Many medical advances dramatically impacted the lives of a limited number of individuals.
A few were “game changers”: Two of these helped all humans. Others altered the futures of substantial clusters of sick people.
People born after 1977 know little about the ravages of small pox. A contagious viral infection, the ailment has plagued the human race for at least 10 centuries. It’s claimed that as many as three in 10 of those infected died, and many who survived were permanently scarred. Commonly occurring in epidemics, the viral disease was brought to the new world by Columbus and his followers. It subsequently played a major role in the deaths of hundreds of thousands of Native Americans. In 1796 an inventive British physician named Jenner heard that dairymaids were protected from smallpox after they were infected with a harmless virus called cowpox; he decided to check it out. He inoculated an 8 year old with the mild virus, and then exposed him to small pox. Cow pox, it turned out, was indeed protective. It took years- decades before people believed Jenner and even longer before they started vaccinating their young with an attenuated strain of cowpox called Vaccinia. In the 1800s vaccinations became increasingly common, but the disease survived. It’s claimed that in the 20th century smallpox took the lives of “an estimated 300 million individuals.” In The second half of the last century a world wide effort to eradicate the curse was undertaken. Most of the planet’s young were vaccinated, and the bug’s last known victim was infected in 1977. Medical visionaries are currently trying to similarly eradicate polio, and they’re close.
In the years following the Second World War Penicillin and a large number of other antibiotics turned infections that were once lethal into treatable, usually curable, conditions. They’re such a part of the modern world that it’s hard to imagine what life was like beore they became commonplace.
And In the last half of the 20th century two classes of drugs—each in their own way– altered the futures of huge swaths of the planet’s ill. I call these medications “game changers.”
The immune industrial complex.
The immune system (and our skin, and intestinal wall) protects us from micro creatures that live in and on our body. It recognizes protein that doesn’t belong, tries to destroy cancerous cells, and it mounts a defense when we encounter the flu bug, a vibrio that causes cholera, or the tuberculosis bacillus.
At times our defense system thinks that a part of us is an enemy, and it attacks joints (rheumatoid arthritis) bronchial tubes (asthma), intestines (colitis) the brain (multiple sclerosis).
We can temporarily control many of the body’s immunologic assaults with cortisone derivatives, but our body pays a price. In recent decades a number of immune modulators have emerged. Some have huge annual revenues: like Humira at $14 billion a year, or Enbrel at $8 billion–and most of the new innovative creations are quite pricey.
Then, on more than 34,000 occasions in 2017, foreign tissue from donors dead and alive —livers, kidneys, hearts and lungs–were implanted 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 control the immune system, our “three drug anti rejection regimen”, according to Thomas Starzl, “wasn’t very effective or safe.” Starzl, a transplant pioneer, performed close to 200 dog transplants before he came to the University of Colorado. “After surgery his dogs were normal for almost a week; then they began to reject their liver.” As late as 1978 “Graft survival was unsatisfactory and patient mortality high.” (Starzl-the puzzle people. P.208)
Then Cyclosporine burst onto the scene and everything 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, last 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 transplant, they (almost always) reject the intruder if they don’t take an immunosuppressant daily for life. A few different anti rejection drugs are currently available. There’s a marketplace and competition.
In 2012 Pharma spent $3 billion on consumer ads and “$24 billion marketing directly to health care professionals.” (John Oliver numbers) The promotion budget is almost always much higher than the amount spent on research. The biggest spender in 2013, Johnson and Johnson, “shelled out $17.5 billion on sales and marketing, and half as much, $8.2 billion for research and development.”
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 collect “soil samples that might contain unique microorganisms.” (They were looking for the next great antibiotic.) A fungus in a sample of Norwegian dirt produced a metabolite (Cyclosporin) that lowered the immune response of lymphocytes. It seemed to be relatively safe, and some, apparently, thought it could potentially become an anti rejection drug.
That’s as far as Sandoz was willing to go. By 1973 the lab’s 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.
In 1976, J.F. Borel, the Sandoz researcher who discovered the immune modulating effect of cyclosporine, presented his findings to the British Society of Immunologists. A transplant surgeon in the crowd, Sir Roy Calne “asked Borel for samples”. Calne used them to try to prevent the destruction of organs transplanted in rats and dogs. The drug’s effect was dramatic. 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.” In the early 1980s, an American transplant surgeon named Starzl used it successfully on liver transplant recipients. With his results in hand the FDA fast tracked approval of the medication, and it became available for use in the U.S. in 1983. (Currently made generically by a number of countries Cyclosporine’s (Wikipedia) wholesale price is not outrageous. $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.
Read more: http://www.discoveriesinmedicine.com/Com-En/Cyclosporine.html#ixzz4ocaXJCDC
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 working in a big Pharma lab. (At Fujisawa, a company that later merged and became Astellas, the world’s 14th largest). In renal transplant recipients Prograf led to improved graft and patient survival, and that lead to it’s routine use in U.S. renal and pancreas transplant recipients. the FDA made it official in 1994. The year before Prograf had a generic competitor, Astellas sold up to $2.1 billion dollars worth of the medication.
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.
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 President Nixon signed a bill that (apparently as an after thought) added chronic dialysis to Medicare. Kidney failure wasn’t part of the bill the Senate debated during a rare Saturday morning session on September 30, 1972. Nor was it part of the legislation passed earlier by the House of Representatives. The amendment that added dialysis to the Medicare bill was introduced late that Saturday morning. There was 30 minutes of debate before it was accepted by a 52 to 3 vote. Weeks later a House, Senate Committee discussed the kidney amendment for 10 minutes, and left it in the bill. Nixon, who was a pro health care president, signed the legislation with a flourish a week before he was re elected.
If someone on dialysis 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 them: because of side effects, or they cost too much, 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.
As newer anti-rejection compounds hit the market, and generic medications started competing, the cost of these drugs has waxed and waned. The price seems to have little to do with the original research and development costs and much to do with current market forces.
Adjusted for inflation and expressed in 2012 dollars the U.S. cost to keep a kidney or liver alive was $9000 in 1993. It climbed to more than $33,000 in 2007, and went down to $18,000 (twice the original price) in 2011.
The lure of riches versus the “better angels of our nature”.
In the 1980s hospitals were full of young men and women who had HIV and were afflicted with a devastating infection. When an immune system is no longer able to control the host of bugs that hang out in our body, one or another will emerge and cause a severe illness. For over a decade almost everyone who had HIV died.
Then scientists developed drugs that, when used in combination, turned a killer into a chronic, controllable malady. And the entrepreneurs and corporations who made the life saving medications had to deal with their desire or need to make money and enhance stockholder value, while at the same time facing the desperate needs of millions of sick and dying people.
After they identified the virus, scientists methodically, learned how the HIV virus attaches to the cell and “punches” its way through the outer membrane, sheds its protective coat, and uses a special enzyme it brought with it, (reverse transcriptase), to make a DNA copy of the viral RNA.
Each phase the virus passed through was a potential area of vulnerability, a moment or point where a drug developed by a researcher could block the progress of the evildoers.
The counter attack started when scientists at Burroughs-Wellcome synthesized compounds that might obstruct the activity of the reversetranscriptase enzyme. In 1985 they sent eleven promising compounds to researchers at the National Cancer Institute, and people at the NIH identified a chemical that worked in the test tube. The drug was given to people with HIV, and their lives were prolonged.
25 months later the FDA approved the drug, and it was marketed by GlaxoSmithKline. The company sold 225 million dollars worth in 1989.
In the late 1980s and in the 1990s manufacturers started cranking out (and selling) anti HIV drugs. Some of the agents targeted an enzyme the virus brought with it when it entered the cell. Called protease the chemical was “essential to viral replication”. The first Protease inhibitors became available in 1996.
Nucleoside reverse transcriptase inhibitors, drugs that work against the enzyme that copies HIV RNA into new viral DNA were invented by Emory university professors. They discovered FTC (emtricitabine) and a chemically similar compound, 3TC (lamivudine) “Everyone was intrigued but skeptical about our work—no one realized the importance of what we had found,” Schinazi (the physician who developed the drug) said. He “pushed Emory University to file patent applications. They did and less than ten years later the University was paid $540 million…a lot of money but considerably less than big Pharma often pays to control a significant drug. .
.A recent therapeutic manual for doctors listed drugs that block the virus at several transitional sites. We now have more than 10 reverse transcriptase inhibitors, 9 protease inhibitors, 2 entry inhibitors and an integrase inhibitor. All drugs have side effects. People who can’t tolerate one reverse transcriptase inhibitor often have no problem taking a different one. When a combination of medications is used, the viral biochemical assembly line is blocked in more than one location, and resistant viruses are uncommon. Refractory HIV can develop when a person stops and starts the medications. That happens when people can’t afford their co-pay, when they live in a remote part of the world and don’t have access, or if they merely decide to take a “drug holiday”.
In the U.S. combinations of the two or more drugs that are needed to control a person’s HIV usually costs between $1500 and $3000 a month. People with “decent” health insurance are commonly required to pay two thirds of the needed dollars.
In 2004 a small percentage of the people with HIV lived in high income countries. In the U.S. HIV was becoming a well controlled chronic disease. People in the rest of the world kept dying. More than 36 million people (close to 2 million of whom are children) are infected. Over 25 million HIV carriers live in Sub Sahara Africa.
Drug companies tried to guard their exclusivity with all the money and influence they could muster. In 1995 the World Trade Organization was formed. It required members “to honor 20 year patents on drugs”. Poor countries were given until 2005 to comply with the mandate. (Half the big drug makers are headquartered outside the U.S.)
Poor countries couldn’t and wouldn’t comply with the WHO directive. HIV was a killing their people. 143 countries favored relaxation of patent protection. The Bush administration initially thought the constraints should stand.
In 2001 Indian generic drug manufacturer, Cipla, announced that it would sell a generic copy of a triple-therapy antiretroviral for US $350 per patient per year. The following year Shanghai’s Desano pharmaceuticals started producing a three drug regimen. The cocktail was sold for $350 a year. Other countries were ready to join in.
The South Africa Competition Commission found two drug companies guilty of anti competitive behavior. Facing fines and maybe jail time the corporations struck a deal. Several big pharmaceutical companies, including Glaxo, agreed to allow generic manufacturers to make and sell HIV drugs. The company took a 5% fee.
Prior to 2003, the U.S hung tough. Then the Irish singer Bono got together with one of the day’s more important Republican senators, Jesse Helms, and attitudes changed. When they met the Senator was 80 and walked with a four-pronged cane. He was a rightwing evangelical Christian who had exploited racial prejudices in his election campaigns and had called homosexuals “weak, morally sick wretches”.
Bono, by contrast, had publically supported Greenpeace, Amnesty International, and had joined Jubilee 2000, a 40 country movement that advocated cancelling third world debt for the millennium. At one point the Jubilee campaign asked Bono to get the Baptist Nigerian President to write a letter to Baptist churches across southern US states. He was supposed to explain the Biblical principles behind debt cancellation.
The Baptist leaders listened, and Bono suddenly had access to a lot of strongly Christian Republicans. That’s why he was able to meet and speak with Jesse Helms. Helms had been very tough on the concept of foreign HIV drug assistance. “He’s a religious man”, Bono said, “so I told him that 2103 verses of scripture pertain to the poor, and Jesus speaks of judgment only once – It’s not about being gay or sexual morality, but about poverty. I quoted that verse of Matthew chapter 25: ‘I was naked and you clothed me.’ He was in tears. And later publicly acknowledged that he was ashamed…”
After the meeting vice president “Dick Cheney walked into the Oval office, and told President Bush that, ‘Jesse Helms wants us to listen to Bono’s idea.” That led to negotiations and Bush’s 2003 plan.
That January in his State of the Union message President Bush announced his policy towards HIV had changed. He would ask congress to spend $15 billion dollars over 5 years to combat the disease. Since its creation in 2003, the “President’s Emergency Plan for AIDS Relief (PEPFAR)” received more than $70 billion in congressional funds …$6.56 billion in fiscal 2017. The Trump budget plans to cut the amount the government contributes in 2019 by a billion dollars.
In 2017, per the U.N., 19.5 million people, more than half those infected, are being treated. The UN thinks they can end the epidemic if 90% of those infected know they are infected. And if 90% of them take anti retroviral drugs; and if 90% of people being treated take enough medicine to suppress the virus. Seven countries, one of which is in Africa, have achieved the 90/90/90 goal.
In the U.S. people are treated with one of many combinations of drugs. Most have not been generic. (But that’s changing. 3 major drugs were FDA approved in recent years, and in 2016 the agency authorized a generic version of Truvada—the pill that when taken daily by high risk individuals cuts the risk of infection by over 90%. ) The CDC recently estimated the average annual cost of HIV drugs was about $20,000 ($360,000 lifetime.) Most Americans with HIV get their medication through their insurer, but they have to pay deductibles, and copayments. That can be a problem. In the appropriate age and income situations Medicare and Medical supply the meds. The non-profit Ryan White Foundation helps when health plans are incomplete and people can’t afford the drugs. There are federal programs that help needy women and children. For the right population the Indian Service and the VA get involved.