Guidance for the Public, Industry, and CMS Staff: Coverage with Evidence Development

This guidance represents the Centers for Medicare & Medicaid Services' (CMS') current thinking on this topic.  It does not create or confer any rights for or on any person and does not operate to bind CMS or the public.  Where warranted by unique circumstances, CMS may consider a modified approach if it satisfies the requirements of the applicable statutes and regulations.  Individuals interested in discussing an alternative approach are encouraged to contact the CMS staff responsible for this guidance. 

Contact:  Rosemarie Hakim, PhD
Email:  rosemarie.hakim@cms.hhs.gov

For information regarding national coverage determinations (NCDs), local coverage determinations (LCDs), or other coverage materials, including those referenced throughout this guidance document, please see the Medicare Coverage Center website at http://www.cms.hhs.gov/center/coverage.asp.%20 

I.     Purpose of this Guidance Document

While CMS has several policy vehicles relating to evidence development activities including the investigational device exemption (IDE), the clinical trial policy, national coverage determinations and local coverage determinations, this guidance document is principally intended to help the public understand CMS’ implementation of coverage with evidence development (CED) through the national coverage determination process.  The guidance describes the history of CED, its statutory basis, and reflects public comments received on a draft guidance document published on November 12, 2012.  We received comments representing medical technology trade associations, individual drug and device manufacturing companies, physician professional societies, and the general public, which are addressed in a separate document.

II.     Background

CED is a paradigm whereby Medicare covers items and services on the condition that they are furnished in the context of approved clinical studies or with the collection of additional clinical data.  In making coverage decisions involving CED, CMS decides after a formal review of the medical literature to cover an item or service only in the context of an approved clinical study or when additional clinical data are collected to assess the appropriateness of an item or service for use with a particular beneficiary. 

History

Although Medicare generally does not cover experimental or investigational items and services as reasonable and necessary under section 1862(a)(1)(A) of the Act (and regulations at 42 CFR 411.15(o)), the Medicare program has adopted coverage policies that relate to clinical studies before the formal articulation in 2006 of the CED paradigm.  In 1995, CMS (then known as the Health Care Financing Administration (HCFA)) established coverage for certain items furnished in FDA-approved IDE trials (42 CFR 405 Subpart B).  CMS updated the coverage criteria for certain items and services in IDE trials effective January 1, 2015 (78 FR 74429-74437). In response to a June 7, 2000 Executive Memorandum, CMS (then HCFA) issued an NCD for coverage under the authority of section 1862(a)(1)(E) of routine costs in clinical trials, commonly referred to as the Clinical Trial Policy (Section 310.1 of the NCD Manual).  The Clinical Trial Policy was revised in 2007 through the NCD reconsideration process. 

In 2005, CMS began to implement NCDs requiring study participation (for example: NCD Manual §50.3 Cochlear Implantation Moderate Hearing Loss; NCD Manual §220.6.13 FDG PET for Dementia and Neurodegenerative Diseases).  Subsequently, CMS issued guidance on the CED paradigm in the 2006 guidance document entitled National Coverage Determinations with Data Collection as a Condition of Coverage: Coverage with Evidence Development.  The 2006 document introduced two arms of CED which included Clinical Study Participation (CSP) and Coverage with Appropriateness Determination (CAD).  While the concepts behind both arms are described in this document, we are no longer using this terminology to distinguish the two.

While CMS has embraced an evidence-based medicine coverage paradigm, CMS is increasingly challenged to respond to requests for coverage of certain items and services when we find that the expectations of interested parties are disproportionate to the existing evidence base.  At the same time, we believe that CMS should support evidence development for certain innovative technologies that are likely to show benefit for the Medicare population, but where the available evidence base does not provide a sufficiently persuasive basis for coverage outside the context of a clinical study, which may be the case for new technologies, or for existing technologies for which the evidence is incomplete.

Coverage in the context of ongoing clinical research protocols or with additional data collection can expedite earlier beneficiary access to innovative technology while ensuring that systematic patient safeguards, including assurance that the technology is provided to clinically appropriate patients, are in place to reduce the risks inherent to new technologies, or to new applications of older technologies. 

III.     Statutory Basis

Sections 1862(a)(1)(A) and 1862(a)(1)(E) of the Social Security Act (42 U.S.C. 1395y)

Sections 1862(a)(1)(A) and 1862(a)(1)(E) of the Act read:

Two of the earliest CED decisions were made under section 1862(a)(1)(A) of the Act.  In 2005, CMS made two national coverage determinations, the NCD for automatic implantable cardioverter-defibrillators (ICDs) (NCD Manual §20.4) and the NCD for 18F-fludeoxyglucose positron emission tomography (FDG PET) for oncologic conditions (NCD Manual §220.6.17).  In both NCDs, data were submitted to CMS-approved registries.  While the intent of these CED NCDs was to monitor the appropriateness of use of these items and services, we recognized that the data could also be used to generate useful clinical evidence.  More recent NCDs have tended to rely on section 1862(a)(1)(E) of the Act, in which CED is used to support clinical research.

Section 1142 of the Act

Section 1142 of the Act describes the authority of the Agency for Healthcare Research and Quality (AHRQ) to conduct and support research on outcomes, effectiveness, and appropriateness of services and procedures to identify the most effective and appropriate means to prevent, diagnose, treat, and manage diseases, disorders, and other health conditions.  That section includes a requirement that the Secretary assure that AHRQ research priorities under Section 1142 appropriately reflect the needs and priorities of the Medicare program. 

The coordination of AHRQ priorities under section 1142 with the needs and priorities of the Medicare program is accomplished through direct collaboration between the AHRQ and CMS.  AHRQ reviews all CED NCDs established under Section 1862(a)(1)(E) of the Act.  Consistent with section 1142, AHRQ also indicates its support for clinical research studies that CMS determines address the CED questions and meet the general standards for CED studies.

IV.     Principles governing the application of CED:

• CED will occur within the coverage determination process, which is transparent and open to public comment.    
• CED will not be used when less restricted coverage is justified by the available evidence. 
• CED will generally expand access to medical technologies for beneficiaries.
• CED will lead to the production of evidence complementary to existing medical evidence.
• CED will not duplicate or replace the FDA’s authority in assuring the safety, efficacy, and security of drugs, biological products, and devices.
• CED will not assume the NIH’s role in fostering, managing, or prioritizing clinical trials. 
• CED will be consistent with federal laws, regulations, and patient protections.

V.     CED under Section 1862(a)(1)(A)

In some cases CMS requires as a condition of coverage for certain items and services under section 1862(a)(1)(A) the collection of additional clinical data, which allows CMS to ensure that items and services are provided appropriately to patients meeting specific characteristics as described in an NCD. 

VI.     Requirements for CED under Section 1862(a)(1)(E)

As CMS and AHRQ have gained experience with CED under section 1862(a)(1)(E), we have developed the following list of general requirements for clinical studies supported by AHRQ.  We expect that all CED clinical studies under section 1862(a)(1)(E) will demonstrate adherence to these requirements, which will be included (with occasional minor modifications) in the applicable coverage determination.  We would not anticipate approving a study that does not meet these requirements.

1. The principal purpose of the study is to test whether the item or service meaningfully improves health outcomes of affected beneficiaries who are represented by the enrolled subjects.  
2. The rationale for the study is well supported by available scientific and medical evidence.
3. The study results are not anticipated to unjustifiably duplicate existing knowledge.
4. The study design is methodologically appropriate and the anticipated number of enrolled subjects is sufficient to answer the research question(s) being asked in the National Coverage Determination.
5. The study is sponsored by an organization or individual capable of completing it successfully.
6. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found in the Code of Federal Regulations (CFR) at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it is also in compliance with 21 CFR Parts 50 and 56.  In addition, to further enhance the protection of human subjects in studies conducted under CED, the study must provide and obtain meaningful informed consent from patients regarding the risks associated with the study items and/or services, and the use and eventual disposition of the collected data.
7. All aspects of the study are conducted according to appropriate standards of scientific integrity.
8. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements.
9. The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Such studies may meet this requirement only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options.
10. The clinical research studies and registries are registered on the www.ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject.  Registries are also registered in the Agency for Healthcare Quality (AHRQ) Registry of Patient Registries (RoPR).
11. The research study protocol specifies the method and timing of public release of all prespecified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early.  The results must be made public within 12 months of the study’s primary completion date, which is the date the final subject had final data collection for the primary endpoint,   even if the trial does not achieve its primary aim.  The results must include number started/completed, summary results for primary and secondary outcome measures, statistical analyses, and adverse events. Final results must be reported in a publicly accessibly manner; either in a peer-reviewed scientific journal (in print or on-line), in an on-line publicly accessible registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for studies with negative or incomplete results).
12. The study protocol must explicitly discuss beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations in the trial.  If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary.
13. The study protocol explicitly discusses how the results are or are not expected to be generalizable to affected beneficiary subpopulations. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility.

VII.     Coverage of Control Groups in CED Studies under 1862(a)(1)(E): Standard of Care and Placebo controls; and Blinding or Masking

In the most rigorous experimental designs, a new treatment is compared to something else for purposes of studying effectiveness and to control for the placebo effect or other observation biases.  For example, a carotid stent procedure may be compared to the current best standard of medical care; in a drug trial, some subjects may be randomized to receive a placebo medication; or to study an orthopedic procedure for back pain, the control group may be randomized to receive a placebo procedure to preserve blinding.  The purpose of a placebo control group is to account for the placebo effect; that is, to exclude from the study certain effects that do not depend on the treatment itself. Such factors can include participants’ knowledge that they are receiving a treatment and receiving extra attention from health care professionals, and the expectations of a treatment's effectiveness by those running the research study. Without a placebo group to compare against, it is not possible to know or measure the effect of the treatment itself.  These methods effectively blind or mask patients and investigators, if the trial is double blinded, to their treatment assignment.  Placebo controls can be critical in evaluating endpoints that may be vulnerable to subjective interpretation, such as changes in pain levels or depression.  

While the items and services furnished as placebo controls may not be considered reasonable and necessary under section 1862(a)(1)(A) of the statute because they have no health benefit, these items and services can be necessary in order to conduct a scientifically valid clinical study.  As such, these services can be covered under section 1862(a)(1)(E) when furnished in the context of a clinical study where coverage is necessary to preserve the scientific integrity of the study. 

In section 184 of the  Medicare Improvements for Patients and Providers of 2008 (MIPPA), Congress added a new subsection 1833(w) of the Act which allows the Secretary to develop alternative methods of payment under Medicare Part B for items and services provided under clinical trials and comparative effectiveness studies sponsored or supported by an agency of the Department of Health & Human Services: “to the extent such alternative methods are necessary to preserve the scientific validity of such trials or studies, such as in the case where masking the identity of interventions from patients and investigators is necessary to comply with the particular trial or study design.”  We may use this authority, for example, to ensure that a placebo control group is not undermined by differences in Medicare payment methods that would otherwise reveal the group to which a patient has been assigned.  

Under CED, routine costs of an approved clinical trial in both the treatment arm and the control (standard of care or placebo) arm are paid.  Routine costs include all items and services that are otherwise generally available to Medicare beneficiaries (i.e., there exists a benefit category, coverage is not statutorily excluded, and there is not a national non-coverage decision) that are provided in either the experimental or the control arms of a clinical trial.

VIII.      Ending CED

We expect that the studies conducted under a CED NCD will produce evidence that will lead to revisions to Medicare coverage policies, such as to the NCD that included CED as a component of the decision (for example, NCDs for oncologic uses of FDG PET, and ventricular assist devices).  Studies with a specific design, such as randomized clinical trials, have established start and end dates.  When enrollment and follow up are complete, the data are to be analyzed and published in the peer reviewed medical literature. 

When an NCD requires CED under 1862(a)(1)(E), it is because the available evidence about a particular item or service is insufficient to support coverage outside the context of a well-designed clinical research study.  While CMS does not believe that beneficiaries should have broad access to these items or services when scientific results are unavailable, there are ways to avoid or minimize the gap between the end of clinical studies under a CED NCD and a revised coverage decision based on the results of CED studies.  Sponsors should build interim analyses into their study design and communicate these results to CMS.  If the results support consideration of a change in the coverage status of the item or service, a revised NCD could be expedited.

A CED cycle is considered completed when CMS completes a reconsideration of the CED coverage decision, and removes the requirement for study participation as a condition of coverage.  As with any NCD, any member of the public may request to reopen the NCD that requires CED.   In addition, CMS may internally generate a request to develop or reconsider an NCD.  Once initiated, this process is similar to the externally-generated request process. CMS will review the evidence generated by the CED studies and any other available evidence.  The NCD process is described in the Federal Register (78 FR 48164).

IX.     Transparency of CED

The NCD process, in general, is a transparent one.  Requesters may meet with CMS and frequent, informal contact is possible.  A tracking sheet is posted on the CMS website that allows interested individuals to participate in and monitor the progress of the review.  A proposed decision is issued for public comment within six months of opening the NCD review.  The proposed decision generally includes details of CED study design, which are also open to public comment.  Consistent with section 1862(l)(3)(B) of the Act, we provide 30 days for public comment on the proposal.  There may be a Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) meeting, which is open to the public.  Not later than 60 days after the close of the 30-day public comment period, we issue a final NCD.  The LCD process is also transparent.  The MACs issue a draft LCD, receives public comments, and responds to those comments before finalizing an LCD.

CMS expects that results of all CED approved studies under 1862(a)(1)(E) will be analyzed and published in peer reviewed clinical journals.  CMS has used and will continue to use the results of published CED studies to inform new or revised coverage decisions.  CMS intends to maintain information on ongoing CED research studies via NCDs on its website along with links to the ClinicalTrials.gov website maintained by the National Library of Medicine and the Registry of Patient Registries (RoPR) maintained by AHRQ when appropriate.  We also plan to include links on our website to CED study results.

All studies seeking Medicare coverage under CED should be registered with ClinicalTrials.gov and if the CED study is a registry, on AHRQ’s Registry of Patient Registries (RoPR) (see standard j).  Registrants at ClinicalTrials.gov must submit a standardized set of data elements to describe the study design, eligible populations, outcome measures, and other parameters and results.  Registration on this site, for most studies, serves as a vehicle for Medicare beneficiaries to learn about, and identify studies in which they may want to participate.  When reporting of results are required, it also offers an assurance of quality because, generally, public access to information enables a higher level of accountability in the accurate reporting of the clinical study protocol and results, and in the conduct of the trial itself.  This accountability derives both from public access to information about studies and from the risk of penalty for submitting false or misleading clinical trial information. Registration with ClinicalTrials.gov also assures that Medicare beneficiaries and their treating healthcare professionals will have pertinent information about CED studies, and we expect this may facilitate better informed decision-making.  Similarly, registry studies that registered at AHRQ’s RoPR are advised to follow the set of best practices on methodologies and on the technical, legal, ethical, and analytical considerations for designing, operating, and utilizing registries and registry data as described in AHRQ’s Registries for Evaluating Patient Outcomes: A User’s Guide.

X.     The role of Medicare Administrative Contractors (MACs) and Coverage with Evidence Development

Although the definition of local coverage determination (LCD) in the Social Security Act does not support the use of CED under 1862(a)(1)(E) of the Act, MACs may use LCDs to determine coverage of items and services to the extent that they do not conflict with national Medicare policy. 

XI.     Additional Information

We believe that CED can be applied to coverage of drugs and biologics.  However, we do not contemplate the application of CED to drugs or biologics that have not been approved by FDA for at least one indication.  Additionally, many drugs and biologics are self-administered, falling outside the scope of Medicare Part A and B, and therefore, outside the scope of CED.  Self-administered drugs are usually addressed under the scope of Medicare Part D.