Author: stevefredman

 

“If you prick me do I not bleed?” —Shakespeare

The notion that blood circulates and that it can be transfused was “based” on the observations of a Brit named William Harvey. In the 1600s he cut open a few living fish and snakes, and learned (and wrote) that the ancients were wrong.  Blood didn’t come from the liver and slowly ebb through the body.  Its flow was “propelled by the heart” and the red stuff traveled through tubes called arteries.  In the 1800s a few doctors used a syringe to remove blood from one person and directly inject it into the vein of another.¹ It helped some and harmed others.

Before the 20th century, doctors rarely considered transfusing people who bled profusely. Blood solidifies when it is outside the body, and when fresh blood from one person’s veins was infused into the veins of another, it often caused fever, kidney failure, and death.

In a test tube, blood separates into two components. Red stuff, cells, occupy the bottom half of the tube, and clear fluid, serum, fills the top half. In the early 1900s, a Viennese immunologist named Karl Landsteiner mixed his red cells with the serum of others and noticed that some combinations clumped and others didn’t. He wrote a paper and in a footnote suggested there probably were several “types” of blood antigens. Then he and his students spent eight years working out the details. By 1909, they knew there were two populations of antigens on the surface of red cells and two populations of antibodies in the serum. They labeled them A and B and discovered that:

When red cells have B antigens on their surface, their serum contains antibodies that destroy “A” red cells.

When the cells have A antigens on their surface, their serum contains antibodies that break up B red cells.

When the exterior of red cells are not covered with A or B antigens, their serum has antibodies that break up both A and B red blood cells.

When red cells have both A and B antigens on their surface, their serum does not contain A or B antibodies.

During the next few years Landsteiner, a significant Austrian researcher, “discovered how to infect monkeys with the syphilis bacterium and he helped prove polio was an infectious disease,” but his blood group findings didn’t seem to have a practical application.

Karl was 6 when his father’s life ended and he was 40 when his mother died.  He was so devoted to her that he “had her death mask taken” and hung it on his wall for the rest of his life.  He married 8 years after her demise.    

In 1914, the rulers of the great European empires declared war, and 9 million young soldiers killed one another.

In 1917, the U.S. entered the Great War and Oswald Robertson, a doctor from Fresno, California, was sent to the front. He had learned about Landsteiner’s work on blood types and knew that a series of doctors  had recently discovered that when sodium citrate is added to blood it doesn’t clot.  While caring for wounded troops, he collected blood in glass bottles, added sodium citrate to keep it from solidifying, and stored the liquid in ice. During the war, he transfused hundreds of wounded soldiers. Near the end of the conflict, he was teaching doctors from other units how it was done.

After the war, Robertson became a pneumonia researcher in New York. In 1923, he helped develop a school of medicine in China. While there, he developed a bad case of typhus, and when he recovered he returned to the U.S. He continued to be a researcher for most of his life, but he apparently was never again interested in blood or transfusions. He spent the last years of his life working in a laboratory in California’s Santa Cruz Mountains where he studied the death of Pacific salmon.

During the two decades that followed the Great War, there were no blood banks and probably not many transfusions.

When the war ended Karl Landsteiner was living in Vienna. It had been the capital of the vast Austro-Hungarian Empire and was on the losing side of the First World War. The imperial lands were carved into many of the nations of modern-day Europe and there were shortages. That winter, Landsteiner’s laboratory wasn’t heated and a group of poor people “cut down the trees around his house for firewood and tore away his fences.” Feeling personally threatened, Landsteiner moved to Holland with his wife and children. During the next three years, he performed experiments and was assisted by a manservant and a nun who was “very devout and frequently quit the lab for prayers or to serve as an organist in the chapel.” A year or so later, Landsteiner accepted a position at the Rockefeller Institute and moved his family to New York City. On the ship that crossed the Atlantic, he told another passenger how much he loved living in the “little cottage with a rose garden” in the seaside town of Scheveningen, Holland. When he got to New York, he was surrounded by a new and different environment. He lived “on the floor above a butcher shop on a street with trolley cars.” Avoiding social activities, he spent his days in the lab, and read and thought at night “until the late hour.” In 1930, he received the Nobel Prize.  In 1937 Alexander Wiener added another red cell surface antigen, the RH (Rhesus factor), to his equation.

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The first blood bank was set up by in Russia in 1932. Doctors at Chicago’s Cook County Hospital are given the credit for opening the first American facility that, in 1937 started to “save and store” donated blood.  San Francisco’s Irwin Memorial blood bank started 3 years later.  

When blood, plus a chemical that prevents clotting is put in a test tube, the cells settle to the bottom and the plasma floats to the top.  For blood loss and significant anemia we transfuse packed red cells or erythrocytes. Each tiny disc lives for 120 days.  In transfused blood half the red cells are new and half old, so the average cell in a unit of blood should last 60 days. 

Just above the red cells in the test tube there’s a thin layer of white cells and a stratum of platelets.  Each lives but a few days.  Platelets are particles that plug holes and help stop bleeding.  When chemotherapy suppresses the bone marrow their levels can get extremely low. In special situations blood banks have machines that dialyze off platelets, and make them available for use in another’s body. Then the platelet poor blood is infused back into the donor. 

White cells are an important contributor to our defense against infection, but in transfused blood they can cause adverse reactions; as a result they aren’t collected and reused. The plasma contains proteins that, among other things, provide clotting factors. 

Before blood is dripped into a body the receiving patients are screened for antibodies in their plasma/serum that might react with transfused red cells. Some of the recipient’s serum is mixed with cells that are about to be transfused.  We need to make sure the cells won’t agglutinate, stick together.

In 1940, a year and a half before the U.S. became combatants in the Second World War, London was being bombarded by Nazi planes.  Many in the U.S. wanted to aid the wounded, and an effort to provide the cell free portion of the blood, the plasma, to the Brits was started in New York.  Called Blood for Britain, the organizers attempted to collect thousands of units of blood, separate the cells from the plasma, and under sterile conditions ship the fluid across the Atlantic.  It was a huge undertaking and Charles Drew, the man in charge had previously only organized a group of people once.  As a young man, he coordinated the paper routes of ten childhood friends who were delivering 2,000 newspapers a day. 

Drew, was a doctor.  When he was a trainee he studied the preservation of blood product, and he knew how to produce plasma that had a two month shelf life.  His doctoral thesis was titled “banked blood.”  Gathering, transporting and processing thousands of units of blood was a complex undertaking but he pulled it off and was able to send close to 15,000 pints of the precious fluid to the Brits.  An African American, Drew was born in Washington D.C. and was an outstanding high school athlete. He was Amherst universities’ most valuable football player in 1926, went to medical school at McGill University in Canada, and graduated in 1933. In 1941 he became the director of the first U.S. Red Cross blood bank.  He left after learning the organization labeled each unit of blood with the donor’s race and didn’t give the blood from a black donor to a white patient. He’s credited with saying “No official department of the Federal Government should willfully humiliate its citizens; there is no scientific basis for the practice; and people need the blood.”  Drew returned to Howard University and became the chief surgeon at Freedmen’s Hospital.⁷

By the time I entered med school (1958) blood drives had come to my campus annually, and I had been a donor twice.  The Red Cross proudly boasted that it saved the lives of wounded service men and women.  People who were hemorrhaging or very anemic often needed transfusions.   When I graduated in 1962 there were already 4400 hospital blood banks and 178 Red Cross and community facilities.  I never knew what medicine was like before transferable blood was readily available. 

In 1997 several San Francisco Bay area blood banks merged and called themselves Blood Centers of the Pacific.  The non -profit corporations collected huge amounts of blood (200,000 units a year) from willing voluntary donors.  They then checked it for blood type and for disease, fractionated the fluid into its various components, and sold– supplied it to more than 60 hospitals.  Their annual budget exceeded $40 million.

The blood supply is relatively safe, in part because of the outrage of an angry man.  In the 70s a California legislator named Paul Gann capped our property taxes.  That made him famous.   But the legislation that bears his name, the Gann Act, has nothing to do with property tax.  It deals with transfusions.   It seems that around 1982 Gann had heart surgery and was transfused.  5 years later he discovered he had HIV.  The blood he received came from someone who was infected with the AIDS virus.  Either the blood donor had not been adequately screened or the blood Gann received was not tested carefully enough.  Gann was furious and apparently felt:  “there oughta be a law.”  So he wrote one. 

Prior to elective surgery California doctors must tell patients that they can store their own blood and have it available should they require a transfusion.  Stock piling blood prior to planned surgery can be tedious and costly.  But it’s intuitively better to get your own blood back than it is to receive that of another.  It’s also the law, so if the patient wants it we do it.  The act also says people can refuse blood from the “bank” and, instead get it from a donor they designate.  The idea makes sense, but the blood from a friend or loved one is no longer safer than banked fluid. Before it’s given all blood must be tested for the usual suspects, and it’s logistically near impossible to collect, check, and process designated blood in an acute or urgent situation. 

Before Gann’s outrage some blood bank executives argued that if they looked at blood too carefully they would have to reject many donors, throw away too many units.  Doctors wouldn’t be able to treat the ill.  People would die.  After the Gann incident blood banks (which were pretty good at questioning people about risk factors) got serious about screening blood for HIV, HTLV, Hepatitis B, Hepatitis C, (and a few other illnesses such as mosquito born West Nile virus, Zika, Cytomegalovirus, Chagas, a parasitic disease whose normal habitat is Central and parts of South America, and Babesia, a parasite that is transmitted by ticks and is found in New England.)

We’re apparently NOT yet testing the 11 million units of blood Americans use each year for:  dengue, a viral disease transmitted by mosquitoes that’s common in the tropics, Chikungunya a viral illness found in Asia and Africa,  that is spread by mosquitoes and was the cause, between 2014 and 2016, of  fever and joint pain in 4000 American travelers, most of whom had recently visited a Caribbean island.⁵;  we’re also not checking the blood we transfuse for Hepaitis E, the most common type of acute hepatitis in India and parts of Asia.² 

Before 1996 blood banks identified viral diseases by checking for the presence or absence of specific antibodies in the serum.  When a virus invades a body, the immune system reacts and makes detectable antibodies.  It was believed that blood that did not contain certain antibodies should not be infectious.  To prove they were right blood banks participated in studies on people who were transfused with blood whose antibody levels had been tested.  2.3 million transfusions were given during the study period and people were subsequently evaluated to see if they remained disease free.  One in every 493,000 infused units caused HIV; Hepatitis C was seen after one in a hundred thousand transfusions; Hepatitis B one in 63,000, and HTLV one in 640,000 units.³ Screening was good but imperfect.  During the early weeks after a person is infected, the virus incubates and its number grow.  It takes a while before measurable antibodies develop.  So blood can be contagious when the antibody tests are negative. 

Over time PCR technology improved and we were able to directly detect and measure miniscule amounts of virus. (PCR is like a Xerox machine for DNA.  It allows technicians to make millions of copies of the original, to turn a tiny amount of material into a wad large enough to analyze and learn what we are dealing with.)   In 1999 blood banks started using the technique to screen all 66 million units of blood that were transfused.  Between 2006 and 2008, with PCR testing being used, the recipients of 3.5 million Units of blood were checked to see if they had been infected with any of three common chronic viral diseases.  One in 1.85 million units of blood that were free of “measurable” viral particles caused an HIV infection; one in 246,000 transmitted hepatitis C, and one in 410,000 gave the recipient Hepatitis B. We’re not perfect yet.⁴ 

While blood is donated freely, screening the donor, and acquiring, testing and distributing the red stuff is expensive.  A recent survey put the cost of a unit of transfused blood at $522 to $1,183.  In most hospitals much of the blood is used at the time of surgery.   Hospitals vary in size and in the numbers and the types of operations performed.  So it’s not surprising that, in the same survey, acquired blood cost $1.6 million to $6 million per hospital annually. 

                                                                          

1. http://www.animalresearch.info/en/medical-advances/timeline/blood-transfusion/
2. NEJM Sept 28, 2017 
3. N Engl J Med June 27, 1996 
4. N Engl J Med January 20, 2011
5. UPTODATE–Chikungunya
6. https://www.nobelprize.org/prizes/medicine/1930/landsteiner/biographical/
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651504/ https://en.wikipedia.org/wiki/Charles_R._Drew https://www.fda.gov/vaccines-blood-biologics/complete-list-donor-screening-assays-infectious-agents-and-hiv-diagnostic-assays#Multiplex%20Assays
8. https://royalsocietypublishing.org/doi/pdf/10.1098/rsbm.1947.0002

Blind as a bat– -Better than a poke in the eye—–

During the last one and one half centuries we’ve learned how to treat or correct most of the conditions that inhibit our ability to see.

One of them, Trachoma, has been a problem for mankind for thousands of years.  Hippocrates thought it made eyelids, look like cut ripe figs.  During the Napoleonic wars, it “raged” through the armies of Europe; and over the centuries it often occurred in clusters within villages or families.¹¹ Caused by a Chlamydia, a type of bacteria that lives and reproduces inside the cell of the host, it leads to scarring of eyelids, and causes eyelashes to damage the cornea.  Antibiotics kill the bug, but it tends to recur.⁹    The number of people who currently have “the late blinding stage of the disease dropped to 2.5 million in 2019.” 

The prevention of river blindness remains another work in progress. Found chiefly in parts of Africa, the condition is caused by a tiny parasite and is spread by black flies that “breed in fast flowing streams.” In the 1990s The African Programme for Onchocerciasis Control (APOC) successfully treated more than a million at risk people with the anti parasitic drug Ivermectin, and it made a significant difference. Globally, it is estimated that 18 million people are infected and 270,000 have been blinded by the condition.  It’s called onchocerciasis.⁶”

There’s little available data on infants who survive wars, droughts, suffer from malnutrition and develop a vitamin A deficiency.  The resulting dryness and scarring of the conjunctiva, the mucous membrane that coats the inside of the eyelids, can cause them to lose their ability to see.¹

The leading causes of blindness in this country are cataracts, glaucoma, macular degeneration, and diabetes.⁵

Cataracts:  To create a sharp image the eye like the microscope and the telescope needs two lenses. Cataracts occur when the eye’s inner lens becomes cloudy and opaque.  Most develop slowly as we age, though they are sometimes seen in children for a variety of reasons.  Worldwide they diminished vision in many and are the leading cause of blindness.   

A century ago when a person’s lens got so dense that they couldn’t see, the structure was surgically removed.  Afterwards a person could see light and little more unless they wore thick glasses.  No on liked wearing Mr. Magoo glasses, and everyone hated feeling helpless when they woke and couldn’t locate their spectacles.  I remember the days when people didn’t have cataract surgery until they were literally no longer able to see.  The lens removal operation is, apparently, still done in some countries.

Harold Ridley of England is the father of the implantable lens.  The son of a physician he spent his early doctoring days working on cruise ships.  During the Second World War he spent 18 months in Ghana.  Later in Burma, he provided care for former British prisoners of war who had nutritional amblyopia, lazy eye. At some point he treated members of the RAF whose airplanes were damaged by enemy fire and whose cornea’s, the front lens of the eye, had been penetrated by pieces of the plane’s windshield.  The acrylic plastic did not cause an inflammatory reaction. Years later, he was removing a cataract and he recalls one of his students remarked: “It’s a pity you can’t replace the cataract with a clear lens.” That got Ridley thinking.  He started crafting implants from the material that was used to make airplane cockpits and he implanted them into eyes after he removed an opaque lens.” “Sterilization of the lenses was a major problem and he was afraid to tell anyone.  Powerful colleagues had shown hostility to the idea of putting a foreign body in the eye.¹⁰There was a learning curve but Ridley and a pupil perfected the surgical technique and a company in East Sussex (Rayner) manufactured the implant.  In 1981 the FDA approved the use of implantable lenses in the U.S. and American eye surgeons adopted the approach.  It’s now part of the bread and butter of ophthalmology. 

The last 50 plus years have witnessed the development and modification of many replacement lenses.  By 2015, 9000 American ophthalmologists were replacing 3.6 million lenses a year.  Worldwide 20 million cataract surgeries are performed annually.²

In the U.S. most surgeons numb the eye, insert a small ultrasound probe, and phacoemulsify (liquify) the dense lens.  Then they suck out the debris, insert a small plastic or silicone lens, and if necessary, sew the incision shut.  My ophthalmologist at Kaiser Oakland told me she doesn’t specialize in cataract surgery.  The eyes she deals with often have additional problems.  So on her surgical half days she only performs 9 operations.  Each takes 6 to 14 minutes.  The complication rate for Canadian surgeons who performed 50 to 250 operations a year was 8 in a thousand.  It was one in a thousand for surgeons who replace a thousand cataracts a year.  In poorer countries phacoemulsification is less common.  Most Americans who need cataract surgery are of Medicare age and the government pays $2500 per eye.  Special lenses can cost an extra $1500 to $2500.  

In India, a land with over a billion inhabitants, cataract surgery took a giant step forward in 1983 when an American Doctor named David Green met a 58 year old eye surgeon named Govindappa Venkataswamy.  When they reconnected 5 years later the Indian physician had mortgaged his home, built an 11 bed hospital and was performing 5000 eye operations a year, 70 percent of them at no charge.  Given the need he was barely scratching the surface.  In the late 1990s it was estimated that 9.5 million people in India were blind as a result of cataracts and 3.8 million were losing their vision annually. The cost of implantable lenses, $100 to $150 per eye was too high for the average Indian. Green and the doctor established a nonprofit manufacturing plant in India and were able to produce an inexpensive quality lenses.  In 2016 the company they founded, Aurolab, manufactured 2.6 million intra ocular lenses, 10% of all produced in the world.  The majority of the lenses are “distributed to NGOs in India and in developing countries.” The company is profitable.
 In 1999 doctors in India performed 1.6 to 1.9 million surgeries in a single year and plans were made to increase the numbers of operations that would be carried out. By 2006 cataract surgery in India, Nepal, and Bangladesh was costing $20 and the lens sold for less than $5.³

Glaucoma:  Often caused by elevated pressures in the eye, Glaucoma is a number of conditions that damage the nerve that transmits images from the eye to the brain. The dramatic, painful eye of angle closure glaucoma is a medical emergency and can lead to visual loss. It occurs relatively infrequently. Open angle glaucoma, on the other hand is relatively common. Experts have learned a lot about the more usual condition, but we don’t know what causes it, and it’s no longer defined merely as a condition where the pressures inside the eye are too high–though they commonly are.  The middle of the eye produces a watery aqueous fluid.  It flows through the pupil, enters the space in the front of the eye, and exits through the spongy tissue that surrounds the edge of the cornea.  In people with the condition fluid is over produced or doesn’t drain normally. The retinal nerve layer thins. People lose peripheral vision and eventually can substantially lose much of their ability to see.

In the western world some ophthalmologists spend a year or more becoming glaucoma specialists.  They learn how to carry out and interpret tests, and when and how to perform one of many operations.  Sophisticated machines allow experts to photograph and follow the appearance of the layers of the retina, the nerve rich stratum that collects the focused light that our brain turns into images.  Gadgets that detect early loss of peripheral vision and that measure the pressure in the eye have entered the digital era. 

The drugs that control the pressure in the eye include beta blockers and prostaglandin inhibitors. Beta blockers cause the eye to produce less fluid and Prostaglandin inhibitors promote drainage. In 2004 when the FDA gave Pfizer the exclusive right to the prostaglandin inhibitor Xalatan, they sold $1.23 million worth of the drug.  Before a generic competitor entered the U.S. market, a month’s worth was costing $80 a month.  Pfizer manufactures and sells its products worldwide and has 43 manufacturing plants in: Ireland, Puerto Rico, the U.S., UK, Germany, Amboise, France; Ascoli, Italy; Belgium and Perth, Australia. 

According to the World Bank, “almost half the world’s population — 3.4 billion people — live on less than $5.50 a day.  For them eye drops aren’t an option. Laser surgery can increase the outflow of fluid.  If that doesn’t work an older operation called a “trabeculectomy”, removing a bit of the mesh network the fluid pours through, can create “a new drainage path.”  In 20 percent of the people who undergo surgery the openings stop working during the first year and two percent fail each year thereafter.¹⁵

Researchers checked the records of 113 Brits with open angle glaucoma who failed their last glaucoma appointment due to death.  They had been followed for 7 to 25 years.  During those years about half had undergone surgery for cataracts and 45% for glaucoma. “At final visit, vision was inadequate for driving in the UK in close to half. In 18%, this was due to glaucoma alone, while in 28.9%, other ocular pathologies contributed to poor vision.¹³”  

AMD, age related macular degeneration, is a major cause of vision loss as we get older.  Something goes wrong in the layer under the retina, and the macula, the part of the eye that provides sharp, central vision, is damaged or destroyed.  The so called “dry” form of the disease mainly affects white people who are 80 or older and we have no effective treatment.                

The less common “wet” form of the disease is sometimes helped by laser coagulation or photodynamic therapy and is commonly treated with Avastin, an antibody that “blocks” the growth of the new blood vessels.  When an ophthalmologist injects the medication into the eye of someone with wet macular degeneration, the disease process slows or turns off.  “Blindness is prevented in most patients, and the majority of treated patients go on to have some improvement in vision.”

Before using it the doctor evaluates the patient.  He or she discusses the risks of injecting the drug, and explains downsides like bleeding and retinal detachment.  On the appointed day the patient is brought to the procedure room and checked.  The edge of the eye is injected with a numbing agent.  A second needle is then passed into the inner cavity of the eye, a chamber full of a gelatinous material known as the vitreous.  The medication is injected and the pressure in the eye is raised for a brief period of time.  Vision is temporarily blurry.  After a period of observation the patient can go home. 

A law caps the amount a U.S. doctor can charge for an Avastin injection.  It can’t be more than 6% of the drug’s price.  The small amount needed to treat an eye had a cost of $50, so the fee Medicare paid for the injection and observation was capped at $3.

Avastin was FDA approved as a drug that slows the growth of cancer.  When the FDA approves a medication for one indication (cancer), the company that produces and markets it is not allowed to talk about other possible ways the drug can make a difference.  Doctors who read the medical literature and learn a drug helps an additional–different condition, do have the legal right to use it for that condition. The doctor does not have to wait for the drug company or the FDA to act.  In spite of the economics eye doctors were injecting Avastin into the eyes of people with wet macular degeneration.  In 2006 the FDA approved a biosimilar, Lucentis.¹⁷ It was an almost identical antibody that blocked the growth of blood vessels, was made by the same company as Avastin, and it worked as well.  In 2014 the company was selling it for over $2000 a month, and doctors who used it in their office were able to charge $180 for the visit and the injection.¹⁶

Refractory problem:  At some point in most of our lives we can’t see well because our eyes are unable to focus light on the layer of cells at the back of our eyeballs, the retina.  Some people are born with refractory errors.  Others find it increasingly difficult to read small print after they turn 40.  Wearable eye glasses have been used for many centuries. 

In the 1950s people started correcting their vision by placing a thin lens on the surface of their eye.  Contact lenses were initially small and had to be removed at night.

In 1965 Bausch and Lomb, bought the rights to contact lenses that were soft and were created in the kitchen of a Czech chemist.  Once they owned the product’s license the once American, currently Canadian company started a billion dollar industry.¹⁴

The man who developed the lens, Otto Wichterle, was a Czech dissident who was jailed by the Nazis in 1942.  In 1958 he lost his University job because he criticized the country’s Communist government.  Continuing his work on the kitchen table of his Prague apartment, he used an instrument made from a child’s building kit (similar to an erector set) and a phonograph motor, and he produced four hydrogel contact lenses.¹⁷  When he put them in his own eyes they were comfortable.  Ever a protester, Otto was expelled from the nation’s chemistry institute in 1970 because he supported Czechoslovakia’s attempt to become independent of Russia—the Prague Spring of 1968.  When the cold war ended Otto resumed his scientific activities.  In 1962 he patented his invention and produced an additional 5500 lenses.  At one point he met and learned to trust an American optometrist named Robert Morrison.  When he was harassed by patent attorneys Otto asked Morrison to come to Prague.  “Wichterle said, “Robert, I have decided that I must give patent rights to the gel to someone who can use them in the Western Hemisphere and, perhaps, in some other areas as well.¹⁸”   Ulitmately the US National Patent Development Corporation (NPDC) bought the American rights to the lenses from the Czechoslovak government for $330,000.  Then they sublicensed the patent to the Bausch and Lomb Corporation.  Wichterle was paid less than 1/10 of 1 % of the money, but he was now free to speak and travel and he had no regrets. 

In 1989 Gholam A. Peyman, an ophthalmologist and inventor patented Lasik, a laser and computer assisted device that allowed doctors to peel back a flap of the outer skin of the cornea, the front lens of the eye.  The inner corneal layer could then be altered with the beam of a laser, and eyes could focus better.  At the end of the procedure the flap was replaced.  The inventor, Dr. Peyman, was born in Shiraz Iran and went to medical school in Germany.  He’s a constant innovator and has held more than 100 patents.  In 2010 it was estimated that 8 million Americans have undergone the Lasik procedure at a cost of about $2000 per year.

Finally, no sooner is one problem solved than a new one develops.  In a country where the incidence of obesity is increasing as a result of our high caloric diets and diminished activity, more and more individuals become diabetic.  People with longstanding diabetes develop a number of eye problems and can go blind. 

By 2010 close to 7 billion people lived on earth and about 32 million, one in 200 were blind.  An additional 191 million, one in 40, were visually impaired. 

Blood sugars usually have to be elevated for ten to 15 years before blood vessels on the surface of the retina become permeable and weepy and the amount of oxygen that reaches the cells of the eye decreases.  New vessels, signaled by VEGF, grow and impair eyesight.  “Left untreated, nearly half of eyes that develop proliferative diabetic retinopathy will have profound vision loss.”

Lasers are used to destroy the blood vessels that are overgrowing, and the antibodies that block VEGF, the hormone that encourages new blood vessel growth, are injected into eyes.  In 2020, the Medicare paid $1000 to $1800 a session for the VEGF inhibitors that were FDA approved for use in the eye. 

REFERENCES:

In 2019, according to the NIH, the most common causes of blindness are:  Cataracts (51%); Glaucoma (8%);Age-related macular degeneration (5%);Corneal opacification (4%); Childhood blindness (4%; Refractive errors (3%); Trachoma (3%); Diabetic retinopathy (1%)  https://www.ncbi.nlm.nih.gov/books/NBK448182/ 

https://www.who.int/news-room/fact-sheets/detail/trachoma

Trachoma, is it history by H.R. Taylor  https://www.nature.com/articles/eye2008432https://www.who.int/news-room/detail/27-06-2019-eliminating-trachoma-who-announces-sustained-progress-with-hundreds-of-millions-of-people-no-longer-at-risk-of-infection

 https://www.who.int/apoc/onchocerciasis/en/ http://sped.wikidot.com/malnutrition-a-cause-for-visual-impairment

CATARACTS:  Harold Ridley and the intraocular lens     https://rayner.com/wp-content/uploads/2019/02/Invention_of_the_IOL.pdf  https://www.reviewofophthalmology.com/article/thoughts-on–cataract-surgery-2015

https://www.seva.org/site/SPageServer/;jsessionid=00000000.app272a?NONCE_TOKEN=D331A52171C42E9234E1E43A336A29B0&pagename=25_Years_of_Aurolab       https://www.mitpressjournals.org/doi/pdf/10.1162/itgg.2006.1.3.25 

RIVER BLINDNESS  (PAHO-Pan American Health Organization.)  (see: setting the price–Ivermectin)

MACULAR DEGENERATION  https://www.jci.org/articles/view/77540 A Conversation with Napoleone Ferrara

diabetic retinopathy  NEJM 2011;365:1520-6

https://www.nejm.org/doi/exam/10.1056/NEJMcme1909637?ef=article

phttps://www.cbsnews.com/news/nearly-half-the-planets-population-lives-on-less-than-5-50-a-day-worlf-bank-reports/ (half the planets population lives on $5.50 or less a day)

 Glaucoma  https://www.nature.com/articles/6702284

https://www.hopkinsmedicine.org/wilmer/services/glaucoma/book/ch17s01.html

Soft contact lenses phttps://b-c-ing-u.com/celebrities/hard-life-of-otto-wichterle/ 

Lucentis wet macular degeneration https://www.businessinsider.com/price-difference-lucentis-and-avastin-2014-6

soft lenses https://www.mayoclinicproceedings.org/article/S0025-6196(16)00071-9/fulltext

How Soft Contact Lenses Came to the USA

“Never go to a doctor whose office plants have died.” —Erma Bombeck

At 80 he was grey, trim, and smiled a lot. His heart had been damaged by a prior heart attack, but it still pumped well enough to get him through his daily 9 holes of golf. 

His abdominal aorta, the main blood conduit in his abdomen, was bulging, had an aneurysm that was visible on X ray because a rim of calcium that had formed on the inner wall of the large artery.  When it reached a size where the risk of rupture and sudden death outweighed the hazard of an operation I sent him to a surgeon.  The operation went well and 6 weeks post op he was again golfing; his only complaint was abdominal pain that was tolerable but strange.  I ordered an x ray.  Later that day the radiologist called.  The surgeon had left a sponge in the abdomen.  Surgical sponges are marked with radio opaque threads and are easy to spot on x-ray. 

Replacing an aorta is bloody business.  A portion of the large vessel has to be closed off at both ends before the replacement graft is sewn or stapled in.  When it’s cut blood leaks into the abdomen and the surgical team suctions some from the cavity and blots the rest with cotton diaper like “sponges”.  The outside of the intestines and organs are covered with a red film and it gets hard to tell a rag from normal tissue.  When the sponges are thoroughly soaked, they are removed and stacked in a corner of the room.  Before the operation starts the sponges are counted and before the abdomen is sewn shut they are counted again.  If a sponge is missing the abdomen is scoured until the fabric is found.  In this man’s case someone obviously counted wrong. 

Large foreign materials left in the abdomen don’t always cause problems, but they can get infected and their presence is a clear sign that a mistake was made another operation is indicated.  The Latin term res ipsa loquitur, the thing speaks for itself, indicates a situation where lawyers don’t need a witness to prove malpractice.  The evidence of “wrong doing” is obvious and irrefutable. 

I called the patient and told him about the x ray findings.  When he met with the surgeon my colleague was contrite and offered to perform another operation.

First thing doctors are taught in malpractice lectures.  If there’s a mistake admit it as soon as you know something went wrong.  Accept the blame.  Treat the injured party as you would like to be treated.  Most mistakes don’t lead to a law suit.  Legal action becomes more likely when the harm is great and prolonged or when the patient or family is upset with the care they received and/or the attitude of the medical staff.

My patient wasn’t angry or vengeful, and he didn’t want to risk a second operation.  He filed a law suit and asked for $50,000.  Our insurance people reviewed the file, admitted guilt, and offered $10,000.  They may have been low balling him, but it didn’t work.   

Months passed, neither side was giving in, and an expensive trial seemed imminent.  Then one day my patient had a heart attack on the golf course and died.  His family was not compensated.

During the last 50 years the price of medical care has grown and “medical liability costs (excluding malpractice insurance premiums) are thought to be the source of 2.4 percent of the money we spend.¹¹   Medical providers have grown in their ability to improve the quantity and quality of the average person’s life, and physicians and patients are taking more risks. 

Unfortunately at times doctors and nurses seem to have poor people skills.  We doctors may be good students, technically proficient, and methodical.  But too often we are running late.  Our schedules are too tight; we seem to be impatient; and –in the age of computerization– we spend too much of the visit looking at a screen. .    

Errors happen.  The wrong medicine. The wrong dose.  Bed sores.  A preventable fall that leads to an injury.  A sponge left in an abdomen.  A cancer that should have been discovered early. Harm at the time of birth that has lifelong consequences. 

The majority of physicians in a quoted survey said that when something goes wrong they provide “only a limited or no apology; limited or no explanation; and limited or no information about the cause.”   The article’s author, a physician who specializes in malpractice, thinks that too often the problem is caused by a physician’s  need to protect his or her ego and a system that allows doctors to blame shift.¹

Prior to 1970 medical malpractice suits were rare.   That year an estimated 12,000 claims were filed but a third were quickly dropped.  Many who had a legitimate case did not sue; of those who did, four of five cases ended in favor of defendant.  Many of the awards didn’t cover the victim’s litigation cost.¹³

As the 20^th century wore on the legal rules of the road changed in one state after another.  Lawyers were increasingly allowed to file claims based on errors that were so obvious that –res ipsa loquitur – the blunder “spoke for itself.”  Claims could be based on the absence of adequate informed consent.  Charitable and nonprofit hospitals had for decades had been shielded from litigation—in the belief that “paying money to the victims could damage the facility’s ability to treat patients.”  In one state after another, they now became responsible for errors that were their fault. (Massachusetts limited their financial vulnerability to $20,000.⁷)  Jury awards started fluctuating wildly.  At one point injured parties in “California and Nebraska” on average received awards that were 20 times higher than they were in “low-activity states, such as Maine⁸..

The majority of the injured don’t sue.  In one analysis “Approximately 70 percent of claims were closed with no payment.  Defendants won the majority of cases that went to trial.”  People who litigate tend to have more severe injuries and there has been an increase in the number of million dollar plus awards.  (In New York in 1984 one percent (20,000) of the people who had been hospitalized suffered an in- hospital “negligent adverse event” and 7000 died, but only 3500 of the injured filed a law suit.¹¹)

During the last half century there were three periods of time when malpractice insurance premiums rose dramatically and insurers left some states.  When the lack of “coverage” for medical care was deemed “critical” some legislatures established patient-compensation funds and joint underwriting associations.”   In 1975 California lawmakers limited medical malpractice non-economic damages—compensation for “pain and suffering to $250,000.  No limit was place on the amount of money that could be awarded for costly medical care, lost income, or inability to earn a living because of the malpractice.^10.’

Insurance policies have gotten pricey, and they contribute to the cost of medical care.  Between 2008-2017 for example, the annual cost of insurance for obstetricians and gynecologists in Connecticut, Illinois, and Pennsylvania was in the $170,000 to $200,000 range.  In California similar premiums had price tags of $50,000 to $60,000 a year.¹² 

I was a salaried doctor in a large physician owned group (Kaiser). During my 40 years I was sued a few times, and it was emotionally painful.  I’d prefer to not judge myself.

I don’t really know what happens to physicians who practice fee for service medicine.  Some share small offices with one or several colleagues.  When sued I assume they are forced to deal directly with representatives of an insurance company. 

I never had to pay a malpractice premium.  Kaiser, my employer, was big enough to be self insured.  In the event of a multi-million dollar settlement—a severe injury that led to expensive lifelong care—an umbrella insurance policy kicked in.

I wasn’t forced to deal with a representative of an insurance business or company lawyers whose chief tactic was delay and endless expensive depositions. 

Suits that alleged malpractice initially went to a fellow physician who was not always that sympathetic, but who usually was one of the groups brightest and best.  Our malpractice doctor typically spent half of his or her time deal with legal allegations and the other half dealing with patients.  After a lawsuit arrived on his or her desk, our colleague read the chart, evaluated the case, and reached a preliminary conclusion. 

All doctors who participated in the care of the injured person were always named, and everyone who was being sued was informed. In serious cases the group hired one or several outside experts and asked them to assess the case.  When necessary they got opinions from additional experts. Physicians who were paid for advising us could not become a witness or consultant for the plaintiff.  If the outside experts thought we were negligent, our people tried to settle.

A large medical-legal department handled the paper work, the release of information and the technical matters associated with lawsuits.  Skilled, knowledgeable company lawyers gave advice and guided physicians through depositions.  When indicated, outside lawyers were hired to handle each case.      .

In my later years working for Kaiser everyone insured by the plan signed an arbitration contract. Cases could not go to a jury.  The Judges chosen were acceptable to the lawyers from each side.  I’m told the approach does not affect overall malpractice costs, but it was easier on the psyche.

 When a plaintiff is awarded compensation in excess of $30,000 the state of California gets involved.  If the case was settled our group has to name the physician most responsible, and that name is posted on a state web site.   If there was a trial and the money was awarded by a judge, the board of medical examiners gets to decide who to blame.    

Doctors responsible for larger settlements often have to appear before a really tough California medical board.  Most walk away with a reprimand, but about one in 10 medical licenses are revoked or suspended.  .

Our tort system is based on blame and fault.   To prevail a plaintiff has to prove that the defendant owed a duty of care, that the defendant breached the duty, and that the breach caused an injury.”

In California people must file suit within a year after they learn they were negligently harmed. (As mentioned previously) the state capped the amount that’s paid for pain and suffering at $250,000 per person.  There is no dollar limit on actual injuries. 

Plaintiffs’ attorneys usually work on a contingency-fee basis, and take a percentage of the award when they win and nothing when they lose. 

Numerous surveys have concluded that in most cases of negligence the doctor was not sued, and when doctors are sued the harm was usually NOT the result of negligence.

In one recent study (12,000 to 17,000 insurance policies a year), 7.4% of the doctors were sued at least once annually.  Most of the allegations were dropped or dismissed, but 1.6% of those suing were paid some money.  The most targeted subspecialties were neurosurgeons, chest surgeons, and general surgeons.  On average 15 to 19 percent of them were sued each year.  That turns out to be an average of a suit every 5 to 6.5 years. The least targeted physicians were generalists, pediatricians and psychiatrists.  Physicians in these specialties generally got legal notice every 20 to 40 years, or one to two times during their medical careers.²

The number of “paid medical malpractice claims” decreased significantly between 2001 and 2016.  They went from 16,000 to 8500 a year, and the average payout “dropped about 23%”.  During that 15 year period the number of suits where people are paid more than half a million dollars didn’t change much.  They led to annual payouts of about $2.5 billion.  Between 2012 and 2016 as many as 60 in a million people filed malpractice claims in our two most litigious states New York and New Jersey.³

Some doctors claim that the fear of malpractice leads to unnecessary testing and plays a major role in health care costs.

“Many countries- like Sweden, Finland, New Zealand, Quebec Canada, and Australia, have a no-fault system”.  Compensation is based on proof of “causal” connection between treatment and injury. Their structure awards damages to patients without proof of provider’s fault or negligence, and it encourages physicians to collaborate in their search for the cause of the injuries.  Although the application of no-fault system differs slightly in each country, the basic idea is to eliminate fault or blame and make the claim process simple so patients with meritorious cases can access the system easily.” It also makes it easier to identify and fix problems.⁴

It’s possible to get some sense of what would happen if American physicians could no longer be sued for medical malpractice.  Doctors in the military aren’t immune from patient complaints or administrative action, but the government can’t be sued.

In the 1940s a serviceman died after a surgeon “left a towel in his abdomen”.  The family sued. In 1950 the U.S. Supreme court, by creating a “doctrine” called the Feres rule, decided the government was not liable.  The decision was later extended to include anyone receiving medical care from “the government.”  The court rationalized the approach by discussing the special relationship that exists between service members and the U.S. and by pointing out that the laws of malpractice vary from state to state.  That makes litigation complex.  They noted that injured service members who were disabled were paid accordingly.  Some judges apparently feared law suits might affect military discipline.  The decision of the court has been challenged.  Additional suits have been filed, but the court did not choose to re-hear the matter. 

In a recent article a few lawyers felt “repeal (of Feres) may not serve the best interests of service members.”  Most people who are harmed, they pointed out, don’t sue.  Without the threat of legal action, mistakes could be openly discussed, problems could be identified and the system could be improved.   We don’t know, they argued, that giving lawyers standing would make the care people received any better or safer.  “There is little empirical evidence,” they wrote, that civilian malpractice litigation provides incentives to improve the safety of care.⁵”

Sometimes doctors can’t fix or help some sick people because we don’t know how.  Metastatic cancer and dementia top the lack of knowledge list.  But too often the knowledge exists but we don’t deliver.  Gawande.¹⁵ (paraphrase)

Delays in retrieving a person’s records, time pressures, and illegible physician notes are common impediments.  Robert Pearl, the former head of Kaiser thinks a computerized health record that pops up every time a physician is visited, one where a person’s medical information is presented to each treating doctor, should make a big difference.¹⁶

1. Medical MalpracticeDavid M. Studdert, LL.B., et al.   January 15, 2004 N Engl J Med 2004; 350:283-292 https://www.healthaffairs.org/doi/full/10.1377/hlthaff.W4.20
2. https://www.statnews.com/2017/01/13/medical-errors-doctors/
3. https://www.mdedge.com/clinicalneurologynews/article/48642/health-policy/most-doctors-face-malpractice-claim-age-65
4.   http://truecostofhealthcare.org/malpractice_statistics/
5. http://siteresources.worldbank.org/INTRUSSIANFEDERATION/Resources/Malpractice_Systems_eng.pdf
6. https://digitalcommons.wcl.american.edu/cgi/viewcontent.cgi?referer=&httpsredir=1&article=1608&context=aulr In Defense of Feres: An Unfairly Maligned Opinion. 
7. Twenty Years of Evidence on the Outcomes of Malpractice Claims Philip G. Peters, JD
8. 7. https://www.clf-law.com/Medical-Malpractice-Newsroom/Charitable-Immunity-for-Nonprofit-Hospitals.shtml

8.  https://www.nejm.org/doi/full/10.1056/NEJMhpr035470

9.  Robinson GO. The medical malpractice crisis of the 1970’s: a retrospective. Law Contemp Probl 1986;49:5-35

10.  https://www.nolo.com/legal-encyclopedia/how-does-the-micra-damage-cap-affect-california-medical-malpractice-case.html 

11.  Brennan TA, Leape LL, Laird NM, et al. Incidence of adverse events and negligence in hospitalized patients: results of the Harvard Medical Practice Study I. N Engl J Med 1991;324:370-376

12.  file:///C:/Users/User/Documents/policy-research-perspective-liability-insurance-premiums.pdf Medical Professional Liability Insurance Premiums for $1M/$3M Policies, Selected Insurers,

United States. Department of Health, Education, and Welfare. Secretary’s Commission on Medical Malpractice-1973-Medical Malpractice Report.   https://books.google.com/books?id=2PqUFmmYtVIC&pg=PA6&lpg=PA6&dq=in+1970+12,000+malpractice+claims+were+filed&source=bl&ots=_AeitZqpvz&sig=ACfU3U1lIEO0ET8N2IBLcMwBgPmdfJ_F7Q&hl=en&sa=X&ved=2ahUKEwil3M_std7nAhWSKH0KHVksC1QQ6AEwB3oECA8QAQ#v=onepage&q=in%201970%2012%2C000%20malpractice%20claims%20were%20filed&f=false

14.  National Costs of the Medical Liability System Michelle M. Mello, et al. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048809/#!po=0.892857

15. Atul Gawande: VoxSep 16, 2016, by Jeff  Stein for the first time in human history ineptitude is a bigger problem than ignorance.

16. Mistreated by Robert Pearl M.D., Public Affairs press, 2017. https://www.hcinnovationgroup.com/policy-value-based-care/article/13028465/oneonone-with-dr-robert-pearl-the-permanente-medical-group-ceo-at-world-health-care-congress

INNOVATION, BUSINESS, AND HIGH PRICES.

This segment of the book tells the stories of :

Innovative medications that were created in the labs of big Pharma, privately funded startups, research hospitals, Universities, or the National Institute of Health.

Funding for research and development that was raised by selling stock at the time of an IPO –initial public offering, or paid for by entrepreneurs, government grants or with donated dollars

New medicines that large pharmaceutical companies tweeked, developed, manufactured, distributed, promoted, and aggressively priced.

And mergers and acquisitions in which company “A” paid billions of dollars to buy company “B” because they wanted to own one or several medications. Then “A’, now saddled with billions of dollars in new debt, needed to sell a lot of their new medicine and they had to charge a lot for the product..

• A.  Setting the Price
• B. 2019 Senate hearings
• C.  Tax and Donated dollars
• D.  Swiss take control
• E. Dominating the market
• F. Artemisinin a drug that the Western World didn’t accept for 30 years, but that has already saved millions of lives

The new drug was developed in China in the 1960 and 1970s the person who led the team that developed the medication, Youyou Tu received the Nobel Prize for her efforts in 2015.  This is the story she told when she received the award:

“I was born on December 30, 1930 in Ningbo, a city on the east coast of China with a rich culture and over seven thousand years of history.

My father worked in a bank while my mother looked after my four brothers and me, the only girl in our family. Our family’s long history of highly valuing children’s education and always considering this as the family’s top priority allowed me to have good opportunities for attending the best schools in the region –I unfortunately contracted tuberculosis at the age of sixteen and had to take a two-year break and receive treatment at home.  Then I resumed my study at the private Ningbo High School (1948–1950) This experience, being ill and cured, led me to make a decision to choose medical research for my advanced education and career After graduation from high school, I attended the university entrance examination and fortunately I was accepted by the Department of Pharmacy and became a student at the Medical School of Peking University.

Most pharmacy courses were designed and taught by returnees such as Professors Lin Qishou (林启寿) and Lou Zhicen (楼之岑) who had received educations and advanced degrees in Western countries. Professor. Lin Qishou gave a comprehensive introduction and hands-on training on how to extract active ingredients from the plants, how to select proper extraction solvents, how to carry out chemistry studies and determine the structures of the chemicals isolated from the plants etc. These courses provided scientific insights into the herbs and plants and more importantly.  They explained how these herbal medicines work, in a way different from traditional Chinese medicine.

China lacked medical resources in the early 1950s. There were only around twenty thousand physicians and several tens of thousands of traditional Chinese medical practitioners in the country   The Ministry of Health of China organized a number of full-time training courses in the late 1950s . In my two and a half year training program, I learned traditional Chinese medical theory and gained experience from clinical practice. Another training program I attended was on the processing (炮制) of Chinese Materia Medica.. Knowledge of such processing, in combination with the scientific explanation, benefited my work enormously.

Malaria is a life-threatening epidemic disease. It was, however, effectively treated and controlled by chloroquine and quinolines for a long period of time. Then most of the plasmodium parasites became drug resistant. 

n the late 1960s following the catastrophic failure of a global attempt to eradicate malaria. Resurgence rapidly increased mortality posed a significant global challenge, especially in the South East Asian countries.

 In the 1960s, the Division of Experimental Therapeutics at the Walter Reed Army Institute of Research (WRAIR) in Washington, DC launched programs to search for novel therapies to support the US military presence in South East Asia. US military force involved in the Vietnam War suffered massive casualties due to disability caused by malaria infection. Up to 1972, over 214,000 compounds were screened with no positive outcomes.”

China was in the middle of the great cultural revolution. “According to Wikipedia the cultural revolution wasa violent movement launched by Mao Zedong that lasted  from 1966 until 1976.  Its stated goal was to preserve Chinese Communism by purging remnants of capitalist and traditional elements.  Mao called on the young people to rebel and insisted that revisionists who formed red guards to grab power.

The Cultural Revolution damaged China’s economy and traditional culture, with an estimated death toll ranging from hundreds of thousands to 20 million. There were a number of massacres.  Red Guards destroyed historical relics and artifacts and ransacked cultural and religious sites. Tens of millions of people were persecuted, purged, exiled and imprisoned. Notable scholars and scientists were killed or committed suicide. Schools and universities were closed and over 10 million urban youths were sent to the countryside.

According to Wikipedia the cultural revolution wasa violent movement launched by Mao Zedong that lasted  from 1966 until 1976.  Its stated goal was to preserve Chinese Communism by purging remnants of capitalist and traditional elements.  Mao called on the young people to rebel and insisted that revisionists who formed red guards to grab power.

The Cultural Revolution damaged China’s economy and traditional culture, with an estimated death toll ranging from hundreds of thousands to 20 million. There were a number of massacres.  Red Guards destroyed historical relics and artifacts and ransacked cultural and religious sites. Tens of millions of people were persecuted, purged, exiled and imprisoned. Notable scholars and scientists were killed or committed suicide. Schools and universities were closed and over 10 million urban youths were sent to the countryside.”

 Youyou:  “Almost every institute was impacted and all research projects were stalled. A lot of experienced experts were sidelined. After thoughtful consideration, the academy’s leadership team appointed Youyou Tu to head and build a Project 523 research group at the Institute of Chinese Materia Medica. My task was to search for antimalarial drugs among traditional Chinese medicines.

As a young scientist, I was so overwhelmed and motivated by this trust and responsibility. I also felt huge pressure from the high visibility, priority, challenges as well as the tight schedule of the task. The other challenge was the impact on my family life. By the time I accepted the task, my elder daughter was four years old and my younger daughter was only one. My husband had to be away from home attending a training campus. To focus on research, I left my younger daughter with my parents in Ningbo and sent my elder daughter to a full-time nursery where she had to live with her teacher’s family while I was away from home for the project. This continued for several years. My younger daughter couldn’t recognize me when I visited my parents three years later, and my elder daughter hid behind her teacher when I picked her up upon returning to Beijing after a clinical investigation.

Our long journey searching for antimalarial drugs began with collection of relevant information and recipes from traditional Chinese medicine.

Malaria was one of the epidemic diseases with the most comprehensive records in traditional Chinese medical literature, such as Zhou Li (周礼), a classical book in ancient China published in the Zhou Dynasty (1046–256 B.C.).

After thoroughly reviewing the traditional Chinese medical literature and folk recipes and interviewing experienced Chinese medical practitioners, I collected over two thousand herbal, animal and mineral prescriptions within three months after initiation of the project. From these two thousand recipes, I summarized 640 prescriptions

After multiple experiments and failures, I re-focused on reviewing the traditional Chinese medical literature. One of the herbs, Qinghao (青蒿) (the Chinese name for the herbs in the Artemisia family), showed some effects in inhibiting malaria parasites during initial screening, but the result was inconsistent and not reproducible. I repeatedly read relevant paragraphs in the literature where the use of Qinghao was recorded as relieving malaria symptoms.

In Ge Hong’s A Handbook of Prescriptions for Emergencies (肘后备急方), I noticed one sentence “A handful of Qinghao immersed in two liters of water, wring out the juice and drink it all” (青蒿一握, 以水二升渍, 绞取汁, 尽服之) when Qinghao was mentioned for alleviating malaria fevers. Most herbs were typically boiled in water and made into a decoction before taken by the patients.

This unique way of using Qinghao gave me the idea that heating during extraction might have destroyed the active components and the high temperature might need to be avoided in order to preserve the herb’s activity. Ge Hong’s handbook also mentioned “wring out the juice.” This reminded me that the leaf of Qinghao might be one of the main components prescribed. I redesigned experiments in which the stems and leaves of Qinghao were extracted separately at a reduced temperature using water, ethanol and ethyl ether.

Sample no. 191 was a symbolic breakthrough in artemisinin discovery.  We produced extracts from different herbs including Qinghao using the modified process and subsequently tested those ethyl ether, ethanol and aqueous extracts on rodent malaria. On October 4, 1971, we observed that sample number 191 of the Qinghao ethyl ether extract showed 100% effectiveness in inhibiting malaria parasites in rodent malaria. In subsequent experiments, we separated the extracts into a neutral portion and a toxic acidic portion. The neutral portion showed the same effect when tested in malaria-infected monkeys between December 1971 and January 1972.

Starting in March 1972, the team started to produce large quantities of Qinghao extract in preparation for clinical studies. Most pharmaceutical workshops were shut down during the great cultural revolution. Without manufacturing support, we had to extract herbs ourselves using household vats etc. The team worked very long hours every day including the weekends. Due to lack of proper equipment and ventilation, and long-term exposure to the organic solvents, some of my team members included myself started to show unhealthy symptoms. This, however, did not stop our efforts.

Some conflicting information was seen from the animal toxicological studies. It was already in the middle of the summer and very limited time was available to us before the malaria epidemic season would end. We would have to delay the study for at least a year if we continued our debate on toxicity. To expedite the safety evaluation, I got permission to take the extracts voluntarily. In July 1972, two other team members and myself took the extracts under close monitoring in the hospital. No side effect was observed in the one-week test window. Following the trial, another five members volunteered in the dose escalation study. This safety evaluation won us precious time and allowed us to start and complete the clinical trial in time.

Traditional Chinese medicine started with a story: “Shen Nong tasted a hundred herbs.” Shen Nong was an ancient Chinese medical practitioner. To understand the efficacy and toxicity of the herbs, he tasted over a hundred herbs himself and recorded all the details, which left us with a lot of precious information. Although Qinghao was prescribed as an herbal medicine for thousands of years, the dose of the active ingredients in these prescriptions was much lower than that in the Qinghao extract we tested. Our desire to get the clinical trial completed and have the medicine for our patients as soon as possible was the real driving force behind our action.

The first clinical trial on the Qinghao extract was carried out in Hainan province between August and October 1972. We treated a total of twenty-one local and migrant malaria patients, nine infected by Plasmodium falciparum, eleven infected by Plasmodium vivax and one with mixed malaria infections. The trial was successful: all patients recovered from the fevers and no malaria parasites were detected

We started isolation and purification of neutral Qinghao ethyl ether extract parallel with the clinical trial in 1972. We carried out a clinical trial of artemisinin between August and October 1973 using artemisinin tablets, which however did not yield the desired results. We examined the tablets returned from the clinical center and found that the tablets were too hard to disintegrate. We resumed the study using artemisinin capsules at the end of September 1973. Dihydroartemisinin was found in September 1973 in an experiment where I tried to derivatize artemisinin for a structural activity relationship evaluation. In a subsequent test in rodent malaria, we noticed that a significantly reduced dose was sufficient to achieve the same efficacy as artemisinin when dihydroartemisinin was administered.

. Dihydroartemisinin is ten times more potent than artemisinin clinically, again demonstrating the “high efficacy, rapid action and low toxicity” of the drugs in the artemisinin category.  “Bench to bedside” – collaboration expedited translation from a discovery to a medicine. 

The herb Qinghao was frequently mentioned in the traditional Chinese medical literature for various clinical applications besides alleviating malaria symptoms. These applications include relieving itches caused by scabies and scabs, treating malignant sores, killing lice, retaining warmth in joints, improving visual acuity, etc. However, little explanation was given on either the species or effective parts of the plant in the traditional Chinese medical literature.

We carried out a thorough investigation and confirmed that only Artemisia annua L. (sweet wormwood) contains artemisinin. In addition to identification of the right species, we also verified the best regions for growing Qinghao, the best collection season and the officinal part of the plant.”

China and Vietnam provide 70% and East Africa 20% of the raw plant material.^[58] Seedlings are grown in nurseries and then transplanted into fields. It takes about 8 months for them to reach full size. The plants are harvested, the leaves are dried and sent to facilities where the artemisinin is extracted using a solvent, typically hexane a straight-chain alkaline with six 6 atoms that is a colorless liquid, odorless and is widely used as a cheap, relatively safe, largely unreactive, and easily evaporated solvent.  Alternative extraction methods have been proposed.^[59] The market price for artemisinin has fluctuated widely, between US$120 and $1,200 per kilogram from 2005 to 2008.^{[60] it also works on Shistosomiasis}

By the beginning of the 1980’s, China started to open up to the rest of the world and the Chinese scientists, including Li Guoqiao contacted professors David Warrel and Nicholas White from the Wellcome Trust and gave them access to data related to the use of artemisinin in the treatment of malaria. These data were first mentioned in a Wellcome Trust publication entitled A present from Chairman Mao (Gardner, 2002), which made these compounds known internationally. After this first encounter Nicholas White became a great advocate of artemisinin and through intense lobbying managed to convince the scientific community to take an active interest in these drugs This is also how a first Western company, Rhône- Poulenc Rorer (RPR, now Sanofi-Aventis), decided to study the potential of these drugs and license one of them, injectable artemether, from Kunming Pharmaceuticals. It took four years from the time of the first meeting in September 1989 to the launch in 1993. Negotiations were difficult as the manufacturer could not conduct direct discussions with a foreign company and had to go via a state organisation (Citic Group), which did not necessarily follow the same goals. Moreover, the Chinese government suddenly decided to promote its relationship with other emerging countries and all the negotiators found themselves having to pursue their talks in Brazil! Nevertheless, a contract was finally signed in July 1990 in the presence of Deng Zhifang, Deng Xiaoping’s youngest son (Fig. 1). But work only started: the technical dossier was not receivable and had to be totally re-written. New studies were requested, including animal toxicity studies though the product had already been widely used in man! Two major clinical trials were conducted, one in Vietnam (Hien et al., 1996) and one multi-centre in different African countries (Bougnoux & Ancelle, 1993; Danis et al., 1996). Finally an approval for a limited use in French hospitals was granted, which allowed RPR to market this product in endemic areas.

These data were first mentioned in a Wellcome Trust publication  intense lobbying convinced the scientific community to take an active interest in these drugs (White et al., 1999). This is also how a first Western company, Rhône- Poulenc Rorer (RPR, now Sanofi-Aventis), decided to study the potential of these drugs and license one of them.  . It took four years from the time of the first meeting in September 1989 to the launch in 1993. Negotiations were difficult as the manufacturer could not conduct direct discussions with a foreign company and had to go via a state organisation (Citic Group), which did not necessarily follow the same goals. Moreover, the Chinese government suddenly decided to promote its relationship with other emerging countries and all the negotiators found themselves having to pursue their talks in Brazil! Nevertheless, a contract was finally signed in July 1990 in the presence of Deng Zhifang, Deng Xiaoping’s youngest son (Fig. 1). But work only started: the technical dossier was not receivable and had to be totally re-written. New studies were requested, including animal toxicity studies though the product had already been widely used in man! Two major clinical trials were conducted, one in Vietnam (Hien et al., 1996) and one multi-centre in different African countries (Bougnoux & Ancelle, 1993; Danis et al., 1996). Finally an approval for a limited use in French hospitals was granted, which allowed RPR to market this product in endemic areas.  Not in 2010 washington u. manual

it was found that the artemisinin do not only affect the malaria parasites, but are also active against juvenile schistosomes, which was first shown by Chen et al. [25] at the end of the golden decade of antiparasitic drug discovery in the 1970s. In fact, this discovery predates that of scholarly articles on qinghaosu’s use against malaria, which remains its main application.

From the New England Medicine.  “Artemisinin derivatives, used in carefully developed combinations, have recently served as the first-line drugs against most uncomplicated malaria infections. Artemisinins are combined with other drugs so that the fast-acting artemisinin can immediately reduce parasitemia, allowing remaining parasites to be removed by a long-acting partner drug. Monotherapy with the artemisinin compound artesunate is used for initial management of severe disease.

A slowdown in the clearance of parasites in patients treated with artesunate sounded alarms when it was first reported from Cambodia. Subsequently, similar delays in parasite clearance were noted in countries in Asian territories, including Myanmar, Thailand, Laos, and China, collectively referred to as the Greater Mekong Subregion.¹ It was determined that parasites that were cleared more slowly after artemisinin treatment carried mutations in the propeller domain of the malarial kelch13 (K13) gene. Although K13 mutations are not reliably associated with increased risk of treatment failure, parasites bearing these mutations are now called “artemisinin-resistant.” Phenotypically, “artemisinin resistance” is defined as a delay in parasite clearance. These parasites recrudesce more frequently than artemisinin-sensitive parasites after standard 3-day therapeutic courses with artemisinin combination treatments (ACTs).

However, 3-day courses do not contain the full treatment doses of artemisinins needed to cure infections, which last 7 to 10 days, according clinical studies conducted in China. When a 7-day treatment course of artesunate is used, it is effective even when early parasite clearance is delayed.² The same is not true of resistance to other classes of antimalarials, which results in a failure to cure the infection after a full treatment course.

Should a delay in parasite clearance with artemisinin treatments be defined as drug “resistance” or “tolerance”? Either way, 3-day therapeutic courses are losing their efficacy against malarial parasites in the Greater Mekong Subregion. So what matters most to patients and populations at risk is how we handle this emerging threat.

Treatment failures with artemisinin combination therapy can be directly attributed to the partner drug, despite delayed-parasite-clearance phenotypes.² For example, if piperaquine–dihydroartemisinin treatment is failing in a given region, another combination, such as mefloquine plus artesunate, may prove very effective. May 30, 2019 NEJM. “

https://www.nejm.org/doi/full/10.1056/NEJMp1901233

cultural revolution https://en.wikipedia.org/wiki/Cultural_Revolution#:~:text=The%20Cultural%20Revolution%2C%20formally%20the,China%20from%201966%20until%201976.

https://www.nobelprize.org/prizes/medicine/2015/tu/biographical/ Tu Youyou
The Nobel Prize in Physiology or Medicine 2015

On Feb 26, 2019 the heads of 7 pharmaceutical manufacturers appeared before a congressional committee.  The CEO’s of Roche and Novartis—the Swiss—were notably absent.   Senators were trying to learn why the cost of medicine was much higher in America than it was in any other advanced country.   At the end of her 5 minute interrogation Debbie Stabenow of Michigan seemed frustrated by the evasive non-answers she was evoking, and she concluded that companies raise prices because they can. 

She was right and wrong.  I believe CEO’s believe they have no choice.  They are accountable to stock holders. If the company is not profitable their jobs are in jeopardy.  The marketplace they face is not one where their “competitors” are trying to grow market share by cutting their prices.  Quite the contrary.  Industry leaders are charging more each year.  As long as price increases stay below 10% and are some odd number, they don’t seem arbitrary.  Most importantly, when pharmaceutical prices rise no one who matters seems to care.

Not that the spokespeople that defend Pharma are wrong.  Some of the drugs that company researchers spend years developing fail.  When tested, they aren’t effective or are they are toxic, or they don’t have a market niche that makes them profitable. When company money makers lose their exclusivity, generics move in.   

Most advanced nations keep prices down by using a system called “reference pricing”.  They cluster medications that “have identical or similar therapeutic effects”.  Then some insuring nations (like Italy) pay the cost of the cheapest drug in each grouping, and in other countries (like Germany) shell out the price of the average medicine in the collection.  In America the government hasn’t instituted a pharmaceutical price control system. Insurers, phamaceutical benefit managers and the VA negotiate drug prices; Medicare, by law, can’t. ¹ 

 Many of the CEOs that were in Washington that day seemed less than proud of their contribution to the price problem.  Some seemed anxious to lower prices and/or tie increases to inflation.  In return they wanted to stop giving discounts and rebates to middle men and women–pharmaceutical managers– or give rebates directly to the person that needs them. And if they were going to lower prices they wanted the other companies to follow suit.

Kenneth Frazier, the son of a janitor, and grandson of a South Carolina share cropper was the CEO of Merck. A graduate of Harvard, he was the first black man to head a fortune 500 corporation.  Initially a member of the defense team when Merck was sued because its arthritis medication, Vioxx, increased the risk of heart attacks and strokes, he had also practiced criminal law. He was part of a legal team that won a new trial and eventual acquittal for an Alabama man who had been convicted of murder.⁵  He told the senators that he felt his company had a duty to be responsible in pricing practices and to contribute to solutions that address patient affordability.  He said that the previous year Merck had decided to not annually increase the net price of their portfolio by more than inflation.  And he pointed out that his company had deployed 70k doses of experimental Ebola vaccine in the Congo. 

The French company Sanofi’s head, Olivier Brandicourt, had, as young doctor “spent two years in the Republic of the Congo. He had then studied malaria during his eight years at the institute of infectious and tropical diseases in Paris.”  He said that two years earlier his company had pledged to keep price increases at or below the U.S. national health expenditure projected growth rate.  He talked about the gap between net and list prices.  Lantus, the company’s long acting insulin had seen a 30% decrease in net at a time when U.S. patients out of pocket costs had increased 60%.  He felt dealing with list price alone would not solve the problem of patient out of pocket costs.⁶  

Pascal Soriot head of Astra-Zeneca agreed:  “The government has to step up and change the rules.”  Born in France, Soriot currently calls Australia his home. An avid bicyclist he keeps a road bike in the Alps, another in the US, and a third one in Cambridge England.⁷ He grew up in the north of Paris and when young was a member of a “team”. His story suggests it might have been a bit like a gang. There were “many fist fights.” He was trained in veterinary medicine before he started working for Pharma.   

The new CEO of Pfizer apparently believed the group was not brought to Washington to provide certain senators with an opportunity to publically chastise big shots and show their voters they cared.  He thought the senators wanted suggestions.  Named Albert Bourla, he was a Greek veterinarian who was a former director of Pfizer’s animal health group.  When his turn came he stated he was “particularly humble to take part in such an important policy discussion within the U.S. Senate.  When he immigrated 18 years earlier he could never have imagined such an honor.”  And he told the senators–at the end of the session–that he had made it clear to investors: Pricing will not be a growth driver for the company now or in years to come.  (I wonder how long he will last.)

  Unlike the other CEOs he didn’t point out how many billions of dollars his company was spending on research, how they desperately wanted to discover and develop a new super drug for mankind—not for their bottom line.  And he didn’t talk about his company’s risks and failures.  The suggestions he made provided a decent summary of what everyone (aside from AbbVie) was saying.

Medical breakthroughs, he said, “won’t do anyone any good if patients can’t afford them, and unfortunately the horribly misaligned incentives within our health care system often makes medicines unaffordable for American patients.  We need to fix this.”  

In part restating the thoughts of the other CEOs, Bourla presented four ideas:

All rebates should go to patients. He believes too much money is being swallowed up in the supply chain. His company paid $12 billion this year in rebates.  He didn’t think any of the money found its way to patients.  If discounts were provided to the people who take medications, seniors could save hundreds of dollars a year.  

Medicaid covers the costs of the prescription drugs used by the people it cares for.  “To help ensure that the taxpayer sponsored program receives the lowest price available for all prescription drugs” Congress passed the Medicaid best price rule in 1990.  Pharmaceutical manufacturers, who sell products to people covered by Medicaid can’t charge the U.S. more than they charge a tough bargaining private insurer. 

And as part of the Affordable Care Act, to “offset the overall cost of Medicaid prescription drugs,” 600 brand-name drug manufacturers (under duress) agreed to pay a rebate to the states and Federal government. The amount of rebate is based on a statutory formula: it is a percent of the  Average Manufacturer Price (AMP)—the average price that manufacturers receive from the wholesalers who distribute medicines to retail pharmacies. 

• For recently approved –“innovator” drugs—the first to contain a “specific active ingredient” –manufacturers pay at least 23.1 percent of the AMP.
• For blood clotting factors and pediatric medications at least 17.1 %,
• and for generic drugs at least 13%⁹. 
• In 2016, Medicaid drug rebates totaled $31.2 billion.” 

Bourla repeated the longstanding dream of many in the health care field.  If a drug has less value it should cost less.  If a pill prevents heart attacks its price should be tied to the number of lives it saves.  Or—as Dr Peter Bach of Sloan Kettering pointed out — when Tarceva is used to treat lung cancer people live, on average, an extra year.  If it’s given to someone with pancreatic cancer their life is extended, on average, a week and a half.  The drug’s effectiveness varies but its cost doesn’t.   (So how would Bach and Bourla price penicillin, transfusions, or emergency heart stents?)

Bourla suggested capping seniors out of pocket medicines cost. Americans are increasingly paying a greater percentage of the cost of their medicines (14%) than they do for their time in the hospital (3%).  If someone doesn’t take a needed medication and as a result lands in the hospital, it’s more costly to the health care system.  (Lids on drug costs will also get some of the noisy voters off the backs of the companies and the legislators).

Finally Bourla touched on the problem that congress created and that only congress could fix.  Our laws are keeping Biosimilars off the American market.

Biosimilars are antibodies that bind to the same antigen as an approved monoclonal antibody. They are the generics of the day.  Half are mouse antibodies.  They come from special mice, creatures that were genetically altered.  When they were mere embryos some of their DNA was replaced with human DNA.  As a result when a protein—an antigen—is injected into one of the rodents, the creature makes antibodies that the homo sapiens immune system believes is human in origin.  When one of these “human-ish” antibodies is injected into a person our lymphocytes don’t destroy it.

Monoclonal antibody tutorial: 

• There are Billions of B cells in a body. 
• Each can only recognize one of the billions of different antigens it encounters.  (Antigens: viruses, toxins, pollen.) 
• When a B cell identifies its fated antigen it creates a unique antibody. 
• The B cell also clones itself; it makes billions of identical copies of itself. 
• Each cell in the clone makes the same unique antibody. 
• The antibodies are thus identical and monoclonal.

In the lab a chosen antigen is injected into a mouse. The animal is given time to recognize the antigen and clone itself–grow billions of B cells that each make the same special antibody. Because large numbers of B cells are present in the spleen, a large bore needle is inserted into an animal’s organ and blood rich in B cells is sucked out. 

• B cells don’t live long. 
• Myeloma cells don’t die. 
• When B and Myeloma cells are fused chemically or electrically, a hybrid cell is created. 
• It makes and keeps making the antibody; and it doesn’t die. 
• The mixture of B and fused cells (hybridomas) are put in a special medium. 
• It allows and encourages un-fused B cells to die off; and it allows hybridomas to multiply, thrive, and make lots of monoclonal antibody. 
• The basic technology for making monoclonal antibodies is not new or obscure.  It was developed in 1975, and its inventors won the Nobel Prize. 

Humira is a mouse antibody –it blocks—inactivates—some of the body’s important immune modulators— molecules that play a role in the inflammatory process. The cytokine group it obstructs is called TNF, tumor necrosis factor.  When TNF is blocked it’s like a jack knifed truck on the freeway.  The immune/inflammatory reaction is shut down.  To make a biosimilar to TNF, trained researchers must inject the molecule into a humanized mouse, harvest the lymphocytes that produce the desired antibody, fuse the lymphocytes with myeloma cells, and create cells that should live “forever.” They test the antibodies that the cells produce and learn if they are safe and effective.  No two antibodies are, chemically speaking, exactly the same (they are not technically generics.) But like Shakespeare’s rose, good biosimilars “would smell as sweet.”  The\ biosimilars need to be and are as good as the original drug.  To date four pharmaceutical manufacturers have developed and tested effective Humira biosimilars.

In 2009 congress was sold a bill of goods.  They were told something like: we want to make it easier for biosimilars to enter the market.  We want to speed up the process.  So let’s make sure they work, that they are safe and effective.  But let’s not force them to go through extensive controlled trials.  Let’s speed up the process. 

The Biosimilars Act of March 23, 2010, gave biosimilars 12 years of marketplace exclusivity.  Standard medications were getting a 5 year monopoly.  At the end of those years (in the absence of legal gamesmanship) the first standard generic (biosimilar) would theoretically be allowed to compete —unless a valid patent stood in the way. And that’s the rub. All new pharmaceuticals are “protected” by significant and insignificant patents. Pharmaceutical companies have long used insignificant patents –that their lawyers could allege were important–to keep generics off the market for a few years. They have long used a provision in the 1984 Hatch-Waxman act to delay the entry of competitors. Then in 2010, in the guise of speeding biosimilars to the market, industry lobbyists did it again. They shaped a new rule as an amendment to the Public Health Service act.  They titled it an innovation, and they slipped it into the Affordable Care Act—Obama care.  And Ron Wyden, the senator who was most troubled when AbbVie used the loophole, voted for the bill.
AbbVie used loopholes in the law to keep four Humira biosimilars, off the American market for 5 years. Presumably they would have driven down the price of Humira. The company’s lawyers probably had one or several patents that were allegedly being infringed. Abbvie owns 126 Humira patents.  Most (I assume) have little nothing to do with the core drug. Under the new law when there was a patent dispute–in the place of litigation “negotiation was encouraged”.  The bargaining rules (called a dance) are complex, Byzantine.³

In Humira’s case the manufacturers reached an agreement. 4 companies were allowed to market their biosimilars in all countries of the world outside the U.S.  AbbVie kept exclusive control of the American market.  That’s over $9 billion a year for 5 years.  Thanks to our legislators, the U.S. will have to wait for biosimilars until September 2023.⁴ Bourla explained our law created “reverse incentives that favor higher cost biologics and are keeping biosimilars from reaching patients.  In many cases insurance companies decline to include lower price biosimilars in their formularies because they would risk losing rebates from higher cost medicines.”

Parenthetically Bourla suggested that the administration should obtain trade agreements that prevent foreigners from freely using American innovations.  He didn’t think Americans should pay less for drugs. He thought people in the other western countries should pay more.  “The price control mechanisms of many nations are giving others a free ride on American innovations.”

Richard Gonzalez, the CEO of AbbVie was the target of Senator Wyden’s wrath; One of Pharma’s few CEO’s without a college degree, Gonzalez worked for Abbott for 30 years and retired when he developed throat cancer.  Declared cured, he returned in 2009 as head of a spinoff called Abbvie.⁸ Gonzalez stated there’s no one solution; and he did his best to avoid discussing the biosimilar elephant in the room.  He pointed out that since its inception in 2013 his company had spent 50 billion dollars in research and had a hepatitis C drug that financially failed. He felt price was only a part of the problem.  Stating a willlingness to work with the committee, he pointed out that his company is charitable. 81,000 patients got free drugs (for an unspecified period of time.)

AbbVie, he explained, has 30,000 employees (and they need to eat). Senator Wyden, in turn, pointed out that Gonzalez’s salary was $22.6 million.  And he got a bonus of $4.3 million dollars.  Was, Wyden asked, the bonus tied to the financial performance of Humira.

In September 2018 congress passed John Sarbanes’ Biosimilars Competition Act.  It is supposed to “shine a light” on backroom, “so-called “pay-for-delay” deals – often made in secret.  They must now be reported to the federal trade commission who, with the justice department, will review agreements, look for anti- trust and anti-competitive behavior and “punish bad actors.”  In other words if a company has a drug with an annual revenue of $10 billion and they keep other drugs off the market for 5 more years (and make an additional $50 billion in U.S. sales) they may be sued, and their lawyers may be forced to settle with the government, admit no wrong, and pay a fine of a few million dollars.  Great law.   

“By 2014” (according to a Harvard Public Health school intellectual-property consultant) “biologics were expected to account for half of all pharmaceutical sales.”  Their prices are often quite high. If congress doesn’t modify the rules we can expect high priced biologics for a long time.

1.  https://www.nytimes.com/2015/10/20/upshot/to-reduce-the-cost-of-drugs-look-to-europe.html)
2. https://www.americanactionforum.org/research/primer-the-medicaid-drug-rebate-program/  https://www.americanactionforum.org/research/primer-the-medicaid-drug-rebate-program/ Tara O’Neill Hayes –Feb 7 2019).
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008392/
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008392/
5. https://www.inquirer.com/philly/business/20101201_New_Merck_CEO_Kenneth_C__Frazier_has_Philadelphia_roots.html
6. https://web.archive.org/web/20150407084544/http://en.sanofi.com/investors/corporate_governance/corporate_management/bio-brandicourt.aspx?
7. https://www.affarsvarlden.se/bors-ekonominyheter/soriot-my-son-never-had-a-single-fist-fight-in-his-whole-life-and-i-had-so-many-6810336
8. https://www.chicagotribune.com/business/ct-xpm-2011-10-20-ct-biz-1020-abbott-white-gonzalez-20111020-story.html
9. https://www.medicaid.gov/medicaid/prescription-drugs/medicaid-drug-rebate-program/index.html

CSPAN:  PRESCRIPTION DRUG PRICING. https://www.c-span.org/video/?458198-1/lawmakers-press-pharma-ceos-rising-drug-prices

There are many reasons to question the widely held notion that high drug prices and innovative research are inextricably linked.⁹ EZEKIEL J. EMANUEL

For decades companies have been buying one another, combining, and attempting to control segments of the market.  Large pharmaceutical companies purchase small startups or large competitors to gain control of a drug and/or the technology that led to its creation.  Many acquisitions cost billions.  To survive the purchasing company has to sell a lot of product, so they market aggressively and charge as much as they dare.  And we all pick up the bill.

In 2011 Gilead bought Pharmasset for $11 billion and gained control of the company’s potent medication, sofosbuvir.  When combined with a second, though less potent anti – viral, Pharmasset’s medication cured most people quickly with minimal side effects. Gilead researchers had developed a drug ledipasvir, that suppressed hepatitis C, but when used alone it wasn’t curative. 

The drug combination was great news for the 2.7 to 3.9 million Americans and the 71 million worldwide who carry the bug.  Some of the people who are chronically infected with Hepatitis C develop cirrhosis or liver cancer; the virus is responsible for the deaths of 400,000 people each year.

Hepatitis C was identified in the 70’s by researchers in at the Emeryville startup called Chiron.  It’s one of several viruses that inflames the liver, turns a person’s skin and eyeballs yellow, and drains their energy.  It becomes chronic in 70-85% of those who acquire the disease when they are adults.   A third of the infected people aren’t visibly ill.  But the disease smolders, they develop cirrhosis, and they die within 20 years.  A third never have significant problems. And in a third the virus isn’t harmful for many years, but at some point, for some reason, their liver slowly and progressively becomes inflamed.

By contrast, hepatitis A doesn’t become chronic.  Hepatitis E can become a persistent problem in people who are immune-suppressed.  Hepatitis B usually causes a self limited illness in newly affected adults, but becomes a lifelong problem for infants who acquire the disease from their infected mother.

For decades “C” was treated and often cured with interferon.  A year long ordeal, the treatment consisted of weekly injections that cause fever and exhaustion.  The bad effects usually last a few days and subside before it is time to get the next shot.   As I once explained to a young man who developed a fever and had no energy for the first two days after he received interferon:  “If you get an injection on a Friday you will be sick on Saturday and Sunday, but will probably be well enough to go to work Monday.  Would you like to be treated that way?” 

 “And ruin my weekend?” he shook his head.  “I don’t think so.”   He requested and I wrote him a year- long excuse from work.

My colleagues and I treated hundreds of people using this regimen.  The process was emotionally trying, but the people who desperately wanted to be cured, endured the weekly draining days.  In a significant minority the treatment didn’t eradicate their disease.  And for many that was heartbreaking.  

The doctors who developed the curative drug were scientists at Emory University.   One of them, Raymond Schinazi, was a Jew who was born in Alexandria Egypt.  In 1956 Israel and Egypt fought a war and Egyptian Jews became personae non grata.  His family moved to Italy, and he later studied at Bath in the UK.  “As a student he lived on 100 English pounds a month, worked as a parking attendant to help pay his way, and didn’t have real money in his pocket until he won 3000 pounds in the Spanish lottery.”  After receiving his British degree he did his post doc work in Yale and spent three years making “chemicals similar to Nucleosides.” A bear-sized man who speaks bluntly, negotiates fiercely, and favors splashy, multicolored shirts, Dr Schinazi enjoyed the science but not the weather at Yale.” –. “We had two really cold winters in a row in New Haven, with tons and tons of snow.⁵” So he moved south.

When the world learned HIV was caused by a virus, Schinazi was a professor of Pediatrics at the VA hospital in Atlanta.  As he explained (in interviews) he “couldn’t just sit around and do nothing.  We had the tools, the brains and the information” (He had done research on the Herpes Virus.)  He wanted to attack the virus with nucleoside analogues.  The VA resisted then assented, and Schinazi helped develop two of the more significant anti HIV drugs.  Profits from the sale of the medication went to his university.

Encouraged by his success Schinazi wanted to try to develop an anti Hepatitis C drug.  The NIH, allegedly, turned down his application for the project.  He and a partner got venture funding and founded Pharmasset.  One of their company chemists, Michael Sofia, developed Sofosbuvir, a drug that, with a little help, cured hepatitis C. “

“Pharmasset planned to sell the drug at a total cost for the treatment of around $30,000.⁴  

In 2011 Gilead  bought Pharmasset for $11 bn.   Schinazi received $440 million and went on to do further research. Gilead now had to sell and charge a lot for the medication.  The original list U.S. price for the company’s two drug combination, Harvoni, was $94,000.

During an interview with journalist Jon Cohn, Shinazi was asked about “Sofosbuvir’s price tag of $1000 per pill.”Shinazi pointed out that Gilead decides on the price, and he called it  “obscene” but not unreasonable. “Is it fair to pay $3 for a bottle of water when you’re thirsty? This is something that cures you from a disease.”

For most of those infected treatment wasn’t urgent, but Gilead had to move a lot of their product before competitors developed a drug combination that worked as well as Solvadi.  The company spent $60 to $80 million on TV ads in which people said they were “ready” to be cured.

Approved late in 2013, Gilead’s drug combination, Harvoni (ledipasvir/sofosbuvir) created revenues of more than $10 billion in 2014.  Then Gilead marketed two additional anti viral combinations. Each was made up of sofosbuvir plus one or two other drugs that suppressed Hepatitis C.  Each cured most people who had the disease.  Gilead’s revenue from the sale of the anti-virals neared $20 billion in 2015.

In August of 2017 the FDA approved a second combination of anti Hepatitis C drugs.  Called Mavyret, “It was initially priced at $13,200 per month, or $26,400 per treatment course, before discounts.” At the time a curative course of Gilead’s three Sofosbuvir combinations:  Epclusa, Solvadi, and Harvoni were priced at $74,760, $84,000, and $94,500 respectively.  Gilead sold $13 billion worth of anti virals in 2015.  In 2018 the company projected “$3.5 billion to $4 billion in U.S. sales.”

When companies spend billions to control the sale of a drug, we all pick up the bill.¹

Gilead, the company that made the $11.9 billion gamble was founded in 1987 by John Riordan, a 29 year old M.D. and business major.  During its first 15 years the company created a few drugs,“took in 2 billion dollars from investors and lost ¾ billion dollars.” 

In 1990, the head of Gilead embarked on a new approach.  He convinced John Martin, the Bristol Myer Squibb head of antiviral chemistry, to jump ship and come to his failing company.  When Squibb decided “they no longer wanted to develop” a promising antiviral that was created in Prague by the intuitive Czech researcher, Antonin Holy the rejection “hit like a ton of bricks”.  It came 2 years after Czechoslovakia had been allowed, by Gorbachev, to free itself from Russia’s grip.  John Martin, realizing Squibb’s error, because he phoned Holy and convinced him to sign a licensing agreement with Gilead….which they did a few months later—on a napkin–in a restaurant near the Eiffel Tower.¹² (I tell this story in the chapter on HIV)  Gilead tweeked the nucleotide and it became the basis of several potent Gilead medications that are currently used to prevent and treat HIV and active hepatitis B.  They helped Gilead become solvent, and they, no doubt, added to the confidence and fire power it took for Gilead to purchase Pharmasset and later Kite, the company that is developing CAR-T therapy for lymphoma.⁸   In 1996 Martin became Gilead’s chief executive, replacing Riordan, who retired to Paris.¹⁰

————————————————————————————————-

In 1999, as part of a hostile takeover Pfizer paid $90 billion and swallowed Warner Lambert, the corporation that owned/controlled Lipitor.  Pfizer went on to sell a lot of the medication. It became the world’s best selling drug.  In a 12 year span (1997-2009) Pfizer sold more than $80 billion of the pharmaceutical for $5-$6 per 20mg pill.

To understand the drug’s appeal we have to remember that 800,000 people a year–one in three deaths in this country are the result of a heart attack or stroke.  92 million adults are living with heart disease or the after effects of a stroke.  Vascular disease isn’t preventable, but it’s more likely to occur in people with a family history, high blood pressure, diabetes, or to those who smoke or have a high serum cholesterol.

Since the 1950s doctors have believed that if they could lower the level of cholesterol in the blood they could prevent some heart attacks.  A low fat diet helps, but major dietary restrictions sometimes fail.  Our bodies require cholesterol.  It’s a component of cell membranes, hormones and much more.  And we produce it, mainly in the liver.  When we make too much our blood levels rise and we are at risk for heart disease.  Over a few decades researchers have unsuccessfully sought a molecule that would block the synthesis of cholesterol.  The chemicals they came up with were toxic or not very effective.

In 1973 a researcher in Japan, Akira Endo extracted a statin from a blue-green mold.  When taken by a human it caused the blood cholesterol level to drop.  Born in a rural northern Japan Endo “grew fascinated with mushrooms and other molds when he was young.”  As a college student he read and was inspired by a biography of Alexander Fleming, the man who discovered penicillin in a blue-green mold.  What other amazing juices do these growths produce? After a few years as a researcher he spent 2 years in the U.S and “was surprised by the rather rich dietary habits of Americans compared to those of the Japanese.” While living in the Bronx he recalled seeing ambulances that took people who had suffered a heart attack to the hospital. When he returned to Japan he became an investigator for a Japanese pharmaceutical company.  At one point he wondered if “fungi like molds and mushrooms could produce antibiotics that affected the synthesis of cholesterol.”  His company allowed him to choose his field of research, and over a number of years he studied the “juice”–the metabolites and toxins produced by over 6,000 types of fungi.  In the early 1970s he cultured the fluid produced by a blue green mold that was growing on a rice sample in a grain shop in Kyoto.¹³   It blocked the cholesterol synthesis pathway and became the first statin.  Endo’s discovery was huge.⁶ The recipe it provided was, over time, modified and tweeked by researchers who developed increasingly better cholesterol lowering medications.  

After confirming Endo’s findings, Merck scientists, used an aspergillus (and Endos methods) to create the cholesterol lowering drug Lovastatin.¹¹   A 1994 Scandinavian study showed that statins “led to a sharp drop in fatal heart attacks for patients with heart disease.”  The following year Merck sold more than 4 billion dollars worth of Simvastatin and Lovasatin.

Many tried to make a superior statin.  Bruce Roth, a researcher at Warner Lambert in Ann Arbor synthesized Lipitor and showed it was very potent –the strongest available.  Growing up outside Philadelphia and loving the night sky, Roth, initially wanted to be an astronomer.  He was in high school when he “realized” that “there were only like three jobs in the whole world for astronomers,” and he decided to become a chemist.  As he learned the craft he came to believe that “there really are true artists in organic chemistry.” He got his Ph.D. and played intramural softball at Iowa State University.  And when he was 30 he moved to Ann Arbor, Michigan, where he “used his skills” to create the statin molecule called Atorvasttin.¹⁴

After it was tested and FDA approved, Warner Lambert joined forces with Pfizer, and the drug was “aggressively” priced and promoted.

Then (apparently) something went wrong and Warner sought to be acquired by someone other than Pfizer.  Pfizer wasn’t having it.  In 1999, as part of a hostile takeover, Pfizer paid $90 billion, swallowed Warner Lambert, and went on to sell lot of Lipitor.  When Pfizer’s monopoly ended their profits dropped and the company attempted to avoid U.S. taxes by moving their headquarters to Ireland.³

“To sustain a $20 billion-a-year business (a firm like Pfizer”) needs to add one new blockbuster medication to its portfolio each year”…” to maintain their revenue base, large companies need four “$1 billion-per-year drugs…,”  (That’s the conclusion of  Bernard Munos, a leading thinker.)  He says the pharmaceutical industry of the 1980s was a “haven” for creative scientists whose work was based on “cutting edge discoveries coming mostly from academia.” Proceeding at their own pace and pursuing clues as they went, these researchers steered their own course and pace.  Industry assumed they would eventually create a commercial product.  The approach was “risky”– but it led to a lot of innovative medications.⁷

In the 1990s business savvy CEOs became the leaders of most of the large corporations.  They tended to be scientifically untrained or illiterate, and they were troubled by the apparent disarray in their R and D divisions.  Scientists kept changing course.  There were no deliverables.   “To them (what they saw) epitomized mismanagement.”  So the CEOs changed the culture.  Researchers were now expected to be “responsive to the marketplace”.  A “process” driven–goal driven culture was created, and true innovation was largely “destroyed.” Munos believes leading edge innovators aren’t focused on the existing customers and markets.  They want to make something that “transforms—obliterates” the status quo.²

http://fortune.com/2018/04/12/hepatitis-c-cure-300-dollars/. https://www.goodrx.com/blog/fda-approves-mavyret-for-hepatitis-c/https://cen.acs.org/articles/95/i5/year-new-drugs.html https://www.youtube.com/watch?v=ZKHEARXDFKo

https://cen.acs.org/articles/95/i5/year-new-drugs.html

https://www.nytimes.com/2015/10/30/business/dealbook/allergan-pfizer-deal.html

p.115  Mistreated by Robert Pearl.  Public Affairs Press.  2017

https://joncohen.org/2015/05/08/king-of-the-pills /     https://www.ft.com/content/e7925e46-fc86-11e3-86dc-00144feab7de

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108295/

https://www.researchgate.net/publication/40042500_Munos_B_Lessons_from_60_years_of_pharmaceutical_innovation_Nat_Rev_Drug_Discov_8_959-968

https://www.youtube.com/watch?v=fcgo2IOwkM4  https://www.radio.cz/en/section/panorama/belgian-virologist-de-clercq-remembers-czech-chemist-antonin-holy-and-their-work-on-revolutionary-hiv-drug

The Atlantic.  March 23, 2019.  https://www.theatlantic.com/health/archive/2019/03/drug-prices-high-cost-research-and-development/585253/

The Golden Age of Antiviral Drugs October 27, 2003 Forbes https://www.forbes.com/global/2003/1027/090.html#163387a0753b

Robert Hauser, Heart Stories, chapter 11

Cold War Triangle, by Renilde Loeckx, 2017.  https://books.google.com/books?id=jnw0DwAAQBAJ&pg=PT120&lpg=PT120&dq=michael+riordan+steps+down+at+gilead&source=bl&ots=6IGTV570g-&sig=ACfU3U0xOYfOTgJrU7RzsHhdWGBHloEL6Q&hl=en&sa=X&ved=2ahUKEwj2kaGUxuHoAhUvJzQIHVMRC5AQ6AEwCHoECAwQLw#v=onepage&q=michael%20riordan%20steps%20down%20at%20gilead&f=false

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108

https://www.gene.com/stories/a-star-in-his-own-right

Margaret Mead https://www.loc.gov/exhibits/mead/field-samoa.html

There are many reasons to question the widely held notion that high drug prices and innovative research are inextricably linked.⁹ EZEKIEL J. EMANUEL

.”

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