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J Oncol Pract. 2005 May; 1(1): 12–14.
PMCID: PMC2793551

Centers for Medicare & Medicaid Services: Off-Label Use of Colorectal Cancer Drugs Allowed in Select Clinical Trials

The Centers for Medicare & Medicaid Services (CMS) announced on January 28, 2005, that a final National Coverage Determination (NCD) for off-label uses of drugs approved for the treatment of colorectal cancer had been reached.1

The decision allows for Medicare coverage in specific clinical trials for off-label use of oxaliplatin (Eloxatin; Sanofi Aventis, New York, NY), irinotecan (Camptosar; Pfizer Oncology, New York, NY ), cetuximab (Erbitux; ImClone Systems Inc, New York, NY ), and bevacizumab (Avastin; Genentech, South San Francisco, CA ). Those selected trials, identified by the CMS, only include trials sponsored by the National Cancer Institute (NCI). (Table 1). Complete details on these trials can be found on the NCI website2 or the CMS website.3

Table 1.
Selected NCI Clinical Trials with CMS Coverage: Brief Overview2

While this decision was welcomed by the clinical trial community, it contained no change in existing directives of Medicare coverage for any off-label uses of these drugs outside of the specific clinical trials identified in the decision memorandum. The complete decision memorandum can be accessed on the CMS website.1

This article presents the background issues that led to the decision, selected comments received by the CMS from ASCO and other professional organizations, the importance of this decision to the practicing physician, and future steps ASCO is considering or undertaking to clarify and expand Medicare coverage for clinical trial participation.


In February 2003, the CMS began an extensive NCD review of the off-label use of colorectal cancer drugs to evaluate when such use was “reasonable and necessary” in the Medicare population. The CMS modified the original NCD review analyses several times to eventually create an NCD draft memo that would establish guidelines for off-label uses of oxaliplatin, irinotecan, bevacizumab, and cetuximab that are not listed as indicated in one or more of the major drug compendia. (See sidebar)

Subsequently, the CMS held multiple meetings with the product manufacturers and consulted with public and private sector cancer experts. Substantive information regarding off-label uses of the drugs was reviewed during this time.

The CMS also met with the NCI to discuss clinical and scientific issues including identifying high-priority clinical questions and ways to facilitate the collection of evidence about the optimal use for these four anticancer agents.

In November 2004, the CMS published the proposed NCD memorandum and solicited public comment on the decision, the NCI trials that it recommended for Medicare coverage, the process involved for selecting future trials for coverage, and the process contractors use to approve off-label use of anticancer drugs. The public comment period ended December 31, 2004.

ASCO and Others Responded

During the initial and subsequent comment period, ASCO took an active role in the various discussions. ASCO issued a clinical guideline in August 2004, which was the only statement from a medical society that was published within the final NCD memo. It stated, “ASCO does not recommend the routine use of adjuvant chemotherapy for medically fit patients with stage II colon cancer. However, ASCO notes that that there are populations of patients with stage II disease that could be considered for adjuvant therapy, including patients with inadequately sampled nodes, T4 lesions, perforation, or poorly differentiated histology.”4

The CMS decision “…is important to patients because it will ensure that the drugs used in these trials will be available to Medicare patients if pharmaceutical companies do not provide them.”

ASCO President David H. Johnson, MD

In all, CMS received a total of 95 letters during the public comment periods, most (58 of 95 letters) from medical oncologists representing private practices, group practices, and cancer centers throughout the United States. Letters were also received from Congressional and state elected officials, as well as from representatives of cancer advocacy groups.

Some of the comments included: “adjuvant therapy provides an unmet need for those patients whose physician has determined the treatment clinically indicated and desirable”; “recent clinical studies report an increased overall survival and improved quality of life with use of oxaliplatin for first-line colorectal cancer therapy”; “a noncoverage determination for oxaliplatin and irinotecan for off-label use in treatment of colorectal cancer would limit patient access to care”; “a noncoverage determination for off-label use would hinder research and discovery of new advances in colorectal chemotherapy;” and “CMS lacks the legal authority to noncover off-label uses of anticancer chemotherapy drugs.”

Once the final NCD memorandum was published, the CMS received an additional 27 comments from national professional associations, national associations of cancer centers, biotechnical and pharmaceutical companies, cancer patient advocacy groups, caregivers, and patients with cancer.

While the majority of responders commended the CMS for the decision to expand patient access to anticancer chemotherapy and for improving the evidentiary basis for coverage through clinical trial enrollment, others stated that the proposal was not an expansion in coverage and should be withdrawn because sponsors often provide the drugs involved in clinical trials free of charge. In general, the responders expressed concerns related to the clinical trial selection and design (restricting coverage only to specific NCI-sponsored trials); the potential unintended consequences of the coverage decision; the perception of restricting contractor discretion; and the choice of issuing an NCD to launch major changes in coverage requirements.

On the issue of clinical trials selected for coverage, many responders stated that the proposed NCD left too many unanswered questions regarding trial selection criteria and design to allow full endorsement; that the nine chosen NCI-sponsored clinical trials are too limited in scope and number; and that covering drugs only for selected NCI-sponsored trials could potentially decrease patient accrual rates to other trials.

Some of the potential unintended consequences of the decision, responders noted, were that beneficiaries who do not meet the requirements of the trial protocol would be unable to enroll and that patients on Medicare may have increased out-of-pocket expenses for participating (especially those who do not carry a Medicare supplemental insurance policy).

In addition, some responders stated that the proposal creates a potential danger of reducing industry support for clinical trials with the result of requiring additional public funding through Medicare, and that a beneficiary who is a potential participant in competing clinical trials may be steered toward the trial in which the drug is provided free of cost, thus creating the potential that clinical trial enrollment will be skewed due to financial considerations.

Next Steps

ASCO is working with the CMS to continue the established “open dialog” that will be of benefit to patients with cancer whose healthcare services are covered by Medicare. In a letter sent immediately following the release of the final NCD memo, ASCO President David H. Johnson, MD, stated that the CMS decision “... is important to patients because it will ensure that the drugs used in these trials will be available to Medicare patients if pharmaceutical companies do not provide them.” Dr. Johnson also expressed that ASCO “look(s) forward to discussions with CMS about other clinical trials that should be granted similar coverage. These other trials include NCI trials in other diseases and involving other drugs; trials sponsored by industry; and trials involving rare or ‘orphan' cancers where there is less incentive to study new uses for marketed drugs.”

Dr. Johnson also stated that “ASCO envision(s) an ongoing dialogue and partnership with CMS and the patient advocate community to make certain that our patients continue to benefit from our nation's investment in clinical cancer research.”

“ASCO envision(s) an ongoing dialogue and partnership with CMS and the patient advocate community to make certain that our patients continue to benefit from our nation's investment in clinical cancer research.”

ASCO President David H. Johnson, MD

In a statement submitted by Dr. Johnson during the January 2005 President's Cancer Panel meeting held at Memorial Sloan-Kettering Cancer Center, he remarked that, “ASCO continues to work with our members and Medicare officials to ensure thorough and consistent implementation of Medicare clinical trials coverage. ASCO has determined that, although Medicare policy and related state statutes remove or at least reduce the financial barrier to clinical trials participation, they do not necessarily encourage participation.”

Based on recent communications from Dr. Johnson and others within the cancer community to the CMS, the release of the NCD memo is just the first step in a long process to obtain Medicare coverage for off-label uses of anticancer agents in clinical trials. To date, no changes have been made in existing directives of Medicare coverage for any off-label use of these agents beyond the specified clinical trials. While it is unknown what the long-range ramifications of this memo will be, practicing physicians will be able to encourage their patients to enroll in the specified clinical trials without fear of negative coverage decisions by Medicare contractors.

Medicare Off-Label Coverage Policy and Drug Compendia5

Off-label use of drugs in anticancer chemotherapeutic regimens MUST be covered by Medicare if they are supported by a citation in at least one of the following compendia: American Hospital Formulary Service Drug Information, American Medical Association Drug Evaluations,* United States Pharmacopoeia (USP) Drug Information.*

Off-label use of a drug in an anticancer chemotherapeutic regimen MUST be covered by Medicare if the use is supported by peer-reviewed articles published in certain journals (outlined in the Medicare Benefit Policy manual).

If an off-label use of a cancer drug is NOT in the compendia or the specified journals, Medicare carriers have the discretion to cover the use under their general authority to cover off-label uses that they determine are medically accepted.

An in-depth article outlining compendia issues will appear in a future edition of JOP..


*The AMA publication merged with the USP publication in 1996 and now appears only under the latter title.


1. The Centers for Medicare & Medicaid Services: Decision Memo for Anticancer Chemotherapy for Colorectal Cancer (CAG-00179N).
2. National Cancer Institute: Clinical Trials.
3. The Centers for Medicare & Medicaid Services: Medicare Coverage—What's New.
4. Benson AB 3rd, Schrag D, Somerfield MR, et al: American Society of Clinical Oncology Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer. J Clin Oncol 22:3408-3419, 2004. [PubMed]
5. American Society of Clinical Oncology: Practical Tips for the Practicing Oncologist: 3rd Edition, Alexandria, VA, American Society of Clinical Oncology, 2004, 33

Articles from Journal of Oncology Practice are provided here courtesy of American Society of Clinical Oncology