When to Go Off Label

“Off label use” may sound like something you are supposed to avoid. In fact, many off label uses are the standard of care for a particular condition. And doctors who avoid off label use could be considered behind the times. But how to proceed if you are unsure of which path to take?

Dr. Paul McAfee

Dr. Paul McAfee, Director of the Scoliosis and Spine Center of Maryland, says, “The rule of thumb in approaching on versus off label use of a medical device or drug is to do what is best for the patient. At one time or another, all orthopedic surgeons get difficult referrals which are often complicated by the fact that it is difficult to tell what’s on and off label. You can go to the FDA website and figure it out, but most surgeons don’t do that. In fact, most of the time orthopedic surgeons do not actually know when they apply a device off label. Rather, they use a device for indications that they, in their independent medical judgment, deem to be appropriate."

Thus there is a bit of wandering in the orthopedic desert regarding the on/off label issue. Dr. McAfee: “There is not much in the literature regarding what is on and off label use of devices; doctors must just use their best judgment. Take, for example, a compression hip screw, the most common way to treat fractures. The manufacturers put in a disclaimer saying that it is not for use in subtrochanteric fractures, the most complicated fracture, but most doctors never read this. The general guideline is that as soon as a device is approved for anything, even a small indication, then it can be used across the board. For example, if something gets approved for an arthritic condition then it is often used for fractures. And if a doctor feels that there is no better alternative for the patient, then he or she should use that particular device or drug.”

Sometimes you can find existing backup, other times you have to conduct a study, however imperfect, to find the data. “Do some research to determine if there is there a solid track record behind the device or the drug and if that information has been published, ” advises Dr. McAfee. “There is, however, always a lag between what’s practiced, what’s in the peer reviewed literature, and what is approved by the FDA.”

Because of this lag, sometimes you need to conduct a study, however imperfect, to find the data. Dr. McAfee: “The quality hierarchy regarding scientific data means that a level 1, prospective, randomized trial is the top tier. But you are not usually able to do such an advanced study. Let’s say we have a device approved for arthritis, but now I want to do a study to see if I can get it approved for something else. As soon as it is approved for the first indication there is no way I’m going to be able to conduct a prospective randomized study.”

“This is the typical scenario: the patient comes in and you tell them that if they participate there is a 50% chance they will receive the treatment. If the implant is approved by the FDA for another indication, the patient can just go to another doctor in the hospital who can treat him or her with a 100% chance of being properly cared for. Because of this situation you can’t thoroughly study a device for other indications; at best you can do a retrospective study.”

Surprises can be positive or negative…so it is with device use. “You can’t predict ahead of time what the best indications are going to be for a device or drug, ” says Dr. McAfee. “For example, many devices started out for scoliosis but turned out to be useful in treating arthritis patients. And most big spine devices started out as deformity treatments in pediatric orthopedics. We then said, ‘If it works and can stabilize the spine it should be good as a one level adult device. There are many such examples from outside the orthopedic world as well. The ubiquitous Ace bandage was actually labeled, ‘Not for circumferential use on an extremity.’”

“On the drug side, baby aspirin is widely used for prophylaxis in arteriosclerotic heart disease. The most notorious example of a drug which is commonly applied in an unintended application is Viagra (sildenafil). It was originally developed as a potent drug for dilating blood vessels to treat angina. Viagra started as a cardiac medication, was discovered to cause dilation of the blood vessels of the penis (priapism) and the rest is advertising history. Here is an example of a drug which is now reported in the literature in treatment of pediatric right heart failure, yet it is off label for use in cardiac disease, its original indication, because the drug maker decided there was more money to be made in treating male erectile dysfunction than in saving lives.”

Then there are also times when on label use isn’t best for the patient. Dr. McAfee explains, “Pedicle screws were approved for use in bone and that meant that they were completely on label for use in the sacrum. It turned out that this is the riskiest area for their use, much more so than in the lumbar spine, which originally was off label.”

For those surgeons who are cognizant of this complex issue, exploring off label use can mean a fair amount of work. Dr. McAfee describes his process: “I will usually hear about an off label usage at a society meeting and discuss the details with my colleagues. Additionally, I reach out to European surgeons who have used xyz device for hundreds of patients and I may even go to Europe to watch the surgery. All of this due diligence helps me decide if going off label is the best, safest alternative for certain patients. Part of this decision is knowing that even if the device fails I can still treat the patient with the best alternative device.”

Other questions to consider, recommends Dr. McAfee, are, “Should this procedure first be practiced in the cadaver laboratory? Is there institutional permission to perform this procedure in the hospital? Does the Institutional Review Board (IRB) have to be notified? Does the patient understand that ultimately this is an experiment and that he or she is the subject?”

While a device might not undergo a trial for each specific indication, it does, says Dr. McAfee, undergo a five year trial run. “Being off-label in my practice of innovative spine surgery is actually a positive thing because at least this means that the product I’m using has been approved by the FDA for some indication. For decades I operated on 400 patients a year using products like pedicle screws that were not only off label but were products for which physicians were being sued. During this time doctors were also studying their use and presenting their use in scientific spinal societies. The first five years of any innovative product are invariably off label. This includes things such as pedicle screws (bone screws), interbody fusion cages (cement restrictors), posterior cervical lateral mass screws (still off-label 10 years after description by Paul Anderson in peer reviewed studies), and PMMA for vertebral compression fractures. This means that any spine surgeon who is only practicing on-label surgery is performing surgical procedures that are a minimum of five years out of date. He or she is practicing below the standard of care, something that borders on malpractice.”

Before using products off label, however, be sure to consult the experts. Take, for example, the off label use of INFUSE, a Bone Morphogenetic Protein (BMP) biologic. Dr. McAfee: “INFUSE was only supposed to be used for the anterior spine within the confines of only one brand of lumbar interbody LT cages, but there are estimates indicating that 90% of its use is currently off label. There are even allegations now that there are more off label complications than have been reported.”

“If someone is being treated in the cervical spine at a tertiary referral center, the surgeons there are savvy enough to know that for a particular off label indication you must use one fourth the dose to get a good result. But out in the community there are some doctors using regular doses of BMP in the cervical spine and patients are having respiratory complications. Part of this is a legal issue. Because companies can’t talk about off label use, they can’t put warnings about the correct dosage for other indications. So doctors are left to their best judgment, often calling an expert in the area who recommends, ‘Yes, for xyz indication you must only use one fourth of the normal dose.’”

The bottom line? “There are too many diagnoses and applications to test each drug and implant for every possible use, ” says Dr. McAfee. “The entire field of oncology depends on the rapid evolutions of combinations of drugs, very few of which are approved on label in that particular cocktail or combination. The best oncology groups have rapid, current means of modifying these combination chemotherapeutic cocktails so that they are optimally effective—all are invariably off label. It is best to do your own research and come to your own conclusions. Politicians sometimes feel they should be making these decisions, but doctors and nurses think that on or off label should be a medical decision. And it can’t be left to the companies. A number of them started marketing and promoting off label use of certain devices, resulting in litigation. Now most companies train their sales reps not to promote such use.”

Dr. Jeffrey Wang

Dr. Jeffrey WangDr. Jeffrey Wang, Chief of Spine Surgery for the Department of Orthopaedic Surgery and Executive Co-Director of the UCLA Comprehensive Spine Center, has faced the on/off label decision many times. “This complicated issue puts doctors in a bad position. We are taught in residency to do what is best for the patient, which sometimes conflicts with what is approved by the FDA. The best decision often comes down to what is the standard of care and what is best for that individual patient. More and more, patients know what is and isn’t the standard of care and what is on/off label. The increased public awareness and explosion of new devices has perhaps contributed to the growth of this as an issue to be dealt with. A few years ago there were not as many devices and things were accepted without consideration for what was on/off label because that’s what was taught, used in your community, and considered to be the standard. Now there are new devices every month.”

And the FDA/manufacturer dance isn’t without its missteps. Dr. Wang: “Companies want to go all out with large studies so that they can be on label. The FDA stamp of approval is so important because it really helps to market and sell the product…not to mention get reimbursed. Like so many things, it ultimately has to do with money. In the past you could use things off label and still get reimbursed. Now, insurance companies may not approve procedures unless you are on label and have proven data for a certain indication. You may even have received FDA approval for a device, but because it is being used outside the proper indication, reimbursement is difficult.”

Bringing the patient into the conversation is, says Dr. Wang, increasingly common. “There are many doctors who tell their patients whether something is on/off label and review the pros and cons of an off label device prior to surgery. In my own experience, by the time patients reach me, they have not had success with conservative care and have chosen me and placed their trust in me. We want to do what is best for our patients, and sometimes it involves using something that is considered the standard of care, but it may be an off-label use of a certain product or device. In many cases, if we use a device that is off label, the insurers may not approve the procedure, and the hospital loses money. Our hospital will then try to limit the usage due to the costs.”

So which products or procedures are frequently found to be off label? “The biggest, most controversial use of an off label product involves growth factors like BMP, ” says Dr. Wang. “These bone graft extenders are all designed to eliminate the need for taking the patient’s own bone for spinal fusion. Using the patient’s own bone may not be optimal because someone’s bone quality is poor or because an underlying disease interferes with the healing in a spine fusion. For example, rheumatoid arthritis has a propensity not to heal and many patients are taking medications that inhibit bone healing. The failure of a fusion to heal is a big concern for spine surgeons.”

Dr. Wang continues, “Another off label procedure is posterior cervical fixation into the lateral mass. We are not supposed to teach it in our courses, but it is commonly used in practice because it increases the fusion rate and can stabilize the cervical spine. There is also the porous coated total hip device that was off label and may still be considered off label, but widely accepted as routine. In these situations I don’t know if doctors mention the off label issue to patients because the product is the standard of care…and is backed up by a number of studies.”

As for when to back away from off label use, Dr. Wang advises, “I would not consider off label use for products that are very new, or ones that have not been properly studied. Take a pedicle based motion preservation device, a new area in spine surgery. Many of these types of devices are being used because they have received a 510k approval for fusion, but many surgeons are not using it for fusion. The reason they have access to it is because companies took it through a 510k. Sometimes the device companies use a 510k approval for a certain device, but then surgeons use the product outside the true indication. Five years ago there were a lot spinal cages that were FDA approved as a cement restrictor for the hip, but ended up being used in the spine.”

Dr. Robert Campbell

Dr. Robert Campbell, Jr.Dr. Robert Campbell, Jr., an orthopedic surgeon at the Children’s Hospital of Philadelphia and inventor of the Vertical Expandable Titanium Rib, is clear about off label use. “If we stopped using devices off label there wouldn’t be much left in the orthopedic toolbox. In part because there has been a substantial amount of negative publicity about off label use of orthopedic devices, the Scoliosis Research Society (SRS) and the Pediatric Orthopaedic Society of North America (POSNA) are preparing a policy statement: the ethical use of off label devices is authorized by the FDA and has been part of American medicine for many years.”

“A significant amount of medications and medication dosages have been used in an off label fashion for children because there are no available pediatric studies to validate their use and dosages. The American Academy of Pediatrics (AAP) published a formal statement on this several years ago to reassure pediatricians that ethical off label use is perfectly acceptable and beneficial in many ways. We orthopedists have been in discussion with the AAP about revising this to include all pediatric devices and to spell out the details about off label use.”

Orthopedists are creative, talented tinkerers whose experience and knowledge of nuances can save the day if a perfect solution is not readily available. Dr. Campbell: “If the orthopedist doesn’t have a clear choice for an FDA approved device, and the needs of the patient are such that a device must be used in a different way or a different size, then off label use is absolutely ethical and permissible. Take a situation where you have an unusual fracture and no appropriate fixation device. In that case you may take something meant for another purpose, if it makes biomechanical sense. We have all cut off one end of a device and then used it. I don’t have devices small enough for kids, but I can jerry rig them very well. Also, there are a lot of devices that are approved with limited indications. I’ve been told that growing rods for the treatment of scoliosis is an off label use. Yet this treatment method has been around since the 1980’s and is considered a standard of care…despite not having the FDA stamp of approval. In the end, practicality wins. If using a device off label is the best clinical option for the patient, the device is being used ethically and there is a lot of literature on its off label use, then this is a reasonable way to proceed.”