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The practice of medicine in America is replete with treatments administered for purposes beyond the often narrow indications that originally earned their approval from the Food and Drug Administration. In fact, the typical ophthalmologist’s office would grind to a halt if all the antibiotics and anti-inflammatories being used off-label were removed from the shelves. Just as in pediatric practice, where most prescribed medications have not been rigorously tested on children, the lion’s share of pharmaceuticals used in ophthalmology has not undergone FDA-approval studies for each and every one of their ophthalmic uses.
Regulators ride a white horse. The FDA, however, has stepped up its efforts to ensure that prescription-drug advertising and promotion to physicians and consumers are truthful, balanced and not misleading. Although no one would argue with those goals, some ophthalmologists worry that the increased scrutiny of communications between pharmaceutical representatives and physicians is having a chilling effect on the exchange of important drug information.
This is especially true for medications being used off-label, because appearing to promote the use of one of these drugs for an unapproved indication is a reportable violation of FDA regulations. William B. Trattler, MD, director of cornea at a private practice in Miami, Fla., is concerned that the FDA’s efforts, though laudable, will stymie innovation.
Consumers ride a Google search. In the midst of these developments, patients have become more informed consumers. “There is an increasing demand and expectation for full disclosure, and that is certainly something that I stress,” said George A. Williams, MD, professor and chairman of ophthalmology at Oakland University in Rochester, Mich. “Patients have a right to know whether the medication being prescribed is on-label or off-label and its FDA status, not only of the drug itself but also of that particular indication.” Dr. Williams added that because a medication’s status can have significant reimbursement implications, “patients need to know that going in.”
Avastin, an Example
The use of bevacizumab (Avastin) for an increasing number of ocular conditions has brought the practice of off-label prescribing to the forefront in recent years. The drug’s apparent success in treating a range of neovascular ocular diseases is a testimony to the value of a cooperative—if necessarily arm’s length—relationship between ophthalmologists and pharmaceutical companies.
Getting drugs to patients. “Organized ophthalmology, and the Academy in particular, have been very forceful advocates for expanding the indications for Avastin wherever we believed the data warranted it and the use was clinically appropriate,” said Dr. Williams, who is a member of the Academy’s board of trustees. “The Academy sent letters of support for Avastin, initially for neovascular AMD and subsequently for diabetic macular edema, retinal vein occlusion and a host of less common causes of choroidal neovascularization.”
Getting reimbursement from insurers. Dr. Williams noted that reimbursement logjams over the off-label use of Avastin have lessened in recent years. “Carriers now understand why we are using it, and they have learned that it is cheaper for them to cover Avastin for some of the off-label indications than it is to cover other more expensive drugs. But we have some other off-label drugs where we sometimes still encounter resistance about payment,” Dr. Williams said. “And the fact that off-label drugs typically do not have an appropriate J code for that indication usually means that electronic billing doesn’t work. So those claims have to be filed by hand, and that takes additional time.”
Getting drugs ready for use. Another “hassle factor” involved in prescribing off-label medications is that physicians are often responsible for preparing the drug or for obtaining the drug in a ready-to-use format. “In the case of Avastin, that typically means going to a compounding pharmacy,” Dr. Williams said, “or, in the case of intravitreal antibiotics, compounding the drug themselves.”
Getting everyone past the courthouse. What about liability concerns with the use of off-label drugs? Dr. Williams said he is not aware of any significant problems from a malpractice perspective related to the use of off-label medications, with the possible exception of patients who did not have appropriate informed consent. “The patient has to be an active participant in the discussion and in the decision-making process. Many patients will say, ‘I want you to do whatever you think is best,’ and at the end of the day, at some level, that is what they are paying us to do—to make our best clinical judgment of what is best for that individual. But I think the more information patients have, the better that decision-making process becomes. I try to make it clear to patients what their problem is and give them a clear understanding of their disease. Then I explain that no specific drug has been approved for their condition and that this is the best drug we have to treat their problem. Most people are certainly going to accept that. Where it gets a little more complex is when you have to consider both approved and off-label treatments for the same situation.” Dr. Williams added that these discussions with patients should always be well-documented in the record.
Last year the FDA launched its “Bad Ad” initiative, a professional outreach program aimed at involving health care professionals to stem the tide of false or misleading drug advertising and promotion. Administered by the agency’s Division of Drug Marketing, Advertising and Communications (DDMAC), the program addresses a broad range of drug advertising and promotion. DDMAC has the power to regulate TV and radio advertisements, presentations by pharmaceutical sales representatives, speaker program presentations and all written or printed prescription drug promotional materials.
The Bad Ad program asks health care providers to report violations to the agency, anonymously, if desired. According to the FDA, the most common violations involve omitting or downplaying the risks of a medication, overstating the effectiveness of a drug, promoting off-label uses of pharmaceuticals and making misleading drug comparisons.
Unintended consequences. Directly or indirectly, the FDA’s stepped-up, get-serious approach to misleading prescription drug advertising and inappropriate drug promotion has everyone sitting up and taking notice. Dr. Trattler is concerned that the FDA’s recent push to clamp down on discussions of off-label uses of medications between physicians and pharmaceutical representatives will stifle research and ultimately deny patients access to needed therapies. Next-generation antibiotics are a particular concern. “Pharmaceutical representatives are not allowed to mention or promote the off-label uses of drugs,” Dr. Trattler said. “Because of this, certain pharmaceutical companies have recently decided to no longer have their reps promote the latest generation of topical antibiotics because these medications are so often used off-label.” Drug manufacturers are concerned that a sales rep might inadvertently discuss an off-label use, putting the company at risk of being fined or sanctioned by the FDA.
No more freebies and maybe less research? Dr. Trattler added that some pharmaceutical companies have also stopped distributing samples of medications that are commonly used off-label. He also worries that companies will have very little incentive to develop the next generation of topical antibiotics. With growing antibiotic resistance, ophthalmologists and their patients might then be left without new antibiotics to take over when the current generation loses its effectiveness. “An important consequence of pharmaceutical companies not being able to discuss off-label uses of their medications is that, to a great extent, these companies have stopped funding research for off-label uses,” Dr. Trattler noted. “With a topical nonsteroidal drop, for example, the question might arise—‘How effective is this topical NSAID for preventing cystoid macular edema?’ But the reality is that because the pharmaceutical company can’t discuss with physicians whether or not the drug works, it no longer has the interest to support the funding required to pursue it. That’s really going to hurt our patients because we won’t learn about alternative uses and medication regimens that are off-label.”
Dr. Trattler expressed his concern that ophthalmologists will, over time, find themselves with fewer choices of medications, fewer new medications being developed and an insufficient understanding of how to use the medications they have in ways other than for their approved indications.
Dr. Trattler is a consultant and/or has received research support for/from Alcon, Allergan, Bausch + Lomb, Inspire and Ista. Dr. Williams reports no financial interests.