The FDA Approval Process : How bad drugs and devices get to consumers.
By; Leah Rush Easterby
Biogen Inc.’s stock price soared in June 2021 when FDA approved its new Alzheimer’s drug, Aduhelm (aducanumab), through accelerated approval. While most Alzheimer’s treatments address only dementia symptoms, Aduhelm is the first one marketed to treat the disease process itself.
The FDA advisory committee and independent experts, including doctors who worked on the clinical trials, expressed concern over the trial’s incomplete efficacy evidence. A data monitoring company halted two Phase 3 trials before they were completed because the drug didn’t appear to be benefiting trial participants. Instead, about 40% of Phase 3 volunteers receiving the high dosage of the drug experienced brain swelling or bleeding. Three members of the advisory panel resigned in protest.
Because of questions regarding efficacy, FDA is requiring a Phase 4 trial. But FDA will not be required to withdraw approval even with negative Phase 4 results.
Since Aduhelm was approved, the FDA has been plagued by questions regarding its working relationship with Biogen, including investigations by congressional committees, the Health and Human Services inspector general, the Federal Trade Commission, and the Securities and Exchange Commission. By May 3, 2022, Biogen announced that its CEO would step down.
After a tumultuous rollout of the drug in the U.S., in April 2022, Medicare officially declared it will only cover Aduhelm for patients in clinical trials, landing another serious blow on Aduhelm’s profitability and the FDA’s reputation as a gatekeeper. Medicare typically pays for FDA-approved drug prescriptions. Aduhelm has already increased costs to Medicare Part B recipients, whose 2022 premiums increased, driven in part by the potential that the expensive alzheimer’s drug would be approved and covered.
FDA has a track record of approving drugs and clearing devices that are later recalled. Stories abound where drug proponents conceal evidence from trial investigators and the investigators don’t proactively audit the data they receive. Medical device approval processes have so many loopholes it’s almost impossible to get a rejection letter. And postmarket surveillance is practically nonexistent. FDA ineptitude and apparent conflicts of interest span decades and presidential administrations. As arguably the most important consumer protection agency in the world, why do FDA’s problems persist?
What FDA Approval Means to Consumers
People worldwide look at FDA approval as the benchmark for product safety. But pharmaceutical companies have a heavy influence over FDA regulations. Extraordinary profits are often in direct competition with the best interests of consumers.
With politicization of vaccine safety and effectiveness, FDA approval became a hot-button topic of debate in 2020, when the world needed options more than evidence. Some anxiously awaited FDA approval before taking the COVID-19 vaccine, while others scoffed and rolled up their sleeves. Although most people are unaware what FDA approval requires, most consumers behave as though it’s synonymous with safety.
While it’s true that many products undergo rigorous clinical trials before making it to market, FDA offers drug manufacturers several options to avoid testing. Drug sponsors eagerly use these exceptions, knowingly placing harmful products in the stream of commerce.
How FDA Approves Drugs
Getting a new drug to market takes resilience and money. Research and development can take anywhere from 12 to 15 years, and drug manufacturers invest an average of $2.6 billion in the approval process. It’s no wonder that drug manufacturers cut corners when they get the opportunity, but time and again, FDA fails to exercise its oversight obligation to stop them when they do.
New drug candidates undergo the FDA New Drug Application (NDA) process to get from lab to market. FDA’s Center for Drug Evaluation and Research (CDER) oversees drug approval. There are three stages of premarket testing: pre-clinical trials, clinical trials, and New Drug Application Review.
In preclinical trials, the drug sponsor tests the product on animals to check for toxicity and forecast safety and efficacy for humans. If the drug company’s reporting on test results passes muster, the drug sponsor can then submit an Investigational Drug Application (IDA) to FDA. The IDA includes information about the drug’s ingredients and composition, pre-clinical test results, and clinical trial plan.
After pre-clinical trials, the drug advances to clinical trials, where investigators confirm the drug’s safety, side effects, benefits, and efficacy on humans. Clinical trials typically take three or more years to complete. To file a NDA, the drug must pass three phases of clinical trials.
- In Phase 1, about 100 volunteers receive the candidate drug and are monitored for side effects and adverse events.
- In Phase 2, several hundred volunteers including people with a specified disease or health condition, receive the drug. This stage determines the drug’s effectiveness using comparative studies on patients who receive the drug, a non-active placebo, or another drug.
- In Phase 3, several thousand patients receive the drug. This phase examines efficacy in different demographic populations and drug interactions.
Once the drug passes all three clinical trial phases, the drug sponsor can move to New Drug Application Review for FDA approval. NDA Review is the final push towards getting the product ready to be marketed and has multiple steps that include Drug Labeling Review, NDA Review and Sponsor Meetings, and Manufacturing Facility Inspection.
At least in theory, the key to FDA approval is proving that a product’s benefits outweigh its risks. As a matter of practice, and as was the case with Aduhelm, FDA routinely approves drugs with incomplete and dubious clinical trial data on efficacy and risks.
A fourth phase of oversight continues after the product is on the market to detect adverse events not reported during clinical trials. The drug manufacturer then gets the option to submit voluntary periodic reports to FDA. Many drug-related adverse events go unreported.
FDA has historically taken a lackluster approach to following up on Phase 4 postmarket surveillance, and when problems become apparent, FDA hesitates to revoke drug approval. Science magazine conducted an 11-year review of FDA enforcement actions and found that of 291 official action indicated (OAI) cases, only 71 resulted in a clear regulatory endpoint. Of the 220 remaining OAI cases, Science could not identify a documented outcome. Even when FDA does follow up on problems, it’s slow to enforce. Of the 291 OAI cases cited, FDA took 10 months to 14 years to send a warning letter.
Procedures for following up on FDA cleared and approved products have no teeth. Doctors are not required to report adverse events to FDA. Instead, FDA relies on drug companies to police themselves. When they don’t comply with regulations, FDA is slow to react, and its response is typically meager (such as sending a warning letter and promptly closing the file).
Pharmaceutical companies make millions of dollars in off-label sales each year. Unfortunately, pressure from pharmaceutical lobbyists has encouraged FDA to turn a blind eye to off-label marketing. Several attempts by FDA to crack down on off-label marketing have been thwarted by government and pharmaceutical manufacturers.
Pharmaceutical industry influence over FDA has had devastating impacts on consumers. The opioid crisis that swept the nation saw 20 years of off-label marketing for opiates, resulting in thousands of deaths, not to mention social and financial implications experienced world-wide. Damages awarded in a tsunami of ongoing lawsuits will never undo the harm caused by the off-label marketing of opioids.
Despite paying heavy fines for off-label marketing—in excess of $6 billion since 2009—pharmaceutical manufacturers ultimately find off-label marketing more profitable than covering the cost of proper testing. Instead, drug companies anticipate the inevitable lawsuits their defective labelling will cause and write the cost into their financial plans. Injured or dead Americans are simply the price of doing business.
How FDA Approves Medical Devices
FDA’s Center for Devices and Radiological Health (CDRH) regulates the manufacture and distribution of medical devices in the U.S. Device approval takes from three to seven years to complete.
Devices should get to market through a Premarket Approval Application demonstrating the device’s safety and efficacy. However, not all devices are subject to the same rules, and many can skip the premarket approval (PMA) process altogether.
Congress first gave FDA authority to regulate medical devices through the Medical Device Amendments of 1976. The amendment established three classes of medical devices based on their risk level:
- Class 1 devices are low-risk (dental floss and bandages) and need only apply for FDA registration.
- Class 2 devices are moderate-risk (contact lenses and wheelchairs) and sometimes require premarket review.
- Class 3 devices are high-risk (pace makers) life-supporting or sustaining devices. PMA is mandatory for Class 3 devices marketed after 1976.
Premarket approval is FDA’s most intensive authorization process used for Class 3 devices. To begin PMA, the device manufacturer must develop a prototype for lab testing.
The device then moves to a two to three year testing cycle that includes animal testing, toxicology, and shelf life, among other data. Premarket testing for a new medical device costs from $10 million to $20 million.
For example, Essure was FDA approved in 2002 following expedited review and premarketing approval. Essure is a permanent contraceptive device made of two coils that are inserted in the fallopian tubes. The coils contain nickel, a known carcinogen, that produces scar tissue to permanently seal off the fallopian tubes. Women with Essure have suffered from perforated organs, ectopic pregnancies, autoimmune disorders, unintended pregnancies resulting in septic abortion and death, and sometimes complete hysterectomies.
One woman reported in 2015 finding out she was pregnant two weeks after having Essure implanted. Her OB/GYN said the Essure coils would “bend out of the way” and not affect the pregnancy. She described climbing out of bed at 22 weeks and hearing a loud popping sound, “like a balloon.” As she stood up, water trickled down her legs.
Four days after the popping sound, an ultrasound confirmed her amniotic fluid was low, and a cerclage was performed in hopes of saving the fetus. The cerclage failed to save the pregnancy. The doctor removing the cerclage reportedly stopped mid-procedure and exclaimed, “What the **** is an Essure coil doing in her vaginal tract?” The coil had never properly implanted in the fallopian tube. It ruptured the amniotic sac. The pregnancy was so advanced that the woman had to endure a labor delivery. Baby Daphne lived for 15 minutes and died in her parents’ arms.
While Essure was designed to remain implanted for a woman’s lifetime, few participants in premarket studies were followed longer than one year. Only 71% of women were followed for the requisite five years. Adverse event cases—where the woman became pregnant before the 3-month pregnancy check or had a subsequent hysterectomy—were excluded from the Essure trial reports. Bilateral placement failures were also excluded. Essure then resulted in more than 800 unintended, failed pregnancies.
By the time Merck discontinued Essure sales in 2018, injured women had been filing lawsuits and begging Congress to intervene for years. In 2015, doctors with the New England Journal of Medicine criticized FDA’s inadequate pre- and postmarket evaluations and lack of transparency for allowing the injuries to occur.
The Premarket Notification 510(k) Alternative
An estimated 95% of devices are cleared through Premarket Notification 510(k) (PMN)—the most common pathway to device clearance in the U.S. Via PMN, medical device manufacturers can forego clinical trials if their product is “substantially equivalent” to one already on the market. Substantially equivalent means the new device has
- the same intended use as a legally marketed device and
- the same technology characteristics as the legally marketed device or
- the new technology doesn’t raise novel safety or efficacy concerns.
Any legally marketed device can be used as the “predicate” device for PMN. While the process is highly efficient for getting new iterations of a device to market, it allows manufacturers to entirely forego clinical trials, meaning they may not catch product flaws until the device is implanted in consumers’ bodies. Naturally, corporations cut corners to increase profit margins, making de facto guinea pigs of early adopters.
For example, metal-on-metal hip implants received PMN FDA clearance, relying on ceramic and plastic predicate implants. Metal-on-metal implants have caused serious injuries from shearing of metal debris in patients’ bodies—a problem that didn’t occur with ceramic and plastic devices.
As a matter of practice, medical devices using 510(k) notification can cite predicate devices that have been recalled or weren’t even subject to FDA regulation when introduced on the market (before 1976).
Conflicts of Interest Encourage Corruption
Product manufacturers pay exorbitant fees for FDA approval that accounted for 68% of FDA’s prescription drug budget in 2020.
The 1992 Prescription Drug User Fee Act (PDUFA) allows FDA to collect supplemental revenue from new drug applicants. PDUFA also places time constraints on FDA in conducting NDA Reviews. A 1998 survey of FDA medical officers revealed that many physicians believed NDA Review standards had declined since passage of PDUFA. Medical officers reported being pressured by FDA supervisors to approve new drugs, receiving inappropriate calls from drug sponsors, and interference by FDA in the NDA approval process on the drug sponsor’s behalf.
High level officers within FDA often join pharmaceutical companies in lucrative positions after their FDA terms. According to one report, in 2018, nearly 340 former congressional staffers had moved into the pharmaceutical industry. After decreasing drug manufacturing inspections and accelerating the NDA process, former FDA Commissioner Scott Gottlieb landed at Pfizer with a substantial salary and stock options.
Yet, the backlash to FDA’s Aduhelm decision suggests a potential shift in FDA’s lackadaisical approach to regulation. For example, a drug developed to treat ALS (with much better evidence on efficacy than Aduhelm’s) has stagnated in the FDA approval process, to the consternation of patients and families with few treatment options. At least one commentator has suggested that FDA might now be dragging its feet on approving the drug as a result of the Aduhelm fallout.
When it comes to for-profit healthcare, corruption is inevitable. We cannot expect corporations to quit putting profits over people desperate for treatment options, which leaves the onus on FDA. And while policy experts often demand restrictions and oversight, repairing a broken system insiders don’t want fixed is downright impossible.