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1.  Whether alternative treatments were tried before considering off-label use

2.  Whether there are published recommendations from specialty societies or in other authoritative-based guidelines

3.  Whether authoritative medical literature supports the off-label use. Such literature must include peer-reviewed publications that demonstrate efficacy. Such studies may not include case reports, opinions, book chapters, or abstracts

4.  Whether there is other evidence of broad scientific support 5.  Whether the use is an accepted standard of medical practice.13

For some off-label drug use such as the use of intravitreal antibiotics for endophthalmitis, the above criteria are easily satisfied. For others, such as intravitreal injection of triamcinolone acetonide as either monotherapy or in combination therapy, the evidence is less compelling. As a result, there are variable coverage policies between Medicare carriers concerning off-label retinal pharmacotherapy. Currently, there is considerable controversy involving the off-label use of anti-VEGF agents such as pegaptanib sodium, ranibizumab, and bevacizumab. All Medicare carriers cover pegaptanib sodium and ranibizumab for the labeled treatment of neovascular age-related macular degeneration. All but one of the Medicare carriers covers bevacizumab for the off-label treatment of neovascular age-related macular degeneration as well. However, the coverage for other off-label uses, such as proliferative diabetic retinopathy, diabetic macular edema, retinal vascular occlusions, and neovascular glaucoma, is variable. This irregular coverage is frustrating to both ophthalmologists and patients since many of these conditions have no approved or consistently effective therapy. Medicare carriers often look to professional organizations such as the American Academy of Ophthalmology for guidance on these coverage issues. The American Academy of Ophthalmology in turn looks to the scientific literature for appropriate evidence to support recommendations for coverage, particularly in situations of unmet medical need. The strong support of the American Academy of Ophthalmology for the use of off-label bevacizumab was instrumental in obtaining Medicare coverage.5

NATIONAL COVERAGE DETERMINATION

CMS can establish a national coverage mandate to all Medicare carriers through an NCD. CMS uses a NCD to determine whether an item or service is “reasonable and necessary.” While there is no statutory or regulatory definition of “reasonable and necessary,” CMS has generally interpreted the term to mean that the item or service should improve health outcomes for Medicare beneficiaries.12 CMS may consider an NCD when:

1.  There are questions about the safety, effectiveness or appropriateness of a therapy, including off-label use of drugs

2.  Local coverage policies are inconsistent

3.  There is wide variation in billing practices not related to variation in clinical need

4.  The health technology represents a substantial clinical advance and is likely to result in significant health benefits if it diffuses more rapidly to all patients for whom it is indicated.

To address the above issues, CMS relies on generally accepted principles of evidence-based medicine.12 For drug coverage, an NCD typically requires strong evidence from clinical trials on safety and efficacy for the indication. Interestingly, FDA approval of the indication is not required for CMS coverage. This is the case for the coverage of photodynamic therapy with verteporfin for the treatment of occult with no classic and minimally classic subfoveal choroidal neovascularization and evidence of recent disease progression.2 This indication is not listed in the verteporfin FDA label. However, this NCD is based on multiple clinical trials, an independent review by CMS of the clinical trial data, and the recommendation of a Medicare Carrier Advisory Committee. Such a process typically takes a year or longer. At the present time, CMS believes there are insufficient data to warrant an NCD for either off-label triamcinolone or bevacizumab (personal communication,

CMS coverage team). CMS therefore has deferred these coverage decisions to the local carriers.

CLINICAL TRIALS

A relatively new mechanism by which CMS may cover off-label drug use is through a clinical trial. To be eligible for coverage, the clinical trial must meet a variety of requirements, including:

1.  The principal purpose of the trial should be to test whether the intervention improves the participant’s health outcome.

2.  The trial should either be well supported by available scientific and medical information, or be intended to clarify or establish the health outcomes of interventions already in common clinical use.

3.  The trial must not duplicate existing studies.

4.  The trial must be appropriately designed and sponsored by a credible organization.

One obvious way to conduct such a trial is through the National Eye Institute and such trials on off-label drug use are in progress and include the Comparison of Age-related macular degeneration Treatment Trials (CATT) and the Diabetic Retinopathy Clinical Research Network.14

Currently, nearly all off-label drug use in ophthalmology is at the discretion of the local Medicare carriers. Usually, coverage will hinge on whether the carrier considers the off-label drug use reasonable and necessary. The Medicare Carrier Manual states that if a medication is determined not to be reasonable and necessary, the carrier excludes the entire charge, including any charges for services that were primarily for the purpose of administering a noncovered medication. This means that for intravitreal injection of a therapeutic agent (CPT code 67028), if the drug is not covered then neither is the injection.

Considering the above aspects of off-label drug coverage, how should ophthalmologists proceed when they believe off-label drug is in a patient’s best interest? For Medicare beneficiaries, ophthalmologists should seek specific guidance from their local Medicare carrier. If the carrier declines coverage, the ophthalmologist may bill the patient for noncovered services associated with the off-label drug use by using an advance beneficiary notice (ABN). The necessary ABN form is available on the CMS website (www.cms.medicare.gov). The use of an ABN requires that the patient be informed about why the proposed treatment is not covered by Medicare and that the ABN form be signed prior to the performance of the service. The ABN form is then submitted to the local Medicare carrier with the bill on form 1500, using either the GA or GY modifier. Physicians should contact their local carrier to determine which modifier is preferred and to confirm how the carrier handles the ABN process. With an appropriate ABN, physicians can bill the patient for the noncovered services. For payers other than Medicare, ophthalmologists must contact the individual payer to determine payment policy for off-label retinal pharmacotherapy. Many payers have established payment policy based on the criteria discussed above.

SUMMARY AND KEY POINTS

With the continued development of new and more effective drugs for retinal disease, off-label drug use will escalate as ophthalmologists attempt to optimize treatment outcomes. This is particularly true for combination therapies in which drugs with different mechanisms of action are combined to improve visual outcomes and minimize complications. This increase in off-label drug use carries the responsibility to establish both safety and efficacy in order to allow off-label drugs to become the standard of care. Our patients deserve nothing less.

REFERENCES

1.Off-label use of non-oncology drugs and biologicals LCD No. L18709 AdminiStar Federal, Inc (February 10, 2005).

2.CMS Manual System. Pub 100-103. Medicare National Coverage Determinations. April 1, 2004. Change request 3191.

3.Feinsod M, Chambers WA. A primer on successfully navigating the waters of the Food and Drug Administration. Ophthalmology 2004;111: 1801–1806.

4.US Food and Drug Administration. Available online at: www.fda.gov.

5.American Academy of Ophthalmology. Available online at: www.aao.org.

6.Patient access to treatments prescribed by their physician. H-120.988. Available online at: www.ama-assn.org.

7.US Food and Drug Administration. Off-label and investigational use of marketed drugs. Biologics and medical devices. Available online at: www. fda.gov/oc/ohrt/irbs/offlabel.html.

8.US Food and Drug Administration. Good reprint practices for the distribution of medical journal articles and medical or scientific reference publications on un-approved new uses of approved drugs and approved or cleared medical devices: draft guidance, Feb 2008. Fed Regist

2008;74(34):9342. Available online at: http://www.fda.gov/oc/op/goodreprint. html.

9.Psaty BM, Ray W. FDA guidance on off-label promotion and the state of literature from sponsors. JAMA 2008;299:1949–1951.

10.Food and Drug Association. Available online at:www.fda.gov/foi/warning_ letters/g6147d.htm.

11.Ophthalmic Mutual Insurance Company. Available online at: www.omic. com.

12.CMS Draft Guidance for NCDSs. Available online at: www.cms.gov; accessed March 9, 2005.

13.Off-label use of non-oncology drugs and biologicals LCD No. L18709 AdminiStar Federal, Inc (February 10, 2005).

14.Diabetic Retinopathy Clinical Research Network. Available online at: www. clinicaltrials.gov.

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