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NCCN Compendium Revision Request - CAG-00389

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Date:

02/08/2008

Public Comment Period:

02/08/2008 - 03/09/2008    View Public Comments

Issue

The Social Security Act Section 1861(t)(2)(B)(ii)(I) recognizes the following compendia: American Medical Association Drug Evaluations (AMA-DE), United States Pharmacopoeia-Drug Information (USP-DI) or its successor publication [amended in Section 6001 (f)(1) of the DRA] and American Hospital Formulary Service-Drug Information (AFHS-DI) as authoritative sources for use in the determination of a “medically-accepted indication” of drugs and biologicals used off-label in an anticancer chemotherapeutic regimen. However, AFHS-DI is the only originally named compendium currently in publication.

CMS received a timely complete request for the addition of the National Comprehensive Cancer Network (NCCN) Drugs & Biologics Compendium to the list of compendia for this use.

Requestor Name(s):     National Comprehensive Cancer Network
                                       View Requestor Letter

Formal Request Accepted and Review Initiated:          February 8, 2008

Expected Completion Date:          June 6, 2008

Lead Analyst(s)

Kate Tillman, RN, MA
Katherine.Tillman@cms.hhs.gov

Brijet Burton, MS, PA-C
Brijet.Burton2@cms.hhs.gov

Lead Medical Officer(s):          Lori Paserchia, MD

Actions Taken

February 6, 2008

NCCN formally requested the addition of the NCCN Drugs and Biologics Compendium to the list of statutorily named compendia. The public comment period begins the date of this posting and ends after 30-calendar days. CMS considers all public comments, and is particularly interested in your feedback on the addition of NCCN to the list of compendia.

Formal public comments may be submitted through the highlighted “comment” link located at the top of this web page.

Instructions on how to submit a request to revise the list of compendia may be found at http://www.cms.hhs.gov/CoverageGenInfo/02_compendia.asp#TopOfPage

June 5, 2008

CMS posted decision.

October 24, 2008

TN 96: Compendia as Authoritative Sources for Use in the Determination of a "Medically Accepted Indication" of Drugs and Biologicals Used Off-Label in an Anti-Cancer Chemotherapeutic Regimen


To:                   Administrative File: CAG #00389


From:               Steve Phurrough, MD, MPA
                        Director, Coverage and Analysis Group

                        Louis Jacques, MD
                        Director, Division of Items and Devices

                        Kate Tillman, RN, MA
                        Analyst

                        Brijet Burton, PA-C
                        Analyst

                        Lori Paserchia, MD
                        Lead Medical Officer


Subject:           The National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium™ -
                        Request for addition to the list of compendia for the identification of a medically accepted indication for the off label uses of drugs
                        and biologicals in an anticancer chemotherapeutic regimen


Date:                June 5, 2008

Background

Section 1861(t)(2)(B)(ii)(I) of the Social Security Act (the Act), as amended by Section 6001 (f)(1) of the Deficit Reduction Act of 2005, Pub. Law 109-171, recognizes three compendia American Medical Association Drug Evaluations (AMA-DE), United States Pharmacopoeia-Drug Information (USP-DI) or its successor publication and American Hospital Formulary Service-Drug Information (AHFS-DI)as authoritative sources for use in the determination of a "medically-accepted indication" of drugs and biologicals used off-label in an anticancer chemotherapeutic regimen, unless the Secretary has determined that the use is not medically appropriate or the use is identified as not indicated in one or more such compendia.

Due to changes in the pharmaceutical reference industry, fewer of these statutorily-named compendia are available for our reference (e.g., the AMA- DE and the USP-DI are no longer published; Thomson Micromedex has designated Drug Points as the successor to the USP-DI.). Consequently, CMS received requests from the stakeholder community for a process to revise the list of compendia. In the Physician Fee Schedule final rule for calendar year 2008, CMS established a process for revising the list of compendia, as authorized under section 1861(t)(2) of the Act, and also established a definition for “compendium.” See 72 Fed. Reg. 66222, 66303-66306, 66404. Under 42 C.F.R. §.414.930(a), a compendium is defined “as a comprehensive listing of FDA-approved drugs and biologicals or a comprehensive listing of a specific subset of drugs and biologicals in a specialty compendium, for example, a compendium of anti-cancer treatment.” A compendium: (1) includes a summary of the pharmacologic characteristics of each drug or biological and may include information on dosage, as well as recommended or endorsed uses in specific diseases; (2) is indexed by drug or biological; (3) differs from a disease treatment guideline, which is indexed by disease. See 42 C.F.R. § 414.930(a); 72 Fed. Reg. 66222, 66404.

In addition, CMS increased the transparency of the process by incorporating a list of desirable compendium characteristics outlined by the Medicare Evidence Development and Coverage Advisory Committee (MedCAC) as criteria for decision-making. The list of desirable compendium characteristics was developed by the MedCAC during a public session on March 30, 2006. The goal of this session was to review the evidence and advise CMS on the desirable characteristics of compendia for use in the determination of medically-accepted indications of drugs and biologicals in anti-cancer therapy. As a result of this meeting, the MedCAC generated the following list of desirable characteristics:

  • Extensive breadth of listings.
  • Quick processing from application for inclusion to listing.
  • Detailed description of the evidence reviewed for every individual listing.
  • Use of pre-specified published criteria for weighing evidence.
  • Use of prescribed published process for making recommendations.
  • Publicly transparent process for evaluating therapies.
  • Explicit "Not recommended" listing when validated evidence is appropriate.
  • Explicit listing and recommendations regarding therapies, including sequential use or combination in relation to other therapies.
  • Explicit "Equivocal" listing when validated evidence is equivocal.
  • Process for public identification and notification of potential conflicts of interest of the compendia's parent and sibling organizations, reviewers, and committee members, with an established procedure to manage recognized conflicts.

We did not in regulation assign relative weights to these characteristics. Nor did we identify any characteristics as optional requirements, as we believe that all are necessary to fulfill the purpose for which this designation is made. However, as provided in regulation, CMS may consider additional reasonable factors in its decision. See 72 Fed. Reg. at 66306.

The drugs and biologicals used in the treatment of cancer are not benign agents. Boxed label “black box” warnings, a special FDA regulatory requirement, are commonly seen in many classes of agents: bevacizumab, rituximab, irinotecan, doxorubicin, busulfan, capecitabine, fludarabine, cetuximab, trastuzumab, gemtuzumab and docetaxel are but a few examples. The interests of Medicare beneficiaries who have cancer are safeguarded not only when appropriate uses of these agents are supported by Medicare payment, but equally so when inappropriate uses of these dangerous agents are discouraged by the absence of Medicare payment. Thus the explicit identification of indications that are not medically accepted is as necessary as the identification of indications that are medically accepted.

We believe the public should have access to such materials as necessary to determine if a compendium’s actions are indeed consistent with its stated policies. As Medicare beneficiaries who have cancer have the greatest personal stake in this issue, indeed their lives may hang in balance, we believe that public access is less meaningful if it is not provided broadly. Thus, as provided in regulation, we will consider broad access of the compendia to the general public as an additional reasonable factor. See 72 Fed. Reg. at 66306.

Request

The first formal request, submitted by NCCN for the addition of the NCCN Drugs and Biologics Compendium™ to the list of compendia for the identification of a medically accepted indication for the off-label uses of drugs and biologicals in an anticancer chemotherapeutic regimen, was posted on February 8, 2008 on the CMS website. The American Society of Clinical Oncology (ASCO) submitted its own request for the same addition.

Materials Reviewed

Requestor Letter

As required by CMS, the application submitted by NCCN includes a detailed description of how NCCN believes its compendium meets the CMS definition of a compendium and each of the ten MedCAC desirable characteristics. NCCN also discussed the evaluation of the NCCN Drugs and Biologics Compendium™ at the 2006 MedCAC meeting where it was ranked the highest amongst all evaluated compendia.

ASCO requested the addition of the NCCN Drugs and Biologics Compendium™ to the list of statutorily named compendia. Since it was preceded by NCCN’s own request, we are considering the ASCO request as a secondary request. In its request ASCO addressed how this compendium satisfied each MedCAC identified desirable characteristic and how its free online availability offers the additional characteristic of broad accessibility

The NCCN and ASCO discussed the NCCN’s specific conflict of interest policies and processes that include but are not limited to the definitions of “conflicting interest”, “direct relationship”, “indirect relationship”, and “external entity.” In addition, the NCCN stated that they “publicly disclose a listing of all potential conflicts of interest [and] provides a full disclosure of every organization that has provided funding to the NCCN” online.

Public Comments

As required under 42 C.F.R. § 414.930(b), CMS opened a 30 calendar day public comment period starting on the date this request was posted to receive feedback on the addition of the NCCN Drugs and Biologics Compendium™ to the list of compendia.

CMS received one public comment regarding the addition of the NCCN Drugs and Biologics Compendium™ to the list of statutorily named compendia. The comment came from the biopharmaceutical company, ImClone Systems Incorporated, in support of the addition of the free, web based NCCN Drugs and Biologics Compendium™ to the list of statutorily named compendia. ImClone Systems commented that it believes that the NCCN Drugs and Biologics Compendium™ meets the compendium definition and fulfills the MedCAC identified desirable characteristics. As an additional characteristic of consideration, ImClone Systems discussed the strong qualifications of the experts used on NCCN’s editorial board in the analysis of emerging clinical evidence that may not have the support of prospective, double-blinded clinical studies.

Other Relevant Comments

CMS received a letter from the Senate Finance Committee, signed by Senator Max Baucus, Senator Charles E. Grassley, Senator John D. Rockefeller and Senator Orrin G. Hatch. They expressed a particular interest with the CMS compendia review process, specifically noting “…conflicts of interest on the part of authors who contribute to the compendia.” In the correspondence, it was requested “…that CMS rely solely on compendia that are developed under policies of transparency and financial disclosure…”

The NCCN and ASCO discussed the NCCN’s specific conflict of interest policies and processes that include but are not limited to the definitions of “conflicting interest”, “direct relationship”, “indirect relationship”, and “external entity.” In addition, the NCCN stated that they “publicly disclose a listing of all potential conflicts of interest [and] provides a full disclosure of every organization that has provided funding to the NCCN” online.

NCCN Drugs and Biologics Compendium™

As part of the compendium application submission, CMS requires access to the compendium under review. CMS had unlimited access to the NCCN Drugs and Biologics Compendium™ during the entire review process, which allowed CMS to navigate the compendium database in order to assess its infrastructure and content.

Analysis

  1. The product known as the NCCN Drugs and Biologics Compendium™ is a compendium as defined by CMS in the regulation because it includes a summary of the pharmacologic characteristics of each drug or biological, information on dosage, recommended or endorsed uses in specific diseases and is indexed by drug or biological rather than by disease.

  2. The NCCN Drugs and Biologics Compendium™ addresses each of the MedCAC identified desirable characteristics as noted below.
    • It provides an extensive breadth of listings by including 196 drugs and biologics that cover all major cancer types. The NCCN addresses all anticancer drugs recommended in the NCCN Clinical Practice Guidelines in Oncology. These guidelines are estimated to cover 97% of patients with cancer.
    • It is designed to provide quick processing from application for inclusion to listing by providing updates usually within two to four weeks of a major new published study, a major action by the FDA, or other events such as the stopping of a national trial for positive or negative reasons.
    • It provides a detailed description of the evidence reviewed for every individual listing via its seamless linkage to NCCN Guidelines, which cite specific studies that are the basis for recommendations.
    • It provides for all to see on the NCCN website pre-specified published criteria for weighing evidence that focus on the quality of evidence and the degree of consensus resulting in the creation of a category of evidence and consensus, which directly guide the process of decision-making leading to recommendations in the NCCN Drugs and Biologics Compendium™.
    • It uses a prescribed published process for evaluating therapies, which is available for all to see on its website. When formulating recommendations, disease-specific expert panels develop initial drafts and circulate to member institutions for comment. The staff then collates comments and the panel reconvenes to formulate guidelines. Annual update meetings are held to review guidelines.
    • It uses a publicly transparent process for evaluating therapies including a catalog and description of all changes and updates and a listing of all involved panel members, which are available to the public on its website. In addition, ample opportunity to make comments and suggestions is provided to the health care community via the website as well as via national conferences and regional symposia. Validity assessment is subjective and based on expert panel evaluation.
    • It has a process for delisting an indication and explicitly notes a "Not recommended" listing when validated evidence is appropriate.
    • It provides information regarding the appropriate patient population and appropriate circumstance and time for the use of a drug or biologic alone or in combination and therefore provides explicit listing and recommendations regarding therapies, including sequential use or combination in relation to other therapies.
    • It institutes a policy and procedure that focuses its recommendations based on a specific setting; hence it will explicitly note an "Equivocal" listing when validated evidence is equivocal. This type of listing is available to the public on its website.
    • It incorporates a process for public identification and notification of potential conflicts of interest of the compendia's parent and sibling organizations, reviewers, and committee members, with an established procedure to manage recognized conflicts. The policy, including definitions for pertinent terms such as “conflicting interest” and “direct relationship,” and public disclosure the listing of all potential conflicts of interest and full disclosure of every organization that has provided funding to NCCN on their website. Member dues pay staff and operating costs, while industry grants pay distribution costs.
  1. The NCCN Drugs and Biologics Compendium™ is available via the internet without charge and is updated continually. We note that NCCN’s provision of free online public is an additional factor that we consider to be a significant positive attribute. We believe that this broad access supports public transparency and facilitates the independent review of NCCN’s recommendations by interested outside public parties.

  2. There was only one public comment; we note that it supported the request.

In summary, we have determined that the NCCN Drugs and Biologics Compendium™ meets the definition of a compendium as defined by 42 C.F.R. § 414.930(a); 72 Fed. Reg. 66222, 66404 as well as all of the criteria created by the MedCAC and referenced in regulation. It also provides the additional desirable factor of broad public accessibility.

Indications that are listed in compendia as “Equivocal” are neither “supported” nor “identified as not indicated” as described in §1861(t)(2)(B)(ii)(I). Thus we cannot from such compendia citations identify the use as a “medically accepted indication” nor can we identify the use as “not indicated.” We believe that such scenarios are most appropriately addressed by applying the provisions of the succeeding requirements in §1861(t)(2)(B)(ii)(II), which are manualized in the Medicare Benefit Policy Manual, Chapter 15, Section 50.4.5, subsection D.

Conclusion

The NCCN Drugs and Biologics Compendium™ is an authoritative compendium for such purposes as defined and outlined in 42 C.F.R. § 414.930(a); 72 Fed. Reg. 66222, 66404. Therefore, we are adding the NCCN Drugs and Biologics Compendium™ to the list of compendia in Chapter 15, section 50.4.5 of the Medicare Benefit Policy Manual, for use in the determination of a "medically-accepted indication" of drugs and biologicals used off-label in an anticancer chemotherapeutic regimen, unless the Secretary has determined that the use is not medically appropriate or the use is identified as not indicated in one or more such compendia.

Indications that the NCCN Drugs and Biologics Compendium™ lists as “Recommended” will be considered medically accepted indications for the purposes of determining coverage policy.

Indications that the NCCN Drugs and Biologics Compendium™ lists as “Not Recommended” will not be considered medically accepted indications for the purposes of determining coverage policy.

Medicare contractors, as instructed in subsection D of Chapter 15, section 50.4.5 of the Medicare Benefit Policy Manual, shall consider the peer reviewed medical literature for indications that the NCCN Drugs and Biologics Compendium™ lists as “Equivocal”.

Additional Materials:

Kate Tillman, RN, MA
410-786-9252
Brijet.Burtoncoachman@cms.hhs.gov
410-786-7364
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