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By February 10, 2023June 10th, 2024No Comments

—Herbert Ley, Jr., Commissioner of the FDA 1968-1969

We don’t have safe drugs. The drug industry more or less controls itself; our politicians have weakened the regulatory demands over the years, as they think more about money than patient safety; there are conflicts of interest at drug agencies; the system builds on trust, although we know the industry lies to us; and when problems arise, the agencies use fake fixes although they know they won’t work…   If the American people knew some of the things that went on at the FDA, they’d never take anything but Bayer aspirin.

Len Lutwalk, FDA scientist

In recent decades, FDA oversight has broken down. An editorial in the BMJ (2015), “The FDA’s New Clothes,” said the vast majority of the drugs approved by the FDA from 1978 to 1989 were ineffective. One in five causes serious harm after approval. A second analysis by the same authors reports that 80 to 90 percent of the newest drugs were not improvements over older ones.

FDA whistleblowers have reported what was happening. Ronald Kavanagh, Ph.D., is a pharmacist who reviewed medications for the FDA from 1998 to 2008. Martha Rosenberg interviewed him:

[The] honest employee fears the dishonest employee. There is also irrefutable evidence that managers at CDER (Center for Drug Evaluation and Research of the FDA) have placed the nation at risk by corrupting the evaluation of drugs and by interfering with our ability to ensure the safety and efficacy of drugs. While I was at FDA, drug reviewers were clearly told not to question drug companies and that our job was to approve drugs. We were prevented, except in rare instances, from presenting findings at advisory committees. In 2007, formal policies were instituted so that speaking in any way that could reflect poorly on the agency could result in termination. If we asked questions that could delay or prevent a drug’s approval – which of course was our job as drug reviewers – management would reprimand us, reassign us, hold secret meetings about us, and worse. Obviously, in such an environment, people will self-censor…I frequently found companies submitting certain data to one place and other data to another place and safety information elsewhere so it could not all be pulled together and then coming in for a meeting to obtain an agreement and proposing that the safety issue is negligible and does not need further evaluation… Sometimes we were literally instructed to only read a 100-150 page summary and to accept drug company claims without examining the actual data, which on multiple occasions I found directly contradicted the summary document. Other times I was ordered not to review certain sections of the submission, but invariably that’s where the safety issues would be. This could only occur if FDA management was told about issues in the submission before it had even been reviewed. In addition, management would overload us with huge amounts of material that could not possibly be read by a given deadline and would withhold assistance. When you are able to dig in, if you found issues that would make you turn down a drug, you could be pressured to reverse your decision or the review would then be handed off to someone who would simply copy and paste whatever claims the company made in the summary document… One manager threatened my children – who had just turned 4 and 7 years old – and in one large staff meeting, I was referred to as a “saboteur.” Based on other things that happened and were said, I was afraid that I could be killed for talking to Congress and criminal investigators… I found evidence of insider trading of drug company stocks reflecting knowledge that likely only FDA management would have known. I believe I also have documentation of falsification of documents, fraud, perjury, and widespread racketeering, including witness tampering and witness retaliation.

Of the 5,918 FDA scientists who responded to a 2006 survey by the Union of Concerned Scientists, a fifth said their superiors asked them to exclude, alter, or falsely interpret their conclusions. They were often pressured to approve drugs despite safety concerns. A follow-up survey in 2011 found they feared retribution if they wrote about this in journals or spoke to the press. Many said that political and business interests affect the FDA’s decisions. Over a third felt that a superior had interfered with their work in the past year. The Institute of Medicine reported the same year that there was significant outside interference with the FDA’s scientific work.

Early history: The FDA’s mission is to protect health by evaluating and approving food, drugs, vaccines, tobacco, supplements, cosmetics, blood transfusions, medical devices, and veterinary products. The agency oversees 20 percent of the US economy. The pharmaceutical companies are required to perform drug studies according to an elaborate set of rules and present them to the FDA.

The FDA made its reputation in the 1950s when it saved Americans from congenital disabilities caused by thalidomide. A German pharmaceutical company marketed this drug almost without prior study. Its use was for sleep, anxiety, and morning sickness of pregnancy. It was sold over-the-counter in West Germany and other countries.

In the rest of the world, at least ten thousand babies born from mothers who had taken the drug had missing limbs, eyes, and ears. Half the babies died. Many adults who took the drug had nerve damage.

A heroine FDA regulator had her doubts and stalled its approval. Thanks to her, the thalidomide tragedy here did not reach the scale that it did in Europe. But the company passed out unapproved thalidomide samples and performed two trials on 20,000 patients, resulting in patient harm. As a result, in 1962 the US passed laws that directed manufacturers to prove to the FDA their products worked and were safe before they market them. Prescriptions were required for new drugs.

The FDA, by spinelessly knuckling under to every whim of the drug companies, has thrown away its high reputation, and in so doing, forfeited our trust.

Drummond Rennie, deputy editor of JAMA

In recent years, however, direct payments from drugmakers to the FDA took the oversight process hostage. Since 2002, pharmaceutical companies have paid about two-thirds of the FDA’s $4.7 billion budget through “user fees.” This money from the industry goes straight to the FDA, mostly during the patent process. Critics have said the companies should pay taxes instead. In 2007, four retired FDA commissioners agreed: the system creates the wrong incentives. Jessica Wapner, in a PLOS blog, wrote that the structure puts the FDA in the pockets of the drug industry.

Any student of influence understands how and why this works. The payments, totaling over $3 billion in 2016 alone, create enormous leverage. Michael A. Carome, Director, Public Citizen’s Health Research Group, concluded, “User fees fundamentally changed the relationship between the FDA and the pharmaceutical industry such that the agency now views the industry as a partner and a client, rather than a regulated entity.” Megan McArdle coined a name for this in a Bloomberg article: regulatory capture. She says that the regulators who are in place “to tame the wild beasts of business instead become tools of the corporations they regulate.”

Congress ignored naysayers and ratified the US arrangement again in 2017. The UK has similar issues. There, drug companies pay 70 percent of the budget of their corresponding regulatory agency, the National Institute for Health and Care Excellence (NICE). Worse: sizable and open payoffs occur after the approval process. These reward cooperative FDA advisors on the committees responsible for endorsing drugs.

In 2006, the FDA made it harder for a consumer to sue a pharmaceutical company for harm. The corporations had been trying for decades to get such a law passed through the legislature. It finally influenced someone at the FDA to sneak the measure through as a simple regulation. This created immunity for manufacturers unless plaintiffs proved that a company intentionally committed fraud, which is a high legal barrier.

FDA safety officer David Graham said in a 2004 congressional hearing, “I would argue that the FDA, as currently configured, is incapable of protecting America against another Vioxx [a drug removed from the market for causing fatalities]… Simply put, the FDA and its Center for Drug Evaluation and Research are broken.”

How it all started: In 1992, the FDA began a sped-up drug approval process. This was an incentive to get medicines to the market sooner in response to the HIV epidemic. They allowed “surrogate” outcomes such as lab tests rather than requiring “hard” clinical outcomes such as death or heart attack. And they mandated only a single study. The FDA approved the HIV drugs based on increases in the T white blood cell counts and decreases in blood virus counts. Post-marketing surveillance was to have accompanied the scheme, but the Agency never correctly implemented it.

After the start of the accelerated approval process, a review a few years later found that a full third of the drugs approved by the FDA had safety issues. But there were few recalls. They ultimately only took one medication in twenty off the market. If there was regulatory action, it usually consisted solely of a “black-box” warning on the drug label about the possibility of serious harm. The drugmakers bitterly opposed this step because it limits profiteering. For example, Singulair, a pricey asthma medication, causes psychiatric disasters including suicide, but so far there is no black box because of industry resistance.

The FDA permits data scams. Researchers from the Yale University School of Medicine looked at trials between 2005 and 2012. They found that the FDA based many drug approvals on studies that used various forms of data cheating. Donald Light and Ben Goldacre separately confirmed this story. They wrote:
✪ Thirty-seven percent of the drugs had only a single study.
✪ Forty-five percent of the trials for drug approval used study endpoints such as blood sugar or cholesterol (surrogate markers) rather than hard endpoints such as death or another clinical finding.
✪ Nearly a third of all the studies made a comparison with an older drug. When two drugs are found to be about the same, the companies usually claim some obscure advantage for the recent one. This games the approval process and allows the corporations to market expensive “me-too” medications that offer no benefit over the older ones.
✪  To make a drug look good, the companies often exclude people who are more likely to have adverse outcomes. Other times, they use people who are more likely to have side effects, which can make an older drug look bad.
✪ When companies do nonrandomized trials on unrepresentative populations, they can create almost any result.
✪ Experiments are sometimes run that lack a comparator or control arm. This is called a single-arm trial and has little validity.
✪ Some experimenters do approval studies that are not randomized, controlled, and double-blinded, which is the current standard of proof. Some allow studies that are easily unblinded.
✪ To show benefit, sometimes doses of a test drug are used that are too high for routine clinical use. These studies last long enough to show benefits but are kept short enough to conceal adverse reactions.
✪ The other way this is played is to use high doses of the comparison drug. This creates side effects that make the new drug look great by comparison.
✪ Another often-used ploy is inaccurate measurement and improper reporting of the number needed to treat and the number needed to harm.
✪ Huge trials are sometimes stopped early because results appear beneficial or harmful at that point. This prevents full evaluation and complete reporting.

Physicians should be trained to detect these commonplace forms of deceit when reading medical journals. I spotted them as I learned more.

In a 2012 BMJ editorial analysis, Donald Light and Joel Lexchin wrote that, of all the new products developed in the past 50 years, 85-90 percent produced many harms but few benefits. Most of them are me-too drugs used for established markets. They are not improvements. These medications are 80 percent of the US’s increase in drug spending.

Despite the sad deterioration of the FDA, it is still the most respected and active organization of its kind in the world. Many of its people are idealistic and well-meaning, and they try to maintain standards. They are the only barrier between US consumers and pharmaceutical disasters. To their credit, the FDA is mostly successful at keeping shoddy drugs out of the US. Foreign manufacturers sell these with impunity in Brazil, Africa, Mexico, and Eastern Europe.

POSTSCRIPT: Since a 1975 law was passed, expiration dates were required for drugs. A pharmacist who recalls this event says that his knowledgeable colleagues thought it was ridiculous. But they quickly realized it boosted sales.

In a 2006 study of 122 expired drugs, two-thirds of them were stable in every tested lot. Their sell-by dates were over four years too early. The US military, the CDC, and the Department of Defense understand this and for decades have saved billions of dollars by stockpiling outdated drugs. But the Pharmaceutical Research and Manufacturers of America (PhRMA) lobby claims the short expiration dates are all about safety.

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