My dad was hospitalized last month with a hemorrhaging kidney. He lost between one-third and one-half of his blood. An otherwise healthy man in his late 60s with no history of kidney injury spent six painful, expensive days in the hospital. He’s now home, facing a two-month recovery period.
The scary situation was caused, his healthcare providers agreed, by a severe side effect from a blood thinner. The drug was prescribed to reduce his risk of stroke in the aftermath of a procedure to correct atrial fibrillation—an irregular heart rhythm. The proper dose was dispensed, and my dad dutifully took the pill every day as instructed. He quit taking the drug shortly after the first real warning sign.
You might think that in such a situation, my dad’s doctors would first get him stabilized, and then promptly report the severe adverse drug reaction to the manufacturer and the FDA. That way, even if this was a rare case that the doctor hadn’t seen before, it could be entered in a national database so that someone could look at whether this was a 1-in-1,000,000 anecdote, or a more concerning 1-in-1,000 event with public health implications. Someone at the FDA could look at that kind of contextual data. If this were indeed part of a pattern, then perhaps the drug’s warning label should be updated. If there were enough serious cases like this, or even a string of deaths, maybe an advisory committee could be called to re-evaluate whether the benefits still outweigh the risks. If nothing else, better information would help doctors make more informed prescribing decisions.
That might sound good, but that’s not how our adverse drug reaction reporting system works. We have no real way of knowing whether this drug is safe or not.
The hospital that treated my dad cared about getting him stable, of course. Over and over, healthcare providers asked whether he had fallen or injured himself in a way that might attribute the kidney bleeding to some other source. But there was no injury. All signs pointed to the drug. Even so, no one promptly reported this severe adverse drug reaction to the FDA through a standard Medwatch form. After two weeks of prodding from me, his pain-in-the-neck biotech journalist son, my Dad asked his prescribing physician whether such a report had been filed.
No, the doctor said. But absolutely, he pledged, he would.
One week later, I followed up to make sure. Yes, I was told, a nurse practitioner filed the report.
Most people in this situation, of course, don’t have a family member who knows how the adverse event reporting system is supposed to work and who won’t stop until things are done right. Adverse drug reactions have always been under-reported, and it’s one of the dirty little secrets of the biotech and pharmaceutical industry. Well-controlled, randomized clinical trials are the best thing we have for assessing drug safety and effectiveness before a product hits the market. But they are too small and too selective to provide a representative view of a drug’s safety profile once it starts being prescribed to many patients on the market.
Chances are that many readers of this column have had an adverse drug reaction or have a family member who has suffered from a similar situation. One estimate published in 1998 in the Journal of the American Medical Association said that adverse drug reactions ranked somewhere between the fourth and sixth-leading causes of death in the U.S.
That report, based on data from the mid-1990s, didn’t lead to the sort of change that many hoped. You might think that 20 years later, in an Internet age with powerful information technology tools in so many hands, that drug side effects would routinely be reported in detail, and in real-time.
Nope. Only about 500,000 reports were sent to the FDA in 2010, about one-tenth of the estimated number of serious adverse drug reactions. Things have improved somewhat in the past couple years, as there were about 700,000 such reports of hospitalizations, life-threatening situations, and other severe adverse reactions, according to FDA data. But under-reporting is still the norm. If my dad hadn’t asked his doctor to file a Medwatch report two weeks later, I’m confident he would have been among the vast majority of patients whose severe side effects would have gone unreported.
The post-market safety surveillance system is a mess and always has been. Doctors are busy, and they already have plenty of paperwork. The FDA doesn’t have the resources to do truly rigorous post-market safety surveillance, so it concentrates most of its energy on reviewing data from controlled clinical trials before it allows a drug on the market. The pharmaceutical industry is required to pass along reports of serious adverse events to regulators, but it has always treated this as a cost and a low priority. Lately, the industry has sought to cut costs on drug safety monitoring by outsourcing work to India, as was described recently in the Wall Street Journal.
One systematic review that attempted to measure the magnitude of under-reporting found that across 37 studies, in 12 countries, the median under-reporting rate was 94%, according to results published in 2006 in the journal Drug Safety. Another review published three years later in the same journal found that under-reporting of adverse events was mainly caused by physician ignorance, the fear of looking ridiculous for reporting merely suspected adverse drug reactions, procrastination, indifference, insecurity and complacency. In a twisted bit of logic, the researchers found that many doctors didn’t report adverse events because they figured the FDA only allows safe drugs on the market. Apparently these physicians fail to realize that regulators need to get their data points from somewhere.
Given my job as a biotech journalist, I’ve known about systemic weaknesses in adverse event reporting for a long time. I’ve written about the problem. But it’s one thing to write about in the abstract, and another thing when one of your loved ones is affected by those systemic weaknesses.
When I heard about what happened, I immediately went to the drug’s FDA-approved prescribing information and read the warning label. Like all blood thinners, there was a disclosure about the risk of bleeding episodes. But I saw no Black Box, no severe warning of the kind that my dad experienced. My dad’s doctor had no reason to be on the lookout for such a nasty reaction. I still don’t know if this drug’s benefits outweigh the risk. Neither does anyone else, because of this sort of under-reporting by physicians.
I tried to think about what the best practices are in this situation, which I can share with others. Obviously, patients should insist that their doctors file a Medwatch report whenever they see a severe adverse drug reaction.
But patients can also take matters into their own hands. The FDA has made it easier for patients and consumers to file their own Medwatch reports online (all you have to do is go here, and click on the blue button that says "consumer/patient"). There are also user-friendly sites such as PatientsLikeMe and Iodine where patients can share their experiences with drugs, both good and bad. Many researchers look askance at data from patients that comes outside a controlled clinical trial, but patient-reported data from popular websites can be valuable when large numbers of patients participate, and the user-generated content is combined with other data from other sources, like insurance claims, or from the FDA database.
These are just early steps in the right direction. Until doctors take adverse event reporting more seriously as part of their professional responsibility, we’re going to continue groping around in the dark about drug safety. If we don’t dedicate ourselves to fixing this system with modern data capture and analysis methods, and maybe even give financial penalties to healthcare providers who fail to report adverse events, little will change. We’ll keep hearing stories about the next Vioxx or Avandia, and we’ll be shocked and outraged every time.
It’s going to be hard to come up with a reliable, timely adverse event reporting system, but it’s worth serious investment. People in the biotech and pharmaceutical industry, who talk so much about their desire to serve patients, should take more responsibility and work with physician groups, the FDA, and clever entrepreneurs to create a modern drug safety surveillance system.
