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McDonagh M. Drug Class Review: Disease-Modifying Drugs for Multiple Sclerosis: Single Drug Addendum: Fingolimod: Final Original Report [Internet]. Portland (OR): Oregon Health & Science University; 2011 Feb.

Methods

Inclusion Criteria

Population(s)

Intervention

Generic NameTrade NameForm
FingolimodGilenya™Capsule

Comparators

Generic nameTrade name(s)Form(s)
Glatiramer acetateCopaxone®Injectable
Interferon beta-1aAvonex®
Rebif®
Vial
Syringe
Interferon beta-1bBetaseron®
Extavia®a
Vial
Injectable
MitoxantroneNovantrone®Injectable
NatalizumabTysabri®Vial
Placebo
a

Not available in Canada.

Effectiveness Outcomes

Multiple sclerosis
  • Disability
  • Clinical exacerbation/relapse
  • Quality of life
  • Functional outcomes (e.g., wheelchair use, time lost from work)
  • Persistence (discontinuation rates)
Clinically isolated syndrome
  • Disability
  • Clinical exacerbation/relapse of symptoms
  • Quality of life
  • Functional outcomes (e.g. time lost from work)
  • Progression to multiple sclerosis diagnosis
  • Persistence (discontinuation rates)

Safety Outcomes

  • Overall rate of adverse effects
  • Withdrawals due to adverse effects
  • Serious adverse events
  • Specific adverse events (e.g. cardiovascular, hepatotoxicity, progressive multifocal leukoencephalopathy, secondary cancers, infections, etc.)

Study Designs

  1. For effectiveness, controlled clinical trials and good-quality systematic reviews. Observational studies with 2 concurrent arms of at least 100 patients each and duration ≥1 year are included (e.g. cohort, case-control).
  2. For harms, in addition to controlled clinical trials, observational studies are included.

Literature Search

We searched Ovid MEDLINE® (1996-week 4 December 2010), Ovid MEDLINE® In-Process & Other Non-Indexed Citations (November 08, 2010), the Cochrane Database of Systematic Reviews® (4th Quarter, 2010),the Cochrane Central Register of Controlled Trials ® (4th Quarter, 2010), and Database of Abstracts of Reviews of Effects (DARE) using included drugs, indications, and study designs as search terms (see Appendix A for complete search strategies). We attempted to identify additional studies through hand searches of reference lists of included studies and reviews. In addition, we searched the US Food and Drug Administration Center for Drug Evaluation and Research website for medical and statistical reviews of individual drug products. Finally, we requested dossiers of published and unpublished information from the pharmaceutical manufacturer of fingolimod. The dossier received was screened for studies or data not found through other searches. All citations were imported into an electronic database (Endnote® version X2, Thomson Reuters).

Study Selection

Selection of included studies was based on the inclusion criteria created by the Drug Effectiveness Review Project participants, as described above. Two reviewers independently assessed titles and abstracts of citations identified through literature searches for inclusion using the criteria below. Full-text articles of potentially relevant citations were retrieved and again were assessed for inclusion by 2 reviewers. Disagreements were resolved by consensus. Posters of studies presented at conferences were considered for inclusion on the basis of our ability to conduct a thorough quality assessment based on the information provided in the poster. Results published only in abstract form were not included because inadequate details were available for quality assessment.

Data Abstraction

The following data were abstracted from included trials: eligibility criteria; interventions (dose and duration); population characteristics, including sex, age, ethnicity, and diagnosis; numbers randomized, withdrawn, lost to follow-up and analyzed; and results for each included outcome. We recorded intention-to-treat results when reported. If true intention-to-treat results were not reported, but loss to follow-up was very small, we considered these results to be intention-to-treat results. In cases where only per protocol results were reported, we calculated intention-to-treat results if the data for these calculations were available. Data abstraction was performed independently by 2 reviewers and differences were resolved by consensus.

Validity Assessment

We assessed the internal validity (quality) of trials based on the predefined criteria (see www.ohsu.edu/drugeffectiveness). These criteria are based on the US Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination (United Kingdom) criteria.5, 6 We rated the internal validity of each trial based on the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts, attrition, crossover, adherence, and contamination; loss to follow-up; and the use of intention-to-treat analysis. Trials that had a fatal flaw were rated poor quality; trials that met all criteria were rated good quality; the remainder were rated fair quality. As the fair-quality category is broad, studies with this rating vary in their strengths and weaknesses: the results of some fair-quality studies are likely to be valid, while others are only possibly valid. A poor-quality trial is not valid; the results are at least as likely to reflect flaws in the study design as a true difference between the compared drugs. A fatal flaw is reflected by failure to meet combinations of items of the quality assessment checklist. A particular randomized trial might receive 2 different ratings, one for effectiveness and another for adverse events.

The criteria used to rate observational studies of adverse events reflect aspects of the study design that are particularly important for assessing adverse event rates. We rated observational studies as good quality for adverse event assessment if they adequately met 6 or more of the 7 predefined criteria, fair quality if they met 3 to 5 criteria, and poor quality if they met 2 or fewer criteria.

Included systematic reviews were also rated for quality. We rated the internal validity based a clear statement of the questions(s); reporting of inclusion criteria; methods used for identifying literature (the search strategy), validity assessment, and synthesis of evidence; and details provided about included studies. Again, these studies were categorized as good when all criteria were met.

Two reviewers independently assessed each study and differences were resolved by consensus.

Grading the Strength of Evidence

We graded strength of evidence based on the guidance established for the Evidence-based Practice Center Program of the Agency for Healthcare Research and Quality.7 Developed to grade the overall strength of a body of evidence, this approach incorporates 4 key domains: risk of bias (including study design and aggregate quality), consistency, directness, and precision of the evidence. It also considers other optional domains that may be relevant for some scenarios, such as a dose-response association, plausible confounding that would decrease the observed effect, strength of association (magnitude of effect), and publication bias.

Table 2 describes the grades of evidence that can be assigned. Grades reflect the strength of the body of evidence to answer key questions on the comparative effectiveness, efficacy, and harms of fingolimod. Grades do not refer to the general efficacy or effectiveness of pharmaceuticals. Two reviewers independently assessed each domain for each outcome and differences were resolved by consensus.

Table Icon

Table 2

Definitions of the grades of overall strength of evidence.

For the direct comparisons, the strength of the evidence was rated for the 2 primary effectiveness outcomes, relapse rate and time to progression, as well as overall adverse events and withdrawal due to adverse events.

Data Synthesis

We constructed evidence tables showing the study characteristics, quality ratings, and results for all included studies. We reviewed studies using a hierarchy of evidence approach, where the best evidence is the focus of our synthesis for each question, population, intervention, and outcome addressed. Studies that evaluated fingolimod against another disease-modifying drug provided direct evidence of comparative effectiveness and adverse event rates. Where possible, these data are the primary focus. Direct comparisons were preferred over indirect comparisons; similarly, effectiveness and long-term safety outcomes were preferred to efficacy and short-term tolerability outcomes.

In theory, trials that compare fingolimod with other drug classes or with placebos can also provide evidence about effectiveness. This is known as an indirect comparison and can be difficult to interpret for a number of reasons, primarily heterogeneity of trial populations, interventions, and outcomes assessment. Data from indirect comparisons are used to support direct comparisons, where they exist, and are used as the primary comparison where no direct comparisons exist.

Quantitative analyses were conducted using meta-analyses of outcomes reported by a sufficient number of studies that were homogeneous enough that combining their results could be justified. In order to determine whether meta-analysis could be meaningfully performed, we considered the quality of the studies and the heterogeneity among studies in design, patient population, interventions, and outcomes. When meta-analysis could not be performed, the data were summarized qualitatively. Random-effects models were used to estimate pooled effects.9 Forest plots graphically summarize results of individual studies and of the pooled analysis.10

The Q statistic and the I2 statistic (the proportion of variation in study estimates due to heterogeneity) were calculated to assess heterogeneity in effects between studies.11, 12 Potential sources of heterogeneity were examined by analysis of subgroups of study design, study quality, patient population, and variation in interventions. Meta-regression models were used to formally test for differences between subgroups with respect to outcomes.9, 13 All meta-analyses were conducted using StatsDirect (Camcode, UK).

Public Comment

This report was posted to the Drug Effectiveness Review Project website for public comment. We received comments from 3 pharmaceutical companies: Biogen Idec, Novartis Pharmaceuticals Corporation, and Teva Pharmaceuticals.

Copyright © 2011 by Oregon Health & Science University.
Cover of Drug Class Review: Disease-Modifying Drugs for Multiple Sclerosis: Single Drug Addendum: Fingolimod
Drug Class Review: Disease-Modifying Drugs for Multiple Sclerosis: Single Drug Addendum: Fingolimod: Final Original Report [Internet].
McDonagh M.
Portland (OR): Oregon Health & Science University; 2011 Feb.

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