SURGERY

55 Years ago, as an intern, I slept in a hospital provided room and worked most days.  Meals were free and I was paid $55 every 2 weeks.  When rotating through surgery I rolled out of bed between 5 and 6 A.M. and accompanied the cowboys of the hospital, the general surgeons, as they made in-patient rounds.  We ate breakfast and washed hands for 10 minutes by the clock.  Mornings were spent tugging on a retractor, stretching open the edges of the wound while a gall bladder was being removed.

Long skin incisions were usually needed when the surgeon was operating on someone who presented to the emergency room with severe pain and rigid abdominal muscles, or when merely touching the belly made the patient withdraw.  Sometimes we wondered if the appendix had ruptured?  Was blood pouring into the abdomen of a person who had been shot or stabbed?  Why did the X-Ray show air filling the abdomen?  Did an ulcer perforate?

The lengthy slash through the skin and the fat layer was followed by a pause to buzz (electrically cauterize) or tie off the severed ends of bleeding arterioles.  A series of additional gashes cut a path through layers of fat and muscle.  A scissors sliced open the peritoneum, the membrane that surrounds the organs.  The opening had to be large enough for the surgeons to see what they were doing and to get their tools and hands inside.  Sliding a large light over the opening, an assistant would aim the beam down the long, dark tunnel.  The smaller the gap, the more precise the ray had to be.  Deep inside tissue was cut, clamped, and sewn by skilled people using long handled tools.  Adhesions, fibrous tissue caused by prior operations, created matted intestines and made it hard to identify various organs, blood vessels, or nerves.  By slipping a hand into the cavity and palpating the edges of the liver, pancreas and other organs— by feeling for masses or abnormalities, the surgeon “explored the abdomen”.  Aware of “the possibility and consequences of failure,” the surgeons needed to be able to improvise when they had a complication or encountered something out of the ordinary.  The people doing the cutting had spent many of their waking hours practicing basic techniques like sewing and tying knots, and they were adept.  When I was a junior medical student one of my buddies bragged that the resident let him remove the patient’s appendix.  It made no sense at the time, and it still doesn’t.17

Man has long known how to “suture lacerations, amputate limbs, and drain pus.”   Prior to 1858 the people who cut and sawed learned their craft as apprentices.  When gangrenous or damaged limbs had to be amputated, resections were quick, bloody, and accompanied by loud shrieks. The fastest knife in England was wielded by Scottish surgeon Robert Liston. “Operating with a knife gripped between his teeth,” he could amputate a leg in two minutes. On one occasion he inadvertently cut off the fingers of someone holding a person down.  The stump end of the man’s fingers and the raw end of the hip got infected and both men died.

Elective surgery was uncommon.  Perforations or obstructions of the intestine were not approached.  In the U.S. and Europe, medical school learning was “wholly didactic: seven or eight hours of lectures a day, supplemented by textbook reading. Laboratory work was sparse, and there was no opportunity to work with patients.28

In the 1800s some surgical procedures were carried out in homes.  Doctors at a few prestigious hospitals performed operations on a stage that was surrounded by a semicircle of tiered seats. Observers apparently came to watch and perhaps be “thrilled by spectacular public performances.24

In the mid 19th century we learned about and started using anesthesia to prevent pain.  Surgeons could now enter the abdomen or thorax, but they didn’t know what to do when they got there.  Operating rooms became “quiet and to the observer seemed tedious.” A number of new operations were developed and there were risks, failures, and deaths. Apprentices learned the techniques of one practicing surgeon, then struck out on their own. There were no blood banks or antibiotics.  It’s not clear how often the adage see one, do one, teach one was more than a tall story.25, 26

In 1890, William Halsted, the son of a wealthy “tight-fisted, hard- nosed Presbyterian” started the nation’s first surgical residency program at Johns Hopkins University in Baltimore Maryland.  “Self trained, as were all U.S. surgeons of the day, he spent 1 year as an intern at Bellevue, 1 year as a house physician at New York Hospital, and then 2 years abroad as an observer.” While in Germany, Austria, and Switzerland, he saw how other countries trained young surgeons, and he realized the U.S. system was ineffective.  There was no mechanism for developing and passing knowledge on to other doctors.  Halsted developed the nation’s first residency program at Johns Hopkins Medical School. 30

For many years Halsted trained many of the nation’s future teachers and professors.  The doctors on his service created and modified operations, and they taught one another. 11 of his 17 chief residents started training programs in hospitals in other parts of the country. 

A “bold aggressive surgeon” when young, Halsted was addicted to morphine and heroin when he came to Hopkins.  His operations were performed “almost excruciatingly slowly and meticulously.”  On one occasion he must have been under the influence because he stopped operating and asked an assistant to scoot over.  The man had been standing on his foot for the pervious half hour.”  Outwardly shy, Halsted was adamant about cleanliness, bleeding control and carefully reconstructing tissue.  He had quirks like shipping “dozens of his dress shirts to Paris or London every year for laundering.  His wife was only allowed to burn white oak and hickory in his fireplace.” In his operating room surgeons and nurses wore rubber gloves not to prevent infections but because one of the scrub nurses developed a rash when she immersed her hands in mercuric chloride.          

Dubbed the nation’s father of neurosurgery, Harvey Cushing, was born into status and privilege.  His father, grandfather, and great grandfather were all prominent Cleveland surgeons.  He was a descendent of the Puritans who landed in Boston 18 years after the Mayflower, and he was a descendent of the nation’s 4th ever Supreme Court justice.  At Yale he was a gymnast and would somersault backwards with a lighted cigarette in his mouth.”   After medical school his money and influence allowed him tour Europe and meet and observe the world’s most prominent surgeons.  In 1913, after spending 4 years as one of Halsted’s surgical residents he moved to Boston.  When Harvard’s Peter Brent Brigham opened its doors in 1914 he was the hospital’s first chief of surgery and the founder of the country’s second surgical training program.

During the First World War Cushing performed surgery on soldiers with severe head wounds.  Up to 8 times a day he removed a part of the bone from the skull and exposed the brain.  Later at Harvard he learned and taught many others how to operate on brain tumors.  A talented surgeon, Cushing had removed 2000 brain tumors by the time he retired. His mortality rate was half that of his colleagues.

Described as “a man of ambition, boundless, driving energy, and a fanatical work ethic,” he also had “a penchant for self-promotion and ruthlessness.”  He insulted his residents and operating-room nurses for their errors and tended to blame others for his mistakes. Outside the hospital he paid little attention to his family and had no patience for women.  When “his oldest son, 22 year old William was killed in a traffic accident Cushing received the news in a telephone call in the morning, informed his wife, and continued to the hospital to perform his scheduled surgery.18 

Two decades later in St Louis Missouri, Evarts Graham removed a lung that contained cancer and his patient survived.  Graham went on to become one of the giants of his era. 

Deciding at a young age that he would follow his father’s path and become a doctor, Graham went to Princeton, then Chicago’s Rush Medical school.  His father David, a professor of surgery at a women’s college and a hospital chief of staff, was well connected.  David presumably learned how to operate as an apprentice and he was not (according to his son) “by any means a polished or trained surgeon.”  I suspect he didn’t wear a mask when he operated because his son tells of how, prior to performing surgery, David Graham washed his hands then “washed his beard in antiseptic solution.” 

Evarts, ever ambitious, became the president of his class, performed 50 autopsies while in school, and wrote a number of journal articles.  In 1907 when most graduates “left school and became general practitioners,” he spent five months as a surgical intern.  He assisted his father, “occasionally performed operations under his dad’s supervision,” and at the end of his internship believed he was qualified. 

Joining a group of physicians in Mason City Iowa a town of 22,000, he was appalled when he learned that surgeons paid colleagues a portion of their fee for referring the patient.  Surgeons, he believed, should not be chosen on the basis of how much they pay the referring doctor.  Becoming embroiled in a campaign to end “fee splitting,” he was considered an upstart by some colleagues, and was the brunt of “personal attacks.” When the U.S. entered the First World War in 1917 he volunteered for the army and left town. 

Unable to become a battlefront surgeon because his vision was “defective”, he became an assistant Surgeon General.  Young and inexperienced, he was sent to Alabama and given orders to take charge of the local military hospital.  When he presented his papers to the facility’s medical commander, the doctor refused to step down.  He “didn’t give a damn about Graham’s orders” and called Graham a fly-by night major.  Evarts fought back, tried to label the Colonel a German sympathizer, and got the Surgeon General involved.  The hospital eventually became Graham’s, but the facility wasn’t sent to Europe until November 1918, the month the war ended.  Graham was in charge during the 1917 and 1918 influenza pandemic.  It devastated the world and killed more soldiers than the enemy fire had. 

While in the military, Graham studied empyema, pus that developed in the space just outside the lungs but inside the thorax, in some people who had pneumonia.  The smelly material had to be removed but “open drainage resulted in a high immediate mortality rate.”32 Graham was part of a group that figured out the safest time to draw off the fluid.  In civilian life the infected liquid was usually a result of pneumococcal pneumonia.  It typically appeared after the infection was improving, at a time when the lung was partially attached to the chest wall by scar tissue. Drainage was safe. 

In people with battlefield wounds the pneumonia was often caused by streptococcus.  The fluid appeared early, was massive and thin “like pea soup.”  Adhesions would not form for a few weeks   When a large amount of fluid was drained too early the mediastinum, the structure that encased the heart, often shifted dramatically and the good lung collapsed.  Many died.35

After the war ended, based on recommendations from doctors in Chicago, Graham was chosen to be the professor of surgery at Washington University in St. Louis, a school that was growing and reorganizing.  In the early 1900s the university had been rated as “a little better than the worst”.  After the world war it received funding from Rockefeller and Robert Brookings, a St Louis millionaire who grew rich selling wooden spoons and bowls.  The school was hiring and paying full time professors.  No longer needing a private practice on the side, doctors were salaried and could devote all their time to teaching and research.  The concept was new, but Graham embraced it, his department developed surgical subspecialties, and the school flourished. After he successfully removed a cancerous lung Graham operated on two more cancer patients.  Both died.  Then 5 in a row survived.

An avid smoker Graham “openly scolded colleagues for suggesting that cigarettes caused lung cancer. “Yes, there is a parallel between the sale of cigarettes and the incidence of cancer of the lung, but there is also a parallel between the sale of nylon stockings and the incidence of lung cancer.” Shortly before he died of lung cancer in 1957 Graham publically conceded cigarettes were responsible for his malignancy.  In 1965 his successor Thomas Burford, a heavy smoker who operated on countless smokers with lung cancer told a Senate committee that he did not believe cancer was caused by cigarettes.  His death was in part due to emphysema caused by his heavy smoking22 

In the early 20th century surgeons increasingly learned how to remove tonsils, appendices, gallbladders, and cancers.  Other skills and techniques were acquired while caring for the wounded in First World War.  As the century wore on operating rooms became cash cows for many hospitals. 

In 1961, during my third year in medical school I spent a week with a physician in a small town an hour drive from St. Louis.   The doctor was a friend of the family and had removed my tonsils when I was 6.  Like most general practitioners of the day he cared for common injuries, delivered babies, and performed a few operations.  People who needed complex interventions were sent to an experienced surgeon in St. Louis.  For standard operations like hernias and diseased gall bladders a surgeon came from the big city once a week and operated in the local hospital.  The visiting surgeon earned a bit of money and taught the local docs who assisted him.  They scrubbed in and learned how and when to cut into an abdomen.  They needed to know because some problems couldn’t wait.  On occasion a patient’s condition was such that he or she might not survive if their operation was delayed for the few hours it took to travel to St. Louis and find an available surgical crew and operating room suite.   

Prior to the 1950s, with a few documented exceptions, the inside of the heart and major blood vessels were off limits. 

One of the “exceptions” occurred when bullets and shrapnel entered a soldier’s heart during battle.  During the Second World War, Dwight Harken, a battlefield surgeon wrote his wife about a time he used a clamp to grasp a piece of metal deep in a heart’s ventricle.  He felt the pressure force the fragment to jump out.  It was sudden and like uncorking a bottle of champagne.  “Blood poured out in a torrent.”  Harken sewed the opening in the muscle closed and the patient survived.  He later removed bullets and shrapnel from 56 wounds “in or in relation to the heart.” 

Son of a physician who made house calls on horseback and a former prize fighter, Harken was harsh, energetic, and aggressive.  He became a Harvard professor and at one point decided to fix “rusty” mitral valves.  That’s the gate that opens and closes when blood flows from the atrium (the collecting chamber) to the ventricle (the muscular compartment that forces blood out.) The valve can become calcified and stiff.  Harken thought he could pry the area open with a finger or cut it open with a blade that he inserted through an incision in the atrium.  In 1948 he operated on 10 patients.  In the process he sometimes loosened a blood clot, it traveled to the person’s brain, and they had a massive stroke.  Six of his first ten patients died.  Harken kept at it and 14 of the next 15 patients survived19.   

The other notable “heart exception” took place in the major vessels just beyond the heart.   The fetus receives oxygen rich blood from the placenta and shunts most of it around the lung.  .  A surgical resident named Richard Gross learned how to seal a detour between the upper aorta and the pulmonary artery that generally closes by the time a newborn is 6 weeks old.  When the ductus (we still call it by its Latin name) remains “patent” it puts pressure on the right side of the heart and the baby has problems. 

In 1938 Gross was a chief resident at Boston Children’s Hospital and he learned how to close the defect in dogs.  He wanted to try his technique on a child, but his chief of service “forbade” human surgery.  Gross waited till the chief was on vacation.  Then he operated on a 7 year old girl.  The anesthesia nurse who helped him “was scared to death.” The operation had been tried at another hospital and the child had died.  Gross’ patient did well, but the chief of service was “furious.” “Some accounts say Gross was fired.”  Years later when the chief retired Gross succeeded him. 

The son of a German immigrant, Gross was blind in one eye.  He had a congenital cataract.  To compensate for his lack of depth perception his father encouraged him to take clocks apart and put them back together.  The exercise helped him develop depth perception and motor skills and it “instilled a love for tinkering.”  A cardiac innovator he once said “an academic surgeon has to pull a new rabbit out of a hat every few years.20

In 1950 president Harry Truman called heart disease “our most challenging medical problem” and federal funding started flowing.   In 1947 the NIH was spending $4 million a year and by 1950 $46 million.  A number of medical schools wanted some of that money and recruited and hired talented physicians who were ambitious and wanted to make a difference. Two of the major programs were located 90 miles apart in Minnesota.

The major defects that were tackled early were openings between the heart’s receiving chambers, the right and left atria or between the heart’s pumping chambers, the right and left ventricles.  They couldn’t be sewn or patched shut because a surgeon couldn’t see what he or she was doing when the heart was beating and full of blood.  When the “defects” stayed open blood was pushed from the left to right side with each heart beat.  The left heart muscle is more powerful than the right.  Over time the atria or ventricle on right side gets would get full, then stuffed and stretched. 

By the time cardiac surgeons started tackling the problem started John Gibbon had spent 15 years trying to build a machine that could keep the body alive when the heart chambers were empty.  To work, his pump had to be filled with a lot of blood.  It was hard to sterilize and would periodically break down.  In 1935 using his machine Gibbon kept a cat whose heart wasn’t beating alive for 20 minutes.  That made the papers.  In the 1950s he was introduced to Tom Watson, head of IBM, and Watson asked one of his engineers to help Gibbon.  Three years later the Gibbon machine kept a young woman alive long enough for Gibbon, a surgeon, to sew shut a hole between the upper chambers of her heart.  His efforts and limited success showed that much could be done if surgeons had a good heart lung machine. 

The descendent of a long line of doctors Gibbon was the 6th physician in the chain.  As a sophomore he wanted to quit medicine and become a writer, but his father talked him out of it and convinced him to use his writing urge to promote medical research. Graduating from medical school in 1927, he was an intern when a young woman who broke her leg developed a blood clot that traveled to her lungs and killed her. He thought he could have saved her life if he had a machine that bypassed the lungs, a “heart lung machine.”  In the 1930s as a Harvard research fellow, he tried to construct such an apparatus.  Harvard gave him a small grant.  The chief of surgery, who thought the project was nonsense, gave Gibbon lab space. 

A surgeon by day, Gibbon spent his evenings “in the little room in the cellar of the Massachusetts General Hospital.”  A nurse helped him.  They were together every night, and they eventually married9” and moved to Philadelphia.  The machine Gibbon developed was a conglomeration of a filter from here and a pump from Michael DeBakey, a future vascular surgeon.  DeBakey’s device, designed when he was a medical student, was based on the irrigation pump developed by the Sicilian Archimedes in the 2nd century B.C. 

When the Second World War ended Gibbon became a medical school professor in Philadelphia.  After he successfully sewed an interatrial septal defect closed in 1953, Gibbon operated on 5 kids with holes in their hearts.   They all did and Gibbon “led a movement to have Congress ban or have a moratorium on heart lung surgery for an indefinite time.  It didn’t succeed.

By the early 1950s surgeons at the Mayo Clinic and 90 miles away at the University of

Minnesota started operating on kids with congenital heart defects.  Each group used a different heart lung machine and each center suffered through the tragic deaths of a number of children. 

 The University of Minnesota group was led by Walt Lillehei, a bright talented suburban kid whose father was a doctor.  During the Second World War Lillehei accompanied the troops that landed on the Italian coast, 35 miles south west of Rome.  The Germans allowed them to come ashore then mercilessly bombarded them for four months.  Seven thousand Americans and Brits were killed and 80,000 were wounded, missing, or hospitalized.  Lillehei “saw the horrors of modern warfare” and it may have had an effect on the way he emotionally dealt with death.

In 1945 he became one of the young surgeons at the University of Minnesota.   Wangensteen, the chief of surgery at the time, was the son of an immigrant farmer.  He had a photographic memory and was the best student in each class, but he didn’t want to be a doctor.  Then his father exposed him to the harsh reality of farming.  The summer before he was scheduled to enter medical school Wangensteen spent his days hauling manure.  At the end of the summer he decided “anything would be better than this.” When fall rolled around and classes began Owen was a medical student and excelled.  

The Mayo Clinic attempt to fix heart defects was led by a young surgeon named John Kirklin.  He graduated from Harvard Medical School In 1942 and was stationed in Missouri during the Second World War.  Before returning to Minnesota Kirklin visited Gibbon, and he brought a Gibbon heart lung machine and/or its specs with him to Minnesota.  He then convinced a few engineers to help him improve it. In 1955, after 9 of 10 dogs survived the machine, Kirklin used the heart lung bypass and operated on 8 kids with congenital heart problems. 4 died and Kirklin learned what he was doing wrong. By the end of the year Kirklin had sewn closed holes between the upper chambers of the heart in 29 additional kids without another death.

            Fixing the gap between the two ventricles proved to be risky. The wiring that stimulates the pumping chambers sits on the edge of the opening between the right and left pumping chambers. When the wiring is inadvertently tied off, the heart slows and sometimes stops beating. 

The Lillehei heart lung machine didn’t always supply enough oxygen and early on  surgeons got extra oxygen rich blood by connecting the arteries and veins of the patient with those of a parent.  That put two individuals in harm’s way.  Thomas Starzl was present during one of those operations and “witnessed a tragedy.”  A parent veins were pumped full of air when a pressurized bottle ran out of fluid and no one noticed.  Her heart stopped, she was resuscitated, and she had permanent brain injury.  Ultimately she died.”  After a few cases Lillehei stopped using cross circulation.  16 of the kids he operated on had ventricular septal defects and over half survived23

In the early 1950s the heart-lung pump wasn’t very good and Bill Bigelow, a Canadian Surgeon told the world about hypothermia.  Bigelow began pondering the effect of cold on a body after he cut the fingers off a man who developed frost bite, then gangrene.  He, of course, knew that some animals hibernate and survive “cold dark winters by turning down their metabolism.” One day he awoke with the thought that maybe hypothermia could be used to “decrease the body’s need for oxygen and thus allow surgeons to operate on a heart.”  Working in a basement room in Toronto he learned how to control a dog’s shivering and lowered the animal’s body temperature to 68 degrees Fahrenheit. After waiting 15 minutes he warmed the animal.  It was unharmed.  He presented his findings at a medical meeting and John Lewis, a Minnesota cardiac surgeon was inspired.33,34.

Working with dogs Lewis learned how to safely cool the animal and clamp the vessels that supplied blood to the heart.  In 1952 he slowly lowered the temperature of a 5 year old girl who had a hole between the atria of her heart.  When it fell below 86 degrees Fahrenheit Lewis blocked blood flow to and from the organ, opened the atria, and sewed the defect shut within 5 minutes.  During the next 3 years he repeated the operation in 60 more people21

In the spring of 1958 Dr. Albert Starr was running the only heart surgery team in Oregon, and was mainly performing surgery on kids with congenital defects.  He was “up to his eyeballs” in clinical work when a 60 year old engineer with a “background in hydraulics” Miles Edwards, arranged a meeting.  They talked about an artificial heart and decided to “start” improving the heart one valve at a time.  It took two years before they were able to implant an artificial gate that opens to let blood through, then closes to prevent it from pouring back in the chamber that ejected it.  The valve was handmade and acrylic.  Later valves were made of stainless steel, and still later a non corrosive material10.    By 2018, 182,000 metal and tissue heart valves were being replaced each year in the U.S.11

Periodically a technique or technology shook things up and made surgery easier or better.  Doctors slowly adjusted, and the new gradually became the norm.

In 1984 Eddie Joe Reddick, the doctor who made surgeons alter their approach, moved to Nashville.  He came “in part because he loved the music.” The grandson of an Arkansas soy bean farmer, Reddick went to medical school, was drafted, and while in the army became a trained surgeon.  As a military doc, he used a long hollow tube with a light on its end, a laparoscope, to help a colleague locate and biopsy a liver.  He learned how to manipulate the instrument.  After he was discharged, he moved to Music City and wrote country music.  (His song, “I’m Listening to Hank” made it to number 70 on the country music billboard.)

As the new guy in Nashville he struggled financially for a while, and made a little money assisting gynecologists perform laparoscopic procedures.  Early scopes that allowed us to see areas deep in the abdomen were rigid metal tubes with tiny bulbs on the end.  Gynecologists could introduce a laparoscope, and insert grasping or sewing instruments through the scope or through adjacent tiny incisions.  They would watch through a magnifying lens as they tied fallopian tubes shut, biopsied suspicious growths, checked out ovarian cysts, or tore through adhesions. In the early 1960s, older models were gradually replaced by instruments that used quartz light rods.  A few decades later, video chips on their tips allowed surgeons and their assistants to see what was happening by studying TV monitors.  

In 1988 Reddick met a Georgia surgeon named McKernan at a medical meeting, and he was intrigued by his fellow doctor’s plan to remove a gall bladder using the laparoscope.  A few months later, McKernan found a willing patient and would have become the first American to remove a gall bladder through a tiny hole, but the stone in the “bile bag” was big, and McKernan had to make an incision to get it out.  Two days later, this time in Nashville, Reddick used a laparoscope. Assisted by a scrub nurse he excised a diseased gall bladder and pulled it out through the tiny hole.  He cut through tissue with a laser, and didn’t use a needle and thread to tie off the cystic duct and artery.  He clamped them shut with a homemade clip.  The patient recovered and went home in short order. 

People obsessed with detail are quick to point out that the two southern doctors were not the first to remove a gall bladder laparoscopically.  A surgeon in Germany named Muhe removed one in 1985.  His patient died post–operatively and there was a subsequent legal hassle.  Two Frenchmen removed gall bladders by this technique in 1988, but their colleagues apparently didn’t think it was a big deal, and they temporarily ended their venture. 

Reddick’s patients by and large got well quickly, and his complication rate was low.  He had the touch, the knack, the hidden quality that makes some surgeons really good.  But he didn’t come from a big medical school, wasn’t a professor, and I suspect he was looked down on by the men who gave lectures and wrote books.  Reddick published his results and wrote about the successes of McKernan and a doctor named Saye.  At a medical meeting the following September, he gave a talk and played a three-minute video of a gall bladder being removed laparoscopically.  In subsequent months, surgeons were invited to his O.R. to watch and assist.  A few came.  Some of the surgeons at his hospital were nervous and “urged that he not be allowed to perform the procedure,” but the hospital review board gave him the green light. 

Someone alerted the media.  The Wall Street Journal wrote an article about the medical maverick, and ABC World News ran a story that was seen by millions.  At a subsequent surgical meeting, a few instrument companies ran tapes of his surgeries in their booths, and crowds of doctors gathered around.  Then Reddick and Saye opened a training center in Nashville for doctors who had long since completed their formal training.1

As skills grew and people recovered from their operations relatively quickly, surgeons increasingly removed stone–filled gall bladders that may or may not have been causing problems.  Within a few years, twice, then four times as many of the muscular sacs were excised annually.  Over the subsequent 20 years, surgeons learned to perform a slew of additional operations laparoscopically.  Inflamed appendices were removed, hernias were plugged from the inside, and cancer containing portions of colon were resected.  Renamed minimally invasive surgery, the approach was used to treat heartburn that was caused by the reflux of stomach juices and hadn’t responded to pills.  It was long known that the problem could be controlled by wrapping the upper stomach around the esophagus, but a surgeon had to get his or her hand into the narrow space under the rib cage.  Access was difficult, and the spleen (which was often in the way) was sometimes damaged.  The laparoscope made the procedure safer.  The minimally invasive approach was also used to turn many a large stomach into a receptacle the size of a shot glass, and to thus help obese people lose weight. 

Chest surgeons increasingly used scopes inside the thoracic cavity to identify and biopsy abnormalities, to remove parts of a lung or pleura, and to perform a number of procedures on the esophagus, the swallowing tube that runs through the back of the chest.  Problems that used to require a long incision and spreading of ribs could often be solved with VATS, –video–assisted thoracic surgery. 

Using a similar rigid scope and a camera, orthopedists entered knee joints without damaging the surrounding muscles and ligaments.  They repaired torn internal ligaments and injured cushions (menisci).  Some used the approach to mend torn shoulder rotator cuffs and to patch tears in the cartilage that lines the rim of the shoulder joint—the labrum.

Back surgeons call surgery performed through a small incision using a scope with a camera on it–minimally invasive surgery.  They are sometimes able to employ the technique to remove herniated discs and fuse vertebrae.  A few years back I had sciatica.  The pain was in the left leg and was caused by pressure on the nerve that traversed the space between my 4th and fifth lumbar vertebrae.  The MRI showed a cyst was causing the problem.  A back surgeon inserted a scope, removed the cyst, the pain disappeared, and I went home. 

Ear, nose, and throat surgeons who wanted to visualize and remove head and neck tumors had approached growths with incisions made in the chin or neck.  Over time, they learned to put a thin video endoscope through the mouth and advance it until they saw the enemy.  Jaws were only “cracked” when a tumor had invaded.  Called “small field” surgery, the approach allowed experts to destroy tissue and control bleeding with cautery or the beam of a laser.  After a growth was removed, the remaining tissue was biopsied and pathologists could tell if cancer cells were left behind.  Less blood was lost, and vocal cord function was preserved.

Fiber optic and later video endoscopes and colonoscopies were used by gastroenterologists.  They allowed ENT doctors to better evaluate vocal cord paralysis and other benign laryngeal problems.  Plugged sinuses could be opened and debris sucked out.

Neurosurgeons used scopes to remove pituitary tumors.  The gland they tackled is normally the size of a grape; it hangs below the brain in a “bony hollow in the base of the skull.” Some of the organ’s small tumors produce hormones that cause harm in dramatic and weird ways.  Before a local neurosurgeon entered a patient’s skull, my ENT colleague would “shove” his scope through the nose and breech the wall between the adjacent sinus cavity and the brain.  The abnormal pituitary growth usually looked like the top of an ice cream cone.  A neurosurgeon would take over and remove all or part of the gland piecemeal.   

A company called Di Vinci developed flexible small internal robotic hands whose actions could be monitored through a three–dimensional viewer.  Surgeons maneuvered the appendages remotely, using external, space age, knob-dial–fingers.  Those who mastered the approach claimed their resections were more precise.  The technique required a person to visualize tissue a little differently, and there was a learning curve. 

Medicine, like industry, has innovators who can mentally visualize the “possible” and find a way to make it happen.  In 1964 Michael DeBakey a Houston doctor used a vein from a person’s leg to create a tube that bypassed a narrowing in one of the coronary arteries.  The vein allowed blood from the aorta to circumvent the diseased vessel.  He didn’t report it to the medical community until 1973, when he could prove the graft had remained patent.9

“You learn on animals.  We did hundreds of bypasses on dogs and were 50% successful.  The first coronary bypass was an accident.  The patient was scheduled for an endarterectomy, separating the plaque (the deposit of cholesterol and fiber) from the inner lining of a diseased vessel.  We’d been doing the operation since 1964.  The nature of the first patient’s coronary artery blockage was such that we couldn’t separate the plaque.  His coronary arteries were so bad that we couldn’t get him off the table (and expect him to survive.)  So we did what we had been doing in dogs.  It was the first heart bypass. Fortunately it worked.  You have to take risks.  The first carotid endarterectomy was done on a man with recurrent episodes of temporary paralysis —TIA’s.  The carotid artery supplies blood to the brain and his artery had plaques.  He was a bus driver.  Surgery stopped his TIA’S. He lived for 19 years and died of a heart attack.  The first aneurysm of the aorta in the chest was causing pain.  We knew how to fix aneurysms in the abdomen and the man was hurting so he took the risk and agreed to surgery.13

DeBakey virtually created vascular surgery.  The son of Lebanese immigrants and a combat surgeon during the Second World War, he “convinced the surgeon general to form what would become the mobile army surgical hospital MASH unit.”  Later, as a Baylor University surgeon, he revolutionized our approach to narrowed blood vessels.  “In 1953, he performed the first successful carotid endarterectomy;” (he cleaned out one of the arteries that supplied blood to the brain.) 

As a youth he liked working with his hands. He and his brother took apart car engines and reassembled them. His mother taught him to knit and sew and “By the age of ten he could cut his own shirts from patterns and assemble them.14

He later used his boyhood skills to create a vascular graft from Dacron.   As he said in an interview: “When I went down to the department store … she said, ‘we are fresh out of nylon, but we do have a new material called Dacron.’ I felt it, and it looked good to me. So I bought a yard of it. … I took this yard of Dacron cloth, I cut two sheets the width I wanted, sewed the edges on each side, and made a tube out of it. .. . We put the graft on a stent, wrapped nylon thread around it, pushed it together, and baked it. … After about two or three years of laboratory work (and performing experiments in dogs), I decided that it was time to put the graft in a human being. I did not have a committee to approve it. … In 1954, I put the first one in during an abdominal aortic aneurysm. That first patient lived, I think, for 13 years and never had any trouble.2”  

Years later as a medical student at Baylor, TV doc Gabe Mirkin recalled that Debakey liked to visit the patients he had recently operated on at 5 AM.16  “He often was accompanied by an entourage of more than 50 people composed of medical students, surgeons-in-training and some of the most famous surgeons from all over the world. Mirkin “saw first-hand his incredible drive for perfection. As medical students, we would often study at the medical school through much of the night, and I saw the light at his office stay on as he wrote papers often beyond 3:00 in the morning.”27 

Three years after his first wife died, the 67 year old surgeon met and married an attractive 33 year old German woman “who dabbled in acting and painting.”  When the pastor performing the ceremony asked if Debakey preferred to sit during the ceremony his bride said “he stands for hours for his operations.  He’ll stand for this.”  Debakey performed over 60,000 operations in his lifetime and became a surgeon to the stars.  His patients included the Duke of Windsor and the Shah of Iran. 

The transplantion of one person’s organs into the bodies of another is a story of surgery, immunosuppression, and delivery of care.  It’s in the game changer chapter.

Many of the tasks of general surgeons are now performed by interventional radiologists.  Over the last half–century our ability to see structures within the body increased dramatically.  X-ray doctors who call themselves “Interventionalists” use the fluoroscope and drain pockets of fluid, biopsy shadows that look like tumors, pass catheters through blood vessels, and perform complicated procedures that halt or prevent blood loss. 

Some interventionists perform TIPPS in people with cirrhosis and stretched out esophageal veins that bleed.  The livers of these individuals are scarred; blood from the intestines can’t flow into or through them, and the vessels that carry blood around the organ enlarge and can leak or rupture.  To decompress the situation, trained radiologists create a tunnel through the liver. 

Cataracts, cloudy eye lenses, are now removed and replaced with artificial implants in 6 to 14 minutes—then people go home.

Knees are resurfaced; hips are replaced- and people with the new joints walk out of the hospital the same day.

Video scopes allow gastroenterologists to screen colons and stomachs, to biopsy or remove abnormalities, control gi bleeding, remove bile duct stones, remove foreign bodies—and much more.

Our approach to combat injuries has changed.  In a recent war, surgical teams—surgeons, nurses, and medics, traveled in Humvees directly behind the troops.  When a soldier was wounded they would “focus on damage control, stop bleeding from the liver with sterile packs, staple perforated bowels, and wash out dirty wounds.”  Since blast injuries can cause bleeding from multiple locations, they would cut the abdomen open, pack areas at risk, and cover the area with saran wrap. When the surgeons had done their best–and always within two hours–the injured were flown by helicopter to a hospital less than an hour from the zone of combat.4

Worldwide “about 234 million operations performed annually.5

 ”44,000 and 98,000 patients die each year in the United States as a result of preventable medical errors. “Adverse events in surgery account for between one-half and two-thirds of all such events in hospitals and half are potentially preventable.”8

In 2007 Atul Gawande, a Harvard surgeon, wrote an article that promoted the use of checklists before during and after surgery.  He pointed out that even surgeons who are super-specialists sometimes neglect small details.   The idea of a directory of procedural steps had previously been developed by the aircraft industry, as a result of crashes that were caused by a minor oversight. 6 

In 2008, the World Health Organization (WHO) published a 19-item checklist intended to be globally applicable, and hospital operating rooms became even more compulsive.  Are antibiotics or blood available?  Did we mark the breast or limb that we’re going to operate on? 

Between 2007 and 2008 the WHO checklist was used in 3733 surgeries in 8 hospitals in Canada, New Zealand, the U.S., England, India, Jordan and the Phillipines. The death rate fell from 1.5% to 0.8%, and inpatient complications decreased from 11 to 7 percent.7 The checklists, however, did not make a detectable difference in hospitals in Ontario Canada. They are increasingly being required by governments in certain U.S. states and in various countries, and they were mandated by the U.K. National Patient Safety Agency in 2009.8

A medical educator interviewed by Atul Gawande asserted the innately exceptional surgeon, the doctor who, as a trainee, can figuratively “see one, do one, and teach one” is pretty rare. For the vast majority competence is not the result of a God given skill.  It’s the result of diligence and by young doctors who keep practicing difficult tasks.    

And (Gawande again) “while the best possible care is more important than teaching novices, everyone is harmed if no one is trained.”  Not surprisingly in “teaching” hospitals, the poorest, the uninsured, and the demented” are disproportionally the responsibility of surgical trainees. That’s how it always was and still is.

REFERENCES:

“An Unsung Hero of the laparoscopic revolution” by Leon Morgenstern, M.D., https://journals.sagepub.com/doi/10.1177/1553350608325119  Surgical Innovations: Oct 22, 2008

A Time for All Things by Craig Miller. Oxford University Press. 2019 https://www.mdedge.com/vascularspecialistonline/article/83514/vascular-surgery-chronicles-michael-e-debakey

“The Puzzle People” by Thomas Starzl. University of Pittsburg Press. 1992

Casualties of War — Military Care for the Wounded from Iraq and Afghanistan by Atul Gawande, M.D.  December 9, 2004 N Engl J Med 2004; 351:2471-2475 https://www.nejm.org/doi/full/10.1056/NEJMp048317

Weiser TG, Regenbogen SE, Thompson KD, et al. An estimation of the global volume of surgery: a modeling strategy based on available data. Lancet2008;372:139-144

New YORKER DECEMBER 10, 2007 THE CHECKLIST By Atul Gawande  https://www.newyorker.com/magazine/2007/12/10/the-checklist

https://www.nejm.org/doi/full/10.1056/NEJMsa0810119 Alex B. Haynes, M.D N Engl Med 2009; 360:491-499

A detailed review of their emergence, development, and relevance to neurosurgical practice.  Douglas J. McConnell et al.  Surg Neurol Int. 2012; 3: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279961/

https://pubmed.ncbi.nlm.nih.gov/14667692/

https://www.youtube.com/watch?v=voTxtx72niU10. http://www.quotehd.com/quotes/dr-john-kirklin-quote-surgery-is-always-second-best-if-you-can-do-something-else

https://www.uptodate.com/contents/identifying-newborns-with-critical-congenital-heart-disease/abstract/1

https://profiles.nlm.nih.gov/spotlight/fj/feature/biographical

https://pubmed.ncbi.nlm.nih.gov/7052001/

https://www.annalsthoracicsurgery.org/article/S0003-4975(03)01822-8/fulltext

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1448951/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2384244/

https://www.nejm.org/doi/full/10.1056/NEJMbkrev3911

https://www.annalsthoracicsurgery.org/article/0003-4975(92)91474-N/pdf        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413991/

https://www.jtcvs.org/article/S0022-5223(12)00164-X/fulltext

https://www.annalsthoracicsurgery.org/article/S0003-4975(09)01080-7/pdf

https://www.jtcvs.org/article/S0022-5223(12)01542-5/fulltext

https://www.annalsthoracicsurgery.org/article/S0003-4975(09)01080-7/pdf

http://www-personal.umd.umich.edu/~jonsmith/19cmed.html

Surgery 1890s and 1900s.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865939/#fnr38

Mirkin https://www.drmirkin.com/histories-and-mysteries/dr-michael-debakeys-famous-surgery.html

medical education  https://www.encyclopedia.com/history/united-states-and-canada/us-history/medical-education

LISTER   https://www.britannica.com/biography/Joseph-Lister-Baron-Lister-of-Lyme-Regis

Halsted; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1190776/pdf/annsurg00027-0013.pdf

surgery in the heart  Dwight Harken  https://books.google.com/books?id=2Fv9dRT9TC4C&pg=PT77&lpg=PT77&dq=dwight+harken+stuck+an+instrument+into+a+heart&source=bl&ots=0tgDYqQXd-&sig=ACfU3U00-5lfW_fBWX08ZXuptIeNlWjt2Q&hl=en&sa=X&ved=2ahUKEwiWhu27xYjqAhXTop4KHdS1BdAQ6AEwAHoECAoQAQ#v=onepage&q=dwight%20harken%20stuck%20an%20instrument%20into%20a%20heart&f=false

Evarts Graham and empyema https://pubmed.ncbi.nlm.nih.gov/11740708/

Empyema https://academic.oup.com/cid/article/34/2/198/311368

Wilfred Bigelow  https://onlinelibrary.wiley.com/doi/pdf/10.1002/clc.4960190327 hypothermia https://books.google.com/books?id=pejGYnnkddwC&pg=PA58&lpg=PA58&dq=john+lewis+and+hypothermia+dog&source=bl&ots=oqqENtzdYU&sig=ACfU3U300Rrt8gSiO88NN06oP_TLSZD0rA&hl=en&sa=X&ved=2ahUKEwiE94eViYrqAhXE6Z4KHW_GCHIQ6AEwAHoECAkQAQ#v=onepage&q=john%20lewis%20and%20hypothermia%20dog&f=false

Bigelow:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC556354/

Kirklin https://twitter.com/fredwumd/status/981301806537039872?lang=es 36.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413991/

“Evarts A. Graham” by Barbara Mueller. 2002 BC Decker Inc.

“Complications”by Atul Gawande

“Better” by Atul Gawande

COSTLY DRUGS

Chapter 15 –understanding expensive drugs

“We shall find the answer when we examine the problem.  The problem is never apart from the answer.  The problem is the answer.”  Bruce Lee.

  1. SETTING THE PRICE

“The cost of a thing is the amount of what I will call life which is required to be exchanged for it, immediately or in the long run.”
― Henry David Thoreau, Walden

To appreciate how and when Pharma learned it can charge as much as it thinks it can get away with, it helps to scrutinize the price trajectory of Gleevec.  The first of many drugs that attacked cancer in a new manner, its cost was high and kept rising.  No one seemed to care and the other pharmaceutical manufacturers noticed. 

Malignancies start when a newly born single celldoesn’t die when it’s supposed to.  It reproduces relatively rapidly; its offspring learn how to escape detection by the body’s immune system; it spreads; and it takes root in distant parts of the body.15    

When I entered medical school in 1958, aside from nitrogen mustard derivatives, cancer altering chemicals were virtually non-existent. In the subsequent decades a number of drugs that attacked rapidly growing cells, malignant or otherwise, were developed.  In the 1960s doctors started using combinations of several of these medications to cure some lymphomas and leukemias.  The chemicals also commonly eradicated a few uncommon malignancies—like some metastatic testicular cancers and choriocarcinoma.   

Our medications were toxic and often caused major side effects, but when they were given to people with widespread cancers, tumors would shrink and some lives were extended. 

They were later used to destroy “probable” metastases. We knew that malignant cells from some surgically removed cancers had already seeded parts of the body. The “seeds” were not visible, not detectable; but we could identify the cancers that were at risk, the tumors that would statistically benefit from chemotherapy. 

Gleevec (Imatinib), a “small molecule”, was the first of many drugs that attacked cancer in different way. Conceived and fully developed over many years in the labs of big Pharma, it changed the way the industry valued the drugs we use to treat certain malignancies.  At $26,000 a year (in 2001), the medication’s introductory cost was deemed “high but fair” by the Chairman and CEO of NovartisThen the company started increasing the price in parallel with “the purchasing power of money.”  After 2005 yearly boosts started exceeding inflation by 5 percent, and the government did not significantly object.  By 2007 Gleevec was costing consumers “$3,757 a month ($45,000 a year).”  Again there were no substantial objections. The cost of the drug took off in 2009.  Its price point passed $60,000 in 2010, and it exceeded the $100,000 a year mark in 2013.1

          The approach helped lead to a new valuation model.  Certain classes of medications fresh out of the gate had exorbitant “list prices” and their cost was “adjusted” annually—often in an upward direction.

The product of decades of research at the Ciba-Geigy labs in Basel Switzerland, Gleevec was discovered by a research team chasing a dream, a theory, a hypothesis.  Alex Matter, a Swiss M.D. advocated looking for a small molecule that would get inside cancer cells and stop them from growing.

“Inspired by the likes of Louis Pasteur and Marie Curie”,  Matter was 12 years old when he began dreaming that he would one day be involved in the discovery of important new medicines.”  I don’t know if he ever practiced medicine, there’s not much written about his private life, but in 1983 he became a Ciba researcher in Basel,  a centuries old city that straddles both shores of a bend in the Rhine River.   

At the time he was apparently wondering what happens when the offspring of a normal cell turns out to be cancerous.  Could it be that one of its numerous tyrosine kinase enzymes, proteins that “function as an “on” or “off” switches, gets stuck in the “on” position, and causes the cell to grow and grow”?

Each part of the body is made up of cells.  Within each of these small units, traffic is directed down various metabolic pathways by enzymes called kinases.16  These enzymes control the functions of cells.  At the appropriate time they cause them to “grow, shrink, and die.”  Malignant tumors are sometimes created when one of the kinases gets stuck in the pro-growth position.  The cells don’t die when they are supposed to, and the collection of abnormal cells gets bigger and spreads.

What if we could block a corrupting kinase without harming a cell’s other 90 or so tryosine kinases?  Could we cure that cancer?  That was the dream.

Kinases have inlets on their outer surfaces.  When these are filled by a small molecule that “fits,” the cell dies.  Locating the bad kinase and plugging it with the appropriate small molecule is a little like finding a needle in a haystack.  But that’s what the Swiss Geigy team lead by Alex Matter and Nick Lydon set out to do.  They started with a small molecule that they knew would selectively inactivate one and only one of the 90 or so “tyrosine kinases” found in each cell.  Making various small alterations to the protein, they created new molecules and tested them one by one.  A few seemed promising.  Gradually they made dozens of blockers, each of which inhibited the activity of one and only one kind of kinase.  The project took years and must have been quite costly. Geigy funded the studies “reluctantly.” At the time Matter’s was told to keep investigating other approaches to cancer.  The kinase program was supposed to be “very very small—hidden in plain sight. “

In the 1980s Lydon went to Boston in search of a cancer that might be susceptible to one of his kinase inhibitors.  He met Bryan Drucker, a lanky, soft-spoken physician from St. Paul Minnesota who had spent 9 years at the Dana Farber Institute, was studying chronic myelocytic leukemia and was interested in the drug.28 For technical and legal reasons—lawyers for the drug company and the Dana Farber institute “could not find agreeable terms”–it took a few years before Drucker, then in Oregon, was able to obtain and test the kinase inhibitors.  When he did, he found a blocker that caused chronic myelocytic leukemia (CML) cells to die.

Most cases of Chronic Myelocytic Leukemia (CML) are caused by a genetic accident.  The tips of two chromosomes have “broken off”, switched location, and fused.  The resulting “hybrid” gene, called the Philadelphia chromosome, causes the abnormal cells to keep reproducing themselves. The defect had been elucidated and explained a decade earlier by a hematologist named Janet Rowley.

In the absence of a marrow transplant Chronic Myelocytic Leukemia (CML) was usually lethal.  If a person had an HLA identical sibling, and if they underwent a stem cell transplant, they subsequently had a 60-80% chance of surviving and being disease free five years out.  Without someone else’s’ bone marrow, half of the affected were dead in 3 years; less than one in 5 lasted 10.2

But now a dream was being realized.  A small molecule could selectively inhibit an enzyme and control or cure cancer.  Turning the protein into a drug a human could use required proving its safety in animals, then people.  Several hundred million dollars needed to be spent before the company could market the medication.  And it would only help a few thousand people.

Novartis (the company created by the Ciba-Geigy—Sandoz merger) decided to give the chemical a shot, to see what it did to the cancer in question.  It proved to be amazingly effective.  Chronic myelocytic Leukemia wasn’t cured but it became a chronic disease, and an entirely new era of research was launched.

The first clinical trial of Imatinib mesylate (Gleevec), took place in 1998.  In 2001 the FDA approved the new medication and granted Novartis a 5 year monopoly.

When it first came out the company knew that when patients had CML—chronic myelocytic leukemia, and they took a Gleevec pill each day, they were alive and well three years out.  But they worried because most cancers eventually become resistant to therapy.  They were pleasantly surprised.  Gleevec and a slightly altered later iteration “changed the natural course of the malignancy. 

Each year an additional group of people developed CML, and they started taking a pill a day for the rest of their lives.  A 2015 study of people who had taken the drug for 10 years, found that 82% of them were alive and progression-free3.”    By 2018 “an estimated 8,430 people in the United States” were living with the diagnosis.

And they were living with the price– which “passed $60,000 a year in 2010, and exceeded the $100,000 a year mark in 20134.”  The increases “sparked a nationwide conversation on cancer drug prices and value.”

Then the first generic form of the drug entered the U.S. market and it wasn’t much cheaper5. (Though it was selling in Canada at a third the U.S. price.)    

 In 2015 Novartis sold $4.65 billion of the drug.  Between 2001 to 2011, sales of Gleevec world wide totaled $27.8 billion.  Its 2015 price in the U.K. was “$31,867, France paid $28,675 and Russia spent $83706.” 

The company, no doubt, spent millions, maybe more than a billion dollars over the years bringing a great drug to market.  But even if the initial price reflected their research and development costs, it clearly had little bearing on the subsequent annual increase in the price point.25  

In the U.S the consumer typically pays a percentage of the official list price for the very expensive medications.  By 2014 the drug’s list price was close to a $100,000.  Medicare is (by law) not allowed to negotiate.  Insurers and pharmacy benefit managers can bargain.  They sometimes obtain significant rebates and discounts, but they are usually not passed on to the consumer. Our current system creates a burden for many7.     

In 1970 India allowed drug makers to patent their manufacturing processes but not the active chemical or the drug.  As a result a number of cheap generic drugs were developed and marketed. In 1993 Novartis filed a patent application for Gleevec and in 1998 they filed a patent for a new form of the medication.  A few years later India joined the World Trade Organization, and started allowing companies to patent the drugs themselves.  That year Novartis filed a patent for the 1998 form of Gleevec, and their claim was challenged and rejected.  The court felt the company didn’t prove the new iteration worked better than the form that was being sold in India.  They accused the company of “evergreening, extending the life of a medication by altering it just enough to warrant patent extensions without changing the underlying mechanism of the drug.”  Indian law seems to be more in tune with the needs of their nation’s people than they are with the tricks used by the powerful pharmaceutical industry to further enrich itself.8

Novartis researchers, looking for a molecule that was as effective as or better than Gleevec,” modified the protein and tested some of their creations.  One of the new molecules, Nilotinib (Tasigna), did a better job at targeting the kinase in question.  It rescued some people whose disease no longer responded to Gleevec.  In new patients it more rapidly and effectively reversed the biochemical markers of chronic myelocytic leukemia. But it was not better than Gleevec at halting disease progression–and it wasn’t worse.  In 2007 the FDA released Tasigna and Novartis started selling it.  A few years later a Canadian study showed that 5-6% of people treated with the new medication developed an arterial disease and had a heart attack, stroke, or some other “atherosclerosis-related ailment.”  The FDA allowed the company to keep marketing the medication, but Novartis had to put a black box warning on the drug insert9

The year Nilotinib was approved it was costing people $6900 a month. (Median monthly payment). 7 years later, a month of medicine was costing $8806.  According to the watchdog web site FiercePharma, generic Gleevec was selling for as little as $40 to $50 a month in 2018.  That year Nilotinib was expecting revenues in excess of $2.5 billion.  Some doctors and people seem to believe that newer is better. 

Researchers for Bristol Myers Squibb created another drug that successfully controlled CML: Sprycel (dasatinib).  Like Nilotinib it “produced a faster, deeper response,” but didn’t make people live any longer.  It also did not significantly price compete.  When approved by the FDA it sold for $5477 a month.  In 2014 its monthly list price was $9300.

On August 1, 2019 the New England Journal of Medicine published a study that showed that Ibrutinib, a small molecule– kinase inhibitor that interferes with signals within lymphocytes– improves the survival of people with Chronic Lymphocytic Leukemia.  Its side effects: hypertension and heart rhythm problems, were discussed in great detail, but its cost was treated as little more than an afterthought. “Indefinite use of Ibrutinib therapy has been associated with substantial expense.”  To the authors and editors of the journal, a price that made a medication unobtainable for some was not a significant side effect. “The typical cost of ibrutinib in the United States will be about $148,000 a year”.  People insured by Medicare D typically have co-pays that are 1/3 of the list price.

A second inhibitor of the tyrosine kinase that lymphocytes need to survive, Acalabrutinib, was approved for sale in the U.S. in 2017.  It was created by a Dutch-run startup and was developed in the biotech center of the world, California.

In 2018, the cost of 30 days’ treatment with the Dutch drug, Acalabrutinib was $14,064.  Thirty days of Ibrutinib was costing $12,180. Competition didn’t seem to significantly affect price.27 

Our “free enterprise capitalist economy” encourages innovation by protecting the price of a new medication with patents and a multiyear FDA granted exclusivity.  When their monopoly ends, theoretically at least, the amount manufacturers charge should be modified by competition. 

When Roy Vagelos was head of Merck, the company “vowed to only increase prices in line with the Consumer Price Index, plus or minus one percent.  About half the industry followed suit.”  When some companies used loopholes in the drug laws to extend the patents of their successful drugs, Vagelos refused to join in.

Vagelos, a physician and academic lipid researcher, became the company’s CEO in 1966. The son of immigrant Greeks, as a young man Roy spent his after school  time working in the family restaurant and playing the violin.  His father’s father had been a physician in the old country and had died young.  Roy’s father felt that to succeed in life Roy would need a good education, and Vagelos studied hard and went to college on a scholarship.  While there, he developed a love for chemistry.  During his first year in medical school he “had a very tough time because he had a terrible memory.  Anatomy almost wiped him out.”  Fortunately, there was also biochemistry and he “survived” and became a talented researcher.

Under Vagelos’ leadership Merck developed Lovastatin and Simvastatin, the first drugs that limited the body’s production of cholesterol.  The company then sponsored studies that proved that the drugs lowered the risk of heart attacks and death.

Merck started in Germany in the 1800s and opened its U.S. branch in 1891.  In its early days it made medicinal morphine and codeine, and it had been the birthplace of one of the first medical books for the masses, the Merck Manual.  While Vagelos was in charge, one of the company’s labs developed a drug that killed a number of the worms that attacked cattle, sheep and horses.  Called Ivermectin it was marketed as a means of preventing heartworm in dogs, but it didn’t do much for the hookworm like parasites that lived in the intestines of man.  Its commercial value seemed limited.  Further research on the chemical was suspended, and it was shelved until the day that Mohammed Aziz, a staff researcher, met with Vagelos and got permission to perform additional studies.  Aziz had been in Africa and had seen people infected with the filariae that caused river blindness.  100 million Africans were at risk for the condition and the parasite had blinded 18 million of them.  The invading worm existed in two forms: adults, which can be 6 to 15 inches long and exist as lumps under an infected person’s skin; and the filariae, a small organism that infiltrated the skin and caused intense itching.  The black fly that lived in the river spread the parasites from one person to the next.

People who had the problem were constantly scratching themselves.  When kids scraped their skin, then touched their lids, the microfilaria got into their eyes.  The subsequent eye inflammation, lead to scarring and blindness.  In some villages 25% of the inhabitants couldn’t see.  In an attempt to escape, many moved away from the river to less fertile ground and suffered from malnutrition.

Ivermectin, a Merck drug that had been one of the large pharmaceutical company’s financial failures, destroyed the filariae that attacked horses.  Aziz suggested it might have an effect on the creatures that blinded so many Africans.  Merck produced a quantity of pills, and Aziz went to Senegal to study their effect. Pinch biopsies of the skin of infected people showed huge numbers of the filariae.  Half of the people who were infected got a pill and the other half didn’t.  A month later a second biopsy showed the filariae had been eradicated from the people who had been treated.

Based on the positive results Merck spent years performing tests that proved Ivermectin was safe and effective.  Then they went to the African leaders and tried to sell it for a dollar a pill.  The government had no money. The discussion went something like: OK, 50 cents a pill, a dime.  The governments really didn’t have enough money.  The World Health Organization was spraying rivers with insecticides (though the black flies were already becoming resistant to the spray).  The WHO wasn’t interested. Officials in the U.S. State department and at the White House were excited but “the government was broke.”  (Ronald Reagan was president.)  The French were about to approve the drug. (There were cases in Paris that had originated in colonial Africa), but in the U.S. the FDA wasn’t interested.

Merck was in business to make money and to enrich its officers and stockholders.  But the drug was ready.  These were the 1980s, and Roy Vagelos was a doctor as well as a business man.  The leadership at Merck decided they would provide the medication free of cost to anyone who would use it.  They had spent millions to develop the medication.  Providing it gratis would cost the company (and its shareholders) tens of millions of dollars, but Vagelos made the announcement and waited to see how the stockholders would react.  He claims he received a lot of positive feedback but he didn’t get one negative letter.  For years, thereafter, the best of the best researchers in the country wanted to come to and work for Merck.  And Vagelos stayed on as head of Merck for an additional 6 years.

When he reached the mandatory retirement age in 1994, Merck “was number one in sales, size, and marketing force”.  As a successor Vagelos recommended a number of Pharma savvy colleagues, but the world was changing.  The board chose a real business man—a non-scientist, Harvard MBA, and former CEO of a medical device company named Ray Gilmartin.13

In 2017 Roy Vagelos, former CEO of Merck took part the great debate on the ethics of drug pricing.  He wasn’t pleased with the way Pharma had changed.  He maintained that “The industry has a lousy image and it should, until it reforms itself.”  “He attributed Pharma’s failings to “a lack of understanding of what people respect, and a lack of respect for human beings.11

Some think the astronomical increase in drug prices was the result of greed.  Others blame the trust that pharmaceutical companies built during the early post world war 2 decades.  The healthy didn’t seem to detect the dramatic rise in medication fees, and the ill were too demoralized to speak up.  Too few of the people in power seemed to be paying attention.  Unlike the frog that, if placed in boiling water would have jumped out, the populace of the U.S. was plunked into cold water and we didn’t realize the liquid was slowly being brought to a boil. 

I don’t believe the leaders of industry are to blame.  They just did what comes naturally.  Congress passed laws, and lobbyists for the industry fashioned loopholes that could be exploited. Companies became corporations with stockholders.  CEOs reported to boards of directors.  Pharmaceutical companies acted more and more like real businesses.  In house investigators with quirky innovate ideas and notions were reigned in.  Researchers were increasingly tasked to focus, to develop marketable products.

After a specified number of years best selling drugs would lose their exclusivity and generic competitive products would enter the market.  If the company didn’t have an emerging replacement, revenues and the price of the company’s stock would fall. To maintain the bottom line industry leaders started raising prices. 

The initial price increases must have pleased stockholders and boards of directors.  If industry leaders wanted to keep their jobs or get bonuses they had to raise prices the subsequent year, and the year after that.  If a CEO wasn’t willing to charge substantially more each year he or she could easily be replaced.

Companies also exploited loopholes in the laws, rules that gave them a few more years of exclusivity.  For a blockbuster drug that meant at least an additional billion dollars of revenue per year.   Legal teams that took advantage of the cracks in the system proved they were worth the big bucks. (If a football team is losing by a touchdown and its coach doesn’t try an onside kick or a Hail Mary pass during the last seconds of the game –he or she is not trying to win, and will be fired.)  Corporations were in the business of making money.  Failure of a corporate lawyer to exploit the available legal gimmicks was akin to misconduct.

The increases started at companies with targeted treatments for cancer.  They “set the bar” that led to prices that “were many times more than most people’s yearly salaries, prices that were not necessarily related to value.” 

The true costs of getting a drug to market are a black hole and are largely irrelevant.   

The success of Imatinib-Gleevec showed researchers that it’s possible to develop small molecules that are highly specific to one of the hundreds of tyrosine kinase inhibitors…medications that can inactivate a specific critical enzyme in chosen targeted cell.  There were a few known targets.17—so called low hanging fruit– and researchers in startups and in the labs of big Pharma started making thousands of molecules and testing them with their biologic assays.  Not that it was easy.  Developing a molecule that targeted a specific genetic alteration took time, luck, optimism, and money.17.

Most of the targeted cancer drugs are made in the labs of big companies and we don’t know much about the true cost of their research and development.17   The Tarceva story provides a window.  An EGFR (epidermal growth factor receptor) blocker, in a minority of cancers it blocks the activity of a kinase that causes malignant cells to grow and divide.  It was developed by OSI, a small pharmaceutical company that was originally called Oncogene Science.  It was founded by Gary Takata, a “shaggy-haired, Manhattan-based venture capitalist who, in March 1983 persuaded an entire laboratory of National Cancer Institute scientists to join his new company and start developing drugs.29 Located in Long Island, New York, it employed 20 people when Colin Goddard became its CEO in 1989, and it had a biology and a small molecule discovery group. A Brit, its leader Goddard had a biochemistry degree.  He had been a runner and soccer player at his university and had considered a career in sports.  Then a friend developed a brain tumor, a Glioma, and Goddard decided “maybe there are other things in life to do besides play sports.” The startup was looking for a chemical that would modify EGFR.  They had a relationship with researchers at a nearby mega company, Pfizer, and people at OSI persuaded investigators at the big company to screen a number of their small molecules.  At the time Pfizer was evaluating molecules for a different cancer target: Her-2 Neu, and they needed a “control.”  When they checked the compounds for OSI, Pfizer scientists identified Tarceva. OSI subsequently kept the “lead rights” to the chemical and Pfizer had some ownership.

Pfizer agreed to give the drug to a few people with advanced cancer and see what happened.  They bailed when they learned the drug caused a rash.

About this time Pfizer was buying the company that owned Lipitor.  It was an expensive hostile takeover, and Pfizer gave their Tarceva ownership back to OSI—free.  (They later went on to acquire the company that owned Lipitor.)

OSI raised $440 million, ran clinical trials, and found out their drug, in fact, made some people with cancer live longer.

A few years back an athletic, non smoking friend had a nagging back ache that kept getting worse.  An MRI showed bony defects caused by metastatic lung cancer.  His brain was involved, and it was radiated.  The X-ray treatment caused terrible side effects–a month of no appetite or thirst.  When he recovered he knew he was not interested in conventional, toxic chemotherapy.  But he spoke of a dream– of sitting on a boat in the bay and fishing.  Would that be possible?  His tumor was positive for EGFR and he was given Tarceva.  His back pain improved, he got stronger, and he was able fish and enjoy life for about a year.  Then the tumors in his brain started growing. 

Genentech and Roche bought $35 million worth of OSI stock and commercialized Tarceva.

The internet says Tarceva costs Americans $2600 a month.  That’s more than the British National Health Service was willing to pay.  In 2007 the Swiss drug maker Roche negotiated and agreed to cut the U.K. price from $2766 a month to $2133 a month.  The online Canadian pharmacy, Northwest, claims they get drugs from reputable factories in many parts of the world, then ship it directly to patients who mailed valid prescriptions.  Their price for brand name Tarceva 150 mg per month is $3174.  Their generic version goes for $1384 a month.  Approved by the FDA in 2004, it became a $94,000-a-year drug.  Genentech sold $564.2 million of Tarceva in 2011 and over a million dollars worth in 2016.  (An article in the LA times questioned its effectiveness.14)

In India, in 2012, the Cipla pharmaceutical company produced a generic version of Tarceva, and lowered the price of the medicine from $459 dollars a month to $182 dollars a month.  The Delhi court ruled that the Swiss patent was valid, but that the generic product didn’t infringe.12

Some argue that pharmaceutical companies make the majority of their profit in the U.S.  Our high prices are subsidizing the rest of the world, and people in other countries aren’t paying enough.

Others contend that Pharma makes so much profit in America that they don’t have to bargain in good faith with other nations.  When a company has a new important drug and there’s no competition they can hang tough.  Negotiators can pay the asking price (with a small discount); or they can leave it./“

1.4.  Price of Gleevec  https://www.forbes.com/sites/joshuacohen/2018/09/12/the-curious-case-of-gleevec-pricing/#30e1487654a3 

2. 3.  Treatment of chronic myelocytic leukemia UPTODATE.

5.  Gleevec generics https://www.ascopost.com/issues/may-25-2016/the-arrival-of-generic-imatinib-into-the-us-market-an-educational-event/

6.  Gleevec in other countries.  https://www.statista.com/statistics/312011/prices-of-gleevec-by-country/

7.  Out of pocket cost burden for certain drugs https://www.kff.org/medicare/issue-brief/the-out-of-pocket-cost-burden-for-specialty-drugs-in-medicare-part-d-in-2019/

8.  Novartis loses Gleevec battle in India https://www.wsj.com/articles/SB10001424127887323296504578395672582230106

9.  Tasigna black box  https://www.consumersafetyguide.com/drugs/tasigna/

11.  The ethics of drug prices https://www8.gsb.columbia.edu/leadership/ethicsofpricingt

12.  Tarceva patent India https://www.lexology.com/library/detail.aspx?g=bc7dd620-6e3a-4888-a18a-21ada73cd544

13.  Gilmartin heads Merck  https://www.nytimes.com/1994/06/10/business/merck-gets-outsider-as-new-chief.html

14. Effectiveness of Tarceva https://www.latimes.com/archives/la-xpm-2005-dec-04-fi-letters4.2-story.html

15.  How cancer starts. https://www.cancerresearchuk.org/about-cancer/what-is-cancer/how-cancer-starts

16.  The Emperor of all Maladies, by Siddhartha Mukeherjee, Scribner 2011

18.  The Philadelphia Chromosome by Jessica Wapner: 2013 

19.  https://cns.utexas.edu/news/a-score-to-settle-with-cancer

20.  https://www.nejm.org/doi/full/10.1056/NEJMoa1817073

21.  https://www.seattletimes.com/business/technology/pharmacyclics-miracle-cure-a-cancer-drug-saves-a-biotech-company/

22. https://pubmed.ncbi.nlm.nih.gov/11904381/

23. https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor

24. https://podcasts.google.com/?feed=aHR0cDovL2ZlZWRzLm5hdHVyZS5jb20vbmJ0L3BvZGNhc3QvY3VycmVudA

25. Vagelos https://www.annualreviews.org/userimages/ContentEditor/1337783424709/P.RoyVagelosTranscript.pdf

26. EGFR https://www.cancer.gov/publications/dictionaries/cancer-terms/def/egfr-inhibitor

27. Cost comparison https://secure.medicalletter.org/w1559d

28.  drucker  https://www.smithsonianmag.com/science-nature/a-triumph-in-the-war-against-cancer-1784705/

29.  https://www.nytimes.com/1985/12/28/business/small-concerns-battle-cancer.htmlhttps://xconomy.com/new-york/2013/05/14/osi-pharma-long-island-biotech-bellwether-shut-down-by-astellas/

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