Muckrakers, a righteous senator, and a gene therapy walk into a bar
by Tom Culman
As Engagement Associate at RA Capital Management, Tom Culman manages a variety of educational, outreach, and advocacy-oriented projects.
February 3, 2022
Ah, the American Old West. Where the buffalo roamed, cowboys fought, and Coke still had cocaine. A LOT of things had cocaine. Only the most vigilant and educated physician or pharmacist could hope to keep harmful or useless drugs off their shelves. And if we can still find physicians prescribing ivermectin for COVID today, imagine how hard finding reliable information must have been back then.
So how did we get from there to today, where companies can spend billions trying to prove that their drugs are safe and effective? And given the ever-changing nature of the drug industry, what's next for regulators?
Setting the Stage
The turn of the 20th century was a golden age for muckraking journalism. Industrialization led to massive leaps in food production, processing, and distribution, but that brought new problems. Soon, food quality regulation was in even greater demand than drug regulation, and it didn’t take long for simultaneous outcry from journalists and the public to tie those efforts together.
Harvey Washington Wiley, who would become the first head of the FDA (before it was called the FDA), funded exposés about milk contaminated with toxic amounts of formaldehyde and beans laced with copper sulfate. Upton Sinclair’s The Jungle was meant to expose the plight of factory workers and explore the values of socialism, but readers were mostly horrified by scenes depicting the day-to-day operations of a meatpacking plant. Sinclair once said about the book, "I aimed at the public's heart and by accident I hit it in the stomach.”
The drug industry wasn’t in a much better position. In a series for Collier’s Magazine, Samuel Hopkins Adams published “The Great American Fraud,” laying out everything wrong with the pharmaceuticals of the day. Patent medicines of those days weren’t even patented and hardly counted as medicines; manufacturers were putting pretty much whatever they wanted in them and making all kinds of claims.
“Infant soother” was often made with opium, and “herbal remedies” were usually suspended in grain alcohol. In a way, those might have been some of the more effective medicines of their day; at least they really could reduce pain and help with insomnia - whether or not that’s what they were prescribed for. Other products, like Clark Stanley’s infamous “Snake Oil,” contained turpentine and other toxic ingredients, without even any of the Omega-3 fatty acids of traditional Chinese snake oil (made from actual snakes).
Pure Food and Drug Act of 1906
And so an outraged public demanded the government do something. The resulting Pure Food and Drug Act of 1906 created the FDA in all but name, to prevent “the manufacture, sale, or transportation of adulterated or misbranded or poisonous or deleterious foods, drugs or medicines, and liquors.” It was plenty popular, passing the House of Representatives by a vote of 143-72 and the Senate 63-4.
The new law had two specific goals: To ensure what was in the bottle matched what it said on the label, and to mandate clear labeling for certain medicines known to be addictive. There was no rule saying that any medicine had to be safe or effective. All in all, this law wouldn’t affect reputable manufacturers much, as many of them were already taking precautions against faulty products for the sake of their reputations.
But not all manufacturers were so careful. Perhaps nothing exemplified the case for more regulation as well as Banbar, a phony treatment for diabetes that contained mostly horsetail and milk sugar (yes, sugar, while claiming to treat diabetes). When the proto-FDA attempted to regulate the drug, outraged customers wrote in with claims of its effectiveness. Some accused the organization of encroaching on their freedom. When the manufacturer, Lee Bartlett, sued, officials followed up on those letters. As it would turn out, many of those patients had died in the time between writing their letters and the lawsuit because the medication left their diabetes essentially untreated. Even so, the courts ruled in Bartlett’s favor because the FDA could not prove an intent to deceive, as the law required if the product were to be removed from the market.
Federal Food, Drug, and Cosmetic Act
Cosmetics also worked their way into the public eye with products like Lash-Lure, an eyelash dye that permanently blinded at least one woman. But what really recauptured the public’s attention was elixir sulfanilamide, a product marketed for pediatric use that contained an antifreeze analogue and caused more than 100 deaths, and would be a driving force behind new legislation.
In 1938, a new generation of muckrakers and politicians ushered in the first version of the Federal Food, Drug, and Cosmetic (FD&C) Act, a law that is still with us today. Among other things, this new law created the New Drug Application (NDA) processes, though they were not nearly as rigorous as today’s. Even with this framework, it was still generally understood that drugs were more likely to be approved than not.
Manufacturers needed to prove only safety, not efficacy, and there was little regulation around what NDAs needed to include for approval. Companies that knew they had a bad product could muddy the waters in their application, hope the FDA wouldn’t notice, and - with a little luck - get their drug to market, saving huge sums of money by cutting corners on R&D.
Many will be familiar with the story of thalidomide, a drug developed in West Germany in 1957. It was the era’s latest “wonder drug” for insomnia, colds, morning sickness, and more, and would eventually be marketed in 47 countries. But when its American manufacturer, Richardson-Merrell, applied for marketing approval, the FDA denied the application on the grounds that their trials were not up to snuff.
“The clinical reports were more on the nature of testimonials, rather than the results of well-designed, well-executed studies,” said Frances Oldham Kelsey, the FDA reviewer in charge of the application. Thalidomide’s application for approval was her first assignment at the FDA and she wasn’t about to mess it up. Despite multiple NDAs and pressure from Richardson-Merrell, the manufacturer never produced evidence that met her standards, so Kelsey never caved.
It wasn’t long before Kelsey was proven correct. German doctors noticed a profound uptick of babies born with deformities. In about half of those pregnancies, the mother had been on thalidomide for morning sickness at some point in her first trimester. More than 10,000 children worldwide were born with deformities because of the drug. But thanks to Kelsey, only 17 of them were in the US.
Kefauver-Harris Amendment
Around the same time, Senator Estes Kefauver, riding the fame he earned televising hearings on organized crime and later running for vice-president, turned his spotlight on the pharmaceutical industry. Those hearings, along with the thalidomide incident, left the public wary enough to push through the Kefauver-Harris amendment to the FD&C Act. And with that, the agency suddenly became a lot more like the one we know today: an organization with the mandate to rigorously evaluate drugs for both safety and efficacy.
The Kefauver-Harris Amendment introduced regulation and standardization for clinical trials. Though wary of interfering too much at first, the FDA started giving more and more guidance to drug companies on how to best design their trials. Eventually, Congress would end up mandating meetings between manufacturers and the FDA to design clinical trials, concluding that sloppy trials helped no one, certainly not patients.
Today, drugs that work have to prove themselves across a whole series of trials looking at safety, efficacy, drug-drug interactions, sometimes addiction, and various other parameters. Most trials fail, which means that the regulatory process is working, sparing nearly all patients (except those in the trials) exposure to unsafe and/or ineffective medicines. Those failures add up; each year, 40-50 drugs are approved and the industry spends about $200B in total on R&D, working out to $4-5B per drug.
Innovation Thrives in the Spotlight
For more historical perspective on the drug industry, check out this story on the development of penicillin.
But that’s for new drugs developed to meet new standards. What about all of the drugs already on the market? By the time the FD&C Act was amended, there were 24 years’ worth of drugs approved as safe, but not yet evaluated for efficacy. This dilemma required another solution: the Drug Efficacy Study Implementation (DESI) program. Together with the National Research Council of the National Academy of Sciences, the FDA weighed clinical evidence on more than 3,400 drugs - over 1,000 of which would end up removed from the market due to lack of efficacy.
Interestingly, among those that stayed on the market were aspirin and acetaminophen, two drugs available over the counter. They certainly work, but we now know that aspirin can cause internal bleeding and acetaminophen can cause liver failure. Tens of thousands of people go to the ER each year because of the side effects of drugs even a child can buy. Some doubt they would be approved by today’s FDA, but they were grandfathered in under a different standard and made it through DESI. I’m not complaining – but I’m not bleeding internally.
Today and Tomorrow
The FDA has never escaped public scrutiny, no matter how hard they try. Drugs aren’t safe enough? Let’s raise the bar. Drug approvals taking too long? Let’s pick up the pace with breakthrough designations and Emergency Use Authorizations. The question then becomes: What’s next?
Having witnessed how quickly the FDA worked with industry to speed COVID vaccines and therapeutics to market, many people have wondered why the FDA can’t be faster in reviewing everything else; faster IND reviews, faster clinical trial authorizations, faster NDA processes. To be fair, the FDA was fast with COVID in part because it pulled staff away from reviewing other products, creating delays elsewhere. But still, what if the FDA were better funded and had more people? Could all regulatory engagement occur on “COVID time,” like some camera trick from the Matrix?
Maybe the next trend at the FDA will be nuanced approvals, as we saw in the case of Aduhelm, Biogen’s anti-amyloid-beta (ABeta) antibody for Alzheimer’s. The FDA approved the drug based on its ability to lower ABeta – without recognizing lower ABeta as a validated surrogate for clinical benefit. Until further studies can be run, the FDA has essentially left it up to the rest of society – patients, physicians, payers, media, etc – to decide whether Aduhelm works.
Many in the industry expected this to be controversial, but most stakeholders were united in their opinion that FDA should have required Biogen to run additional studies to answer the efficacy question definitively. If such trials clearly showed clinical benefit, it would validate Aduhelm as a therapy and validate ABeta as a surrogate marker for clinical benefit, creating a path by which other such drugs might come to market faster.
On top of all that, the FDA could stand to work on their communication. Drugmakers are constantly trying to interpret signals from the FDA with mixed success. BioMarin’s hemophilia drug, Roctavian, for instance, received breakthrough therapy designation, priority review, and orphan drug designation. All of that came with even more meetings and guidance from the FDA, but their application for approval was still denied, though safety and efficacy data seemed clearly favorable. This sudden turn of events appeared to leave BioMarin blindsided and the rest of the industry doubting the guidance they’d been getting, especially in gene therapy. When investors are too unsure about something, they hold back capital. When companies can’t get capital for gene therapy projects, they are forced to do something else.
The FDA has been justifiably called too conservative and slow to approve medicines for HIV, and, a couple decades later, overly permissive with opioids. But it’s easy to find fault. They’re tasked with a subjective balancing act, with a drug like acetaminophen still on the market while Vioxx isn’t. But through it all, history shows us that, as long as we hold them accountable, the FDA learns and evolves alongside the scientific community.
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Further Reading
