Working Papers

Working papers on clinical trial capacity, drug approval delay, and the cost of medical evidence.

Author

Affiliation

Mike P. Sinn

Each paper publishes its parameters, sources, and calculations with it. All are working papers under CC BY 4.0, and the code and data are in the public repository.

The Continuous Evidence Generation Protocol: Two-Stage Validation (RWE → Pragmatic Trials)

We present the Predictor Impact Score (PIS), a novel composite metric operationalizing Bradford Hill causality criteria for automated signal detection from aggregated N-of-1 observational studies. Combined with pragmatic trial confirmation (based on evidence from 108+ embedded trials), this two-stage framework would generate validated outcome labels at 44.1x (90% CI: 12.8x-210x) lower cost than traditional Phase III trials. This enables continuous, population-scale pharmacovigilance and precision dosing recommendations.

Ubiquitous Pragmatic Trial Impact Analysis: How to Prevent a Year of Death and Suffering for 84 Cents

Only 15 diseases/year (95% CI: 8 diseases/year-30 diseases/year) get their first treatment each year. With 6,650 diseases (90% CI: 5,700 diseases-8,232 diseases) lacking effective treatments, the backlog would take 443 years (90% CI: 255 years-841 years) to clear. Integrating pragmatic trials into standard healthcare increases trial capacity 12.3x (90% CI: 4.92x-50.8x), cutting that timeline from 443 years (90% CI: 255 years-841 years) to 36 years (90% CI: 8.15 years-106 years). The average untreated disease gets a treatment 212 years (90% CI: 124 years-398 years) earlier, saving 10.7 billion deaths (90% CI: 6.24 billion deaths-20.3 billion deaths) at $0.842 (90% CI: $0.264-$1.49) per year of healthy life saved.

The Invisible Graveyard: Quantifying the Mortality Cost of FDA Efficacy Lag

After proving a drug is safe, the FDA requires 8.2 years (90% CI: 4.84 years-11.5 years) to prove it works before patients can access it. We estimate this delay cost 102 million deaths (90% CI: 50.8 million deaths-169 million deaths) among people waiting for approved drugs (1962-2024). The human cost in death and disability of blocking good drugs is 3,389 (90% CI: 1,811-5,734) higher than the cost of approving bad ones.

Drug Development Cost Increase Analysis

Rigorous analysis of the 105x (90% CI: 72.8x-149x) increase in drug development costs from pre-1962 to 2024, using Baily (1972) academic study with CPI adjustments and sensitivity analysis

Right to Trial & FDA Upgrade Act

A universal right to try, with evidence. The Act authorizes commercial access after initial human safety testing and makes every covered treatment use teach us something.

Patient’s Right to Trial Act: Potential Impact of Adoption in All 50 States

A conditional schedule-shift model of state legislation that lets post-Phase-1 treatments finance their own evidence generation and accelerates treatments for global diseases and aging.

References

NIH Common Fund. NIH pragmatic trials: Minimal funding despite 30x cost advantage. NIH Common Fund: HCS Research Collaboratory https://commonfund.nih.gov/hcscollaboratory (2025)

The NIH Pragmatic Trials Collaboratory funds trials at $500K for planning phase, $1M/year for implementation-a tiny fraction of NIH’s budget. The ADAPTABLE trial cost $14 million for 15,076 patients (= $929/patient) versus $420 million for a similar traditional RCT (30x cheaper), yet pragmatic trials remain severely underfunded. PCORnet infrastructure enables real-world trials embedded in healthcare systems, but receives minimal support compared to basic research funding. Additional sources: https://commonfund.nih.gov/hcscollaboratory | https://pcornet.org/wp-content/uploads/2025/08/ADAPTABLE_Lay_Summary_21JUL2025.pdf | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604499/

NIH. Antidepressant clinical trial exclusion rates. Zimmerman et al. https://pubmed.ncbi.nlm.nih.gov/26276679/ (2015)

Mean exclusion rate: 86.1% across 158 antidepressant efficacy trials (range: 44.4% to 99.8%) More than 82% of real-world depression patients would be ineligible for antidepressant registration trials Exclusion rates increased over time: 91.4% (2010-2014) vs. 83.8% (1995-2009) Most common exclusions: comorbid psychiatric disorders, age restrictions, insufficient depression severity, medical conditions Emergency psychiatry patients: only 3.3% eligible (96.7% excluded) when applying 9 common exclusion criteria Only a minority of depressed patients seen in clinical practice are likely to be eligible for most AETs Note: Generalizability of antidepressant trials has decreased over time, with increasingly stringent exclusion criteria eliminating patients who would actually use the drugs in clinical practice Additional sources: https://pubmed.ncbi.nlm.nih.gov/26276679/ | https://pubmed.ncbi.nlm.nih.gov/26164052/ | https://www.wolterskluwer.com/en/news/antidepressant-trials-exclude-most-real-world-patients-with-depression

GiveWell. GiveWell cost per life saved for top charities (2024). GiveWell: Top Charities https://www.givewell.org/charities/top-charities

General range: $3,000-$5,500 per life saved (GiveWell top charities) Helen Keller International (Vitamin A): $3,500 average (2022-2024); varies $1,000-$8,500 by country Against Malaria Foundation: $5,500 per life saved New Incentives (vaccination incentives): $4,500 per life saved Malaria Consortium (seasonal malaria chemoprevention): $3,500 per life saved VAS program details: $2 to provide vitamin A supplements to child for one year Note: Figures accurate for 2024. Helen Keller VAS program has wide country variation ($1K-$8.5K) but $3,500 is accurate average. Among most cost-effective interventions globally Additional sources: https://www.givewell.org/charities/top-charities | https://www.givewell.org/charities/helen-keller-international | https://ourworldindata.org/cost-effectiveness

World Health Organization. WHO global health estimates 2024. World Health Organization https://www.who.int/data/gho/data/themes/mortality-and-global-health-estimates (2024)

Comprehensive mortality and morbidity data by cause, age, sex, country, and year Global mortality: 55-60 million deaths annually Lives saved by modern medicine (vaccines, cardiovascular drugs, oncology): 12M annually (conservative aggregate) Leading causes of death: Cardiovascular disease (17.9M), Cancer (10.3M), Respiratory disease (4.0M) Note: Baseline data for regulatory mortality analysis. Conservative estimate of pharmaceutical impact based on WHO immunization data (4.5M/year from vaccines) + cardiovascular interventions (3.3M/year) + oncology (1.5M/year) + other therapies. Additional sources: https://www.who.int/data/gho/data/themes/mortality-and-global-health-estimates

U.S. Bureau of Labor Statistics. CPI inflation calculator. (2024)

CPI-U (1980): 82.4 CPI-U (2024): 313.5 Inflation multiplier (1980-2024): 3.80× Cumulative inflation: 280.48% Average annual inflation rate: 3.08% Note: Official U.S. government inflation data using Consumer Price Index for All Urban Consumers (CPI-U). Additional sources: https://www.bls.gov/data/inflation_calculator.htm

ACS CAN. Clinical trial patient participation rate. ACS CAN: Barriers to Clinical Trial Enrollment https://www.fightcancer.org/policy-resources/barriers-patient-enrollment-therapeutic-clinical-trials-cancer

Only 3-5% of adult cancer patients in US receive treatment within clinical trials About 5% of American adults have ever participated in any clinical trial Oncology: 2-3% of all oncology patients participate Contrast: 50-60% enrollment for pediatric cancer trials (<15 years old) Note: 20% of cancer trials fail due to insufficient enrollment; 11% of research sites enroll zero patients Additional sources: https://www.fightcancer.org/policy-resources/barriers-patient-enrollment-therapeutic-clinical-trials-cancer | https://hints.cancer.gov/docs/Briefs/HINTS_Brief_48.pdf

ScienceDaily. Global prevalence of chronic disease. ScienceDaily: GBD 2015 Study https://www.sciencedaily.com/releases/2015/06/150608081753.htm (2015)

2.3 billion individuals had more than five ailments (2013) Chronic conditions caused 74% of all deaths worldwide (2019), up from 67% (2010) Approximately 1 in 3 adults suffer from multiple chronic conditions (MCCs) Risk factor exposures: 2B exposed to biomass fuel, 1B to air pollution, 1B smokers Projected economic cost: $47 trillion by 2030 Note: 2.3B with 5+ ailments is more accurate than "2B with chronic disease." One-third of all adults globally have multiple chronic conditions Additional sources: https://www.sciencedaily.com/releases/2015/06/150608081753.htm | https://pmc.ncbi.nlm.nih.gov/articles/PMC10830426/ | https://pmc.ncbi.nlm.nih.gov/articles/PMC6214883/

C&EN. Annual number of new drugs approved globally: 50. C&EN https://cen.acs.org/pharmaceuticals/50-new-drugs-received-FDA/103/i2 (2025)

50 new drugs approved annually Additional sources: https://cen.acs.org/pharmaceuticals/50-new-drugs-received-FDA/103/i2 | https://www.fda.gov/drugs/development-approval-process-drugs/novel-drug-approvals-fda

IQVIA Report. Global trial capacity. IQVIA Report: Clinical Trial Subjects Number Drops Due to Decline in COVID-19 Enrollment https://gmdpacademy.org/news/iqvia-report-clinical-trial-subjects-number-drops-due-to-decline-in-covid-19-enrollment/

1.9M participants annually (2022, post-COVID normalization from 4M peak in 2021) Additional sources: https://gmdpacademy.org/news/iqvia-report-clinical-trial-subjects-number-drops-due-to-decline-in-covid-19-enrollment/

10.

Nature Medicine. Drug repurposing rate ( 30%). Nature Medicine https://www.nature.com/articles/s41591-024-03233-x (2024)

Approximately 30% of drugs gain at least one new indication after initial approval. Additional sources: https://www.nature.com/articles/s41591-024-03233-x

11.

Biotechnology Innovation Organization (BIO). BIO clinical development success rates 2011-2020. Biotechnology Innovation Organization (BIO) https://go.bio.org/rs/490-EHZ-999/images/ClinicalDevelopmentSuccessRates2011_2020.pdf (2021)

Phase I duration: 2.3 years average Total time to market (Phase I-III + approval): 10.5 years average Phase transition success rates: Phase I→II: 63.2%, Phase II→III: 30.7%, Phase III→Approval: 58.1% Overall probability of approval from Phase I: 12% Note: Largest publicly available study of clinical trial success rates. Efficacy lag = 10.5 - 2.3 = 8.2 years post-safety verification. Additional sources: https://go.bio.org/rs/490-EHZ-999/images/ClinicalDevelopmentSuccessRates2011_2020.pdf

12.

Institute for Health Metrics and Evaluation (IHME). IHME global burden of disease 2021 (2.88B DALYs, 1.13B YLD). Institute for Health Metrics and Evaluation (IHME) https://vizhub.healthdata.org/gbd-results/ (2024)

In 2021, global DALYs totaled approximately 2.88 billion, comprising 1.75 billion Years of Life Lost (YLL) and 1.13 billion Years Lived with Disability (YLD). This represents a 13% increase from 2019 (2.55B DALYs), largely attributable to COVID-19 deaths and aging populations. YLD accounts for approximately 39% of total DALYs, reflecting the substantial burden of non-fatal chronic conditions. Additional sources: https://vizhub.healthdata.org/gbd-results/ | https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)00757-8/fulltext | https://www.healthdata.org/research-analysis/about-gbd

13.

Sinn, M. P. Private industry clinical trial spending estimate. (2025)

Estimated private pharmaceutical and biotech clinical trial spending is approximately $75-90 billion annually, representing roughly 90% of global clinical trial spending.

14.

Sinn, M. P. The Political Dysfunction Tax. https://manual.warondisease.org/knowledge/appendix/political-dysfunction-tax.html (2025) doi:10.5281/zenodo.18603840

Quantifying the gap between current global governance and theoretical maximum welfare, estimating a 31-53% efficiency score and $101 trillion in annual opportunity costs.

15.

World Health Organization. Life expectancy at age 60 (years): Global health observatory. (2021).

16.

SIPRI. Global military spending ($2.72T, 2024). SIPRI https://www.sipri.org/publications/2025/sipri-fact-sheets/trends-world-military-expenditure-2024 (2025).

17.

PMC. Only 12% of human interactome targeted. PMC https://pmc.ncbi.nlm.nih.gov/articles/PMC10749231/ (2023)

Mapping 350,000+ clinical trials showed that only 12% of the human interactome has ever been targeted by drugs. Additional sources: https://pmc.ncbi.nlm.nih.gov/articles/PMC10749231/

18.

Calculated from Orphanet Journal of Rare Diseases (2024). Diseases getting first effective treatment each year. Calculated from Orphanet Journal of Rare Diseases (2024) https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03398-1 (2024)

Under the current system, approximately 10-15 diseases per year receive their FIRST effective treatment. Calculation: 5% of 7,000 rare diseases ( 350) have FDA-approved treatment, accumulated over 40 years of the Orphan Drug Act = 9 rare diseases/year. Adding 5-10 non-rare diseases that get first treatments yields 10-20 total. FDA approves 50 drugs/year, but many are for diseases that already have treatments (me-too drugs, second-line therapies). Only 15 represent truly FIRST treatments for previously untreatable conditions.

19.

PMC. Standard medical research ROI ($20k-$100k/QALY). PMC: Cost-effectiveness Thresholds Used by Study Authors https://pmc.ncbi.nlm.nih.gov/articles/PMC10114019/ (1990)

Typical cost-effectiveness thresholds for medical interventions in rich countries range from $50,000 to $150,000 per QALY. The Institute for Clinical and Economic Review (ICER) uses a $100,000-$150,000/QALY threshold for value-based pricing. Between 1990-2021, authors increasingly cited $100,000 (47% by 2020-21) or $150,000 (24% by 2020-21) per QALY as benchmarks for cost-effectiveness. Additional sources: https://pmc.ncbi.nlm.nih.gov/articles/PMC10114019/ | https://icer.org/our-approach/methods-process/cost-effectiveness-the-qaly-and-the-evlyg/

20.

Tufts CSDD. Cost of drug development.

Various estimates suggest $1.0 - $2.5 billion to bring a new drug from discovery through FDA approval, spread across 10 years. Tufts Center for the Study of Drug Development often cited for $1.0 - $2.6 billion/drug. Industry reports (IQVIA, Deloitte) also highlight $2+ billion figures.

21.

Lichtenberg, F. R. How many life-years have new drugs saved? A three-way fixed-effects analysis of 66 diseases in 27 countries, 2000-2013. International Health 11, 403–416 (2019)

Using 3-way fixed-effects methodology (disease-country-year) across 66 diseases in 22 countries, this study estimates that drugs launched after 1981 saved 148.7 million life-years in 2013 alone. The regression coefficients for drug launches 0-11 years prior (beta=-0.031, SE=0.008) and 12+ years prior (beta=-0.057, SE=0.013) on years of life lost are highly significant (p<0.0001). Confidence interval for life-years saved: 79.4M-239.8M (95 percent CI) based on propagated standard errors from Table 2.

22.

Nature Reviews Drug Discovery. Drug trial success rate from phase i to approval. Nature Reviews Drug Discovery: Clinical Success Rates https://www.nature.com/articles/nrd.2016.136 (2016)

Overall Phase I to approval: 10-12.8% (conventional wisdom 10%, studies show 12.8%) Recent decline: Average LOA now 6.7% for Phase I (2014-2023 data) Leading pharma companies: 14.3% average LOA (range 8-23%) Varies by therapeutic area: Oncology 3.4%, CNS/cardiovascular lowest at Phase III Phase-specific success: Phase I 47-54%, Phase II 28-34%, Phase III 55-70% Note: 12% figure accurate for historical average. Recent data shows decline to 6.7%, with Phase II as primary attrition point (28% success) Additional sources: https://www.nature.com/articles/nrd.2016.136 | https://pmc.ncbi.nlm.nih.gov/articles/PMC6409418/ | https://academic.oup.com/biostatistics/article/20/2/273/4817524

23.

Research and Markets. Global clinical trials market 2024. Research and Markets https://www.globenewswire.com/news-release/2024/04/19/2866012/0/en/Global-Clinical-Trials-Market-Research-Report-2024-An-83-16-Billion-Market-by-2030-AI-Machine-Learning-and-Blockchain-will-Transform-the-Clinical-Trials-Landscape.html (2024)

Global clinical trials market valued at approximately $83 billion in 2024, with projections to reach $83-132 billion by 2030. Additional sources: https://www.globenewswire.com/news-release/2024/04/19/2866012/0/en/Global-Clinical-Trials-Market-Research-Report-2024-An-83-16-Billion-Market-by-2030-AI-Machine-Learning-and-Blockchain-will-Transform-the-Clinical-Trials-Landscape.html | https://www.precedenceresearch.com/clinical-trials-market

24.

SofproMed. Phase 3 cost per trial range. SofproMed https://www.sofpromed.com/how-much-does-a-clinical-trial-cost

Phase 3 clinical trials cost between $20 million and $282 million per trial, with significant variation by therapeutic area and trial complexity. Additional sources: https://www.sofpromed.com/how-much-does-a-clinical-trial-cost | https://www.cbo.gov/publication/57126

25.

Ramsberg, J. & Platt, R. Pragmatic trial cost per patient (median $97). Learning Health Systems https://pmc.ncbi.nlm.nih.gov/articles/PMC6508852/ (2018)

Meta-analysis of 108 embedded pragmatic clinical trials (2006-2016). The median cost per patient was $97 (IQR $19–$478), based on 2015 dollars. 25% of trials cost <$19/patient; 10 trials exceeded $1,000/patient. U.S. studies median $187 vs non-U.S. median $27. Additional sources: https://pmc.ncbi.nlm.nih.gov/articles/PMC6508852/

26.

Kinch, M. S. & Griesenauer, R. H. Lost medicines: A longer view of the pharmaceutical industry with the potential to reinvigorate discovery. Drug Discovery Today 24, 875–880 (2019)

Research identified 1,600+ medicines available in 1962. The 1950s represented industry high-water mark with >30 new products in five of ten years; this rate would not be replicated until late 1990s. More than half (880) of these medicines were lost following implementation of Kefauver-Harris Amendment. The peak of 1962 would not be seen again until early 21st century. By 2016 number of organizations actively involved in R&D at level not seen since 1914.

27.

Baily, M. N. Pre-1962 drug development costs (baily 1972). Baily (1972) https://samizdathealth.org/wp-content/uploads/2020/12/hlthaff.1.2.6.pdf (1972)

Pre-1962: Average cost per new chemical entity (NCE) was $6.5 million (1980 dollars) Inflation-adjusted to 2024 dollars: $6.5M (1980) ≈ $22.5M (2024), using CPI multiplier of 3.46× Real cost increase (inflation-adjusted): $22.5M (pre-1962) → $2,600M (2024) = 116× increase Note: This represents the most comprehensive academic estimate of pre-1962 drug development costs based on empirical industry data Additional sources: https://samizdathealth.org/wp-content/uploads/2020/12/hlthaff.1.2.6.pdf

28.

Think by Numbers. Pre-1962 physician-led clinical trials. Think by Numbers: How Many Lives Does FDA Save? https://thinkbynumbers.org/health/how-many-net-lives-does-the-fda-save/ (1966)

Pre-1962: Physicians could report real-world evidence directly 1962 Drug Amendments replaced "premarket notification" with "premarket approval", requiring extensive efficacy testing Impact: New regulatory clampdown reduced new treatment production by 70%; lifespan growth declined from 4 years/decade to 2 years/decade Drug Efficacy Study Implementation (DESI): NAS/NRC evaluated 3,400+ drugs approved 1938-1962 for safety only; reviewed >3,000 products, >16,000 therapeutic claims FDA has had authority to accept real-world evidence since 1962, clarified by 21st Century Cures Act (2016) Note: Specific "144,000 physicians" figure not verified in sources Additional sources: https://thinkbynumbers.org/health/how-many-net-lives-does-the-fda-save/ | https://www.fda.gov/drugs/enforcement-activities-fda/drug-efficacy-study-implementation-desi | http://www.nasonline.org/about-nas/history/archives/collections/des-1966-1969-1.html

29.

Oren Cass, Manhattan Institute. RECOVERY trial cost per patient. Oren Cass https://manhattan.institute/article/slow-costly-clinical-trials-drag-down-biomedical-breakthroughs (2023)

The RECOVERY trial, for example, cost only about $500 per patient... By contrast, the median per-patient cost of a pivotal trial for a new therapeutic is around $41,000. Additional sources: https://manhattan.institute/article/slow-costly-clinical-trials-drag-down-biomedical-breakthroughs

30.

NHS England; Águas et al. RECOVERY trial global lives saved ( 1 million). NHS England: 1 Million Lives Saved https://www.england.nhs.uk/2021/03/covid-treatment-developed-in-the-nhs-saves-a-million-lives/ (2021)

Dexamethasone saved 1 million lives worldwide (NHS England estimate, March 2021, 9 months after discovery). UK alone: 22,000 lives saved. Methodology: Águas et al. Nature Communications 2021 estimated 650,000 lives (range: 240,000-1,400,000) for July-December 2020 alone, based on RECOVERY trial mortality reductions (36% for ventilated, 18% for oxygen-only patients) applied to global COVID hospitalizations. June 2020 announcement: Dexamethasone reduced deaths by up to 1/3 (ventilated patients), 1/5 (oxygen patients). Impact immediate: Adopted into standard care globally within hours of announcement. Additional sources: https://www.england.nhs.uk/2021/03/covid-treatment-developed-in-the-nhs-saves-a-million-lives/ | https://www.nature.com/articles/s41467-021-21134-2 | https://pharmaceutical-journal.com/article/news/steroid-has-saved-the-lives-of-one-million-covid-19-patients-worldwide-figures-show | https://www.recoverytrial.net/news/recovery-trial-celebrates-two-year-anniversary-of-life-saving-dexamethasone-result

31.

Manhattan Institute. RECOVERY trial 82× cost reduction. Manhattan Institute: Slow Costly Trials https://manhattan.institute/article/slow-costly-clinical-trials-drag-down-biomedical-breakthroughs

RECOVERY trial: $500 per patient ($20M for 48,000 patients = $417/patient) Typical clinical trial: $41,000 median per-patient cost Cost reduction: 80-82× cheaper ($41,000 ÷ $500 ≈ 82×) Efficiency: $50 per patient per answer (10 therapeutics tested, 4 effective) Dexamethasone estimated to save >630,000 lives Additional sources: https://manhattan.institute/article/slow-costly-clinical-trials-drag-down-biomedical-breakthroughs | https://pmc.ncbi.nlm.nih.gov/articles/PMC9293394/

32.

ICER. Value per QALY (standard economic value). ICER https://icer.org/wp-content/uploads/2024/02/Reference-Case-4.3.25.pdf (2024)

Standard economic value per QALY: $100,000–$150,000. This is the US and global standard willingness-to-pay threshold for interventions that add costs. Dominant interventions (those that save money while improving health) are favorable regardless of this threshold. Additional sources: https://icer.org/wp-content/uploads/2024/02/Reference-Case-4.3.25.pdf

33.

FDA Study via NCBI. Trial costs, FDA study. FDA Study via NCBI https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248200/

Overall, the 138 clinical trials had an estimated median (IQR) cost of $19.0 million ($12.2 million-$33.1 million)... The clinical trials cost a median (IQR) of $41,117 ($31,802-$82,362) per patient. Additional sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248200/

34.

DOT. DOT value of statistical life ($13.6M). DOT: VSL Guidance 2024 https://www.transportation.gov/office-policy/transportation-policy/revised-departmental-guidance-on-valuation-of-a-statistical-life-in-economic-analysis (2024)

Current VSL (2024): $13.7 million (updated from $13.6M) Used in cost-benefit analyses for transportation regulations and infrastructure Methodology updated in 2013 guidance, adjusted annually for inflation and real income VSL represents aggregate willingness to pay for safety improvements that reduce fatalities by one Note: DOT has published VSL guidance periodically since 1993. Current $13.7M reflects 2024 inflation/income adjustments Additional sources: https://www.transportation.gov/office-policy/transportation-policy/revised-departmental-guidance-on-valuation-of-a-statistical-life-in-economic-analysis | https://www.transportation.gov/regulations/economic-values-used-in-analysis

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