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 Gold Standard Inc. Clinical Pharmacology compendium to the list of compendia for this use.
Requestor Name(s): Gold Standard Inc., Elsevier Health Sciences
View Requestor Letter
Formal Request Accepted and Review Initiated: March 4, 2008
Expected Completion Date: July 2, 2008
Kate Tillman, RN, MA
Brijet Burton, MS, PA-C
Lead Medical Officer(s): Lori Paserchia, MD
March 4, 2008
Gold Standard Inc. requested the formal addition of Clinical Pharmacology 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 Clinical Pharmacology 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
July 2, 2008
October 24, 2008
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 #00392
From: Steve Phurrough, MD, MPA
Director, Coverage and Analysis Group
Louis Jacques, MD
Director, Division of Items and Devices
Kate Tillman, RN, MA
Brijet Burton, PA-C
Lori Paserchia, MD
Lead Medical Officer
Subject: Clinical Pharmacology - 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: July 2, 2008
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 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. 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.
A formal request submitted by Gold Standard Inc. and Elsevier Health Sciences for the addition of Clinical Pharmacology to the list of compendia for the identification of a medically accepted indication for the off-label use of drugs and biologicals in an anti-cancer therapeutic regimen was posted on March 4, 2008 on the CMS website.
As required by CMS, the application submitted by Gold Standard Inc. and Elsevier Health Sciences includes a detailed description of how Gold Standard Inc. and Elsevier Health Sciences believes its compendium meets the CMS definition of a compendium and each of the ten MedCAC desirable characteristics.
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 Clinical Pharmacology to the list of compendia.
CMS received a general public comment from the Biotechnology Industry Organization (BIO) in support of the addition of all compendia for which a request to add such publication 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 had been submitted. BIO commented that the content of each compendium differs “in publication schedules, priorities, review processes, local practices and methods of describing the evidence of each listing”. However, BIO commented that it believes that the addition of all these compendia is critical to the improvement of Medicare beneficiaries’ access to time-sensitive cancer treatment options.
CMS received a total of four comments during the public comment period in regard to the addition of Clinical Pharmacology to the list of statutorily named compendia. These comments were representative of industry, a health care facility, and the general public. All four commenters supported the addition of Clinical Pharmacology to the list of compendia. The commenters attributed the usefulness of the Clinical Pharmacology compendium for off-label use to its broad accessibility, timeliness and user-friendly format. Commenters also noted although they view this compendium as a vital clinical resource, formal recognition of the Clinical Pharmacology would allow it to be an authoritative resource for Medicare coverage determinations.
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….”
As part of the compendium application submission, CMS requires access to the compendium under review. CMS had unlimited access to the Clinical Pharmacology during the entire review process, which allowed CMS to navigate the compendium database in order to assess its infrastructure and content.
- The product known as Clinical Pharmacology 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.
- Clinical Pharmacology addresses each of the MedCAC identified desirable characteristics as noted below.
- It provides an extensive breadth of listings by including greater than 50,000 products including FDA-approved prescription drugs and biologics, non-prescription products, many dietary supplements and investigational drug agents.
- It is designed to provide quick processing of new information about a drug or biologic by conducting an ongoing editorial review of the primary literature and regulatory announcements. The review process takes between one to four weeks. An urgent update can be published within hours of the initial announcement in the public domain.
- It provides a description of the evidence reviewed for every individual listing and fully cites specific studies that are the basis for recommendations.
- Using the Strength of Recommendation Taxonomy (SORT) methodology to assess evidence, Clinical Pharmacology has pre-specified criteria for weighing evidence that focus on patient-oriented outcomes and evidence quality.
- It uses a prescribed published editorial policy and process for evaluating therapies. The editorial team is comprised of clinical pharmacists with experience in drug information; the majority of the editors have a doctorate in Pharmacy. To formulate a recommendation, the clinical staff develops a draft, which is reviewed and finalized by the Managing Editor. For oncology medications, a Senior Editor with expertise in oncology will also review the draft prior to finalization. An external review may be conducted for certain off-label uses of medications.
- It presents the process used for evaluating therapies to subscribers via its website and also includes a listing of current and past members of the editorial team. The staff is available to take inquiries regarding the editorial policy and processes; contact information via phone or email is provided on the website.
- It explicitly notes when validated evidence indicates that the use of a drug or biologic is not recommended or when evidence for a use is “unsupportive.”
- 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 specifically and explicitly notes when the evidence for an indication is inconclusive (i.e., when validated evidence is equivocal).
- It incorporates a process for identification and notification of potential conflicts of interest of the compendia's internal and external reviewers, editors and committee members, with an established procedure to manage recognized conflicts. The policy is disclosed to subscribers via its website as is a listing of all potential and real conflicts of interest.
- Clinical Pharmacology is available to subscribers via the internet.
- There were four public comments specific to Clinical Pharmacology; we note that they all supported the request.
In summary, we have determined that Clinical Pharmacology 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 for broad public accessibility.
Uses that are noted in the compendia as “inconclusive” 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 off label use as a “medically accepted indication” nor can we identify the off label use as “not indicated.”
Clinical Pharmacology 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 Clinical Pharmacology 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.
Uses that Clinical Pharmacology lists as “Indications” will be considered medically accepted indications under Section 1861(t)(2)(B)(ii)(I).
Uses that Clinical Pharmacology notes are “not recommended” or where the evidence is “unsupportive” will not be considered medically accepted indications under Section 1861(t)(2)(B)(ii)(I).
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 Clinical Pharmacology lists as “inconclusive.”