![](media/image1.png){width="5.96875in" height="0.41944444444444445in"}

Top of Form

## Complete Summary

#### GUIDELINE TITLE

Neutralizing antibodies to interferon beta: assessment of their clinical
and radiographic impact: an evidence report. Report of the Therapeutics
and Technology Assessment Subcommittee of the American Academy of
Neurology.

#### BIBLIOGRAPHIC SOURCE(S)

Goodin DS, Frohman EM, Hurwitz B, O\'Connor PW, Oger JJ, Reder AT,
Stevens JC. Neutralizing antibodies to interferon beta: assessment of
their clinical and radiographic impact: an evidence report: report of
the Therapeutics and Technology Assessment Subcommittee of the American
Academy of Neurology. Neurology 2007 Mar 27;68(13):977-84. \[57
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17389300)

#### GUIDELINE STATUS

This is the current release of the guideline.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references a drug(s) for which important revised regulatory and/or
warning information has been released.

-   [March 16, 2005, Avonex (interferon
    beta-1a)](http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#avonex):
    Revisions to the WARNINGS, PRECAUTIONS/Drug Interactions and ADVERSE
    REACTIONS/Post-Marketing Experience sections and Medication Guide
    regarding reports of severe hepatic injury, including cases of
    hepatic failure.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Multiple sclerosis

#### GUIDELINE CATEGORY

Management\
Technology Assessment\
Treatment

#### CLINICAL SPECIALTY

Neurology

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

To evaluate the clinical and radiographic impact of neutralizing
antibodies to interferon-beta in the treatment of multiple sclerosis

#### TARGET POPULATION

Individuals being treated for multiple sclerosis with interferon beta
(IFN beta)

#### INTERVENTIONS AND PRACTICES CONSIDERED

1.  Treatment with interferon beta (IFN beta): IFN beta-1a, IFN beta-1b

2.  Measurement of seroprevalence and titers of neutralizing antibodies
    (NAbs) to interferon beta

3.  Clinical and radiologic assessment of multiple sclerosis activity

#### MAJOR OUTCOMES CONSIDERED

-   Persistence of neutralizing antibodies (NAb) to interferon beta (IFN
    beta)

-   Clinical impact of NAb to IFN beta on severity of multiple sclerosis
    (MS)

-   Radiographic impact of Nab to IFN beta on severity of MS

-   Rate of NAb production

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Hand-searches of Published Literature (Primary Sources)\
Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

A panel of neurologists analyzed the evidence relating to neutralizing
antibodies (NAbs) using a literature search with the key words
antibodies and interferon beta. The MEDLINE database was searched from
1966 to 2005. In addition, the reference lists of the articles
identified were reviewed to identify articles not found by the computer
search. Using these methods 627 articles were identified.

#### NUMBER OF SOURCE DOCUMENTS

Twenty-seven articles in the English language reporting clinical or
radiographic outcomes in both antibody positive and antibody negative
patients were reviewed.

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

**Classification of Evidence for Therapeutic Intervention**

**Class I**: Prospective, randomized, controlled clinical trial with
masked outcome assessment, in a representative population. The following
are required: a) primary outcome(s) clearly defined; b)
exclusion/inclusion criteria clearly defined; c) adequate accounting for
dropouts and crossovers with numbers sufficiently low to have minimal
potential for bias; and d) relevant baseline characteristics are
presented and substantially equivalent among treatment groups or there
is appropriate statistical adjustment for differences.

**Class II**: Prospective matched group cohort study in a representative
population with masked outcome assessment that meets a--d above OR a
randomized controlled trial in a representative population that lacks
one criteria a--d.

**Class III**: All other controlled trials (including well-defined
natural history controls or patients serving as own controls) in a
representative population, where outcome is independently assessed, or
independently derived by objective outcome measurement.\*

**Class IV**: Evidence from uncontrolled studies, case series, case
reports, or expert opinion.

\* Objective outcome measurement: an outcome measure that is unlikely to
be affected by an observer\'s (patient, treating physician,
investigator) expectation or bias (e.g., blood tests, administrative
outcome data).

#### METHODS USED TO ANALYZE THE EVIDENCE

Systematic Review with Evidence Tables

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

The entire panel classified the level of evidence provided by each
article. Several studies were classified as providing Class II evidence,
despite a randomized placebo-controlled trial design. This is because
evidence associated with NAb status is always post hoc and because
patients can never be randomized with respect to their ultimate Nab
status. Therefore, one can never exclude the possibility that there are
patient-specific factors, which both predispose certain patients to the
development of Nabs and, in an unrelated manner, make them more or less
susceptible to multiple sclerosis (MS) attacks. If so, this will make
Nabs artificially appear to increase or decrease the MS attack rate,
underscoring the fact that evidence of an association cannot prove
causation.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

**Classification of Recommendations**

**A** = Established as effective, ineffective, or harmful for the given
condition in the specified population. (Level A rating requires at least
two consistent Class I studies.)

**B** = Probably effective, ineffective, or harmful for the given
condition in the specified population. (Level B rating requires at least
one Class I study or at least two consistent Class II studies.)

**C** = Possibly effective, ineffective, or harmful for the given
condition in the specified population. (Level C rating requires at least
one Class II study or two consistent Class III studies.)

**U** = Data inadequate or conflicting; given current knowledge,
treatment is unproven.

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

Draft guidelines were reviewed for accuracy, quality, and thoroughness
by the American Academy of Neurology (AAN) members, topic experts, and
pertinent physician organizations.

Final guidelines were approved by the Therapeutics and Technology
Subcommittee on July 28, 2006; by the Practice Committee on November 11,
2006; and by the AAN Board of Directors on January 4, 2007.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

Definitions of the strength of the recommendations (A, B, C, U) and
classification of the evidence (Class I through Class IV) are provided
at the end of the \"Major Recommendations\" field.

1.  Treatment of multiple sclerosis (MS) with interferon beta (IFN beta)
    (Avonex, Betaseron, or Rebif) is associated with the production of
    neutralizing antibodies (Nabs) to the IFN beta molecule (**Level
    A**).

2.  It is probable that the presence of NAbs, especially in persistently
    high titers, is associated with a reduction in the radiographic and
    clinical effectiveness of IFN beta treatment (**Level B**).

3.  It is probable that the rate of NAb production is less with IFN
    beta-1a treatment compared to IFN beta-1b treatment (**Level B**).
    However, because of the variability of the prevalence data, and
    because Nabs disappear in the majority of patients even with
    continued treatment (especially in those with low-titer NAbs), the
    magnitude and persistence of any difference in seroprevalence
    between these forms of IFN beta is difficult to determine.

4.  It is probable that the seroprevalence of Nabs to IFN beta is
    affected by one or more of the following: its formulation, dose,
    route of administration, or frequency of administration (**Level
    B**). Regardless of the explanation, it seems clear that IFN beta-1a
    (as it is currently formulated for intramuscular injection) is less
    immunogenic than the current IFN beta preparations (either IFN
    beta-1a or IFN beta-1b) given multiple times per week subcutaneously
    (**Level A**). Because NAbs may disappear in many patients with
    continued therapy, the persistence of this difference is difficult
    to determine (**Level B**).

5.  Although the finding of sustained high-titer NAbs (\>100 to 200
    NU/mL) has been associated with a reduction in the therapeutic
    effects of IFN beta on radiographic and clinical measures of
    multiple sclerosis disease activity, there is insufficient
    information on the utilization of NAb testing to provide specific
    recommendations regarding when to test, which test to use, how many
    tests are necessary, and which cutoff titer to apply (**Level U**).

**[Definitions]{.underline}**:

**Classification of Evidence for Therapeutic Intervention**

**Class I**: Prospective, randomized, controlled clinical trial with
masked outcome assessment, in a representative population. The following
are required: a) primary outcome(s) clearly defined; b)
exclusion/inclusion criteria clearly defined; c) adequate accounting for
dropouts and crossovers with numbers sufficiently low to have minimal
potential for bias; and d) relevant baseline characteristics are
presented and substantially equivalent among treatment groups or there
is appropriate statistical adjustment for differences.

**Class II**: Prospective matched group cohort study in a representative
population with masked outcome assessment that meets a--d above OR a
randomized controlled trial in a representative population that lacks
one criteria a--d.

**Class III**: All other controlled trials (including well-defined
natural history controls or patients serving as own controls) in a
representative population, where outcome is independently assessed, or
independently derived by objective outcome measurement.\*

**Class IV**: Evidence from uncontrolled studies, case series, case
reports, or expert opinion.

\* Objective outcome measurement: an outcome measure that is unlikely to
be affected by an observer\'s (patient, treating physician,
investigator) expectation or bias (e.g., blood tests, administrative
outcome data).

**Classification of Recommendations**

**A** = Established as effective, ineffective, or harmful for the given
condition in the specified population. (Level A rating requires at least
two consistent Class I studies.)

**B** = Probably effective, ineffective, or harmful for the given
condition in the specified population. (Level B rating requires at least
one Class I study or at least two consistent Class II studies.)

**C** = Possibly effective, ineffective, or harmful for the given
condition in the specified population. (Level C rating requires at least
one Class II study or two consistent Class III studies.)

**U** = Data inadequate or conflicting; given current knowledge,
treatment is unproven.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is identified and graded for each
recommendation (see \"Major Recommendations\").

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

A better understanding of the impact of the development of neutralizing
antibodies (NAbs) in patients treated with interferon beta (IFN beta)
for multiple sclerosis on:

-   Reduction in biologic action and effectiveness of IFN beta

-   Persistence of NAB positivity

-   Differences in seroprevalence between different IFN beta agents

#### POTENTIAL HARMS

Not stated

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

This statement is provided as an educational service of the American
Academy of Neurology. It is based on an assessment of current scientific
and clinical information. It is not intended to include all possible
proper methods of care for a particular neurologic problem or all
legitimate criteria for choosing to use a specific procedure. Neither is
it intended to exclude any reasonable alternative methodologies. The AAN
recognizes that specific patient care decisions are the prerogative of
the patient and the physician caring for the patient, based on all of
the circumstances involved.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Living with Illness

#### IOM DOMAIN

Effectiveness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Goodin DS, Frohman EM, Hurwitz B, O\'Connor PW, Oger JJ, Reder AT,
Stevens JC. Neutralizing antibodies to interferon beta: assessment of
their clinical and radiographic impact: an evidence report: report of
the Therapeutics and Technology Assessment Subcommittee of the American
Academy of Neurology. Neurology 2007 Mar 27;68(13):977-84. \[57
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17389300)

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2007 Mar 27

#### GUIDELINE DEVELOPER(S)

American Academy of Neurology - Medical Specialty Society

#### SOURCE(S) OF FUNDING

American Academy of Neurology (AAN)

#### GUIDELINE COMMITTEE

Therapeutics and Technology Assessment Subcommittee

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Primary Authors*: D.S. Goodin, MD; E.M. Frohman, MD, FAAN; B. Hurwitz,
MD; P.W. O\'Connor, MD; J.J. Oger, MD, FRCPC, FAAN; A.T. Reder, MD; and
J.C. Stevens, MD, FAAN

*Therapeutics and Technology Assessment Subcommittee Members*: Janis
Miyasaki, MD, FAAN (*Co-Chair*); Yuen T. So, MD, PhD (*Co-Chair*);
Carmel Armon, MD, MHS, FAAN (*ex-officio*); Vinay Chaudhry, MD, FAAN;
Richard M. Dubinsky, MD, MPH, FAAN; Douglas S. Goodin, MD (*ex-officio,
facilitator*); Mark Hallett, MD, FAAN; Cynthia L. Harden, MD; Kenneth J.
Mack, MD, PhD; Fenwick T. Nichols III, MD; Michael A. Sloan, MD, MS,
FAAN; James C. Stevens, MD; Paul W. O\'Connor, MD, FAAN

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

The American Academy of Neurology (AAN) is committed to producing
independent, critical and truthful clinical practice guidelines (CPGs).
Significant efforts are made to minimize the potential for conflicts of
interest to influence the recommendations of this CPG. To the extent
possible, the AAN keeps separate those who have a financial stake in the
success or failure of the products appraised in the CPGs and the
developers of the guidelines. Conflict of interest forms were obtained
from all authors and reviewed by an oversight committee prior to project
initiation. AAN limits the participation of authors with substantial
conflicts of interest. The AAN forbids commercial participation in, or
funding of, guideline projects. Drafts of the guideline have been
reviewed by at least three AAN committees, a network of neurologists,
*Neurology* peer reviewers, and representatives from related fields. The
AAN Guideline Author Conflict of Interest Policy can be viewed at
[www.aan.com](http://www.aan.com/). With regards to this specific
report, all authors have stated that they have nothing to disclose.

#### GUIDELINE STATUS

This is the current release of the guideline.

#### GUIDELINE AVAILABILITY

Electronic copies: A list of American Academy of Neurology (AAN)
guidelines, along with a link to a Portable Document Format (PDF) file
for this guideline, is available at the [AAN Web
site](http://www.aan.com/go/practice/guidelines).

Print copies: Available from the AAN Member Services Center, (800)
879-1960, or from AAN, 1080 Montreal Avenue, St. Paul, MN 55116.

#### AVAILABILITY OF COMPANION DOCUMENTS

The following are available:

-   AAN guideline development process \[online\]. St. Paul (MN):
    American Academy of Neurology. Available from the [American Academy
    of Neurology Web
    site](http://www.aan.com/go/practice/guidelines/development).

-   Supplemental material. Overview of interferon biology. St. Paul
    (MN): American Academy of Neurology. Electronic copies: Available
    from the [American Academy of Neurology Web
    site](http://www.neurology.org/cgi/content/full/68/13/977/DC1).

#### PATIENT RESOURCES

None available

#### NGC STATUS

This summary was completed by ECRI Institute on May 14, 2007.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is
copyrighted by the American Academy of Neurology.

### DISCLAIMER

#### NGC DISCLAIMER

The National Guideline Clearinghouse™ (NGC) does not develop, produce,
approve, or endorse the guidelines represented on this site.

All guidelines summarized by NGC and hosted on our site are produced
under the auspices of medical specialty societies, relevant professional
associations, public or private organizations, other government
agencies, health care organizations or plans, and similar entities.

Guidelines represented on the NGC Web site are submitted by guideline
developers, and are screened solely to determine that they meet the NGC
Inclusion Criteria which may be found at
<http://www.guideline.gov/about/inclusion.aspx> .

NGC, AHRQ, and its contractor ECRI Institute make no warranties
concerning the content or clinical efficacy or effectiveness of the
clinical practice guidelines and related materials represented on this
site. Moreover, the views and opinions of developers or authors of
guidelines represented on this site do not necessarily state or reflect
those of NGC, AHRQ, or its contractor ECRI Institute, and inclusion or
hosting of guidelines in NGC may not be used for advertising or
commercial endorsement purposes.

Readers with questions regarding guideline content are directed to
contact the guideline developer.

Bottom of Form

© 1998-2008 National Guideline Clearinghouse

Date Modified: 11/10/2008