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June 2006

Going Beyond an Approved Use: When Off-Label Is On Target
By Miriam Karmel, Contributing Writer


Ophthalmologists, like most physicians, often treat their patients with medicines that were originally tested and approved for other patients with other diseases. How safe, legal and effective is this practice?

Last fall, after attending the Academy’s Annual Meeting, Lee M. Jampol, MD, reported on Medscape that the retina community was polarized over the use of bevacizumab (Avastin) for treating age-related macular degeneration. Some physicians were using the drug often and reporting good anecdotal results. Other physicians were using it cautiously as an appealing salvage therapy. And a third group refused to use it at all.

Flash forward to a recent conversation in which Dr. Jampol described a shift in allegiances. “The camp using Avastin for many patients and many things has grown enormously since the Academy Meeting,” he said, while the second camp has shrunk. And that third group? It no longer exists, he said. Dr. Jampol described a sea change that was so swift and profound that colleagues are calling it “Avastin mania.” He said that the anti-VEGF drug “is being used because it looks so promising. And it’s being used widely.”

It’s also being used off-label.

Unapproved But Not Uncommon

Because Avastin has engendered such frenzy, with its use swiftly spreading by word of mouth around the globe, it shines a spotlight on a practice that is not uncommon in ophthalmology, or, for that matter, in medicine generally: prescribing a drug for an indication that has not been specifically approved in the product labeling by the FDA. Any unapproved use is described as “off-label.”

Avastin mania also illustrates how desperation to contain blinding disease can shift the risk-benefit calculation in favor of less-proven treatments. And it highlights the ingenuity of ophthalmologists who, in this case, took a drug approved for the treatment of colorectal cancer and injected it into the eye.

Off-label is off and running. “Off-label use has always been widespread in ophthalmology,” Dr. Jampol said. Because few drugs are specifically FDA-approved for the eye, ophthalmologists, particularly vitreoretinal surgeons, commonly inject a number of off-label gases, antibiotics, corticosteroids and anti-inflammatory agents into the eye. “Virtually nothing has been FDA-approved for injection into the vitreous,” he said. “But this has been going on for 30 years.”

The list of off-label treatments is long. Ophthalmologists use intravitreal triamcinolone acetonide (Kenalog), labeled for intramuscular use, to treat AMD, diabetic macular edema and retinal vein occlusion. They use steroid drops post-LASIK and nonsteroidal anti-inflammatory drugs, approved for postoperative inflammation, to relieve pain from viral conjunctivitis or to reduce swelling in the posterior segment due to cystoid macular edema. Glaucoma surgeons use 5-FU and mitomycin C (MMC) for glaucoma surgery, while comprehensive ophthalmologists use it to prevent the recurrence of pterygia following excision.

“We use glue on the cornea. That’s not an FDA-approved use of that glue. But we do it anyway,” said Frederick W. Fraunfelder, MD, who maintains a national eye drug side effects registry that was started in 1976. “So off-label use is very common,” he said. “Using things off-label is sometimes the standard of care.” But, he added, “You just have to make sure you’re doing what the standard of care dictates.”

Standard of Care: Yes, but Whose?

Why should standard of care matter? Because it’s what patients deserve. And, not coincidentally, because off-label applications of drugs increase the potential for liability. An article by the Ophthalmic Mutual Insurance Company (OMIC) on medicolegal risk states, “An ophthalmologist may face increased liability for off-label uses if a reasonable number of similar specialists or subspecialists are not using the same new treatment.”1

OMIC advises physicians to consider whether off-label use poses significantly increased risks to the patient, and then to consider whether the drug’s use can be expected to bring good results without a higher complication rate. “If it presents no more risk to the patient than that of daily living, proceed with its use,” OMIC advises.

Indeed, according to OMIC risk manager Anne M. Menke, RN, PhD, “OMIC acknowledges that off-label use is a legal, common and necessary part of the practice of medicine.”

Peer perspective. Physicians should question their peers to see if they would use the therapy in question. OMIC says, “Ask yourself if at least a reasonable number of physicians in your specialty are using the treatment; that is, have peer-reviewed articles been published supporting the use of the new treatment and is the treatment being used by a reasonable number of other practitioners with the same level of training as you?”1

Doctors who want to proceed should have the patient sign a consent form. A number of off-label consent forms are posted on OMIC’s Web site (, including forms for Avastin; MMC when used in glaucoma and refractive surgery; and off-label PRK.

When glaucoma specialist Dale K. Heuer, MD, uses either MMC or 5-FU, he usually tells patients that he’s using a drug off-label. He explains that these are drugs approved by the FDA for cancer, not for the eye. Then he explains that glaucoma experts use these drugs almost routinely because they enhance the surgery’s success rate by inhibiting the scarring process. Then he documents in the written chart that this conversation took place.

Community consensus. But Dr. Heuer acknowledged that he is “not as compulsive” about explaining the off-label use of antimetabolites as he was early on, before they were embraced by the ophthalmic community. Today, he said, “Their use is so clearly the standard of care that it is no longer substantially different from a subconjunctival antibiotic or corticosteroid injection after intraocular surgery, since use of either of those latter medications is also probably off-label.”

Listen to Reason

Dr. Jampol’s decision to use Avastin followed a typical off-label course. Prior to the Annual Meeting, neither he nor his colleagues at Northwestern University had used Avastin. “Now it’s being used daily,” he said, explaining that his conversion occurred after listening to presentations, reading journals and talking to colleagues. “Each person,” he said, “makes a reasonable decision.”

Michael S. Ip, MD, agrees. “I think there’s nothing wrong with off-label use, per se. As long as you feel that you’re doing the best thing for your patient, I think that it’s acceptable,” he said. “You’re going to be more comfortable if it’s a community norm. You’re safer if people in the community are using it as well.” Dr. Ip added that it helps if the published literature shows some evidence of a drug’s safety and efficacy.

It seems effective, we hope it’s safe. Safety, though, is hard to prove outside carefully conducted studies. “My concern is things get so much good press for efficacy, that we lose sight of concern for the safety,” said Dr. Heuer. “We as physicians tend to run to the effectiveness because we’re so desperate to treat our patients. But sometimes the safety is harder to tease out because you need time and larger studies. So unless the alternative is so dismal, we do need randomized long-term studies.”

Currently, the intravitreal injection of triamcinolone is the focus of two randomized clinical trials, including the Standard Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE) study. Dr. Ip, who coheads the study, said that SCORE should address safety concerns. “We have been using intravitreal injections of triamcinolone without any indication of its efficacy and safety for years. The SCORE study was undertaken to provide us with information on the long-term safety and efficacy of intravitreal triamcinolone injection for retinal vein occlusion. However, this study is looking at a new formulation of triamcinolone, the active drug in Kenalog, and therefore the study could potentially find an FDA label for triamcinolone.”

You want data? Show me the money. In the meantime, as Dr. Heuer noted, off-label use without data from randomized clinical trials happens all the time. “In ophthalmology, so many of the medications we use come from other parts of medicine. And they’re never tested because of the rigor it would take and the small numbers.” Only one or two glaucoma drugs have an indication for children, Dr. Heuer said. “Because the numbers of cases are so small, and the costs of study would be so high, ophthalmologists basically have to wing it.”

When Doctors Grow Wings

Winging it, thankfully, is not against the law. “Once approved for any use, a drug may be prescribed by individual physicians for any indication without violating federal law,” Paul P. Lee, MD, JD, writes in Ophthalmology.2 In fact, noted Dr. Lee, the FDA does not concern itself with what it considers “the practice of medicine.”

The FDA’s Wiley A. Chambers, MD, concurs. “If you believe, on the evidence you have available to you, it’s in the patient’s best interest, that’s the practice of medicine. We don’t regulate the practice of medicine. We regulate interstate commerce.”

Say, however, that you’re not completely certain that an off-label drug is in the patient’s best interest, but you’re intrigued enough to want to test its effect. “That’s a study,” Dr. Chambers said. In that case, you’re expected to file an investigational new drug application (IND) to conduct your study. Among the reasons for filing an IND to study a new application of a drug in humans is a significant dose change or different route of administration.

Go ahead, ask. One question often put to Dr. Chambers is why a particular product is not approved. “The answer most of the time is that nobody ever asked us,” he said. “We can’t approve things that people don’t ask us to approve.”

Yet the approval process requires studies, and there may be disincentives to launching large, expensive trials. “One of the problems we have as ophthalmologists is the market for the things we’re using is so small that nobody is going to do the studies and make them a labeled use,” said Dr. Heuer. The pediatric glaucoma market, he noted, is a prime example. The same applies to mitomycin C and 5-FU, which he described as “high-profile, not-approved uses of approved drugs.” While almost every trabeculectomy is done with one of those two drugs as an adjunct, he said it’s not likely that anybody will invest in a safety study, particularly for off-patent drugs.

Calling Uncle Sam. Consider the case of Avastin, which eventually will compete with Lucentis, a promising treatment still under FDA review. Ideally, there would be a study comparing the two, but Genentech, maker of both drugs, announced in March that it has no plans to test Avastin for treatment of ophthalmic diseases.

Nevertheless, Philip J. Rosenfeld, MD, PhD, associate professor of ophthalmology, Bascom Palmer Eye Institute, predicts that a study will happen, and hopes that the NEI will step up to the plate. “This is the role of government,” he said. “There are no other organizations like the NEI and the NIH in the world. The whole world is looking toward us to study this drug in a comprehensive, large, prospective, randomized trial. Meanwhile, smaller prospective studies are being planned or are under way.”

But patients can’t always wait. At the end of the day, in the absence of clinical trials and the FDA’s seal of approval, doctors find themselves, as Dr. Heuer noted, winging it. Sometimes, he said, the patient’s condition is so devastating and the doctor and patient so desperate, and the results, at first blush, so dramatic, “that the physician and patient figure the risk-benefit ratio favors going out into unexplored territory.”

“It’s always nice to have controlled trials,” said Dr. Rosenfeld, who was the first ophthalmologist to use Avastin in the eye. “Sometimes we have to practice medicine without knowing all of the facts. Above all, we have to think of our patients first. After an open, frank discussion about all the potential risks, as well as the potential benefits, we reach agrement with them on how best to proceed,” he said. “Doctors need to know that there is nothing inherently wrong with using drugs off-label. It’s how they’re used that matters.”


1 E. R. Craven, MD, and E. C. Moran, JD, OMIC’s Digest, Winter 1996,
2 Ophthalmology 1991;98:1071–1074.

From a Twinkle in Your Eye

Baby steps. That’s how it happens. Using an approved drug for an unapproved purpose happens step-by-step. Take the case of Avastin.

“Avastin was not used in a vacuum,” said Dr. Rosenfeld, who was the first physician to inject into the eye this full-length antibody approved as an intravenous treatment for colorectal cancer. Dr. Rosenfeld described his decision to try Avastin intravitreally as “a natural progression,” that followed from his experience with both systemic Avastin and intravitreal Lucentis (a similar drug, still awaiting FDA approval for treatment of AMD).

I Think, Therefore I Treat. A sequence of rational conclusions paved the way. “Both Avastin and Lucentis are derived from the same murine monoclonal antibody,” he explained. “There were a lot of data to support the idea that Avastin would have the same biological activity as Lucentis, and there was nothing in the solution of Avastin that was thought to be toxic to the eye, and Lucentis had already displayed impressive clinical efficacy.”

There Were Precedents. Before Avastin and Lucentis, doctors were treating a variety of retinal vascular conditions with intravitreal Kenalog (triamcinolone acetonide), which was packaged for intramuscular use. “Kenalog was the ‘Avastin’ of three years ago,” said Dr. Ip. “Kenalog was one of the early widespread off-label uses through intravitreal injection.” And, like Avastin, Kenalog wasn’t used in a vacuum, according to Dr. Ip, who described the cascade of events that leads to the eventual off-label use of a drug.

There Were Pioneers. “Initially, the use of intravitreal Kenalog was a radical departure from what we consider community norms,” Dr. Ip said. “We were always taught never to inject Kenalog into the eye.” But at the time Kenalog was being popularized in the United States, ophthalmologists already were treating CMV retinitis with intravitreal injections of ganciclovir and foscarnet. Even that seemed aggressive at the time, but the benefits appeared to outweigh the risks, he said.

So by the time the idea of using Kenalog in the eye arose, ophthalmologists had adjusted to the notion of intravitreal injections. Similarly, ophthalmologists were more readily prepared to inject an anti-VEGF aptamer (Macugen) into the eye because of the earlier Kenalog experience. Having done that, “It doesn’t seem much of a stretch to inject Avastin into the eye,” Dr. Ip said.

"On-Guards" for Off-Labels

OMIC recognizes the value of off-label prescribing and yet advises Eye M.D.s to plan protection for themselves as well as their patients:

  • Familiarize yourself with the published literature and the experience of colleagues.
  • Be reasonably confident that patients would benefit from the drug.
  • Discuss all options with patients, and be clear if your recommendation is an off-label use.
  • Heed the drug’s history of adverse events, and advise and monitor patients accordingly.
  • Document the decision-making process and the informed-consent discussion that led to using a drug off-label.


Wiley A. Chambers, MD Deputy division director for anti-infective and ophthalmology products, FDA.

Frederick (Rick) W. Fraunfelder, MD Assistant professor of ophthalmology, Oregon Health & Science University, Portland. Financial interests: Has consulted with most major drug companies in the area of pre-marketing development.

Dale K. Heuer, MD Professor and chairman of ophthalmology, Medical College of Wisconsin, Milwaukee. Financial interests: Receives speaker honoraria, ad hoc consulting fees, and/or contract research from Alcon, Merck and Pfizer.

Michael S. Ip, MD Associate professor of ophthalmology, University of Wisconsin, Madison. Financial interests: Member of Genentech advisory board.

Lee M. Jampol, MD Professor and chairman of ophthalmology, Northwestern University. Financial interests: Has been a consultant to Novartis, QLT, Bausch & Lomb, Eyetech/Pfizer, Genentech and Medscape.

Anne M. Menke, RN, PhD Risk manager, Ophthalmic Mutual Insurance Company, San Francisco.

Philip J. Rosenfeld, MD, PhD Associate professor of ophthalmology, Bascom Palmer Eye Institute. Financial interests: No equity interest in any company; receives clinical research funds from Genentech, Eyetech and Alcon; member of scientific advisory boards for Genentech, Novartis and Allergan; received past funding from Novartis and QLT.