On November 5, 2015, the Food and Drug Administration convened an Advisory Committee to consider “The Benefits and Risks of Systemic Fluoroquinolone Antibacterial Drugs.” The full briefing document is available at the FDA’s website.


There will be a lot to say in the coming weeks about that 617-page document, and FloxieHope already hit upon the two biggest points: the FDA “noted that fluoroquinolones are no more effective than placebos in treatment of sinus infections, bronchitis in those with COPD, and uncomplicated urinary tract infections. They have also noted that fluoroquinolones can cause a constellation of symptoms across multiple body systems, and that those symptoms can lead to disability.” It turns out, for all the hoopla surrounding Levaquin, Cipro, Proquin, and Avelox — and the other fluoroquinolones that 22 million patients take every year — the drugs are often ineffective and they can cause severe, permanent disabilities in everything from the nerves to the muscles to the senses and to the heart.


Medscape reports the FDA advisory committee “voted overwhelmingly that the benefits and risks for the systemic fluoroquinolone antibacterial drugs do not support the current labeled indications” for treatment of Acute Bacterial Sinusitis (ABS), Acute Bacterial Exacerbation of Chronic Bronchitis in Patients Who Have Chronic Obstructive Pulmonary Disease (ABECB-COPD), or Uncomplicated Urinary Tract Infections (uUTI). That’s a big deal, considering many patients, and perhaps most, took the drugs for one of those conditions. For example, urinary tract infection accounts for 43% of Cipro prescriptions and Levaquin is the second-most prescribed medication for acute bacterial exacerbation of chronic bronchitis. But the truth is, the drugs and their uses are so poorly understood that the CDC’s own website for healthcare professionals about fluoroquinolones includes among its frequently-asked-questions, “Why are there so many fluoroquinolones on the market?”


The bigger question today is: why did it take so long for the FDA and the medical profession to see the real side effects of fluoroquinolone?


Medical Research Has Consistently Shown That Fluoroquinolones Can Cause Damage To The Heart, The Tendons, The Eyes, And The Nervous System


Concerns have been raised about the drugs for more than 15 years, including concerns about neurotoxicity. Way back in 2002, medical researchers had already described how fluoroquinolones could, on a molecular level, cause damage to the central nervous system. A study in 2005 detailed central nervous system toxicity injuries including “agitation, delirium, confusion, acute organic psychosis, and abnormal vision,” as well as damage to entire body systems, like “cardiovascular system (rate-corrected electrocardiographic QT interval prolongation), musculoskeletal system (tendinitis and tendon rupture), endocrine system (glucose homeostasis dysregulation), renal system (crystalluria, interstitial nephritis, and acute renal failure), and the CNS (seizures).”


But it wasn’t until 2008 that the FDA forced the makers of fluoroquinolone drugs to add warnings about tendon injuries. Then, in 2013, the FDA again made the makers add warnings about nerve damage. Now it’s 2015 and all we have is a recommendation that the FDA start taking seriously the possibility for permanent injuries and giving them a real, concrete diagnosis, i.e., Fluoroquinolone-Associated Disability (FQAD).


Why Has It Taken So Long For The FDA To Start Recognizing The Risk Of Permanent, Severe Injuries?


As the FDA wrote, “Over the life-cycle of these drugs, several adverse reactions have been reported, and most of them were not evident in the pre-approval safety databases. While the actual incidence of each adverse reaction is difficult to ascertain, the seriousness of certain uncommon adverse reactions deserves attention, such as tendinitis/tendon rupture, peripheral neuropathy, or cardiac arrhythmias.” (Page 38.)


The key phrase there is, “several adverse reactions have been reported, and most of them were not evident in the pre-approval safety databases.” The safety of prescription drugs is evaluated in two ways, both of which have severe limitations: pre-approval clinical trials and post-approval surveillance.


Clinical Trials Rarely Reveal The Real Side Effects Of Prescription Drugs


When the drug company wants to obtain FDA approval for a new prescription drug, the drug company gets to design and operate the clinical trials itself. Sure, there are FDA Guidelines on how to do the clinical trials, and the FDA has the power to impose changes on these trials, but let’s be realistic: the FDA has nowhere near the resources to police every clinical trial performed on every new drug, and so typically the drug manufacturers get to set up the trials however they want.


The drug companies employ teams of doctors, statisticians, molecular biologists, and other professionals with advanced training with a mission of getting these drugs approved. It should come as no surprise that these teams are very good at designing clinical trials that just so happen to inflate the benefits of their drugs while minimizing the risks. Even when everyone involved wants to think they are acting in good faith, who, really, wants to be the naysayer when millions, sometimes billions, of dollars are on the line?


Post-Marketing Drug Surveillance Is Not Taken Seriously Enough


The primary way that the FDA and drug companies look for side effects after a drug is approved is through the review of “adverse events” reported by physicians.


Have you ever heard of your doctor reporting an “adverse event?” Probably not, because most doctors don’t report them. As PBS recounted four years ago in a report on fluoroquinolones:


It’s hard to know how many Americans are harmed by quinolones, or any prescription drug, for that matter, because the U.S. has no accurate way to track them. The Food and Drug Administration does have something called the Adverse Events Reporting System, or AERS, but even FDA says that picks up only about 10 percent, which means about 90 percent of all adverse drug reactions go unreported.


And an FDA advisory board report this month found there was universal agreement that the current AERS database is outdated and inadequate to the tasks of the agency. But even with that inadequate system, AERS picked up reports of 2,500 deaths linked to, but not necessarily caused by quinolones between 1997 and 2010. Another 45,000 negative side effects were picked up in the same time period.


Even though the “AERS” system, also known as “MedWatch,” only picks up about 10% of complications, there were still tens of thousands of reports by 2011, and still FDA didn’t act. Why not?


In short, because the drug companies are so good at downplaying the importance of the MedWatch system.


Many researchers have argued “the existing system is not adequately protecting patients and underscores the importance of recent reports urging far-reaching legislative, policy, and institutional changes.” As a matter of common sense and statistical science, if you have a database that you know only shows you 10% of the problems, then you should take problems even more seriously, because they often represent just the tip of the iceberg. The drug companies, however, have teams of epidemiologists and biostatisticians ready to go with complicated (and often misleading)  arguments that the adverse events collected are merely noise, and at the adverse events database can’t be used to really tell if a drug has a problem or not.Drug companies typically spend far more time, energy, and money explaining away adverse events than actually trying to get to the bottom of them. It’s not hard to see why: money.


Thus, these adverse events often keep piling up and piling up until, finally, the FDA uses its limited resources and puts together an advisory committee, just like the one that released the report on Fluoroquinolone-Associated Disability.


It’s not supposed to work this way. We’re not supposed to wait until the FDA sees a serious problem with drugs. Rather, as the Supreme Court ruled in 2009, “It is a central premise of the Food, Drug, and Cosmetic Act (FDCA) and the FDA’s regulations that the manufacturer bears responsibility for the content of its label at all times.”


The System Has To Change

The sad truth about this story is that it isn’t unusual. Our whole system for approving and monitoring prescription drugs is broken. The drug companies are the ones responsible for discovering and warning about side effects and complications, but they, of course, have every economic incentive to ignore, avoid, and deny those very same problems. It’s like if we had a high school classroom where everyone gets to write their own grades.


A variety of scholars and authors have suggested potential changes, but the first change needs to be in how we view prescription drug regulation. The drug industry simply doesn’t have the track record where we can simply trust them to look out for our safety first and their profits second. At a minimum, the system in place for post-market surveillance of drug complications needs to be changed so that, whenever adverse events reach a certain threshold, the manufacturer of the drug is obligated to convene and pay for a panel of outside experts to independently review the data and to report back to the FDA.


Otherwise, we’ll just continue to see these exact sort of problems over and over again, where drugs can cause injuries to thousands of people for years until the drug industry and the FDA take notice.


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