Recommendations
The Executive Committee of the National Clinical Advisory Board of the National Multiple Sclerosis Society (NMSS) has adopted the following recommendations regarding use of the current multiple sclerosis (MS) diseasemodifying agents: (in alphabetical order) glatiramer acetate (Copaxone®), interferon beta 1a-intramuscular (Avonex®), interferon beta 1asubcutaneous (Rebif®), interferon beta 1b (Betaseron®), mitoxantrone (Novantrone®), and natalizumab (Tysabri®).
The Society recognizes that the factors that enter into a decision to treat are complex and best analyzed by the individual patient’s neurologist.
- Initiation of treatment with an interferon beta medication or glatiramer
acetate should be considered as soon as possible following a definite
diagnosis of MS with active, relapsing disease, and may also be considered
for selected patients with a first attack who are at high risk for MS. - Natalizumab is generally recommended by the US Food and Drug
Administration (FDA) for patients who have had an inadequate response to,
or are unable to tolerate, other MS therapies. - Treatment with mitoxantrone may be considered for selected relapsing
patients with worsening disease or patients with secondary progressive MS
who are worsening, whether or not relapses are occurring. - A relapse (also known as an exacerbation or attack) is conventionally
defined as the development of new or recurring symptoms lasting for at
least 24 hours and separated from a previous attack by at least one month. - Patients’ access to medication should not be limited by the frequency of
relapses, age, or level of disability. - Treatment is not to be stopped while insurers evaluate for continuing
coverage of treatment, as this would put patients at increased risk for
recurrent disease activity. - Therapy is to be continued indefinitely, except when there is a clear
lack of benefit, there are intolerable side effects, or better therapy
becomes available. - All of these FDA-approved agents should be included in formularies and
covered by third-party payers so that physicians and patients can
determine the most appropriate agent on an individual basis. Failure to
do so is unethical and discriminatory. - Movement from one disease-modifying medication to another should
occur only for medically appropriate reasons. - None of the therapies has been approved for use by women who are
trying to become pregnant, are pregnant, or are nursing mothers.
The management of MS has been substantially advanced by the availability of the disease-modifying agents glatiramer acetate, interferon beta 1a and 1b, mitoxantrone, and natalizumab. A number of positive outcomes have been demonstrated in people with relapsing disease, including: reduction in the frequency of relapses1 (Betaseron,2–5 Avonex,6–9 Copaxone,10–11 Rebif,12–14 Novantrone,15 Tysabri16); reduction of brain-lesion development, as evidenced by magnetic resonance imaging (MRI) (Betaseron,2,17–18 Avonex,6–9 Copaxone,19–21 Rebif,12–14,22–23 Novantrone,24 Tysabri16); and the possible reduction of disability progression25 (Betaseron,2,17–18 Avonex,6–9 Copaxone,10–11 Rebif,12–14 Novantrone,15,24 Tysabri16).
Based on several years of experience with glatiramer acetate, interferon beta 1a and 1b, and mitoxantrone, and the more recent experience with natalizumab, it is the consensus of researchers and clinicians with expertise in MS that these agents are likely to reduce future disease activity and improve quality of life for many individuals with relapsing forms of MS, including those with secondary progressive disease who continue to have relapses. For those who are appropriate candidates for one of these drugs, treatment must be sustained for years. Cessation of treatment may result in a resumption of pre-treatment disease activity.26
Clinical trials are designed to evaluate the smallest number of people over the shortest period of time at the lowest cost. In order to accomplish this, inclusion criteria are necessarily narrow. These restricted parameters of clinical trials are not intended to regulate subsequent clinical use of the agent. Given the demonstrated benefit to people with MS of continued use of glatiramer acetate or interferon beta 1a or 1b, it is critical that each of these therapies be made available early, and that mitoxantrone and natalizumab be available for judicious use in aggressive relapsing disease and for those not responding to other disease-modifying therapies.
Background
In August 1994, the Quality Standards Subcommittee of the American Academy of Neurology (AAN) published an advisory statement on the selection of patients with MS for treatment with interferon beta 1b. Since then, five additional agents that modify the underlying disease process have been approved by the FDA: glatiramer acetate, interferon beta 1a (intravenous and subcutaneous formulations), mitoxantrone, and natalizumab. The benefits of these agents include direct evidence of disease modification,1–24 with inferred advantage to function and quality of life. The NMSS has maintained the timeliness of its consensus statement as additional agents have been studied and approved and new clinical trial data have become available. The current revision references all of the currently approved drugs.
Significant obstacles to obtaining these agents exist for appropriate candidates with MS. One is the lack of adequate information reaching primary care providers and general neurologists, who each may have only a few patients with MS, but collectively care for a large percentage of the MS population. Another is misunderstanding by some policy makers and insurers of the benefits of disease-management therapy, leading to inadequate coverage both initially and in the long term. This NMSS Disease Management Consensus Statement addresses these barriers, while acknowledging that the field is in flux and frequent review of recommendations is essential. Other obstacles, such as non-adherence to protocols and ‘drop-out’ by those already on drugs, are not addressed in this statement. The controversial area of neutralizing antibodies is mentioned only to state that sufficient data do not yet exist to base clinical decisions exclusively on the results of neutralizing antibody assays.
Discussion
The NMSS Disease Management Consensus Statement is an education and advocacy tool. It is a component of the Society’s professional education programs and is used to promote increased access to the approved disease modifying agents through legislative, judicial, and regulatory determinations. This Consensus Statement serves as a communication device for interactions with insurers, both nationally and locally. The following points highlight the issues:
- Among patients who report that they have relapsing–remitting MS, 43%
are not on disease-modifying therapy (NMSS-funded Sonya Slifka
Longitudinal MS Study, unpublished data). - This is of particular concern in light of numerous studies27–30 confirming that
axonal damage can coincide with destruction of the myelin sheath in the
MS disease process, suggesting that even early relapses that appear benign
may have permanent neurological consequences. Serial MRI studies31–32 of
individuals who are in clinical remission have demonstrated ongoing brainlesion
development and atrophy, despite a seemingly benign clinical course.
These findings strengthen the argument for early intervention with a
disease-modifying agent. - Government advocacy is critical to address regulations regarding areas
such as Medicare reimbursement for these agents. Legislative measures
are being debated regarding this and other issues, and some judicial
decisions have broad implications for access to treatment. In one
dispute, a patient was denied coverage for an MS disease-modifying
drug based on her non-ambulatory status. This Consensus Statement
supports efforts to expand governmental coverage to appropriate levels
for this and similar cases. - Variable and sometimes detrimental policies by insurers exist regarding the
use of the disease-modifying therapies, most likely resulting from
insufficient information about the short- and long-term benefits of these
drugs, or strict interpretation of the original trial criteria. Insurance barriers
include the following: - selection and availability of only one or two of the agents for
coverage, or a financial penalty to a patient for not being treated
initially with the highest tiered medication approved by his or her
health plan; - evaluation of the need for ongoing treatment by cessation of
treatment for a period of time; - interpretation of absence of attacks as an indication for
discontinuation of a drug; - arbitrary restrictions, such as ambulatory status, full recovery from an
attack, and age; - requirement of two relapses within the preceding year in order to
begin or continue on a drug; - placement of a ceiling on cost of treatment; and
- non-coverage of injectable agents.
The recommendations contained within this Consensus Statement address
these issues.
Process
The Executive Committee of the Society’s National Clinical Advisory Board (formerly called the National Medical Advisory Board) identified the need for the Society to develop and periodically update a formal position on the topic of disease management with the disease-modifying agents. A Medline search was conducted to document major studies in this area. A task force was activated to develop the statement, and the Executive Committee of the Society’s National Clinical Advisory Board provided a final review of the document. The document has been updated as needed, with all revisions reviewed by the Executive Committee.
Role of the National Multiple Sclerosis Society
The mission of the NMSS is to end the devastating effects of MS. Various strategies are employed, including professional education and advocacy. As a representative body and advocate for both people with MS and the medical/health professionals who provide their care, the Society is positioned to provide structure and support for a consensus statement to facilitate access to therapies for disease management. The NMSS has a nationwide network of chapters, each with a Clinical Advisory Committee composed of community health professionals with expertise in MS. Over 330,000 Society members have self-identified as having MS, and are part of a mailing list of almost 600,000 people interested in MS-related issues. Regular communication is made with these various audiences through national and chapter publications. This extensive network and process for dissemination will ensure that the updated Consensus Statement is expeditiously communicated to care providers, insurers, and people with MS.
