Key Moments
#133 - Vinay Prasad, M.D., M.P.H: Hallmarks of successful cancer policy
Peter Attia MDKey Moments
Dr. Vinay Prasad discusses the complexities of cancer policy, drug approval, and healthcare economics.
Key Insights
Medical reversals are common, where widely accepted practices are later found ineffective or harmful.
The average benefit of many new cancer drugs is marginal, often extending life by only a few months at immense cost.
Clinical trials often use highly selected patient populations, leading to an overestimation of drug efficacy in real-world settings.
Conflicts of interest deeply permeate the medical field, influencing guidelines, research, and prescribing patterns.
Affordability of cancer drugs is a global crisis, with the US often subsidizing R&D for the world at exorbitant prices for marginal benefits.
Current drug approval processes prioritize surrogate endpoints (like tumor shrinkage) over patient-centric outcomes (survival, quality of life).
Increased, stable funding for blue-sky basic science, separated from political cycles, is crucial for true innovation.
A JOURNEY INTO MEDICAL SKEPTICISM
Dr. Vinay Prasad, a hematologist-oncologist and 'meta-researcher,' shares his journey from medical school to becoming a critic of health policy. His initial experiences in residency, particularly observing the widespread use of cardiac stents for chronic stable angina despite evidence showing no survival benefit, sparked his interest in medical practices lacking strong empirical support. This early skepticism expanded as he recognized similar inconsistencies across various medical specialties, leading him to dedicate his career to understanding and addressing structural problems in medicine, especially oncology.
THE PHENOMENON OF MEDICAL REVERSAL
Prasad highlights the concept of 'medical reversal,' where established practices are later found to be ineffective or even harmful, not just replaced by something better. Examples include hormone replacement therapy for postmenopausal women (initially believed to prevent cardiovascular disease but later found to increase risks) and anti-arrhythmic drugs post-heart attack (intended to suppress PVCs but shown to increase mortality). These reversals demonstrate that smart, well-intentioned practitioners, following plausible pathophysiology and observational studies, can still be wrong. This underscores the critical need for rigorous, randomized control trials to validate medical interventions.
THE DILEMMA OF CANCER DRUG EFFICACY AND COST
A major concern in oncology is the celebratory reception of drugs offering marginal benefits at astronomical costs. Many new cancer drugs extend median survival by only a few months (averaging 2.1 months across 71 drugs), yet cost hundreds of thousands of dollars annually. Prasad points out the stark disconnect between this limited efficacy and the public's perception, often fueled by enthusiastic presentations at conferences. This issue raises profound questions about the societal value and affordability of cancer treatments, especially when considering alternative healthcare investments that could yield greater collective health benefits.
SELECTION BIAS IN CLINICAL TRIALS
A critical flaw in cancer drug development is the use of highly selected patient populations in clinical trials. These patients are typically younger, healthier, and have fewer comorbidities than the average cancer patient, often resembling individuals who could 'run a marathon and also happen to have cancer.' This careful curation maximizes the chances of a statistically significant outcome, but it means the observed benefits often evaporate or diminish significantly in real-world populations. For instance, a liver cancer drug showing a three-month survival benefit in trials might offer no benefit to Medicare patients, highlighting a 'grand canyon' between trial results and real-world efficacy.
STRUCTURAL CONFLICTS OF INTEREST
Prasad emphasizes the pervasive influence of conflicts of interest. Pharmaceutical companies heavily fund patient advocacy groups, and many FDA employees transition to industry roles after their regulatory service. Most critically, expert oncologists, who often shape treatment guidelines, receive substantial payments from pharmaceutical companies, creating a potential bias towards promoting questionable drugs. These financial ties foster a system where guidelines, which mandate Medicare coverage, may be influenced by commercial interests rather than solely by objective evidence, leading to routine use of therapies with dubious benefits.
MEASURING WHAT MATTERS: SHIFTING ENDPOINTS
The second hallmark emphasizes the need for 'evidence' that truly measures what matters to patients: living longer or living better. Currently, two-thirds of cancer drug approvals are based on surrogate endpoints like tumor shrinkage or delayed tumor growth (progression-free survival), not overall survival or quality of life. The 30% tumor shrinkage cutoff, a key metric, originated from a 1976 study of doctors measuring marbles. This arbitrary historical standard, rather than a clinically meaningful one, frequently drives drug approvals. A policy shift towards requiring clear survival or quality-of-life benefits would lead to fewer, but more impactful, drugs reaching the market.
THE RELEVANCE OF REAL-WORLD PATIENTS
The 'relevance' hallmark calls for clinical trials to study populations that reflect average Americans, complete with their typical age, comorbidities, and health status. The current practice of testing drugs on 'super-healthy' patients means that when these drugs are administered to the broader population, their efficacy and tolerability are often compromised. Incorporating more diverse and representative patient cohorts in trials would provide more realistic data on drug effectiveness, likely leading to more modest but more accurate success rates, and better informing clinical decisions for everyday patients.
ADDRESSING UNAFFORDABILITY IN CANCER CARE
The 'affordability' crisis is exacerbated by systemic issues, particularly in the US. Medicare is legally bound to pay for any FDA-approved cancer drug, and cannot negotiate prices. Furthermore, it must cover drugs recommended by industry-influenced guidelines, even for off-label uses. Prasad advocates for giving Medicare price negotiation power and encouraging state-level experimentation with drug coverage policies. He criticizes the paradox of subsidizing marginal drugs at the same high rates as transformative ones, leading to global inequities where life-saving drugs remain inaccessible to billions.
FOSTERING BLUE-SKY SCIENCE AND INNOVATION
The 'possibility' hallmark calls for a substantial and stable increase in funding for basic, 'blue-sky' science, separated from political cycles. NIH funding, while significant, is often insufficient and heavily weighted towards translational research with immediate promises of cures. Prasad argues for dedicated funding for pure inquiry—science for science's sake—recognizing that many groundbreaking discoveries were serendipitous outcomes of curiosity-driven research (e.g., Jim Allison's Nobel-winning immunotherapy). Reforming grant-giving processes to reduce extreme funding disparities and allow for more risk-taking in research is also crucial.
STRATEGIC AGENDA FOR CANCER RESEARCH
The 'agenda' hallmark addresses the fragmented and often duplicative landscape of cancer clinical trials. The pharmaceutical industry frequently pursues numerous 'me-too' drugs, leading to redundant trials in similar tumor types or settings. This not only wastes resources but also depletes the scarce patient populations willing to participate in trials, sometimes leading to more trials than available patients for rare cancers. A more coordinated and strategic approach to the clinical trial agenda is needed to avoid unnecessary duplication, ensure efficient use of resources, and foster meaningful progress in oncology, rather than just random positive results.
THE ROLE OF TUMOR GENOME SEQUENCING
While tumor genome sequencing (NGS) is invaluable in specific cancers (e.g., lung cancer, melanoma, colon cancer) where targeted therapies exist or for identifying patients for clinical trials, its broader application warrants caution. Prasad notes that outside of these well-defined scenarios, acting on every mutation can be problematic. Some mutations may not be primary drivers, and different tumor sites in the same patient might show varying mutational profiles, undermining 'precision' claims. He also highlights concerns about the consistency of results across different commercial NGS companies. The seductive allure of a 'key-in-a-lock' approach for less-understood mutations can sometimes lead to less effective choices than traditional therapies with established track records.
LIQUID BIOPSIES: A PROMISING FRONTIER
Prasad expresses cautious optimism regarding liquid biopsies for solid organ tumors. While acknowledging the approved tests and their utility in avoiding invasive procedures for known important mutations, he raises questions about their sensitivity and the need for complementary tissue biopsies for certain diagnostic or subtyping purposes. The real potential, he suggests, lies in their serial nature—the ability to non-invasively track disease progression or treatment response over time, which could fundamentally change patient monitoring and management. Further rigorous clinical trials are needed to fully define their role.
BALANCING SKEPTICISM AND ACTION
Prasad reflects on the fine line between healthy skepticism and paralyzing inaction. He cites his support for early dexamethasone use in severe COVID-19, based on a press release and transparent protocol, as an instance where immediate action was justified despite some critics demanding full peer-reviewed publication. He navigates this balance by grounding his critical analysis in his clinical practice, where the need to make decisions for real patients with imperfect information is constant. His philosophy is to empower patients with comprehensive, unbiased information about risks and benefits, allowing them to make choices aligned with their values, even if those differ from his own, fostering trust and shared decision-making.
Mentioned in This Episode
●Software & Apps
●Companies
●Organizations
●Books
●Studies Cited
●Concepts
●People Referenced
Common Questions
Medical reversal refers to practices that were widely adopted but later found not to work as intended, or even be harmful, after rigorous studies. Examples include hormone replacement therapy for cardiovascular disease prevention and antiarrhythmic drugs to suppress PVCs after a heart attack, both of which were found to increase adverse events. Many of these reversals stem from initial low-evidence adoption.
Topics
Mentioned in this video
Practicing hematologist and oncologist, Associate Professor of Medicine at UC San Francisco, author of 'Ending Medical Reversal' and 'Malignant', host of 'Plenary Session' podcast.
Luminary oncologist and author who pioneered the idea of anti-angiogenesis, cutting off blood supply to tumors to stop their growth.
Peter Attia's mentor at NCI, known for his work in immunotherapy and his compassionate approach to end-of-life care, emphasizing that therapy failing the patient, not the patient failing therapy.
Prior podcast guest with whom Peter Attia discussed structural failures in medicine related to cancer.
Sociologist from the University of Pennsylvania who wrote 'Forgive and Remember' after spending 18 months with surgical residents.
Colleague, former teacher, mentor, and friend of Vinay Prasad with whom he co-authored 'Ending Medical Reversal'.
A Nobel Prize-winning immunotherapy doctor whose early work was once considered foolish but led to a blockbuster class of drugs.
Mentioned as a former administrator at HHS, involved in denying states the ability to experiment with Medicaid drug coverage.
Federal department that denied states like Massachusetts the ability to experiment with Medicaid coverage of drugs.
Regulatory body responsible for approving drugs; concerns are raised about the lowering bar for drug approval and the incomplete information released in press releases.
University where Vinay Prasad is an Associate Professor of Medicine, also has a campus in Parnassus with views of the city.
Vinay Prasad's medical school, described as having an intense, 'gritty city hospital feel' akin to East Coast medical education.
Vinay Prasad's undergraduate university where he initially majored in sciences before adding philosophy.
An East Coast institution Peter Attia considered for residency, known for its rigorous training environment.
Government body that funds basic science research, identified as needing increased and stable funding for blue-sky science.
Where Vinay Prasad completed his residency, also in Chicago, where he met influential oncologists.
Peter Attia's medical school, described as relaxed, and a friend of Prasad's was doing doctoral work there.
Guideline-writing body whose recommendations for drug use are mandated by law for Medicare coverage, and whose writers often have industry funding.
Vinay Prasad's second book, which discusses structural issues in cancer drug development and policy.
A book by Charles Bosk about the culture of surgical residency training, potentially based at the University of Chicago.
One of Vinay Prasad's books, focusing on medical practices that were widely adopted but later proved ineffective or harmful.
Cell-based immunotherapy that has shown great promise in some people, particularly for lymphoma and pediatric acute lymphoblastic leukemia, but may have fleeting remissions in other conditions like multiple myeloma.
The largest payer in the US, mandated to pay for any FDA-approved cancer drug and drugs recommended by certain guidelines, without price negotiation.
A randomized controlled trial in postmenopausal women, halted due to an increase in thromboembolic and cardiovascular events in the estrogen supplementation arm, reversing prior observational findings.
A randomized trial that investigated antiarrhythmic drugs to suppress premature ventricular contractions after a heart attack, finding that the drugs increased the risk of dying.
A UK trial that studied dexamethasone for COVID-19 patients, releasing results via press release that were considered good enough to act upon immediately due to the pandemic context.
A randomized trial that studied Olaparib in pancreatic cancer patients with BRCA mutations, showing progression-free survival but no overall survival benefit.
A drug for liver cancer that could not be treated by surgery. While it extended median survival by about three months in clinical trials, real-world data showed little to no benefit, and it only provided a 50% survival duration compared to the placebo arm in trials.
A terrific drug developed in the late 1990s for a certain type of breast cancer, but still out of reach for many people globally due to affordability issues, as shown by one in one hundred people accessing it in India.
A transformative drug effective for chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST), shifting median life expectancy from years to near-normal for CML.
A checkpoint inhibitor that shows clear survival benefits in specific oncology settings, but has also been disappointing in others, making its effectiveness case-by-case.
An anti-VEGF compound initially approved for colon cancer. It extends survival by only a couple of months at a high cost, leading some countries to refuse to pay for it.
A drug that, according to the UK's Recovery trial, benefited hospitalized COVID-19 patients requiring oxygen, but potentially harmed those not needing supplemental oxygen.
A targeted drug for pancreas cancer patients with germline BRCA mutations; in the POLO trial, it showed progression-free survival benefit but no overall survival benefit when compared to sugar pill, leading to questions about its real efficacy and high cost.
Pharmaceutical company mentioned as an example of industry offering consulting opportunities to junior faculty, creating potential conflicts of interest.
Social media platform where Vinay Prasad is active, providing tutorials on clinical trials and critical thinking.
Pharmaceutical company instrumental in promoting hormone replacement therapy as a cardiovascular preventative.
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