Summary

Makary is treating FDA turnaround as a strategic asset rather than administrative hygiene. In his first 10 months, he says the agency announced 42 reforms, published rejection letters, met 100% of its 2025 user-fee decision dates, preserved scientific reviewers through back-office consolidation, and said it was hiring 1,500 new scientists—later referring to 1,000 new scientists being onboarded. The mission is “more cures and meaningful treatments faster,” not fighting misinformation.
The U.S.–China biotech race will be won by compressing development time, not protectionism alone. Friedberg noted that Chinese companies rose from 5% of licensing deals in 2022 to 42% in 2025, while China now publishes 50% more scientific papers than the U.S.; Makary contrasted Chinese four-week and Australian six-week Phase 1 timelines with a Johns Hopkins survey that spent 18 months in IRB review without approval. His answer is centralized IRBs and contracting, lower fees for domestic trials, and AI that cuts FDA completeness checks from 60 days to one.
The most immediately tradeable reform is a reset of clinical-development economics. FDA is moving from two default pivotal trials to one properly designed study, which Makary estimates can save $100 million to $300 million for some companies, while eliminating many animal-testing requirements—including official chimpanzee-study submissions for monoclonal antibodies, where 144 chimpanzees are typically used—and substituting computational models and organ-on-a-chip systems. One executive told him the savings meant, “We can run twice as many drugs through large pivotal trials.”
Continuous trials and real-time surveillance could support both earlier approval and faster detection of harm. Makary wants Bayesian analysis and “endpoints in the cloud,” replacing periodic data cuts and giant applications with continuously visible efficacy and safety signals. He cited the five years before Vioxx was understood to have potentially killed 38,000 people and 15 years of opioid prescribing as failures that big-data surveillance should catch sooner: “We’re using computers now, not stone tablets.”
Cell, gene, and CAR-T therapies are getting pathways scaled to bespoke medicine rather than mass-produced pills. FDA is customizing manufacturing rules, removing some PPQ requirements for batches, and using a “plausible mechanism pathway” where randomized trials are impossible; Makary cited baby KJ’s gene-editing treatment as the model. With CAR-T still costing roughly $500,000 to $1 million, the thesis is faster reuse of proven platforms—while Makary says he immediately stopped a program that shipped Americans’ cells to China for editing.
Makary’s food and research agenda shifts attention from treatment toward metabolic and environmental causes. He says 60%–70% of children’s calories are refined carbohydrates, 38% have prediabetes or diabetes, and 40% have a chronic disease; the revised food pyramid therefore elevates protein, whole foods, and metabolic health. He likewise describes NIH changes as reallocation—not aggregate cuts—from genetic and treatment-heavy work toward food, sleep, school lunches, microbiome science, and environmental exposures.
The vaccine reset is a trust strategy built around hierarchy rather than blanket rejection. After comparing 20 developed countries, the administration identified a “core essential” list of about 38 doses, versus 72 total doses in the prior U.S. recommendation, while leaving every vaccine recommended and covered; Makary argues “38 is better than zero” when absolutism over COVID boosters causes parents to reject measles vaccination too. Friedberg pressed him on states creating rival schedules, but Makary’s answer was scientific humility rather than political engagement: sometimes “we don’t know” is the responsible position.
Drug-cost policy attacks every layer: international pricing, biosimilar barriers, prescription gates, PBMs, and advertising. Makary contrasted a $1,300 U.S. GLP-1 with an $88 London price, promised most-favored-nation pricing and a $149 introductory level, and said biosimilar reforms could remove more than $100 million of development cost and shorten the timeline from 5–8 years to roughly 2½ years or more. FDA also sent 1,500 advertising enforcement letters, wants many safe drugs moved over the counter in 2026, and will leave consumer AI and wearables broadly open unless they automate treatment or claim “medical grade” accuracy.

Deep dive

1. FDA’s new operating doctrine makes delay an observable harm

Makary traces his appointment to hospital-price-transparency work at Johns Hopkins: his book reached the first Trump White House, its proposal became an executive order, and Trump offered him FDA commissioner days after reelection. The lesson he carried forward was that government could implement “common sense ideas.”
His COVID-era dissent supplied the governing philosophy: Makary opposed toddler masking, mandates for young students, repeated boosters for healthy children, dismissal of natural immunity, and prolonged school closures once data emerged. He describes the deeper failure as “sacrificing the basic principles of science to question everything.”
Anonymous conversations with individual reviewers became his reform engine. Most offered little, but occasionally someone would explain that an entrenched process “makes no sense” and propose a better one; FDA ran with those suggestions, announcing 42 major reforms in 10 months and making rejection letters public to expose the agency’s reasoning.
Makary’s response to reports of chaos is numerical: before his arrival, FDA had roughly 20,000 employees, including 2,000 in HR and 1,500 in IT; consolidation spared scientific reviewers, turnover remains at its historical 5%–7%, and he described hiring 1,500 new scientists, later referring to 1,000 new scientists being onboarded. One emblem of the old silos was a drug file physically carried between centers because lawyers said it could not be emailed.

2. Winning the biotech race requires fixing Phase 1 at home

Friedberg’s competitive framing was stark: Chinese companies went from 5% of licensing deals in 2022 to 42% in 2025, 3SBio’s Pfizer deal brought $1.25 billion upfront and $6 billion in potential value, and China moved from publishing half as many scientific papers as the U.S. to 50% more.
Makary agreed there is a race and said the U.S. entered the administration “getting clocked” by China, Australia, and other faster jurisdictions. Protectionist measures might help, but his primary answer is to make American INDs and Phase 1 trials more competitive.
The best specimen of domestic friction came from Makary’s own nutrition survey: Johns Hopkins’ institutional review board spent a year and a half reviewing it and still did not approve it. China can conduct Phase 1 studies in four weeks and Australia in six, so he wants centralized IRBs and hospital contracts covering networks rather than site-by-site margin negotiations.
FDA itself sometimes took 60 days merely to say whether a supplemental application would be considered—or whether a submission was complete. Makary wants AI to reduce the completeness check to one day and higher user fees for Phase 1 studies conducted overseas; meanwhile, FDA hit 100% of its 2025 user-fee target dates and recorded nine approvals in one month at its Center for Biologics Evaluation and Research.

3. One pivotal trial and fewer animal studies reset development economics

Makary laid out the conventional ladder: an IND, a small Phase 1 generally testing healthy subjects, a limited Phase 2 in patients with the condition, and a large randomized Phase 3 pivotal trial. FDA’s new default moves from two pivotal trials to one well-designed, properly controlled study.
His statistical claim is that one trial can supply the same power, saving some companies $100 million to $300 million and significant time. One pharmaceutical executive translated that directly into portfolio throughput: “That means we can run twice as many drugs through large pivotal trials.”
Preclinical reform targets requirements that can mislead as well as delay. A monoclonal-antibody program typically used 144 chimpanzees, yet Makary said 90% of drugs passing animal studies later fail for human safety or efficacy; FDA has removed the official requirement to submit chimpanzee studies and is advancing computational prediction and organ-on-a-chip testing.
A priority-voucher pilot now covers about 18 products and produced its first decision in 55 days. Eligibility follows declared national priorities—major unmet need, manufacturing returned to America, or affordability—and the operating fix is to align a dozen reviewing offices whose staff previously had little incentive to finish before the year-long deadline.

4. Continuous evidence can trade earlier access for tighter surveillance

Beyond hybrid Phase 1/2 and Phase 2/3 designs, Makary wants continuous trials using Bayesian statistics, which FDA had just announced it would accept. With “endpoints in the cloud,” reviewers could recognize efficacy or danger in real time instead of waiting for a committee’s twice-yearly data cut and another giant application.
Continuous postmarket evidence is the other half of the bargain. Makary cited the five years before Vioxx was understood to have potentially killed 38,000 people and 15 years of opioid prescribing without recognizing a national addiction pattern; big data should instead identify subgroups, drug interactions, and safety signals immediately.
Friedberg’s Waymo analogy captured the political obstacle: autonomous vehicles might reduce deaths 95%, yet one visible fatality dominates coverage. Makary’s reply was that delay also carries risk—144 chimpanzees can hold back a cure eight months, and an unresolved issue deserves “a night to sleep on it, not nine months.”
He says he has signed 100% of Right to Try requests reaching his desk, subject to company participation. The boundary remains safety and stewardship: patients should not face $3 million “snake oil” financed by church GoFundMe campaigns, but where a credible signal exists, “who are we to say you can’t?”

5. Cell and gene therapies are getting rules sized to the patient

FDA is replacing uniform manufacturing rules with requirements customized to the treatment and population. Makary singled out mandatory PPQ runs for batches as an ill fit for bespoke cell and gene therapies created for a handful of patients.
Baby KJ’s gene-editing treatment illustrates the “plausible mechanism pathway.” With too few children for a randomized trial, FDA combines evidence that the scientific and vector platforms work with the specific intervention—what Makary called “gold standard science with common sense”—and creates a route for individualized treatment.
CAR-T could benefit from the same flexibility as it expands from blood cancers toward autoimmune disease, though current prices remain roughly $500,000 to $1 million. Makary described the class as “mind-boggling”: a patient’s own T cells are edited, returned, and directed against a defined target.
Flexibility does not mean surrendering supply-chain control. Makary discovered an earlier approval to ship Americans’ CAR-T cells to China for gene editing and then return them for infusion; “we shut that thing down so fast.”

6. The food reset replaces fat dogma with protein and metabolic health

Makary says 60%–70% of an American child’s calories now come from refined carbohydrates, 38% of children have prediabetes or diabetes, and prevailing guidance supplied roughly half the protein needed to thrive. The administration therefore inverted the food pyramid around protein and “real food”; Friedberg’s vegetarian pushback was that nuts and beans deserved more prominence, which Makary conceded.
His causal chain rejects a pure industry-capture story: food companies followed medicine’s mandate to solve insecurity through cheap calories, stripped fiber for mass production, and created cereals, breads, and pastas that function metabolically like sugar. Repeated insulin spikes then drive insulin resistance and general inflammation, which Makary places near the root of chronic disease.
The saturated-fat case exemplifies his complaint about self-protecting dogma. In the 9,000-person Minnesota randomized study, Makary said, the low-fat group experienced more heart attacks rather than fewer; Friedberg added that the results were suppressed for 16 years, quoting the senior author as saying they “didn’t turn out the way we expected.”
FDA is also moving to close the GRAS self-affirmation loophole, which Makary says let more than 1,000 chemicals barred elsewhere enter the U.S. food supply; Froot Loops even used different formulations in Canada and America. He nevertheless told Friedberg that cellular meat and seafood are not doomed: new products continue to emerge, with FDA registration keeping the agency informed.

7. GLP-1s treat the failure; research dollars should chase the causes

Friedberg asked whether incretin mimetics could reach 60% of Americans as testing expands across roughly 60 indications. Makary did not endorse that forecast, but said the food system has already failed: 40% of children have a chronic disease, and highly engineered foods make obesity more than a “willpower problem.”
GLP-1s mimic a natural hormone, increasing satiety and slowing gastrointestinal motility. Makary said possible cardiac and addiction benefits may reflect reduced insulin resistance and inflammation, but added that “we’ll see.” His regulatory posture remains that FDA is “a referee”: promising effects still need products to arrive quickly and safely.
On research funding, Makary categorically said the administration had not cut a dollar from NIH funding or the overall Medicaid budget and that the proposal for the future was to increase Medicaid by $200 billion. Friedberg’s pushback was that individual scientists clearly were losing grants; Makary answered that money was being reallocated toward food, school lunches, sleep, microbiome science, autoimmune triggers, and environmental causes.
Makary claimed 14% of NIH funding had gone to DEI research within a roughly $47 billion agency, with somewhat over $20 billion distributed externally. He supported reducing disparities but argued that repeatedly describing them does not improve access; his broader criticism was that genetics and downstream treatments had crowded out causal research.

8. A 38-dose vaccine core is Makary’s wager on restored trust

Friedberg said he and his family declined newborn hepatitis B vaccination when there was no household exposure; Makary described the same debate for his newborn. Friedberg framed the relevant exposure as sexual or bloodborne later in life, while Makary mocked the culture in which asking whether a first-hour injection is necessary makes a parent feel “like you’re a fugitive of the law.”
After comparing 20 developed countries, the administration identified roughly 38 doses as a core essential list, versus the previous U.S. recommendation of 72 total doses from birth through age 18. Every vaccine remains recommended and covered; the hierarchy is intended to prevent skepticism about a sixth COVID booster from spilling into refusal of measles vaccination.
His mammography analogy made the anti-paternalism case: 40% of eligible women do not obtain mammograms, yet physicians rarely offer ultrasound, which he said detects 90%–95% of the lesions a mammogram would pick up, because it violates the gold standard. “Meeting people where they’re at” could produce more protection than insisting on perfect adherence.
Friedberg pressed him on California creating a rival schedule and casting federal changes as political. Makary offered no outreach campaign, instead arguing for humility and preserving “we don’t know” as a valid answer; he cited the 1999 rotavirus vaccine withdrawal for intussusception and said rotavirus was not in the core list. After mass vaccination, deaths had fallen from 3,000 to 1,600 per year, which Friedberg rounded to about 2,000.

9. Drug affordability runs through reference pricing, biosimilars, and shelves

Makary called U.S. pricing “the great American ripoff”: a GLP-1 could cost $1,300 domestically and $88 in London. Most-favored-nation agreements are intended to produce the developed world’s best price, including $149 for the first three months of GLP-1 treatment, while other countries absorb more of an R&D burden he says America financed at 60%.
Biologics are the fastest-growing component of drug spending, but biosimilars have required five to eight years and roughly $300 million to develop. By treating structural similarity more like the small-molecule generic standard, FDA expects to remove more than $100 million of R&D cost and shorten the timeline from 5–8 years to roughly 2½ years or more, opening the “floodgates” beyond the limited competition seen after Humira.
Moving safe products onto store shelves supplies another pricing mechanism: visible prices and even a minority of comparison shoppers discipline the market. It also bypasses opaque PBM transactions, including brokers whom Makary said can receive $6.50 per prescription merely for placing an employer with a benefit manager.
The proposed over-the-counter test is straightforward: no abuse potential, acceptable safety, no required laboratory monitoring, no need for close clinical tracking, and no usefulness in producing illicit drugs. Friedberg’s reimbursement objection remains unresolved; Makary acknowledged insurers must modernize, but made nonprescription conversion a major 2026 goal and cited estimates that 60% of U.S. antibiotic prescriptions are unnecessary.

10. Medical claims—not information itself—draw the new enforcement line

Makary accepted Friedberg’s argument that advertising can alert patients and physicians to new therapies, but distinguished awareness from singing-and-dancing ads that create misleading demand for expensive biologics. FDA’s regulatory line is “fair balance,” not a ban on pharmaceutical speech.
A 35-person office sent no enforcement letters in the year before Makary arrived; under him, FDA sent 1,500, including more than 100 cease-and-desist letters. The agency is also closing the “adequate provision” loophole that let advertisers move risks to a website, while Makary urged companies to redirect some of their 20%–25% marketing spend toward lower prices.
AI requires the same distinction between information and intervention. Attempting to certify every generated statement would make even Google search impossible—“We can’t outrun this lion”—so general decision support gets a consumer lane, while systems that automatically trigger treatment or make specific medical claims face FDA review.
Wearables may freely report heart rate, blood pressure, glucose, and other physiological parameters. Claiming “medical grade” performance changes the obligation: FDA wants validation against the gold standard before patients use a reading to adjust medication.

11. Makary admits autism uncertainty but sees real therapeutic leaps

On autism’s cause, Makary’s answer was explicit: “I don’t know.” He nevertheless argued that diagnosis alone cannot explain one in 12 California boys being identified or the generational difference in repetitive behaviors and self-harm, making environmental and immunological hypotheses worth testing.
One hypothesis involves antibodies blocking folate receptors at the blood-brain barrier; some doctors report clinical improvement with leucovorin. Another involves microbiome disruption. Makary noted that 90% of serotonin is produced in the gut and that the average two-year-old has received more than 2.5 antibiotic courses. He separately cited a randomized protease study and, in JAMA, a randomized probiotic trial in children with autism; he said the latter needs replication and that he does not know whether the result is real.
His desired end-of-term wins include meaningful treatments for type 1 diabetes and ALS, cancers treated by PD-1 blockers or KRAS inhibitors without surgery or chemotherapy, a universal flu vaccine, and something powerful for PTSD. The personal urgency is more than 7,000 veteran suicides annually: “The wars are over, but our men and women keep dying.”
Reviewers tell him roughly 90% of early programs offer no major leap, but rare exceptions trigger immediate vouchers. He cited a gene-therapy/device combination that gave normal hearing to a couple of roughly 12 children and a multiple-myeloma therapy he believed was three times better than alternatives, with about 80% progression-free survival at a couple of years out; FDA contacted the latter company within 24 hours. “What are we waiting for?”

The (Working) Theory of Weird Markets No Priors Ep. 10 | With Copilot's Chief Architect and founder of Minion.AI Alex Graveley