Why So Many Newly Approved Drugs for Rare Diseases Cause Unknown Side Effects

Unknown Side Effects

It’s almost as if it’s just a matter of time before a safety warning is issued for each new drug approved by the FDA stating an unexpected side effect. One-third of the drugs the FDA approved between the years 2001 and 2010, later received an alert, safety warning, or recall.

“Some of the side effects were minor and easily managed. But sometimes the “side effect” is death.”

Why it Happens

Does this mean the FDA isn’t doing its job? Approving drugs that aren’t safe? That could literally cause someone to lose their life? It’s actually much bigger than that.

Issue #1

The first problem is a lack of diversity in clinical trials, which is an issue that’s been discussed over and over again, unfortunately, without much change. The fact of the matter is, if a certain drug isn’t tested on a certain population of people, there’s no way to know for sure how that drug may affect those individuals. For example, if a clinical trial excludes the elderly, but then elderly people start taking the drug after its approved, new side effects may emerge that hadn’t been documented in the trial.

Issue #2

The second problem is that often, clinical trials don’t include enough participants to detect all of the side effects that might arise. Some trials include thousands of patients, which may seem like a lot. However, its estimated that it would take an analysis of tens of thousands of people in order to detect all risk.


There has recently been a black box warning issued for the drug called febuxostat, used to treat gout. The medicine was approved in 2009. Due to some earlier investigations which indicated the drug may cause an increased risk of cardiovascular issues, the FDA required the company who developed the drug to conduct additional research. This new investigation found that when compared to the drug allopurinol, an older treatment, there was an increased risk of cardiovascular death as well as death from other causes. The black box warning was issued. It stated the newly determined risk and advised patients to try the drug allopurinol first.

Tofacitinib is a drug that was approved in 2012 for the treatment of rheumatoid arthritis (RA). However, a study utilizing twice the approved dose of the drug (which is actually the approved dose for other illnesses such as ulcerative colitis) and patients who had an increased cardiovascular disease risk, showed unexpected concerns. Higher numbers of blood clots within the lungs and a higher rate of death was found in those given this therapy. Of course, the dose was different from typical RA and the participants in this study did already show risk, but the FDA was still concerned and a safety warning was issued.

If you are currently taking either of these drugs, talk with your doctor to determine what is the best next step for you.

Types of Safety Warnings

The FDA is responsible for issuing safety warnings through their post-marketing surveillance of approved drugs. These can come in any of the below forms, depending on the severity of the warning.

  1. Medication Guides: Routinely printed reports regarding side effects of medications
  2. Prescription Drug Labeling: Insert within the package of a drug that provides detailed information on the medication
  3. Drug Safety Communications: Public health advisories
  4. Black Box Warning: A notice at the front of a package insert that informs the user about severe/life-threatening side effects.
  5. Drug Recall: Most frequently come from drug developers themselves. May be permanent or temporary.
  6. Drug withdrawal: FDA reverses a drug approval and the drug is taken off of the market.

What We Can Do

So now that we know more about these unknown side effects, why they happen, and how the safety warnings are provided, you may be wondering- what can we do about it?

The first thing that we can do is work to increase diversity in clinical trials.

The second thing that can be done, is something that’s already in place. It’s called post-marketing surveillance. This refers to the monitoring the FDA does of all of their approved drugs. The high number of safety alerts/warnings in some ways shows that this process is working well, finding undetected issues and publicizing them to the patients who critically need to know.

The third thing that can be done is only possible with the help of extremely dedicated patients. In addition to reporting side effects to your doctor, you also can notify the FDA’s MedWatch Safety Information and Adverse Event Reporting Program online or by phone at 800-332-1088. Your report could help to identify a problem with a medication that is currently unrecognized.

It’s almost inevitable that some things will be missed in the process of research. That is why post-market surveillance is so important. That includes not just FDA evaluation but the stories and experiences of patients. Your voice is critical to the conversation.

You can read more about this issue here.

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