THE FDA. DAMNED IF YOU DO. DAMNED IF YOU DON’T.
There is a paradox with respect to clinical trials. One day you may see an article criticizing the FDA for not approving a promising drug that is in clinical trials, because it may benefit people right away. And the next day you may see another article criticizing the FDA for approving a drug too soon, because side effects appeared several months later, outside the window of the clinical trials.
Recently the current HHS Secretary echoed that paradox when he said that “If you want to take an experimental drug—you can do that; you ought to be able to do that.” On the other hand, only 4 days later he said that “The 76 shots that children this country received between birth and 18 years old, none of them have been safety tested against the placebo, which means that we don’t understand the risk profile of those products.”
Damned if you do. Damned if you don’t.
The FDA was founded in 1906, and in 1939 it began to regulate pharmaceuticals.
The pharmaceutical industry, regulated by the FDA has saved an estimated 50 million life-years since 1990. Basic research into how the human body works has led to dozens of treatments for diseases that had previously resulted in the deaths of our parents and grandparents.
This history of drug approvals has been remarkably noteworthy. But that does not mean that it has been perfect. Trying to walk the line between making drugs available to the public, while maintaining safety and value/effectiveness is an imperfect art.
There have been mistakes made in all the variations of the approval process. I have categorized some of the most notable below. They fall in four basic categories.
Drugs that were approved and then withdrawn for safety issues uncovered after approval.
Drugs that were approved before clinical trials were complete (Accelerated Approval) and were successes.
Drugs that were approved before clinical trials were complete, but were then withdrawn because completed trials did not show effectiveness.
Drugs that were approved before clinical trials were complete but withdrawn when dangers were discovered after release.
The following is a list of examples of this paradox. I list them to give you a sense of the complexity of this issue. I would encourage you to read through them because they will give you a sense of how the system works.
DRUGS WITH APPROVALS THAT WERE WITHDRAWN
I am not going to speak about vaccines here. None have ever had their FDA approval withdrawn (one Hepatitis B vaccine was withdrawn, not for any safety reasons, but because the company went out of business and shuttered its facilities). All vaccines went through placebo trials during the approval process, and all have had long-term safety studies.
Although rare, several high-profile drugs have been withdrawn from the market after approval. Here are some examples:
THE DRUG MAY CAUSE SERIOUS SIDE EFFECTS FOR THE TARGET POPULATION BUT BE USEFUL FOR OTHERS.
Thalidomide.
Approved in 1957 for morning sickness, it was withdrawn 4 years later due to as association with birth defects. It is still used today for treating certain cancers like multiple myeloma. The issue here was that the adverse effects could not be measured within the time limits of the clinical trials.
THE ADVERSE AFFECTS OF THE DRUG WERE NOT IDENTIFIED DURING APPROVAL BECAUSE WE COULDN’T MEASURE THOSE AFFECTS AT THE TIME OF APPROVAL
Phenylpropanolamine *Contac, Robitussin CF, Triaminic DM)
Approved in the 1930’s for treating nasal congestion, it was withdrawn in 2000 due to a demonstrated correlation with increased risk of hemorrhagic stroke.
The issue here was that at the time the drug was approved, we had not identified or quantified the resultant clinical complication.
THE DRUG WAS REMOVED BECAUSE THE SIDE AFFECTS HAD NOT BEEN LOOKED FOR DURING THE CLINICAL TRIALS
Rofecoxib (Vioxx)
Approved in 1999 as a pain reliever and arthritis treatment, it was withdrawn 5 years later due to an association with an increased risk of heart attacks and strokes.
The issue here was that the clinical studies were not designed to look for these cardiovascular events, and the safety studies that became important were not submitted
to peer-reviewed journals until a year and a half after FDA approval. The issues were not uncovered until Rheumatologists were able to do longer-term studies.
EVEN WHEN A DRUG IS WITHDRAWN, IT SOMETIMES REMAINS ON THE MARKET
Sibutramine (Meridia)
Approved in 1997 as an appetite suppressant, this SSRI was withdrawn in 2010 due to an increased risk of heart attack and stroke.
Even though approval was withdrawn in 2018, FDA analysis has found that in 12 tested OTC weight loss supplements, all 12 contained this drug. These supplements usually are imported from countries such as Ireland, China, and the Philippines and include products such as Payouji tea, Slim Fast, 7-Days Diet, and Pai You Guo Slim Capsules.
The issue here is that even when a drug is withdrawn from the drug marketplace, it sometimes remains in the consumer pipeline.
FDA-MANDATED LONG-TERM SAFETY STUDIES REVEALED HEALTH DANGERS
Lorcaserin (Belviq)
Approved in 2012 for weight loss in obese patients, it was withdrawn in 2020 due to an increased risk of cancer.
The issue here is that even after initial approval, the FDA required continued safety studies. In 2016, studies of cardiovascular risk showed no increased risk, but subsequent large
studies did show an increased risk of developing cancer.
MANUFACTURING-RELATED CONTAMINATION CAN RESULT IN HEALTH PROBLEMS THAT WOULD NOT HAVE BEEN SEEN IN CONTROLLED CLINICAL TRIALS
Ranitidine (Zantac)
Approved in 1983 for the treatment of excess acid in the stomach, it was withdrawn in 2020 due to the potential of cancer from a contaminant.
The issue here is that during the manufacture of the drug, or upon exposure to high heat, there can be a contamination with NBMA, a cancer causing chemical.
SHOULD WE APPROVE DRUGS MORE QUICKLY TO HELP PATIENTS?
The flip side of this issue is the question of whether the FDA is too slow to approve drugs that might help you or a loved one because of the imposed rigor of clinical trials.
Sometimes, drugs that look very promising in Phase 2 trials, fail in Phase 3 trials. Some examples:
Exenatide
A drug that showed some promise for treating Parkinson’s patients during Phase 2, but no significant improvement in patients was found in Phase 3 and it was withdrawn.
Gantenerumab
It showed some ability to reduce amyloids in Alzheimer’s patients but failed to slow clinical decline during Phase 3 trials.
Relyvrio
It failed to show any success in Phase 3 trials with ALS patients.
THE FDA DOES HAVE A PROCEDURE TO ACCELERATE APPROVAL
The FDA has a program called the Accelerated Approval Program that allows for approval of drugs more quickly if they show value for serious or life-threatening conditions. For example, if an anti-cancer drug shows significant tumor reduction in Phase 2 trials, or early in Phase 3 trials, the FDA may approve the drug more quickly than normal.
Some examples:
Keytruda
Approved for various cancers prior to the completion of Phase 3 and traditional approval
Elahere
Approved for treating ovarian cancer prior to traditional approval
Scemblix
Approved for the treatment of chronic myeloid leukemia
Amondys 45, Vyondys 53, and Viltepso
Approved for Duchenne muscular dystrophy.
Oxbryta
Approved for sickle cell disease
ACCELERATED APPROVAL DOESN’T ALWAYS PAN OUT.
Sometimes, drugs that receive accelerated approval, don’t show benefits in the long term, and are withdrawn. Some examples:
Pepaxto
Developed to treat multiple myeloma, it was granted accelerated approval in 2021; however longer-term studies showed little to no clinical benefit and an increased risk of death. It was withdrawn in 2024.
Ukoniq
Developed to treat lymphoma, it was granted accelerated approval in 2021; however longer-term studies showed an increased risk of death and was withdrawn in 2022.
Gavreto
Approved in 2020 for the treatment of a variety of cancers, approval was withdrawn in 2023 for the treatment of some cancers, but approval remained for several others.
Mylotarg
This is an interesting example. It was approved under the Accelerated Approval Program in 2000 for patients over 60 years old with acute myelogenous leukemia. Within a year, studies showed an increased risk of other life-threatening disease. In 2010 it was voluntarily withdrawn from the market.
But, in 2017, a new application was submitted based on a large-scale study of prior results, and re-approval was granted.