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