Aprepitant for Chemotherapy-Induced Emesis

In our earlier comments, attached, GSK noted that under our interpretation of the law and our understanding of the FDA approved product labeling, we believe that Medicare Part B coverage would not be appropriate under the law because the product labeling clearly specifies the therapy as adjunctive to other anti-emetic therapies and not a full replacement for an injectible therapy. Never-the-less, we are very aware of how important anti-emetic therapy can be to patients receiving chemotherapy and appreciate the humanity of the decision to extend coverage of aprepitant to patients who have demonstrated unresponsiveness to other anti-emetic regimens.

If the decision to extend Medicare Part B coverage to aprepitant is not reconsidered given current law and aprepitant’s FDA approved product labeling, GSK strongly encourages CMS to implement its decision in such a manner that, at a minimum, requires providers to show documentation that the patient meets both of the conditions contained in the analysis and that the DMERC uses previous Medicare claims for the patient to verify that the conditions of the analysis were, in fact, met.

Again, thank you for the opportunity to comment on this issue. If you have any questions or require additional information, please feel free to contact me.

Attachment

Previous Comment from GSK on this issue: GlaxoSmithKline (GSK) appreciates the opportunity to comment on the National Coverage Analysis (NCA –CAG—00248N) ) to explore whether it would be appropriate for the Medicare program to provide Medicare coverage for aprepitant, trade name Emend. That notice states that CMS would be expected to make a decision regarding coverage in April 2005, with, presumably, implementation somewhat later.

The prescribing information approved by the Food and Drug Administration (FDA) states that aprepitant, “in combination with other anti- emetic agents, is indicated for the prevention of acute and delayed nauseas and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high dose cisplatin.” Unlike some other anti-emetic agents, aprepitant does not have an indication for prevention or treatment of post operative nausea and vomiting. The comments below suggest that there is no data to support a conclusion that aprepitant is a “full replacement” for intravenous therapies to treat chemotherapy induced nausea and vomiting and, thus, CMS should not extend coverage under Part B.

GSK is a multinational drug company, formed in 2001 through the merger of GlaxoWellcome and SmithKline Beecham and has significant experience with anti-emetic therapy. Prior to the merger, Glaxo Wellcome marketed Zofran (ondansetron HCl) and SmithKline Beecham marketed Kytril (gransetron HCl). Since the merger, the combined company markets Zofran, having divested ownership of Kytril. In fact, both legacy companies were actively involved with the drafting and eventual passage of the legislation that first established Medicare coverage for oral anti-emetics. We are hopeful that our involvement with anti-emetic therapies and with the passage of the legislation that allowed select Part B coverage of oral anti- emetics will be helpful to CMS as the agency evaluates potential coverage options for aprepitant.

While GSK continues to support Medicare coverage for all therapies to treat cancer patients that qualify under Medicare policies, we also understand the importance of coverage decisions that are consistent with Medicare statutory and regulatory policies, as well as in the best interest of Medicare patients. Based on our experience with and understanding of the original legislation and our review of clinical data, GSK believes that it would not be appropriate to provide Part B coverage for aprepitant. Instead, GSK believes that, given current law, it would be appropriate to allow for the immediate inclusion of aprepitant under the current Medicare discount card program and for coverage under Part D, when the program is implemented in 2006.

EXECUTIVE SUMMARY

Our rationale is summarized as follows:

1. Aprepitant does not meet the statutory standard as a “full replacement for the anti- emetic therapy which would otherwise be administered intravenously”.

2. There is not sufficient scientific evidence at this time that supports aprepitant’s safety and effectiveness as a full replacement therapy in Medicare patients,

3. CMS can achieve congressional policy goals by extending coverage to aprepitant under Medicare Part D as per the recent Medicare Modernization Act.

OVERVIEW OF MEDICARE COVERAGE FOR ORAL ANTI- EMETICS

Coverage of oral anti-emetics was enacted into law under Section 4557 of the Balanced Budget Act (BBA) of 1997 (Public Law 105-33). More specifically, for services furnished on or after January 1, 1998, the BBA added coverage under Section 1861(s)(2) of the Social Security Act for "an oral drug (which is approved by the Federal Food and Drug Administration) prescribed for use as an acute anti-emetic used as part of an anticancer chemotherapeutic regimen if the drug is administered by a physician (or as prescribed by a physician) (i) for use immediately before, at, or within 48 hours after the time of the administration of the anticancer chemotherapeutic agent; and (ii) as a full replacement for the anti-emetic therapy which would otherwise be administered intravenously.''

The language of that law is specific. It stipulates that coverage would be extended to “an oral drug” in the singular, and does not specify that coverage be extended to an anti-emetic regimen that includes an oral drug. The language also specifies that the newly covered drug be prescribed “as a full replacement for the anti-emetic therapy which would otherwise be administered intravenously.” This language is clear. An oral anti-emetic would not be covered by Medicare if an intravenous anti-emetic therapy must also be administered to the patient to gain the required therapeutic effect.

Further, from our direct experience in working with Congress to craft that language, discussions surrounding the language revolved around replacing intravenous anti-emetic therapy with an oral version of that therapy. Both the intravenous and oral versions of the therapies that were discussed in relation to the BBA language had the same active ingredient. At present, all oral anti-emetics covered by Medicare Part B have the same active ingredient as an intravenous form of the product they replace.

That law was implemented by CMS in Program Memorandum AB-97-26 for intermediaries and carriers. That program memorandum specifically reiterates that the oral anti-emetic must be used as “full therapeutic replacements for intravenous anti-emetics that would have otherwise been administered at the time of the chemotherapy treatment.”

The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (“MMA”) did not amend the oral anti-emetic coverage provisions in BBA but CMS’ implementation of a required demonstration project to extend coverage to selected oral replacement drugs suggests that a careful standard be maintained. Section 641 of MMA requires CMS to implement a replacement drug demonstration program that will cover certain self-injected or oral drugs not normally covered under Medicare Part B. To determine the criteria for defining a "replacement" drug under Section 641, CMS established an inter-agency panel of clinicians and considered public feedback. As a result of these efforts, to be covered as a #8220;replacement” drug under the demonstration, a drug or biological must meet the following criteria:

APREPITANT DOES NOT MEET STATUTORY REQUIREMENTS FOR PART B MEDICARE COVERAGE

Aprepitant is approved by the FDA to be used only in conjunction with other approved drugs, each with an individual mechanism of action. It is not approved by the FDA for use as an individual drug, let alone full replacement for an existing intravenous drug. Neither is aprepitant included as a single agent in major, established anti-emetic guidelines.

The Dosage and Administration section of the prescribing information for aprepitant approved by the FDA states that aprepitant “is given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT3 antagonist.” Further, the product information cites only clinical studies that included aprepitant, dexamethasone, and the full dose (32 mg IV) of ondansetron. Further, the prescribing information states that clinical “studies show that aprepitant augments the anti-emetic activity of the 5HT3 receptor antagonist ondansetron and the corticosteroid dexamethasone.”

Further, there are well established anti-emetic guidelines such as those created by Multinational Association for Supportive Care in Cancer (MASCC), American Society of Clinical Oncology (ASCO), and the National Comprehensive Care Network (NCCN) that clearly do not recommend single agent therapy with aprepitant for prevention of acute chemotherapy-induced nausea and vomiting. Additionally, for moderately emetogenic chemotherapy, aprepitant is not included in the recommendations. 5HT3 antagonists remain as the gold standard antiemetic, which is evident in these recommendations.

Currently, the guidelines recommend the following regimens:

A clinical study evaluating the antiemetic efficacy of aprepitant as a single agent for the prevention of CINV (highly or moderately emetogenic chemotherapy) has not been conducted, and there has been only one study that compared aprepitant + dexamethasone to a 5HT3 antagonist + dexamethasone regimen:

Campos et al (J Clin Oncol 2001;19:1759-1767) conducted a multicenter, double-blind, parallel- group study in 351 cisplatin-naive patients to evaluate the efficacy of aprepitant + dexamethasone vs. a 5HT3 (granisetron) + dexamethasone for prevention of acute (day 1) and delayed (days 2-5) CINV associated with high-dose cisplatin. Merck & Co. funded and conducted this study prior to FDA approval, thus aprepitant is referred to as MK-869. This study utilized higher doses (acute-400mg, delayed-300 mg) of aprepitant than the FDA- approved doses for both acute and delayed phases (125 mg, 80 mg, respectively).

Although granisetron + dexamethasone was not statistically superior to aprepitant + dexamethasone, it “yielded a numerically superior control of acute emesis compared with the groups that received dual therapy with MK-869 [aprepitant] + dexamethasone (57% vs. 46% and 43%)”. Only the 3-drug regimen (granisetron + dex + aprepitant) was statistically superior to granisetron + dexamethasone. Aprepitant- containing regimens were statistically superior to granisetron + dex for the prevention of emesis in the delayed phase (days 2-5). Campose et al concluded that the “combination of the 5HT3 antagonist + dexamethasone was numerically superior to MK-869 [aprepitant] + dexamethasone in reducing acute emesis. Confirming and extending previous findings, the triple combination of a 5HT3 antagonist, MK-869 [aprepitant], and dexamethasone provided the best control of acute emesis.”

Finally we wish to note that there has been some preliminary research, as described in an abstract presented at a recent ASCO meeting that might suggest that aprepitant could have a therapeutic effect when prescribed with an oral 5HT3 agent. That study has not been published in any peer reviewed journal. Neither has this use of aprepitant been incorporated in any compendia or generally accepted guidelines for the treatment of chemotherapy induced nausea and vomiting. If these data are validated by additional, peer reviewed research, it is our view that this product would still not qualify for Part B coverage because the law refers to coverage of oral drug in the singular, and not a multi- product drug regimen.

For all of the above reasons, aprepitant does not meet the requirement of the BBA, which states, as noted above, “ -an oral drug…as a full replacement for the anti-emetic therapy which would otherwise be administered intravenously.” APREPITANT DOES NOT REPLACE AN INTRAVENOUS OR INJECTABLE FORM OF NEUROKININ 1 ANTAGONISTS. As mentioned above, discussions surrounding the crafting of the BBA language revolved around the full replacement of an intravenous formulation of anti-emetic therapy with an oral version of the therapy with the same active ingredient. Aprepitant is the first of its kind neurokinin 1 antagonist (“NK1”) for use as an anti-emetic. There are no intravenous or injectable forms of NK1 anti-emetics approved by the FDA. The Medicare statute requires among other things that Medicare can cover oral anti-emetics "as a full replacement for the anti-emetic therapy which would otherwise be administered intravenously." 42 U.S.C. sec.1395x(s)(2)(T). Aprepitant cannot serve as a "full replacement" because there is no intravenous NK1 that it would replace. All other Medicare covered oral anti-emetics had intravenous precedents of the same drug. That policy gave Medicare patients assurance of the safety and effectiveness of the oral form as a "full replacement." CMS would be contravening its past practice to extend coverage to aprepitant, which has no intravenous formulation.

APREPITANT DOES NOT NEED TO BE COVERED NOW BY MEDICARE UNDER PART B

There are already several replacement drugs covered and available to Medicare beneficiaries. It is not clear if extending coverage for aprepitant in the coming year will significantly improve patient access compared to coverage that will be available under the drug discount program now available and under Part D. It would appear that Medicare can effectively advance patient access by utilizing existing authorities, rather than expending resources in the coverage process.

CONCLUSION

As indicated above, given existing law, aprepitant should not be covered under Medicare Part B because it is not used as a single drug to be a full replacement for an intravenous therapy. GlaxoSmithKline does believe that all appropriate cancer therapies, including supportive care therapies should be available without restriction under the new Medicare Part D benefit. Even if the law as defined in the 1997 BBA was not clear with regard to Part B coverage, it would be duplicative and possibly unnecessary for CMS to proceed with a full coverage analysis and determination now, recognizing that this product should qualify for coverage soon under the new Part D drug coverage benefit. Moreover, when so covered, Medicare may likely realize the cost savings that Congress intended when it created the special authority to cover anti- emetics.

We hope that these comments will be of assistance as CMS continues to evaluate this issue. Please feel free to contact me either by email or telephone with any questions or requests for additional information.

Less

Legal Issues

ASCO understands that questions were raised regarding whether a regimen including aprepitant and other oral anti-emetics would qualify as covered by Medicare under § 1861(s)(2) (T)(ii) of the Social Security Act as a “full replacement” for intravenous anti-emetic therapy. However, the Medicare Benefits Policy Manual (15, §50.5.4) makes clear that “[m]ore than one oral anti-emetic drug may be prescribed and may be covered for concurrent use if needed to fully replace the intravenous drugs that otherwise would be given.” Thus, CMS’s analysis concluding that the terms of the statute are satisfied by the oral combination of aprepitant and other anti-emetics is, in ASCO’s view, correct and completely consistent with both the letter and the spirit of the Medicare law. Having resolved the legal issue, CMS must determine how best to implement coverage consistently with the medical evidence and good clinical practice, reflecting what is “reasonable and necessary” for beneficiaries in cancer treatment.

Clinical Criteria for Determining Usage

What is “Highly Emetogenic Chemotherapy”?

The Food and Drug Administration (FDA) approved aprepitant “in combination with other anti-emetic agents, for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin.” In order to determine which chemotherapy regimens should be covered by Medicare, more information is required as to what should be considered “highly emetogenic” beyond the obvious example of high-dose cisplatin, which is typically used in clinical trials for anti- emetics because it is the anti-cancer drug most likely to induce emesis.

CMS determined that, for this purpose, the best tool would be the classification scale developed by Paul Hesketh, MD. However, this scale is not routinely used or understood by clinical oncologists, and ASCO believes that it would be more efficient to identify “highly emetogenic” chemotherapy by reference to more widely employed measures such as those in the guideline published by ASCO.* That guideline, last revised in 1999, identifies specifically non- cisplatin chemotherapy drugs that qualify for “high emetic risk” and may represent the most comprehensive list of such drugs. ASCO’s revision of its guideline for emesis control is currently underway and may result in some changes to the 1999 list, but the ASCO guideline nevertheless remains the best source for identification of drugs qualifying as “highly emetogenic.”

It is also important to consider that mere listing of individual “highly emetogenic” chemotherapy drugs may not be sufficient since anti-cancer drugs are almost always given in combination, and some combinations may prove “highly emetogenic” even if the drugs would not rise to that level if administered individually. We urge that CMS coverage policy be responsive to the possibility of heightened emetic impact from certain drugs administered in combination, even where such drugs would not trigger coverage when used individually, and, as always, carriers should have the flexibility to recognize newly approved “highly emetogenic” chemotherapy drugs even before they are incorporated into guidelines. The goal here, shared by both ASCO and CMS, is to provide higher quality cancer care for Medicare beneficiaries, and that goal will be best served by a flexible and accommodating policy that recognizes the dynamic nature of anti-cancer chemotherapy treatment standards.

Which Medicare Patients Should Qualify for Coverage?

While ASCO believes that CMS has made an appropriate decision to cover aprepitant under the Medicare statute generally and, with adjustments, supports the limitation of coverage to “highly emetogenic” chemotherapy regimens, there are significant concerns about the criterion used to identify exactly which patients will qualify to receive the benefit. Under the CMS proposal, it appears that a patient would qualify for coverage only if he or she had “demonstrated unresponsiveness to other anti- emetic regimens not containing aprepitant.” This limitation is not legally required for Part B coverage and is inconsistent with the FDA- approved labeling for the drug. Further, it is not in keeping with current guidelines and good clinical practice. ASCO strongly urges revision of the coverage memorandum accordingly.

Language in the draft decision memo suggests that CMS’s proposed restriction of coverage to patients who have failed on standard oral anti-emetic therapy may somehow be requiredby Part B coverage requirements. We do not see any basis for such a conclusion. As the Benefits Policy Manual quoted above recognizes, Part B coverage is available for a combination of multiple oral anti-emetic drugs that replace intravenous therapy, and nothing in the Manual provision, or in the underlying statute, limits coverage to patients who have failed on some other therapy.

Aprepitant was approved by FDA in 2002, in combination with other anti-emetics, “for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy.” The CMS proposal would undermine the ability of this important new drug to prevent nausea and vomiting associated with initial courses of chemotherapy by limiting its use to situations where patients had already received highly emetogenic chemotherapy with unsatisfactory results.

Aside from the inconsistency of this approach with the FDA-approved usage of the drug, the CMS proposal would result in very unfavorable outcomes for patients. The clinical trials supporting approval of aprepitant, as well as subsequent studies published in the Journal of Clinical Oncology (JCO), indicate that the drug should be administered at the outset of cancer chemotherapy as a preventative against chemotherapy-induced nausea and vomiting. Use of the drug in response to failure of other anti- emetics would not be efficacious in many instances. Clinical trials have demonstrated that aprepitant can provide significant additional protection when combined with other oral anti-emetics, but only prior to chemotherapy. If the drug is not used to prevent nausea and vomiting associated with initial doses of chemotherapy, it is not clear how useful it would prove subsequently. Indeed, failure to use it in initial chemotherapy might contribute to more severe incidence of anticipatory nausea and vomiting associated with subsequent rounds of chemotherapy.

ASCO firmly believes that CMS’s appropriate legal analysis regarding coverage of this significant new drug class can be rendered effective only if the drug is utilized as approved by FDA and as reflected in most up-to-date guidelines—i.e., aprepitant should be used to prevent nausea and vomiting for all patients undergoing highly emetogenic chemotherapy in connection with both initial and repeat doses of chemotherapy. Most importantly, this result will optimize patient benefit, will encourage compliance with otherwise difficult treatment regimens and may ultimately prove cost-effective for Medicare by increasing the efficiency of cancer chemotherapy.

What is the Role of the FDA-Approved Labeling?

As ASCO has previously noted in a variety of communications with CMS on the topic of coverage of cancer drugs, Congress has enacted special coverage rules for drugs included in cancer chemotherapy regimens, referenced in §1861 (t)(2) of the Social Security Act. Under these rules, “a medically acceptable indication” for a drug used in a cancer chemotherapy regimen “includes any use which has been approved by the Food and Drug Administration.” ASCO believes this provision requires coverage of any use as approved by FDA and set forth in the FDA- approved labeling. Thus, coverage of aprepitant must be determined in a manner consistent with the approved labeling for the drug—i.e., it is to be used in combination with other anti-emetic agents “for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy.” The limitations suggested by CMS, which essentially convert the use of aprepitant to second-line therapy, cannot be reconciled with the FDA-approved labeling and violate the terms of §1861(t)(2).

We note that the proposed decision memo would limit Medicare Part B coverage to situations in which dexamethasone is the corticosteroid used even though the FDA-approved labeling refers to use with a corticosteroid, without limitation. ASCO objects to the proposed narrowing of coverage to a particular corticosteroid when FDA has determined that any corticosteroid would be safe and effective in this regimen. CMS should defer to FDA’s determination.

CONCLUSION

ASCO enthusiastically endorses the CMS decision to cover aprepitant in combination with other oral anti-emetics, but strongly urges reconsideration of the limits imposed on that coverage. Aprepitant used in combination with other oral anti-emetics should be considered “reasonable and necessary” and should be covered by Medicare for all patients receiving initial and repeat courses of cancer chemotherapy with a “high emetic risk” as determined in the ASCO guidelines and by carrier decision. This broader approach to coverage of an important new class of anti-emetic drug would be consistent with respected guidelines, with the FDA approval on usage, with longstanding Medicare coverage policy, and with the best interests of patients.

* Richard J. Gralla, et al. Recommendations for the Use of Antiemetics: Evidence-Based, Clinical Practice Guidelines, 17 J. Clin. Onc. 2971 (1999).

Less