Bias Domain

Source of Bias

PossibleAnswers

Selection

(1) Was the method of randomization adequate?

Yes/No/Unsure

Selection

(2) Was the treatment allocation concealed?

Yes/No/Unsure

Performance

(3) Was the patient blinded to the intervention?

Yes/No/Unsure

Performance

(4) Was the care provider blinded to the intervention?

Yes/No/Unsure

Detection

(5) Was the outcome assessor blinded to the intervention?

Yes/No/Unsure

Attrition

(6) Was the drop‐out rate described and acceptable?

Yes/No/Unsure

Attrition

(7) Were all randomized participants analyzed in the group to which they were allocated?

Yes/No/Unsure

Reporting

(8) Are reports of the study free of suggestion of selective outcome reporting?

Yes/No/Unsure

Selection

(9) Were the groups similar at baseline regarding the most important prognostic indicators?

Yes/No/Unsure

Performance

(10) Were cointerventions avoided or similar?

Yes/No/Unsure

Performance

(11) Was the compliance acceptable in all groups?

Yes/No/Unsure

Detection

(12) Was the timing of the outcome assessment similar in all groups?

Yes/No/Unsure

Other

(13) Are other sources of potential bias unlikely?

Yes/No/Unsure

1

A random (unpredictable) assignment sequence.

Examples of adequate methods are coin toss (for studies with 2 groups), rolling a dice (for studies with 2 or more groups), drawing of balls of different colours, drawing of ballots with the study group labels from a dark bag, computer‐generated random sequence, preordered sealed envelopes, sequentially‐ordered vials, telephone call to a central office, and preordered list of treatment assignments.

Examples of inadequate methods are: alternation, birth date, social insurance/security number, date in which they are invited to participate in the study, and hospital registration number.

2

Assignment generated by an independent person not responsible for determining the eligibility of the patients.
This person has no information about the persons included in the trial and has no influence on the assignment sequence or on the decision about eligibility of the patient.

3

Index and control groups are indistinguishable for the patients or if the success of blinding was tested among the patients and it was successful.

4

Index and control groups are indistinguishable for the care providers or if the success of blinding was tested among the care providers and it was successful.

5

Adequacy of blinding should be assessed for each primary outcome separately. This item should be scored “yes” if the success of blinding was tested among the outcome assessors and it was successful or:
‐ for patient‐reported outcomes in which the patient is the outcome assessor (e.g. pain, disability): the blinding procedure is adequate for outcome assessors if participant blinding is scored ‘‘yes’’
‐ for outcome criteria assessed during scheduled visit and that supposes a contact between participants and outcome assessors (e.g., clinical examination): the blinding procedure is adequate if patients are blinded, and
the treatment or adverse effects of the treatment cannot be noticed during clinical examination
‐ for outcome criteria that do not suppose a contact with participants (e.g., radiography, magnetic resonance imaging): the blinding procedure is adequate if the treatment or adverse effects of the treatment cannot be
noticed when assessing the main outcome
‐ for outcome criteria that are clinical or therapeutic events that will be determined by the interaction between patients and care providers (e.g., cointerventions, hospitalization length, treatment failure), in which the care
provider is the outcome assessor: the blinding procedure is adequate for outcome assessors if item ‘‘4’’ (caregivers) is scored ‘‘yes’’
‐ for outcome criteria that are assessed from data of the medical forms: the blinding procedure is adequate if the treatment or adverse effects of the treatment cannot be noticed on the extracted data

6

The number of participants who were included in the study but did not complete the observation period or were not included in the analysis must be described and reasons given. If the percentage of withdrawals and drop‐outs does not exceed 20% for short‐term follow‐up and 30% for long‐term follow‐up and does not lead to substantial bias a ‘‘yes’’ is scored. (N.B. these percentages are arbitrary, not supported by literature).

7

All randomized patients are reported/analyzed in the group they were allocated to by randomization for the most important moments of effect measurement (minus missing values) irrespective of noncompliance and cointerventions.

8

All the results from all prespecified outcomes have been adequately reported in the published report of the trial. This information is either obtained by comparing the protocol and the report, or in the absence of the protocol, assessing that the published report includes enough information to make this judgment.

9

Groups have to be similar at baseline regarding demographic factors, duration and severity of complaints, percentage of patients with neurological symptoms, and value of main outcome measure(s).

10

If there were no cointerventions or they were similar between the index and control groups.

11

The reviewer determines if the compliance with the interventions is acceptable, based on the reported intensity, duration, number and frequency of sessions for both the index intervention and control intervention(s). For example, physiotherapy treatment is usually administered for several sessions; therefore it is necessary to assess how many sessions each patient attended. For single‐session interventions (e.g. surgery), this item is irrelevant.

12

Timing of outcome assessment should be identical for all intervention groups and for all primary outcome measures.

13

Other types of biases.
‐ Industry‐sponsored trials. The conflict of interest (COI) statement should explicitly state that the researchers have had full possession of the trial process from planning to reporting without funders with potential COI having any possibility to interfere in the process. If, for example, the statistical analyses have been done by a funder with a potential COI, usually ‘‘unsure’’ is scored.

Paracetamol, NSAIDs and opioid analgesics for chronic low back pain: network meta‐analysis

Patient or population: non‐specific chronic low back pain

Settings: primary and secondary care, (additional detail unknown at protocol stage)

Intervention: paracetamol, NSAIDs or opioid analgesics

Comparison: intervention A vs intervention B, of X possible comparisons (unknown at protocol stage)

Outcomes

Outcome type

Outcome measure

Comments

Pain

Continuous

Pain intensity on 0 to 100 mm VAS

Measured at end of treatment

Safety

Dichotomous

Proportion of participants that experience a serious adverse event during treatment

GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.