Like most novel treatments in medicine, it took an index patient for pediatric otolaryngologist Michael Rutter, MD, to realize the off-label potential of Ciprodex to treat granulation tissue in the airway.
In this case, the patient was a young woman in the mid-2000s who was seriously injured after a drunk driver T-boned her car and ejected her through the windshield. She was intubated at the hospital, and metal stents were put in her airway. But the metal reacted with her trachea, and major granulation issues eventually sent her to Dr. Rutter, who is clinical director of the aerodigestive program at Cincinnati Children’s Hospital Medical Center in Ohio.
Dr. Rutter’s team removed the metal from her trachea “wire by wire” and reconstructed it. But every few days post-surgery, she would return “with basically life-threatening granulation in her airway,” Dr. Rutter said. “I’d clean it all out, I’d say I’ll see you in a week, and for about a month this happened. She actually looked like she was at risk of dying.”
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Then, the mother of invention kicked in. “More out of desperation than anything, I thought, ‘How do we stop the granulation tissue?’ I told her to start putting Ciprodex drops down her trach tube, and do it just like you would with an ear,” said Dr. Rutter. “We were doing three drops three times a day. And she came back a week later, and her trachea basically looked normal. And a few weeks later, we took her trach out. She’s gone on to get married, she’s had kids, she’s had a family, and literally, it saved her life.”
Welcome to the world of off-label use for otolaryngologists. In a field as relatively small as otolaryngology, figuring out treatment options, procedures, and equipment that can be used effectively isn’t just limited to the world of FDA approval. Examples include dripping Ciprodex into the airway; shooting Botox into salivary glands to reduce saliva production; injecting Avastin into the nose for patients with hemorrhagic telangiectasia; watering down budesonide as a rinse for chronic sinusitis; prescribing proton pump inhibitors for laryngeal reflux; and designing and hand-carving stents for laryngeal stenosis using silastic and other materials.
“If the only thing we did was stick to on-label, FDA-approved uses, there would be a great many patients whom we couldn’t treat, and there would be no advances in the field that led to additional on-label uses,” said Robert Sataloff, MD, DMA, professor and chairman of the department of otolaryngology–head and neck surgery at Drexel University College of Medicine in Philadelphia. “Practically everything that is on label started off as off label. People had to have a problem that needed a solution, and an idea of how to solve that problem, and then usually a pilot study, which sometimes was formal, but sometimes meant trying it and seeing how the patients did.”
Off Label Doesn’t Mean No Proof
While off-label uses may not have FDA approval or the gold standard of randomized controlled trials, otolaryngologists are careful to ensure there is clinical experience and basic science to balance the risk-reward.
Take the use of Botox to reduce saliva production. While its primary indication is as a cosmetic application, some physicians use it to treat sialorrhea, a condition in which people cannot control saliva production and often drool uncontrollably. Botox binds acetylcholine and prevents its release at the neuromuscular junction, which provides significant relief, helps with oral hygiene, and can make life easier on caregivers. It should, however, be administered using ultrasound guidance, as it weakens muscles and needs to be injected directly into the salivary gland.
If the only thing we did was stick to on-label, FDA-approved uses, there would be a great many patients whom we couldn’t treat, and there would be no advances in the field that led to additional on-label uses. —Robert Sataloff, MD
“There has to be some level of evidence,” said M. Boyd Gillespie, MD, MSc, professor and chair of the department of otolaryngology–head and neck surgery at the University of Tennessee-Memphis. “You have to have a certain body of lower-level evidence in the literature that shows the effect, [and] you have to have a certain number of experts in the field agreeing that a procedure is acceptable. If I was in private practice, I would look to some of the academic leaders and some of the research leaders to provide at least a base of evidence that I could confidently act upon. In academia, often we are a little bit more on the leading edge, and if we’re going to be doing off-label things, we really should have it be part of a research protocol.”
But Dr. Gillespie said that otolaryngologists are used to dealing with lower levels of evidence, and then applying common sense. “So, the reason I can use Botox on salivary glands and know that it works is because I know the effect size is profound,” he added. “I will inject a salivary gland, and within three to four days, the drooling of the patient ceases. It’s objective evidence that you can witness. Whenever the effect size is objective and large, it makes weaker levels of evidence acceptable.”
Kara Detwiller, MD, adjunct assistant professor of otolaryngology–head and neck surgery in the division of rhinology and sinus surgery at Oregon Health & Science University in Portland, said safety is a major factor in off-label use. She points to the low-risk and common approach of adding saltwater to the topical steroid budesonide to create a rinse suitable for patients dealing with chronic rhinosinusitis.
“With a patient you can say, ‘Look, we’ve tried standard-of-care types of things, and that hasn’t worked,” Dr. Detwiller said. “So, the next option is starting to be some of these less-commonly used interventions. And some of them I don’t worry too much about … I feel like the side-effect profile from that is pretty low. I’m not worried. We can have a discussion about risks and benefits, but the risks are really pretty small.”
Dr. Sataloff said some off-label procedures are considered safe because they are already approved in other countries, providing otolaryngologists comfort that their use is not unprecedented. He adds that another pathway for off-label treatments is to extrapolate them from medications that have similar on-label uses. “People are always more comfortable using something off label that has a medically approved use for something else on label,” he added. “For example, very few people are uncomfortable using proton pump inhibitors for laryngeal reflux knowing they are approved for gastroesophageal reflux.”
But, to figure that out, otolaryngologists often must make an informed leap of faith. “There is still a place for art amongst the science,” Dr. Rutter said. “There’s still a place for clinical judgment.”
Cost Sometimes a Factor in Approval
But, once that leap is made, success is often found. Ciprodex works to treat granulation. Botox effectively treats salivary conditions. Yet, neither treatment has been put on label.
Why not? Money, of course. “Botox is a relatively expensive drug,” Dr. Gillespie said. “A vial of it can run between $300 and $500. … The company makes so much money from the cosmetic use, there’s very little motivation to try to get it approved for medical use.”
Dr. Gillespie said that the size of the specialty of otolaryngology makes it difficult for pharmaceutical companies to justify spending time and money for federal approvals. “We deal with a variety of problems that are somewhat uncommon,” he said. “Whenever you’re dealing with diseases where there’s not [a] large [patient population], the evidence base tends to be weaker. If you’re treating hypertension or diabetes or COPD or heart disease, there are trials with thousands of people comparing medications in randomized, blinded fashion. However, when you’re dealing with salivary gland disorders where only one in 20,000 people [are affected] … it’s different.”
The cost and time of on-label usage needs to make sense to a company’s bottom line—and that is often even more true for medical devices.
Dr. Rutter said he tends to use a laparoscopic needle driver when inserting stiches in the larynx, even though the device is not approved for that. “If I’ve got a pouch in the trachea and I want to marsupialize it, there’s a forceps designed for laparoscopic work that works brilliantly for that particular problem,” he said. “Again, it’s a problem-solving exercise, and while it wasn’t designed for that particular use, it might work extremely well for doing it. And, if you’re dealing with the things that are a little unusual, no one’s going to make a tool just for you for something that is comparably rare.”
You have to have a certain body of lower-level evidence in the literature that shows the effect, [and] you have to have a certain number of experts in the field agreeing that a procedure is acceptable. —M. Boyd Gillespie, MD, MSc
Dr. Sataloff did, actually. He holds a patent on a thyroplasty implant that could help patients with glottic insufficiency or vocal fold paralysis. But the process to get it FDA approved could cost in the ballpark of $1 million. “I can talk about this because I make no money from it, because I doubt it will ever be manufactured,” he said. “It’s a better device than anything that we have available, but … the fact that it’s a better device is irrelevant. It’s unaffordable to get it approved because companies will never sell enough of them to get their money back.”
Reimbursement
A further complication with off-label usage is physician compensation.
Dr. Detwiller said that insurance companies will often point to conflicting research when looking to deny an off-label use. She has run into that when it came to using Avastin to treat hereditary hemorrhagic telangiectasia (HHT). “It’s getting harder to do because I think there was a study that showed no benefit with it. Now, the insurance companies say, ‘Well, there’s this one study that shows no benefit.’ And the medication is so expensive, it’s understandable. We only have so many healthcare dollars to go around, you want to give the patient the treatment that is most efficacious. We do run into that. Apart from writing letters back saying, ‘Well, that study shows one thing, but there are other studies that show something else,’ there’s not a lot we could do.”
In the case of HHT, Dr. Detwiller said the medication is so expensive that when insurance companies won’t pay, she would recommend other treatments. When an insurance company won’t agree to cover using budesonide to treat chronic rhinosinusitis, Dr. Detwiller’s workaround is to use compounding pharmacies to make it at a reasonable cost.
Dr. Gillespie said his nurses sometimes spend an hour of their time fighting with insurance companies over the use of Botox for off-label clinical purposes. Sometimes, they’re not reimbursed.
“There is a cost-benefit analysis,” he said. “I think physicians routinely do things realizing that they’re not going to be reimbursed, but their hope, at the end of the day, is that they don’t lose money. As long as you’re not losing money, you’re still in the game. Once you start losing money repeatedly, then you can’t keep your lights on. You can’t employ your people … if you’re getting repeated denials and losing money repeatedly, you’re actually wrong to continue to offer the service because if you have to close your office, you aren’t serving anyone.”
Dr. Detwiller added that, reimbursable or not, off-label uses will continue as long as otolaryngologists keep hunting for novel ways to help patients. “Ideally, I wish we lived in a world where we had these perfect algorithms for treating disease,” she said. But “you’re going to have patients where you do all of what’s in the guidelines, and you try everything, and they’re not getting better. They’re still having problems, and you do go to these more off-label uses.”
Richard Quinn is a freelance medical writer in New Jersey.
Key Points
- Otolaryngology is a small field, and doesn’t always have the volume of patients or the market for industry to conduct RCTs to obtain FDA approval.
- Physicians are careful to ensure there is clinical experience and basic science to balance the risk–reward of off-label use.
Talking to Patients about Off-Label Use
When it comes to off-label use, Dr. Detwiller thinks informed consent is the best approach. And not just because it’s an ethical issue; it also makes patients more comfortable. “As long as you and the patient have had an informed consent, and you’ve really weighed the potential benefit against the risk at what is happening, it helps,” said Dr. Detwiller.
But talking to patients about a term—“off-label”—that sounds more jarring to them than to physicians can sometimes unnecessarily worry patients.
Dr. Sataloff said he puts patients at ease, in part, by never using a scripted message. “I tailor my discussions to the individual patient. Sometimes that happens with extremely bright, well-educated people. Sometimes that happens with people with no medical knowledge at all, who just went onto the Internet,” he added. “Depending on who they are and what their concerns are, we explain to them what we’re doing, why we’re doing it, what the alternatives are—which, in many cases, are no treatment—and what the risks are associated with no treatment.”
Usually, that does the job.
“There are always people who get it in their head that something is not right, and, no matter what you tell them, you can’t change their mind,” Dr. Sataloff said. “But they are a small minority.”
Dr. Gillespie suggested explaining to patients that the term off label is really what he calls a “bureaucratic decision.”
“That really doesn’t say much about the state of the science, because the FDA will often accept things on label with lower levels of evidence than Level 1 evidence,” he said. “It’s really just that someone’s taken the time to go through the government application process to get the government’s stamp of approval on a particular treatment.
Dr. Gillespie noted that if a patient trusts their otolaryngologist, then they shouldn’t be put off by the lack of a randomized, controlled trial backing that physicians’ recommendation. “There’s never been a randomized, controlled trial on whether a parachute works,” he said. “But we know that if you jump out of a plane without a parachute, things will not go well. And there’s things as equally evident that we do … that almost make a randomized, controlled trial unnecessary.”—RQ