stevefredman – Page 6 – THE WONDERS WE CREATED AND THE POTHOLES WE DUG

T CELL & CANCER

September 23, 2018February 13, 2021 by stevefredman

Immunotherapy and Willie Nelson

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In 2018 Jim Allison was awarded the Nobel Prize

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

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

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

DONATED & TAX $$

September 22, 2018February 13, 2021 by stevefredman

Your tax and donated dollars at work

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

SHORTAGES

May 8, 2018February 13, 2021 by stevefredman

On one level we’re talking supply and demand–the quantities of a medication that are required and available at various price levels.

When a drug is needed for a non life-threatening conditions and it costs too much, people who don’t have the money don’t buy it. In “developed” countries, doctors and patients who are facing a life threatening illness expect the needed drugs to be accessible when they need them.

Climate is what we expect. Weather is what we get– Mark Twain.

“With the proper drugs” 90 percent of the 3.000 children a year who are afflicted by T-cell acute lymphoblastic leukemia are curable. “Between 2009 and 2019, nine of the eleven medications doctors used to treat the disease were intermittently hard to get.⁵” In 2019 two companies were producing Vincristine and one of them, Teva, stopped. “This is truly a nightmare situation,” one pediatric oncologist complained. “Vincristine is our water. It’s our bread and butter.” Another doc added: “You either have to skip a dose or give a lower dose, or beg, borrow or plead.” We will still be able to cure childhood leukemia but it’s harder “with one hand tied behind your back.¹⁴”

Bruce Chapner, an investigator at the National Cancer Institute, wrote about the limited availability of “workhorse cancer drugs”: and the astounding short supply of generic drugs: antibiotics, blood pressure meds, anesthetic agents and electrolyte solutions.²¹

56 percent of hospitals surveyed by the FDA reported they had changed patient care or delayed therapy in light of scarcities: 36.6 percent said they had rescheduled non-urgent or emergent procedures. “In Europe, the past five years have seen global shortages of at least ten essential oncology drugs. Two of five European doctors surveyed said the problems occurred on a weekly basis and typically last a few months.”²⁰

After a new pharmaceutical is created it can’t be marketed until it’s shown to be beneficial and relatively safe. In the U.S. its creator is then given a multiyear monopoly. When that ends others can fabricate and distribute the medication. Most of the drugs people take are generics, and many are made by one of the planet’s three top generic manufacturers:

Teva, an Israel based company that has $9 billion in sales, and factories in many countries,
Sandoz—a Swiss company that is the generics division of Novartis and has $8.5 billion in sales, 25,000 worldwide employees and 30 manufacturing sites, and
Actavis, a $70 billion company that is headquartered in Dublin Ireland and has 10,000 employees.¹

More than 50% of our generic drugs are supplied by one or two manufacturers. Some medications have “Thin profit margins that can lead to shortfalls, manufacturing delays, or decisions to discontinue a drug altogether.¹⁶” When several companies manufacture a medication, competition can lead to a “race to the bottom.”– A destructive drop in the prices.

In the 21^st century U.S. more than 100 meds were hard to get “at any given time” Sixty three% of them were generic sterile injectable drugs.¹⁵

As meds became less profitable, manufacturers often don’t upgrade. They keep producing the drugs in “older and less efficient production facilities.” When contamination leads to plant closures manufacturers don’t always rebuild.³ Companies with factories that need updating “need predictability– incentives in the form of guaranteed-volume contracts to mitigate the risks of making investments.” “Without accurate information about the expected demand for low-volume, low-margin medications, companies have been reluctant to create additional manufacturing capabilities.²”

Limited availability is also affected by business difficulties. In December 2017, facing falling profit margins, Teva laid-off 14,000 workers and closed a few manufacturing facilities. They were under pressure in the U.S. from “major chains, wholesalers and benefit managers who had gotten together and demanded discounts.” To survive and be profitable they planned to discontinue some drugs and close or sell “a significant number of manufacturing plants in the United States, Europe, Israel and other markets.^4”

In June 2018 after 31 senators wrote a letter to the head of the FDA “requesting his assistance with the availability problem” The agency task force suggested using “incentives” to encourage drug makers to produce scarce products. They wanted the FTC– federal trade commission to “review drug company mergers and acquisitions.⁵”

In 2011 there were 257 new drug shortages. The next three years there continued to be 250 shortfalls a year, and in 2019 the number of meds in short supply started rising. In 2015, acting on Obama’s executive order, the FDA published a number of rules to help alleviate the problem. Before companies stop making any or enough of a needed drug, (within the limits of the law) they are supposed to notify the agency. The government can then “determine if other manufacturers are willing and able to increase production”

The FDA “was told to expedite inspections and reviews of submissions from manufacturers attempting to restore production, and from manufacturers who were interested in starting new production.

The agency was also told to bend a few rules: “Exercise temporary enforcement discretion for new sources of medically necessary drugs;” help affected manufacturers identify the reason there wasn’t enough of the needed medication. They developed risk mitigation measures, like using sterile filters, to allow individual batches of a drug product initially not meeting established standards to be released.¹⁷

Currently the FDA says it has 4 “officers” and others working on the shortage problem. Most companies were notifying the FDA as required by law, and the FDA was encouraging, talking, strategizing—and increasingly relying on foreign inspection histories. But the agency was toothless. They couldn’t require manufacturers to do anything.

In 2017 “Due to the ongoing critical lack of injectable drugs used in critical care” the FDA extended the expiration date of a number of Hospira injectable medications.⁶

“The effectiveness of a drug may decrease over time, but much of the original potency still remains even a decade after the expiration date. Excluding nitroglycerin, insulin, tetracycline and liquid antibiotics, most medications are long-lasting”. So: why are drugs dated? A law passed in 1979 requires drug manufacturers to stamp an expiration date on their products. It marks the final month and day the company can guarantee the full potency and safety of the drug. In August 2018 the FDA reported on a stockpile of expired drugs that was tested for the military. As long as 15 years after their expiration date, 90% of the hundred prescription and over-the-counter medications “were perfectly good”.⁷

There’s a grey market. Nobody wants to run out of needed medications or infusions, and some facilities have paid a premium and stockpiled them. That’s illegal you say. Tell that to the person with a serious infection who needs the right antibiotic now.

Global demand is increasing, and some shortages are worldwide. In Brazil, a three-year shortage of benzathine penicillin G (BPG) occurred at a time when the country was having an outbreak of syphilis, a disease linked to severe malformation in babies. Benzathine penicillin G is the only long acting antibiotic known to cross the placenta and prevent mother-to-child transmission of syphilis. Worldwide, “just four companies produce the active ingredient for penicillin. The medicine offers little profit, and those companies keep production levels low.⁸”

In the US, the number of people with syphilis has grown. In 2019 more than 115,000 cases were reported to the CDC. The drug that best treats the disease, Procaine Penicillin, is produced for the U.S. by Pfizer. It was in short supply prior to March 2019. It’s currently available.

According to the FDA approximately 20 million IV saline bags are used per month in the United States. IV fluids are used to hydrate, as a vehicle for infusing medication, and much more. In the U.S. they are largely supplied by: Baxter, a U.S. company with 3 manufacturing plants in Puerto Rico. (They also have “12 manufacturing sites in the continental U.S. and eleven in Latin America and Canada.”); Bags are also manufactured by B.Braun Medical–The American branch of a German company that has operations in 64 countries: and Hospira (a Pfizer owned company).

The supply of sterile solutions in the U.S. had been borderline for years. In September 2017 Hurricane Maria with sustained wind of 155 mph blew through Puerto Rico and knocked out the islands power. When we visited San Juan the following January the warm Caribbean sun and the gentle island breezes masked the destruction. The hotels that functioned were filled with construction workers and there were no tourists. The power in Ponce had been turned on the very day we visited a shop and spoke with the tanned, smiling proprietor. If someone in an apartment building had a generator electric wires from other apartments hung from windows and were plugged in. Some houses were roofless. For others blue tarps kept the rain out.

Baxter asserted that their “3 Puerto Rico sites were minimally damaged and that they had resumed “limited production activities within a week using diesel generators”; but the U.S. needed bags; and the FDA acted. The agency can’t require a manufacturer to make more. But in March they “checked out Fresenius Kabi, Norway’s saline producing facility. It passed inspection and the agency “temporarily allowed Fresenius Kabi to distribute normal saline in the U.S.” In April 2017 the FDA allowed Baxter to temporarily import normal saline produced in Spain.⁹

The world will soon face a shortage of antibiotics that treat drug the resistant bacteria that, according to the CDC, infect at least 2.8 million Americans a year and contribute to 35,000 deaths. In the last decade at least two start ups created a drug that destroys resistant organisms. The FDA approved their use, and they are available. But the involved companies aren’t selling enough medicine, and they are considering bankruptcy.²²

https://www.thebalance.com/top-generic-drug-companies-266311
http://www.pewtrusts.org/en/research-and-analysis/reports/2017/01/drug-shortages
http://www.nejm.org/doi/full/10.1056/NEJMp1112633#t=article
https://www.nytimes.com/2017/12/14/business/dealbook/teva-pharmaceuticals-generic.html
https://www.fda.gov/media/132058/download http://www.ajhp.org/content/early/2018/03/14/ajhp180048?sso-checked=true
https://www.wisc-asc.org/news/382129/FDA-Approved-Drug-Extended-Use-Dates-List-.htm
https://www.health.harvard.edu/staying-healthy/drug-expiration-dates-do-they-mean-anything
https://www.aljazeera.com/indepth/features/2017/05/world-suffering-penicillin-shortage-170517075902840.html
http://www.jhconline.com/iv-shortage-tests-providers-and-suppliers.html
(N Engl J Med 2014: 371: 1761-1763)
https://www.kccllc.net/achaogen/document/8851500190415000000000003
https://www.in-pharmatechnologist.com/Article/2019/06/10/Achaogen-sells-remaining-assets
https://www.fiercebiotech.com/special-report/30-xerava
https://www.nytimes.com/2019/12/25/health/antibiotics-new-resistance . https://www.sec.gov/Archives/edgar/data/1373707/000119312513048887/d441172ds1.htm
https://www.nytimes.com/2019/10/14/health/cancer-drug-shortage.html
causes and non causes of drug shortages by Albert Brill. http://getmga.com/wp-content/uploads/2017/04/HSCA-drug-shortages-Jan-2017.pdf Drug Shortages: Root Causes and Potential Solutions A Report by the Drug Shortages Task Force 2019 a report chaired by the FDA https://www.fda.gov/media/131130/download
The generic drug industry has brought huge cost savings. That may be changing.By Carolyn Y. Johnson Washington Post. August 1, 2017 https://www.washingtonpost.com/business/economy/the-generic-drug-industry-has-brought-huge-cost-savings-that-may-be-changing/2017/08/01/ee128d0a-68cf-11e7-8eb5-cbccc2e7bfbf_story.html
Third Annual FDA Report to Congress on Drug Shortages for Calendar Year 2015 https://www.fda.gov/media/96113/download
file:///C:/Users/User/Documents/Bipartisan%20letter%20to%20FDA%20on%20Drug%20Shortages%20from%20the%20Senate.pdf
https://www.pewtrusts.org/en/research-and-analysis/articles/2020/01/16/antibiotic-sales-for-animal-agriculture-increase-again-after-a-two-year-decline
https://cancerworld.net/spotlight-on/shortages-of-generic-cancer-medicines-are-harming-patients-so-why-cant-we-fix-it/
Bruce A. Chabner, M.D.December 8, 2011N Engl J Med 2011; 365:2147-2149 https://www.nejm.org/doi/full/10.1056/NEJMp1112633 \
For a startup to be financially successful they have to develop a very expensive medication (see gene therapy), create something that is truly innovative, or sell a lot of product. Vis-à-vis antibiotics, if physicians start giving one of the new antibiotics to every sick person whose infection might be caused by resistant bacteria, the drugs will be over used. With regard to the companies that developed the medications we need: Achaogen, incorporated in 2002, “developed and commercialized an “antibiotic treatment against multi-drug resistant gram negative infections.” Their research was funded “in part by a $124.4 million contract” with BARDA, part of the government agency that “was established to secure our nation from biological threats…as well as emerging infectious diseases.” Investors apparently hoped their drug, Plazomycin –Zemdri, would bring in millions. (It’s reported revenue was $800,000 during the last 6 months of 2018)–‘Unfortunately the new antibiotic is not a true innovation. It is an altered version of a drug that was developed in 1963 by scientists employed by Schering. They worked with a naturally occurring product of a bacterium, a micromonospora, and they produced the antibiotic gentamycin.. Scientists were later able to chemically modify it and produce other antibiotics: neomycin—then Amikacin– and now plazomycin. All are aminoglycosides and can harm a person’s kidney or hearing. Doctors mainly use them when they are really needed.¹¹

Another new antibiotic in financial trouble, the tetracycline Xerava—Eravacycline was developed by a start up using technology pioneered at Harvard. A legit medical advance, the drug was launched in 2018 at an announced wholesale cost of $175 per day. It effectively treats a variety of Gram-positive and Gram-negative bacteria, including multi-drug resistant strains, such as MRSA and a resistant enterobacteriae.

The medication apparently got off the ground when Congress was convinced that its creation would have biotech signficiance. In 2011 and 2012 Congress authorized $67 million for the development of eravacycline “for the treatment of disease caused by bacterial biothreat pathogens.” Currently the government money is running out; doctors are using the medication appropriately–only when indicated. Its developer, Tetraphase, has investors and it’s struggling.¹²

There’s a nonprofit at Boston University that’s working on the antibiotic resistance problem. It’s called CARB-X and it claims to be “the world’s largest pre-clinical and early development pipeline of antibiotics and other therapeutics. Since it was established in July 2016, it has invested $160.6 million in 52 projects in seven countries.” (Like an average of $3 million per project to develop a next generation drug. Hmm.) It is funded by the US Department of Health and Human services, The Wellcome Trust, A UK Innovation Fund, and the Bill & Melinda Gates Foundation.¹³

GOUGING

May 7, 2018February 13, 2021 by stevefredman

To be audacious with tact you must know when you’ve gone too far. Jean Cocteau

When I started learning about Martin Shkreli I expected to find a canary in a coal mine– the Edward Snowden of drug prices– an in your face rebel trying to force the country to stare hard at its absurd drug pricing system. But that wasn’t who he was. Shkreli, the son of immigrants, went to business school and worked on Wall Street. He allegedly (when young and new) exaggerated or lied to some of his hedge fund clients. He insists the people who stuck with him all made a profit, so no harm done. He later became the head of a pharmaceutical company and overpaid for a drug called Daraprim.

The medication was developed 75 years ago and was originally used to fight Malaria. It was one of many drugs developed by Nobel Prize winner Gertrude B. Elion, a woman who rose to the top in a discipline dominated by men. The daughter of a Lithuanian dentist who was bankrupted by the 1929 stock market crash, she graduated from tuition free Hunter College, and worked as a lab assistant to earn the money needed for her graduate studies. When she was finally able to study advanced chemistry she noticed she was the only female in the class.

The medication she created, Daraprim was owned by Glaxo Smith Kline. It had been around for decades and couldn’t have been very profitable. In 2010 the drug was sometimes used to treat Toxoplasmosis, a parasite transmitted by cats that can damage the eyes and brains of newborns.

In people with advanced AIDS, people whose immune system has lost its ability to protect them from the microscopic organisms that live harmlessly and unobtrusively in our bodies, the parasite can invade the central nervous system. After it gets a foothold it can cause focal cranial lesions and encephalitis, a potentially lethal inflammation of the brain. Daraprim, also known as pyrimethamine, plus sulfadiazine and anti viral therapy is the treatment of choice for the infection.

HIV destroys T cells, immune cells that protect us from invaders. Over years untreated people with HIV have fewer and fewer of these defenders. When their CD4 count, the number of circulating T cells, drops below 200, the person affected has the full blown disease– “AIDS”. Creatures that were barely surviving start to wreak havoc. When the CD4 count goes below 100, the parasite that causes Toxoplasmosis can become a problem.

A little over a million Americans are living with HIV. The majority are taking drugs every day. The virus is suppressed and is not destructive. 15% of those infected are unaware. A little over 6000 U.S. deaths annually are attributed to HIV. I don’t know how often Toxoplasmosis contributes to their demise.

Made in a few places in the world, Daraprim had long been available and cheap. Glaxo Smith Kline couldn’t or wouldn’t raise the drug’s price for practical, philosophic, and public perception reasons. So it was kind of a financial loser. One of several drugs that was sold or dumped by GSK, Daraprim was briefly owned by a drug company called Tower holdings. After a series of drug company acquisitions and mergers the drug became the property of Impax of Hayward California.

The company (allegedly) claimed they sold $9 million dollars worth each year and made little or no profit. In August 2015 they got rid of the product. They convinced Turing Pharmaceutical to buy it for $55 million. At the time Turing was a privately held start up with offices in Switzerland and New York. According to its LinkedIn page, the company once had 50 to 200 employees.

After the drug was acquired, Turing tried to start campaign to make mothers aware of the possibility of transmitting Toxoplasmosis to their fetus. I’m not sure why. Toxoplasmosis in newborns is uncommon. Of the 4 million children born in the U.S. each year, an estimated 400 have Toxoplasmosis. That’s .01 percent. When Daraprim (pyrimethamine) is fed to pregnant animals many of their offspring are born with abnormalities. So we avoid giving the medication to pregnant women.

Once Daraprim was part of Turing’s arsenal, the company’s CEO, Shkreli, raised its price from $13.50 to $750 per pill. A self professed Republican he chose to not explain the price hike. It was legal. Drug companies raise their prices all the time.

“You can get away with high drug prices if you do it right,” Barrie Werth once said. “If he had raised the price 30 times instead of 5,000 times, he could have gotten away with it.¹“

Because of its high cost, pharmacies and hospitals were reluctant to stock the medication, and it was hard to obtain on short notice. Then a person with AIDS was hospitalized with a Toxoplasmosis brain infection. His doctor found it difficult to get the drug and Dr. Judith Aberg, the head of infectious disease at a New York medical center got involved. Outraged by the price she told the person’s story to the New York Times and Shkreli was vilified.¹²

And he wasn’t contrite. When he later appeared before a congressional committee he refused to answer questions. He took the fifth. The amount charged for the drug was legal, and Shkreli was not apologetic. He was interviewed repeatedly by Journalists and became infamous.

His company, Turing was sued by Impax. They no longer owned the drug but, reportedly, still owed the government $30 million for Daraprim related Medicaid requirements. Impax wanted Turing to pay, but a judge found it wasn’t part of the contract. Then the department of justice indicted Shkreli for alleged misconduct as a hedge fund manager. He was found guilty on 5 of 8 charges, he lost his job, and the company laid-off a lot of people.

As Shkreli said on an internet talk show (edited) “in life you can play the game or you can give up the fakeness and be yourself. It has drawbacks. We saw a major insider trading case that was settled by the SEC. Big banks take millions in fines. No one gets arrested. There was a security charge that I manipulated stock price and another that I defrauded investors. They all made money.”

“People with insurance or under Medicaid don’t pay for their drugs. They pay co-payments”…. (which can be quite significant.) Much of the cost of Daraprim, like most expensive drugs, is borne by the tax payer or it becomes part of the rising cost of health insurance. And that wasn’t Shkreli’s problem. He wasn’t a rebel. He had no cause.

I don’t know what Daraprim costs today. Shkreli, who was out on bail was rearrested for a stupid internet prank, and the judge had him imprisoned. I have no idea what makes him tick, but I know his antics have little to do with the high cost of many drugs in this country.

Numerous Americans are bothered by the cost of the medications they take, but they don’t usually focus their ire on the big pharmaceutical companies. Instead they talk about “the gougers”—the notorious few who dramatically jacked up the price of the drug that helped a few people who were dying of AIDS or Epipen. Their antics grabbed the headlines. Congress held publically televised hearings, and in the eyes of many Martin Shkreli, and Heather Bresch, became public enemy number one and two.

When Heather Bresch appeared before Jason Chaffetz’s congressional committee in September 2016, the congressmen and women probably assumed she would quietly accept their outrage and verbal reprimand then continue “getting filthy rich at the expense of their constituents…and have no remorse.” As a leader at Mylan Pharmaceuticals she was in charge of a product, EpiPen. Her company had purchased the contrivance from Merck in 2007. There was a marketing campaign. The awareness of the device’s importance as an emergency treatment for severe allergic reactions had grown. The company “had pushed through legislation that made EpiPen a main stay in schools.” And the sale and price of EpiPen grew dramatically.

After her congressional appearance, in at least one subsequent TV interview Bresch, a mother of 4, and the daughter of West Virginia Senator Joe Manchin, appeared thoughtful and concerned. She answered questions like a well schooled politician–with her talking points: The system incentivizes higher prices for brand named products. Too many schools did not stock Epipens. They were underserved. The company spent a billion dollars improving access and awareness about severe allergic reactions and how to treat them.

The Autoinjector, the device that automatically squeezes the drug into a person’s body, was invented in the mid 1970’s The FDA approved its use in 1987. It is presumably no longer patented.

The drug, epinephrine, was one of the world’s first hormones. Isolated from the adrenal glands of animals in the late 1800s, it was purified and patented in 1902 by Jokichi Takamine, a Japanese chemist liing in the U.S., and has long been the antidote for a severe allergic reaction. (13). When a susceptible individual senses his or her body reacting to an allergen, when they develop hives, wheezing, or become faint because their blood presure is dropping–if they are severely allergic to bees, have just been stung, and are starting to react, they take out their device, remove the top, put the needle end against their thigh, and press a button. A sharp painless needle bursts out of the syringe, pops through their clothes and skin, and enters their thigh muscle. Then the “plunger” automatically pushes the drug into the person’s body.

Between 2007 and 2016 the list price of a two-pack went from $94 to $609, an increase of 500%.²EpiPen generated $184 million in net sales revenue in 2008, and Mylan thought they would take in $1.1 billion in 2016. That was a fivefold increase in gross income. At the time of the Congressional hearings two prefilled syringes were selling for over $600. A Congress person derided company’s “simple corrupt business model.” Find an older cheap drug that has virtually no competition and raise the price over and over, taking advantage of the monopoly.

Bresch was repeatedly asked how much of the money was profit, and she kept changing the subject. The FDA representative sitting next to Bresch said the agency would review new applications for epinephrine injectors within 10 months.

The rapid rise in price had created a stir. Representatives and reporters needed to express their indignation. And they did. The publicized outrage also alerted a few entrepreneurs who were watching or reading about the hearing. Some saw a way to earn a quick buck. If EpiPen could bring Mylan hundreds of millions in profits each year, and if there was nothing keeping other companies from making and selling an identical product, why not get a piece of the action.

A few companies joined the fray and by the summer of 2017 EpiPen must have been feeling the heat. In Canada and the U.S. the price of EpiPen and a recently approved self injecting epinephrine Allerject sold for $130 a syringe.

CVS Health had a deal with epinephrine syringe provider Impax Labs, and was selling their authorized generic product, Adrenaclick, for $109.99 for a 2-pack.

And by 2011 a fourth epinephrine auto injector Symjepi, produced by San Diego’s Adamis company had been approved but had not yet been priced.

Bresch may have been unashamed, but the massive price hike opened a few eyes; and they saw gold in them there syringes.

THE PRODUCT NO ONE WANTED

In October 2010 GSK (Glaxo Smith Kline) dumped/sold a loser–the U.S. marketing rights for albendazole. Amedra, a small American drug company picked them up. The details of the deal were not disclosed (or at least I couldn’t find them on the web.)

As part of the agreement GSK agreed to continue manufacturing the drug for Amedra in the short run. They also renewed their pledge to the world health organization. They would continue to give the organization 600 million tablets per year as their contribution to the struggle to free the world from Lymphatic Filiariasis. A condition caused by microscopic thread worms that block the flow of lymphatic fluid the “neglected tropical disease” can cause an arm, leg, or testicle to swell and disfigure. As explained by the CDC the mosquito-borne condition affects 120 million people in 80 countries.” The Global Alliance is trying to rid the planet of the parasite by annually giving albendazole and ivermectin to all of the occupants of communities that are at risk.³

GSK proudly proclaimed their company “is committed to improving the quality of human life by enabling people to do more, feel better and live longer.” (I suspect GSK didn’t seriously consider raising the U.S. price, in part because they didn’t want to deal with the publicity such a move would engender.)

Albendazole was patented in 1975. It was invented by Robert J. Gyurik and Vassilios J.Theodorides, after Vassilios, a biochemist working for GlaxoSmithKline, read an article and had an insight. Raised in a small Greek village near the Macedonian border, the drug’s inventor never forgot the morning when German soldiers surrounded his town and marched its occupants to the village center. He was 10 years old. The soldiers told everyone to bring out their guns. Then they searched the houses. Finding shotguns in two homes they publically shot the men who had not obeyed. After the war Vassilos was briefly a shepherd. One day when he was 14 he left his flock of 200 lambs grazing in the public pasture and walked 11 kilometers to take a high school entrance exam. He was in another village studying the day in 1947 that Communist soldiers burned his village and killed 48 people. Some of them were relatives. Schooling was easy—natural. After he finished high school, planning to become a mathematician he visited the university office and asked where the mathematics school was. The clerk asked: what’s wrong with the Veterinary school? And he checked it out. As a veterinary student he developed an interest in research. Deciding he needed a PhD and knowing his future wife’s family had emigrated to Boston, he came to the U.S. and earned a PhD. As a young struggling postgraduate he worked for Pfizer in Terra Haute Indiana for two years. The town had a total of two Greek families. The mayor was Greek, and Vassilos wife was unhappy. So they moved to Pennsylvania for a research job at Smith Kline and French laboratories. One day, years later he read an article, and he had an “aha” moment. Unexplainably he somehow “knew” how to design the chemical that became Albendazole. (He quotes Pasteur: “God helps the minds that are prepared.”) Introduced in 1977, the medication was initially given to animals in Australia and New Zealand, but it was not approved for people in the U.S. because someone at the FDA decided it was carcinogenic. Vassilios met with people at the agency and showed them that their “mathematical approach in evaluating its potential carcinogenicity was incorrect.” They agreed, and humans started using the medication in 1982.

The bugs Albendazole kills exist in the intestines of 1.5 billion people. Most of the people who carry the parasites live in places that have poor sanitation. The bugs enter our bodies in childhood, with food that’s not thoroughly cooked or when we drink tainted water. Some penetrate the skin of a child or adult who walks “barefoot on contaminated soil.”

They come in a variety of sizes and shapes: tapeworms, long, flat, segmented ribbons that enter when we don’t cook the animals we eat. Pinworms, half an inch long nematodes that cause anal itching; ascaris, tiny snake like creatures. hookworms that suck our blood, and many more.

One day when my grandson, who had never lived in a third world country, was 3 or 4, he passed a worm. My daughter checked the internet, identified the creature and put it in a jar. When she showed it to her doctor he was taken aback, amazed. His nurse who had grown up in a village in the Phillipines merely shrugged. We still have no clue as to where or how the worm got in the kid’s body.

In India Albendazole commonly sells for $18. According to Wiki, in some countries it costs a penny to 6 cents a dose. In 2016 Amedra purchased the medication as part of “a portfolio of 15 generic drugs from Teva and Allergan for about $586 million.” A subsidiary of Impax, the publically held pharmaceutical company’s website says they are “engaged in the development of propriety pharmaceuticals.

”With the U.S. rights in their pocket Amedra raised the price pretty dramatically. In late 2010, the average wholesale price for the medication was “$5.92 per typical daily dose”. By 2013 it had jumped to $119.58. Medicaid spent less than $100,000 per year on Albendazole in 2008, and more than $7.5 million in 2013. Doctors in this country are prescribing it more often because the CDC thinks we should presume that refugees that come here from poor countries have parasites in their intestines, and we should treat them. Part of the stepped up spending is the result of increased demand.

The year after Amedra bought Albendazole, Teva, stopped manufacturing the drug’s only U.S. competitor, Mebendazole (brand name-Vermox). That made Amedra the only U.S. player in the intestinal parasite business.

“U.S. antitrust laws protect consumers only from anticompetitive strategies such as price fixing among competitors.
Manufacturers of generic drugs that legally obtain a market monopoly are free to unilaterally raise the prices of their products.
The Federal Trade Commission will not intervene without evidence of a conspiracy among competitors
or other anticompetitive actions that sustain the increased price.¹⁰”

Amedra does have a program that supplies the medication to the impoverished, “but these programs often have complicated enrollment processes.⁴”

A few years back a Philadelphia drug manufacturer got exclusive FDA rights (a many year U.S. monopoly) to a drug I had been using for 40 years. The medication, Colchicine, is a plant extract that was used to treat gout before Jesus was born. It is one of a handful of ancient cures that withstood the test of time. The flower that produces the alkaloid was introduced to the new world by none other than Ben Franklin, an innovative guy who used the ancient remedy to treat his painful joints. I learned about the medication in medical school, and have advised many to take it. It has its share of side effects, and over the years has helped many of my patients, while making a few sick. The books back then told doctors to give repeated doses to people with acute painful joints. We didn’t stop till the pain subsided or the patient became nauseated or developed loose bowels. That turned out to be too aggressive for a few of my patients, and I quickly adjusted my approach.

For centuries physicians have successfully used it, but no one did a double blind controlled study. Most docs would have thought withholding the drug from the control group would neither be necessary nor ethical. Then, 23 years ago, doctors in New Zealand did the study. Their 1987 paper was titled: Does colchicine work? The results of the first controlled study in acute gout.⁹ Half the people with an acutely inflamed joint took the real drug; the other half a placebo (an inert look alike pill.) People taking colchicine improved more rapidly and more completely.

In the company’s defense, clinical experience is sometimes misleading. On occasion useful drugs fail or people get well in spite of us. But colchicine has been used a lot over the centuries, and if the test of time means anything, the medication has always passed with flying colors.

The drug was available, cheap, on the pharmacy shelf. No one had to go to the FDA to bring it to market. Then some whiz kid figured out how his company could get exclusive rights to the old herbal remedy. They ran a trial where neither the investigator nor the patient knew what substance was being used. (Though, frankly, it’s hard to not know when the pill you are testing causes nausea and diarrhea at high doses.) Colchicine, of course, worked. The results were presented to the FDA and the whiz kid’s company got exclusive rights to sell the herb extract in this country. “After the FDA approved Colcrys, the manufacturer brought a lawsuit seeking to remove any other versions of colchicine from the market; and it raised the price by a factor of more than 50, from $0.09 per pill to $4.85 per pill.” Since this is a widely used medication they apparently stand to take in an additional 50 million dollars a year during the next 7 years. (The manufacturer received 3 years of exclusivity for gout and 7 years for Familial Mediterranean Fever, although no new FMF studies were conducted). (Outside the U.S. colchicine still costs 9 cents a pill.)

On May 6^th 2018 the TV show 60 minutes explored Mallinckrodt Pharmaceutical’s decision to sell Acthar Gel for $40,000 a vial. (7 years earlier the same vial was priced at $40.)

The product is one of many hormones made in the pituitary, a small gland located at the bottom of the brain. Acthar, the brand name for a hormone called ACTH, is extracted from slaughtered pigs, and it tells the adrenal gland to make cortisol. In the early 1950s it was a means of giving some patients cortisone. In 1955 prednisone became available and doctors largely stopped using Acthar. The product was left with but two “accepted” indications: It uniquely helped a rare seizure disorder– infantile spasm; and it was used to help diagnose the cause of adrenal insufficiency. By 2001 doctors were only prescribing Acthar now and then, and it was a money loser. But some kids needed it, and its manufacturer, Aventis, apparently felt someone should keep producing it. That year the French pharmaceutical company managed to sell the drug to Questcor, a California “pharmaceutical company” that was losing money. Questcor paid $100,000 for the medication, raised the price, promoted the hormone for a few additional “indications”, and turned a profit. In 2013 Forbes named Questcor the best small company of 2013; and in 2014 Mallinckrodt paid 5.6 billion for Questcor and its money maker, Acthar.

In 2018 the FDC charged Mallinckrodt with price fixing. To keep the price high the company paid Novartis $135 million dollars and acquired the rights to Synacthen, a drug that is biologically similar to Acthar and was Acthar’s only competition. “Then they put the drug on the shelf.” At the time Synacthen was selling for 33 dollars in Canada.¹¹ Mallinckrodt was charged with antitrust and, admitting no wrong, settled the case for a hundred million dollars. The company makes more than a billion dollars a year on Acthar alone. With only 2000 cases a year of infantile spasm, the company then started marketing their hormone stimulator for a few additional diseases, like rheumatoid arthritis. And they were successful. According to 60 minutes, in 2015 “Medicare was spending half a billion a year on Acthar⁶.”

In April 2017 Maryland passed a price gouging law. It empowered the attorney general to indict companies if they “shocked the conscience” by dramatically raising the price of an off patent drug. The following year the Court of Appeals ruled the law was unconstitutional, and the Supreme Court did not weigh in. Absent a new amendment to the Constitution, Americans who “shock the conscience” have the inalienable Right to Gouge.⁷

9. Aust N Z J Med 1987; 17:301-304.
10. Excessive Pricing in Pharmaceutical Markets. Organization for economic co-operation and development https://www.ftc.gov/system/files/attachments/us-submissions-oecd-2010-present-other-international-competition-fora/excessive_prices_in_pharmaceuticals_united_states.pdf
11. Rockford Illinois lawyer Dan Havilland https://www.businessinsider.nl/rockford-mallinckrodt-express-scripts- drug-pricing-lawsuit-2018-5/
12. https://www.nytimes.com/2015/09/21/business/a-huge-overnight-increase-in-a-drugs-price-raises-protests.html By Andrew Pollack Sept. 20, 2015
13. epinephrine https://digital.sciencehistory.org/works/5x21tf430

SWISS MOVE IN

May 7, 2018February 13, 2021 by stevefredman

SWISS MOVE IN

The Swiss take control

Thirty percent of the money spent on pharmaceuticals is used to purchase a relatively small number of very expensive “designer” drugs. The medications are often extremely pricey (in large part–I believe) because the company that produces and markets them needs to recoup the billions they paid to acquire the drug and/or the company that created it.

Novartis and Roche, two of the top 4 Pharma companies, with gross incomes in 2018 of $35 and $46 billion–are headquartered in Switzerland. I have no doubt they are two of the many “Pharma companies that seem to believe acquisitions are the only way to keep their revenues growing as fast as investors expect. With today’s complex breakthrough medicines, it’s often cheaper for a company to acquire the next blockbuster drug than to develop it in-house.¹”

In 2006 Novartis paid $5.4 billion, took over Chiron, and planted its feet solidly on American soil. The company they bought was 25 years old and had been created by Bill Rutter, a visionary biochemistry professor.

The son of a Mormon elder from Liverpool England, Rutter was born and educated in Malad a small town in southern Idaho. His grandfather had been a British Army officer in India and had told William about the poverty and exotic parasitic diseases he had witnessed. As a youth William wanted to go to the school of tropical medicine in Calcutta. At age 15 he spent a year at Brigham Young University then lied about his age and joined the navy. World War Two was raging. When the conflict ended Rutter went to Harvard and was drawn to science. After he graduated he was accepted to Harvard medical school, attended a few medical school classes with a cousin, and realized he wanted to be a scientist, not a doctor. He earned a Ph.D. at the University of Illinois and spent a decade as a researcher and professor at the University of Illinois, Stanford, and the University of Washington.

In 1968, after refusing the job offer three times, he agreed to become the chief of the biochemistry department at the University of California in San Francisco. The unit had been leaderless for six years and (he once quipped) “every good scientist in the United States had probably been asked to take that job and turned it down.” He claimed he accepted the post because twenty faculty positions were open, and that was a “bonanza for recruiting^1”Rutter gathered top notch researchers and got them to work collaboratively. In academia investigators don’t always cooperate and share. He knew “science was competitive. “Everyone is trying to beat you and will use every trick in the book. You try to cover your bets in many different ways.⁸”His associates shared their knowledge.

In 1981, deciding NIH would not allow him to use genetic engineering to develop a hepatitis B vaccine, he acquired venture funding, hired great researchers, and formed Chiron. “It was not an issue of damn the torpedoes, full speed ahead. The business of the company initially was research, pure and simple–understanding the potential of a set of technologies. The major pharmaceutical companies didn’t want to become polluted by something that was “controversial” like genetic engineering, and they stayed on the sidelines. He had great confidence he’d be able to do things that helped human beings.”¹⁴

. The disease he wanted to put a stop to, Hepatitis B was caused by a virus. It was present, though usually inactive, in the livers of over 200 million people, 1.2 million of whom were Americans.⁸

Maurice Hilleman at the pharmaceutical company Merck had developed a vaccine that prevented the disease, by inactivating live viruses. His creation was safe and effective but people were afraid to use it. They recalled how, in 1955, the Cutter lab was making the Salk vaccine and failed to adequately kill the polio virus. Two hundred children were partially paralyzed and 10 died. I remember British Liver Professor Sheila Sherlock giving a lecture to a group of doctors back then and asking how many had taken the B vaccine. When but two hands went up she said: “Shame on you. Shame.”

Rutter had worked with Herbert Boyer and others at the University of California. He knew how to genetically engineer yeast and make it grow the shell of the virus. Researchers could then use the viral surface protein to create the vaccine. The idea of using implanted genes frightened some politicians, and the NIH might not fund the research. “Some portion of scientists was genuinely concerned. Others enjoyed the debate and the public controversy.”

There was a Senate hearing on the topic of genetic engineering and Bill Rutter attended. Margaret Mead arrived wearing a huge long robe and carrying a shepherd’s staff. “Adlai Stevenson, a Senator and a lawyer who would later run for the presidency of the U.S., ran the proceeding and introduced Margaret Mead as a world-renowned scientist who could give guidance on these issues.” Mead was an anthropologist who became famous after she spent 9 months in Samoa and learned that “adolescence on the island was not a stressful time for girls because their cultural patterns were different than those in the U.S.”¹⁸

At the hearing stood and repeatedly said something like, “You’re going to hear today from these scientists that this (genetic engineering) is not dangerous. I’m here to tell you it is dangerous.” After each repetition of her statement she pounded the floor with her staff for emphasis. “Boom! Boom!¹⁶” To Rutter “A social anthropologist with her shepherd’s staff giving advice on molecular, microbiological, and physiological science’” seemed incongruous. Observing the theatrics and attitudes Rutter realized that if he wanted to make the hepatitis B vaccine his way he would have to give up his job as chief of biochemistry and go private.

Growing the hepatitis B surface antigen in yeast, Rutter’s team “demonstrated how to do it in the laboratory.” Working with Merck, Chiron marketed a successful “B” vaccine. Then, since the company had money and talent, their researchers solved a whodunit that had eluded investigators for years. They identified the virus responsible for Hepatitis C, and we learned 200 million people worldwide and more than 2 million Americans were carrying the intruder in their liver. Some of them would develop cirrhosis and liver cancer.

Located in the right upper abdomen just under and below the ribs the liver is the body’s largest organ. Blood carrying nutrients from the intestine, filters through it before it enters the circulation. The organ metabolizes, detoxifies and produces needed proteins. It dumps unwanted wastes into the yellow bile that it secretes. It’s also commonly infected by several viruses, two of which, Hepatitis B and Hepatitis C often set up shop and become lifelong inhabitants.

Over the next few years Chiron acquired a number of European and U.S vaccine businesses and became one of the world’s largest vaccine makers. With a second company Chiron commercialized DNA and RNA tests that allowed blood banks to make transfused blood safer. The process they developed could detect minute amounts of live hepatitis and HIV viruses in donated blood. Chiron had a biopharmaceutical division, and to the displeasure of their Swiss partner Novartis, often participated in joint ventures with other pharmaceutical companies. In 1984 their scientists worked on the first sequencing of the HIV genome, and in 1987discovered, sequenced, and cloned the Hepatitis C virus.⁸

In 2006, already owning 49 percent of Chiron, Novartis bought the other 51%, started wearing the mantle of a U.S. corporation, and began to act more like a commercial business. In 2015 the company marketed and charged a little less than a competitor for the first U.S. biosimilar, Zarxio. It’s a medication that stimulates the bone marrow to produce more neutrophilic white cells. In 2018 Novartis paid $8.7 billion for the therapeutic gene that treated and hopefully prevented the worsening of spinal muscular atrophy, a lethal genetic disease. (As mentioned earlier they plan to sell the treatment to Americans for $2.1 million for a course of therapy.)

By 2009 the other Swiss giant, Roche, had a 15 year history pharmaceutical company acquisitions–like Syntex in 1994 and Chugai Pharmaceuticals in 2002. Their CEO was an Austrian born economist. Married with three children he skied, hiked, and made movies in his spare time. Initially thought of as shy he led the company when it plunked down billions and entered the cancer drug fray. Buying California based Genentech for $46.8 billion, Roche acquired a lot of debt and three antibodies that were used to fight cancer: bevacizumab, herceptin, and rituximab. They also had to deal with a “clash of cultures between a freewheeling Californian biotech company and a buttoned-up Swiss multinational.” There was plenty that could go wrong. The California innovator “was full of smart people who were very upset and worried about the idea of another company coming in and making the decisions.⁶”

The cost of their acquisition virtually cemented Roche’s need to charge high prices and to sell a lot of these drugs. If, at the time, some companies were uncomfortable charging a lot for anti cancer drugs, seems to me that they now no longer had much of a choice. Their shareholders would (no doubt) expect little less than a $100,000 a year price tag for significant products.

The entity Roche purchased, Genentech had started as a company that used genetic engineering to produce hormones. Hormones are molecules that are made in glands. They travel to, turn on and off, and adjust the activities of target organs in various parts of the body.

The existence of these important proteins was unknown before the 20^th century. Prior to the 1970s they had been extracted from the glands of dead animals and human cadavers. They were then purified and manufactured. Contaminants were always a concern.

The seed that grew into Genentech was planted during a meeting that took place in 1973. A scientist from UCSF and one from Stanford discussed the small collections of DNA in the cell’s cytoplasm. They met at a conference in Hawaii and at the end of a long day “took in the balmy evening air as they strolled and talked.”¹²

One of them, Herbert Boyer, “blue jean clad, with a cherubic face; outwardly relaxed and unassuming”, grew up in a small railroad town near Pittsburg. As a college student he had at times hitchhiked to classes at a nearby college. Majoring in biology and chemistry he was “really taken with the Watson-Crick structure of DNA”, and he earned his PhD in bacteriology. At age 37 he was a researcher at the University of California in San Francisco when one of his graduate students isolated an important enzyme. It sliced DNA at a specific position. The raw exposed nucleotide ends were sticky. Lengths of DNA could be attached.

The other man who walked leisurely in the warm air that evening was Stan Cohen, a 36 year old “trim, bald, bearded” Stanford hematologist. When he was young he wrote a pop song that made the hit parade. He was studying circles of DNA in the cytoplasm of bacteria that were spreading antibiotic resistance from one germ to another—plasmids.

The two investigators wondered if it was possible to use Boyer’s enzyme to hook a DNA fragment, a gene, onto the sticky ends of a plasmid’s DNA. Would the gene then tell the bacteria what to do and make? Would the transformed plasmid survive and clone itself?

It took a few months to do the research, but the following March they tested their idea and it worked. In November 1974 both medical schools filed a patent application, and the academic world debated the potential hazards of genetic engineering.

Over the next few years, surviving on money gathered by a venture capitalist named Bob Swanson, Boyer formed a company and called it Genentech. In its early years the company made somatostatin. A peptide that reduces secretory diarrhea and that blocks the action of some hormones like insulin and growth hormone. The product was not a big money maker.

Genentech then produced genetically engineered human insulin. At the time people were using purified animal insulin. It’s chemically a bit different from human insulin, but it works well. Genentech also produced genetically engineered human growth hormone. It too was not a big money maker.

In 1978 the start-up leased a 10,000 square foot section of an airfreight warehouse near the San Francisco Airport.

In 1980 the company’s technology was up and running and Genentech had a public stock offering. It was wildly successful and Swanson, one of the founders, called gene cloning “the cornerstone of a future billion dollar business.”

During the next decade Genentech developed TPA, Tissue Plasminogen Activator, protein that dissolves clots. It was used to treat “massive pulmonary embolisms” –blood clots that traveled from a person’s legs to their lungs.”

They also developed several cancer fighting medications. One of them, the antibody Avastin, inhibited the growth of the blood vessels that nourished tumors. In 2010 it generated $7.4 billion in revenue for its new Swiss owner, Roche.

The concept that tumors produce a gene that stimulates the growth of the blood vessels that nourish it–wasn’t originally Genentech’s. It was conceived of by Judah Folkman, a surgeon who would later quip that science goes where you imagine it. As a boy, Judah accompanied his rabbi father when he visited people in the hospital. “His father would pray through oxygen tents and Judah would sit in a chair and be very quiet. About age seven to eight he noticed doctors could open the tents and do things, and he told his father he wanted to become a doctor not a rabbi. He thought his father would be upset, but has dad wasn’t. He said you can be a rabbi-like doctor, and Folkman knew he thought it was fine”.²¹

He served in the navy for two years, went to med school, and became a surgeon. In the 1950s “he developed the first implantable pacemaker that targeted the atrioventricular region of the heart, and he “pioneered the first implantable polymers that allowed drugs to be released slowly. And at age 34 Folkman was “the youngest ever Harvard Professor of surgery.¹⁷” He had a research lab and studied the blood supply of tumors. By 1971 he had learned about the way cancers develop their blood supply and he shared his findings in an article in the New England journal of Medicine.

“The growth of solid neoplasms is always accompanied by vigorous new capillaries that come from the host.” Time-lapse movies of an animal experiment demonstrated vessels advancing towards and penetrating a tumor implant and establishing blood flow. If new vessels don’t develop, most solid tumors stop growing when they are 2 to 3 mm in size. They don’t die but the growths become inactive. Folkman’s lab isolated a factor that stimulated rapid formation of new capillaries in animals, and his people tried to develop an antibody to the factor. They were not successful.¹¹”

Folkman kept promoting the concept of cancer enlargement being slowed by blocking a factor that stimulated blood vessel growth.¹⁹ In the years that followed Folkman’s paper he noticed that when he rose to speak at medical meetings a number of doctors in the audience filed out. Some physicians thought his idea was farfetched and were apparently tired of hearing his pitch. Believing there’s a fine line between persistence and obstinacy Folkman kept at it.⁹

In 1989, a Genentech investigator isolated and cloned 3 isoforms of“vascular endothelial growth factor” (VEGF), a gene that caused blood vessels to grow. Then they developed an antibody to VEGF. Subsequently a slew of additional vascular stimulating factors have been discovered.

The researcher in charge of developing the antibody, Napoleone Ferrara, was born in Catania, a Sicilian town near the Mediterranean Sea and not far from the highest volcano in Europe. His interest in science was ignited by his grandfather, a high school science teacher who had a 5000 book library. The Sicilian went to medical school. Then he heard the fascinating lectures of a charismatic Professor of Pharmacology named Umberto Scapagnini, and he decided to become a researcher. Joining Genentech in 1988, Ferrara and his group spent years characterizing the protein and developing the humanized antibody that became Avastin. The years of research were costly. They were funded by Genentech, and the company was ultimately richly rewarded. Ferrara was lecturing in Sienna the day he learned that a pivotal study had shown that his antibody successfully helped treat colon cancer. He recalled he celebrated by drinking a whole bottle of Chianti.

Avastin remains pricey and is not always covered by insurers. Using it can create an additional burden for people who are living on a tight budget and have widespread disease.⁷

In 2008 Roy Vagelos, the chief executive of Merck commented on the price trend. His remarks were reported in the New York Times. He said he was troubled by an unnamed drug (thought to be Avastin) that “costs $50,000 a year and adds four months of life. He called it a shocking disparity between value and price.²”

Vagelos was 79 at the time. His attitude and remarks were influenced by what he did when he was the CEO of Merck in the 1960s. In his New York Times quoted speech he said the high prices charged for Avastin were, “not sustainable.” He was wrong.

Keeping the price of Avastin high has been a struggle. That year (2015) the British National Health Service and some insurance companies were disturbed by the thought of spending tens of thousands of dollars for the extra months of life the drug could provide. Headquartered in Switzerland, Hoffman La Roche–According to “The Street’—had to resist an effort by many European countries to lower the price of their expensive, cancer fighting drugs. “A bid to push down drug prices by the Swiss health ministry “infuriated drugmakers”.. and the company warned that such a move would hurt employment and would have a “negative impact on their future contribution to the Swiss economy.” In the years subsequent to its release Avastin’s annual revenue always topped $5 billion.³

The second drug Roche acquired, herceptin, was also an antibody. Most cancer causing genes “are sequestered deep in the cell.” By contrast, the gene in question, neu, is connected to the cell membrane and “a large fragment hangs outside.”

It was discovered in the 1970s after a researcher (working with Robert Weinberg at MIT) injected the “DNA from neurological tumors in rats, into normal mouse cells. The injected cells turned cancerous.” After the gene was discovered it was “more or less forgotten,⁴” and largely ignored before one Genentech’s scientists, Axel Ulrich made an antibody that targeted it.

After Ulrich’s antibody attached to neu it created an abnormal complex. A macrophage, a white cell that “engulfs and rids the body of cellular debris” would float by. It would sense the antigen-antibody combination, know it didn’t belong, and clean up the “mess,” obliterate the antibody and the cell that it’s attached to.

Once created, the antibody to neu might have intrigued some people but it was not really useful. Ulrich talked about it when he gave a seminar at UCLA in 1986. One of the attendees, Dr. Dennis Salmon, was interested.

A university hematologist, Salmon grew up in a coal mining town and, as a boy, had been impressed by the doctors who came to the house to tend to his father. His dad survived two mine cave-ins, then lost a leg in an auto accident. The doctors making house calls “made people feel better.” Salmon “saw the respect my parents gave them. So (he) always thought it would make a pretty cool profession.” In high school he “developed a keen interest in biology.” and in college he spent summers working in a steel mill. The job was tolerable for a few months, but the experience showed him what his life as a factory worker could be like and it “cemented his resolve. This wasn’t what I wanted to do with my life.” After med school Salmon had offers, but took a job at UCLA because “It wasn’t ossified, and if you had some resources and a good idea, you could pursue it.¹⁵”

According to Mukherjee, Salmon thought he and Ulrich should collaborate. Ulrich gave UCLA a DNA probe that identified neu, and Salmon checked his array of cancer samples to see if any of them were, perhaps, driven by the gene. Until that time it had only been found in mouse brain tumors. There didn’t seem to be much chance that it would turn up in a human tumor.

But it did. The oncogene, now called Her-2/neu, was found in some breast cancers, and it turned out to be an important reason for their rapid growth. Some breast cancers made and used it in large quantities. Scientists implanted Her-2 containing cancers in a mouse and watched them grow wildly. Traztuzumab, the antibody that inactivated Her-2 caused the cancer cells to die.

The scientific findings were intriguing, but it took a while before Genentech was fully committed to the idea of making a cancer drug. It would be a first for them. A drug that interfered with cancer was still a reach.

Salmon kept working the project. They couldn’t use the standard mouse monoclonal antibody. It could trigger an immune response. They found a Genentech scientist who knew how to create a mouse that produced monoclonal antibodies that a body would think came from a human. In the summer of 1990 they successfully created Herceptin. Women with breast cancer became experimental subjects. 15 were studied in 1992. 900 were given the drug in 1996. It kept making a difference. When, in 1998, the drug application was submitted to the FDA it was quickly approved. Its initial monthly price was $3,208. It rose to $4,573–$54,000 a year in 2013.

The research and development costs were part of the overall lab costs of Genentech, and before the company found a useful antibody their scientists probably produced a lot of duds. The overall cost of creating a new drug was significant. Testing, development, and getting FDA approval cost a lot. I suspect hundreds of millions of dollars were spent in the process.

But the reward, $6 billion plus a year, dwarfs the expenses. The high price tag has little to do with research and development and much more to do with the way the market works. The pharmaceutical manufacturer has a five year monopoly. During that time they have no competition and can charge whatever they think they can get away with. People with insurance often have a co-pay, and it can be substantial. But no company would price compete. They wouldn’t want to charge less for a new cancer medication. Others might follow suit, and that might upset the apple cart. To enhance stockholder value prices need to stay high. And of course once they owned the drug the Swiss company Roche “needed” to recoup the $46.8 billion they paid when they bought Genentech in 2009.

When Roche announced their revenues in 2016, the third antibody they had acquired from Genentech, Rituximab topped the list. With $7.3 billion in annual sales worldwide and $3.9 billion in the U.S., the drug was on fire.

When pharmaceutical spokes people justify the high price of drugs they commonly invoke the cost of research, but are unable to supply details. Rituximab provides a window into how much it really costs to create an innovative medication when researchers have a strong sense of where they are going and how they are planning to get there.

Approved by the FDA in 2012 the injectable antibody has revolutionized the treatment of some lymphomas. It targets a unique protein called CD20 that is found on the surface of only one kind of human cell: the B cell. Part mouse and part human (chimeric) in origin, the antibody was first tested for dose and toxicity in 1994. After rituximab is infused it circulates and “tends to stick to the side of B cells that’s rich in CD20. Natural killer cells then destroy up to 80%of a body’s B cells.”

The drug was developed by a San Diego start up called Idec. Its founders included several Stanford university researchers and Ivor Royston, a San Diego immunologist.

The son of a Polish sheet metal worker who entered Great Britain via the beaches of Dunkirk, Royston always remembered the summer when he and his mother lived in the castle his father was re-roofing that was once the home of Henry VIII and Anne Boleyn. In 1954 the family moved to America. In the U.S. Ivor, a good student, went to medical school, and married. His first wife’s father was a successful business man who liked to “challenge the young man with business problems.” If the son-in-law couldn’t solve the problem, his father-in-law would tell Ivor how stupid he was.” Years later when he was running Idec, Royston “wasn’t afraid to get involved with business people because “if I could deal with my father-in-law, I could deal with anybody.”

After medical school Royston carried out research at the NIH, became board certified in oncology and tried “to understand how the body recognizes cancer cells, and how can we get the body to make an immune reaction to cancer cells.” When he was a low level research doc at Stanford, Royston was stirred when he learned how to make monoclonal antibodies. “You could produce antibodies by fusing lymphocytes with myeloma cells and create a cell that don’t die and keeps making antibodies.” A colleague went to England, contacted the physicians who made the discovery, brought back cells from the “the myeloma line, the immortalizing cell line” and gave a few of the precious “hybridomas” to Royston. Ivor spent the next 22 years trying “to figure out how to make antibodies against cancer cells.¹³”

From the outset (1985) Idec researchers were looking for a monoclonal antibody that could be used to treat B-cell lymphomas. There are about 240,000 cases of the disease in the U.S. each year. The antibody they were trying to develop could also be used to improve some autoimmune and inflammatory diseases. Their efforts consumed millions of dollars.

In 1991 they needed more money and had an initial public stock offering. The proceeds netted enough money to get through FDA phase one testing–(toxicity and dose) and phase 2: treating patients without a control group to see if the drug seemed to work. The company had allegedly spent $80 million to this point. But they did not have the money necessary to perform the phase 3, the double blind, control versus treatment group, studies that the FDA requires before they approve a drug. The startup couldn’t get the medication to market.

In 1995 their CEO, a former Genentech guy, signed a collaboration agreement with his former employer, Genentech. The giant chipped in $60 million and acquired “a majority of the sales and profits that Rituxan would generate if it earned FDA approval.”

It was initially approved in 1997. Out of the gate Genentech charged $3475 for a month’s worth of the infusion. In 2002 $1.47 billion of the drug was sold. Genentech got most of the money. Idec got $370 million. By 2013 the average 30 day cost of infusions had gone up to $5031.

Vis-a-vis the price having something to do with the cost of development, Idec spent $80 million and walked away with $370 million. Genentech spent $60 million and hit the jackpot. The cost of research, development and getting the drug to market was $140 million. In 2017 it brought in over $7000 million—$7 billion.

In 2017 the antibodies Roche acquired with Genentech accounted for more than half of the company’s revenue. That year they sold $7 billion worth of Avastin; $7.4 billion worth of Herceptin; and $9.2 billion worth of Rituxan.⁵

1 http://fortune.com/2015/07/28/why-pharma-mergers-are-booming/

2. http://www.nytimes.com/2008/07/06/health/06avastin.html

3. Switzerland takes on its top drug makers in price row Reuters Sept 16, 2014. https://www.reuters.com/article/us-swiss-medicine-prices/switzerland-takes-on-its-top-drugmakers-in-price-row-idUSKBN0HB0XA20140916

4. http://www.nytimes.com/books/first/b/bazell-her.html

5. https://www.genengnews.com/a-lists/the-top-15-best-selling-drugs-of-2017/

6. https://www.ft.com/content/ee986108-e689-11e3-b8c7-00144feabdc0

7. https://www.jci.org/articles/view/77540 Siddhartha Mukherjee, The Emperor of All Maladies. Scribner 2010

8. https://www.strategy-business.com/article/16383?gko=6321f https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5251a3.htm https://www.ft.com/content/313c6abe-5628-11e9-a3db-1fe89bedc16e
http://cws.huginonline.com/N/134323/PR/200604/1045686_5_2.htmlh ttps://history.library.ucsf.edu/rutter.html

9. https://tvst.arvojournals.org/article.aspx?articleid=2503070 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268723/ https://www.scientificamerican.com/article/quiet-celebrity-interview/ https://news.harvard.edu/gazette/story/2008/01/m-judah-folkman-biomedical-pioneer-dies-at-74/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541201/

10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1383764/

11. Tumor Angiogenesis by Judah Folkman, NEJM, 197112.

18 rutter https://oac.cdlib.org/view?docId=kt7q2nb2hm;NAAN=13030&doc.view=frames&chunk.id=d0e357&toc.depth=1&toc.id=d0e357&brand=oac4

Folkman https://books.google.com/books?id=t7BhDwAAQBAJ&pg=PA1&lpg=PA1&dq=atrioventricular+pacemaker+folkman&source=bl&ots=6NTCN4vaMl&sig=ACfU3U2l1LLdD_uOp7hiOSShm3-NlLQb-g&hl=en&sa=X&ved=2ahUKEwjiwfKdzbbqAhXiJTQIHWYAD10Q6AEwAHoECAkQAQ#v=onepage&q=atrioventricular%20pacemaker%20folkman&f=false

ORPHAN DRUGS & GENE THERAPY

April 11, 2018March 13, 2021 by stevefredman

Each year 100 American babies are born with Pompe’s disease. The children are floppy, their muscles barely work, and their heart is enlarged. Few survive infancy. A genetic, recessive condition, the disease is only seen when both parents carry the defective gene.

The malady is the result of an enzyme deficiency. The kids’ cells don’t make enough lysosomal acid alpha-glucosidase, a protein that’s used to convert stored glycogen into glucose—energy.

We eat carbohydrates and sugar, and we turn what we don’t use into a storage polysaccharide called glycogen. We stockpile the excess fuel in our muscles and liver. Between meals, when we need sugar to keep going, we use enzymes like lysosomal acid alpha glucosidase to turn glycogen back into glucose. Babies who lack the enzyme won’t stay alive long.

The condition was “characterized” by and named for a Dutch pathologist–Joannes Pompe. A member of the Dutch resistance, he was executed by the Nazis in 1945. The absent enzyme, Lysozyme, was isolated in Belgium in 1955, and the responsible GAA gene was identified in 1979. (It differs a little from one family to another.)

The needed enzyme was first made at Duke University by a dedicated team of researchers. Their leader, Dr. Chen, the chief pediatrician, started his quest after he went to the funeral of an infant who died of the disease. The pastor said God must have given the child life for some reason. Chen took the message to heart, and decided to assemble a team of Duke University researchers and go to work.

The inspiration came at the right time. Researchers knew how isolate the gene (the segment of DNA) that was needed. Bioengineers could make copies of the gene—clone it, and plant the DNA segment into a plasmid. Plasmids occur naturally in some bacteria. They are small circular segments of DNA that replicate but are not part of the nucleus. After the new gene becomes part of its structure, the plasmid is inserted into a cell, and the cell starts making the desired protein.

After scientists spend years isolating and characterizing a gene and are ready to move on, most want to preserve and immortalize the fruits of their endeavor. So they send a copy of their gene in a plasmid to Addgene, a Massachusetts based non-profit. Since 2004, Addgene has collected and stored more than 80,000 plasmids that contain genes. The plasmids came from the labs of 4000 investigators around the world.

The Duke researchers could have, presumably, purchased the plasmid that contained the gene that’s defective in Pompe’s disease. They made the missing protein by inserting the plasmids into cells derived from the ovaries of Chinese Hamsters. It’s one of the mammalian cell lines that are currently used mass production of therapeutic proteins¹. It took the researchers three years to make enough Lysozyme for their early tests. The produced enzyme was injected into a quail that had been bred to be Lysozyme deficient. The poor bird was in bad shape. It couldn’t get off its back, much less fly. Post injection the creature stood and even flew a little.

After 6 years of successful research, the Duke scientists got some manufacturing help. Production rights were licensed to Synpac, a British/Taiwanese company with a presence in Durham, Dukes home. Synpac, in turn “used experienced contractors to manufacture the enzyme.” (Having done the heavy lifting, the Duke scientists gave a lot away, but they retained some royalty rights.)

Once the company had produced enough enzyme, physicians at Duke infused the protein into three kids with Pompe’s disease. Lysozyme replacement worked.

In 2006 Synpac made a deal with Genzyme. It was a “15 year royalty sharing agreement that was potentially worth $821 million.” At the time Genzyme was huge. Based in Boston, their 2010 revenue was $4 billion. The company planned to spend more than $500 million dollars creating production facilities for Myozyme (their name for the enzyme).

The following year Genzyme was acquired by the French Pharmaceutical giant, Sanofi for $20 billion. As part of the process Duke University was paid $90 million, and relinquished its royalty rights. In 2016 Sanofi sold $800 million worth of the needed enzyme.

Now called Lumizyme, the enzyme is currently made in large sterile factories. Babies with the disorder get an injection of the protein every two weeks.

In this country “according to Sanofi, the average annual cost of treatment is $298,000.” If it works the first year it’s needed the second and third year. By the time a child is 10 years old—if no one develops a less expensive generic product, the system (insurance companies and Medicaid) will have shelled out $1 to $3 million dollars per child and big Pharma will have been handsomely compensated.

For those who feel health care is too expensive: You ain’t seen nothin’ yet. Scientists have started to effectively attack and control an increasing number of genetic diseases. Insurers are not allowed to deny coverage to anyone who has a pre existing condition nor can they impose lifetime or annual coverage limits. Given the way our economy works, the treatments and cures that create so much hope, will cost a bundle. And no one knows how we’re going to control their price tags.

During my early days as a Kaiser gastroenterologist a colleague, a neurologist named Frank, asked me to take over the care of a 40 year old woman with uncontrollable diarrhea and incontinence. He had been seeing her because her legs were weak and numb and she could barely walk. She spent her days in a wheel chair. She had a disease that affects “about 10,000 people worldwide” and is called genetic amyloidosis. People in her family had a 50-50 chance of being born with a gene that caused their body to make a form of the protein transthyretin (TTR) that didn’t fold normally. The substance was produced in the liver and in its normal form “carried both the thyroid hormone thyroxine and vitamin A in the blood.” People who are born with the abnormal gene were well when they were young. By the time they reached their 30s, their bodies were saturated with the misfolded protein and it started damaging their nerves, hearts, kidneys, and intestines. When it affected the small bowel some developed uncontrollable diarrhea. A cousin in a nearby town was a little older and acquired new problems a few weeks before B got them. B had been sick for a few years and was badly incapacitated but she somehow accepted her fate and didn’t complain. I couldn’t do much but I did what I could. Following diagnosis, most people with the condition have a life expectancy of 3 to 15 years.”

Frank (the neurologist) contacted a researcher at Boston University. It turned out she had an unproven diagnostic tool that could predict who among children had the gene. The researcher wanted to test her tool and Frank was game. They invited relatives from all over the country to a funded reunion. I didn’t go, but I was told the get-together was a disaster. Family members met distant cousins who were in different stages of deterioration. Everyone was visibly shaken by the clear picture of what was going to happen to their bodies.

B’s daughter C didn’t want to be tested. She was in her late teens and she just didn’t want to know. I don’t remember exactly when or how B died, but after she was gone I didn’t see her daughter for more than a decade. Then one day I got a phone call. It was C and she wanted to see me. She had chronic diarrhea that she originally thought it was caused by colchicine, a pill she took. When she stopped the pill the diarrhea didn’t stop and she knew what that meant. Over the years she had read everything she could about the disease. I had too. We both knew that in many people a liver transplant stopped the progression of the condition. C wanted my assistance and I helped her get on the list for a liver transplant at UCSF. The university hepatologists were initially going full tilt. Then C said she didn’t smoke marijuana and her blood or urine test showed she had lied. That created a problem. There are never enough livers and some people are always dying without a transplant. To create an aura of fairness the societies have created rules that exclude some people, like chronic alcoholics who are still drinking. At the time marijuana wasn’t legal and a person who lied about smoking it was automatically disqualified. I don’t remember how we convinced the transplant people to give C a second chance but we did. They came up with a creative way around C’s infraction. She would become a research subject. A 32- year-old ex-convict had died in an accident. My patient was given his liver and a 67 year old grandmother with liver cancer received my patient’s liver. In the right body C’s liver didn’t make the toxic protein. Her liver helped the grandmother a period of time. It was San Francisco’s first domino transplant.³⁰

C had diarrhea and was often somewhat dehydrated. She was stable for a while, but to prevent rejecting the new liver she was on drugs that suppressed her immune system. Then she started developing urinary tract infections and she repeatedly became septic. The immune-suppressing drugs made it hard to treat her. Antibiotics worked at first but the sepsis recurred. Each time the bacteria causing the flare were resistant to the drugs. A few years after he got the liver C became very septic and died. During her life when I saw her she often talked about her two sons. She wanted the boys to be tested before they considered having children, but she knew that if they had the genetic disease they wouldn’t be able to get health insurance.

A few decades passed but I never forgot about the C and B and the disease. Recently I read the story of a surgeon named Carlos Heras-Palou. In 2004 he experienced pain in my hands and feet and was diagnosed with hereditary transthyretin (hATTR) amyloidosis. As he told his story, at the time of his diagnosis Carlos was “39, married with two children aged 1 and 2, and had his dream job working as a surgeon. After my diagnosis, I could not see how we would manage as a family if I had to stop working because the disease was affecting my hands. I was worried about telling my brother and sister, and the impact of the news on them and their families. The prognosis was very bad, but after a short period of despair, I felt I had to put up a fight even if I could see no chance of winning it.” This was before CRISPR but Carlos had read about two young researchers who, in In 2006 received the Nobel Prize for discovering interfering RNA. Their names were Craig Mello and Andrew Fire. In their Nobel interview they spoke of the fun of scientific research. Mello was born in New Haven, Connecticut in 1960. His father, James Mello, was a paleontologist and his mother, Sally Mello, was an artist. The grandparents came to the U.S. from the Azores. Craig, like his father, became a paleontologist.

1986 two researchers began working together at the Carnegie institute in Baltimore. “Craig Mello: [Laughing] we’re studying these animals, trying to figure out these really ancient mechanisms of inheritance, how its DNA information passed on, and there was something really fundamental that we didn’t understand. We figured out how to introduce DNA into the germ line so that we could get progeny that have the DNA that we added. It’s sort of like gene therapy for worms.” The worm they worked on was the size of a comma on a printed page. It was a nematode called C. elegans and it had a nervous system, muscles and an intestine. The creatures ate bacteria and “you can put them through hundreds of generations in a year.” When they added the DNA the researchers also added a piece of RNA that looked like a piece of an m-RNA. The DNA they added was supposed to cause the worm to make a protein. The researchers, presumably could monitor the effect of the DNA by measuring the protein. Unexpectedly, when they injected the RNA anywhere into this animal, it silenced the DNA signal. The DNA was turned off in all the cells of the body. The researchers then developed double stranded RNA, that matched the gene, and the RNA turned off the gene. In 1998 they published the paper saying, “There’s this incredibly weird response to double-stranded RNA. You put double-stranded RNA into the animal and it will find matching information and turn it off.” That was totally unexpected. And, moreover, our paper had no explanation for it.”

In 2002 a number of prominent RNA researchers and financiers started Alnylam, a drug company in Cambridge, Massachusetts. They were trying to use RNA interference (RNAi) to treat genetic diseases. They began to look for a disease model, a validated gene target. It had to be made in an organ to which a drug could be delivered, and for which gene-silencing would result in the reduction of a measurable biomarker.

In 2004, when Carlos Heras-Palou learned he had genetic amyloidosis, he visited Philip Hawkins, the clinical director at the National Amyloidosis Centre in London. They talked about a theoretical approach to fighting amyloidosis. Perhaps they could silence the gene that encodes TTR, and block production and halt the progression of the disease. Hawkins discussed the option with the Alnylam research team and they started working on hATTR amyloidosis.

“Within a year, the company was reliably manufacturing silencing RNAs—siRNAs. The early molecules were plagued by a surplus of negative charges, making them prone to degradation. A delivery system had to be designed and tested. To avoid immune destruction and to get the medicine to the appropriate cells scientists immersed it in very small Lipid nanoparticles. (~100 nm in size). They administered the medication intravenously. It took a total of 10 years to develope the medicine.

“In 2013, Carlos’ younger sister was also diagnosed with hATTR amyloidosis. She was one of 29 people who received different doses of an RNA interfering drug.”

“In the subsequent phase III trial, two-thirds of participants received Patisiran, the silencing medication, and one-third received a placebo. Carlos was one of the 225 people enrolled in that study, which ran from November 2013 until August 2017. The results were published in July 2018 (D. Adams et al. N. Engl. J. Med. 379, 11–21; 2018) and found that the drug reduced TTR production by about 81%.. Patisiran was approved for medical use in the United States and in the European Union in August 2018. It is expected to cost around US$345,000 to US$450,000 per year.” Alnylam is trying to create a new form of the drug that can be injected subcutaneously once every three months, instead of the current intravenous infusion every three weeks. Carlos and his sister are apparently doing well.

(During its first 16 years Alnylam invested about US$3.5 billion into RNAi therapeutics. Most of it was spent developing a cholesterol lowering drug with a Pharma company called the Medicine’s company. In 2019 Novartis paid $9.7 billion for the cholesterol lowering drug and the Medicine’s company.)

Nature 574, S7 (2019)

https://www.nature.com/articles/d41586-019-03070-w

https://www.pewtrusts.org/-/media/assets/2018/09/atf-transcript_episode-37.pdf

DNA is present as two connected sequences of building blocks. Nucleotides from one strand “hold the hand” of a complementary nucleotide on the other strand. When DNA wants to instruct a cell to make a certain protein it creates a single strand of messenger RNA.

One side of the DNA is used as a template for the messenger RNA. For each DNA nucleotide there is an appropriate and opposite RNA nucleotide. Where there is a DNA adenosine there is an RNA thymine etc. The side of DNA that is used as a guide is called the “anti-sense” sequence. The RNA that is created looks like the other DNA strand –the sense side.

“In the 1990s Andrew Fire and Craig Mello were investigating the expression of a muscle gene in a nematode worm. They injected sense, then anti sense mRNA and the behavior of the worm didn’t change. Then they injected sense and antisense RNA together, they the worms started twitching. Similar movements were seen in worms that completely lacked a functioning gene for the muscle protein.

“When sense and antisense RNA molecules meet, they bind to each other and form double-stranded RNA. They wondered if a double-stranded RNA molecule silenced the gene carrying the same code as this particular RNA? Fire and Mello injected double-stranded RNA molecules containing the genetic codes for several other worm proteins. In every experiment, injection of double-stranded RNA carrying a genetic code led to silencing of the gene containing that particular code. The protein encoded by that gene was no longer formed.”

They showed that RNA interference is specific for the gene whose code matches that of the injected RNA molecule, and that RNA interference can spread between cells and even be inherited. It was enough to inject tiny amounts of double-stranded RNA.

(It was later determined that double-stranded RNA binds to a protein complex, Dicer, which cleaves it into fragments. Another protein complex, RISC, binds these fragments. One of the RNA strands is eliminated but the other remains bound to the RISC complex and serves as a probe to detect mRNA molecules. When an mRNA molecule can pair with the RNA fragment on RISC, it is bound to the RISC complex, cleaved and degraded. The gene served by this particular mRNA has been silenced.

RNA interference is important in the defense against viruses, particularly in lower organisms. Many viruses have a genetic code that contains double-stranded RNA. When such a virus infects a cell, it injects its RNA molecule, which immediately binds to Dicer (Fig 4A). The RISC complex is activated, viral RNA is degraded, and the cell survives the infection.” https://www.nobelprize.org/prizes/medicine/2006/press-release/

In 1983 researchers found the first genetic disease marker. It was linked to Huntington’s, a dominant malady that strikes in midlife. The disorder became well known after Woody Guthrie, the Oklahoma folksinger who wrote “This Land is Your Land” learned, at age 40, that his jerky movements, rigidity, clumsiness and inability to think clearly were caused by the disease. Abandoned at age 14 by his mother, who was hospitalized with Huntington’s, and his father, who moved to nearby town for a job, Guthrie spent his teenage years sleeping at various friend’s homes. He was able to rejoin his dad after a few years, but was more interested in his guitar than he was in high school. Guthrie married when he was 19 and the couple had three children. During the dust bowl Woody was living near the Oklahoma panhandle. Giant clouds of dust periodically blew in, filled lungs and killed cattle and a few children. The clouds were the result of decades of farming in an ecosystem that had adapted to long droughts. Farmers had pulled out the deep seeded grass that had covered and protected the dirt for over a century. During the wet years the crops were bountiful. Then came years when it barely rained. The soil became hard and the winds were fierce. Called the center of the dust bowl the area was now barely habitable and people were pulling up stakes and heading to California. Woody decided to join them. He left his family and headed west. 2 of Woody’s first three children developed Huntington’s in their early 40s. During his 55 years Woody served in the merchant marines, lived in California and New York and was a popular entertainer. He married two more times and wrote 1000 songs, one of which turned out to be his final message: “so long it’s been good to know yuh.”

The nucleus of each cell in our body contains 23 strands of DNA, 23 chromosomes. That’s where the 20,000 genes that are unique to each person are found. These genes account, at most, for 3 percent of the DNA in each nucleus.

Over several decades researchers identified the nucleotide sequences responsible for one genetic disease, then another. In 1990 scientists started mapping the entire human genome; the task was “declared completed” in April 1993, and genetic research got a huge boost. . We also learned that after a cell makes a protein it has to coil and fold into a specific three-dimensional shape. Misfolding produces inactive or toxic proteins and causes a number of genetic diseases.²⁴

Every so often a child is born with one of over 2000 really bad genetic diseases, and his or her family has to raise a disabled infant who will die young. Researchers working on the problems, have developed treatments that supply or teach the body to replace a vital protein. The number of children currently alive with each disorder is increasing.

Companies that market these life saving products charge a lot, too much for most people. It’s estimated that “orphan drugs will make up one fifth of worldwide prescription sales, amounting to $242bn in 2024. Much of the money will go to either big Pharma or big biotech.²” “The cost per patient per year of the top 100 orphan products was $150,854 in 2018.” Insurance companies that stay in the market and ultimately the taxpayers will have a new flood of costs they will increasingly have to deal with.

In the U.S. 49% of our health dollar is spent on 5% of the people. The total cost of care in the 2 ½ decades between 1980 and 2004,”has gone from $1,106 per person ($255 billion overall) to $6,280 per person ($1900 billion overall).”

There was a time when drugs for uncommon diseases had a difficult time getting FDA approval. Tests involving large numbers of affected people were needed before the FDA would conclude a new drug was safe and effective. That usually wasn’t possible when relatively few people were afflicted.

Then parents got together, pressured members of Congress, and the legislature acted. In 1983 Congress passed and the president signed the Orphan Drug Act. Companies that manufactured drugs for less than 200,000 Americans got a lot of rewards: Their FDA monopoly lasted seven, not five years. Companies got tax credits—they could write off half of the development costs. If the disease was rare, developers skipped the usual wait and joined the “fast-track” line.

The law worked better than anyone could have predicted. There are 7,000 rare diseases affecting 25 million to 30 million Americans. In the first 20 years 249 orphan drugs were marketed.

The FDA has approved 3 drugs that help people with cystic fibrosis. They were developed using seed funding from the Cystic Fibrosis Foundation –$47 million over 5 years; and $20 million from the Gates foundation.

In kids with Cystic Fibrosis the mucous that collects bacteria and foreign particles is not watery, not easily swept out of the lungs and swallowed or coughed up. It’s thick, “glue like”, and people with the disease have a hard time getting rid of it. They periodically develop pneumonia, and over time they lose lung function. A century ago most of the afflicted weren’t aggressively treated like they are now with inhaled bronchodilators, physical therapy, postural drainage, and appropriate antibiotics. Few survived childhood.

The condition is genetic, and recessive. If both parents are carriers, one of four offspring is afflicted.

The Cystic Fibrosis Foundation has established 117 centers of excellence. They are manned by experienced health care professionals and have guidelines, “best” practices, and public monitoring. As a result of their aggressive approach the average person with Cystic Fibrosis now lives an average of 35 years, though getting kids through their teen age years is typically tough.

Vertex, a biochemical startup that spent $4 billion during its first 22 years without developing an approved drug was not anxious to get into the Cystic Fibrosis business. There were only 30,000 Americans with the condition. If the company found a potential drug, it would cost $100,000 to test each person. In the company’s mind the expense of getting involved was “prohibitive.” Richard Aldrich, a deal maker and advisor, thought Vertex should only work with the CF (cystic fibrosis) foundation “if the foundation agreed to fund some of the early stage (drug) development.”

The Vertex research team was headed by Eric Olson. An experienced research biologist, he was interested in CF. A Colleague/friend’s daughter had the disease.

The faulty piece of DNA, the cause of the disease, was located in 1989 by a group of Canadians geneticists working with Hong Kong born Lap-Chee Tsui. The mutation responsible for most cases of cystic fibrosis occurs when three nucleotides are deleted from a gene on chromosome 7. Called Cystic fibrosis trans-membrane conductance regulator (CFTR), the abnormal gene causes the cell to make a defective membrane protein, one that doesn’t “fold” normally. Appropriately folded protein regulates the amount of chloride, salt and water that flows in and out, of the cell. The fluid travels through “channels” in the cell’s outer wall or membrane. In people with Cystic Fibrosis, salt accumulates outside the cell and secretions are thick. Sweat is salty.

By June of 2011 Vertex had two drugs that dropped the salt content of sweat. They decreased the exacerbation rate, and the unexplained “worsenings” that contributed to a more rapid decline in pulmonary function. In the early 2000s Vertex added a third drug. It had an effect people who have a “Phe508del CFTR mutation.” It’s the most common abnormal gene. 90 percent of people with cystic fibrosis have at least one copy of the mutated DNA. One analyst felt the triple-drug combo will rake in close to $4.3 billion by 2024.

——————————————————————————————-

The most common genetic cause of death in infancy, Spinal Muscular Atrophy “causes severe weakness by 6 months of age and inability to breathe by the age of two.” The gene that directs cells to make an essential protein is deleted or mutated. In the absence of the protein, the nerves that send signals to muscles die.

We all have a second gene that’s similar and that isn’t genetically affected. But it doesn’t work. It’s not able to make the needed protein. And that’s OK because most of us don’t need it.

Scientists at Cold Harbor Laboratory, a huge nonprofit, developed a “segment of RNA” that, when injected into the spinal fluid, allowed the second gene to make the needed protein. It was a great accomplishment and it wasn’t easy. The chemical, called nusinersen, was developed with the assistance of researchers at Isis pharmaceuticals. Another for-profit firm, Biogen Pharma, paid for the testing. Once nusinersen was shown to be effective Biogen paid millions and bought everyone else out. When the drug was approved by the FDA its owner decided to charge $125,000 for each dose, or $750,000 the first year and half as much each subsequent year.²⁷

A physician at the University of Utah who cares for “about 150 patients with the disease, complained in an article that if each child was treated with nusinersen, the cost would be $113 million the first year and $56 million thereafter.¹⁰”

In November 2017 an Ohio company developed alternative approach to the problem. Their therapy was based on research performed at Nationwide, a Columbus Ohio children’s hospital, by Brian Kasper. An employed researcher, he studied adeno-associated viruses (AAVs). (He presumably was learning how to put plasmids that contained genes into harmless viruses. The viruses would then infect a body, enter its cells, and dump the plasmids.)

One day his team discovered a viral serotype that penetrated the blood brain barrier. There are 50 serotypes of adenoviruses. They don’t usually make people sick, and most can’t get into the brain.

Kaspar and team believed they had “a new way of delivering genes to widespread regions of the central nervous system. The drug companies they approached allegedly weren’t interested. So in 2013 with the help of a biotech entrepreneur, Kasper formed a startup, AveXis. They raised $75 million and licensed the therapy from the Columbus hospital. To this point all research and development was paid for by the U.S. government and charitable funds.

Researchers placed a gene that promoted the production of the needed protein into an adenovirus. I presume that the SMN1 and SMN2 genes in plasmid form were available and could be purchased from Addgene for $65.

They infused a high dose of the virus that contained the gene into the bloodstream of 12 affected children who were about 6 months old. After 1 ½ to two years 11 of the children were able to speak, 9 could sit unassisted for at least 30 seconds, 11 achieved head control, 9 could roll over, and 2 were able to crawl, pull to stand, stand independently, and walk independently. The research was presumably paid for by some of the startup’s $75 million. ¹²

In April 2018 Novartis bought Avexis for $8.7 billion. After the FDA approved the therapeutic approach, Novartis named the treatment Zolgensma. In an attempt to recover their multi-billion dollar investment, and make a profit the Swiss set a high price for a treatment. Novartis will charge each child or their insurer $2.125 Million.²⁹

Currently “there are more than 800 cell- and gene-therapy programs in clinical development. Several of these therapies have been approved by the FDA.”—And the science is in its infancy. Some of the treatments on the market are owned by Biomarin, a company headquartered in San Rafael California. Founded in 1997 the company has acquired 6 biomedical startups in the last 15 years. In 2016 were marketing 5 orphan drugs.

When a tear occurs in a blood vessel people bleed, platelets plug the hole, and a sequence of proteins pile on. A clot won’t form if the person’s serum doesn’t contain enough clotting factor 8 or clotting factor 9. People who genetically don’t make sufficient amounts of either of these proteins have hemophilia.

A genetic condition that “occurs in approximately one in 5000 live births,” hemophilia is sex linked– which means that women carry the gene and their sons get the disease. When injured, affected males whose factor 8 or 9 is low don’t stop bleeding. Their joints periodically and very painfully fill up with blood. Over time they develop joint deformities.

Victoria, the queen of Great Britain from 1837 to 2001 was a carrier of the hemophilia B gene. She passed the condition through her daughter Alexandra to her grandson Alexei, the only son of Russian Tsar Nicholas. The couple had 4 daughters. The boy’s painful and frightening bleeds seemed to be helped by a self proclaimed holy man named Rasputin. During the First World War Tsar Nicholas spent a lot of time at the front, and his wife was in charge of the government. Much to the chagrin of the Moscow elite she seemed to be “under the spell” of the holy man.

The war went badly for Russia. Over 5 million soldiers were killed or wounded. After two years the Russian people had enough and they rebelled. They deposed the Tsar and Russia withdrew from the conflict. Some believe that hemophilia and the power of the mystic played a big role in 1917 fall of the empire.²⁶

Men whose blood level of clotting factor 8 is at or below one percent have a severe condition. Those whose blood levels are 5 to 40 percent have a moderate problem and mainly receive factor 8 infusions before surgery or if there is a need.¹⁴

In the 1980s, during the height of the AIDS epidemic, small amounts of the factor that stopped hemophiliacs from bleeding was collected from each of hundreds of units of plasma that was obtained from donors. One of the units usually came from a person who had HIV but didn’t know it. When the young men with hemophilia received the contaminated factor they developed AIDS, a disease that, at the time, was lethal.

Researchers at the University College London recently put a portion of the factor 8 gene into an adeno-associated virus and “infected” a number of men. With the gene floating in their cytoplasm, cells in the liver made the missing protein. In 6 of 7 patients receiving high doses of genes “factor 8 increased to a normal level and stayed there for a year. None of the 7 bled during that time.” After 2 to 3 years the treatment was still providing a clinically relevant benefit.²¹”

10 men with hemophilia B whose blood had less than 2% of the needed clotting factor were infused with an adeno virus containing a replacement gene. During the subsequent year their clotting levels rose and stayed at a mean level of 33 %, bleeding virtually stopped, and only 2 patients needed a factor infusion.

Scientists seem to be getting close to solving hemophilia.

As explained on 60 minutes, “Francis Collins of the NIH thinks we can cure sickle cell anemia by using CRISPR gene editing to increase blood levels of fetal hemoglobin (HbF). HbF is the form of hemoglobin that fetuses use to efficiently extract oxygen from the placenta and deliver it to their bodies. Shortly after birth a gene causes most children stop producing Hemoblobin F and adult hemoglobin takes over.

People with Sickle Cell disease have a genetic abnormality that affects adult hemoglobin. Red cells that should be round and flexible start looking like sickles or crescent moons. They clump, stick in small blood vessels, and cause severe pain, anemia, stroke, pulmonary hypertension, organ failure, and far too often, early death.

Researchers at Vertex and CRISPR Therapeutics collected stem cells from a person with severe Sickle cell disease. In the lab they used CRISPR to destroy the gene in the stem cells that shuts down production of fetal hemoglobin. Then they destroyed the remaining bone marrow with chemotherapy and infused the edited cells into the patient.²³ It seemed to be working.¹⁸

CRISPR derived gene therapy is new, exciting and not fully developed, but will be widely used in future gene editing. The investigators who did many of the studies and developed the concept were publically funded and were—at the time—trying to learn how bacteria defend themselves from assaulting viruses. They were trying to understand CRISPR.

The following theory of how CRISPR came into being helped me understand the process: When a virus assaults a bacteria, the invader enters the cell, takes over its DNA, and directs the bacteria to make billions of viral particles. Most bacteria are enslaved, then destroyed. A few mount a defense and survive. Some of the survivors create a “DNA memory file.” The identifying characteristics of the bad viruses are stored in the DNA’s CRISPR area, and the memory–sequence becomes a “gene” that is passed on to future bacteria. In subsequent generations the memory DNA creates strands of RNA that float around inside the bacteria. When a segment of RNA recognizes an invading virus it latches on. Then it cuts the virus apart with an enzyme called Cas9.

After they understood how bacteria identify and destroy unwanted viruses, researchers tried to use the system to edit genes. They chose a target–a “twenty-letter DNA sequence” that was part of the gene they wanted to delete. Then they “converted” a collection of nucleotides “into a matching 20 letter strand of RNA.” This RNA was an exact replica of the DNA. It would guide the Cas-9 past the cell’s 3 billion pairs of DNA nucleotides and it would eventually identify the desired strand of DNA.

They planted the genetic instructions for making Cas9—the knife—into one plasmid. They put the genetic instructions for “guide RNA” –-into a second plasmid.

Their concoction was able to search a cell’s DNA—3 Billion pairs of nucleotides—and find the desired segment of DNA–and unwind the DNA –and use Cas 9 to cut apart the strand of nucleotides. In other words they could irreparably damage a chosen gene. (Cells know how to repair a break in their DNA. The cut ends either come together on their own.– Or the gap can be bridged by a segment of DNA.)

The study group was led by UC Professor Jennifer Doudna and Emmanuelle Charpentier. Doudna, the daughter of a professor of English, grew up in Hawaii and spent the summer that followed her college freshman year in a lab studying a fungus that was invading papayas. “It turned out to be a lot of fun”, she hungered for more, worked in a few labs, made a few discoveries. After a decade she became the head of a research lab at the University of California in Berkeley, a campus that was often blanketed in fog, but on clear days provided a spectacular view of the Golden Gate Bridge and the Pacific.

Doudna met Emmanuel Charpenier, a French professor who was working in Sweden, at a 2011 conference in Puerto Rico. Described as “Small and slight, with eyes so dark that they seem black” Charpentier was a PhD student at the Pasteur Institute in Paris when she “realized she had found her environment.” After that she spent more than 20 years performing research in 9 different institutes in 5 different countries.²⁹

The two women discussed possibly collaborating while they explored the narrow cobbled lanes of old San Juan.

In June 2012 Doudna and Charpentier published a study that showed how RNA and Cas9 could be used for “site-specific DNA cleavage and RNA-programmable genome editing”. Investigators around the world took notice and got busy.

Scientists already knew how to add a new, good gene. Mario Capecchi, years back learned that genes intuitively know where, amidst the 3 billion pairs of DNA nucleotides, they belong. If good genes are developed and put into cells, they migrate and attach to “their place.²².”

After Doudna’s paper was published Kevin Esvelt (currently at MIT) explained how using CRISPR + selfish genes in the germ line can create changes that will be inherited by future generations of cells.

Sensing that there wasn’t time to write grants and get government funding, Doudna and other scientists formed a venture capital company– Editas Medicine. Charpentier and others founded CRISPR therapeutics. Both firms, according to their web sites, are trying to cure Sickle Cell disease, cystic fibrosis, and a few other genetic conditions.¹⁹

Medical thinkers have argued that: given our current experience with the price of drugs we should start thinking about how we’re going to pay for “future success in gene therapy.”²⁰

Wurm FM (2004). “Production of recombinant protein therapeutics in cultivated mammalian cells”. Nature Biotechnology. 22 (11): 1393–1398. doi:10.1038/nbt1026. PMID 15529164.
Orphan Drug Report 2019 https://info.evaluate.com/rs/607-YGS-364/images/EvaluatePharma%20Orphan%20Drug%20Report%202019.pdf?mkt_tok=eyJpIjoiWWpVMk1UVmtNRFpqT0dFeiIsInQiOiIrcmZ3QjNwamZWWVwvZ1ZkcU5XS2E3Rk5oNXA5MXZJVUVCRitMQXpQd0sxMGJPU0JhdGRWbVJQQkZrc0xZNDNPSXRNM09wMGh2OEFXNXFNN1wvb1plT
https://archive.ahrq.gov/research/findings/factsheets/costs/expriach/ http://www.paradigmglobalevents.com/events/orphan-drugs-rare-diseases-2017-americas/
(Victoria Sato, president of Vertex– Page 69). Barry Werth, The Antidote. Simon and Schuster, 2014
http://www.nejm.org/doi/full/10.1056/NEJMe1712335
(Science: Dec 20, 2019) https://www.nejm.org/doi/full/10.1056/NEJMoa1908639
John Cohen, Science. Page 130, January 10, 2020
https://www.nejm.org/doi/full/10.1056/NEJMoa1908639?query=featured_home https://www.fool.com/investing/2019/06/12/5-most-valuable-pipeline-drugs-in-development-and.asp
http://btn.com/2017/06/10/how-iowa-and-rutgers-are-taking-down-a-rare-and-devastating-disorder-btn-livebig/
N Engl J Med 2017; 377:1723-1732 https://hbr.org/2017/04/the-cost-of-drugs-for-rare-diseases-is-threatening-the-u-s-health-care-system
NEngl J Med 2017; 377:1713-1722. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3900005/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895694/ Nat Biotechnol. 2009 Jan; 27(1): 59–65. Crystal, Ronald g. Adenovirus: The First Effective In Vivo Gene Delivery Vector Hum Gene Ther. 2014 Jan 1; 25(1): 3–11. https://www.nejm.org/doi/full/10.1056/NEJMoa1706198
https://xconomy.com/national/2019/04/15/how-an-ohio-kids-hospital-quietly-became-ground-zero-for-gene-therapy/
High, Katherine, N Engl J Med 2019; 381:455-464 . N Engl J Med 2020; 382:29-40 https://www.nejm.org/doi/full/10.1056/NEJMoa1708483
https://www.nejm.org/doi/full/10.1056/NEJMra1706910
NEJM Aug 1, 2019. NEJM Dec 7, 2017. https://www.nejm.org/doi/full/10.1056/NEJMoa1708538
N Engl J Med May 14, 2015 https://www.nejm.org/doi/full/10.1056/NEJMoa1414221 6 http://www.cnn.com/2017/10/12/health/fda-gene-therapy-blindness-vote/index. html https://www.forbes.com/sites/matthewherper/2017/12/11/spark-shadows-biomarin-in-hemophilia-gene-therapy-race/#7af39d156106 http://www.ucl.ac.uk/news/news-articles/1217/131217-UCL-research-leads-to-haemophilia-therapy-success
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870126/ Highly efficient therapeutic gene editing of human hematopoietic stem cells. Nat Med. 2019 Mar 25. CRISPR Therapeutics and Vertex Announce FDA Fast Track Designation for CTX001 for the Treatment of Sickle Cell Disease , CRISPR Therapeutics News Release, Jan. 4, 2019. https://www.nhlbi.nih.gov/news/2019/nih-researchers-create-new-viral-vector-improved-gene-therapy-sickle-cell-disease-0 )
A Crack in Creation by Jennifer Doudna and Samuel Sternberg: Mariner Books. 2018.
(“Stuart Orkin, MD, and co-author Philip Reilly, MD, JD, of Third Rock Ventures, tried to “catalyze the discussion” by suggesting several new models for valuing, pricing and developing gene therapy.”) Orkin, P. Reilly. Paying for future success in gene therapy. Science, 2016; https://www.nejm.org/doi/full/10.1056/NEJMra1706910
(After three years: 2 –who received a lower gene dose (2 x 10¹³or less) had very low levels of factor 8–1 IU per deciliter. 7—who received a higher dose (6 x 10 ¹³) had a median factor VIII level of 20 IU per deciliter; None of the 7 bled and none were treated with factor 8. (Before treatment the 7 were receiving 138.5 infusions annually.) (6—who received a median dose (4 x 10 ¹³) were followed for two years. At the end of that time the median factor VIII level was 13 IU. None of the 6 bled, but three had received one infusion of factor 8 per year. (Before treatment the average person was getting an infusion every other week.¹⁵)
(Mario Capecchi of the University of Utah made the discovery in 1982, and won the Nobel prize in 2007).
Company claims signs of success with CRISPR-edited stem cell transplants for two genetic diseases By Jon Cohen Nov. 19, 2019, Science.
http://news.mit.edu/1993/huntington-0331

https://www.genome.gov/25520322/online-education-kit-1983-first-disease-gene-mapped https://www.genome.gov/25520322/online-education-kit-1983-first-disease-gene-mapped
https://www2.le.ac.uk/projects/vgec/schoolsandcolleges/topics/dnageneschromosomes
Nicholas and Alexandra by Raymond Massie. Random House ; 1967
. https://smanewstoday.com/2015/02/23/exclusive-new-insight-into-sma-from-dr-adrian-krainer/
Gene therapy for spinal muscular atrophy https://www.nejm.org/doi/full/10.1056/NEJMoa1706198
Charpentier https://www.nature.com/news/the-quiet-revolutionary-how-the-co-discovery-of-crispr-explosively-changed-emmanuelle-charpentier-s-life-1.19814
Amyloidosis https://www.sfgate.com/health/article/The-Domino-Effect-Woman-gets-new-liver-gives-3238583.php

NEGOTIATING

March 5, 2018February 13, 2021 by stevefredman

When we talk about the cost of a unique new life saving medication (see gene therapy) the process is a little like hostage negotiation. The government gives the pharmaceutical manufacturer a 5 year monopoly and allows the company to set the price. The insurer has meetings with itself and decides how it’s going to deal with the situation, and to the patient and family it becomes a “your money or your life” situation.

When legislators decry Medicare’s inability to negotiate with a pharmaceutical company they are revisiting a politically influenced law that Congress passed in the wee hours of the morning December 8, 2003. (see FDA chapter) Some believe Medicare D could save a lot of money if they were allowed to negotiate with the companies that sell costly medications. Currently by law they can’t.

The law didn’t become a big political issue because of a later law that protects most of the people on Medicare. If the yearly outlay for a drug exceeds $6350, the situation is officially a “catastrophe,” and the Medicare recipient is only responsible for a small copayment.

The legislation that authorizes the government to pay the other 80 percent of the annual cost of the expensive drugs started as a bill that limited “total out-of-pocket charges for people on Medicare.” It was championed by Otis Bowen. A country doctor from a town of 5000 in northern Indiana, Otis was his state’s governor before he was appointed secretary of Health and Human Services by Ronald Reagan. Known as “Doc” Bowen, he “kept a prescription pad handy, and recommended remedies to cure the common cold and sore throat for both colleagues and members of the press.” When his bill to help people on Medicare was introduced Reagan wasn’t keen on the idea. But his administration was caught red handed giving weapons to Iran and money to the Central American counter revolutionary fighters known as “contras.” His party was in the midst of a huge scandal and the Republicans lost control of Congress.

In 1988 a few liberal senators promoted the Medicare Catastrophic Coverage Act. It included a tax that was controversial, and it had a drug benefit that, at the time, didn’t amount to much.

Senator Lloyd Bentsen made sure the legislation didn’t cover most medicines. It was just for catastrophes and at the time, there weren’t many. Bentsen, the senator who brokered the compromise, was a fearsome poker player. You never knew what cards he held. He was a B-24 bomber pilot during the Second World War and was shot down on twice. Looking and dressing like Hollywood’s version of a successful politician, the senator was tall and thin, had a deep, voice, and wore elegant clothes. When he went to a party and his wife wouldn’t leave he, famously, would playfully toss her over his shoulder like a sack of potatoes and carry her out.¹⁹” In 1988 when Michael Dukakis was the Democratic presidential candidate, Bentsen was his running mate and they lost.

In most of Europe, when a new drug becomes available countries go through a process. Germany makes sure the medication is safe and effective. Then the country allows the manufacturer to set a price and sell it. During its first year the new drug is compared to existing therapies and its relative “value” is determined. Then the company and government authorities bargain and usually arrive at an acceptable price. If they disagree they arbitrate. The panel of five that hears both sides includes a representative of the government and a person who speaks for the insurer, and their decision is binding—if the manufacturer doesn’t strongly disagree and doesn’t choose to stop selling the drug in the country. In seven years Germany has assessed “More than 300 drugs and fewer than 30 were withdrawn.¹⁸”

In the U.S. doctors often don’t know (and many don’t want to know) how much people pay for their medications. Health insurance policies often have formularies that cover part of the cost, so some people pay more out-of-pocket than others for the same drug.

Most of the medications people take are generics. When there are more than two manufacturers price competition can be intense.

Pharmaceutical Manufacturers handle the negotiations for unions, hospitals, benefit managers, the military, and the Veterans Administration. Formulary management works for the Veterans Administration. They, for example, only carry one or two beta blockers. Companies bid for the contract. All the VA business goes to the brand that provides the best price.

Medicaid doesn’t have to parley. The law says the program automatically gets the best price available.

In the world where everyone negotiates, health insurance plans include a prescription drug benefit. Their programs are managed by PBM’s, prescription drug management companies. Some of them are owned by a large health insurance company. Three independent management corporations control 75% of the market. They bargain, receive a service fee from their clients, share their financial gains with health plans,” and commonly determine the drugs that insurers cover, and their “tier” position.³

Cheap generics have low co-pays. Preferred brand name drugs are up a step. The newer, very expensive medications are typically in the top row. The person who takes the pricy drug and is not on Medicare commonly has to pay a percent of the list price.

For illustration, the formulary of the University of Maryland Health Advantage has 5 drug levels, and five escalating sums of money. The following is taken from their web site. It is the 30 day co-pay for each filled subscription.¹³

Tier one: $4 co-pay for preferred generic drugs.
Tier two: $15 co-pay for generic drugs that didn’t make the preferred list.
Tier three: $47 co-pay for preferred brand name medications.
Tier 4: $100 co-pay for brand named products that didn’t make the preferred list.
Tier 5: 33% of the manufacturer’s list price.

The medications on the top row are “specialty drugs” and typically cost $50,000 to $100,000 a year. The amount Medicare Part D spent on specialty drugs nearly quadrupled in the five years between 2010 and 2015. Their cost rose from $8.7 billion to $32.8 billion a year. By 2015 they accounted for 31 percent of the programs net spending.⁴Drugs in the most expensive group usually include:

combinations of anti retroviral (HIV) drugs,
multiple sclerosis modifying agents,
Orphan drugs—medications that are not in high demand for people over 65.
A number of the very expensive, cancer fighting medications.

Thirty three percent of a costly drug’s list price is a lot of money for most Americans who are not on Medicare. Pharmacy committees that place the drugs in tiers meet regularly. When the drug insurer also covers a person’s general medical care, committees realize some expensive prescriptions are not being filled. If a person can’t afford a needed medicine, the drug’s absence may allow their condition to become so bad that they need to be hospitalized. If that happens, the insurer will be on the hook for the cost of at least part of the resulting medical care. Thus these committees need to walk the tight rope between keeping their plan solvent and avoiding prices that make people choose between their money and their health.⁵

One variety of $60,000 to $100,000 per year drugs that are on the top tier are medications used to help prevent flares of multiple sclerosis. These are among the medications whose prices matter the most to manufacturers because they account for a major part of the profits. An estimated million Americans are living with the chronic neurologic condition. The cause is unknown but the immune system of people with the problem, attacks and destroys the myelin, the insulation that surrounds nerve fibers. Over time the axons, the part of the nerve cell that conducts electrical impulses, can be destroyed. “The disease has a highly variable pace and many atypical forms.¹⁶.” In 85% of the people neurologic deficits (which come in many forms and can be quite significant) come, stay for a while, and then disappear. Symptomatic remissions can then improve or disappear over a period of time.

A number of drugs that block parts of the immune system seem to minimize the flares. They are different in many ways, but each requires years of follow up on or off therapy to see if they prevent symptomatic flares or MRI changes. And each of them, for unclear reasons, costs about $62,000 a year⁶

CURRENT CASH PRICES FOR A ONE MONTH SUPPLY OF Multiple Sclerosis MEDICATION

DRUG NAME——-DOSE————-WALMART–WALGREEN


Aubagio (Genzyme)	14MG (30)	(Pharmacist could not locate in database)	$4,757.19
Avonex (Biogen Idec)	Prefill 30MCG/0.5ML Kit	$4,877.08	$5,058.19
Betaseron (Bayer)	0.3MG INJ (14)	$5,154.54	$5,809.69
Copaxone (Teva)	20MG 1PK=30 INJ	$5,507.32	$6,000.09
Extavia (Bayer)	0.3MG INJ (15)	$4,430.46	$5,589.99
Gilenya (Novartis)	0.5MG CAP (28)	$5,372.18 FINGOLIMOD	$4,790.19
*	…	…	…
Rebif (Merck KGaA/Pfizer)	44MCG/0.5SYG INJ (12)	$5,150.54	$5,304.49
TysabriBiogen idec			$$5629.49

The man responsible for the 1990 law that ties the costs of drugs provided by Medicaid to the bargains obtained by insurance companies was Senator David Pryor. The son and grandson of sheriff’s, he was “arguably the most popular Arkansas politician of the modern era.” In 1975, when he was the state’s governor his “frazzled wife ran away from the state’s mansion and left her three sons in the care of her husband, setting Little Rock on its thoroughly Southern ear.” She went to school for two years, and produced a feature length film, a “kind of a witchcraft western”. Then she returned to her family “as a complete person.”¹⁴

As the Chairman of the Senate Special Committee on Aging, Pryor believed “the high cost of prescription drugs was one of the biggest problems burdening seniors.” He held hearings and “attacked drug Industry leaders.” Then he decided to help Medicaid—the government program for the poor and disabled. It covers the cost of nursing homes for many and is funded by the state and federal government. The feds on average, pay 57%, of the costs: 50% in wealthier states: up to 75% in states with lower per capita incomes. The program provides health coverage to about 64 million Americans.

In the late 1980s many states were in financial trouble. They tried to limit the use of prescribed drugs by people on Medicaid by creating “restrictive formularies, co-pays, and monthly maximums.” It didn’t work and their costs remained high. At the time states were paying full sticker price for prescribed medicine while insurance companies and the VA were often given discounts of 30% to 40%.

Two states tried to bargain with Pharma and were attacked by industry. Pharma argued that if states withheld “brand-name drugs without generic equivalents from a Medicaid enrollee (they would be) endorsing “second-class medical treatment for the poor.”

In the late 1980s President George H.W. Bush and his White House staff decided to “shrink the budget deficit by about $50.5 billion. The legislation they produced was “massive”– 533-pages long—“the 5-year Omnibus Budget Reconciliation Act (OBRA 1990)”. Its size and scope allowed Pryor and colleagues to add their “Medicaid Prescription Drug Rebate Program” to the bill. It granted Medicaid “most-favored customer” status, and required drug manufacturers to sell their meds to Medicaid at the “best price” available to any other purchaser. If a company wanted their products to be covered by each state’s Medicaid prescription program they had to accept the federal pricing provisions.

In 1992 Congress created the 340B program. It protected hospitals and some clinics from drug price increases.⁸

Countries around the world negotiate, but each nation does it a little differently:

In most countries governments create formularies–lists of medicines they will, at least partially pay for.
When a new drug is introduced in France the drug makers sign a series of five year price contracts.
The Brits won’t pay for a cancer medication if an extra month of life costs too much. The country’s “excellence institute,” NICE, usually only approves drugs that cost less than 30,000 pounds ($39,000) per quality adjusted life-year, which is equal to a year of life in perfect health.”

The Brits with prostate cancer recently bumped up against the institute and refused to keep a stiff upper lip. Enzalutamide and abiraterone are expensive drugs. Each of them can stop the growth of castration resistant prostate cancer for months. They work in different ways and it’s possible that when one fails the other might still be effective.

Enzalutamide was approved by the British National Health Service in October 2013. The following January NICE tried to prevent the government from paying for Enzalutamide if a man in England or Wales had already been treated with another expensive drug for prostate cancer, abiraterone. Men in Scotland weren’t affected and they could still receive Enzalutamide. There was an outcry and a petition. Political leaders and “Tackle Prostate Cancer”, (an organization) protested. And NICE changed its guidance saying: “there is not enough evidence to make a recommendation about how the two drugs should be used.”

https://www.kff.org/medicare/fact-sheet/an-overview-of-the-medicare-part-d-prescription-drug-benefit/
https://www.pbs.org/newshour/health/why-a-patient-paid-a-285-copay-for-a-40-drug
https://www.pewtrusts.org/en/research-and-analysis/blogs/stateline/2019/02/12/drug-price-debate-targets-pharmacy-benefit-managers
https://www.cbo.gov/system/files/2019-03/55011-Specialty_Drugs_WP.pdf
https://www.brookings.edu/wp-content/uploads/2017/05/wp28-formatted-new_.pdfhttp://files.kff.org/attachment/Issue-Brief-Medicare-Part-D-A-First-Look-at-Prescription-Drug-Plans-in-2017
https://www.healthline.com/health-news/ms-why-are-ms-drug-prices-so-high-071913#1
https://dash.harvard.edu/bitstream/handle/1/8965555/Berman.pdf?sequence=1
Discounted Drugs for Needy Patients and Hospitals — Understanding the 340B Debate. Walid F. Gellad, M.D., M.P.H., and A. Everette James, J.D., M.B.A. N Engl J Med 2018; 378:501-503 https://en.wikipedia.org/wiki/340B Drug Pricing Program
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802694/ https://www.parliament.uk/documents/post/postpn_364_drug_pricing.pdf https://www.bloomberg.com/businessweek The Pharmaceutical Journal21 APR 2017 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049385/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802694/ UK: http://www.dailymail.co.uk/health/article-2702145/NHS-limits-use-prostate-cancer-drug-Guidelines-mean-life-prolonging-medicine-not-given-men-received-new-treatment.html#ixzz4ruOLMLao http://www.telegraph.co.uk/business/2017/07/15/nhs-became-embroiled-global-drugs-price-clash/ http://apps.who.int/medicinedocs/documents/s20974e http://apps.who.int/medicinedocs/documents/s20974en/s20974en.pdf
NEJM Oct 10, 2019. https://www.nejm.org/doi/full/10.1056/NEJMp190979
Unions and employers negotiate the price of group health care premiums. People who receive emergency care in an out-of-network hospital are sometimes presented with a crazy high bill—but the amount they pay is negotiable.
Page 8 University of Maryland Health Advantage—2018 comprehensive formulary https://www.ummedicareadvantage.org/Portals/3/Documents/2018%20Website%20Documents/CIA%202018/March_CY%202018%20Comprehensive%20Formulary.pdf
https://encyclopediaofarkansas.net/entries/david-hampton-pryor-118/ https://www.washingtonpost.com/archive/local/1979/03/16/barbara-pryor-is-back-as-a-complete-person/eca3ec90-0de8-4162-a40d-bd1ace642827/
https://www.commonwealthfund.org/publications/issue-briefs/2019/nov/what-can-united-states-learn-drug-spending-controls-france
Ellen Mowry, associate professor of Neurology–Johns Hopkins. (uptodate)
https://www.who.int/medicines/technical_briefing/tbs/TBS2016_Pricing_Policies.pdf
https://www.commonwealthfund.org/blog/2019/arbitration-answer-high-drug-prices
https://www.nytimes.com/2006/05/24/washington/24bentsen.html https://www.nytimes.com/1989/10/09/us/retreat-congress-catastrophic-care-debacle-special-report-new-medicare-law-fell.html

FDA AND THE RULES

February 20, 2018February 13, 2021 by stevefredman

The protection of a man’s person is more sacred than the protection of his property. Thomas Paine.

If some critics were correct, if it once took too long for new drugs to be evaluated and approved, that’s no longer the case. If anything, the FDA is tilted in the other direction:

Drugs are often approved when their long term effect won’t be known for years.

Cancer drugs that may or may not make people live longer are marketed.

And physicians don’t have to wait for FDA approval before they prescribe an experimental medication. There’s a mechanism that allows physicians to legally use a drug that is still being tested. Called the IND, (Investigational New Drug) permit, the process has been around since 1987. If a therapy is needed urgently and a manufacturer has an experimental product that might help, a doctor can apply. The FDA received over 500 commercial, research, and emergency IND requests in 2018 and in 2019.¹

Using a different tool, 5 months into the coronavirus epidemic the Food and Drug Administration made the anti-viral drug remdesivir available under an “emergency-use authorization.” A month long study of over 600 hospitalized patients with severe disease had shown that the median time for recovery in people NOT given the medication was 15 days. For those who received Remdesivir intravenously daily for 10 days it was 11 days.²²

The TV is full of ads for diabetic drugs that lower the A1C. That’s a marker of a diabetic’s average blood sugar. Tight control may or may not lead to a better outcome. When the average blood sugar is close to normal there’s less damage to the small blood vessels of the eyes and kidney. But in a study of the frail elderly, an emphasis on keeping the average blood sugar low led to “increased mortality and did not significantly reduce major cardiovascular events.” Hypoglycemia, a blood sugar that’s very low, can cause irrational behavior, falls, and even death.²

The FDA protects us from harm and misrepresentation. That’s what it is there for. And it likes to illustrate how important this can be by retelling the story of Thalidomide.

When it was introduced in 1958, the medication was hailed as the tranquilizer of the future. It put you to sleep without the expectation of a hangover, could be used for “over tired” children, and wasn’t fatal, even in a massive overdose. Chemie-Gruenthal, the manufacturer quickly found acceptance for its product thorough out the world. Three countries held out against approval: France cited “technical reasons”; Israel kept delaying without giving a reason. And in the United States there was Frances Kelsey.

Competent and a bit over educated for her FDA position, Frances had, as she put it, “entered college in the depth of the depression and graduated when there were absolutely no jobs.” Deducing she could choose “either to do graduate studies or join the breadline,” she studied and acquired a Masters degree. There still were no jobs so she earned a PhD. In 1943 she was a biochemist at the University of Chicago and she met and married a fellow biochemist. At the time “two members of the same family could not be employed in the same department”, so (she wrote) “needing all the help I could get to obtain a job I entered medical school.¹⁶”

She was hired to be a medical reviewer for the FDA at a time when the agency was required to pass on a drug within 60 days or it would automatically be approved. By chance, Kelsey was assigned to the thalidomide case. It would be marketed by Merrell under the name Kevadon. As the sixty-day period came up Dr. Kelsey routinely rejected Merrell’s application as “incomplete.”

She was dissatisfied with the quality of thalidomide application. The submitted clinical reports were testimonials, not well-executed studies. She learned that when the sedative was taken for a period of time it sometimes caused peripheral neuritis, a very painful tingling of the arms and feet. The effect had been recognized in Europe, and was the main reason the medication had lost its over-the-counter status in Germany. About that time, the FDA was also an interested in the effects of drugs on the fetus. Embryos and newborns are unable to handle drugs in the same way that an adult can. If a person taking the medication for three or four months could develop a severe neuropathy, how would it affect an infant that might be exposed to it for months? “We were NOT thinking in terms of absent arms or legs, but just– if it did something to the adult over time, it might just as well have an adverse effect on the child.¹⁶“

Within a year of the introduction of Thalidomide a very rare deformity in newborn babies began to appear in Germany. It was called phycomelia. In the place of arms and legs babies were born with something like fins. From 12 cases in 1959 the number grew to 83 in 1960 and 302 in 1961. Near the end of 1961 a Hamburg pediatrician made a statistical connection between this ominous health problem and mothers who had taken Thalidomide while pregnant. The manufacturer was sufficiently concerned, and withdrew the drug from the market just as Israel was about to approve it. According to the FDA 10,000 people in 20 countries were victims of the simple sedative.³

At the time Senator Estes Kefauver was investigating “the escalating expense of lifesaving prescription drugs.” He openly berated pharmaceutical executives for profiteering. Doctors were portrayed as dupes of the companies that produced our medications.¹⁹ A household name in the 1950s, the Tennessee Senator campaigned for office wearing the kind of coonskin cap David Crockett wore when, in 1836, he died defending the Alamo. Kefauver’s committee had questioned mob leaders on live TV, and in 1956 he ran for Vice President of the U.S. and lost.

The “endlessly polite Southern senator in horn-rimmed glasses” unsuccessfully attempted to require newly approved drugs to “generate competitive markets after 3 years” and he failed to eliminate the promotion of “me-too drugs” and “molecular modifications.^5,22”

But, thanks to thalidomide, the Kefauver-Harris amendments to the Food, Drug, and Cosmetic act of 1938 became law in 1962. Proving a drug was safe in mice and a rat was no longer enough. A drug now had to be shown effective as well as relatively safe.

The drug companies fought back in the courts. In 1974 the Supreme Court allowed the FDA to rule that drugs in use before 1962 were no longer protected by a “grandfather clause.” It gave the FDA full authority to demand double-blind studies.”

A federal agency with more than 22,000 employees, the modern FDA does much more than give marketing approval to drugs and monitors their side effects in humans. Among other tasks, it ensures “the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices.” And, of course, it’s responsible for the safety of our food supply.

Its precursor was created in 1906 when Congress passed the original Pure Food and Drugs Act. The law “prohibited misbranded and adulterated foods, drinks and drugs in interstate commerce.” After spending time as a subdivision of the department of agriculture, the FDA became an independent agency in 1930.

The FDA’s next boost in responsibility came after Bayer developed, but was unable to patent mankind’s first antibiotic, Sulfanilamide. It was made and sold in pill form by manufacturers throughout the world, and it was widely used. Then a company in Tennessee created an elixir. Their chemist dissolved the medication in diethylene glycol, a compound normally used as antifreeze. Flavored with raspberry extract, saccharin, and caramel it was a commercial success.²⁰ But it was also toxic and caused kidney failure and the death of over 107 men, women and children. As a PhD student, Frances Kelsey had been part of the team that, after Sulfanilamide had been recalled, tried to understand what went wrong. She gave the solvent to rats, and watched as their urine turned red and they died. In its liquid form the antibiotic had never been tested in animals. “It was just put right on the market and sold like wildfire.”

Following a public outcry about the “wonder drug”, Congress passed, and President Franklin Roosevelt signed the Federal Food, Drug, and Cosmetic (FD&C) Act of 1938. “For the first time, manufacturers were required to show a drug was safe before it could be marketed³

In 1980 congress passed the Bayh-Dole act. At the time research and discoveries that were paid for with government (tax payer) moneys were available to all comers. They were in the “public domain.” The legislation changed the rules. After 1980 universities and the NIH were allowed to patent their discoveries, and they could sell licenses to drug companies. With the license in hand the drug companies could use the “taxpayer funded research” as a basis for pharmaceuticals.

In India, the patent law of 1970 took a different approach. New medications –the drugs themselves–could not be patented, but the process, the way it they were produced, could. In 2005, as part of the international agreement–TRIPS (Trade-Related Aspects of Intellectual Property Rights)–product patents became available.¹⁴

In 1984 the Hatch-Waxman Act “created a period of exclusivity, an amount of time when a drug that was newly approved by the FDA was protected from competition.¹⁸ The law also made it easier for generic drugs to come to market. Companies making these medications had been forced to repeat clinical controlled trials, to start from scratch even though the drugs had been used for years and were relatively safe. The law ended that requirement and the market for copy cat drugs went wild. (See chapter on generic drugs.)

After 1984, when a drug’s FDA granted monopoly ended, a generic company could ask for permission to produce the medicine. The law gave the first appropriate applicant a 180 day restricted head start on the competition…unless the product was covered by a “valid patent”. If the drug was “protected,” the original manufacturer could file suit and allege violations. That was the loophole that lobbyists presumably inserted.

Most drugs were initially covered by a patent whose 20 year life-span starts early in the research process. Additional patents are typically filed at various stages of the medication’s development. Many deal with non essential ingredients, like the color of a pill or the starches used as filler. When a drug’s years of private ownership ended, the additional patents were sometimes used by a company to sue alleging its product was “patent protected”.

When a very profitable drug’s “privilege” expired, they filed. The legal allegations were often capricious. But that didn’t matter. The law said that once the suit was filed, the FDA had to automatically delay the approval of the generic drug for 30 months “to permit litigation.”

At this point both manufacturers knew the generic drug maker would probably win, but lawyers know how to drag things out. Court battles are lengthy and expensive. So lawyers got together. The company that owned the revenue generating medicine typically paid millions of dollars a month, and the generic drug maker waited a bit before it produced and marketed their version. There were 33 pay-for-delay settlements in 2010. In 2013 the Supreme Court ruled the practice was subject to antitrust laws and in 2015 the generic drug company, Teva, settled a pay for delay lawsuit for $1.2 billion. In 2012, 40 pay-for-delay law suits were filed. The number dropped to 29 in 2013 and 21 in 2012.

In 1992, after Congress passed the Prescription Drug User Fee Act (PDUFA), Two thirds of drug approval expenses were paid by big Pharma. The fox was paying the regulators who were guarding the hen house.

In 1997 drugs that had only been tested on adults were sometimes given to children and Congress passed a law. It required medications that were prescribed for kids to be proven safe and effective IN KIDS, and it gave the manufacturers who got approval an additional 6 months of exclusivity.

That, of course meant that when a drug that brought in more than a billion dollars a year was about to lose its monopoly, a company could give the medication to a few kids, write up a study, and shut generic drug makers out of the market for an additional 6 months.

The FDA uses a number of advisory boards, groups of physicians who are experts in the field. The FDA officer makes the final decision, but, in tough situations, it must be nice and at the same time awful to have a group of M.D.’s who serve as a sounding board and buffer.

The 2007 their approach to Avandia (rosiglitazone)—a “glitazone” that is used to lower the blood sugar level in diabetes– is an example of how wrong these boards can be. Made by SmithKline Beecham, Avandia had a side effect. It raised the level of cholesterol in the blood. You don’t have to be a doctor to know that a high serum cholesterol creates an additional risk for people with diabetes. The condition increases the likelihood that they will have a heart attack or stroke.

The other glitazone, (Actos),Pioglitazone didn’t worsen blood lipids.

In 1999 the agency approved both rosiglitazone (Avandia) and pioglitazone (Actos)for use in people with diabetes. Doctors could prescribe either, but the FDA wanted companies to monitor the drugs for problems.

By 2006 both drugs were grossing more than 1.5 billion dollars a year.

Actos did not increase the risk of coronary disease, but Avandia did. It also, sometimes caused heart failure, fluid in the lungs and legs. FDA panels were convened. The experts voted to keep Avandia on the market, but black box warnings were added to the packaging. Physicians on the panels hoped doctors would read them and use the drug sparingly.

They didn’t, and a 2007 medical study convincingly showed that Avandia caused heart disease. The drug’s sales dropped, but a million prescriptions a year were still being written.

The panels of experts convened by the FDA agreed that Avandia “posed significant cardiovascular risk”. Then they voted. Twelve of the 33 doctors thought the drug should be removed from the market.

The chairman and 9 others voted for much stricter controls. The doctor in charge wrote that “several meta-analyses revealed a significant increase in the risk of myocardial ischemic events among patients taking rosiglitazone… But a second analysis, failed to demonstrate a similar risk.” Then he added a little gibberish: “the results regarding the safety of rosiglitazone raised new questions about relative and absolute risks.^4”

In July 2010 the manufacturer of Avandia settled a lawsuit for the harm the medication did for $460 million. Compared to revenue of $1.1 billion dollars the prior year and much more in the years before the 2007 hearings, the monies paid did relatively little harm to the company’s bottom line. Pioglitazone– Actos, is still being widely used.

Then in the early morning hours of June 27, 2003 a controversial law was enacted. A mere thirteen years had passed since Congress granted Medicaid “most-favored customer” status, and required drug manufacturers to sell their meds to Medicaid at the “best price” available to any other purchaser. This time, however, congress passed a law that said pharmaceutical manufacturers can charge what they want to charge and the government can’t price negotiate. The Secretary of HHS was prohibited from negotiating lower drug prices on behalf of Medicare Part D beneficiaries. When asked why he thought House leaders had scheduled the vote long after most Americans had gone to bed, Representative Dan Burton (R-IN) said “a lot of shenanigans were going on that night (that) they didn’t want on national television.” According to Walter Jones, a disgusted North Carolina Republican who voted “no”, it was the “ugliest night” he had witnessed in more than two decades as a member of Congress. “Pharmaceutical lobbyists wrote the bill;” ¹⁷

Touted as a means of providing cheap or free drugs for people on Medicare, the bill did not include any new taxes. The entitlement was not funded, though part of the cost was paid by enrollees. Seniors paid $265 to receive the benefit, and then kicked in $25 + a month. When a person took and expensive drugs and the annual cost exceeded $2400 a year the government stopped paying for a while. Enrollees had to shell out for the next $4000 worth. If the annual drug cost exceeded $6400 a year, the government started paying again. The $4000 was called the donut hole, and it was eliminated by Obamacare.

After the bill was passed the government accounting office claimed that American prescription drug prices rose 6.6% a year between 2006 and 2010. By contrast the price of generic pharmaceuticals increased by 2.6 percent annually and overall medical costs rose 3.8% a year.

“Representative Billy Tauzin (R-La.),the “Cagey Cajun”–he came from a French Speaking Louisiana family– coauthored the bill, then negotiated a $2-million-per-year job as a lobbyist for the drug industry’s trade organization.” Thomas Scully, a Bush Medicare official who misstated the program’s cost, became a health industry lobbyist.”

During the following decades the FDA used a number of techniques to drugs that seemed promising to people who were willing guinea pigs.

(FOR THOSE INTERESTED IN THE DETAILS: At the height of the AIDs epidemic, activists protested the delay between a new drug’s submission and approval. In response the agency created fast-track rules that sped up the development, assessment, and sales of new treatments– for life threatening conditions. The FDA also made unapproved drugs available to people who had AIDS (and other serious conditions) who were unable to enroll in clinical trials.²³

In the 1980s it created “treatment INDs.” To obtain a medication a provider has to submit a form that can usually be filled out in 45 minutes. The agency then takes up to 4 days to process a non-emergency application; emergency requests are approved in less a day. Between 2005 and 2014, 1200 forms were submitted each year; over 99% were approved. Most were for a single patient and half were for an emergency.¹³

In 1970 a strong demand for experimental cancer drugs led the FDA to adapt an early-access policy. In 1992, the agency started allowing speedy approval on the basis of end points that were seen as “reasonably likely to predict patient benefit.”

During the 2014 African Ebola outbreak, acting on preliminary data, the FDA authorized the use of six tests that rapidly identified infected patients, and they reviewed IND applications for 2 investigational vaccines in less than a week. Then they allowed developers to proceed with phase 1 clinical trials.⁷)

In 1992 Congress passed the prescription drug user act. It authorized the FDA to collect money from pharmaceutical manufacturers, and told the FDA to review special drug applications within 6 months. Ordinary applications had to be assessed within a year.

As therapies were developed and authorized more quickly, the FDA started “requesting” post approval studies. Under the 2007 FDA amendments act, congress allowed the FDA to “require” studies after a drug was approved.

In spite of the law only half of the post approval studies were completed within 5 years. “20% had not been started; and 25% were delayed or ongoing.”¹⁵

In 2012 the FDA didn’t approve Solanezumab. “The drug binds the amyloid-B peptides that form plaques in the brain”, that many believe are the cause of Alzheimer’s dementia. They hoped the Solanezumab monoclonal antibody would help clear amyloid from the brain. The company’s original placebo study, performed 4 years earlier, had shown Solanezumab didn’t work—“didn’t improve cognitive function in people with mild to moderate Alzheimer’s.”

At the same time “there appeared to be a statistically significant benefit for the subgroup of patients with mild dementia–a 34% reduction in cognitive deterioration” Maybe Lilly had something. The company went to the FDA and sought tentative approval, and the FDA turned them down. They demanded further testing.

In recent years, the FDA’s testing requirements have been under attack. One section of a new law “allows the secretary of health and human services to rely more heavily on surrogate measures, or “drug development tools,” Using these softer criteria, FDA leaders could theoretically have approved the drug. It seemed safe enough. The agency could have then required post marketing testing–studies that take years to perform. But why would anyone with mild dementia risk getting a placebo rather than the real thing?

Lilly enrolled 2100 people with mild dementia and followed them for 18 months. They learned their drug didn’t slow the disease. The money saved by waiting was substantial. People are desperate for something that can stop, prevent, or reverse Alzheimer’s. 2.5 million Americans would have been able to access the medication. Drugs like this almost always cost more than $10,000 per patient per year. So, using surrogate criteria, we would have paid billions for a useless drug.⁸

Legislators probably thought they were making one-small-step towards lower drug prices when they passed the Biologics Price Competition and Innovation Act (BPCI Act) of 2009. (The Europeans took similar action in 2006). Our country now allows companies to market “interchangeables”– medications that are “different chemically” but work as well and are just as safe as a currently marketed drug.

In fact, industry had been marketing biosimilars for years. But– in the past they didn’t “price compete.” Companies marketed biosimilars so they could charge higher prices. Prilosec, a drug that stops the stomach from making acid, is chemically the mirror image of Nexium. Their actions are the same and they are similarly safe and effective. The milligram dose is a little different. 40 mg of Nexium has the same acid lowering effect as 20 mg of Prilosec. The new drug was introduced at a time that Prilosec was losing its hold on the market. The owner, AstraZeneca, funded a study that showed that in people with severe erosive esophagitis, 80 mg of Nexium was more effective than 20 mg of Prilosec. In other words doubling the dose of the drug decreased the amount of acid a stomach makes a bit more. The idea wasn’t new. We doctors had long been using double doses of Prilosec for severe esophagitis. The company marketed Nexium as a new drug, and they used clever marketing to gross over $5 billion a year for a few years. For starters they sold their old drug, Prilosec over the counter for 75 cents to a dollar a pill. That can be $30 a month. Nexium was a prescription and was covered by most drug plans. So for people with good drug insurance Nexium could be purchased with a low co-pay. That made it cheaper than Prilosec.

People who take the Prilosec or Nexium for a period of time can’t stop easily. The medications keep the stomach parietal cells from making acid. That’s what some gastric cells do—they make hydrochloric acid. Over time stomachs respond to the absence of acid by growing more and bigger parietal cells. These cells are inactive as long as a person keeps ingesting a pill a day. When or if a chronic user stops the drug for a day or two, the parietal cells wake up and go to work. The stomach starts producing huge quantities of acid, and many people develop chest pain or severe heartburn.⁹

Despite the cleverly crafted loopholes in the law and pressure from industry, amid a culture where there’s a tendency to mainly recognize government employees when they screw up, the FDA is doing what it’s supposed to do. It was created to keep us safe and it’s doing its job. And that’s good.

https://www.accessdata.fda.gov/scripts/fdatrack/view/track.cfm?program=cber&id=CBER-All-IND-and-IDEs-recieved-and-actions/
N Engl J Med June 12, 2008; 358:2545-2559.
“Forbidden Cures” By Steven Fredman MD; Robert E Burger Stein and Day, 1976
https://www.nejm.org/doi/full/10.1056/NEJMp078167 The Rosiglitazone Story — Lessons from an FDA Advisory Committee Meeting.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101807/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690175/ This article examines the history of efforts to add prescription drug coverage to the Medicare program.
https://www.fda.gov/news-events/congressional-testimony/examining-medical-product-development-wake-ebola-epidemic
FDA Regulation of Prescription Drugs: Edward Campion, M.D., N Engl J Med Feb 16, 2017
Digestive Diseases and Sciences, Vol. 41, No. IO (October 1996), pp. 2039-2047.)
https://www.fda.gov/drugs/developmentapprovalprocess//approvalapplications/therapeuticbiologicapplications/biosimilars/default.html https://www.biopharma-reporter.com/Article/2016/01/29/Sandoz-s-biosimilar-Zarxio-gradually-eroding-Amgen-s-Neupogen-sales
https://www.nejm.org/doi/full/10.1056/NEJMhle1800125 https://ipandtech.hillwallackblog.com/wp-content/uploads/2017/12/BPCIA_DoYouWannaDance_RichardCatalinaJr_-NewJerseyLawyer_August-2017.pdf
https://www.patentdocs.org/followon_biologics/\
https://www.ncbi.nlm.nih.gov/pubmed/27917324 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739083/?report=reader https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443564/
https://www.lexology.com/library/detail.aspx?g=3f92413f-107c-4886-aca7-24633a341e22
https://www.business-standard.com/article/companies/40-years-ago-and-now-cipla-the-crusader-for-affordable-drugs-takes-the-patent-battle-to-mncs-114122400009_1.html
The Fate of FDA Postapproval Studies, by Steven Woloshin M.D. et al September 21, 2017 N Engl J Med 2017; 377:1114-1117
https://www.fda.gov/media/89162/download
https://billmoyers.com/story/the-man-who-made-you-pay-more-at-the-drugstore/
https://www.everycrsreport.com/reports/R44643.html
Crime in America, by Estes Kefauver; paper back 1951
Sulfa in ethylene glycol https://www.the-scientist.com/foundations/the-elixir-tragedy-1937-3

21. Kefauver https://www.smithsonianmag.com/history/the-senator-and-the-gangsters-69770823/

22. Remdesivir https://www.nejm.org/doi/full/10.1056/NEJMoa2007764

https://www.reuters.com/article/us-health-coronavirus-india-gilead-scien/india-approves-gileads-remdesivir-to-treat-severe-covid-19-cases-idUSKBN2390VL

23. Expanded access https://www.ncbi.nlm.nih.gov/books/NBK234129/

CANDADIAN PHARMACIES

February 20, 2018February 13, 2021 by stevefredman

I used a Canadian Pharmacy to buy the eye drops I needed for my glaucoma. The medicine would have cost $90 a month in the U.S. Ordered through a Canadian pharmacy the thirty day price was $30. I chose an online pharmacy that, best I could tell, was legit. After speaking to a representative by phone, I placed my order, supplied proof that I was a licensed physician, and e-mailed a hand written prescription. At the time I was able to pay with a credit card. (That was three years ago and cards are no longer accepted. I wonder why?)

Under the Prescription Drug Marketing Act of 1987, it is illegal for foreign “e-pharmacies” or anyone other than the original manufacturer to bring prescription drugs into the country. My medication never touched ground in Canada. It was processed by a Canadian pharmacy, but was mailed directly to my home from a factory in Germany (once) and Turkey (once.) The drops were brought into the country legally.

I’m a doctor and Bernie Sanders thinks everyone should be able to do what I did. In 2017 the senator from Vermont introduced a bill that would allow the importation of prescription drugs from Canadian pharmacies, as long as they meet certain safety standards.” Bernie’s bill, of course, went nowhere.

For Americans who live near one of the nation’s boundaries, it’s possible to buy cheaper drugs by walking or driving over the border. There are special lanes in Tijuana for U.S. citizens to cross to Mexico and buy medications. A million Americans use them each year. The FDA told Vice News: it is “illegal” for individuals to import drugs into the U.S. for personal use. As a practical matter, customs allows Americans to bring in 90 days worth of medications for personal use.

Vice news used the price of insulin to show why so many people turn to medical tourism. The list price for a 5 pack of a brand of insulin made by Eli Lilly, (according to Vice) was $147 in 2007, $295 6 years later, and $530 by 2017. Insulin was first isolated and purified in the 1920s. People injected various forms of animal insulin for over 70 years and the medicine was safe and effective. In the late 1970s scientists at Genentech using microbes and recombinant technology learned how to make human insulin and since the 1980s most American diabetics have been injecting the human hormone.

90 percent of the global supply of insulin is made by Eli Lilly, Novo Nordics, and Sanofi. Eli Lilly told Vice News that their net cost to make a box of insulin pens is $122. That includes “manufacturing, labor, research and development, regulatory fees, promotional expenses, insulin donations and profits.” The list price is $530. In May 2019 Lilly introduced the generic version of its insulin (same drug, same packaging, and the same manufacturer). The price was cut in half. The head of the diabetic association, like the manufacturers who appeared before Congress, argued that the discounts that currently go to pharmacy benefit managers should go to the patient.³

In most states drugs ordered through legit Canadian pharmacies are not paid for by insurance or Medicaid or Medical. They require a lot effort by doctors and patients and take two weeks to get processed. If they are newly released they often aren’t cheap. Half of the businesses that sell pharmaceuticals on the web are located in the U.S. Some call themselves prescription referral services.

The National Association of Boards of Pharmacy claims “Rogue websites may be selling drugs that are counterfeit, contaminated, or otherwise unsafe.” I’m sure they are right. People have always been tricked by charlatans promoting cure-alls. It’s hard to know how often we or our friends have been fooled by internet fraudsters. People who use Canadian Pharmacies need to be attentive and cautious.

A number of international internet pharmacies import, process, and directly dispense medications. A private company earns its keep by certifying their legitimacy. Called PharmacyChecker.com, the “verifying” company charges an annual fee and insists that a licensed pharmacist makes sure the “medication is selected and labeled correctly.”

To be an “approved” marketer a pharmacy needs a license. US pharmacies also need a DEA (drug enforcement authority) license. International pharmacies are not allowed to send controlled substances to U.S. buyers. Each medication filled must have a valid prescription.

“In countries with the strongest regulations, Pharmacy Checker inspectors don’t visit pharmacies. They verify their licenses with the relevant governing body like the College of Pharmacists of Manitoba, and the Singapore Ministry of Health.

In Mauritius, Turkey and Singapore, company representatives conduct onsite inspections during the application process and every 1-2 years thereafter. In India they only certify pharmacies that dispense drugs that are made by manufacturers that have a global presence.

With regard to the drugs these pharmacies dispense: More than half the medications Americans take are made in other countries. The Swiss company Novartis produces pills in factories located in Spain, Germany, Switzerland, the U.S., the UK, Slovenia, Belgium, and Poland. Most of the North American supply of aspirin comes from China. Over the counter Prilosec and the cholesterol lowering drug Simvastatin often come from Puerto Rico and India.

FDA inspectors are supposed visit the plants that supply our drugs and make sure they “are clean, follow proper manufacturing techniques and contain what is on the label (and nothing else)” To date agency inspectors have visited a little over half of the factories they have approved. One day the FDA will have the money and manpower to comply with the law Congress passed but didn’t fund.

An agency of the Canadian government that regulates “foreign-sourced drug products… “conducted 35 inspections at foreign sites in the last five years” 76% of drug products imported into Canada come from countries whose plants Canadians (apparently) don’t inspect.

The companies that run American pharmacies are large and presumably politically influential. The two largest by revenue in 2014 were CVS and Walgreen. CVS Health took in $48 billion that year. One billion seven hundred thousand prescriptions accounted for over 70% of the company’s revenue. Mail-order service added an additional $88.4 billion. Walgreen’s gross income was over $76.billion and prescription drugs accounted for nearly 2/3 of sales.⁵