Thomson Micromedex DrugDex® Compendium Revision Request - CAG-00391

Issue

Requestor Name(s):           Thomson Micromedex
                                             View Requestor Letter

Formal Request Accepted and Review Initiated: February 19, 2008

Expected Completion Date: June 17, 2008

Lead Medical Officer(s):          Lori Paserchia, MD

February 19, 2008

June 10, 2008

October 24, 2008

To:		Administrative File: CAG #00391

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:		Thomson Micromedex DrugDex® - 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 10, 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). 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.

Request

A formal request submitted by Thomson Healthcare for the addition of Thomson Micromedex DrugDex® 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 19, 2008 on the CMS website.

Materials Reviewed

Requestor Letter

As required by CMS, the application submitted by Thomson Healthcare includes a detailed description of how Thomson Healthcare believes its compendium meets the CMS definition of a compendium and each of the ten MedCAC desirable characteristics.

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 Thomson Micromedex DrugDex® 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 has been submitted. BIO stated that it recognizes 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 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 public comment opposing the addition of Thomson Micromedex DrugDex® to the list of statutorily named compendia. The American Society of Health-System Pharmacists (ASHP) stated that it does not support the addition of DrugDex® to the list of compendia unless CMS determines that Thomson meets the transparency and conflict of interest criteria identified by MedCAC. ASHP cited in support of this concern one Wall Street Journal article that discusses “[DrugDex®] connections with the pharmaceutical industry.” Following this publication, ASHP notes the deletion of “author attributions in [the DrugDex®] database.” The only other support ASHP provided was that of author Marcia Angell, MD, referenced from her book, The Truth about the Drug Companies: How They Deceive Us and What to Do about It, that according to ASHP is “highly critical of the influence of pharmaceutical manufacturers on DrugDex®”. We attempted unsuccessfully to contact Dr. Angell to determine if this is an accurate representation of her current position on this issue. In addition, ASHP questioned the authority of CMS to recognize DrugDex® during the sub-regulatory compendia review process because “Thomson is requesting that its DrugDex® [compendium] be included by the CMS in the list of compendia appropriate for identifying medically accepted indications for purposes of Medicare Part A and B” even though ASHP states that the compendia review process is only applicable to Medicare Part B.

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, the Senators requested “…that CMS rely solely on compendia that are developed under policies of transparency and financial disclosure…”

Thomson Healthcare submitted a letter responding to the transparency and conflict of interest issues raised by ASHP pertaining to DrugDex®. In its response, Thomson refers to its conflict of interest policy that it states “is consistent with industry standards” and “easily reviewed on [its] website”. Within the discussion of its conflict of interest policy, Thomson Healthcare also outlines the disclosure and disqualification requirements for “individuals involved with literature evaluation and content development” to address the concerns of ASHP that these individuals “are not influenced by financial conflicts of interest,” such as those that can originate through ties to the pharmaceutical industry. In addition, Thomson Healthcare states that Medicare Part A references were only included in its compendia request to complete its application, not for recognition by CMS in the Medicare Part B compendia review process.

Thomson Micromedex DrugDex®

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 Thomson Micromedex DrugDex® 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 Thomson Micromedex DrugDex® 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. Thomson Micromedex DrugDex® addresses each of the MedCAC identified desirable characteristics as noted below.

   • It provides an extensive breadth of listings by listing more than 2300 drugs and biologics including prescription, non-prescription and investigational products. FDA-approved indications and off-label uses are presented as well.
   • It is designed to provide quick processing from application for inclusion to listing by conducting an ongoing editorial review of the world’s primary literature published in thousands of peer-reviewed journals, FDA-approved product labeling, clinical judgment and recommendations, regulatory standards and compliance, national healthcare trends, editorial board suggestions, external requests, and policy changes in health and disease management from professional health organizations. Online updates of the compendium are provided weekly.
   • It provides a detailed description of the evidence reviewed for every individual listing and fully cites specific studies that are the basis for recommendations.
   • It provides on the DrugDex® website pre-specified published criteria for weighing evidence that focus on the efficacy, strength of recommendation and strength of evidence, which directly guide the process of decision-making leading to recommendations.
   • It uses a prescribed published process for evaluating therapies, which is available for subscribers to see on its website. When formulating recommendations, clinical staff develops drafts, which are reviewed by internal experts and the Chief Medical Officer. The draft may also be reviewed by an Oncology Advisory Board if the subject involves a new FDA-unapproved use related to oncology or a significant ratings change related to oncology. The staff then collates all comments and formulates the final document.
   • It presents the process used for evaluating therapies to subscribers via its website including a listing of all involved panel members. There is an opportunity for the public to request the inclusion of information , such as specific articles or studies, in the compendium; the policy and process regarding an external request is presented to subscribers via the website.
   • It explicitly notes when the use of a drug or biologic is not recommended (denoted with a “Class III” rating) 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 (denoted as “Class indeterminate”) when validated evidence is equivocal. This type of listing is available to subscribers via its website.
   • It incorporates a process for identification and notification of potential conflicts of interest of the compendia's parent and sibling organizations, internal and external reviewers and internal and external committee members, with an established procedure to manage recognized conflicts. The policy and process are disclosed to subscribers via its website along with a listing of all potential and real conflicts of interest.
   
   

3. DrugDex® is available to subscribers via the internet.

4. There was only one public comment specific to DrugDex®; we note that it opposed the request and made mention that the compendia review process is only applicable to Medicare Part B. Section 1861(t) of the Act, which defines drugs and biologics for the Medicare benefit, does not restrict its scope to determinations under Medicare Part B. Thus, we find that the objection is not pertinent to the question at hand. We note that the commenter, ASHP, publishes its own compendium, AHFS Drug Information, which is recognized as an authoritative compendium for the identification of a medically accepted indication for the off-label uses of drugs and biologicals in an anticancer chemotherapeutic regimen.

   The commenter called attention to potential conflict of interest and transparency issues pertinent to DrugDex®. However we were not provided with primary evidence, i.e. what materials may have been considered by the authors of the newspaper article and the book. In addition we were unable to confirm that the opinion of Dr. Angell cited by the commenter is an accurate representation of her current opinion. Thus, we assign less evidentiary weight to those materials than to systematic technology assessments and MedCAC recommendations. We note that the 2006 MedCAC, which considered such a technology assessment as well as broad public input, expressed overall confidence that DrugDex® has adequately stated evidence based criteria and that it adheres to evidence based criteria and processes in making recommendations.

   We would in the future consider additional evidence if provided, as well as a request to remove DrugDex® from the list. However we have determined at this time that the currently available body of evidence does not support the denial of Thomson’s request.

In summary, we have determined that Thomson Micromedex DrugDex® meets the definition of a compendium as defined by 42 C.F.R. § 414.930(a); 72 Fed. Reg. 66222, 66304 as well as all of the criteria created by the MedCAC and referenced in regulation.

Conclusion

Thomson Micromedex DrugDex® 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 Thomson Micromedex DrugDex® 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 DrugDex® lists as “Class I, Class IIa or Class IIb” recommendations and/or efficacy will be considered medically accepted indications for the purposes of determining coverage policy.

Indications that DrugDex® lists as “Class III” recommendations and/or efficacy will not be considered medically accepted indications for the purposes of determining coverage policy.

Indications that are listed in the compendia as “Class indeterminate” are 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. We believe that these situations are most appropriately addressed under §1861(t)(2)(B)(ii)(II) .

• The product known as Thomson Micromedex DrugDex® 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.

Thomson Micromedex DrugDex® addresses each of the MedCAC identified desirable characteristics as noted below.

• It provides an extensive breadth of listings by listing more than 2300 drugs and biologics including prescription, non-prescription and investigational products. FDA-approved indications and off-label uses are presented as well.
• It is designed to provide quick processing from application for inclusion to listing by conducting an ongoing editorial review of the world’s primary literature published in thousands of peer-reviewed journals, FDA-approved product labeling, clinical judgment and recommendations, regulatory standards and compliance, national healthcare trends, editorial board suggestions, external requests, and policy changes in health and disease management from professional health organizations. Online updates of the compendium are provided weekly.
• It provides a detailed description of the evidence reviewed for every individual listing and fully cites specific studies that are the basis for recommendations.
• It provides on the DrugDex® website pre-specified published criteria for weighing evidence that focus on the efficacy, strength of recommendation and strength of evidence, which directly guide the process of decision-making leading to recommendations.
• It uses a prescribed published process for evaluating therapies, which is available for subscribers to see on its website. When formulating recommendations, clinical staff develops drafts, which are reviewed by internal experts and the Chief Medical Officer. The draft may also be reviewed by an Oncology Advisory Board if the subject involves a new FDA-unapproved use related to oncology or a significant ratings change related to oncology. The staff then collates all comments and formulates the final document.
• It presents the process used for evaluating therapies to subscribers via its website including a listing of all involved panel members. There is an opportunity for the public to request the inclusion of information , such as specific articles or studies, in the compendium; the policy and process regarding an external request is presented to subscribers via the website.
• It explicitly notes when the use of a drug or biologic is not recommended (denoted with a “Class III” rating) 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 (denoted as “Class indeterminate”) when validated evidence is equivocal. This type of listing is available to subscribers via its website.
• It incorporates a process for identification and notification of potential conflicts of interest of the compendia's parent and sibling organizations, internal and external reviewers and internal and external committee members, with an established procedure to manage recognized conflicts. The policy and process are disclosed to subscribers via its website along with a listing of all potential and real conflicts of interest.

DrugDex® is available to subscribers via the internet.

• There was only one public comment specific to DrugDex®; we note that it opposed the request and made mention that the compendia review process is only applicable to Medicare Part B. Section 1861(t) of the Act, which defines drugs and biologics for the Medicare benefit, does not restrict its scope to determinations under Medicare Part B. Thus, we find that the objection is not pertinent to the question at hand. We note that the commenter, ASHP, publishes its own compendium, AHFS Drug Information, which is recognized as an authoritative compendium for the identification of a medically accepted indication for the off-label uses of drugs and biologicals in an anticancer chemotherapeutic regimen.

The commenter called attention to potential conflict of interest and transparency issues pertinent to DrugDex®. However we were not provided with primary evidence, i.e. what materials may have been considered by the authors of the newspaper article and the book. In addition we were unable to confirm that the opinion of Dr. Angell cited by the commenter is an accurate representation of her current opinion. Thus, we assign less evidentiary weight to those materials than to systematic technology assessments and MedCAC recommendations. We note that the 2006 MedCAC, which considered such a technology assessment as well as broad public input, expressed overall confidence that DrugDex® has adequately stated evidence based criteria and that it adheres to evidence based criteria and processes in making recommendations.

We would in the future consider additional evidence if provided, as well as a request to remove DrugDex® from the list. However we have determined at this time that the currently available body of evidence does not support the denial of Thomson’s request.

In summary, we have determined that Thomson Micromedex DrugDex® meets the definition of a compendium as defined by 42 C.F.R. § 414.930(a); 72 Fed. Reg. 66222, 66304 as well as all of the criteria created by the MedCAC and referenced in regulation.

Conclusion

Thomson Micromedex DrugDex® 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 Thomson Micromedex DrugDex® 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 DrugDex® lists as “Class I, Class IIa or Class IIb” recommendations and/or efficacy will be considered medically accepted indications for the purposes of determining coverage policy.

Indications that DrugDex® lists as “Class III” recommendations and/or efficacy will not be considered medically accepted indications for the purposes of determining coverage policy.

Indications that are listed in the compendia as “Class indeterminate” are 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. We believe that these situations are most appropriately addressed under §1861(t)(2)(B)(ii)(II) .