Table 1.

American Academy of Neurology Risk of Bias Classification System.

Class I
Randomized controlled clinical trial (RCT) in a representative population Triple masked studies (i.e. the patient, treating provider and outcome assessors are unaware of treatment assignment) Relevant baseline characteristics of treatment groups (or treatment order groups for cross-over trials) are presented and substantially equivalent between treatment groups, or there is appropriate statistical adjustment for differences Additional Class I criteria: Concealed allocation No more than 2 primary outcomes specified Exclusion and inclusion criteria clearly defined Adequate accounting of dropouts (with at least 80% of participants completing the study) and crossovers For non-inferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*: The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or non-inferiority The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose, and dosage adjustments are similar to those previously shown to be effective) The inclusion and exclusion criteria for participant selection and the outcomes of participants on the standard treatment are comparable with those of previous studies establishing efficacy of the standard treatment The interpretation of the study results is based on a per-protocol analysis that accounts for dropouts or crossovers For crossover trials, both period and carryover effects are examined and statistical adjustments performed, if appropriate
Class II
RCT that lacks one or 2 Class I criteria a–e (see above) Cohort studies employing methods that successfully match treatment groups on relevant baseline characteristics (e.g., propensity score matching) meeting Class I criteria b–e (see above) Randomized crossover trial missing one of the following 2 criteria: Period and carryover effects described Baseline characteristics of treatment order groups presented All relevant baseline characteristics are presented and substantially equivalent across treatment groups (or treatment order groups for crossover trials, or there is appropriate statistical adjustment for differences Masked or objective** outcome assessment
Class III
Controlled studies (including studies with external controls such as well-defined natural history controls) Crossover trial missing both of the following 2 criteria: c. Period and carryover effects d. Presentation of baseline characteristics A description of major confounding differences between treatment groups that could affect outcome** Outcome assessment performed by someone who is not a member of the treatment team
Class IV
Studies not meeting Class I, II or III criteria.

*Numbers i–iii in Class Ie are required for Class II in equivalence trials. If any one of the 3 is missing, the class is automatically downgraded to Class III.

**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).