by Aaron Johnston, WFU JD Candidate ’21
When I was just starting to move out of the “weed-out” engineering college courses—calculus, physics, circuits, and chemistry—and into the core tenets of bioengineering, one conversation with my professor has always stuck out in my mind. I had to write a final paper in the form of a National Institute of Health-style proposal. The goal was to think outside the box and attempt to put something together from the building blocks we had at the time. After one class, I wandered up to the front of the room, apparently with a half-concerned, half-perplexed look on my face.
“What’s wrong?” my Professor asked.
“Well, I wanted to run this methodology by you to see what you thought. I’m not sure it will work.” I started sketching out my revolutionary idea. I knew it wouldn’t live up to an NIH proposal, but nevertheless, I was proud of it.
“. . . and then I’ll use BMP-2 to . . .”
“Wait, BMP-2? I’d be careful about BMP-2, people have been having issues with it.”
“But I thought BMP-2 was great for stimulating bone growth in mesenchymal stem cells.”
“It is, but one thing you will eventually learn is that once people are afraid of something, research is stifled. Go take a look at Medtronic.”
I didn’t think much about that conversation at the time: it was right after new studies about BMP-2 had come to light. Four years later, however, upon entering my first torts class in law school and having our first discussion of products liability, the thought of Medtronic came to mind again. If BMP-2 was such a great, new, innovative method of stimulating bone growth, what could have possibly gone wrong? It turns out, a lot.
Progress in modern medicine is often defined by heroic triumphs of innovation through technology. Year after year, technology improves, putting humanity within new grasps of curing cancer, allowing paraplegics to walk again, and pushing the boundaries of what was considered only remotely possible a decade before. Despite the constant string of innovation, the law struggles to keep up. It is critical that modern medicine continues the development of new technologies at a breakneck pace, but some of the legal practices controlling these technologies have gone unchanged for decades while the technology has changed relatively quickly. Is it time to reconsider some of these legal practices?
A perfect example of this is off-label drug and device usage. The Food, Drug and Cosmetic Act (FDCA) requires that the Food and Drug Administration ensure the safe and effective use of all prescription drugs via comprehensive testing. This testing also means that the manufacturer has to list at least one approved usage. The FDA, however, does not require an investigation of all the possible uses of a drug. Medical professionals have the discretion to use drugs in methods and for purposes not approved specifically by the FDA. This is termed “off-label” use.
The question naturally following is, how far should off-label use be expanded? The FDA reviews a huge amount of data per year, and the burden of reviewing every use of every drug would likely be insurmountable; during a pandemic, impossible. At the same time, drug manufacturers, in some cases, have adopted practices where they get a drug approved for one use, and then advertise or sell that product for a completely different use. The only way this occurs is by directing medical professionals to use their discretion to use the drug off-label. Medtronic along with several other device and drug manufacturers have acknowledged using such methods in the past.
In 2002, the FDA approved Medtronic’s Infuse device for spinal fusion surgery. Infuse was innovative because it specifically used recombinant human bone morphogenic protein-2 (BMP-2), a growth factor, to induce bone grown in the spine. The BMP-2 is carried in a collagen sponge inside a delivery cage. Infuse works by inducing mesenchymal stem cells to migrate to the area of the implant. Then the growth factor binds to the external surface of cells to drive specific differentiation. This means that the patient’s body grows new bone between the vertebrae, which has certain benefits compared to more traditional methods of inducing bone growth, such as grafts.
After studies in the late 1990s, the FDA originally approved the use of Infuse for specific lumbar spine operations. However, many of the devices were implanted in patients with problems in the cervical part of the spine, or used in alternative techniques for lumbar fixation, both off-label uses. After numerous problems were reported detailing unexpected side effects of such use, a 2011 paper revealed that issues with the use of BMP-2 for spinal fusion were 10 to 50 times higher than originally expected. A substantial number of prior studies had declined to report adverse events.
Medical professionals have often lauded the benefits of off-label usage in practice. Off-label usage gives patients more options for treatment and doctors more flexibility in practice. Typically, doctors only prescribe medications of such a nature when scientific data can be used to back up the benefits. Additionally, many doctors make sure to discuss the potential drawbacks of off-label usage with the patient. Having the patient sign a consent form is common. That being said, nearly 21% of all prescriptions were for an off-label use. It is considered by many to be an entrenched part of medical practice. In many cases, getting the approval for multiple different uses of a drug can be extremely time-consuming and costly, so off-label usage has been considered an effective “fast-track” to better serve patients.
Between 2002 and 2007, Infuse became a market leader, and later was used in between 30 and 50 percent of all spinal fusion procedures. As time went on, discrepancies in data sets began to emerge. Industry-sponsored studies rarely reported problems, whereas FDA data and non-industry studies had a greater number of complications. Many of the industry-sponsored studies were receiving up to $23 million annually for various activities. As a result of “occasional complaints”, Medtronic had begun looking into various post-operative issues with 3,647 surgeries, mostly off-label, of which there were 1,923 reported adverse events. However, the FDA didn’t see this data until 2013, because it was lost sometime around 2008.
That year, the FDA warned doctors about using Infuse for cervical implantation. At the time, Infuse was being used in about 1,500 cervical cases per month. Infuse was also found to have been used as an off-label treatment in 70 to 80 percent of cases. In 2012, a Senate report accused Medtronic of “obscur[ing] evidence of adverse events and promot[ing] off-label use.” Other statments accused Medtronic employees of reviewing, drafting and inappropriately “shaping” the content of medical journal articles. The justice department ultimately closed the federal investigation into Medtronic’s marketing practices, without finding evidence of wrongdoing. Predictably, the entire debacle brought on a number of legal challenges. A decade later, one has to wonder what really happened.
Patients had a variety of legal avenues to pursue relief from Medtronic regarding Infuse. Many directed their efforts against doctors. Off-label usage has become a common issue in medical malpractice cases where patients were not given informed consent. Issues surrounding such usage has spurned discussion of the freedom of speech of medical professionals discussing treatment plans with their patients. This came to a point in US v. Caronia where a sales representative promoted the drug Xyrem for off-label use and was found guilty of conspiracy to introduce a misbranded drug into interstate commerce. The central tenet of the claim was that the off-label use effectively mislabeled the drug, since the use was not for the purpose articulated by the FDA and did not include instructions for the off-label use. The Second Circuit found that the conviction violated Caronia’s right of free speech.
An important aside to note is that the FDA does not regulate the practice of medicine, only the drugs and devices used in it. This disconnect has created a number of problems and the FDA’s stance on off-label usage has been complicated. Drug manufacturers can distribute and discuss peer-reviewed journals surrounding a product’s off-label usage to medical professionals upon request. However, no direct-to-consumer marketing can be done for off-label uses. In 2010, the FDA introduced a program to report bad direct-to-consumer marketing, which has caused a number of high-profile settlements with large drug companies. The FDCA makes it clear that it is a crime to misbrand a drug, but “regulations do not expressly prohibit or criminalize off-label promotion.” In Caronia, the second circuit construed that expanding the restriction in the FDCA to cover off-label promotion would run afoul of the first amendment, relying heavily on Sorrell v. IMS Health, Inc, in which the Supreme Court ruled that “[s]peech in aid of pharmaceutical marketing . . . is a form of expression protected by the . . . First Amendment” as it is the “physician’s role to consider multiple factors.”
This has resulted in an interesting dynamic. Often doctors are sued for off-label usage, but have the security of the affirmed consent. The companies behind the drug are in the shadows, despite having actively promoted the drug to doctors. The reason for this, appears to be, in some ways, a preemption issue between the drug manufacturer and the patient. Deference regarding these issues often goes to the FDA, but as discussed above, that may not be effective.
There are a range of ways that plaintiffs have attempted to sue Medtronic for problems related to Infuse. A few of suits have included claims that off-label uses are a violation of the FDCA, allegations of the overpromotion of off-label uses, and claims for failure to warn, fraud, and products liability. That being said, Medtronic has escaped liability in a number of cases, but did settle 950 cases for $22 million in 2014. It also ended up paying $43 million to settle a lawsuit from its own investors. There were over 6,000 claims of patients injured by Infuse.
Many claims were diffused by the preemption clause of the FDCA. Under 21 U.S.C. § 360K(a), claims that impose a state law requirement are preempted. Manufacturers that have premarket approval (PMA) from the FDA can assert preemption from product liability claims. Since 2008, there have been nearly 500 cases surrounding PMA preemption.
As explained in Perez v. Nidek, three cases control the Supreme Court’s judgement of preemption under the Medical Device Act (MDA): Lohr, and Riegel for express preemption, and Buckman for implied preemption. Under Lohr, the Court held that the MDA does not preempt state requirements that are substantially equal to requirements under the MDA, specifically for devices cleared under § 510(k). But Riegel held that § 360K preempted common law claims regarding negligence, strict liability, and implied warranties had to do with safety aspects because of the PMA nature of the device. As a result, largely, failure to warn claims have been preempted. Retooling these claims as fraud, either fraudulent concealment or fraud by omission, has been ineffective. Ultimately, the gap for plaintiffs to get around § 360K is very narrow. To make matters worse, different circuits have construed these cases differently. A good summary would be that “the plaintiff must be suing for conduct that violates the FDCA, but the plaintiff must not be suing because the conduct violates the FDCA.” A bit of a Catch-22.
After all of this, is it time to reevaluate off-label usage? It appears so. But, there’s another side to the coin, which has become especially apparent in light of the COVID-19 pandemic. At the beginning of the COVID-19 pandemic, researchers acknowledged some potential treatments of COVID-19 using hydroxychloroquine and chloroquine, drugs used frequently in the treatment of malaria. Because of off-label usage, doctors could administer drugs like hydroxychloroquine to patients in need, even with the understanding that the drugs were not approved by the FDA for use against COVID-19. It is exactly this flexibility of treatment methods that is the novelty that makes off-label usage valuable to so many patients and practitioners.
At the same time, when doctors started to use drugs to treat COVID-19 that were an off-label use, the FDA cautioned doctors to keenly assess the “potential benefits versus the risks for [each] patient[.]” In addition to the more general off-label use, the FDA also has emergency use authorization (EUA) privileges that allows the FDA to release drugs for certain patient treatment when clinical trial data is not available. While doctors had success with the use of hydroxychloroquine for COVID-19, the FDA pulled the EUA for the use of the drug to treat patients on June 15, 2020, after clinical trials demonstrated limited treatment effectiveness with concern of disruptive side effects. Other drugs have been used by doctors under off-label headings for treatment of COVID-19 around the world. However, some have cautioned that other researchers have used off-label medications to engage in a trial-and-error type pseudo-research for COVID-19, raising further ethical issues and dilemmas.
Obviously, a middle ground must be reached. Off-label usage has an extremely valuable use, which should not be disturbed if possible. Nevertheless, issues similar to what occurred with Medtronic should not happen. Furthermore, FDCA preemption often seems to get in the way of patients negatively affected by off-label uses. In the alternative, it at least significantly slows down their chance of receiving compensation.
Perhaps the best route to focus on would be to consider what is best for the patient. Off-label use should be considered a stopgap measure to allow doctors the freedom they need when working with patients, especially during a pandemic. If doctors want to use a drug for an off-label use with the patient’s consent, then they should be allowed to do so. But this stopgap should not be overused to the point that drugs can be snuck through the system for one purpose, to then be used primarily for an entirely different purpose.
One potential avenue without treading into First Amendment rights and dampening the doctor’s relationship with the patient would be the creation of a new pathway for easier proof of liability for those individuals affected by the off-label use of a drug where multiple, severe adverse events have come from the improper usage of the off-label pipeline. This would incentivize manufacturers to get FDA approval for products that are used for majority off-label purposes. Another option would be to give the FDA more teeth to regulate the over-use of off-label devices. This could potentially work by making an exception to the preemption cause of § 360K(a) for off-label use of medical devices or creating an entirely new subset of laws dealing with claims regarding off-label use. This would not be all that different from state law claims made against devices given FDA clearance under the § 510(k) process, which are not preempted. Furthermore, the Medtronic situation (as well as the COVID-19 pandemic) illustrates the incredible importance and value of peer-reviewed scientific journals. It is not just a critical part of the scientific method, but also a critical part of patient safety. Conflicts should be disclosed at every level, and in my opinion, even to the patient.
Ultimately, the Infuse debacle brought to light some serious issues surrounding off-label use of devices, the FDA’s unclear objective regarding off-label usage, and companies pushing products for relatively untested uses, which unfortunately injured many patients. The COVID-19 pandemic shows that it should be a top priority for doctors to have the operational freedom to work with the patients using drugs off-label, but those drugs should also have enough scientific validity to ensure patient safety. While I ended up changing up my growth factor to the more ubiquitous BMP-7, BMP-2 is still in use today. Innovation always comes at a cost, but hopefully never a human one.