Aprepitant for Chemotherapy-Induced Emesis

The Centers for Medicare & Medicaid Services (CMS) is expanding coverage in section 110.18 of the Medicare National Coverage Determinations (NCD) Manual to include:

1. The three-drug regimen of oral aprepitant, an oral 5HT₃ antagonist and oral dexamethasone is reasonable and necessary for beneficiaries receiving moderately emetogenic chemotherapy (MEC) immediately before and within 48 hours after the administration of the anticancer treatment.  This all-oral regimen is covered when it is administered in that time frame with any of the following chemotherapeutic agents, administered either singularly or in combination: alemtuzumab, azacitidine, bendamustine, carboplatin, carmustine, cisplatin, clofarabine, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, lomustine, mechlorethamine, oxaliplatin, and streptozocin.
2. Medicare Administrative Contractors may determine coverage for other all-oral three-drug antiemesis regimens of aprepitant or any other FDA approved oral NK-1 antagonist in combination with an oral 5HT₃ antagonist and oral dexamethasone with the chemotherapeutic agents listed above, or any other anticancer chemotherapeutic agents that are FDA approved and are defined as highly or moderately emetogenic.  CMS is defining highly emetogenic chemotherapy and moderately emetogenic chemotherapy as those anticancer agents so designated in at least two of three guidelines published by the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and European Society of Medical Oncology (ESMO)/Multinational Association of Supportive Care in Cancer (MASCC). The inclusive examples are: NCCN plus ASCO, NCCN plus ESMO/MASCC, or ASCO plus ESMO/MASCC.

To:		Administrative File: [CAG-00248R1] 
 
From:	Louis Jacques, MD 
		Director, Coverage and Analysis Group 
 
		Tamara Syrek Jensen, JD 
		Deputy Director, Coverage and Analysis Group 
 
		James Rollins, MD, PhD 
		Division Director 
 
		Susan M. Miller, MD 
		Medical Officer 
 
		Cheryl Gilbreath, PharmD, MBA, RPh 
		Analyst 
 
Subject:		Decision Memorandum for Aprepitant for Chemotherapy Induced Emesis  
 
Date:		May 29, 2013

I.   Decision

The Centers for Medicare & Medicaid Services (CMS) is expanding coverage in section 110.18 of the Medicare National Coverage Determinations (NCD) Manual to include:

1. The three-drug regimen of oral aprepitant, an oral 5HT₃ antagonist and oral dexamethasone is reasonable and necessary for beneficiaries receiving moderately emetogenic chemotherapy (MEC) immediately before and within 48 hours after the administration of the anticancer treatment.  This all-oral regimen is covered when it is administered in that time frame with any of the following chemotherapeutic agents, administered either singularly or in combination: alemtuzumab, azacitidine, bendamustine, carboplatin, carmustine, cisplatin, clofarabine, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, lomustine, mechlorethamine, oxaliplatin, and streptozocin.
2. Medicare Administrative Contractors may determine coverage for other all-oral three-drug antiemesis regimens of aprepitant or any other FDA approved oral NK-1 antagonist in combination with an oral 5HT₃ antagonist and oral dexamethasone with the chemotherapeutic agents listed above, or any other anticancer chemotherapeutic agents that are FDA approved and are defined as highly or moderately emetogenic.  CMS is defining highly emetogenic chemotherapy and moderately emetogenic chemotherapy as those anticancer agents so designated in at least two of three guidelines published by the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and European Society of Medical Oncology (ESMO)/Multinational Association of Supportive Care in Cancer (MASCC). The inclusive examples are: NCCN plus ASCO, NCCN plus ESMO/MASCC, or ASCO plus ESMO/MASCC.

See Appendix A for the NCD manual language.

II. Background

Epidemiology

Patients beginning cancer treatments regularly document chemotherapy induced nausea and vomiting (CINV) as a major and fearful concern [Hesketh 2008].  Poorly controlled nausea and vomiting (N&V) can result in significant and severe physiologic consequences, including nutritional derangements, metabolic imbalances, anorexia, esophageal tears, fractures, and wound dehiscence.  Not surprisingly, inadequate control of N&V can also lead to deterioration of an individual’s functional condition as well as force withdrawal from potentially beneficial chemotherapy [Langford 2010, National Cancer Institute 2012].  Control of CINV is therefore of paramount importance in the total care of the cancer patient.

The main risk factor in the prediction of CINV is the emetogenicity of the chemotherapeutic agent itself [Jordan 2005].  Several classification plans have been developed to define the emetogenic potential of chemotherapeutic agents.  In 2004, by expert consensus, intravenously administered chemotherapeutic agents were divided into four risk groups based on emetogenic potential: of high (> 90%), moderate (30%-90%), low (10%-30%), and minimal (< 10%).  The percentages noted correspond to the proportion of individuals who are likely to have one or more emetic episodes if provided a chemotherapeutic drug without prophylactic antiemetic therapy being administered.  However, the chemotherapeutic agents that comprise the groupings are not universally agreed upon.  Furthermore it is recognized that the current schema do not necessarily account for the emetogenic potential of combinations of chemotherapeutic agents [Grunberg 2011, Hesketh 2008, Jordan 2007, NCCN 2012].

Other risk factors for the development of post chemotherapy N&V are multiple and include the female gender, a younger age, low alcohol intake, experience of emesis during pregnancy, history of motion sickness and a high pretreatment expectation of severe nausea [dos Santos 2012, Hesketh 2008, Jordan 2005, Jordan 2007].

Disease Process

CINV is usually classified into categories.  Acute onset of CINV occurs within 24 hours of the administration of the chemotherapeutic agent.  Delayed onset N&V occurs 24 hours to several days after initial treatment. Anticipatory N&V is thought to be a learned response where this sign and symptom is observed in patients whose emesis is triggered by taste, odor, thoughts or anxiety secondary to a history of poor response to previously administered antiemetic agents [Hesketh 2008, Jordan 2005].

Vomiting is thought to result from a multiple step pathway that is controlled by the brain.  It is triggered by incoming impulses sent to the medulla from the chemoreceptor trigger zone, pharynx, gastrointestinal tract and cerebral cortex.  Emesis occurs when the outgoing impulses are sent from the vomiting center to the salivation center, respiratory center, abdominal muscles and cranial nerves [NCCN 2012].

Treatment Options

There are many neurotransmitter receptors thought to be involved in the emesis process.  The principle neuroreceptors involved are the dopamine and serotonin, specifically 5-hydroxytryptamine₃ (5HT₃) receptors.  The 5HT₃ antagonists (e.g. ondansetron) are considered an effective class of antiemetic agents.  Steroids (e.g. dexamethasone) are also considered important medications to prevent CINV.  Other neuroreceptors involved in the vomiting phenomenon include acetylcholine, histamine, cannabinoid, opiate and neurokinin-1 (NK-1) receptors [NCCN 2012].

Aprepitant was the first U.S. - marketed agent in the class of drugs that blocks the NK-1 receptor in the central nervous system and gastrointestinal tract [Jordan 2005, Jordan 2007].  The NK-1 antagonist has little to no affinity for the other receptors that are targeted by 5HT₃ antagonist or corticosteroid therapies [Curran 2009].  It also appears to be safe and well tolerated as demonstrated in a pooled analysis of fifteen trials involving 4798 patients who received either highly emetogenic chemotherapies (HEC) or moderately emetogenic chemotherapies (MEC) [Jin 2012].  However, in those receiving high dose cisplatin based chemotherapy (> 70 mg/m²), investigators discovered that the rate of severe infection was more frequent among the patients who received NK-1 antagonists compared to those who received standard therapy.  It is unknown if these drugs were the cause of these adverse events, whether the increase in infection was due to the immunomodulatory effects of the chemotherapy, or some other cause could be held responsible for this occurrence.  Future investigations will be needed to evaluate this phenomenon [dos Santos 2012].

No single common pathway to the emetic response has been identified; therefore, no single antiemetic agent can be expected to provide complete relief from CINV. The various medications used to diminish or eliminate CINV can synergistically act with each other to potentiate their effects against vomiting. Nausea however, is not as responsive to current antiemetic regimens as is vomiting [NCCN 2012].

III. History of Medicare Coverage

On April 4, 2005, CMS determined that the evidence was adequate to conclude that the use of the oral three-drug regimen of aprepitant, a 5HT₃ antagonist and dexamethasone is reasonable and necessary for a specified patient population.  We defined the patient population for which the use of the oral three-drug regimen of aprepitant, a 5HT₃ antagonist and dexamethasone is reasonable and necessary as only those patients who were receiving one or more of the following anticancer chemotherapeutic agents:

- Carmustine
- Cisplatin
- Cyclophosphamide
- Dacarbazine
- Mechlorethamine
- Streptozocin
- Doxorubicin
- Epirubicin
- Lomustine

See section 110.18 of the Medicare National Coverage Determinations Manual.

A. Current Request

On February 14, 2012, the National Comprehensive Cancer Network (NCCN) sent to CMS a formal request for reconsideration of the NCD 110.18.  The NCCN specifically requested the following;

1. Expand the use of aprepitant in combination with dexamethasone and a 5HT₃ antagonist to include the patient population receiving anticancer chemotherapeutic agents currently considered moderately emetogenic chemotherapy agents classified using the Hesketh emetogenic classification system or listed in at least two published evidence-based guidelines including:
   
   - Alemtuzumab
   - Azacitidine
   - Bendamustine
   - Carboplatin
   - Clofarabine
   - Cyclophosphamide
   - Cytarabine
   - Daunorubicin
   - Doxorubicin
   - Epirubicin
   - Idarubicin
   - Ifosfamide
   - Irinotecan
   - Oxaliplatin

2. Expand coverage of aprepitant in combination with dexamethasone and a 5HT₃ antagonist for use with future chemotherapy agents classified as highly emetogenic or moderately emetogenic using the Hesketh emetogenic classification system or listed in at least two published evidence-based guidelines
3. Expand the current NCD acceptable list of 5HT₃ antagonists for use with aprepitant and dexamethasone to include palonosetron
4. Allow use of therapeutically equivalent doses of any available 5HT₃ antagonist, dexamethasone and aprepitant formulations (oral, transdermal, intravenous)
5. Allow for oral dexamethasone taken by the patient at home during the time period of chemotherapy administration
6. Allow for the intravenous administration of dexamethasone in place of oral dexamethasone
7. Allow for aprepitant in combination with 5HT₃ antagonists in patients shown to be dexamethasone (corticosteroid) intolerant or if the physician wishes to avoid dexamethasone (corticosteroids) because the patient is diabetic

We believe that requests 3-7 raise questions about broadening the scope of the Medicare Part A or Part B benefit for oral antiemetic therapy, and fall outside the scope of this NCD reconsideration.  We have discussed this with the requestor and referred the issues to the appropriate parts of the agency.  We will not discuss them further in this memorandum.

B. Benefit Category

Medicare is a defined benefit program.  An item or service must fall within a benefit category as a prerequisite to Medicare coverage [§1812 (Scope of Part A); §1832 (Scope of Part B); §1861(s) (Definition of Medical and Other Health Services)].

Medicare Part B generally does not cover drugs or biologicals that are usually self-administered, unless expressly authorized by statute.  Section 4557 of the Balanced Budget Act (BBA) of 1997, Pub. L. No. 105-33, amended §1861(s)(2) of the Social Security Act and the definition of “medical and other health services” to include coverage of oral antiemetic drugs under the conditions specified below:

“an oral drug (which is approved by the Federal Food and Drug Administration) prescribed for use as an acute antiemetic used as part of a chemotherapeutic regimen if the drug is administered by a physician (or as prescribed by a physician) –

1. for use immediately before, at, or within 48 hours after the time of the administration of the anticancer chemotherapeutic agent; and
2. as a full replacement for the antiemetic therapy which would otherwise be administered intravenously.”

  Social Security Act §1861(s)(2)(T).

IV. Timeline of Recent Activities

V. FDA Status

On March 27, 2003, the FDA approved the new drug application (NDA) for oral Emend® (aprepitant) capsules in combination with other antiemetic 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.

On October 28, 2005, the FDA approved the new indication for oral aprepitant in the prevention of N&V associated with initial and repeat courses of MEC.

According to the current FDA approved labeling, oral aprepitant is to be given for three days as part of a 3-drug regimen that includes a corticosteroid and a 5HT₃ antagonist.  The recommended dose of oral aprepitant is 125mg orally one hour prior to chemotherapy treatments (day 1) and 80mg orally once daily in the morning on days 2 and 3.

On January 25, 2008, the FDA approved an intravenous pro-drug formulation of Emend® (fosaprepitant) 115mg that would be used as a substitution to the oral drug on day 1 during the chemotherapy treatment. On November 12, 2010, the FDA approved a new dosage for the use of a single intravenous pro-drug formulation of Emend® (fosaprepitant) 150mg, dosed concomitantly with a 5HT₃ antagonist and corticosteroid, for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy.

On September 24, 2012, the FDA approved an abbreviated new drug application for generic oral aprepitant capsules.

VI. General Methodological Principles

When making national coverage determinations, CMS generally evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.  The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for beneficiaries.  An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary.

A detailed account of the methodological principles of study design that the Agency utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix B.

Public commenters sometimes cite the published clinical evidence and provide CMS with useful information.  Public comments that provide information based on unpublished evidence, such as the results of individual practitioners or patients, are less rigorous and, therefore, less useful for making a coverage determination.  CMS uses the initial comment period to inform its proposed decision.  CMS responds in detail to the public comments that were received in response to the proposed decision when it issues the final decision memorandum.

VII. Evidence

A. Introduction

This section provides a summary of the evidence we considered during our review.  The evidence reviewed to date includes the published medical literature on pertinent clinical trials of aprepitant.

B. Discussion of Evidence Reviewed

1. Question

In order to determine if aprepitant, added to other oral antiemetic medications improves the health outcomes of Medicare beneficiaries receiving MEC, we pose the following question:

Is the evidence adequate to conclude that an oral three-drug regimen of aprepitant, a 5HT₃ antagonist and dexamethasone administered immediately before and within 48 hours after the administration of moderately emetogenic anticancer chemotherapy improves health outcomes in Medicare beneficiaries?

We are most interested in the prevention of vomiting to enhance the tolerability of anticancer chemotherapy as a health outcome.

2. External Technology Assessments

CMS did not request an external technology assessment (TA) on this issue.

3. Internal Technology Assessment

Literature search methods

The reviewed evidence was gathered from articles submitted by the requester, and from a literature search of PubMed and OVID performed by the CMS staff.  Search terms used included the following: aprepitant, moderately emetogenic chemotherapy, and adverse events.

For the purposes of this analysis, we reviewed clinical trials that met the following inclusion criteria:

• adults requiring anticancer chemotherapy with MEC as classified using the Hesketh emetogenic classification system or listed in at least two of the published evidence-based guidelines referenced in this decision memo
• randomized controlled studies where aprepitant was added to standard therapy (5HT₃ antagonist and dexamethasone) for the prevention of CINV
• key outcome measures pertinent to our analysis of the prevention of chemotherapy-induced emesis.  These outcomes included:
1. the proportion of patients who achieved a complete response from their antiemetic regimen during all or a portion of the 120 hours post chemotherapy administration.  (Complete response is defined as no emesis and no use of rescue medications during the specified time.)
2. the proportion of patients who experienced no vomiting after ingesting their antiemetic regimen during all or a portion of the 120 hours following chemotherapy administration.

Studies including data on individuals receiving both HEC and MEC were included only if subgroup analyses were performed meeting the above criteria.

Single Study Investigations

We found four single study investigations that fit our inclusion criteria.  The details of these investigations are presented in Appendix C and are summarized below.

Herrstedt J, Muss HB, Warr DG, Hesketh PJ, et al. Efficacy and Tolerability of Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Emesis over Multiple Cycles of Moderately Emetogenic Chemotherapy. Cancer. 2005;104:1548-1555.

In this randomized, double-blinded study, 866 patients with breast cancer were treated with a multi-cycle treatment course of a cyclophosphamide-based chemotherapy.  Ninety-nine percent of the subjects received either doxorubicin or epirubicin in combination with the cyclophosphamide.  The patients were randomized to receive either an oral three-drug antiemetic regimen of aprepitant, ondansetron and dexamethasone or an oral control regimen of ondansetron and dexamethasone.  Patients, who completed Cycle 1 of chemotherapy in the study by Warr [2005] noted below, were invited to continue in this study, which collected data for up to three more cycles.  The purpose of the investigation was to compare the efficacy and tolerability of the oral three-drug regimen of aprepitant, ondansetron and dexamethasone versus that of the control regimen over multiple cycles of chemotherapy.  Complete response (defined as no emesis and no use of rescue medications) was the primary outcome measure.  Tolerability profiles of the two arms of the study were also compared.

The percentages of patients who experienced a complete response in Cycle 1 and sustained a complete response in Cycles 2-4 are shown below.  Also shown are the percentages of individuals who experienced no vomiting in Cycles 2-4.

The authors concluded that a complete response was greater with the oral three-drug regimen of aprepitant, ondansetron and dexamethasone as compared to the control regimen over the four cycles of chemotherapy.  Furthermore they stated that the pattern of clinical and laboratory adverse events was comparable in both groups.

Rapoport BL, Jordan K, Boice JA, Taylor A, et al. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double blind study. Support Care Cancer. 2010;18:423-431.

This study was designed to evaluate aprepitant in patients with a diversity of tumor types (breast, colon, lung, ovarian) who were treated with a variety of MEC agents.  Eight hundred forty eight (848) patients were randomized to receive either an oral three-drug regimen of aprepitant, ondansetron and dexamethasone or an oral control regimen of ondansetron and dexamethasone to prevent CINV during the 120-hour period post chemotherapy.  The primary hypothesis was that the three-drug regimen would be more effective in decreasing vomiting brought about by the chemotherapy treatment, but that the safety and tolerability of the two antiemesis therapy courses would be similar.  The secondary hypothesis was that the three-drug regimen would provide a complete response (defined as no vomiting and no rescue therapy) that was superior to the control regimen in the first 120 hours post administration of chemotherapy.

In this study, the proportion of patients who experienced a complete response or no vomiting for 120 hours following the administration of all chemotherapies is noted below:

A post-hoc analysis was also performed in order to compare the outcomes noted above in the separated groups of patients who received an anthracycline and cyclophosphamide (AC) based chemotherapy (48% of patients) and those who did not (52% of patients).  The results are below:

The authors concluded that the three-drug regimen of aprepitant, ondansetron and dexamethasone was superior to the control treatment in prevention of CINV in a range of patients receiving various MECs, including AC-based and non-AC based chemotherapy.

Warr DG, Hesketh PJ, Gralla RJ, Muss HB, et al. Efficacy and Tolerability of Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Patients with Breast Cancer After Moderately Emetogenic Chemotherapy. Journal of Clinical Oncology. 2005; 23(12): 2822-2830.

This investigation is a randomized, double-blinded study of 857 patients designed to compare the efficacy and tolerability of an oral three-drug antiemetic regimen of aprepitant, ondansetron and dexamethasone to an oral control regimen of ondansetron and dexamethasone for the prevention of CINV in breast cancer patients treated with cyclophosphamide ± doxorubicin or epirubicin.  The primary hypothesis was that a higher proportion of those individuals treated in the aprepitant group would demonstrate a complete response (no vomiting/no use of rescue medications) to antiemesis therapy than would those in the group not receiving aprepitant.  The secondary hypothesis was that those receiving aprepitant, as compared to the control group, would have a higher proportion of patients with minimal to no impact of emesis on activities of daily living.  Self-reported data on nausea, vomiting, and the use of rescue medications were collected, as were the effects of nausea and vomiting on daily living.

The relevant results are below:

In addition to the above, the authors noted that the results of the Functional Living Index-Emesis (FLIE) Questionnaire indicated that significantly more patients taking the three-drug oral regimen reported minimal or no impact of vomiting on daily living overall, as compared to the control group. The authors concluded that the three-drug regimen of aprepitant, ondansetron and dexamethasone was more effective than the control regimen for the prevention of CINV in their patient population.

Yeo W, Mo FKF, Suen JJS, Ho WM, et al. A randomized study of aprepitant, ondansetron and dexamethasone for chemotherapy-induced nausea and vomiting in hinese breast cancer patients receiving moderately emetogenic chemotherapy. Breast Cancer Research Treatment. 2009; 113:529-535.

The primary purpose of this randomized trial was to compare the efficacy of an oral three-drug antiemetic regimen of aprepitant, ondansetron and dexamethasone to an oral control regimen of ondansetron and dexamethasone for the prevention of CINV in 127 Chinese breast cancer patients who received the first cycle of MEC (doxorubicin and cyclophosphamide).  The secondary purpose of the study was to compare the quality of life in the two groups of patients.  Data on nausea, vomiting and the use of rescue medications was collected as were the effects of nausea and vomiting on daily living.

The pertinent data demonstrated the following:

From this data, the authors concluded that there was no significant difference in the proportion of individuals who reported a complete response or no vomiting during the 120 hours post chemotherapy administration.

Furthermore, the authors used the FLIE Questionnaire to determine the impact of nausea and vomiting on the quality of life of the clinical subjects.  Comparing the scores for vomiting demonstrated a statistically significant difference favoring the use of aprepitant, ondansetron and dexamethasone (p = 0.0002).

Systematic Review

Chapell R and Aapro MS. Efficacy of aprepitant among patients aged 65 and over receiving moderately to highly emetogenic chemotherapy: A meta-analysis of unpublished data from previously published studies. Journal of Geriatric Oncology. 2012; http://dx.doi.org/10.1016/j.jgo.2012.08.008.

In this meta-analysis, the authors searched Merck internal records for double-blind, randomized, placebo controlled, parallel group studies in which an antiemetic regimen incorporating aprepitant was compared to a standard antiemetic regimen for the prevention of CINV in those patients receiving either HEC or MEC.  The purpose of the study was to answer the following questions:

1. Does aprepitant, when administered as part of an antiemetic regimen including a 5HT₃ inhibitor and a corticosteroid, increase the number of patients age 65 and over who experience a complete response (no vomiting or use of rescue therapy) to the antiemetic therapy compared to a regimen without aprepitant?


2. Is there a difference in the relative risk of experiencing a complete response to antiemetic therapy between patients under age 65 and those age 65 and over?

Studies were included in the meta-analysis only if (a) they enrolled patients both under and over 65 years of age and if (b) results were stratified by age as part of the a priori investigational design.  Post-hoc analyses were also performed, comparing patients over and under age 75, and comparing patients age 75 and over to those under age 65.

When only patients, receiving MEC, age 65 years and older were analyzed, the risk of experiencing a complete response (no vomiting/no use of rescue medications) with the three drug antiemesis regimen (aprepitant, ondansetron and dexamethason) relative to the two drug antiemetic combination(ondansetron and dexamethasone) was 1.11.  The confidence intervals are not specifically stated, but cross 1[Warr 2005].

4. MEDCAC

A Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) meeting was not convened on this issue.

5. Evidence-based guidelines

The pertinent evidence-based guidelines are summarized below.

Basch E, Prestrud AA, Hesketh PJ, Kris MG, et al. Anti-emetics: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical Oncology. 2011; 29(31):4189-4198.

In 2011, the American Society of Clinical Oncology (ASCO) updated its previous recommendations concerning the use of antiemetics to relieve the N&V of chemotherapeutic treatment.  In preparation for the update, the society evaluated systematic reviews and reports from randomized controlled trials that met the following criteria:

- the intervention was for the treatment of N&V secondary to cancer therapy;
- nausea and/or vomiting outcomes were reported;
- patients were observed for a minimum of five days (120 hours) after the intervention; and
- each trial arm included a minimum of 25 randomly assigned patients.

To determine the relevant literature to be evaluated, a search was performed on MEDLINE, the Cochrane Collaboration Library and a systematic review on the topic of antiemetics performed by the Agency for Healthcare Research and Quality (AHRQ).  In addition, posters and full presentations from the ASCO and Multinational Association of Supportive Care in Cancer (MASCC) annual meetings (available since 2006) were reviewed.

The ASCO reported that in patients receiving MEC agents, limited evidence supports adding aprepitant to the combination of a 5HT₃ antagonist and dexamethasone.  Furthermore, when patients are receiving combination chemotherapy, they should receive antiemetics appropriate for the chemotherapeutic agent with the highest emetogenic risk.  The ASCO guidelines consider the combination of an anthracycline and cyclophosphamide to convey high emetogenic risk.

Roila F, Herrstedt J, Aapro M, Gralla RJ, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy - and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Annals of Oncology. 2010; 21 (Supplement 5): v232-243.

In June 2009, the European Society of Medical Oncology (ESMO) and the MASCC organized an international consensus conference in Perugia, Italy, to update guidelines on the use of antiemetics in oncology.  These guidelines were based on evidence developed through a review of the literature accessed through MEDLINE and other databases.  An expert panel committee evaluated the available evidence.  The guidelines developed from the Perugia Consensus Conference provided several recommendations related to the use of antiemetics to prevent N&V associated with the administration of MEC.  Those that are pertinent to this decision are:

- To prevent acute N&V in women receiving a combination of anthracycline and cyclophosphamide (AC), a triple-drug regimen including a 5HT₃ antagonist, dexamethasone and aprepitant should be given before chemotherapy.
- To prevent acute N&V in patients receiving non-AC MEC, aprepitant is not recommended.
- The use of aprepitant is not the preferred treatment recommended to prevent delayed emesis in patients who have received non-AC MEC.
- In breast cancer patients receiving AC MEC, aprepitant should be used to prevent delayed N&V.

NCCN Clinical Practice Guidelines in Oncology: Anti-emesis, Version 1.2012 National Comprehensive Cancer Network.

The NCCN Guidelines provide a report of evidence and consensus of the authors’ viewpoints of currently accepted treatment practices.  The NCCN Clinical Practice Guidelines concerning the management of emesis associated with the use of MEC offer the following recommendations pertinent to our decision:

- Along with a 5HT₃ antagonist and dexamethasone, on day 1 prior to chemotherapy, an oral or intravenous preparation of aprepitant should be used for selected patients receiving carboplatin, cisplatin, doxorubicin, epirubicin, ifosfamide, irinotecan or methotrexate.
- If aprepitant was used on day 1, the drug should be used again on days 2 and 3.
- Aprepitant is recommended to prevent delayed N&V in patients given AC therapy.

6. Professional Society Position Statements

Other than public comments, CMS received no professional society position statements on the proposed decision.

7. Expert Opinion

Other than public comments, CMS received no expert opinions on the proposed decision.

8. Public Comments

CMS uses the initial public comment period to inform the public of its proposed decision. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. Public comments may contain personal health information that is redacted and protected and are not made available to the public. CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum. On the tracking sheet for this NCD, CMS requested public comments on the evidence speaking to the health outcomes attributable to the use of oral aprepitant in patients receiving MEC.

Initial Comment Period

During the initial 30-day public comment period (10/01/2012 – 10/31/2012), CMS received 53 comments.  Most comments were generally in favor of expanding coverage of the oral three-drug regimen of aprepitant, a 5HT₃ antagonist and dexamethasone for use in patients receiving MEC.  One comment was neutral about coverage, and one comment disagreed with a request item that was beyond the scope of this analysis.

CMS received eleven comments that referred to evidence that were either already received from the requestor or considered later in the analysis.

CMS received a number of comments from physicians, pharmacists and nurses, as well as from other individuals within the healthcare industry, such as medical school professors, hospital administrators, healthcare insurers, etc. CMS also received comments from representatives of manufacturing companies and other businesses and consulting firms. These representatives included lawyers, sales representatives, consultants and executives.

CMS received comments from two professional societies, and twelve comments from various public organizations and patients.

Second Comment Period

CMS received 62 comments during the second comment period 03/20/2012 – 04/20/2012). All of the comments were in favor of the proposed decision expanding the oral three-drug antiemesis regimen of aprepitant, a 5HT₃ antagonist and dexamethasone to the specific chemotherapeutic agents noted in the request.

Comment:
Many of the commenters wrote in support of the use of the term “NK-1 antagonists” as opposed to “aprepitant” in section 110.18 of the Medicare National Coverage Determinations Manual, so that either aprepitant or fosaprepitant could be covered under the conditions of this NCD.

Response:
We believe that our request for comments regarding whether or not the term “NK-1 antagonists,” describing a class of drugs, should be used in the Medicare National Coverage Determinations Manual may have been taken out of context. Therefore we have restated the term “oral” in several places in the final decision for further emphasis. Per Section 4557 of the Balanced Budget Act (BBA) of 1997, Pub. L. No. 105-33, which amended §1861(s)(2) of the Social Security Act, Medicare does not cover under part B oral antiemetic drugs in antiemetic drug combination regimens that are administered in part, via an oral route and in part, via an intravenous route.

Fosaprepitant is an injectable NK-1 antagonist, thus it falls outside the scope of this NCD which only discusses coverage of an all-oral three-drug antiemesis regimen. The substitution of fosaprepitant for aprepitant would remove part B coverage for the three-drug regimen.

Information regarding the process for the administration of a mixed route antiemetic drug combination used in the treatment of cancer can be obtained at http://www.cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/MLNMattersArticles/downloads/SE0910.pdf.

Comment:
Two commenters noted that support should not be given for using the term “NK-1 antagonists” in place of the word aprepitant in the NCD as determination of the clinical appropriateness of any drug for use in the Medicare beneficiary population should be based on both efficacy and safety data made with respect to an individual agent, and not a class of drugs.

Response:
We agree that coverage of a three drug regimen using other oral NK-1 antagonists should be based on the evidence speaking to clinical outcomes resulting from the use of these regimens in our beneficiary population. Our final decision does not establish presumptive national coverage for such regimens. Instead, we are permitting our local Medicare Administrative Contractors (MACs) to determine coverage for those regimens without the need to reconsider this NCD. We expect that the MACs would make coverage decisions consistent with the available evidence.

Comment:
A few commenters misquoted the proposed decision memorandum, stating that they supported the following proposal: Expand coverage of aprepitant in combination with dexamethasone and a 5-HT₃ antagonist for use with future chemotherapy agents classified as HEC or MEC using the Hesketh emetogenic classification system or listed in at least two published evidence-based guidelines such as ASCO, NCCN or ESMO/MASCC.

Response:
We emphasize that the only guidelines that are acceptable in the determination of whether an anticancer chemotherapeutic agent is classified as HEC or MEC are those published by the following: the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and European Society of Medical Oncology (ESMO)/Multinational Association of Supportive Care in Cancer (MASCC).

All comments that were submitted without personal health information may be viewed by using the following link:  http://www.cms.gov/medicare-coverage-database/details/nca-view-public-comments.aspx?NCAId=264

VIII. CMS Analysis

National coverage determinations (NCDs) are determinations by the Secretary with respect to whether or not a particular item or service is covered nationally under title XVIII §1862(l)(6) of the Social Security Act.  In order to be covered by Medicare, an item or service must fall within one or more benefit categories contained within part A or part B, and must not be otherwise excluded from coverage. Moreover, §1862 (a)(1)(A) of the Act states that, with limited exceptions, no payment may be made under part A or part B for any expenses incurred for items or services:

“which …are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member[.]”

This section of the decision memorandum provides an analysis of the evidence we considered during our review.  The evidence includes the published medical literature and guidelines pertaining to the use of a three drug antiemetic regimen provided to patients being administered MEC.  For details of the clinical trials, see Appendix C.

In this analysis, we addressed the question below:

Is the evidence adequate to conclude that an oral three-drug regimen of aprepitant, a 5HT₃ antagonist and dexamethasone administered immediately before and within 48 hours after the administration of moderately emetogenic anticancer chemotherapy improves health outcomes in Medicare beneficiaries?

Antiemesis Capability

In the study by Yeo [2009] of breast cancer patients administered cyclophosphamide and doxorubicin, an oral three-drug regimen of aprepitant, a 5HT₃ antagonist and dexamethasone was compared to a similar regimen without the NK-1 antagonist.  The study did not reveal any significant difference in the percentage of patients who experienced vomiting or a complete response (no vomiting/ no use of rescue medications).

It is interesting however that despite the findings above, the use of the three-drug regimen did provide a statistically significant improvement in the quality of life of the studied patients, as measured by the vomiting domain of the FLIE Questionnaire.  Of note, however, is that this research was conducted only on ethnic Chinese women.  The authors observed that there were likely some cultural differences between the two population groups when compared to a similar study conducted with mainly Western patients [Warr 2005], in terms of their desire to take medications.  The authors postulated from their data that the Chinese patients were more reluctant to take medications that were not thought “absolutely necessary” as compared to the Western subjects.  Consequently, the Chinese women were hesitant to take their rescue medications, thus potentially decreasing the effects of both arms of the protocol and negatively impacting the results of the study.

In the study by Warr [2005] in which patients received cyclophosphamide or cyclophosphamide in combination with an anthracycline (doxorubicin or epirubicin), oral aprepitant combined with an oral 5HT₃ antagonist and oral dexamethasone was found to significantly increase the percentage of patients that reported a complete response (no emesis/no use of rescue medications) for the 120 hours following chemotherapy administration.  In addition, a higher proportion of patients receiving the aprepitant regimen experienced no vomiting during the acute (0-24 hours) and delayed (24-120 hours) phases compared with patients receiving standard therapy of a 5HT₃ antagonist and dexamethasone; however, the treatment group differences failed to reach statistical significance, after multiplicity adjustments [FDA label 2012].

Similar results were found in the study by Rapoport [2010], where patients received not only an anthracycline combined with cyclophosphamide (AC), but also a broad range of non-AC chemotherapeutic agents. In that study, the proportion of patients who experienced no vomiting for 120 hours following the administration of all chemotherapies was significantly greater in the group receiving an oral three-drug regimen of aprepitant, a 5HT₃ antagonist and dexamethasone than in the control group.

Moreover, in the Rapoport study [2010], a post hoc analysis was performed in order to compare the outcomes noted above in the separated groups of patients who received AC (48%) and non-AC chemotherapy (52%).  The results of this analysis demonstrated that in both groups, a larger proportion of patients taking the three drug antiemesis regimen experienced a complete response as well as no vomiting when compared to those individuals in the control group.  This result was evident overall, as well as in the acute and delayed phases of the chemotherapy administration.

Unlike the investigators above, Herrstedt [2005] studied patients who were treated with multiple cycles of chemotherapy.  Specifically, this trial continued to evaluate the patients who were studied by Warr [2005] and who went on to receive multiple cycles of a cyclophosphamide-based chemotherapeutic regimen.  Ninety-nine percent of the subjects received either doxorubicin or epirubicin in combination with the cyclophosphamide.  The percentage of patients who experienced a complete response with their antiemetic regimen in Cycle 1 and who maintained a complete response over Cycles 2-4 (on the same regimens) was greater in those receiving the oral three-drug regimen of aprepitant, a 5HT₃ antagonist and dexamethasone than in the control group (log rank test, p = 0.017).  Furthermore, the percentage of patients who maintained the status of no vomiting throughout each cycle also favored the three-drug regimen (log rank test, p < 0.001).

Based on the totality of evidence presented, CMS finds that oral aprepitant in combination with a 5HT₃ antagonist and dexamethasone improves the control of emesis related to MEC in the patient populations described above, as compared with standard antiemesis regimens that do not contain aprepitant.

Generalizability

When making national coverage determinations, it is important to consider whether the evidence is relevant to the Medicare beneficiary population. In considering the generalizability of the results of the body of evidence to the Medicare population, it is necessary to consider at least the age, race and gender of the study participants.

In the studies discussed above, no subgroup analyses were performed for patients less than or greater than 65 years of age in a prospective study.  However, in 2012, Chapell and Aapro accessed unpublished data and examined the efficacy of the previously described three drug antiemetic regimen as compared to the control regimen among patients aged 65 years and over, who had received MEC in the study by Warr [2005]. Their results demonstrated that for the circumstances of this particular trial, the confidence interval associated with the relative risk of the complete responders in the two arms of the study crossed one, potentially indicating that the older age population does not respond any differently to an oral antiemesis regimen of a 5HT₃ antagonist and dexamethasone either alone or combined with aprepitant. However of the 433 patients studied by Warr [2005] who used aprepitant, only 69 patients were age 65 years or older; of the 424 patients who were evaluated after receiving the control therapy, only 60 patients were age 65 years or older. It is possible that these groups were too small in relation to the entire population of study subjects to demonstrate a statistically significant difference in the relative risk of complete response in those aged 65 and older.

This is particularly likely when reviewing the data discussed in the NDA approval package for the use of aprepitant for HEC [FDA NDA-package 2003].  The application stated, "A total of 311 patients 65 years or older were evaluated in this NDA. The aprepitant regimen was more efficacious than the standard therapy for all age groups.  There did not appear to be a significant "treatment-by-age interaction." Furthermore, the current FDA approved label for aprepitant indicates that no dosage adjustment is necessary in elderly patients taking aprepitant for the prevention of nausea and vomiting associated with initial and repeat courses of MEC in combination with other antiemetic agents, [FDA label 2012]. Therefore, CMS concludes that aprepitant can provide clinically significant outcomes in individuals 65 years and older receiving HEC or MEC.

It is observed that the majority of patients in the evidence presented in this decision memorandum are female and Caucasian.  The question could again be asked if the results of the above studies are generalizable to persons of the male gender and who are not Caucasian.  The FDA labeling notes that clinical pharmacology testing following oral administration of aprepitant demonstrates that there are no clinically significant differences between males and females.  Similar testing in those who are Black, Hispanic, Asian and Caucasian indicate no clinically meaningful differences in bioavailability data.  Therefore, the FDA approved label for aprepitant states that no dosage adjustments for this medication are recommended based on gender or race [FDA label 2012].  From this information, CMS concludes that aprepitant produces significant clinical outcomes in males as well as individuals of color.

Finally, in order to conclude that aprepitant can function in combination with other oral antiemetics to reduce vomiting induced by MEC agents as a class, it is necessary to demonstrate this occurrence over a representative sample of this group of chemotherapeutic agents.  The study by Rapoport [2010] is helpful in achieving this goal.  This study demonstrated that not only did the oral three drug regimen of aprepitant, a 5HT₃ antagonist and dexamethasone produce significant clinical outcomes in those individuals administered AC chemotherapies, but also this regimen produced similar results in those individuals receiving chemotherapies belonging to the class of alkylating agents, antimetabolites, and topoisomerase inhibitors.  CMS believes that this evidence indicates that the oral three drug antiemesis regimen provides clinically significant outcomes in multiple classes of MEC agents.

Based on the discussion above, CMS concludes that the findings in these studies are generalizable to the population of patients who are receiving MEC.  We define MEC as any anticancer chemotherapeutic agent, used singularly or in combination with other chemotherapeutic agents that is characterized as exhibiting moderate emetogenic potential by two of the three guidelines referenced in this decision memorandum (NCCN, ASCO or ESMO/MASCC).

Tolerability

Aprepitant is metabolized by cytochrome P450 3A4 in the liver.  Many other drugs are also metabolized through this isoenzyme, allowing for the potential of drug-drug interactions [Aapro 2010, Jin 2012, Curran 2009].  The FDA approved product label for aprepitant notes that clinical adverse experiences for the CINV regimen in conjunction with highly and moderately emetogenic chemotherapy (incidence >10%) include alopecia, anorexia, asthenia/fatigue, constipation, diarrhea, headache, hiccups and nausea.  Furthermore, as noted in the evidence section, the oral three-drug regimen of aprepitant, a 5HT₃ antagonist and dexamethasone is generally well tolerated in appropriate dosages.

Disparity

CMS notes the absence of evidence about benefits or harms related to population classifiers that have been associated historically with healthcare access or outcome disparities, such as sexual orientation and religion.

Summary

Based on the above discussion, CMS believes that the evidence is adequate to conclude that an oral three-drug regimen of aprepitant, a 5HT₃ antagonist and dexamethasone is reasonable and necessary for Medicare beneficiaries who are receiving MEC. CMS defines moderately emetogenic chemotherapy as any anticancer agents so designated in at least two of three guidelines published by the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and European Society of Medical Oncology (ESMO)/Multinational Association of Supportive Care in Cancer (MASCC).  Currently, those chemotherapeutic agents for which the three-drug regimen is not already covered under NCD 110.18 include alemtuzumab, azacitidine, bendamustine, carboplatin, clofarabine, cytarabine, daunorubicin, idarubicin, ifosfamide, irinotecan and oxaliplatin.

Additionally we consider that approximately 70-80% of all patients receiving chemotherapy experience nausea and vomiting [Curran 2009, dos Santos, 2012].  Not only does chemotherapy induced emesis impair quality of life, it can cause the physiologic/clinical consequences of dehydration, malnutrition, fatigue, confusion, electrolyte imbalance, esophageal tears and aspiration pneumonia.  Equally significant, is that poor control of the emesis can interrupt or force withdrawal from critical chemotherapy [National Cancer Institute 2012].

We are mindful of the relatively minimal risks of the oral three-drug antiemetic regimen containing aprepitant; the severe consequences that can occur if chemotherapy is delayed or halted altogether because of emesis; the ongoing development of new oral NK-1 antagonists; and the frequency with which new anticancer chemotherapeutic agents appear.  We also recognize that the available classification schemes for chemotherapy emetogenicity may evolve as evidence continues to be developed on this problem. In that light CMS believes that as an administrative matter we should allow some future coverage determinations to be made without the need to reconsider this NCD again.

Therefore our Medicare Administrative Contractors may determine coverage for future FDA approved oral NK-1 antagonists to be administered in an all-oral three-drug antiemesis regimen of the oral NK-1 antagonist, an oral 5HT₃ antagonist and oral dexamethasone for beneficiaries receiving HEC or MEC immediately before and within 48 hours after the anticancer treatment.

Our Medicare Administrative contractors may also determine coverage for the all-oral three-drug antiemesis regimen of oral aprepitant (or another covered oral NK-1 antagonist), an oral 5HT₃ antagonist and oral dexamethasone used with other anticancer chemotherapeutic agents that are FDA approved and are defined as highly or moderately emetogenic. CMS is defining highly emetogenic chemotherapy and moderately emetogenic chemotherapy as those anticancer agents so designated in at least two of three guidelines published by the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and European Society of Medical Oncology (ESMO)/Multinational Association of Supportive Care in Cancer (MASCC).

IX. Conclusion

The Centers for Medicare & Medicaid Services (CMS) is expanding coverage in section 110.18 of the Medicare National Coverage Determinations (NCD) Manual to include:

1. The three-drug regimen of oral aprepitant, an oral 5HT₃ antagonist and oral dexamethasone is reasonable and necessary for beneficiaries receiving moderately emetogenic chemotherapy (MEC) immediately before and within 48 hours after the administration of the anticancer treatment.  This all-oral regimen is covered when it is administered in that time frame with any of the following chemotherapeutic agents, administered either singularly or in combination: alemtuzumab, azacitidine, bendamustine, carboplatin, carmustine, cisplatin, clofarabine, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, lomustine, mechlorethamine, oxaliplatin, and streptozocin.
2. Medicare Administrative Contractors may determine coverage for other all-oral three-drug antiemesis regimens of aprepitant or any other FDA approved oral NK-1 antagonist in combination with an oral 5HT₃ antagonist and oral dexamethasone with the chemotherapeutic agents listed above, or any other anticancer chemotherapeutic agents that are FDA approved and are defined as highly or moderately emetogenic.  CMS is defining highly emetogenic chemotherapy and moderately emetogenic chemotherapy as those anticancer agents so designated in at least two of three guidelines published by the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and European Society of Medical Oncology (ESMO)/Multinational Association of Supportive Care in Cancer (MASCC). The inclusive examples are: NCCN plus ASCO, NCCN plus ESMO/MASCC, or ASCO plus ESMO/MASCC.

See Appendix A for the NCD manual language.

110.18 - Aprepitant for Chemotherapy-Induced Emesis
(Rev. XX, Issued: XX-XX-XX, Effective: XX-XX-XX, Implementation: XX-XX-XX)

A. General

CMS is defining highly emetogenic chemotherapy and moderately emetogenic chemotherapy as those anticancer agents so designated in at least two of three guidelines published by the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and European Society of Medical Oncology (ESMO)/Multinational Association of Supportive Care in Cancer (MASCC).  The inclusive examples are: NCCN plus ASCO, NCCN plus ESMO/MASCC, or ASCO plus ESMO/MASCC.

B. Nationally Covered Indications

The three-drug regimen of oral aprepitant, an oral 5HT₃ antagonist and oral dexamethasone is reasonable and necessary for beneficiaries receiving, either singularly or in combination with other drugs the following anticancer chemotherapeutic agents:  alemtuzumab, azacitidine, bendamustine, carboplatin, carmustine, cisplatin, clofarabine, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, lomustine, mechlorethamine, oxaliplatin, and streptozocin.

This all-oral regimen must be administered immediately before and within 48 hours after the administration of these chemotherapeutic agents.

C. Nationally Noncovered Indications

Medicare does not cover under part B oral antiemetic drugs in antiemetic drug combination regimens that are administered in part, via an oral route and in part, via an intravenous route. Medicare does not cover under part B aprepitant when it is used alone for anticancer chemotherapy related nausea and vomiting.

D. Other

Medicare Administrative Contractors may determine coverage for other all-oral three-drug antiemesis regimens of aprepitant or any other FDA approved oral NK-1 antagonist in combination with an oral 5HT₃ antagonist and oral dexamethasone with the chemotherapeutic agents listed above, or any other anticancer chemotherapeutic agents that are FDA approved and are defined as highly or moderately emetogenic.

When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service is reasonable and necessary.  The overall objective for the critical appraisal of the evidence is to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for patients.

We divide the assessment of clinical evidence into three stages: 1) the quality of the individual studies; 2) the generalizability of findings from individual studies to the Medicare population; and 3) overarching conclusions that can be drawn from the body of the evidence on the direction and magnitude of the intervention’s potential risks and benefits.

The methodological principles described below represent a broad discussion of the issues we consider when reviewing clinical evidence.  However, it should be noted that each coverage determination has its unique methodological aspects.

Assessing Individual Studies

Methodologists have developed criteria to determine weaknesses and strengths of clinical research.  Strength of evidence generally refers to: 1) the scientific validity underlying study findings regarding causal relationships between health care interventions and health outcomes; and 2) the reduction of bias.  In general, some of the methodological attributes associated with stronger evidence include those listed below:

• Use of randomization (allocation of patients to either intervention or control group) in order to minimize bias.
• Use of contemporaneous control groups (rather than historical controls) in order to ensure comparability between the intervention and control groups.
• Prospective (rather than retrospective) studies to ensure a more thorough and systematical assessment of factors related to outcomes.
• Larger sample sizes in studies to demonstrate both statistically significant as well as clinically significant outcomes that can be extrapolated to the Medicare population.  Sample size should be large enough to make chance an unlikely explanation for what was found.
• Masking (blinding) to ensure patients and investigators do not know to that group patients were assigned (intervention or control).  This is important especially in subjective outcomes, such as pain or quality of life, where enthusiasm and psychological factors may lead to an improved perceived outcome by either the patient or assessor.

Regardless of whether the design of a study is a randomized controlled trial, a non-randomized controlled trial, a cohort study or a case-control study, the primary criterion for methodological strength or quality is to the extent that differences between intervention and control groups can be attributed to the intervention studied.  This is known as internal validity.  Various types of bias can undermine internal validity.  These include:

• Different characteristics between patients participating and those theoretically eligible for study but not participating (selection bias).
• Co-interventions or provision of care apart from the intervention under evaluation (performance bias).
• Differential assessment of outcome (detection bias).
• Occurrence and reporting of patients who do not complete the study (attrition bias).

In principle, rankings of research design have been based on the ability of each study design category to minimize these biases.  A randomized controlled trial minimizes systematic bias (in theory) by selecting a sample of participants from a particular population and allocating them randomly to the intervention and control groups. Thus, in general, randomized controlled studies have been typically assigned the greatest strength, followed by non-randomized clinical trials and controlled observational studies. The design, conduct and analysis of trials are important factors as well. For example, a well designed and conducted observational study with a large sample size may provide stronger evidence than a poorly designed and conducted randomized controlled trial with a small sample size.  The following is a representative list of study designs (some of that have alternative names) ranked from most to least methodologically rigorous in their potential ability to minimize systematic bias:

Randomized controlled trials
Non-randomized controlled trials
Prospective cohort studies
Retrospective case control studies
Cross-sectional studies
Surveillance studies (e. g. , using registries or surveys)
Consecutive case series
Single case reports

When there are merely associations but not causal relationships between a study’s variables and outcomes, it is important not to draw causal inferences.  Confounding refers to independent variables that systematically vary with the causal variable.  This distorts measurement of the outcome of interest because its effect size is mixed with the effects of other extraneous factors.  For observational, and in some cases randomized controlled trials, the method in that confounding factors are handled (either through stratification or appropriate statistical modeling) are of particular concern.  For example, in order to interpret and generalize conclusions to our population of Medicare patients, it may be necessary for studies to match or stratify their intervention and control groups by patient age or co-morbidities.

Methodological strength is, therefore, a multidimensional concept that relates to the design, implementation and analysis of a clinical study.  In addition, thorough documentation of the conduct of the research, particularly study selection criteria, rate of attrition and process for data collection, is essential for CMS to adequately assess and consider the evidence.

Generalizability of Clinical Evidence to the Medicare Population

The applicability of the results of a study to other populations, settings, treatment regimens and outcomes assessed is known as external validity.  Even well-designed and well-conducted trials may not supply the evidence needed if the results of a study are not applicable to the Medicare population.  Evidence that provides accurate information about a population or setting not well represented in the Medicare program would be considered but would suffer from limited generalizability.

The extent to that the results of a trial are applicable to other circumstances is often a matter of judgment that depends on specific study characteristics, primarily the patient population studied (age, sex, severity of disease and presence of co-morbidities) and the care setting (primary to tertiary level of care, as well as the experience and specialization of the care provider).  Additional relevant variables are treatment regimens (dosage, timing and route of administration), co-interventions or concomitant therapies, and type of outcome and length of follow-up.

The level of care and the experience of the providers in the study are other crucial elements in assessing a study’s external validity.  Trial participants in an academic medical center may receive more or different attention than is typically available in non-tertiary settings.  For example, an investigator’s lengthy and detailed explanations of the potential benefits of the intervention and/or the use of new equipment provided to the academic center by the study sponsor may raise doubts about the applicability of study findings to community practice.

Given the evidence available in the research literature, some degree of generalization about an intervention’s potential benefits and harms is invariably required in making coverage determinations for the Medicare population.  Conditions that assist us in making reasonable generalizations are biologic plausibility, similarities between the populations studied and Medicare patients (age, sex, ethnicity and clinical presentation) and similarities of the intervention studied to those that would be routinely available in community practice.

A study’s selected outcomes are an important consideration in generalizing available clinical evidence to Medicare coverage determinations.  One of he goals of our determination process is to assess health outcomes.  These outcomes include resultant risks and benefits such as increased or decreased morbidity and mortality.  In order to make this determination, it is often necessary to evaluate whether the strength of the evidence is adequate to draw conclusions about the direction and magnitude of each individual outcome relevant to the intervention under study.  In addition, it is important that an intervention’s benefits are clinically significant and durable, rather than marginal or short-lived.  Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits.

If key health outcomes have not been studied or the direction of clinical effect is inconclusive, we may also evaluate the strength and adequacy of indirect evidence linking intermediate or surrogate outcomes to our outcomes of interest.

Assessing the Relative Magnitude of Risks and Benefits

Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits.  Health outcomes are one of several considerations in determining whether an item or service is reasonable and necessary.  CMS places greater emphasis on health outcomes actually experienced by patients, such as quality of life, functional status, duration of disability, morbidity and mortality, and less emphasis on outcomes that patients do not directly experience, such as intermediate outcomes, surrogate outcomes, and laboratory or radiographic responses.  The direction, magnitude, and consistency of the risks and benefits across studies are also important considerations.  Based on the analysis of the strength of the evidence, CMS assesses the relative magnitude of an intervention or technology’s benefits and risk of harm to Medicare beneficiaries.

Study: Chapell (2005)

Study: Herrstedt (2005)

Study: Rapoport (2010)

Study: Warr (2005)

Study: Yeo (2009)

Aapro MS and Walko CM. Aprepitant: drug-drug interactions in perspective. Annals of Oncology. 2010;21:2316-2323.

Agency for Healthcare and Research Quality (AHRQ). Technology Assessment: Consideration of the Evidence on Antiemetic Drugs for Nausea and Vomiting Associated with Chemotherapy and Radiation in Adults. [internet] Available at: http://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id74ta.pdf. Accessed 6 Feb 2013.

American Hospital Formulary Service-Drug Information (AHFS-DI) Editorial Staff: Aprepitant. In: AHFS Drug Information. American Society of Health–System Pharmacists. 2004.

American Society of Health–System Pharmacists-Drug Information (ASHP-DI) Aprepitant/Fosaprepitant Dimeglumine. Jan 2010.

American Society of Health –System Pharmacists (ASHP) therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. American Journal of Health Systems Pharmacology. 1999;56:729-764.

Basch E, Prestrud AA, Hesketh PJ, Kris MG, Feyer PC, Somerfield MR, Chesney M, Clark-Snow RA, Flaherty AM, Freundlich B, Morrow G, Rao KV, Schwartz RN, Lyman GH. Anti-emetics: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical Oncology. 2011;29(31):4189-4198.

Chapell R and Aapro MS. Efficacy of aprepitant among patients aged 65 and over receiving moderately to highly emetogenic chemotherapy: A meta-analysis of unpublished data from previously published studies. Journal of Geriatric Oncology. 2012 [internet] Available at: http://dx.doi.org/10.1016/j.jgo.2012.08.008. Accessed 9 Nov 2012.

Curran MP and Robinson DM. Aprepitant, A Review of Its Use in the Prevention of Nausea and Vomiting. Drugs. 2009;69(13):1853.

Dos Santos LV, Souza FH, Brunetto AT, Sasse AD, da Silveira Nogueira Lima JP. Neurokinin-1 Receptor Antagonists for Chemotherapy-Induced Nausea and Vomiting: A Systematic Review. Journal of the National Cancer Institute. 2012;104(17);1280-1292.

Food and Drug Administration (FDA). Aprepitant-Emend® Prescribing Information. [internet] Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021549s021lbl.pdf. Accessed 7 Dec 2012.

Food and Drug Administration (FDA). Center for Drug Evaluation and Research Approval Package for: New Drug Application Number:21-549. March 2003. [internet] Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-549_Emend_medr_P1.pdf. Accessed 31 Oct 2012.

Food and Drug Administration (FDA). Center for Drug Evaluation and Research Approval Package for: Application Number:21-549/S-008; October 2005. [internet] Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021549Orig1S008.pdf Accessed 31 Oct 2012.

European Medicines Agency [internet] Available at:  http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion_-_Variation/human/000527/WC500026538.pdf Accessed 9 Nov 2012.

Grunberg SM, Warr, Gralla RJ, Rapoport BL, Hesketh PJ, Jordan K, Espersen BT. Evaluation of new anti-emetic agents and definition of antineoplastic agent emetogenicity—state of the art. Support Care Cancer. 2011;19(Suppl 1):S43–S47.

Herrstedt J, Muss HB, Warr DG, Hesketh PJ, Eisenberg PD, Raftopoulos H, Grunberg SM, Gabriel M, Rodgers A, Hustad CM, Horgan KJ, Skobieranda F. Efficacy and Tolerability of Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Emesis over Multiple Cycles of Moderately Emetogenic Chemotherapy. Cancer. 2005;104:1548-1555.

Hesketh PJ. Chemotherapy-Induced Nausea and Vomiting. New England Journal of Medicine. 2008;358:2482-2494.

Jin Y, Wu X, Guan Y, Gu D, Shen Y, Xu Z, Wei X, Chen J. Efficacy and safety of aprepitant in the prevention of chemotherapy-induced nausea and vomiting: a pooled analysis. Support Care Cancer. 2012;20:1815-1822.

Jordan K, Kasper C, Schmoll H-J. Chemotherapy-induced nausea and vomiting: current and new standards in the anti-emetic prophylaxis and treatment. European Journal of Cancer. 2005;41:199-205.

Jordan K, Sippel C, Schmoll H-J. Guidelines for Anti-emetic Treatment of Chemotherapy-Induced Nausea and Vomiting: Past, Present and Future Recommendations. The Oncologist. 2007;2:1143-1150.

Langford P and Chrisp P. Fosaprepitant and aprepitant: an update of the evidence for their place in the prevention of chemotherapy-induced nausea and vomiting. Core Evidence. 2010;5:77-90.

National Cancer Institute. Nausea and Vomiting (PDQ®). Sep 2012. [internet] Available at: http://www.cancer.gov/cancertopics/pdq/supportivecare/nausea/HealthProfessional. Accessed 9 Oct 2012.

National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology, Anti-emesis. Version 1.2012. [internet] Available at: http://www.medicine.wisc.edu/~williams/anti-emesis.pdf. Accessed 9 Oct 2012.

National Coverage Determination (NCD) for Aprepitant for Chemotherapy-Induced Emesis (110.18). [internet] Available at: http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=309&ncdver=1. Accessed 19 Nov 2012.

Rapoport BL, Jordan K, Boice JA, Taylor A, Brown C, Hardwick JS, Carides A, Webb T, Schmoll H-J. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double blind study. Support Care Cancer. 2010;18:423-431.

Roila F, Herrstedt J, Aapro M, Gralla RJ, Einhorn LH, Ballatori E, Bria E, Clark-Snow RA, Espersen BT, Feyer P, Grunberg SM, Hesketh PJ, Jordan K, Kris MG, Maranzano E, Molassiotis A, Morrow G, Olver I, Rapoport BL, Rittenberg C, Saito M, Tonato M, Warr D. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Annals of Oncology. 2010;21(Suppl 5):v232-243.

United States Pharmocopeia-Drug Information (USP-DI) Editorial Staff. Aprepitant. In: Klasco RK (Ed): USP DI^® Drug Information for the Healthcare Professional. Truven Micromedex, Greenwood Village, Colorado. Nov 2012. [internet]. Accessed 17 Dec 2012.

Warr DG, Hesketh PJ, Gralla RJ, Muss HB, Herrstedt J, Eisenberg PD, Raftopoulos H, Grunberg SM, Gabriel M, Rodgers A, Bohidar N, Klinger G, Hustad CM, Horgan KJ, Skobieranda F. Efficacy and Tolerability of Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Patients with Breast Cancer After Moderately Emetogenic Chemotherapy. Journal of Clinical Oncology. 2005;23(12):2822-2830. 

Yeo W, Mo FKF, Suen JJS, Ho WM, Chan SL, Lau W, Koh J, Yeung WK, Kwan WH, Lee KKC, Mok TSK, Poon ANY, Lam KC, Hui EK, and Zee B. A randomized study of aprepitant, ondansetron and dexamethasone for chemotherapy-induced nausea and vomiting in Chinese breast cancer patients receiving moderately emetogenic chemotherapy. Breast Cancer Research Treatment. 2009;113:529-535.