Issue:
The Social Security Act Section 1861(t)(2)(B)(ii)(I) recognizes the following compendia: American Hospital Formulary Service-Drug Information (AHFS-DI), Truven Health Analytics Micromedex DrugDEX (DrugDEX), National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium, and Elsevier/Gold Standard Clinical Pharmacology for use in the determination of medically-accepted indications of drugs/biologicals used off-label in anti-cancer chemotherapeutic regimens.
CMS received a timely complete request for the addition of the Wolters Kluwer Clinical Drug Information Lexi-Drugs database to the list of compendia for use in the determination of medically-accepted indications of drugs/biologicals used off-label in anti-cancer chemotherapeutic regimens.
Requestor Name(s): Wolters Kluwer Clinical Drug Information
View Requestor Letter
Formal Request Accepted and Review Initiated: April 21, 2015
Expected Completion Date: August 19, 2015
Lead Analyst(s) Cheryl Gilbreath, PharmD, MBA, RPh
Lead Medical Officer(s): James Rollins, MD, MSHA, PhD
Actions Taken
April 21, 2015
Wolters Kluwer requested the formal addition of Lexi-Drugs to the list of compendia used by the Medicare program in the determination of a "medically accepted indication" for off-label drugs and biologics used in an anticancer chemotherapeutic treatment regimen. 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 Lexi-Drugs to this 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.gov/Medicare/Coverage/CoverageGenInfo/compendia.html
August 12, 2015
To: Administrative File: CAG #00443O
From: Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Joseph Chin, MD, MS
Deputy Director, Coverage and Analysis Group
James Rollins, MD, MSHA, PhD
Director, Division of Items and Devices
Lead Medical Officer
Cheryl Gilbreath, PharmD, MBA, RPh
Lead Analyst
Subject: Wolters Kluwer Lexi-Drugs® - 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: August 12, 2015
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, recognized 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). 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 & 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:
1. Extensive breadth of listings.
2. Quick processing from application for inclusion to listing.
3. Detailed description of the evidence reviewed for every individual listing.
4. Use of pre-specified published criteria for weighing evidence.
5. Use of prescribed published process for making recommendations.
6. Publicly transparent process for evaluating therapies.
7. Explicit "Not recommended" listing when validated evidence is appropriate.
8. Explicit listing and recommendations regarding therapies, including sequential use or combination in relation to other therapies.
9. Explicit "Equivocal" listing when validated evidence is equivocal.
10. 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.
Based on the process for revising the list of compendia established in 2008, CMS currently recognizes the following four compendia: American Hospital Formulary Service-Drug Information (AHFS-DI), Truven Health Analytics Micromedex DrugDEX (DrugDEX), National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium, and Elsevier/Gold Standard Clinical Pharmacology for use in the determination of medically-accepted indications of drugs/biologicals used off-label in anti-cancer chemotherapeutic regimens.
Request
A formal request submitted by Wolters Kluwer Clinical Drug Information for the addition of Lexi-Drugs® to the list of compendia used by the Medicare program in the determination of a medically accepted indication for off-label uses of drugs and biologicals n an anticancer chemotherapeutic treatment regimen was posted on April 21, 2015 on the CMS website.
Materials Reviewed
Requestor Letter
As required by CMS, the application submitted by Wolters Kluwer includes a detailed description of how it believes Lexi-Drugs® meets the CMS definition of a compendium and each of the ten MEDCAC desirable characteristics. The letter can be found on our CMS website at http://www.cms.gov/Medicare/Coverage/CoverageGenInfo/downloads/covdoc31.pdf.
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 Wolters Kluwer Lexi-Drugs® to the list of compendia.
CMS received a total of six comments. Four of the six comments supported the addition of Wolters Kluwer Lexi-Drugs® to the list of compendia for the identification of a medically accepted indication for the off-label uses of drugs and biological in an anticancer chemotherapeutic regimen. These commenters included one from the Association of Community Cancer Centers and one from a coordinator of cancer care and two from pharmacy directors. These comments described Lexi-Drugs® as "user friendly, comprehensive," and a "reliable reference and one that pharmacists use regularly."
CMS received one public comment from Highmark, Inc. opposing the addition of Wolters Kluwer Lexi-Drugs® to the list of statutorily named compendia but did not cite a reason why the compendia should not be added. We also received a comment from Triple-S Advantage that stated CMS should consider budget constraints when deciding to add compendia. Further, the commenter added that there is no apparent benefit of adding Lexi-Drugs® to the list since most of its information is duplicative to other compendia currently recognized.
We appreciate the comments. CMS uses the desirable characteristics developed by the MEDCAC to determine whether a compendium should be added to the CMS-recognized compendia list. Neither of the reasons cited by the commenter are characteristics CMS reviews to determine the compendia acceptability (See 72 Fed. Reg. 66222, 66303-66306, 66404).
All comments can be viewed in their entirety at on the CMS website at https://www.cms.gov/medicare-coverage-database/details/mcd-view-public-comments.aspx?MCDId=31&ExpandComments=n&bc=AAAAAAAAACAAAA%3d%3d&
Wolters Kluwer Lexi-Drugs®
As part of the compendium application submission, CMS requires access to the compendium under review, which would be available to subscribers of the compendium. CMS was provided with unlimited access to the Wolters Kluwer Lexi-Drugs® delivered on the Lexicomp OnlineTM platform during the entire review process, which allowed CMS to navigate the compendium database in order to assess its infrastructure and content.
Analysis
The product known as Wolters Kluwer Lexi-Drugs® 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. Specifically, it comprises drug monographs and is searchable by generic drug names, brand names, NDC, keyword, and synonyms.
Wolters Kluwer Lexi-Drugs® addresses each of the ten MEDCAC identified desirable characteristics as noted below:
1. Extensive breadth of listings.
Lexi-Drugs® lists more than 2000 drugs and biologics including prescription, non-prescription and investigational products. FDA-approved indications and off-label uses are presented via drug monographs as well as the level of evidence, description of use including therapy statements, references, links to guidelines, or a link to a full off-label monograph. Each drug and biological listing/monograph also includes the following details:
- Dosages
- Clinical Practice Guidelines
- Administration and Storage Issues
- Warnings & Precautions
- Pharmacology and Pharmacokinetics
- Pregnancy & Lactation
- Interactions
- Adverse Reaction
- Pharmacogenomics
- Patient & Therapy Management
- Preparations
- Related Information
- References
2. Quick processing from application for inclusion to listing.
Certain updates to the Lexi-Drugs® system may occur daily (e.g. new drugs, special alerts, major warnings, new FDA labeled indications and dosing information), while other more complex updates may take up to four months. The time-frame depends on the importance of the change, the amount of documentation needed to be collected and reviewed, and the amount of data that is ultimately being incorporated into the database. Wolters Kluwer Clinical Drug Information's surveillance model includes an internal team which identifies changes in prescribing information as well as updates in primary literature and clinical practice guidelines on a daily basis. Other sources for updates include peer reviewed journal surveillance, monthly monograph review, consultation with an external panel of senior editors and practitioners within the U.S. healthcare systems, and unsolicited inquiries from clients including 1200 hospitals.
3. Detailed description of the evidence reviewed for every individual listing.
Lexi-Drugs® provides a detailed description of the evidence reviewed for every individual listing and cites specific studies (e.g. last name author, year) that are the basis for recommendations. The complete reference for each citation is included in the reference list within the specific drug monograph. For each listing it further summarizes efficacy based on all literature reviewed, outlines areas needing additional study, and raises issues that should be considered prior to prescribing.
4. Use of pre-specified published criteria for weighing evidence.
Lexi-Drugs® offers a "Level of Evidence Scale" for oncology off-label use describing the pre-specified published criteria for weighting evidence that focus on the efficacy, strength of recommendation and strength of evidence, which directly guide the process of decision-making leading to recommendations. In this scale, Evidence Level A is for uses with evidence from well-performed randomized, controlled trials or overwhelming evidence of some other form to support the off-label use. Evidence Level B is for uses with evidence from randomized, controlled trials with important limitations (e.g., inconsistent results, methodologic flaws, indirect, imprecise) or very strong evidence of some other research design. Evidence Level C is for uses with evidence from observational studies (e.g., retrospective case series/reports providing significant impact on patient care); unsystematic clinical experience; or potentially flawed randomized, controlled trials (e.g., when limited options exist for condition). And Evidence Level G is for uses that have been substantiated by inclusion in at least one evidence-based or consensus-based clinical practice guideline.
5. Use of prescribed published process for making recommendations.
Wolters Kluwer uses a prescribed process for evaluating therapies, which is available for subscribers to see on its website at http://www.wolterskluwercdi.com/compendia/. The committee to develop the clinical content of the database is comprised of pharmacists with significant clinical and academic experience. Clinical specialists review the primary and secondary literature, clinical guidelines and tertiary reference texts to construct the information in the supporting monographs for each listing. The committee focuses on determining the validity and reliability of the various reports. Both positive and negative studies are discussed, referenced and used as the basis for assigning the database's evidentiary ratings when the committee reaches a consensus.
6. Publicly transparent process for evaluating therapies.
Wolters Kluwer's website (http://www.wolterskluwercdi.com/compendia/) houses all information on their process for evaluating therapies. Two tables entitled, "New Off-Label Uses" and "Off-Label Uses Removed From Database," are updated on a monthly basis with review details of each drug/biological and its proposed off-label use. Also included in the tables are dates of review, participating panel members, voting record, as well as any potential conflict of interest for the voting panel members. These tables are publicly available on their website at http://www.wolterskluwercdi.com/compendia/tables/.
7. Explicit "Not Recommended" listing when validated evidence is appropriate.
Instead of using the phrase "Not Recommended," any off-label use that is no longer valid based upon previously described review would be removed from the "Use: Off-label" field within Lexi-Drugs®. The "Use: Unsupported" field may be used if, based on clinical judgment, it is determined this information is helpful to Lexi-Drugs® users. This field also includes off-label uses or FDA-approved uses that are no longer recommended based on data that suggests such uses are considered unsafe or of questionable efficacy. These off-label uses would also be listed on the publically transparent table titled "Off-label Uses Removed Database" which is publicly available on the Wolters Kluwer website at http://www.wolterskluwercdi.com/compendia/tables/.
8. Explicit listing and recommendations regarding therapies, including sequential use or combination in relation to other therapies.
Lexi-Drugs® lists its therapy recommendations as "Use: Labeled Indications", "Use: Off-Label", or "Use: Unsupported". Lexi-Drugs® includes the use of single drug therapies, as well as drugs used in combination for an anticancer chemotherapeutic regimen. Within a specific drug monograph, the other drugs in the regimen are listed as well as the recommended dosing schedule.
9. Explicit "equivocal" listing when validated evidence is equivocal.
In determining whether to include a proposed off-label use in the Lexi-Drugs® database, Wolters Kluwer includes an explicit "Equivocal" recommendation which is based on the strength of the evidence as described in the table below:
| Strong (for proposed off-label use) |
The evidence persuasively supports the off-label use (i.e., Level of Evidence A). |
| Equivocal (for proposed off-label use) |
Equivocal (for proposed off-label use) The evidence to support the off-label use is of uncertain clinical significance (i.e., Level of Evidence B, C). Additional studies may be necessary to further define the role of this medication for the off-label use. |
| Against proposed off-label use |
Against proposed off-label use The evidence either advocates against the off-label use or suggests a lack of support for the off-label use (independent of Level of Evidence). Additional studies are necessary to define the role of this medication for the off-label use. |
As mentioned above, when the evidence for an off-label use is equivocal, it will be listed in Lexi-Drugs® and given a level of evidence rating of B or C, as defined in the table below:
| B |
Evidence from randomized, controlled trials with important limitations (e.g., inconsistent results, methodologic flaws, indirect, imprecise); or very strong evidence of some other research design. Further research (if performed) is likely to have an impact on confidence in the estimate of benefit and risk and may change the estimate. |
| C |
Evidence from observational studies (e.g., retrospective case series/reports providing significant impact on patient care); unsystematic clinical experience; or potentially flawed randomized, controlled trials (e.g., when limited options exist for condition). Any estimate of effect is uncertain. |
10. Process for public identification and notification of potential conflicts of interest of the compendium's parent and sibling organization, reviewers, and committee members, with an established procedure to manage recognized conflicts.
Wolters Kluwer has a process in place that is used to identify and manage conflicts of interest disclosures. Wolters Kluwer requires that all of its clinical drug information personnel involved with its clinical drug information content development process disclose real, potential, or perceived conflicts of interest. Wolters Kluwer provides an established procedure to manage, review, and assess such conflicts. The complete Wolters Kluwer Clinical Drug Information Conflicts of Interest Standard Operating Procedure is available at: http://www.wolterskluwercdi.com/compendia/.
In summary, CMS has determined that Wolters Kluwer Lexi-Drugs® meets the definition of a compendium as defined by 42 C.F.R. § 414.930(a); 72 Fed. Reg. 66222, 66303-66306, 6640 as well as all of the criteria created by the MEDCAC and referenced in regulation. CMS uses the desirable characteristics developed by the MEDCAC to determine whether a compendium should be added to the CMS-recognized compendia list. CMS considered all public comments in the final determination.
Conclusion
Wolters Kluwer Lexi-Drugs® 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 Wolters Kluwer Lexi-Drugs® 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 listed in Lexi-Drugs® as "Use: Off-Label" and rated as "Evidence Level A" with a "Strong" recommendation for inclusion will be considered medically accepted indications as described in §1861(t)(2)(B)(ii)(I).
Indications listed in Lexi-Drugs® as "Use: Unsupported" with an "Against" recommendation for inclusion will not be considered medically accepted indications as described in §1861(t)(2)(B)(ii)(I).
Indications listed in Lexi-Drugs® as "Use: Off Label" and rated as "Evidence Level B" or "Evidence Level C" or "Evidence Level G" with an "Equivocal" recommendation for inclusion, are considered neither "supported" nor "identified as not indicated" as described in §1861(t)(2)(B)(ii)(I). Thus, we cannot identify whether such compendia citations are medically accepted indications within the meaning of that section. 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 Lexi-Drugs® lists as "Equivocal".
