We all want to think our doctors find a way to keep up with the latest medical and pharmaceutical research. But what if that might lead to more off-label prescriptions that could be potentially harmful and expensive?
Our current U.S. system for new pharmaceuticals and medical devices requires any company that creates a new treatment to gain approval from our regulatory agency, the Food & Drug Administration (FDA) before they are allowed to market and sell it.
Ideally, they go through three phases of clinical trials: Phase I assesses safety, Phase II tests efficacy, and Phase III studies the effects of the drug in randomized and blind tests of large numbers of patients (ideally hundreds or thousands). But increasingly, companies have found ways to either get out of or water down Phase III trials, resulting in a lot of unconfirmed information about the drugs we’re prescribed.
There are, of course, many thousands of Phase III clinical trials in progress, but being able to bring a drug to market without their satisfactory completion is becoming increasingly common, despite plenty of evidence that the drugs can still be shown to be ineffective or harmful at this stage.
The system becomes even more complicated when drugs are allowed to be used “off-label.” These drugs have been through clinical trials and approved for one use, but that doesn’t stop doctors from prescribing them for something other than what they are approved to treat. There are both risks and rewards, of course, to off-label usage, and many people’s lives have been improved by novel uses of drugs.
Once a drug has been approved for one use, further research into efficacy, dosing, side effects, etc. can become spotty. Companies no longer have financial incentive to conduct massive, expensive trials of drugs already on the market if they can find ways to get doctors to prescribe them for other reasons.
Bioethicists from McGill University’s Biomedical Ethics Unit published a piece this week in the Journal of the American Medical Association’s JAMA Internal Medicine, suggesting that some post-approval clinical trials may even promote the use of ineffective and costly off-label usage.
The example they used is a powerful one: Pregabalin, known by its brand name Lyrica, is one of the best-selling drugs in the world. A product of Pfizer, it’s been around since 2004, when it was first approved to treat fibromyalgia and pain associated with nerve damage from diabetes, though it is now commonly prescribed to treat all kinds of acute and chronic pain and serves as an alternative to more addictive opioid painkillers. Despite studies showing it may not be very effective in treating these types of pain, it is now on the list of commonly misused drugs that are sold on the street.
Because Lyrica and other “gabbies,” as they’re referred to by recreational users, can produce feelings of relaxation and mild euphoria, they can also be an easier-to-come-by alternative to increasingly regulated benzodiazepines, like Xanax. And yes, doctors have used Lyrica off-label to treat generalized anxiety disorders, despite the fact that side effects can include worsening depression and anxiety. It’s even been linked to fatal overdoses and suicides in Australia.
When McGill researchers took a closer look at Lyrica’s history in order to understand the popularity of off-label uses, they found that clinicians and clinical guideline creators often relied on published studies that were too small and not rigorous enough to prove efficacy. Some, for example, suggested that Lyrica could be used to treat lower back pain. Despite the weakness of the evidence, physicians felt confident enough to start prescribing it. It’s taken years for more studies to come out showing the drug’s ineffectiveness for treating sciatica and chronic lower back pain.
When no timely follow-ups are conducted on these small and inconclusive studies, unsupported hypotheses and weak evidence become the best information available to prescribers. The influence of those earlier studies, the difficulty of keeping up with the latest research, and the role of anecdotal evidence or reports from dishonest patients mean new research doesn’t necessarily change old habits.
The McGill researchers also warned that if small trials are not followed by confirmatory trials (that is, rigorous, repetitive, Stage III trials) “health care providers who draw on this literature can be left perceiving—but not knowing—that a drug could be clinically useful.” This is a state known as “clinical agnosticism,” and it facilitates the endorsement of off-label prescription.
When contacted about the research, Professor Jonathan Kimmelman, Director of the Biomedical Ethics Unit in the Faculty of Medicine and lead author of the article explained:
…because the drug can legally be used off-label, there is nothing to stop people from using an ineffective drug. And there is very little pressure for companies (or anyone else) to pursue a phase 3 trial confirming efficacy shown in earlier exploratory trials.
Combine faulty, but published, research with desperate patients and the multi-million-dollar marketing campaigns of Big Pharma and it’s easy to see how we ended up with a system where patients and insurance companies shell out billions of dollars for unproven treatments, some of which leave people worse off due to side effects.
But it’s not just remedy-seeking patients and finance-driven industry that propel this system. Academic researchers seeking publications are also a part of the problem. Kimmelman notes that:
It’s important to bear in mind- the dynamics we uncover in our article are a result of decisions made not just by drug companies, but also academic researchers.
This sentiment is echoed by Carole Federico, a Ph.D. student at McGill and co-author of the paper:
We were surprised to find that the problems we document are partly driven by researchers who are receiving funding from federal research agencies and/or their own medical centers.
Conversations about the role of regulation often get politicized. There’s truth to the claim that regulation can slow down innovation, but it’s certainly the case that the regulatory process demands the type of rigorous research that keeps us from being sold dangerous and ineffective products by companies looking to make a quick buck. Unrestricted innovation might sound great if you own stock in the company, but not so much if you’re the one expected to swallow it and wait for the results.
There’s no one arguing that our current medical system is perfect, but it does allow us room to investigate the interventions we’re being offered. And, theoretically, the more inquisitive we become as patients, the more our doctors will expect intelligent questions and be prepared to answer them. There are some helpful questions you can ask before trying a new prescription, such as: “Has this been approved to treat my specific ailment?”; “If not, have you read the studies on off-label uses?”; “If so, did you feel they were large and rigorous enough to produce statistically significant results?”; and “Are the side effects worth the potential risk?”
These are fairly standard things to ask, and even if a patient isn’t interested in or knowledgeable about statistical analyses, it doesn’t hurt to ask a physician if he or she knows anything at all about whether the research their decision is based on is current and convincing.
As the McGill team points out, there has been some debate about whether studies done on off-label uses after a drug is already on the market are even meant to add new knowledge or simply serve as marketing fodder.
What we can say is that, when companies run exploratory trials pre-licensure, they are very motivated to follow up with a confirmatory trial if the results are positive. After a drug is already approved - that motivation appears to wane - at least as judged by the limited amount of confirmatory testing later on. But as we point out in the article, companies can now circulate trial publications describing positive results of testing without violating any FDA rules. In effect, the publication becomes a form of advertisement.
Ethicists have long warned that conducting trials for the sole purpose of influencing physician prescribing behavior undermines the entire research process and increases distrust towards scientists.
Kimmelman and Federico also co-authored a paper in 2017 published in Nature about the lack of rigor in research performed before some human clinical trials are approved. In that piece, Kimmelman pointed out that:
Commercial interests and hope, alone, cannot be trusted to ensure that human trials launch only when the case for clinical potential is robust…Ethics requires a clear-eyed evaluation of a drug’s potential.
It’s frustrating to learn just how corrupt systems designed to protect us have become, but the first step towards consumer protection is becoming knowledgeable about how products are created, tested, and marketed.
A Mayo Clinic study from 2013 found that 7 of every 10 Americans are on at least one prescription drug. Perhaps it’s time to ask some tougher questions about why that is and whether or not these treatments have been developed and tested in a way that makes them worth the expense.
