# Real-World Evidence Historical Success (Pre-1962) ## Historical Evidence: Why Real-World Evidence Works Better Large-scale efficacy trials based on real-world evidence produce better health outcomes. They beat current pharmaceutical industry-driven randomized controlled trials. [![Trials run in the real world with real patients produce better health outcomes than trials run by pharmaceutical companies with carefully selected patients. Reality is more helpful than theater.](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-historical-eviden-bw-academic.jpg)](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-historical-eviden-bw-academic.jpg) Trials run in the real world with real patients produce better health outcomes than trials run by pharmaceutical companies with carefully selected patients. Reality is more helpful than theater. ### 10,000 Years of Dying at 30 For over 99% of human history, average life expectancy was 30 years^([1](../references.llms.md#ref-historical-life-expectancy-30-years)). Ancient Rome: 30 years. Medieval Europe: 30 years. Renaissance: Still 30 years. Kings, peasants, philosophers, farmers - everyone died embarrassingly young. 10,000 years. Zero progress. [![Life expectancy over time. It goes up. Then in 1962 it stops going up as fast. Something happened in 1962.](../../assets/images/life-expectancy-historical.jpg)](../../assets/images/life-expectancy-historical.jpg) Life expectancy over time. It goes up. Then in 1962 it stops going up as fast. Something happened in 1962. ### 1883 – The Year You Figured It Out Then something changed. [![In 1883, doctors started sharing notes. Doctor sees something, writes it down, other doctors check the notes, JAMA says ‘Yes, this is real.’ Collaboration was invented.](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-1883-the-year-you-figured-it-out-bw-academic.jpg)](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-1883-the-year-you-figured-it-out-bw-academic.jpg) In 1883, doctors started sharing notes. Doctor sees something, writes it down, other doctors check the notes, JAMA says ‘Yes, this is real.’ Collaboration was invented. In 1883, doctors founded the Journal of the American Medical Association (JAMA)^([2](../references.llms.md#ref-jama-founded-1893)). They did something novel: they shared information. After 10,000 years someone thought “what if we told each other what works?” **[144 thousand physicians](../../knowledge/appendix/parameters-and-calculations.llms.md#sec-pre_1962_physician_count)** across America (see reference^([3](../references.llms.md#ref-pre-1962-physician-trials))) tried treatments on real patients. They wrote down what happened. “This drug helped.” “This drug killed the patient.” “This drug did nothing but made the patient smell funny.” Leading experts reviewed these case reports. They compiled them into studies and published results. If a medicine worked and didn’t kill people, JAMA gave it a seal of approval. Crowdsourced, observational, objective, peer-reviewed clinical research. And it worked. ### The Result After 10,000 years of zero progress, life expectancy suddenly shot up. It increased by 3.82 years every decade^([4](../references.llms.md#ref-life-expectancy-increase-pre-1962)) (calculated from 1880-1960 data). For 80 years straight. The most linear relationship in medical history. Suspiciously perfect. It lasted from 1883 to 1960. ### 1938 – The FDA Requires Phase 1 Safety Trials Elixir sulfanilamide killed over 100 people^([5](../references.llms.md#ref-fda-the-sulfanilamide-disaster)) in 1937. Congress reacted^([6](../references.llms.md#ref-wikipedia-elixir-sulfanilamide)). They required all new drugs to include: > “adequate tests by all methods reasonably applicable to show whether or not such drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof.” These requirements evolved into the Phase 1 Safety Trial^([7](../references.llms.md#ref-phase-1-safety-trial)). This was reasonable. Test if a compound kills people before giving it to patients. Makes sense. The 3.82 years per decade gain^([4](../references.llms.md#ref-life-expectancy-increase-pre-1962)) stayed the same. It held steady before and after the new safety regulations. Safety testing worked without slowing medical progress. [![Life expectancy before and after the FDA required safety trials. The line goes up both times but at different speeds. Safety has a speed limit.](../../assets/images/fda-safety-trials-life-expectancy.png)](../../assets/images/fda-safety-trials-life-expectancy.png) Life expectancy before and after the FDA required safety trials. The line goes up both times but at different speeds. Safety has a speed limit. The regulations had no measurable impact on developing life-saving treatments. Not positive. Not negative. ### 1950s – Thalidomide: When Safety Regulations Actually Worked Thalidomide hit European markets in 1957^([8](../references.llms.md#ref-wikipedia-thalidomide)) for morning sickness. Doctors thought it was safe in pregnancy. It wasn’t. It caused thousands of horrific congenital disabilities^([9](../references.llms.md#ref-thalidomide-birth-defects)). Existing FDA safety regulations prevented any birth defects in the US^([10](../references.llms.md#ref-thalidomide-no-us-birth-defects)). The 1938 safety framework worked as intended. Zero American babies harmed. The safety regulations succeeded. But newspaper stories like the one below created public outcry for *more* regulation. They targeted efficacy testing. [![Thalidomide babies. This is what happens when you don’t test drugs on pregnant women. So now we test nothing on pregnant women and they take untested drugs.](../../assets/images/thalidomide.jpg)](../../assets/images/thalidomide.jpg) Thalidomide babies. This is what happens when you don’t test drugs on pregnant women. So now we test nothing on pregnant women and they take untested drugs. ### 1962 – The Year You Decided to Make Everything Worse Effective **safety** regulations already existed. They worked. America had zero Thalidomide deaths. Europe had thousands. Safety testing succeeded. [![Before 1962: doctors tested if drugs worked. After 1962: drug companies tested if drugs worked. Costs went up. Time went up. Asking the seller if the product works costs more than asking the buyer.](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-1962-the-year-you-bw-academic.jpg)](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-1962-the-year-you-bw-academic.jpg) Before 1962: doctors tested if drugs worked. After 1962: drug companies tested if drugs worked. Costs went up. Time went up. Asking the seller if the product works costs more than asking the buyer. So naturally, the government responded to this success by adding massive **efficacy** regulations. The 1962 Kefauver Harris Amendment^([11](../references.llms.md#ref-kefauver-harris-amendment-1962)) changed everything. Safety testing wasn’t the problem. That worked fine. The problem? They took efficacy testing away from [144 thousand physicians](../../knowledge/appendix/parameters-and-calculations.llms.md#sec-pre_1962_physician_count) independent doctors. They gave it to drug companies. It got [82x (90% CI: 21.4x-195x)](../../knowledge/appendix/parameters-and-calculations.llms.md#sec-recovery_trial_cost_reduction_factor) times more expensive. It got [32.8x (90% CI: 19.4x-45.9x)](../../knowledge/appendix/parameters-and-calculations.llms.md#sec-fda_to_oxford_recovery_trial_time_multiplier) times slower. #### What Changed Before 1962: - Drug companies spent **[\$24.7 million (95% CI: \$19.5 million-\$30 million)](../../knowledge/appendix/parameters-and-calculations.llms.md#sec-pre_1962_drug_development_cost_2024_usd)** (inflation-adjusted) to prove safety (see reference^([12](../references.llms.md#ref-pre-1962-drug-costs-timeline))) - Once the FDA approved a drug as safe, **[144 thousand physicians](../../knowledge/appendix/parameters-and-calculations.llms.md#sec-pre_1962_physician_count) independent doctors tested efficacy** on real patients (see reference^([3](../references.llms.md#ref-pre-1962-physician-trials))) - The AMA compiled results and published findings After 1962: - The FDA took over efficacy testing - They made the old system illegal^([11](../references.llms.md#ref-kefauver-harris-amendment-1962)) - They required small, controlled trials run by… the drug companies themselves The irony: Regulations meant to ensure drugs work did this by: 1. Banning large real-world trials 2. Requiring small artificial trials 3. Letting drug companies run their own tests [![Before 1962: doctors in charge, cheap, simple. After 1962: drug companies in charge, expensive, complicated. We replaced the people who use the product with the people who sell it.](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-pre-vs-post-1962-regulations-bw-academic.jpg)](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-pre-vs-post-1962-regulations-bw-academic.jpg) Before 1962: doctors in charge, cheap, simple. After 1962: drug companies in charge, expensive, complicated. We replaced the people who use the product with the people who sell it. #### What Happened to Efficacy Data [![After 1962, trials got smaller, patients got less representative, and conflicts of interest got bigger. Making trials more rigorous made them worse at everything except paperwork.](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-what-happened-to-efficacy-data-bw-academic.jpg)](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-what-happened-to-efficacy-data-bw-academic.jpg) After 1962, trials got smaller, patients got less representative, and conflicts of interest got bigger. Making trials more rigorous made them worse at everything except paperwork. The 1962 regulations were about ensuring efficacy. They massively reduced the quantity and quality of efficacy data: - **Trials Got Smaller**: Fewer patients, less data - **Patients Got Less Representative**: They excluded sick people, old people, and people with other conditions. (You know, the people who actually need medicine.) - **Conflicts of Interest Exploded**: Drug companies ran their own trials. Independent doctors lost control. #### What Happened to New Treatments The new regulations immediately **reduced new drug approvals by [70%](../../knowledge/appendix/parameters-and-calculations.llms.md#sec-post_1962_drug_approval_reduction_pct)** (see reference^([13](../references.llms.md#ref-post-1962-drug-approval-drop))). Not gradually. Immediately. [![New treatments per year. The line goes up until 1962. Then it goes down. Regulating medicine made less medicine.](../../assets/images/new-treatments-per-year-2.png)](../../assets/images/new-treatments-per-year-2.png) New treatments per year. The line goes up until 1962. Then it goes down. Regulating medicine made less medicine. #### What Happened to Costs Since 1962, the cost of bringing a new treatment to market exploded. It went from **[\$24.7 million (95% CI: \$19.5 million-\$30 million)](../../knowledge/appendix/parameters-and-calculations.llms.md#sec-pre_1962_drug_development_cost_2024_usd) to over \$1 billion**^([14](../references.llms.md#ref-parliament-4207)) (inflation-adjusted). A [105x (90% CI: 72.8x-149x)](../../knowledge/appendix/parameters-and-calculations.llms.md#sec-drug_cost_increase_pre1962_to_current_multiplier) increase. For worse results. [![Cost to develop one new drug has exploded under FDA regulations (1950-2000)](real-world-evidence-historical-success_files/figure-html/cell-4-output-1.png)](real-world-evidence-historical-success_files/figure-html/cell-4-output-1.png) Cost to develop one new drug has exploded under FDA regulations (1950-2000) This chart shows the exponential increase in the cost to develop a single new drug from 1960-2019, adjusted for inflation to 2020 dollars. The vertical line marks the 1962 efficacy amendment (Kefauver-Harris Amendment). Drug development costs were relatively stable before 1962, then exploded exponentially after the efficacy requirement was added. Costs increased 52x from \$74M (1960) to \$3,861M (2019), making innovation increasingly expensive and inaccessible. #### What Happened to Drug Patents The new regulations created massive delays. The pharmaceutical industry complained about a “drug lag.” [![In 1984, patents got extended to encourage innovation. Prices went up. Availability went down. Safety went down. The incentive to innovate became an incentive to charge more for less.](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-what-happened-to-drug-patents-bw-academic.jpg)](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-what-happened-to-drug-patents-bw-academic.jpg) In 1984, patents got extended to encourage innovation. Prices went up. Availability went down. Safety went down. The incentive to innovate became an incentive to charge more for less. Congress “fixed” this by extending drug patent monopolies^([15](../references.llms.md#ref-drug-price-competition-act-1984)) in 1984. Kefauver’s amendments aimed to make drugs safer and cheaper. Instead they made them: - More dangerous (smaller trials, less real-world data to spot dangerous side effects) - More expensive (monopolies extended) - Less available ([70%](../../knowledge/appendix/parameters-and-calculations.llms.md#sec-post_1962_drug_approval_reduction_pct) fewer approvals) #### Decreased Ability to Determine Comparative Efficacy The placebo-controlled randomized controlled trial helped gauge individual drug efficacy. But it makes comparative effectiveness harder to judge. [![Drug A beats placebo. Drug B beats placebo. No one compares Drug A to Drug B. You know they both work better than nothing. You don’t know which one works better than the other.](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-decreased-ability-bw-academic.jpg)](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-decreased-ability-bw-academic.jpg) Drug A beats placebo. Drug B beats placebo. No one compares Drug A to Drug B. You know they both work better than nothing. You don’t know which one works better than the other. ### What Happened to Life Expectancy (The Part That Matters) Remember that suspiciously linear 3.82-year increase^([4](../references.llms.md#ref-life-expectancy-increase-pre-1962)) every decade from 1883 to 1960? Here’s what happened in 1962: It strangely quickly dropped by 60%^([16](../references.llms.md#ref-post-1962-life-expectancy-slowdown)). To 1.54 years per decade. [![Average Life Expectancy Over Time](../../assets/images/real-world-evidence-in-efficacy-clinical-trials-vs-rcts.png)](../../assets/images/real-world-evidence-in-efficacy-clinical-trials-vs-rcts.png) Average Life Expectancy Over Time From 1880 to 1960: 3.82 years per decade^([4](../references.llms.md#ref-life-expectancy-increase-pre-1962)). From 1962 onward: 1.54 years per decade^([16](../references.llms.md#ref-post-1962-life-expectancy-slowdown)). The break is so clean. You can see the exact year Congress decided to “help.” [![Before 1962: gaining 3.82 years per decade. After 1962: gaining 1.54 years per decade. The line breaks exactly at 1962. Coincidences are supposed to be less precise than this.](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-life-expectancy-slope-change-1962-bw-academic.jpg)](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-life-expectancy-slope-change-1962-bw-academic.jpg) Before 1962: gaining 3.82 years per decade. After 1962: gaining 1.54 years per decade. The line breaks exactly at 1962. Coincidences are supposed to be less precise than this. The detailed chart showing this break over time is presented in the main FDA chapter. ### The “Diminishing Returns” Excuse Some claim “diminishing returns explain the slowdown.” Diminishing returns produce a smooth curve. It flattens over time. [![This is what diminishing returns look like when you smooth out all the noise and variables. A gentle curve. Reality is not a gentle curve. Reality is a sharp break in 1962.](../../assets/images/diminishing-returns.png)](../../assets/images/diminishing-returns.png) This is what diminishing returns look like when you smooth out all the noise and variables. A gentle curve. Reality is not a gentle curve. Reality is a sharp break in 1962. This isn’t what happened. What happened was a straight line. It instantly changed slope in 1962 when the regulations changed. Diminishing returns don’t produce sudden linear breaks. Regulatory changes do. ### The “Correlation Is Not Causation” Excuse True. Correlation alone proves nothing. [![How to prove something caused something else: it happened at the same time, there’s a reason it would happen, and the timing is suspiciously exact. 1962 has all three.](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-the-correlation-i-bw-academic.jpg)](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-the-correlation-i-bw-academic.jpg) How to prove something caused something else: it happened at the same time, there’s a reason it would happen, and the timing is suspiciously exact. 1962 has all three. But correlation + mechanism + temporal precision is how science works. Here’s what you have: 1. **Temporal correlation**: Life expectancy growth dropped by half right after 1962 regulations 2. **Mechanism**: Regulations reduced new treatments by [70%](../../knowledge/appendix/parameters-and-calculations.llms.md#sec-post_1962_drug_approval_reduction_pct). They increased costs [105x (90% CI: 72.8x-149x)](../../knowledge/appendix/parameters-and-calculations.llms.md#sec-drug_cost_increase_pre1962_to_current_multiplier). They banned real-world efficacy trials. 3. **Alternative explanations**: Yes, they exist (increasing disease complexity, higher safety standards). But the timing, magnitude, and linearity of the slope change all point to one event: the 1962 regulations. Other causes would produce gradual change, not a clean break. This is how clinical trials work. Temporal correlation + mechanism of action = inference of causation. If you don’t trust this method, you can’t trust any clinical research. Or science generally. ### Impact of Innovative Medicines on Life Expectancy A three-way fixed-effects analysis^([17](../references.llms.md#ref-three-way-fixed-effects-analysis)) studied 66 diseases in 27 countries. Without new drugs launched after 1981, people would have lost 2.16 times more years of life. The cost? \$2,837 per life-year saved^([17](../references.llms.md#ref-three-way-fixed-effects-analysis)). More treatments lead to more survivors. There’s a [strong correlation](http://valueofinnovation.org/power-of-innovation) between new cancer treatments and cancer survival over 30 years. [![More cancer treatments invented, more people survive cancer. Turns out medical research works. Who knew.](../../assets/images/more-surviving-more-therapies.png)](../../assets/images/more-surviving-more-therapies.png) More cancer treatments invented, more people survive cancer. Turns out medical research works. Who knew. ## The Summary - 10,000 years: Zero progress - 1880-1960: Decentralized real-world trials, 3.82 years/decade progress^([4](../references.llms.md#ref-life-expectancy-increase-pre-1962)) - 1962: Kefauver-Harris passes. Progress drops 60%^([16](../references.llms.md#ref-post-1962-life-expectancy-slowdown)) to 1.54 years/decade - Today: Still stuck with the broken system Humanity solved medical progress in 1883. Congress broke it in 1962. [![Medical progress: 3.82 years gained per decade. Then 1962 happens. Medical progress: 1.54 years gained per decade. We cut medical progress in half with good intentions and paperwork.](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-the-summary-bw-academic.jpg)](../../assets/images/real-world-evidence-historical-success/real-world-evidence-historical-success-section-the-summary-bw-academic.jpg) Medical progress: 3.82 years gained per decade. Then 1962 happens. Medical progress: 1.54 years gained per decade. We cut medical progress in half with good intentions and paperwork. 1\. Our World in Data. Historical life expectancy around 30 years. *Our World in Data: Life Expectancy* (2022) *Average life expectancy at birth:  30 years for most of human history until 1800s 1820: Global average still  30 years; 1800-2000: Rose from 30 to 67 years Context: Low life expectancy driven primarily by high infant mortality ( 1/3 of children died before age 5) Medieval England: Life expectancy at birth = 31.3 years, but life expectancy at age 25 = 25.7 additional years (total 50.7) Roman Egypt: Average in 20s, but many lived into 40s+ if they survived childhood Additional sources: https://ourworldindata.org/life-expectancy \| https://pmc.ncbi.nlm.nih.gov/articles/PMC2625386/ \| https://sc.edu/uofsc/posts/2022/08/conversation-old-age-is-not-a-modern-phenomenon.php \| https://www.discovermagazine.com/the-sciences/what-was-the-life-expectancy-of-ancient-humans* . 2\. Wikipedia. Journal of the american medical association (JAMA) founded in 1883. *Wikipedia: JAMA* *Founded: 1883 by American Medical Association Founding editor: Nathan Smith Davis Superseded: Transactions of the American Medical Association 1960: Obtained current title "JAMA: The Journal of the American Medical Association Evolution: Late 1800s resembled general journalism; 1910s-1920s "turndown era" began rejecting submissions based on quality; routine peer review instituted after WWII Current: Peer-reviewed medical journal published 48 times/year covering all aspects of biomedicine Additional sources: https://en.wikipedia.org/wiki/JAMA \| https://jamanetwork.com/journals/jama/fullarticle/291201 \| https://onlinebooks.library.upenn.edu/webbin/serial?id=jama* . 3\. Think by Numbers. Pre-1962 physician-led clinical trials. *Think by Numbers: How Many Lives Does 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* . 4\. Source: US Life Expectancy FDA Budget 1543-2019 CSV. [US life expectancy growth 1880-1960: 3.82 years per decade](https://manual.warondisease.org/knowledge/data/us-life-expectancy-fda-budget-1543-2019.csv). (2019) *Pre-1962: 3.82 years/decade Post-1962: 1.54 years/decade Reduction: 60% decline in life expectancy growth rate Additional sources: https://ourworldindata.org/life-expectancy \| https://www.mortality.org/ \| https://www.cdc.gov/nchs/nvss/mortality_tables.htm* . 5\. Ballentine, C. The sulfanilamide disaster. *FDA Consumer* (1981). 6\. Wikipedia contributors. [Elixir sulfanilamide](https://en.wikipedia.org/wiki/Elixir_sulfanilamide). (2025). 7\. Wikipedia contributors. [Phases of clinical research: Phase i](https://en.wikipedia.org/wiki/Phases_of_clinical_research). (2025). 8\. Wikipedia contributors. [Thalidomide](https://en.wikipedia.org/wiki/Thalidomide). (2025). 9\. FDA. Thalidomide caused thousands of birth defects. *FDA* *it resulted in thousands of horrific congenital disabilities. Additional sources: https://www.fda.gov/about-fda/fda-history-exhibits/frances-oldham-kelsey-medical-reviewer-famous-averting-public-health-tragedy \| https://www.smithsonianmag.com/science-nature/woman-who-stood-between-america-and-epidemic-birth-defects-180963165/* . 10\. FDA. FDA dr. Kelsey prevented widespread thalidomide birth defects in the US. *FDA: Frances Oldham Kelsey* *Dr. Frances Kelsey (FDA reviewer) resisted pressure to approve thalidomide September 1960-November 1961 Worldwide:  8,000 infants born with missing/malformed limbs; 5,000-7,000 perished in utero United States: 17 confirmed phocomelia cases + 9 likely cases (vs.  8,000 worldwide) Kelsey insisted on hard evidence, refused to be browbeaten; repeatedly requested more information every 60 days Merrell complained to her bosses, calling her "petty bureaucrat" - she persisted Recognition: President’s Award for Distinguished Federal Civilian Service (JFK, 1962) Led to 1962 Kefauver-Harris Amendments requiring drugs prove both safety AND effectiveness Additional sources: https://www.fda.gov/about-fda/fda-history-exhibits/frances-oldham-kelsey-medical-reviewer-famous-averting-public-health-tragedy \| https://www.uchicagomedicine.org/forefront/biological-sciences-articles/courageous-physician-scientist-saved-the-us-from-a-birth-defects-catastrophe \| https://www.smithsonianmag.com/science-nature/woman-who-stood-between-america-and-epidemic-birth-defects-180963165/* . 11\. GovTrack. Kefauver harris amendment of 1962. *GovTrack* (1962) *regulating efficacy testing via the 1962 Kefauver Harris Amendment. The 1962 regulations made these large real-world efficacy trials illegal. Additional sources: https://www.govtrack.us/congress/bills/87/s1552 \| https://www.fda.gov/about-fda/histories-product-regulation/promoting-safe-effective-drugs-100-years \| https://pmc.ncbi.nlm.nih.gov/articles/PMC4101807/* . 12\. Think by Numbers. Pre-1962 drug development costs and timeline (think by numbers). *Think by Numbers: How Many Lives Does FDA Save?* (1962) *Historical estimates (1970-1985): USD \$226M fully capitalized (2011 prices) 1980s drugs:  \$65M after-tax R&D (1990 dollars),  \$194M compounded to approval (1990 dollars) Modern comparison: \$2-3B costs, 7-12 years (dramatic increase from pre-1962) Context: 1962 regulatory clampdown reduced new treatment production by 70%, dramatically increasing development timelines and costs Note: Secondary source; less reliable than Congressional testimony Additional sources: https://thinkbynumbers.org/health/how-many-net-lives-does-the-fda-save/ \| https://en.wikipedia.org/wiki/Cost_of_drug_development \| https://www.statnews.com/2018/10/01/changing-1962-law-slash-drug-prices/* . 13\. Kinch, M. S. & Griesenauer, R. H. [Lost medicines: A longer view of the pharmaceutical industry with the potential to reinvigorate discovery](https://doi.org/10.1016/j.drudis.2019.01.009). *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.* 14\. House of Commons Health Committee. *The Influence of the Pharmaceutical Industry*. (2005). 15\. Wikipedia. Drug price competition and patent term restoration act of 1984. *Wikipedia: Hatch-Waxman Act* *Also known as: Hatch-Waxman Act (Public Law 98-417) Signed by Reagan: September 24, 1984 Sponsors: Rep. Henry Waxman (CA) and Sen. Orrin Hatch (UT) Created modern generic drug regulation system via Abbreviated New Drug Applications (ANDAs) Patent term extension: Up to 5 years (max 14 years total from approval) Generic incentive: 180 days market exclusivity for first paragraph IV certification 5-year data exclusivity for new chemical entities Note: Landmark legislation balancing generic access with innovation incentives. Generic manufacturers only need to show bioequivalence, not repeat clinical trials Additional sources: https://en.wikipedia.org/wiki/Drug_Price_Competition_and_Patent_Term_Restoration_Act \| https://www.congress.gov/bill/98th-congress/house-bill/3605 \| https://www.everycrsreport.com/reports/R44643.html* . 16\. Source: US Life Expectancy FDA Budget 1543-2019 CSV. [Post-1962 slowdown in life expectancy gains](https://manual.warondisease.org/knowledge/data/us-life-expectancy-fda-budget-1543-2019.csv). (2019) *Pre-1962 (1880-1960): 3.82 years/decade Post-1962 (1962-2019): 1.54 years/decade Reduction: 60% decline Temporal correlation: Slowdown occurred immediately after 1962 Kefauver-Harris Amendment Additional sources: https://ourworldindata.org/life-expectancy \| https://www.mortality.org/ \| https://www.cdc.gov/nchs/nvss/mortality_tables.htm* . 17\. 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* (2019). 18\. Baily, M. N. Pre-1962 drug development costs (baily 1972). *Baily (1972)* (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* .