also demands in-group behavior — during, and now exiting the pandemic, the more extreme that one reacted toward Covid, the more one demonstrated their membership in the left wing. (Being double masked and triple vaxxed was for a long time a progressive identity marker.) Quite simply, an extreme vaccination policy, out of step with much of the world yet perfectly accepted in progressive America, announces one’s institution as an unimpeachable member of the tribe.
That there is an association between respect toward free speech and respect toward bodily autonomy — or a lack thereof for each — at academic institutions shouldn’t surprise anyone. Both reflect attitudes either in agreement with or against a libertarian ideal of individual freedom. But the degree of correlation is still disheartening.
…It is an embarrassment that policies at many of our most elite institutions of higher education are the most divorced from scientific evidence, and are now, finally, even alienating mainstream liberals. FIRE’s free speech rankings, alas, help explain how we got to this place.
We live in a diverse society and that requires respect. Unfortunately, at some of our nation’s top universities there is no respect for diversity of opinion or choice.
Emergent Ventures winners, 24th cohort
Shakked Noy, MIT economics, to do RCTs on GPTs as teaching and learning tools.
Gabriel Birnbaum, Bay Area, from Fortaleza, Brazil, to investigate lithography as a key technology used in the manufacturing of microchips.
Moritz Wallawitsch, Berkeley. RemNote is his company, educational technology, and to develop a complementary podcast and for general career development.
Katherine Silk, Boston/Cambridge, general career support and to support advice for early-stage startups.
Benjamin Schneider, Brooklyn. To write a book on the new urbanism.
Joseph Walker, Sydney, Australia, to run and expand the Jolly Swagman podcast.
Avital Balwit, Bay area, travel grant and general career development.
Benjamin Chang, Cambridge, MA. General career support, “I will develop novel RNA riboswitches for gene therapy control in human cells using machine learning.”
Daniel Kang, Berkeley/Champagne-Urbana, biometrics and crypto.
Aamna Zulfifiqar, Karachi, Pakistan, to attend UK higher education to study economics.
Jeremy Stern, Glendale, CA, Tablet magazine. To write a book.
James Meech, PhD student, Cambridge, UK, to work on a random number generator for better computer architectures.
Arthur Allshire, University of Toronto, background also in Ireland and Australia, robotics and support to attend conferences.
Jason Hausenloy, 17, Singapore, travel and general career development, issues surrounding artificial intelligence.
Sofia Sanchez, Metepec, Mexico, biology and agricultural productivity, to spend a summer at a Stanford lab.
Ukraine tranche:
Andrey Liscovich, eastern Ukraine, formerly of Harvard, to provide equipment for public transportation, communication and emergency power generation to civilian authorities of frontline-adjacent areas in Ukraine which have lost vital infrastructure.
Chris Nicholson, Bay area, working as a broker to maintain internet connectivity in Ukraine.
Andrii Nikolaiev, Arsenii Nikolaiev, Zarina Kodyrova, Kvanta, to advance Ukrainian mathematics, help and train math Olympiad winners.
As usual, India and Africa/Caribbean tranches will be reported separately.
Pegylated interferon lambda
A new drug quashes all coronavirus variants. But regulatory hurdles and a lack of funding make it unlikely to reach the U.S. market anytime soon.
So starts the NYT article. Have we learned nothing? As for the drug itself, the news is good:
…a new class of variant-proof treatments could help restock the country’s armory. Scientists on Wednesday reported in The New England Journal of Medicine that a single injection of a so-called interferon drug slashed by half a Covid patient’s odds of being hospitalized.
The results, demonstrated in a clinical trial of nearly 2,000 patients, rivaled those achieved by Paxlovid. And the interferon shots hold even bigger promise, scientists said. By fortifying the body’s own mechanisms for quashing an invading virus, they can potentially help defend against not only Covid, but also the flu and other viruses with the potential to kindle future pandemics.
We will see if this has the opportunity to progress. Fast Grants, working in conjunction with Rainwater Foundation, was a key early funder here.
Oh, and do note this:
As it stands, Eiger executives said that they might seek authorization for the interferon shot outside of the United States. China, for example, has been looking for new treatment options.
And here is an Eric Topol thread on the results.
Yglesias on Operation Warp Speed and the Republicans
Here’s Yglesias on Operation Warp Speed and the Republicans:
The debate over Operation Warp Speed wasn’t just a one-off policy dispute. Long before the pandemic, there was a conservative critique that the Food and Drug Administration is too slow and too risk-averse when it comes to authorizing new medications. Alex Tabarrok, a George Mason University economist, wrote about the “invisible graveyard” that could have been avoided if the FDA took expected value more seriously and considered the cost of delay in its authorization decisions.
The pandemic experience validated this criticism, which came to be embraced by some on the left as well — and it was about more than just vaccines. When it came to home Covid tests, Ezra Klein noted in the New York Times in 2021, “the problem here is the Food and Drug Administration. They have been disastrously slow in approving these tests and have held them to a standard more appropriate to doctor’s offices than home testing.”
And yet, just as the invisible graveyard was becoming seen and the debate was being won and just as a historical public-private partnership had sped vaccines to the public and saved millions, the Republicans abandoned the high ground:
…it’s not surprising that Democrats are comfortable with the bureaucratic status quo and hesitant to ruffle feathers at federal regulatory agencies. What’s shocking is that Republicans — the traditional party of deregulation, the party that argued for years that the FDA is too slow-footed, the party that saved untold lives by accelerating vaccine development under Trump — have abandoned these positions.
At the cusp of what should have been a huge policy victory, Republicans don’t brag about their success, and they have no FDA reform legislation to offer. Instead, they’ve taken up the old mantle of hard-left skepticism of modern science and the pharmaceutical industry.
It’s been painful to see all that has been gained now being lost. Libertarian economists and conservatives argued for decades that the FDA worried more about approving a drug that later turns out to be unsafe than about failing to approve a drug that could save lives; thus producing a deadly caution. But now the FDA is being attacked for what they did right, quickly approving safe vaccines. I hope that he is wrong but I fear that Yglesias is correct that the FDA may now get even slower and more cautious.
The irony of the present moment is that there is substantial backlash to the FDA’s approval of vaccines that haven’t turned out to be dangerous at all.
That’s only going to make regulators even more cautious. Right now the entire US regulatory state is taking essentially no heat for the slow progress on the next generation of vaccines, and an enormous amount of heat for the perfectly safe vaccines that it already approved. And the ex-president who pushed them to speed up their work on those vaccines is not only no longer defending them, he’s embarrassed to have ever been associated with the project.
Like I said, it’s a comical moment of Republican infighting. But it’s a very grim one for anyone concerned with the pace of scientific progress in America.
Will there by an H5N1 pandemic for humans?
Manifold Markets is currently putting the chance at 12%. That seems high to me, but maybe two percent? Which I still regard as leading to a high expected cost, to be clear. There is now mammal-to-mammal transmission. Zeynep Tufekci considers possible preparatory steps (NYT), including more surveillance.
Medical markets in everything?
Or will they be thwarted?
To Nina McCollum, Cleveland Clinic’s decision to begin billing for some email correspondence between patients and doctors “was a slap in the face.”
She has relied on electronic communications to help care for her ailing 80-year-old mother, Penny Cooke, who is in need of specialized psychiatric treatment from the clinic. “Every 15 or 20 dollars matters, because her money is running out,” she said.
Electronic health communications and telemedicine have exploded in recent years, fueled by the coronavirus pandemic and relaxed federal rules on billing for these types of care. In turn, a growing number of health care organizations, including some of the nation’s major hospital systems like Cleveland Clinic, doctors’ practices and other groups, have begun charging fees for some responses to more time-intensive patient queries via secure electronic portals like MyChart.
…a new study shows that the fees, which some institutions say range from a co-payment of as little as $3 to a charge of $35 to $100, may be discouraging at least a small percentage of patients from getting medical advice via email. Some doctors say they are caught in the middle of the debate over the fees, and others raised concerns about the effects that the charges might have on health equity and access to care.
Demand curves do slope downward. And yet:
But a recent study led by Dr. Holmgren of data from Epic, a dominant electronic health records company, showed that the rate of patient emails to providers had increased by more than 50 percent in the last three years.
Perhaps there is a smidgen of room for AI here? But not under the current legal regime, I suspect. Here is the full Benjamin Ryan NYT article.