Skip to main content
Advertisement
  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Genetics
    • Neuroimmunology & Neuroinflammation
    • Education
  • Online Sections
    • Neurology Video Journal Club
    • Inclusion, Diversity, Equity, Anti-racism, & Social Justice (IDEAS)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Topics A-Z
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center

Advanced Search

Main menu

  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Genetics
    • Neuroimmunology & Neuroinflammation
    • Education
  • Online Sections
    • Neurology Video Journal Club
    • Inclusion, Diversity, Equity, Anti-racism, & Social Justice (IDEAS)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Topics A-Z
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center
  • Home
  • Latest Articles
  • Current Issue
  • Past Issues
  • Residents & Fellows

User menu

  • Subscribe
  • My Alerts
  • Log in
  • Log out

Search

  • Advanced search
Neurology
Home
The most widely read and highly cited peer-reviewed neurology journal
  • Subscribe
  • My Alerts
  • Log in
  • Log out
Site Logo
  • Home
  • Latest Articles
  • Current Issue
  • Past Issues
  • Residents & Fellows

Share

November 11, 2003; 61 (9 suppl 5) Section IV: Experience of MS centers with anti-IFN\|[bgr ]\| antibodies

Statistical approaches to assessing the effects of neutralizing antibodies

IFNβ-1b in the pivotal trial of relapsing-remitting multiple sclerosis

A. John Petkau
First published November 10, 2003, DOI: https://doi.org/10.1212/01.WNL.0000092364.87561.F1
A. John Petkau
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Citation
Statistical approaches to assessing the effects of neutralizing antibodies
IFNβ-1b in the pivotal trial of relapsing-remitting multiple sclerosis
A. John Petkau
Neurology Nov 2003, 61 (9 suppl 5) S35-S37; DOI: 10.1212/01.WNL.0000092364.87561.F1

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Permissions

Make Comment

See Comments

Downloads
0

Share

  • Article
  • Figures & Data
  • Info & Disclosures
Loading

Abstract

Carefully conducted large-scale clinical trials have provided strong evidence that type I interferons favorably influence clinical and MRI outcomes in patients with multiple sclerosis. Some patients develop neutralizing antibodies (NAbs) to these treatments, reflecting an immune system response. The clinical significance of these NAbs has been uncertain because titers vary widely, and even highly elevated NAb titers decrease to undetectable levels in some patients. Whether NAbs decrease the efficacy of these treatments is a critically important scientific question. We argue that a longitudinal data analysis is the most appropriate approach to address this question.

In this presentation, we discussed this question in the context of the pivotal trial of interferon-β (IFNβ-1b) in patients with relapsing-remitting multiple sclerosis (RRMS).1–3⇓⇓ In this trial, 372 patients were randomized to placebo, low-dose, or high-dose treatment arms. Patients were followed for at least 3 years, with some patients undergoing blind follow-up evaluation for as long as 5 years. Serum samples were obtained quarterly, usually 12 or 36 hours after the most recent injection, and two assays were subsequently used for antibody measurement. The first, a viral cytopathic effect reduction assay (CPE), was carried out only on the serum samples collected for the first 3 years. Later, a myxovirus A (MxA) assay was developed and used on all serum samples available to the end of the blind follow-up period of up to 5 years.

Objectives of the Statistical Analysis.

We first discussed the key issue of appropriate statistical approaches to assess the effects of neutralizing antibodies (NAbs) on treatment efficacy. To address this, one first must decide what question is to be answered by the statistical analysis. Two possibilities are:

  1. How do the responses of the NAb+ subgroup and the NAb− subgroup compare?

  2. Is the switch from NAb− to NAb+ status associated with deterioration of responses in individual patients?

If the objective is to answer the first question, then cross-sectional analyses that compare the responses of NAb+ and NAb− patients at fixed times (e.g., after 2 years on study) suffice. But if the second question is to be answered, then analyses that compare the responses of patients during periods when they are NAb− and periods when they are NAb+ are required. Such longitudinal analyses require a data set with responses of patients recorded repeatedly during the study period.

Cross-sectional comparisons of the relapse rates (and other responses) for the NAb+ and NAb− subgroups of the low-dose and high-dose treatment arms in the pivotal trial of IFNβ-1b in patients with RRMS have been reported.4 In this report, NAb status was based on the CPE assay, with the time of switching from NAb− to NAb+ status taken as the time of the first positive (at least 20 NU/mL) serum titer for patients having two consecutive positive titers at some point during follow-up evaluation. With this definition, 48 of the 125 patients (38%) on the low-dose arm and 43 of the 124 patients (35%) on the high-dose arm switched from NAb− to NAb+ status. Although more than 60% of these patients subsequently had at least one negative serum titer, a “once NAb+, always NAb+” convention was adopted for the analysis: a patient who switched from NAb− to NAb+ status was considered to remain NAb+ to the end of their follow-up period, irrespective of his or her later serum titers.

For each treatment arm, the relapse rates of NAb+ and NAb− patients were compared within successive 6-month periods (table 2 in reference 4). In these comparisons, the NAb+ subgroup included all patients who became NAb+ before the end of the period. For the high-dose treatment arm, the relapse rates of the NAb+ patients were significantly (p < 0.05) higher than those of the NAb− patients in the 19- to 24-month and the 25- to 30-month periods. Further, in the third year of follow-up evaluation, the relapse rates of these NAb+ patients were comparable with those of the patients receiving placebo. In contrast, for the low-dose treatment arm, the relapse rates of the NAb+ patients were generally lower than those of the NAb− patients in the first 2 years of follow-up evaluation, and the difference was statistically significant in the 19- to 24-month period.

These cross-sectional comparisons are complicated by the changing composition of the NAb+ and NAb− subgroups over time: as patients switch from NAb− to NAb+ status, they switch membership from the NAb− subgroup to the NAb+ subgroup. A different approach, used in most other reports on the effects of NAbs, focuses on the “eventually NAb+” subgroup of patients: those patients who achieve NAb+ status at some point during the trial. The remaining patients make up the “never NAb+” subgroup. Comparisons of the relapse rates of the eventually NAb+ and the never NAb+ subgroups on the low-dose and high-dose treatment arms of the pivotal trial of IFNβ-1b in patients with RRMS led to results that are qualitatively similar to those reported.4

Limitations of Cross-Sectional Analyses.

Some interpret these results for the high-dose treatment arm in the pivotal trial of IFNβ-1b in patients with RRMS (and the results of similar cross-sectional comparisons from other studies) as convincing evidence that the presence of NAbs decreases the efficacy of treatments. Setting aside the issue of how the contrary result observed in the low-dose treatment arm of the pivotal trial of IFNβ-1b in patients with RRMS might be explained, we discussed two serious limitations of such cross-sectional comparisons of the eventually NAb+ and never NAb+ subgroups:

  1. A lack of statistical power of such subgroup comparisons because of the reduced sample sizes involved, and

  2. The cause of any difference detected by such comparisons is unclear because these subgroups may differ on baseline covariates (possibly unmeasured) predictive of NAb development and reduced efficacy.

It is easy to evaluate the power of such subgroup comparisons for a two-armed clinical trial with n patients randomly assigned to each arm. Suppose the trial was designed based on an endpoint analysis of the means of a continuous primary outcome, with type I error of 5% and specified power. Suppose further that the endpoint responses of the eventually NAb+ patients have the statistical behavior postulated for the patients receiving placebo when the trial was designed and the never NAb+ patients behave as was postulated for the treatment patients. The power of the comparison of the endpoint values of the eventually NAb+ and never NAb+ subgroups can then be expressed in terms of the power specified for the clinical trial and the proportion of patients on the treatment arm who belong to the eventually NAb+ subgroup. The resulting power is illustrated in the figure for various values of these inputs. For example, if the power specified for the clinical trial was 80% and the proportion of eventually NAb+ patients on the treatment arm is 40% (slightly more than in the pivotal trial of IFNβ-1b in patients with RRMS), then the power of this comparison of the eventually NAb+ and never NAb+ subgroups is only 28%.

Figure
  • Download figure
  • Open in new tab
  • Download powerpoint

Figure. Power of cross-sectional comparisons of the eventurally NAb+ and never NAb+ subgroups in a two-armed clinical trial.

The second limitation is more fundamental. Because no randomization or other device of experimental design has been used to ensure that the eventually NAb+ and never NAb+ subgroups are comparable in all other respects, it is not possible to conclude that an observed difference is because the eventually NAb+ patients developed NAbs whereas the never NAb+ patients did not. The difference could be the result of some other feature, possibly unmeasured, that differs systematically between these two subgroups. Such cross-sectional comparisons correspond to an observational study of the eventually NAb+ and never NAb+ subgroups and are susceptible to the influence of such confounding factors.

Longitudinal Data Analyses.

These limitations indicate a clear need for other statistical approaches to the analysis of the data. We then described an alternative approach based on longitudinal data analysis methods where the influence of NAbs in patients is assessed by comparing their responses during periods when they are NAb+ with periods when they are NAb−. Such an approach makes more complete use of the available longitudinal data and is intended to more clearly identify the impact of NAb status on the therapeutic efficacy of treatments because it directly addresses the question of whether the switch from NAb− to NAb+ status is associated with deterioration of responses in patients.

Any longitudinal data analysis requires repeated observations of the responses of patients over time, and the more frequently, the better. In the MS context, the approach is ideally suited for relapse data because effectively daily observations are available. However, it is less well suited for responses that are observed only infrequently in patients, such as annual MRI or “time to event” responses.

Finally, we described the results obtained using this approach when we analyzed the relapse rates, Expanded Disability Status Scale scores, and T2 lesion burdens for patients who changed from NAb− to NAb+ status during the pivotal trial of IFNβ-1b in patients with RRMS. The generalized estimating equations approach to longitudinal data analysis5,6⇓ was used to account for the correlation in the repeated responses over time in patients. Separate analyses were carried out for NAb status as identified by the CPE and MxA assays. The analyses adjust for possible time trends in the responses during the course of the trial and were carried out separately for each of the treatment arms. All the analyses were limited to the eventually NAb+ subgroups of patients.

In addition to assessing the effect of the switch from NAb− to NAb+ status, for the relapse data, we also presented the results of analyses examining therelative importance of high and low titers. The results of all of these analyses will be reported elsewhere (Petkau et al., submitted for publication, 2003), so details are not described here. The same longitudinal data analysis approach has been used to address this issue for data from the European trial of IFNβ-1b in patients with secondary progressive MS.7

Acknowledgments

The collaboration of Mr. Rick White, MSc, of the Statistical Consulting and Research Laboratory, Department of Statistics, University of British Columbia, in this research is gratefully acknowledged. This research was partially supported by a grant from the Natural Sciences and Engineering Research Council of Canada.

References

  1. ↵
    The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind placebo-controlled trial. Neurology. 1993; 43: 655–661.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    Paty DW, Li DKB, the UBC MS/MRI Study Group, and the IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind placebo-controlled trial. Neurology. 1993; 43: 662–667.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995; 45: 1277–1285.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first three years. Neurology. 1996; 47: 889–894.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Zeger SL, Liang KY. An overview of methods for the analysis of longitudinal data. Stat Med. 1992; 11: 1825–1839.
    OpenUrlPubMed
  6. ↵
    Liang KY, Zeger SL. Regression analysis for correlated data. Annu Rev Public Health. 1993; 14: 43–68.
    OpenUrlCrossRefPubMed
  7. ↵
    Polman C, Kappos L, White R, et al., for the European Study Groups in Interferon beta-1b in Secondary Progressive MS. Neutralizing antibodies during treatment of secondary progressive MS with interferon beta-1b. Neurology. 2003; 60: 37–43.
    OpenUrlAbstract/FREE Full Text

Disputes & Debates: Rapid online correspondence

No comments have been published for this article.
Comment

REQUIREMENTS

If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
  • Article
    • Abstract
    • Objectives of the Statistical Analysis.
    • Limitations of Cross-Sectional Analyses.
    • Longitudinal Data Analyses.
    • Acknowledgments
    • References
  • Figures & Data
  • Info & Disclosures
Advertisement

Related Articles

  • No related articles found.

Alert Me

  • Alert me when eletters are published
Neurology: 98 (24)

Articles

  • Ahead of Print
  • Current Issue
  • Past Issues
  • Popular Articles
  • Translations

About

  • About the Journals
  • Ethics Policies
  • Editors & Editorial Board
  • Contact Us
  • Advertise

Submit

  • Author Center
  • Submit a Manuscript
  • Information for Reviewers
  • AAN Guidelines
  • Permissions

Subscribers

  • Subscribe
  • Activate a Subscription
  • Sign up for eAlerts
  • RSS Feed
Site Logo
  • Visit neurology Template on Facebook
  • Follow neurology Template on Twitter
  • Visit Neurology on YouTube
  • Neurology
  • Neurology: Clinical Practice
  • Neurology: Genetics
  • Neurology: Neuroimmunology & Neuroinflammation
  • Neurology: Education
  • AAN.com
  • AANnews
  • Continuum
  • Brain & Life
  • Neurology Today

Wolters Kluwer Logo

Neurology | Print ISSN:0028-3878
Online ISSN:1526-632X

© 2022 American Academy of Neurology

  • Privacy Policy
  • Feedback
  • Advertise