Month: September 2018

.”

The authors of the Declaration of Independence didn’t think health care was an “unalienable right that was endowed by our creator” and health care wasn’t one of the many rights that were added to the nation’s constitution in 1791. 

Back then nursing care supported the ill and sped their recovery. Amputations prevented some deaths.  But most of the treatments doctors employed were pretty awful.  Consider—the December morning in 1799 when 67 year old George Washington awoke desperately ill.  He was retired and lived at Mt. Vernon.  The previous day Washington felt well and went out in the snow to “mark trees that were to be cut down.”  Upon awakening the day in question he couldn’t talk and had trouble breathing.  His wife Martha sent for one doctor, then another.  She and her husband were two of the country’s richest people and obviously didn’t need subsidized care.

During the day three prominent physicians came to their home and plied their trade.  The doctors were among the country’s best and they worked hard.  On 4 occasions they bled the sick man and removed a lot of blood.  His throat was swabbed, he gargled, his feet were covered with wheat bran, and he was given an emetic to induce vomiting.  Nothing worked.  When Washington’s breathing got worse he dressed, thanked his 3 doctors, and made arrangements for his burial.  That night he died. (As related by his secretary Tobias Lear)

Before 1800 the educated elites relied on the teachings of the ancients, like the Greek physician Hippocrates, who believed that illness was “due to an imbalance of blood, phlegm, black bile, and yellow bile and the Roman Galen who dissected monkeys and wrote about their anatomy. 

Mankind was not aware of the microscopic creatures who lived in, around, and on us until the late 1700s. 

During the 1800s we gradually learned about their existence.  We started believing and understanding that they were the source of many of our maladies, and we began to take precautions.

In the 1900s our abilities exploded:  We learned how to safely transfuse blood. Hormones were isolated.  Antibiotics and drugs that fought viruses and parasites were developed. Experts learned and taught others how to replace eye lenses that were opaque.  Vaccines were crafted.  Thousands of medical gadgets were devised.  Surgeons were taught how to proceed after they cut a person open, and a large number of effective drugs became available.

In 1965 over 100 million Americans were introduced to socialized medicine—Medicare and Medicaid.  Most loved it. 

In 2003 the entire human genome was “sequenced”.  Scientists determined the exact order, the way the 3 billion pairs of human DNA nucleotides (building blocks) lined up, and our ability to attack and “cure” genetic conditions got a big boost.  

The push and pull between medical care as a shared endeavor or a wealth producing commodity started in the 1900s and intensified over time.  In the last half of the 20^th century “health care” increasingly became a major part of the U.S. economy and obstacles and inequalities were created.  This book seeks to make sense of the wonders that were developed and the challenges we face.

As Elisabeth Rosenthal of Kaiser Health News put it: “there’s money to be made by billing for everything and anything.” And hospitals currently intentionally submit amplified bills for their services.

Each hospital has an all inclusive list of “items billable to a person or a health insurance provider.”  Called “charge masters” they have long been secret in most states; but starting in 2019 they will be posted on line.  They do not include physician charges, and they are intentionally inflated–or in the “speak” of the University of California San Francisco Hospital:  “they are not the amount that either you or your insurer will actually pay. Out-of-pocket costs will be impacted by insurance plan coverage, co-pays and deductibles, if any, (etc.) – so our list should not be used to estimate the actual final cost you will incur.” 

Insurance companies like to flaunt them to demonstrate how much money they are saving their patrons.  And hospitals can claim that overstated prices are useful when they negotiate contracts with insurance companies.  The “fair” cost, the amount insurance companies (on average) really pay for most emergency and hospital visits, is accessible to anyone who has a smart phone. They merely have to open Healthcarebluebook.com or some similar service, and type in their zip code.  

Medicare strictly regulates the amount the government shells out to hospitals.  The agency is constantly updating what it pays for an illness or operation; 98% of American hospitals accept what the Feds dole out as payment in full. 

Exaggerated bills punish the ill and wounded who are cared for in a hospital that does not have a contract.  They hassle the person who is seen in an “out- of-network” facility or who was cared for by a doctor who was not covered by an agreement.  And they are especially harmful to people who don’t have health insurance. 

Paradoxically the people who try to collect the most exorbitant amounts of money commonly tend to blame the injured party. 

 I believe that once hospitals start charging people without insurance fairly, a form of BACK STOP INSURANCE makes sense.  As detailed in the “alternative approach” chapter, when corporations have a big stock offering, they obtain insurance.  If some of the stocks and bonds are not sold on the open market, the investment firm that is handling the transaction has to buy them.  

We need to take a similar approach to people who can afford insurance but don’t have a policy.  Health insurance is rarely used by some because they have a healthy life style, they’re young, and they are lucky.  And because bodies have an innate ability to fight off invaders and heal wounds.

If one of these people is in a “higher income” category,  and they haven’t purchased medical insurance, and they get sick or are injured, they would be best served if the system has “automatically enrolled them in a “backstop” insurance plan.”  If they are seen in an emergency room or are hospitalized the facility should be able to submit a claim and it should be paid by the government.  At tax time the IRS can then decide how much the person owes for a year’s worth of “backstop insurance.”  (As conceived by Matthew Fielder, NEJM:  May 2, 2019.)³

II. HEALTH INSURANCE: Some employer policies are unusable because the co-pays are so high.  In addition to taking care of the people with pre-existing conditions, we need a law or regulations that make health insurance affordably-useable.  There should be caps on premiums and co-pays; out of pocket payments should be based on income—should mirror earnings

Several of the Democratic candidates for president believe in Medicare for All.  Like all “rights” this form of care must be paid for.  That usually means taxes, and people who promise more taxes aren’t usually elected.  In addition to something like the current payroll tax– the government would have to collect the money employers contribute to a person’s insurance and the excess insurance company profits. 

 As an old retired M.D. and a socialist at heart I favor Medicare for all.  But as a realist I’m worried. 

In the 60s and 70s affordable health care was available to those who wanted it via Blue Cross and programs like Kaiser (my people.)   Then insurance companies entered the market and did what insurance companies do.  They risk adjusted.  People who live in the low lands near the Mississippi River pay more for flood insurance, and we in California pay more for earthquake insurance.  Private insurers didn’t sell affordable policies to people with pre existing conditions.  Premiums for the young and healthy were relatively cheap. 

Over the subsequent decades the young, healthy and employed started choosing private insurers; people with problems joined Blue Cross and Kaiser.  Year by year medical care improved and it also became increasingly costly:  CAT scans; MRI’s; organ transplants; angioplasties; artificial joints; and ICU’s aren’t cheap.

As their population increasingly had fewer healthy clients and more people with costly problems, Blue Cross and Kaiser started “hemorrhaging money.”  Ultimately they were on the verge.  After Hilary’s very reasonable Health Care adjustments were rejected, many Blue Cross companies and Kaiser said “uncle”.  They adopted a risk adjusted approach.

Over the subsequent decades people forgot that affordable health care, like the roads or schools, was once widely available.  The young, healthy, and employed grew up assuming they would be able to buy insurance that was good and affordable. It was their “right.”  Understandably, they don’t want to give it up.  And we need their votes. 

My approach:  lower the Medicare age, and keep dropping it. Make affordable Medicare purchasable for those who want it.   At the same time, over a few years–SUBSTANTIALLY LOWER THE MEDICAL LOSS RATIO.  Under the Affordable Care act companies get to keep 15 to 20 % of premiums for expenses, bonuses and stock holders.  The overhead of Medicare allegedly is 3%.  If insurance companies could keep 8% of the premiums, they should still be profitable.  If a yield of 5% isn’t enough, a company can leave the market. And some will. Over time healthy people will increasingly migrate to Medicare.  We may never get to Medicare for All but we’ll get close.  

As a result of the current medical loss ratio, the heads of the health insurance companies are doing quite well. In 2018 as a result of exercised stock options and stock awards, the one year compensation of the head of 49.5 million member UnitedHealth insurance, the nation’s largest, was over $18 million. The leader of Anthem, the 40.2 million policy, second largest was $14.2 million.⁴    

III. We should also extend some of the benefits of the Affordable Care Act (ACA) to traditional Medicare.  The ACA (Obamacare) created an annual lid on the amount people are forced to pay for their care.  In 2018 it was $7350.  By contrast, traditional Medicare, has no cap, no maximum amount a person can be charged.  When people see a doctor or are hospitalized, they are responsible for “copayments, coinsurance, and other gaps in coverage.”  If someone has a very serious illness and is hospitalized for months, the government stops paying the bill “after the 150^th day in the hospital. 

People can buy an insurance policy that pays the bills that are not covered by Medicare. There are 10 levels of “Medigap” plans.  If a person doesn’t buy one of them when they enroll in Medicare, the policies are subsequently only available (most of the year) to people who pass an insurance physical.   

Medicare Advantage plugs a number of the holes in traditional Medicare.  Currently (according to AARP) 44 million Americans are insured by Medicare.  The number opting for Medicare Advantage rose to 20 million in 2018 and it’s going up.  Advantage plans are capitated.  The government gives the insurer a dollar amount per person per year, and “everything” is covered.  Plans may include limited dental care and gym memberships.  Out-of-pocket costs were capped at $5,215 per year in 2018.  (November 14, 2018, NEJM.org.)

According to Wiki “You cannot have both a Medicare supplement (Medigap plan) and a Medicare Advantage plan at the same time.”  It’s time to identify and close the Medicare gaps.

IV: Extra money for health care was supposed to come from a few additional sources.  Congress recently abolished the Medical Device tax, the health insurance tax , and the tax on Cadillac plans.

I suggest re-opening the question of what happens when university and nonprofit hospitals make hundreds of millions of dollars. Should they be taxed? Should they return some of the tax funds they received from the government for use elsewhere in the health care system? Or perhaps charitable and university hospitals should (like the for-profits) generate a bill for the service rendered. The amount charged would be similar to the sum Medicare or insurance companies would actually pay. (Inflated excessive charges should be treated as potential tax fraud.) The institution’s outlay could then be deducted from the hospital’s gross income.  If an institution performs a lot of charity work and has no net income they would owe no taxes.  If they generate a large profit, they, like for-profit corporations, could pay a tax.

Summary:   if our goal is to make quality health care affordable and available :

1.  We need to fix the drug price problem.
2. Pevent hospitals from generating outrageous inflated bills for their services.
3. Eliminate out of network charges. 
4. Eliminate balanced billing. 
5. Allow the medical loss ratio (MLR) to whither. 
6. Put a cap, an upper limit, on the out of pocket Medicare bills that unsuspecting seniors are sometimes forced to pay.
7.  And we should allow people to buy into Medicare. 
8. And perhaps tax the excess profits of University and Charitable hospitals

Is health care a commodity?

https://www.theberylinstitute.org/blogpost/947424/215160/Thoughts-from-a-Commodity

https://www.enttoday.org/article/health-care-as-a-commodity-competition-should-be-focus-of-health-reform-lecturer-says/   https://journals.lww.com/annalsplasticsurgery/Citation/2009/01000/Is_Health_Care_a_Commodity_.1.aspx

https://www.theberylinstitute.org/blogpost/947424/215160/Thoughts-from-a-Commodity

1. .

• Tutorial: Our skin and intestinal track create barriers that protect our bodies from a world full of bacteria viruses, and the other microscopic creatures. 
• Immune cells float through our blood and lymph and identify, imprison, and destroy invaders. 
• In the process of protecting a body they can unleash an inflammatory attack that is painful and debilitating. 
• At times defenders mistake good guys for bad guys and attack joints (rheumatoid arthritis), the intestine (Crohn’s), the kidney (lupus) or the nervous system (multiple sclerosis.). 

There are over ten billion B lymphocytes in the blood and lymphatic systems of each human body.  Like a hive of bees, they are an ecosystem.³ Each can identify one and only one unique sequence of alien DNA or RNA.  When a B cell encounters its fated invader it rapidly clones itself, makes a huge number of carbon copies.  Some of the offspring become memory cells.   Most, now called “plasma cells”, fabricate free floating antibodies that attach themselves to the foreign protein, and mark it for destruction. 

Some immune cells are sentinels that recognize and ingest foreign protein and “process” it.   Called dendritic or antigen presenting cells they don’t destroy, they display the distilled protein on their outer membrane in an area called the “MHC complex.” 

The T lymphocyte has  receptors that recognize the offering and grab it.  Some T-lymphocytes exterminate viruses; others destroy malignant cells. 

Macrophages “surround and kill microorganisms and remove dead cells.”  Much as a caterpillar turns into a butterfly, macrophages begin life as monocytes.²⁸

Immune cells communicate and influence one another by secreting small molecules called cytokines.² Some of these play a role in the inflammation that protects us from invaders.  Others are a major contributor to the pain and damage caused by one of several autoimmune diseases.

We can usually temporarily control immunologic assaults with cortisone derivatives.  To block the inflammatory cytokines physicians are increasingly using monoclonal antibodies. 

TNF—tumor necrosis factor—is a misleading—inappropriate name of the family of cytokines that is the major cause of the pain, swelling and inflammation suffered by people who have any of a number of auto-immune diseases. The name was chosen by researchers who were trying to understand how some malignancies were cured when they were intentionally infected with virulent bacteria.³¹

Intentionally infect a cancer?   Some doctors had tried it here and there for a few centuries, but it wasn’t studied and promoted before William Coley, a physician at a major New York hospital became a believer.   

An upper “crusty,” Coley could trace his American lineage to the Mayflower era.  He graduated from Harvard Medical School in 1988 and during his apprentice years learned that half the surgical repairs of abdominal hernias in kids didn’t work very long. (Hernias are weak areas the belly wall that intestines can protrude through.). He introduced the European approach, using sutures and sewing and resewing, and he was successful and “admired.”³²

He started suspecting that infections can lead to a cure for cancer when he located a man whose malignancy disappeared after he developed erysipelas, a streptococcal infection of his face.  Years later the cancer was still gone.  An influential surgeon Coley decided to infect the throat tumor of an Italian immigrant who couldn’t speak or eat.  Making small incisions in the growth, Coley rubbed streptococcus into the wound.  At one point “the patient became extremely ill and looked like he might die.”  But he survived and the tumor “liquefied.” Coley published a case report and promoted his approach. As head of the bone tumor service at New York hospital he injected streptococcus into 1000 malignant sarcomas. After they were infected  about 10 percent of them regressed and disappeared.²⁹  In subsequent years the drug company Parke-Davis marketed a mixture of two virulent bacteria that could be used to treat cancers.  In 1962 the government clamped down on medications that weren’t proven safe and effective. Coley couldn’t prove his approach worked and Parke-Davis stopped marketing the bacteria.

Decades later a team of researchers in Belgium led by Walter Fiers discovered a cytokine that erradicated human tumors that were planted into laboratory mice.  They named the cytokine family TNF—tumor necrosis factor. 

Researchers have developed antibodies that block TNF cytokines.  The medications they developed are among the most costly and profitable pharmaceuticals of the day.  Humira generated $19.9 billion in 2018.  Enbrel/etanercept had $7.1 billion in revenue.  Remicaid/infliximab-$5.9 billion.

The story of the cytokine TNF and the creation of antibodies that block their action starts in 1980.  A researcher named Hilary Koprowski, “a colorful, prominent Polish-born virologist” patented a process he had used in his research—a method for making monoclonal antibodies.⁴

  The technique was developed 6 years earlier in Cambridge England by George Kohler and Cesar Milstein.  They won a Nobel Prize for the process, but they didn’t bother to file a patent. 

Their project started when they injected purified protein into a mouse.  One of the lymphocytes floating in the creature’s blood realized the injected amino acid was foreign and it had to be destroyed.  The lymphocyte started cloning, making huge numbers of copies of itself.  The numerous identical lymphocytes all made the same antibody.  Days went by.  Then one of the researchers drew blood from the animal’s spleen.  As expected, a large proportion of the mouse’s lymphocytes were now clones of the original cell, and each of the lymphocytes made the same antibody. So far nothing that happened was exceptional.  

At this point they fused some of the lymphocytes to mouse myeloma cells, malignant plasma cells that keep reproducing and don’t die.  The hybrid they created made and kept making large quantities of one and only one antibody.  .  

As Kohler, a shy, gentle Swiss German immunologist later explained, the fusion approach was new and unique.  “If by blind chance the right lymphocyte, the one producing the antibody against the injected antigen had fused with the myeloma cell and was forming daughter cells that were locked into producing the same pure antibody. …it was a long shot.”  Around Christmas 1974 Kohler added the antigen to the fused cells and went home.  If the experiment worked the antibodies produced by the fused cells would combine with the antigens and they would precipitate.  Halos would form around the cells.  He returned hours later and fearing failure brought his wife along to console him.  They looked in the window, saw the halos and were elated.  “I kissed my wife.  I was all happy.²⁶”

Kohler’s partner, Milstein was a Jewish researcher from Argentina.  His 14 year old father had exited Russia the year before the country became embroiled in the First World War.  His Argentina born mother was the head mistress of a school and encouraged her son to study hard and to go to the University of Buenos Aires.  At one point she helped type his PhD thesis.  Married and a post doc researcher, Milstein spent three years in the 50s working at a lab in Cambridge England. He returned to Argentina in 1961 as head of a university department, but a military coup had taken control of the country.  It conducted a campaign against political dissenters, and Millstein had been a prominent anti – Peron student when he was an undergraduate.  It was also targeting Jews.  Milstein felt unsafe and returned to the lab at Cambridge.

In the 1960s and 70s a number of scientists developed mouse myeloma cells (malignant plasma cells) that could be grown in tissue culture and were “immortal”..They or their progeny survived indefinitely.  Milstein learned how to turn two small myeloma cells into one larger cell.  In 1974 he was joined by Georges Kohler, a Swiss postgraduate researcher who was also interested in fusing myeloma cells.  Together they developed the first “hybridoma”—part lymphocyte—part myeloma cell—the first “factory” that produced monoclonal antibodies.  

With a patent in hand, Koprowski owned the process for making monoclonal antibodies.  Along with an entrepreneur named Michael Wall, he formed a company named Centacor, and they tried to figure out how turn mouse monoclonal antibodies into gold. 

In the summer of 1982 Michael re-met Jan Vilcek, a man who studied cytokines and who worked at a New York hospital.  A Czech researcher, Jan was a 6 year old Jewish kid in 1939 when his country was occupied by Nazi Germany.  During the next few years the Nazis rounded up and killed Jews.  Vilcek wrote that he and his parents survived in a hostile environment because they had “a complicated attitude toward their Jewishness.”  At some point they converted to Catholicism.  Later they moved. Jan’s father joined the underground.  One way or another they managed to avoid the death camps.  After the Second World War Russia took control of Czechoslovakia, and the country became part of the Eastern Bloc.  The Soviet Union and the U.S. feared one another, built nuclear missiles, and created armies that could defend their nation.  Travel between the Soviet Bloc and the West was restricted and immigration forbidden.

Vilcek married and became a virology researcher.  When he was in his 20s, fed up with the Czech Communist government, he wanted to “relocate.”    In 1964 the couple received permission to cross the iron curtain for a three day vacation in Vienna. They traveled by auto.  It was October, still warm, and they brought their heavy winter coats.  When they reached the border and their car was being searched Jan worried that the coats would be a giveaway– that the inspectors would realize that Jan and his wife were trying to escape.  He waited while the border guards “hesitated for the longest minutes of his life before letting them pass.⁴”   Once across the line that divided the countries they, of course, didn’t go back.  After the couple reached Germany, life was rough, but within a year Vilcek was hired by NYU, New York University.

After spending a number of years studying interferon, one of the body’s cytokines, Vilceck attended a workshop on a poorly understood immune regulator called Tumor Necrosis Factor. 

In 1984 Genentech scientists determined and published the complete amino acid composition of TNF.  They purified the human TNF protein and they gave some of it to NYU.  Vilcek and his colleagues accepted the gift and “felt like kids in a candy store. –what should we try first?” 

The cytokine turned out to play a role in a body’s ability to fight viral infections.  It had so many actions that one of Vilcek’s graduate students quipped “TNF should stand for too numerous functions.” 

Cytokines are groups of special proteins.  They are discharged by immune cells and they act as chemical messengers.   After they are secreted by a cell, cytokines bind to receptors on the surface of other cells and they regulate the immune response.  They can work alone, work together, or they can work against one another.

In the 80s Centacor (still struggling) on a whim, a hope, produced a next generation monoclonal antibody that would block or inactivate TNF.  It was “chimeric”, a protein that was part human and part mouse.  The development took experts at Centacor 6 months and its patent was owned by NYU (an independent private research University) and Centacor.  The antibody didn’t (as Centacor had hoped) help people with sepsis.  But blocking TNF hindered one of the cascades of pro-inflammatory cytokines. It stopped or hindered inflammation.

When London doctors (Feldman and Maini) injected the medication into the swollen inflamed joint of a person with Rheumatoid Arthritis it usually helped.  The effect lasted three months.  A repeat injection was also successful.  In 1993 a physician from Holland used the antibody to treat a desperately ill 12 year old girl with a severe case of Crohn’s disease, a chronic inflammation of the small and sometimes large bowel.  The disease can cause diarrhea, pain, bowel blockage and fistulas, connections between the intestine and the skin or an organ.  The infusion was very effective for 3 months and it helped 8 of 10 additional people with severe Crohn’s.

10 years after the original mouse antibody to TNF was generated in Jan Vilcek’s NYU lab, doctors had a tool that helped them treat a number of auto immune disorders.⁴  

Part of the research was funded by the NIH (the taxpayer).  Part by Centacor. There was a lot of luck and serendipity along the way.⁵  Both Centacor and NYU were rewarded.  The FDA approved the drug for use in inflammatory bowel disease (for Crohn’s they say it has a positive effect 60 to 70 percent of the time),–and it can be used for ulcerative colitis, rheumatoid arthritis, ankylosying spondylitis and various manifestations of psoriasis.

In 1999 Johnson and Johnson bought Centacor for $4.9 billion.  Revenues from the drug (per J and J) rose annually between 2009 and 2016—from $4.3 billion in 2009 to $7 billion in 2016.⁶

Humira—adalimumab,  another antibody that blocks TNF, was created in mice that were genetically modified in embryo;  the animals make antibodies that human bodies think were made by a homo sapiens.  Some of the research on the drug was performed by researchers at the government funded Cambridge Antibody Technology, U.K.   The FDA licensed Humira at the end of 2002.  By 2005 AbbVie, the company that owned it, was selling more than a billion dollars worth a year, and by 2018 it was bringing in close to $20 billion.⁷

Scientists in many of the world’s labs knew how to make monoclonal antibodies to TNF, but they couldn’t market them until they performed placebo control studies that proved their drug was both safe and effective.  And that was costly, ethically questionable, and medically unnecessary.  Then a new law allowed companies to avoid double blind studies if they  could prove their “new” antibody worked as well as the current one—that it was “biosimilar.”   A provision of the Affordable Care Act, gave the original antibody maker, in this case AbbVie, the exclusive right to sell the monoclonal antibody in the U.S. for 12 years.  At the time the FDA provided exclusivity for other new drugs only lasted 5 yrs.   At the end of the 12 years, as a result of a provision in the act, company lawyers were able to keep biosimilars—the biologic equivalent of generics–off the U.S. market for a few additional years if the claimed that one or several of the drug’s 126 patents were fundamental.  (All the patents are presumably novel, non-obvious, and useful, but some merely protect a step in production or an inactive ingredient.)

Four companies produced effective biosimilars and wanted to steer clear of years of pointless litigation.  In an attempt to market their Humira-like medications, the manufacturers signed an agreement with AbbVie in 2017 and 2018.  It allowed them to market their medications outside the U.S.  AbbVie will retain their $10 billion a year U.S. Humira monopoly until 2023.⁸

Several cytokine families (including interferons) contain both pro and anti- inflammatory molecules.  Inhibitors are currently available to molecules that belong to one of two cytokine groups:  “TNF—tumor necrosis factor” and “interleukins”.

There are a number of the diseases where the  immune- system goes rogue.  Some destroy joints and organs or bring on fatigue, fever, weight loss and an early death. 

An overly zealous cytokine reaction–sometimes called “cytokine storm” may explain why some severe cases of viral pneumonia kill.  High levels of a number of cytokines were found in the blood of  people with infiltrates in both lungs and low levels of blood oxygen caused by SaRS, MERS, AND COVID 19.³³

Some of the cytokine harm is mediated by one of more than 36 known interleukins–“hormones of the immune system”, and pharmaceutical researchers have developed, tested, and marketed humanized monoclonal antibodies that block some of them.²⁷

TRANSPLANTATION

On more than 34,000 occasions in 2017, organs from donors, dead and alive —livers, kidneys, hearts and lungs–were transplanted into the body of someone in the United States–and the immune system was challenged.

We learned organ transplant was possible in 1954 when an identical twin successfully gave his brother a kidney.  That’s as far as it went for decades because we weren’t very good at keeping a body from rejecting someone else’s organ.  Our original attempt to prevent the immune system from destroying foreign tissue, our “three drug anti rejection regimen”, according to Thomas Starzl, “wasn’t very effective or safe.”  

Thomas Starzl is the American who pioneered the effort to replace the diseased liver of one person with a healthy liver from someone who had recently died.  He developed a methodical approach by operating on dogs in his garage.  As a surgical trainee he obtained the poor creatures from the pound and his wife, Barbara, “cared for the animals.”  Eventually Starzl could remove the organ without killing the canine. 

He learned how to deal with the blood flow from the small intetines.  It contained nutrients that don’t normally enter the main circulation until they seep  through the liver and are processed.  Starzl learned that his liver transplants couldn’t accept and process the flow.  They failed when he didn’t shunt blood from the small bowel around the liver.  “After surgery his dogs were normal for almost a week; then they began to reject their new liver.”

In 1961 Starzl became chief of surgery at the Denver VA hospital and used prednisone and immuran to prevent rejection in a few kidneys.  He had a modicum of success, but as late as 1978 “Graft survival was unsatisfactory and patient mortality high.¹⁰   Ambitious and perhaps a little too preoccupied by the rapid changes in his craft, Starzl remembered the day in 1976 when his wife of 22 years casually drove him to the airport in a snow storm.  He flew to London to present a research paper and while there received “ambiguous phone calls from his family, and he “knew” he could not return home.  After 22 years of marriage his wife Barbara’s “forbearance had run out.”   In 1990, having spent most of his life transplanting organs and teaching others he had a heart attack and wrote a memoir. in it he mused that every person who receives someone else’s organ starts seeing the world in a different way, and that medicine’s ability to save a life by transplanting an organ is a legitimate miracle. 

In 1967 Christiaan Barnard in South Africa and Norman Shumway at Stanford each transplanted a human heart.  Neither recipient survived for three weeks.  In 1971 Life Magazine’s story of an “era of medical failure” told readers that subsequent to the first two “166 heart transplants were performed and 143 of the recipients died.²²” 

The son of a pastor and a church organist, Christiaan Barnard, the surgeon who performed the planet’s first heart transplant, was born in a sheep farming region of South Africa.  As a student at the University of Cape Town he was on scholarship, poor, and had to walk five miles to school each day.  After he graduated from medical school Barnard married, had two children, and practiced medicine for 2 years.  Then, deciding he wanted more from life, he accepted a scholarship to the University of Minnesota and spent 30 months (many without his family) working with some of the first surgeons who repaired heart defects in children.  He watched them work, learned techniques, and often operated the machine that oxygenated the bodies of the children whose hearts werent beating. After he returned to South Africa Barnard and his brother who was also a surgeon operated on 48 dogs and they learned how to transplant a heart.  Then he was introduced to a 53 year old man who had severe heart disease, was bedridden, and who was ready to resume his life or die.  The heart Barnard transplanted came from the body of a 25 year old woman who, as the result of a traffic accident,  was brain dead.  The man who received the woman’s liver, survived surgery.  The operation became front page news.  The transplanted heart worked for 18 days before  the patient developed pneumonia, and died.  Reflecting on the man’s decision Barnard later wrote, “For a dying man it is not a difficult decision because he knows he is at the end. If a lion chases you to the bank of a river filled with crocodiles, you will leap into the water convinced you have a chance to swim to the other side. But you would never accept such odds if there were no lion.”

A second heart transplant recipient lived 18 months.  A few years later effective anti rejection medications hit the market.  By 2001, the year Barnard died, doctors in the U.S. were performing 2,400 transplants each year.  87 percent lived for at least a year and ¾ more than five years.

Barnard became a celebrity, let his hair grow, started wearing suits made by an Italian tailor, dated movie stars, and ended his first marriage.  During his life he performed 75 more heart transplants, created a tissue heart valve, and was married two more times.  His rheumatoid arthritis eventually crippled his hands, and when he was 61 he stopped operating.

A month after Barnard performed the first heart transplant Norman Shumway, a California surgeon transplanted the second human heart.  At the time Shumway had been transplanting dog hearts for 10 years and knew technically what to do.  His patient died within three weeks. 

A member of the high school debate team in Kalamazoo Michigan, Shumway originally planned to go to law school, but he was drafted during the Second World War.  One of the soldiers tested when the government decided they needed more doctors and dentists, Shumway scored high and chose medicine over dentistry.  Assigned to a group of men who received pre-medical training at Baylor University, he was a hospital orderly for 6 months before he went to medical school at Vanderbilt.  He was an air force doctor during the Korean War then joined the multitude at the University of Minnesota who were learning how to correct congenital heart defects.  Unable to get much hands-on training he decided to go into private practice and joined an older doctor.  It was not a fit.  Someone convinced him to come to Stanford University, an institution that didn’t have any doctors with heart surgery experience.  A modest man who was relieved when someone else performed the first heart transplant, Shumway became the chief of cardiothoracic surgery at Stanford in 1965.

In 1983, after the FDA sanctified the use of Cyclosporine, the first drug that allowed foreign organs to survive for years, the transplant scene changed.  In the subsequent decades over 700,000 people in this country lived part of their lives with someone else’s liver, kidney or heart.  Kidneys, on average, lasted 12 to 15 years; livers had a shorter lifespan.  That’s going to change now that hepatitis C (a frequent cause of liver destruction) can almost always be cured.  When a person with hepatitis C was transplanted, the new liver was always infected, and had a relatively brief lifespan.

After a person receives a foreign organ, they (almost always) reject the newcomer if they don’t take an immunosuppressant daily for life.  A few anti rejection drugs are currently available.  There’s a marketplace and competition.

Cyclosporine, the first truly effective anti rejection drug, was developed by Sandoz, a Swiss chemical company that, in the 1800s, manufactured dyes and saccharine.  In 1917 the company hired a chemistry professor, and created a pharmaceutical department.  His group isolated ergot from a corn fungus and turned it into a drug used to treat migraine and to induce labor.

In 1958, the company asked employees to take a plastic bag with them when they went on vacation or business trips, and to periodically gather “soil samples that might contain unique microorganisms.”  They knew Penicillin was part of the juice produced by a mold, and they hoped one of their people would find the next great antibiotic.

John Francois-Borel was a company biologist, and reluctant scientist.  He said he originally wanted to make art and he was very gifted.  But, as he put it, “you know how art pays; I am not the Bohemian type.²¹“Borel was the man who discovered cyclosporin.  The drug prevented the body from rejecting foreign tissue and revolutionized the field of organ transplants.  Borel collected a handful of earth when visiting a desolate highland plateau in Southern Norway.¹⁸ A fungus in his sample of Norwegian dirt produced a metabolite (Cyclosporin) that lowered the immune response of lymphocytes.  It seemed to be relatively safe, and some thought it could potentially become an anti rejection drug.¹⁶

In 1976 Borel presented his findings to the British Society of Immunology.   “A small stocky surgeon with a mop of curly black hair (Starzl’s description) who had been working in transplantation since 1959,²⁰” Sir Roy Calne was one of several who “asked Borel for samples”.  Calne used the fungus juice to try to prevent the destruction of organs transplanted in rats and dogs.  The drug’s effect was dramatic. 

By 1973 the Sandoz supply of fungus derived cyclosporine was largely depleted.  Large sums of money (around $250 million,) would be needed to create more, evaluate its anti-rejection potential, develop a drug, and obtain approval from the FDA.  There wasn’t much of an organ transplant market, and the investment didn’t make much sense. But with Borel’s help, Calne presented his findings to decision makers at Sandoz.  “The pharmaceutical company agreed that the drug looked more promising now that there was evidence of its effectiveness.” 

Over time, in addition to performing surgery Calne became a well known artist.  He once wrote that art and surgery “Both require careful planning, skill and technique and familiarity.”

  In the early 1980s Starzl used Cyclosporin successfully on liver transplant recipients.  With his results in hand the FDA fast tracked approval of the medication and in 1983 it became available for use in the U.S.  (Currently made generically by a number of countries Cyclosporine’s wholesale price is not outrageous.²⁴ $106.50 a month in the developing world—GB £121.25 per month in the United Kingdom, and about $172.95 per month in the U.S. (if generic drugs are prescribed.)

Pharma scientists can produce great results.  But to create a truly innovative medication, in addition to money they need a modicum of serendipity, imagination, and stubborn determination.¹¹

The second major, now widely used, anti rejection drug was Tacrolimus (Prograf).  Originally isolated from the “fermented broth of a streptomyces bacteria”, it was discovered and developed in the 1980s by Japanese chemists screening “natural substances in the soil for their anti cancer and anti rejection properties.”   They were working at the Fujisawa Pharmaceutical, a company located at the foot of the Tsukuba Mountain, a green oasis with hiking trails, Shinto shrines, and a good view of Mt. Fuji.   

English scientists tried Tacrolimus in dogs and “declared it too hazardous to test in humans.”  Dr Starzl’s group kept at it; they found the drug kept transplanted organs alive in some animals and “rescued some organs that, despite cyclosporine, were being rejected.” Additional clinical trials “suggested that tacrolimus might be safer and better tolerated than cyclosporine.¹²  ”  

In renal transplant recipients Prograf led to improved graft and patient survival, and that lead to its routine use in U.S. renal and pancreas transplant recipients.  The FDA made it official in 1994.   Fujisawa later merged with and became Astellas, the world’s 14^th largest.¹⁷ The year before Prograf had a generic competitor, Astrellas sold up to $2.1 billion dollars worth of the medication.

In 2011 an average transplant of one kidney had a price tag of $260,000.  Combined heart and lung transplants were costing $1.2 million dollars.   The first 180 days of post transplant medications was costing $18,000 to $30,000, and a number of generic immunosuppressive drugs had been marketed:  “(cellcept was approved in 1995.  Mycophenolate mofetil became available in 2008, Tacrolimus in 2009), and sirolimus in 2014,”

It’s claimed that the annual cost of U.S. transplant immunosuppressive therapy averages $10,000 to $14,000.  If true then the 33,000 transplant recipients in 2016 are (directly or indirectly) paying $330 million to $462 million a year.  That becomes $3.3 billion to $4.6 billion over ten years if drug prices don’t rise or fall.¹³  

In India (where the culture surrounding pharmaceutical prices is quite different from ours), the amount paid for Tacrolimus was slashed 65 percent in 2016.  The average recipient now pays $235 to $314 a month for anti rejection medications.

On October 30, 1972 chronic dialysis and kidney transplant became a Medicare ‘”right.”  If someone receives a kidney transplant (at a cost of hundreds of thousands of dollars) the operation and three years of anti rejection drugs are fully funded by the federal government.  At the end of those years the patient is removed from Medicare, and they have to pay for their own anti rejection drugs.  About 22 % of people on anti rejection medications stop taking them:  because of side effects, high cost, or for other reasons.  When a kidney transplant recipient stops their immunosuppressive drugs they almost always reject their kidney, and they are forced to go back on dialysis or die. This is not theoretical.  It happens.  And it’s a problem.¹⁴

Currently, in addition to brain death, patients who have severe brain injuries but who are not “brain dead” can become organ donors if the patient consents by means of an advance directive, or the patient’s family decide that life support should be withdrawn. “To avoid obvious conflicts of interest, neither the surgeon who recovers the organs nor any other personnel involved in transplantation can participate in end-of-life care or the declaration of death.”

Some countries have a system where an appropriate dead person’s organs can be transplanted in another unless the person explicitly objected while he or she was alive and competent.  The U.S. and a number of other countries require specific consent.

Founded in 1984, a private non- profit organ transplant organization (UNOS) under contract with the government, “oversees all organ procurement and transplant programs in the country and makes the rules about who can do transplants and how organs are to be allocated (given) to patients. “

People on dialysis wait their turn and managing the waiting list can be difficult.  My former employer tried to open their own renal transplant center in 2004, but closed the unit and paid a fine because they (allegedly) mismanaged the transfer of their patients records.

 There aren’t enough livers for everyone and the people on the liver transplant list who are closest to death get the first organ of available for a person with the same blood type.  There are rules that limit the use of organs for people who are addicts, alcoholics, or obese.  If someone’s BMI (body mass index) is too high they can’t be transplanted with a “brain death” liver.  One day I was asked to see a middle aged female who drove a fork lift in a warehouse.  She had never been sick before, was muscular and didn’t drink or have hepatitis; but her liver was full of fat and she had developed hepato-renal syndrome.  Her liver disease had caused her kidneys to stop working.  When renal failure is caused by liver failure, dialysis doesn’t work.  She was in trouble and needed a liver transplant.  I explained the problem to the patient.  She said O.K., and I called the transplant intake doctor at the university.  It was Friday afternoon, time to go home, and the woman’s BMI (weight) was too high.  The university doctor was sorry but he had to turn the patient down.   I explained that part of the weight was caused by fluid retention. Her dry weight BMI (body mass index) wasn’t too high.  “No can do”, the University physician explained.

I told the patient.  She cried.  Her sister who was in her room cried, and the sister offered to donate part of her liver.  The patient refused.  She was given infusions of a few drugs and for some reasons during the next few days her kidney function didn’t get worse or better.  I visited her each day and we talked.  When Friday arrived she was still alive, and on a whim I called the hepatologist on call at the university.  There’s a group of liver specialists who accept or refuse referrals.  Each doctor is on call for a week; then a new physician takes over.  I explained the situation to the new intake doctor and she said “no problem.  Send her over.”  The nurse called an ambulance.  The woman got a new liver and she did well. 

When someone “dies” and donates their organs teams of doctors come to their hospital.  Livers and kidneys are removed without dissection, without traumatizing blood vessels. The organs are cooled, and transported (sometime by plane or helicopter) to a hospital where surgeons and recipients are waiting.   

Once outside the body “The heart is most sensitive to lack of blood flow, “and needs to be planted in a body within 4 hours.   Lungs, with appropriate cooling “remain viable for 6 to 8 hours”, livers 12 hours and kidneys 24 to 36 hours. 

A few years back our former neighbor’s son, learning he was a “match”, decided to donate half his liver to an uncle he didn’t know that well.  His mother was a mess.  Donors are screened.  They must be young and healthy.  But the operation is tricky.  The liver has a large and a small lobe.  The small lobe is adequate for a small child whose liver isn’t working.  An adult needs part of the large lobe.  The liver has to be “split” and a significant amount of tissue has to be removed.  Over time some liver will grow back, but it takes months.  If too much of the organ is removed the donor is in trouble.  There are occasional complications, mainly bile leaks.  And one in 200 donors dies.  There are only a few centers in the country that do at least 100 living donor liver transplants a year.  The young man’s mother is pretty cool; she has a strong social conscience.  But this was hard.  Bottom line: he donated, and survived.  And mother and son are doing well.²⁵

• In the U.S. in 2019: 23,401 kidneys were transplanted as well as
• 8896 livers, 3551 hearts,  and 2714 lungs
• 11,900 of the donors were brain or heart dead.         
• 7397 of the organs came from living donors.      
• In 2019 over 112,000 Americans were on one of many transplant lists and “The wait for a deceased donor was often 5 or more years.²⁵”

1. Additionally:  Once a virus infects a cell, it uses the unit’s protein-synthesis machinery to synthesize more viral proteins. Some of the new creations are degraded into peptide fragments that either exit the cell or are bound to intracellular MHC molecules.  Viral—MHC complexes then move to the surface of the infected cell where they are recognized by roving T cells that induce cell death, by releasing cytotoxic granules.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997009/

1. Scientists have divided the cytokines– mostly small proteins –into five families.  (chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor.)
2. https://www.ncbi.nlm.nih.gov/books/NBK26921/
3. Vilcek Jan, Love and science. 7 stories press.  2016.
4. http://grantome.com/grant/NIH/R35-CA049731-02
5. https://www.biopharma-reporter.com/Article/2017/05/31/Janssen-At-least-5-more-years-of-multi-billion-dollar-Remicade-sales
6. https://www.investors.com/news/technology/abbvie-stock-abbvie-earnings-humira-sales/
7. http://www.gabionline.net/Pharma-News/AbbVie-signs-another-licensing-deal-for-adalimumab-biosimilar
8. https://www.sciencedirect.com/science/article/pii/S0149291817307312https://ycharts.com/analysis/story/the_arthritis_drugmaker_to_watch
9. Thomas E. Starzl.  The Puzzle People.  University of Pittsburg Press.  1991. page 208.
10. http://www.sciencedirect.com/sdfe/pdf/download/eid/1-s2.0-S0269915X98801006/first-page- pdfhttp://www.discoveriesinmedicine.com/Com-En/Cyclosporine.html#ixzz4ocaXJCDC
11. https://www.nytimes.com/1994/04/13/us/government-approves-new-drug-to-assist-in-liver-transplants.html
12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520417
13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2991087/
14. http://timesofindia.indiatimes.com/life-style/health-fitness/health-news/Anti-rejection-drug-prices-cut-by-65/articleshow/52320897.cms
15. http://www.renalandurologynews.com/american-transplant-congress/immunosuppressive-drug-costs-decline-but-still-expensive/article/293973/
16. The Search for Anti-Inflammatory Drugspp 27-63| The History of the Discovery and Development of Cyclosporine (Sandimmune®) by J. F. Borel et.al https://link.springer.com/book/10.1007%2F978-1-4615-9846-6
17. The Search for Anti-Inflammatory Drugspp 65-104     Discovery and Development of FK506 (Tacrolimus), A Potent Immunosuppressant of Microbial Origin by Michihisa Nishiyama, Shizue Izumi;Masakuni Okuhara https://link.springer.com/chapter/10.1007/978-1-4615-9846-6_3
18. http://www.discoveriesinmedicine.com/Com-En/Cyclosporine.html
19. https://web.archive.org/web/20110604225608/http://depts.washington.edu/uweek/archives/1998.08.AUG_20/_article14.html
20. 190-192  The Puzzle People, by Thomas Starzl; University of Pittsburg Press, 1992.
21. https://www.washingtonpost.com/archive/lifestyle/wellness/1988/11/15/jean-francois-borels-transplanted-dream/f3a931b9-e1a1-4724-9f08-a85ec4d3e68f/
22. https://med.stanford.edu/news/all-news/2018/01/50-years-ago-stanford-heart-doctors-made-history.html
23.  
24. Wikipedia
25. http://www.lkdn.org/kidney_tx_waiting_list.html
26. NY Times March 4, 1995 https://timesmachine.nytimes.com/timesmachine/1995/03/04/881995.html?pageNumber=26
    27. Monoclonal antibodies to IL-17 play a role in the joint pain and skin changes of psoriatic arthritis, and a number of other conditions.  Toclizumab and other IL-6 inhibitors are sometimes used in people with rheumatoid arthritis or Still’s disease –“an inflammatory disorder that can be chronic and is characterized by fever, arthritis and rash.^23″

• The infusions are a source of relief—Pharma income– and personal and/or insurance expense.   
• The annual expenditure for infliximab (anti-TNF) runs close to $45,000. 
• Toclizumab IL-6 infusions go for over $36,000 a year. ——————-(Both according to a “model”— based on drug and infusion cost per patient, per year— The other infusions modeled were in a similar price range.)  They all have risks and potentially serious side effects.  No one knows whether or not they are fairly priced.  Like diabetes, HIV, chronic myelocytic anemia–and many other ailments of man, our treatments don’t cure.  But they do turn a number of the illnesses into chronic controllable conditions.⁹
• https://www.cancer.gov/publications/dictionaries/cancer-terms/def/macrophage
• Coleys and TNF 
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732748/
•   millstein: https://www.whatisbiotechnology.org/index.php/exhibitions/milstein/monoclonals/The-making-of-monoclonal-antibodies

31.tnf http://www.vib.be/en/news/Pages/Tumor-Necrosis-Factor-Discovered-Years-Ago.aspx

32. coley https://www.brmi.online/william-bradley-coley
33. cytokine storm https://www.sciencedirect.com/science/article/pii/S1359610120300927

 

A note on sources:   In his bestselling book The Great Crash of 1929, economist John Galbraith noted “everyone needs to know on occasion the credentials of a fact.” At the same time “there is a line between adequacy and pedantry.” 

I started medical school in 1958, was a medical practitioner for forty years, and started researching this book when I retired in 2010.  During the last ten years I browsed hundreds of articles and magazines. Most of my sources are available on the web.  A number can only be found in the books listed below or in subscription-only websites. 

To avoid plagiarism I tried to put quotation marks when I used an authors exact words.  I did not specifically footnote the quotations or the data, but my sources are all listed in the bibliography on my website:  www.savingobamacare.com

Most web references are listed by chapter and are in URL form.  Click the link and go directly to the source of the information– or copy the URL, and paste it in your computer’s browser.  Some of the particulars come from one of the books listed below or was gleaned from subscription only web sites like:  UpToDate, the New England Journal of Medicine, the New York Times and the New Yorker.  In addition to the main bibliography, sources are listed at the end of most of the web chapters.  These sections are earlier, expanded, or newer versions of a segment in the book. 

Selected Bibliography

I gained knowledge from the following books:

Angell, Marcia. The Truth About the Drug Companies. Random House, 2005.

Alvord, Lori. The Scalpel and the Silver Bear. Bantam, 1999.

Barnard, Christiaan & Curtis Bill Pepper. One Life. Macmillan Company, 1969.

Blumberg, Baruch. Hepatitis B. Princeton University Press, 2002.

Breecher, Charles & Sheila Spezio. Privatization & Public Hospitals. 20th                CenturyFund Report, 1995.

Cohen, Jon. Shots in the Dark. Norton, 2011.

Covert, Norman. Cutting Edge. Self-published, 1997.

Doudna, Jennifer & Samuel Sternberg. A Crack in Creation. First Mariner Books,2018.

Eban, Katherine. Bottle of Lies. Harper Collins, 2019.

Ferrara, Napoleone. Angiogenesis. Taylor and Francis, 2007.

Fredman, Steven. Troubled Health Dollar. Virtual Bookworm, 2012.

Fredman, Steven & Robert Burger. Forbidden Cures. Stein and Day, 1976.

Gawande, Atul. Better. Metropolitan Books, 2007.

Gawande, Atul. Complications. Metropolitan Books, 2002.

Hawthorne, Fran. The Merck Juggernaut. John Wiley, 2003.

Hughes, Sally Smith. Genentech. University of Chicago Press, 2011.

Kocher, Theodor. Text-Book of Operative Surgery. Adam and Charles Black, 1895.

Lindorff, Dave. The Rise of the For-Profit Hospital Chains. Bantam Books, 1992.

Loeck, Renilde. Cold War Triangle. Leuven University Press, 2017.

Miller, Wayne. King of Hearts. Random House, 2000.

Mueller, C. Barber. Evarts A. Graham. BC Decker, 2002.

Mukherjee, Siddhartha. The Emperor of All Maladies. Scribner, 2010.

Offit, Paul. Vaccinated. Harper Collins, 2007.

Pearl, Robert. Mistreated. Public Affairs, 2017.

Potter, Wendell. Deadly Spin. Bloomsbury Press, 2010.

Rosenberg, Steven. The Transformed Cell. Putnam, 1992.

Rosenthal, Elisabeth. An American Sickness. Penguin Books, 2017.

Silverman, Milton, and Lee Phillip. Pills, Profits, and Politics. University of California          Press, 1974.

Starzl, Thomas. The Puzzle People. University of Pittsburgh Press, 1992.

Thomas, Lewis. Lives of a Cell. Bantam, 1974.

Vilcek, Jan. Love and Science. Seven Stories Press, 2016.

Wapner, Jessica. The Philadelphia Chromosome. The Experiment, 2013.

Ward, Thomas. Black Physicians in the Jim Crow South. University of Arkansas Press,      2003.

Werth, Barry. The Antidote. Simon and Schuster, 2014.

Werth, Barry. The Billion-Dollar Molecule. Simon and Schuster, 1994.

Additional major sources of information:

“Fire in the blood.” a documentary movie about HIV by Dylan Mohan Gray

“Hillary” Hulu documentary

“Obama’s Deal”—Frontline documentary on the passage of Obamacare

CSPAN broadcast of Feb. 26 2019 house of representative committee hearing on prescription drug pricing

Correspondence with RoseAnn DeMoro-leader of the California Nurses Association

 

GAME CHANGERS

In 1900, 76 million people lived in the U.S., 200,000 miles of railroad tracks crisscrossed the continent, and people traveled in horse drawn carriages and wagons on narrow dirt and gravel roads.  Trains dominated commerce, the modern internal combustion engine was 15 years old and 1575 electric and 900 gasoline powered vehicles were produced each year.

Electricity was new and scarce.  Thomas Edison’s incandescent light bulb was 20 years old and an American city, Cleveland had started using electric lamps to illuminate some of its streets.    

By the turn of the century sixty seven years had passed since drinking water was first pumped into the White House from a nearby reservoir; Chicago’s “comprehensive sewer system” had been up and running for 15 years, and a revolutionary toilet made by Thomas Crapper’s was 9 years old.⁸

My wife had two uncles who died in the 1930s from a strep throat, an infection that’s currently rapidly cured with a few doses of an antibiotic. A family member who had a severe asthma attack and who was getting exhausted responded to medications and didn’t need to be intubated and placed on a breathing machine. Another who was stung by a bee and developed anaphylactic shock was treated aggressively and was well enough to go home the next day.  Either relative could have died a century ago.

As recently as sixty years back, people with new myocardial infarctions were treated with “quiet and rest”.  Nowadays a heart attack victim who doesn’t instantly die can call 911 and be rushed to a hospital where a cardiologist and team are waiting to stent open an occluded artery. 

The 20^th and 21^st centuries were filled with transformative medical advances and I chose a few that I think were game changers. 

1.  Anesthesia, the first “game changer” got its start in 1846.  A monument in the Boston Public Garden commemorates the day that William Morton proved to the world that “the inhalation of ether causes insensibility to pain.”
2.  Early in the 20^th century we learned how to collect, store, and “safely” transfuse blood. 
3. In the 1940s, during and after the Second World War, Penicillin and antibiotics became available.  They revolutionized our ability to fight bacterial infections. 

4. The planet wide eradication of smallpox wasn’t the result of a new drug.  It was the consequence of the expansive use of the century old vaccine that prevented people from developing the infection.  A viral disease that plagued the human race for at least 10 centuries, Smallpox caused high fevers, severe headaches, vomiting, exhaustion, and a papular rash.  It killed as many as three in 10 of those who were afflicted, and the people who survived were sometimes permanently scarred.  George Washington got the disease when he was19 and was visiting Barbados.  He was sick for a month and the disease left him with lifelong facial pock-marks.⁹ 

In1853 and 1867 the British Parliament made vaccination with modified cowpox compulsory. Much as cats and tigers are members of the same species, the viruses that cause cowpox and small pox are members of the same family.  Each can cause pustular lesions. People who develop cowpox sometimes run a fever and are sick for a week.  When a person recovers (or is vaccinated) their body is protected from the oft lethal disease.

Widespread vaccination in the U.S. contained the illness in the early 19^th century.  Then people in the U.S. stopped vaccinating.  There were outbreaks, and states attempted to enforce existing vaccination laws or pass new ones.  The disease disappeared from North America in 1952 and from Europe in 1953.  As recently as 1967 (according to the CDC) 10 to 15 million people in Africa, Asia, Indonesia, and Brazil contracted Smallpox each year. That year 2 million died, many were scarred for life, and the World Health Organization started a program of worldwide vaccinations.  They hoped to eliminate the terrible disease and seem to have succeeded.  The bug’s last known “natural” victim was infected in 1977.⁵ 

Game changer 5:  We learned and are learning how to prevent our immune system from destroying transplanted kidneys, livers, and hearts.  We’re stopping our protectors from attacking our joints (rheumatoid arthritis), intestines (colitis) and our nerve fibers and the myelin that surrounds them. (Multiple sclerosis.) And we’re increasingly, using antibodies and T-lymphocytes to attack and destroy cancer cells.

6.  Controlling HIV:  A once uniformly lethal infection has been turned into a controllable, chronic disease in parts, but not the entire world. 

 7. Gene therapy:  CRISPR and other gene “editing” techniques are up and running.  Scientists using them are on the verge of curing a number of inherited and genetic disorders like hemophilia and sickle cell disease.

8. In 2010 the Bill and Melinda Gates foundation started spending $5 billion a year and using the vast resources of Microsoft to help rid the planets poor and impoverished of many of the diseases that diminish and shorten their lives. 

1.  https://www.nejm.org/do/10.1056/NEJMdo005602/full/  
3. The Troubled Health Dollar by Steve Fredman. Virtualbookworm press 2015.
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1123944/
5.  https://www.cdc.gov/smallpox/history/history.html
6. https://www.businessinsider.com/bill-gates-foundation-helps-invent-tiger-toilets-powered-by-worms-2019-1
7. https://www.gatesnotes.com/2018-Annual-Letter
8. “Inside Bill Gates Brain.”  Netflix
9. https://www.american-rails.com/1900s.html
10. ttps://featherfoster.wordpress.com/2018/04/30/george-washington-and-smallpox/
11. https://www.pbs.org/newshour/show/bill-gates-on-outlook-for-a-covid-19-vaccine-and-where-pandemic-will-hurt-most

History of Cars – The Early 1900s Cars

History Of Plumbing Timeline: The Invention Of Indoor Plumbing

Immunotherapy and Willie Nelson

Discovery consists of seeing what everybody has seen, and thinking what nobody has thought. Albert Szent-Gyorgyi

That’s what Jim Allison had to deal with when he learned how to use the immune system to attack and sometimes cure metastatic cancer.  Allison was from a small town in Texas.  His father was a country physician and his mother died of lymphoma when he was still a boy.  Initially planning to follow in his father’s footsteps, he got interested in research as a high school student. In an interview he said that he was reluctant to become a physician because doctors have to be right almost all the time.  Researchers, on the other hand, develop hypotheses and test them.  If they aren’t wrong most of the time “they’re not on the edge.”  He wrote poetry, liked to read, loved country music and later in his career played harmonica on the stage with Willie Nelson.  At the University of Texas he studied biochemistry and earned a PhD.   After his post doc year he got a job in a small lab that the University of Texas/M.D. Anderson Cancer Center was operating in Smithville… close to Austin.⁶  

While in Texas he worked out the structure of the T cell antigen receptor and gained some notoriety.  T cells, one of the white blood cells that float in our blood, are part of the immune system.  They aren’t very good at recognizing abnormal proteins but they are efficient destroyers.  When a dendritic or other watchdog cell spots a virus it processes the “stranger” and “presents” it to the antigen receptor on the T lymphocyte. Then the T lymphocyte deals with it.  At one time early in Allison’s education he recalls a professor who doubted there was such a thing as a T cell.   After his “receptor” accomplishment Allison took a year sabbatical and became a professor at the University of California, Berkeley.

He considered himself an immunologist and his lab tried to work out the relationship between the T cell and cancer.  In animal studies T cells seemed to recognize and attack cancer cells.  They latched on and released a poison, a protein called CD28 that should have destroyed the malignant cell.  But the cancer somehow survived.

Another protein, CTLA-4, showed up after the CD28 was released.  What was it doing there?  A large pharmaceutical company had concluded it was another cell poison, and the company patented it as a poison.

Allison wasn’t so sure.  So he developed an antibody to CTLA-4 and one of his fellows gave it to a mouse with cancer.  A few days later the cancer was gone. The results surprised Allison.  Blocking a cancer poison should not have contributed to the death of the tumor.  

Allison asked his fellow to repeat the experiment.  Since it was Christmas, he went on vacation.  Allison manned the lab and watched the mouse as the tumors grew for a few days.  Then they faded away.  Allison immediately realized he might have something big, but he had to be sure.  His group injected antibody that blocked CTLA-4 into the bodies of many different strains of mice.  In the absence of CTLA-4 the poison produced by the T lymphocyte– the CD28– was able to destroy one tumor after another.

Allison realized his success meant our understanding of cancer and the immune system was wrong.  “The biology was backwards”.

T lymphocytes, he hypothesized, recognized cancer cells, and they latched on.  They injected a “poison” (CD-28) that should have killed the malignant cell.  But cancer cells made an “antidote” (CTLA-4).  It stopped the poison from working.   His antibody blocked the antidote and it ALLOWED the poison to keep killing the bad cells.  

Bristol Myers Squibb had patented CTLA-4.  Their patent claimed CTLA-4 was the poison not the antidote.  It was wrong—backwards.  But the company had a patent and lawyers and money.

Allison was a valued scientist.  His identification of the T cell antigen receptor was important.  People in the field respected him.  He was a full professor of Immunology at Cal Berkeley.  Bright ambitious students studied with him.

But he wasn’t an M.D.  His only interaction with sick people had occurred when he was a boy in a small Texas town.  He had gone on house calls with his father, the town doctor.

Allison wanted to try his antibody on patients, but he didn’t think he could take the next step without Pharma’s help.  He “spent almost two years going around and talking to a number of large and a few small biotech firms trying to interest them in his idea.  There was a lot of skepticism.  And the fact that Bristol Myers Squibb had a patent put people off.  They claimed the intellectual property was ‘dirty.’

Eventually a small firm, Medarex, decided to give his antibody a shot.  It was a big investment.  Niels Lonborg a scientist at GenPharm, a company that was purchased by Medarex (in 1997), had mice that had made fully human antibodies.   Lonborg created the antibody that later became the drug, Ipilimumab.

A trial of the drug on patients was arranged.  As Allison explained in an interview, he “was totally committed” to the endeavor.    He moved to New York, to be near Sloan Kettering Cancer Center “to make sure nobody hurt his baby– Nobody screwed up.”   He moved to be a nuisance.  The biology of Ipilimumab (the drugs generic name) was different than that of most cancer drugs.  “Usually you treat patients.  If the tumor grows in the face of treatment the drug is a failure.”  But in the treated mice the cancer grew for a while, then withered.  The tumor didn’t always regress but “there was overall survival.”

As shown in Breakthrough, a film that documented the subsequent struggle, his discovery came face to face with the people who ran big Pharma. Immunotherapy had failed in the past and to the conservative corporate money men Allison’s drug seemed like a long shot, not worth the risk.  The doctor coordinating the trials, Rachel Humphrey believed in the product and was it’s chief advocate.   When she faced the board she emphasized the drug’s effectiveness in one person.  Men yelled at her and she took it. 

A competitor, Pfizer, had an immunotherapy drug trial running at the same time.  They halted their effort when the tumors in their patients they treated didn’t shrink 30 percent in 12 weeks.  That was the FDA Standard. 

With Allison’s drug the tumors kept enlarging but the patient’s felt well.  Allison explained that’s how the drug works.  The T cell gets into the tumor and starts killing cancer cells.  It takes a long time before the tumor stops getting larger.  As the trial progressed some of the people who were treated, twent home.  When they were given a drug that hadn’t previously worked they got well.  The recent drug got the credit for the improvement.  Allison knew it wasn’t the recent medication,  it was the T cells that continued to methodically kill the tumor. 

Bristol Myers Squibb, his company eventually agreed to not use the number of people were alive at a year or two as an end point.  They agreed to see if there was an improvement in total survival.   After 3 years the patients who hadn’t received immunotherapy were all dead.  Over 20 percent of the people who received Allison’s drug were alive and well three, four, and later 5 years later.  The company couldn’t call it a cure.  You never know.  The cancer might come back.  But they stayed well.  The treatment sure acted like a cure. 

Allison went to New York in 2004 but the drug wasn’t approved by the FDA until 2011.  During the 7 years Allison lived in an apartment 3 blocks from the hospital.  He gained weight.  He knew the drug cured cancer and was frustrated by his need to keep explaining.  At times he became angry. On one occasion he went into a tirade.  He’d come so far and he was afraid they would conclude the drug failed.  He was single minded and obsessed.  His marriage fell apart.  Malinda, the woman he met when he was a collage student, the coed who always felt he was the only person she ever loved—the most amazing human she ever saw– left. 

In 1997 Medarex acquired GenPharm.  In 2009 Bristol-Myers Squibb paid Medarex $2.4 billion and the companies merged.   

Squibb charged $30,000 for an ipilimumab injection or $120,000 for a course of therapy.  During Ipilimumab’s first year on the market, Squibb sold $706 million worth; they took in $462 million through the first half of 2013.  And they thought they would sell $1.54 billion worth of the drug in 2018.

In 1992 a few Japanese scientists found another poison/antibody combination.  The antidotes were called PD-L1 and PD-1.  Drugs that block them were created by Pharma researchers, tested, approved by the FDA, and sell for about $150,000 a treatment.

In 2017 close to 1300 people with advanced melanoma were assessed 3 years post treatment.  They lived in 21 countries.  All had received a combination of two drugs nivolumab-plus-ipilimumab.  58% were alive and in 39% the disease had not progressed¹. 

In another study: 5 years after the trial was started, Dr. James Larkin of the Royal Marsden in England and others assessed 300 plus people who had metastatic melanoma and who had been treated with two drugs that blocked the antidotes produced by melanoma cell.  Marsden reflected that “Historically, 5-year survival rates among patients with metastatic melanoma were dismal.”  The treatment had been hard on the bodies of the sufferers; only 58 percent seemed to have had a favorable response.  But 52 percent of the 300+ were alive at five years. The median progression-free survival was 11.5 months.  More than half the people treated, most of whom would have died without treatment, were still alive at 60 months.² Doctors evaluating new treatments for advanced cancer are reluctant to use the word cure.  It’s always possible that the tumor will, at some point, start growing again. 

In 2018 the PD-1 inhibor, nivolumab “showed a clinically meaningful survival benefit in some people who had advanced lung cancer.³

The clinical trials, hospital days, and advertising cost a lot of money and the companies that tweeked, developed and manufactured the drugs are working hard to recoup their outlay.  In 2015 Dr Saltz of Sloan Kettering estimated the price tag for the two drugs used to treat melanoma was about $300.000 per person, and the copay, the “out-of-pocket charge was usually $60,000.⁴” 

In 2018 Bristol-Myers Squibb sold $7.5 billion worth of Opdivo/nivolumab and Merck sold $7.1 billion worth of Keytruda/pembrolizumab

In 2018 Jim Allison was awarded the Nobel Prize

FROM A HISTORICAL POINT OF VIEW:  In our ongoing battle with Cancer scientists have:   

• Proven smoking and asbestos are provocative;   
• Learned how to use chemotherapy more effectively;   
• Created means of prevention– like the HPV vaccine for cervical cancer;   
• Produced detection tools: colonoscopy, pap smears, mammograms, prostate and breast biopsies;   
• Developed monoclonal antibodies,  small molecules, and hormone antagonizers that help control and destroy cancer cells; 
•  Hypothesized that our immune system probably eradicates most newly created malignant cells;   
• And have started to learn how to use our T lymphocytes and our immune systems to control some malignancies.

1. https://www.nejm.org/doi/full/10.1056/NEJMoa1709684
2. https://www.nejm.org/doi/full/10.1056/NEJMoa1910836
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681400/
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570079/ /
5. https://www.youtube.com/watch?v=yCi0bUDR7KA
6. https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/side-effects

1. https://www.cancer.gov/news-events/cancer-currents-blog/2017/yescarta-fda-lymphoma    https://www.haaretz.com/science-and-health/.premium.MAGAZINE-the-scientist-who-paved-the-way-for-a-chimeric-cancer-therapy-1.5463978   https://www.nejm.org/doi/full/10.1056/NEJMp1711886

Your tax and donated dollars at work

This chapter takes issue with the Pharmaceutical manufacturer’s claim that they charge astronomically high prices for new drugs because research is costly–that they need high profits if they are going to continue to play an important role in the development of the medical miracles of the future.

It tells the story of two recently marketed medications that improve the lives of people with metastatic prostate cancer.  Each drug was created with dollars (and pounds) supplied by taxpayers and charitable institutions.

The research labs of big Pharma were not part of the process– though Pharma did pay for most of the studies run on humans, and they did manufacture, distribute, and promote the medications, both of which have huge price tags.

I got interested in the medications after I spoke with a young man while our launch was speeding through the dark waters of the Grand Canal of Venice.  He finally, he explained, had enough money to bring his wife and child to Europe, thanks to a bonus he received.  He had recently acquired the rights to a new drug for the pharmaceutical company he worked for.  Called Enzutamide it was a treatment for prostate cancer and it was going to be big.

Prostate cancer, one of the western world’s common lethal malignancies, was found in almost a quarter of a million American prostates last year, and it killed 33,000.  When advanced and widespread the disease is incurable, and if it grows in bones it can be quite painful.

Located between the bladder and the penis, a young man’s prostate is the size of a walnut.  It grows as men age and eventually becomes large enough to slow or obstruct the flow of urine.  Now and then a mutated cell reproduces more rapidly, lives longer, and its offspring form a cluster.  Over time there are additional mutations.  One of the abnormal cells can become cancerous, clone itself, and spread to other parts of the body.  Its growth and spread can be slowed or halted for a period of time by interfering with the hormone that fans the fire, by eliminating testosterone.

We’ve long known that male hormones encourage prostate cancer cells to grow faster, and that surgical castration is therapeutic.  The role of male hormones was firmly established in the 1940’s when  University of Chicago physician, Charles Huggins, showed that metastatic prostate cancer could be controlled for a few years with surgical castration or female hormones.  During the subsequent decades orchiectomy– removing the testicles—commonly kept the cancer from growing for a period of time–after which the malignancy typically started expanding.

In recent years physicians have fought the malignancy with drugs that antagonize testosterone.  When the medications stop working and the disease becomes aggressive, the growth is usually stimulated by a protein inside the cancer cells, a molecule called the androgen receptor (AR).

And that’s what researchers at UCLA and Sloan Kettering tried to neutralize.  Funded by the government and people who donate money to prostate cancer research, the medical teams spent years developing a drug that could block the cancer cell’s androgen receptor (AR).  Starting with a protein that was known to have “a high affinity for the receptor, they spent years chemically altering it.” (Like– take a dress pattern and add one pocket or two pockets; a zipper or buttons.)  They added carbons, hydrogens, etc, came up with 200 candidate molecules.  They tested them in the lab, using “human prostate cancer cells that had been engineered to express increased levels of the receptor.”

Two of the 200 potential drugs seemed promising.  Well absorbed and not toxic, they were effective blockers.  UCLA patented the chemicals in 2006 and tested them on mice.  They worked, –stopped mouse prostate cancer from growing and spreading.

In 2005 Medivation, a San Francisco based “Biopharmaceutical Company” somehow learned about the drug.  Signing a license with UCLA they walked away with a majority of the patent rights.  In return they agreed to fund all costs associated with the development and commercialization of MCV3100 (Enzalutamide).

The next big study was probably not funded by Medivation.  It was performed in 2009 by the U.S. department of defense, and it showed that MCV3100 had “significant antitumor activity.”

In October of 2009 Medivation got a partner.  They made a deal with Astellas, a large Japanese pharmaceutical company.  Medivation received $655 million and Astellas, got global rights” to the drug.  The two companies then financed a huge international assessment:  1600 men with metastatic disease got either the drug or a placebo.  The men who took Enzalutamide on average lived 5 months longer than those receiving placebo.  Treated patients had “a 37% reduction in the risk of death.”

FDA approved the use of Enzalutamide in men who had failed standard chemotherapy.  The initial planned price of Enzalutamide was $7450 a month— $59,000 for 8 cycles — $89,000 a year.

In 2014, based on a new study, the FDA approved the use of Enzalutamide as the first drug given to people with metastatic disease.  Patients didn’t have to first fail treatment with something else.  The new indication meant patients would live longer after they started therapy.  They would now ingest more pills and buy more medicine.  A year of therapy in the U.S. would cost $129,000.

Astellas had international rights and sold the medicine for a lot less in other countries.  A 40 mg pill, for example, was sold in the U.S. for $88.  Medicare paid $69.  And the price for the same product in Canada, France, and the U.K, was $20, $27, and $36.  In the two years between 2012 an 2014, Medicare’s Enzalutamide cost went from $35 million to over $440 million annually.  The price Americans paid troubled some.  There were editorials and the obligatory belt-way outcry.

UCLA owned over 40 percent of the drug’s patent, and in 2016 sold their residual rights to Royalty Pharma for $1.14 billion—paid over many years.  They then settled for an up-front cash payment of $520 million.

In 2015 Astellas sold $2.2 billion of the drug.  The following year Pfizer bought Medivation for $14 billion, and in the first quarter of 2017 sold $131 million worth of the medication.

In the West it seems you almost have to get industry involved if you want to get a drug tested, approved, produced, distributed, and used.  Not that UCLA and Sloan Kettering didn’t know how to run a controlled trial.  They did.  But pharmaceutical companies have big bucks and are better equipped to coordinate the testing of over a thousand people in 15 countries.  They are experienced at moving drugs through the FDA and getting them approved promptly and efficiently.  And, of course, they know how to market.

Once corporations are involved, the price being charged has little to do with the cost of creating a drug.  In the case of Enzalutamide, before they could make a profit Pfizer had to sell enough high priced medication to recover their $14 billion investment.

In the Enzalutamide case many were happy.  UCLA got an infusion of cash.  The poor guy with prostate cancer got an extra 5 months of life, and according to Astellas, he didn’t have to go into bankruptcy to be treated.    ”80% of patients with Medicare or private insurance have a monthly co-payment of $25 or less. 2,000 men with poor or no insurance and household incomes of $100,000 or less received Xtandi free.”

The system we’ve created is not really “capitalism” and it’s not fair to call it “corporate welfare”.  It allowed the lead researchers to claim a”37.5% stake in the drug’s royalty interest.”  Private industry, investors, the Howard Hughes Foundation, and Medivation made money. 

Few seemed  troubled by the fact that a drug developed with public and donated money ended up enriching a few and selling for a pretty penny—a price that was usually paid by a needy taxpayer’s private or public insurance.

Bernie Sanders claims that in 2014 nearly one in five Americans between the ages of 19 and 64–35 million people – decided to NOT fill their prescriptions.  They decided the drugs cost too much. 

At the same time spokesmen for the pharmaceutical industry were repeating their mantra:  the high costs are needed to support medical research.   If we want to cure Alzheimer’s and cancer we need Innovation.

Enzalutamide’s chief competitor, Arbiraterone (Zytiga), was created at Cancer Research UK, a charitable fund with its own research institute.  In 2012 an anonymous donor gave the organization ten million pounds, (13 million dollars) and asserted that “if you do what you’ve always done, you’ll get what you’ve always got.” Promoting scientists who “think differently,” the huge concern finances “the work of more than 4,000 researchers, doctors and nurses throughout the UK, and supports over 200 clinical trials and cancer related studies.”  The drug its scientists created, Arbiraterone (Zytiga), is a bit cheaper than the U.S creation, but for years it was pricey and not really affordable to a guy without good insurance.

Here again Pharma wasn’t brought in until the medication was created and was ready to be tested on humans.  And once more the enemy was testosterone. Researchers wondered if the cells had lost their dependence on male hormones—or if they were responding to testosterone made somewhere in the body.   What would happen, they asked, if a drug totally impeded a person’s ability to make male hormones–androgens?

The body makes male hormones and cortisone from cholesterol.  (Raisins and wine are made from grapes.)  Both use an enzyme, CPY17, for the conversion, and the reaction can be blocked by the antifungal agent, Ketoconazole.  All this was known.

Ketoconazole is toxic and in patients with prostate cancer it’s not a useful drug; so investigators decided to modify it.   Using three dimensional models an Institute of Cancer Research (IRC) team (working in a unit of Cancer Research UK) studied a number of compounds, and they eventually found one that worked.  It didn’t seem to be toxic and it “specifically and irreversibly” blocked CYP17.

The “team” filed a patent and licensed the drug to a German Pharma company, Boehringer Ingleman.  Phase one studies showed the drug blocked androgen and cortisone production in people, but the pharmaceutical company’s scientists believed that late stage prostate cancer no longer needed male hormones to grow.  Feeling they didn’t want to spend money on a lost cause, Boehringer returned the drug’s license and IRC started over.¹

Arguing that they wanted to get the drug into needy people’s hands as soon as possible, the IRC next assigned the rights for commercialization to publically traded BTG, a UK-based healthcare company.  BTG, in turn, licensed the product to Cougar Biotechnology.  And Cougar “began to develop a commercial product”.  Studies proved the drug worked, helped cancer patients.  In May 2009 Cougar was acquired by Johnson and Johnson for about $1 billion.  Two years later the FDA approved arbiraterone’s use in combination with prednisone—a form of cortisone. (In addition to blocking the body’s production of androgens, Arbiraterone blocks the body’s ability to produce cortisone, a hormone the body needs.)  Arbiraterone was approved for use as a treatment for late-stage prostate cancer in men who have already received standard chemotherapy.  Called Zytiga, it initially sold for $5000 a month in the U.S., and it’s not a cure.  After a mean of 8 months the drug stops working or the average patient has died.  Thus the cost of treating a person was averaging about $40,000.

In the UK where it was developed by a charitably funded organization, the drug is marketed by Janssen.  Its original cost was 2930 pounds –$3820 a month, a price that British regulators (NICE) decided was not cost effective.  The National Health Service wouldn’t pay.  The company then negotiated.  The government was willing to walk away so negotiations worked.  The U.K. got a “deal.”  The NHS subsequently paid 2300 pounds ($3000) a month “for the first 10 months of therapy.  For people who remain on treatment for more than 10 months, Janssen agreed to rebate the drug cost of abiraterone from the 11th month until the end of treatment.”

By 2019 two additional very expensive drugs for prostate cancer:  apalutamide and darolutamide—had joined the fray, and the U.S. price of “full-dose abiraterone” had risen to $10,000 per month.  But a $2800 monthly generic form of the medication was now available; and a quarter of the initial dose of arbiraterone was showing “similar benefits and similar pharmacokinetic and pharmacodynamic effects.²”

 “A decade ago cancer drugs cost around $5000 per month; that has now doubled to more than $10,000 per month.  I think (companies) charge what they think they can get away with, which goes up every year,” Peter Bach, MD, Sloan Kettering, New York. 

—-Is a pharmaceutical company really needed when we want to effectively manufacture and distribute an important drug?  The answer seems to be yes.

https://www.icr.ac.uk/news-features/latest-features/abiraterone-a-story-of-scientific-innovation-and-commercial-partnership

https://www.nejm.org/doi/full/10.1056/NEJMe1906363