Draft synthesis: Counter-ion content and its effect on… — submissions
The 16 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
16 submissions were received. Each is published in full below with its declared interest, the secretariat response and the disposition. The Institute publishes submissions it did not accept in the same form as those it did.
A superseded version should remain reachable from the version that replaced it
The respondent states that the draft supersedes an earlier document and that a reader who cited the earlier version has no way to reach it from the new one, which makes it impossible to see what changed.
The respondent asks that every version carry a link both to what it supersedes and to what supersedes it.
The secretariat notes this submission. The corrections and versioning policy already requires bidirectional version links and every superseded document is retained at its own address.
No amendment arises. The requirement is stated in the corrections and versioning policy and the amendment log of this document links to the version it replaced. The respondent is correct that the link was absent from the draft page furnished for consultation, which was a defect of the consultation copy and not of the policy.
References should carry a persistent identifier for every cited source
Several references in the draft carry a journal, a year and a volume but no persistent identifier. The respondent, who works in a library setting, states that retrieval of such a reference is materially slower and that identifiers should be supplied throughout.
The respondent asks in the alternative that where an identifier exists but is not carried, the omission be explained rather than left as a gap the reader must interpret.
The secretariat accepts the second limb of this submission and declines the first. Identifiers are supplied wherever the Institute holds one. Where the Institute does not hold an identifier it will not supply one, because a reconstructed identifier that resolves to the wrong record is a worse defect than an absent one.
Every reference without a persistent identifier now carries an explicit statement that the identifier is not held by the Institute, so that its absence is a recorded fact rather than an apparent oversight.
Studies not published in English were excluded without assessment
The respondent states that a language restriction was applied at screening and that for some of the compounds in scope a substantial literature is published in other languages.
The respondent proposes that the restriction be removed and the review re-run.
The secretariat accepts this submission in part. The restriction is removed prospectively and the records already excluded on language grounds have been retrieved and screened on title and abstract in translation. The full re-run proposed is not undertaken, and the limitation is recorded rather than concealed.
Language restriction is removed from the protocol for the series, the records previously excluded on that ground are listed with their screening outcome, and the residual limitation is stated in the abstract of this review.
A sponsor trial meeting the eligibility criteria was excluded
The submission is made on behalf of the sponsor. It identifies a completed trial of the sponsor's compound that meets the stated eligibility criteria and does not appear in the included set, and supplies the trial report and the registry record.
The sponsor asks that the trial be included and the estimate recomputed. No view is expressed on the direction the recomputation should take.
The secretariat accepts this submission in part. The trial does meet the criteria and has been included. The recomputed estimate is materially unchanged, which the response states explicitly so that the outcome of the correction is on the record.
The trial is added to the included set, the estimate and the certainty rating have been recomputed, and the screening record now states why the trial was missed, which was a database indexing gap rather than a screening judgement. The submission is identified as an industry submission.
The review protocol is described but its registration record is not linked
The respondent asks for the prospective registration record of the review protocol so that the registered outcomes can be compared with the reported ones.
The respondent states that without it the claim of prospective registration cannot be checked.
The secretariat accepts this submission in part. The protocol is published in full on the Institute site with its version history, which permits the comparison the respondent asks for. Where an external registration identifier is not held by the Institute, the review says so rather than supplying one.
Each synthesis now links its own protocol with the version in force at screening, and states explicitly where an external registration identifier is not held, so that the absence is a recorded fact.
An indirect comparison is presented without an assessment of transitivity
The draft compares two interventions through a common comparator. The respondent states that the trials contributing to each side differ in background therapy and in baseline severity, and that the resulting estimate assumes a similarity the draft does not test.
The respondent proposes that transitivity be assessed explicitly and reported before any indirect estimate is presented.
The secretariat accepts this submission. An indirect estimate presented without a transitivity assessment invites a reader to treat an assumption as a result.
Transitivity is now assessed against a stated list of effect modifiers and reported before any indirect estimate, and where the assessment fails the contrast is reported as unestimable with the reason rather than estimated with a caveat.
A funnel plot is presented for a set too small to interpret it
The draft includes a funnel plot for an outcome contributed by fewer than ten studies. The respondent states that asymmetry cannot be assessed reliably at that number and that presenting the plot invites a conclusion the data cannot support.
The respondent proposes that the plot be removed and replaced with a statement that publication bias could not be assessed.
The secretariat accepts this submission. Presenting an uninterpretable graphic is not a neutral act.
The funnel plot is removed for every outcome contributed by fewer than ten studies, and replaced by a statement that small-study effects could not be assessed at that number, together with the count of registered trials identified without posted results.
The same concern is used to downgrade in two domains
The draft downgrades for both indirectness and imprecision citing the same feature of the contributing trials. The respondent states that this double-counts a single concern and produces a rating lower than the framework supports.
The respondent proposes that the rating be raised by one level.
The secretariat accepts this submission in part. The double count is real in one of the two outcomes identified and not in the other, where the two domains rest on different features.
The rating for the first outcome has been raised by one level and the domain reasoning restated, and the reasoning for the second has been rewritten to make clear that the two downgrades rest on different features of the evidence.
Two factual descriptions of the sponsor's programme are inaccurate
The submission is made on behalf of the marketing-authorisation holder and is confined to two matters of fact. The draft describes a trial as terminated where the sponsor closed it at a pre-specified interim analysis, and gives a dose in a unit that does not match the approved labelling.
Supporting documentation, comprising the published trial report and the current summary of product characteristics, accompanied the submission. No view is expressed on the certainty ratings, which the sponsor considers a matter for the assessment committee.
The secretariat accepts this submission. Both points are matters of fact, both were checkable against documents the Institute holds, and both were wrong in the draft.
The trial status now reads as completed at a pre-specified interim analysis, with the analysis identified, and the dose is stated in the unit used in the approved labelling. The submission is identified as an industry submission on its face in accordance with the conflicts policy.
The review does not say when it will be updated or what would trigger an update
The respondent states that a synthesis in a field where trials report frequently is out of date from the day it is published, and that a reader has no way to know whether the version in front of them is current.
The respondent proposes a stated trigger for an update as well as a scheduled review date.
The secretariat accepts this submission. A review date alone tells a reader when the document will be looked at, not whether it should already have been.
Every synthesis now records a scheduled review date and a stated update trigger, being the reporting of a trial that would materially change the contributing evidence, and the registered trials capable of triggering an update are listed by name.
Statistical heterogeneity is treated as though it measured clinical heterogeneity
The draft reports a heterogeneity statistic and proceeds to pool where it is low. The respondent states that a low statistic in a small set of trials is uninformative, and that clinical and methodological similarity should be assessed before any statistic is consulted.
The respondent proposes that the decision to pool be justified on clinical grounds first and that the statistic be reported as a description rather than used as a threshold.
The secretariat accepts this submission in part. The decision to pool is now made on clinical and methodological grounds and stated as such. The statistic continues to be reported, because readers expect it and its absence would be read as concealment.
The decision to pool is now justified in prose against the population, intervention, comparator and outcome before any statistic is presented, and the heterogeneity statistic is reported with its confidence interval and a note of the number of contributing studies.
Analytical surveys are treated as evidence about suppliers when they establish only what was in a sample
Several included surveys purchased material anonymously and analysed it. The respondent states that where the chain from a named supplier to the analysed vial cannot be documented, the result describes a sample and not a supplier.
The respondent proposes that provenance be an explicit eligibility dimension, with surveys reported separately according to whether it could be established.
The secretariat accepts this submission. Moderate certainty evidence from the included surveys supports statements about material circulating in a market; it does not support statements about any named supplier's output.
Provenance is now assessed for every included survey and reported as a study characteristic, surveys without establishable provenance are reported separately rather than pooled with those that have it, and no supplier-level inference is drawn from a sample-level result.
The document set should be published in translation
The respondent notes that the assessments concern compounds supplied internationally and that publishing only in English restricts access to the assessment to readers who work in it.
The respondent proposes machine translation of the document set as an interim measure, with human review of the certainty language.
The secretariat does not accept this submission, and records that the underlying point is sound and that the proposed remedy is the difficulty.
A translation whose certainty language has drifted is a different assessment carrying the Institute's name, and the Institute cannot review translations it does not have the capacity to review. The documents remain in English. The submission is published in full because the access problem it identifies is real and unresolved.
Patient-reported outcomes are collected by the trials and not reported by the review
The respondent, a trustee of a patient organisation, states that several contributing trials measured quality of life and function and that the review reports neither, having selected outcomes on the basis of what could be pooled.
The respondent proposes that these outcomes be reported narratively where they cannot be pooled.
The secretariat accepts this submission in part. The outcomes are reported narratively. The proposal to pool them is declined because the instruments used are not comparable and pooling would produce a figure with no interpretation.
Patient-reported outcomes measured by any contributing trial are now reported narratively by instrument, with the instrument named and its minimum important difference stated where one is published, and the absence of a pooled estimate explained.
The review does not say when it will be updated or what would trigger an update
The respondent states that a synthesis in a field where trials report frequently is out of date from the day it is published, and that a reader has no way to know whether the version in front of them is current.
The respondent proposes a stated trigger for an update as well as a scheduled review date.
The secretariat accepts this submission. A review date alone tells a reader when the document will be looked at, not whether it should already have been.
Every synthesis now records a scheduled review date and a stated update trigger, being the reporting of a trial that would materially change the contributing evidence, and the registered trials capable of triggering an update are listed by name.
Baseline imbalance in a small contributing trial is not remarked on
The respondent identifies a small contributing trial with a baseline difference in the outcome variable, and states that the difference is large enough to account for a share of the reported effect.
The respondent asks that the trial be excluded or that the imbalance be addressed.
The secretariat notes this submission. The imbalance is recorded in the risk-of-bias assessment for that trial, in the domain concerning the randomisation process, where the respondent may not have looked.
No amendment arises. The judgement and the supporting figures are already reported at domain level for that study, and a sensitivity analysis omitting it is reported in the results, which does not change the direction of the estimate.
References cited on this page
References are numbered in order of first citation in this document. Each superscript in the text links to its entry below.
- International Organization for Standardization. ISO/IEC 17025:2017 General Requirements for the Competence of Testing and Calibration Laboratories. ISO/IEC Standard 2017;3rd edition. identifier not held by the Institute
Identifiers are reproduced only where the Institute holds them. Where a digital object identifier or PubMed identifier is not shown, the Institute has recorded the journal and year and has not constructed an identifier.