Drugs are big business in the United States. Between consumers, health care institutions, and insurance companies, Americans spent nearly half a billion dollars on medicines in 2018.
And Americans have a great deal of faith in the U.S. Food and Drug Administration. A 2014 survey found that 39% of respondents believe the FDA approves only “extremely effective” drugs, and 25% of respondents believe the FDA only approves drugs that have “no serious side effects.”
But it is increasingly apparent that this faith is largely misplaced: There are serious problems with the drug approval process in the United States – and it’s killing people.
A Lethal Problem
More than 100 million Americans have received prescriptions for unsafe drugs that later had to be pulled from the market because of safety concerns. Every year, about 2 million Americans experience significant side effects from FDA-approved drugs.
And every year, about 100,000 Americans die as a result.
This according to a 2006 study in the International Journal of Health Sciences.
The same study found that out of every 100 new drugs that make it through the U.S. Food and Drug Administration’s drug evaluation process, there are 27 “black-box” safety warnings and outright market withdrawals within the first 16 years.
Why are so many Americans falling victim to adverse drug effects? The reasons are complex, but many of them are attributable to structural problems with the drug approval process, and with corruption within the U.S. Food and Drug Administration itself.
Who Funds the FDA?
Many people think the FDA is funded directly by the taxpayer. But this is only partially true. As of Fiscal Year 2019, only about 55% of the FDA’s $5.9 billion budget came via Congressional authorization. The other 45%, about $2.7 billion, comes from “user fees” paid by the regulated food and drug companies themselves — an arrangement many observers believe leads the Agency into serious conflicts of interest.
Furthermore, in order to keep the user fees flowing, the FDA must negotiate new user fee terms with the drug industry every five years, as the Prescription Drug User Fee Act expires. This means that the drug industry has a great deal of leverage over their regulators.
As a result, the FDA has to serve the industry it regulates, more than it needs to serve the tax-paying public. But it’s the public who bears the cost of unsafe drugs.
Lower user fees may help lower the cost of new drug development. But it also increases the risk of unsafe drugs being released on the market.
FDA Relies on Big Pharma for Data
When the pharmaceutical presents the FDA with a new drug for approval, it’s generally the drug company that provides the funding for drug reviews. Furthermore, the FDA does not even generate its own safety data. Instead, the Agency relies on the drug manufacturer itself to provide safety data.
Because the FDA relies on Big Pharma for its funding, critics have accused the Agency of relaxing their approval standards to keep pharmaceutical executives happy.
As a result, critics say the prescription drug approval process is fundamentally flawed.
The same is true for the approval of drugs and other products under the FDA’s supervision, including medical devices, foods, and nutritional supplements.
Managing and reducing these conflicts of interest is a serious problem in public health – and FDA regulations, FDA Commissioner Stephen Hahn, the Department of Health and Human Services, the National Institutes of Health, the CDC, and the White House have all come under criticism.
FDA Approval is no Guarantee of Safety
The Food and Drug Administration’s drug evaluation process is not designed to detect and eliminate all risks from prescription drugs. Such a drug safety standard would not be possible for several reasons:
First, most new drugs are only tested on a few hundred or thousand human subjects before receiving final approval. This may not be enough to reliably detect some infrequently-occurring side effects or complications.
Second, clinical trials are limited in duration. They therefore cannot detect side effects or complications that build up over long periods of time.
Pharma companies know this, and often seek expedited approval to minimize the window for the discovery of adverse side effects during clinical trials.
The FDA Approval Process
When a pharmaceutical company discovers a promising new molecule or compound, the company will begin the pre-clinical trial phase. The company will test the compound on lab animals and observe potential toxicity levels and side effects.
At that point, the pharma company submits an Investigational New Drug application to the FDA, along with its plan for continuing research on human subjects.
FDA Human trials explained
Once the FDA approves the IND application, the drug company initiates human trials. There are three phases to this process:
Phase 1 involves a limited sample of participants – generally 20 to 80 subjects. The goal is to identify any very common side effects before introducing the drug to a larger sample of people.
Phase 2 involves measuring the drug’s effectiveness against specific medical conditions. This involves a larger sample of several hundred subjects. Scientists also compare the new drug’s effectiveness against a placebo group. Researchers also observe this group for side effects. But the study period is often too short to adequately observe for some side effects, or the risk of the gradual build-up of toxicity. Researchers can only observe the short-term effects of any given drug at this stage.
Phase 3 trials involve larger groups of subjects – typically over a thousand people. The larger sample size also allows more extensive testing against placebo groups, and more experimentation using different doses. Phase 3 trials also allow for more testing in combination with other drugs, so that scientists can observe any problems with drug interactions.
But this presents another problem: While a phase 3 trial may be large enough to assess the broad characteristics of the drug against one or two medical conditions, the subgroup of study participants who are taking any given potentially reactive drug, or who are taking any given dosage, or who have any given co-morbidity, is much smaller.
As a result, these subgroup sample sizes may be too small to reliably detect side effects under certain conditions.
For example, a compound may be tested on more than a thousand subjects. But out of these, only a few of them are pregnant women, or men with pre-existing heart arrhythmias, or who are taking anti-cancer medications, etc., etc.
Phase 4 – Postmarketing Surveillance
Once the three phases of clinical trials are complete, the drug company then files a New Drug Application with the FDA. This includes a report of the trial phase findings that the drug company wants the FDA to know.
But since the FDA usually does not have an independent source of data, there is significant opportunity for corruption at this stage: After Phase 3 trials, the drug company may have already invested many millions of dollars in research and development into the new drug. If there are any borderline suspicions of adverse side effects, drug interactions, or other problems with the drug, the drug company has every incentive to minimize them or sweep them under the rug. And without their own data, the FDA has little chance of detecting the problem.
For these reasons, it is very common for side effects to slip through the cracks, even after Phase 3 trials. Some side effects only become apparent after FDA approval and use by many thousands of patients.
In some cases, drug safety issues aren’t discovered until the drug has been approved and in use for many years.
A 2014 study from the Journal of Pharmacy Technology found that approximately 51% of adverse drug effects are not detected during the approval process.
Accelerated Approval Problems with the FDA
The danger was exacerbated during the 1980s and 1990s, when the Food and Drug Administration implemented new ‘fast-track’ and accelerated approval programs that expedited the review process. Drugs could be approved and brought to market much faster – and many people with a variety of different medical conditions benefited from the accelerated approval process.
But fast-tracking drug approval also increases the risk of severe side effects — undetected during the trial phase — becoming apparent after mass market approval. And many thousands of people experienced life-shattering complications as a result.
When drug companies cut corners, they are legally liable for the consequences.
A Revolving Door at the FDA
Recently, Scott Gottlieb resigned his position as FDA Commissioner. Two months later, pharmaceutical giant Pfizer announced he would be joining their board of directors. As a director with the company, Gottlieb stands to receive a minimum of $350,000 per year in cash and stock compensation.
Massachusetts Senator and former presidential candidate Elizabeth Warren condemned the move and called for Gottlieb to resign from the Board, saying the move “smacks of corruption.”
But this problem is nothing new. The so-called “revolving door” problem is common with every regulatory agency.
To find qualified experts who can effectively regulate the pharmaceutical industry, the FDA must regularly hire people from within the industry. The same is true for the CDC, the Department of Health and Human Services, and any other similar Agency in Washington, D.C.
Conversely, many regulators eventually leave the FDA to earn more money working at a pharmaceutical company.
FDA regulators know they may want to leave the civil service one day and work in the private sector. They therefore have every incentive to nurture their own relationships with executives at the companies they regulate – and avoid rocking the boat.
They know that displeasing health care and drug company executives could narrow their employment opportunities in the pharmaceutical industry.
The consumer, in contrast, has no such leverage.
According to a 2016 study in The BMJ, researchers looked at the employment histories of 55 former FDA staff and advisory committee members who had conducted hematology-oncology drug reviews over a 9-year period. Out of that group, 26 employees left the Agency. Fifteen of them later took employment or accepted consulting work for the pharmaceutical industry.
Another small study by the editors of Science Magazine found that 11 out of 16 FDA medical examiners who worked on 28 drug approval panels and who subsequently left the Agency were later working for or consulting for the very companies they were recently regulating.
This creates enormous systemic conflicts of interest on the part of regulators – conflicts that are extraordinarily difficult to eliminate.
Hidden payments to FDA approval panels
In some cases, drug companies have provided indirect or after-the-fact payments to FDA review and approval panels. That is, officials who quickly approve new drugs later received large payments in the form of consulting and advisory fees, speaking fees, travel costs, and other perks.
AstraZeneca and the FDA
In one such case, U.K.-based drug manufacturer AstraZeneca, one of the world’s largest pharmaceutical companies, paid hundreds of thousands of dollars to a single cardiologist on the panel that approved the drug ticagrelor – a promising heart medication marketed under the brand name Brilinta.
The company didn’t disclose any conflict of interest at the time. Instead, the payments to the cardiologist came in the form of consulting fees and honoraria over several years.
As it happened, Brilinta was a huge commercial success. And it is effective at helping to prevent blood clots in heart disease and heart attack patients. The drug made the company more than $1 billion. Which meant there was plenty of money for them to pay to the members of the approval panel.
But this one cardiologist wasn’t alone.
AstraZeneca also paid $63,000 to a Duke University cardiologist who sat on a panel that approved quetiapine, an antipsychotic medication marketed under the brand name Seroquel.
But Seroquel, when used in combination with certain other drugs, is associated with a statistically significant risk of sudden cardiac death. This is also true of other compounds that are chemically similar to Seroquel.
According to Science Magazine, the problem arose when AstraZeneca officials were pitching FDA review panels to approve the drug for additional applications: schizophrenia and childhood bipolar disorder. Although researchers knew that Seroquel and similar compounds increased the risk of sudden cardiac death, the company minimized those risks in presenting to the panels.
The panels approved the drug – and the panel members received significant consulting fees, speaking fees, honorariums, and other payments in the months and years after they approved the medication.
This is an example of what critics call a “pay-later” conflict of interest.
- 40 out of 107 physician advisors on drug approval committees studied received at least $10,000 in consulting fees, honoraria, or other benefits within four years of granting approval.
- Twenty-six of those physician advisors received at least $100,000.
- Six of them received over $1 million.
Approvals with Thin Research
We’d like to think that newly-introduced drugs are backed by multiple peer-reviewed studies, and that each expensive new compound achieves a marked improvement over less costly drugs currently on the market or available as generics.
But a 2014 Yale University study published in the Journal of the American Medical Association found that 37 percent of new drugs were approved based on just a single study. Forty-five percent of new drugs were approved based on surrogate endpoints, and over two-thirds of new drugs were compared only to placebos. That is, they were approved because the new drug was better than no intervention whatsoever, but not necessarily better than existing therapies already on the market. .