Draft synthesis: weight change after discontinuation of an… — 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.
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.
The choice of effect measure is not justified and changes the appearance of the result
The draft reports relative effects for benefits and absolute effects for harms. The respondent states that the combination flatters the intervention and that the choice should be justified or made uniform.
The respondent proposes that both relative and absolute effects be reported for every outcome.
The secretariat accepts this submission in part. Both measures are reported for every outcome where the baseline risk needed for the absolute effect can be stated. Where it cannot, the relative effect is reported alone with the reason.
Every outcome now reports the relative effect and, where an assumed baseline risk can be stated and sourced, the corresponding absolute effect, with the baseline risk and its source given in the same row.
The search date is not on the face of the document
The draft carries a publication date and a review date but not the date on which the evidence was last searched. Those are three different dates and only the third tells a reader how current the assessment is. A document published in one quarter may rest on a search run two quarters earlier, and nothing on the page allows that gap to be measured.
The respondent proposes that the search date be printed adjacent to every certainty rating rather than in the methods section, on the ground that a reader who acts on a rating is unlikely to have read the methods section first.
The secretariat accepts this submission. The distinction between publication, review and search dates is real and the draft did not make it visible where it mattered.
The search date is now printed adjacent to every certainty rating and is carried in the document metadata, so that the interval between the search and the reading is visible without reference to the methods section.
The document should state what a reader ought to do
The draft assesses evidence and stops. The respondent, a practising clinician, states that a reader arriving at the document with a decision to make is left to convert an assessment into an action without help, and proposes that each document close with a recommendation.
The respondent argues that other evidence bodies issue recommendations and that declining to do so transfers the difficult part of the work to the reader.
The secretariat does not accept this submission, and records that the point is a reasonable one rather than a misunderstanding.
The Institute assesses evidence and does not issue recommendations, because a recommendation embeds values and a resource context that the Institute does not hold and cannot state. That constitutional limit is published on the methodology page and is not varied by consultation. The submission remains published in full.
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 question is drawn too broadly to be answerable
The respondent states that the population as registered spans groups in which the intervention would be expected to behave differently, and that a single estimate across them is uninformative.
The respondent proposes that the question be split and the review re-registered.
The secretariat does not accept this submission. The breadth was registered before screening, the pre-specified subgroups address the variation the respondent identifies, and re-registering after the results are known would convert a pre-specified analysis into a post hoc one.
The question stands as registered. The point is recorded in the limitations, and the assessment committee has noted it for the protocol of the next version of this review, which will be registered before the search is run. The submission remains published in full.
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 same concept is given three different names in one document
The draft refers to the same quantity as a response rate, a responder proportion and a categorical outcome in different sections. The respondent, who works in health-technology assessment, states that a reader cannot tell whether the three refer to one thing or to three.
The respondent proposes that the glossary term be used at every occurrence and that the glossary entry be linked at first use in each section rather than only at first use in the document.
The secretariat accepts this submission. The variation was stylistic and its cost to the reader exceeds any benefit.
A single term is now used throughout for each defined concept, and the glossary entry is linked at first use within each section rather than once per document.
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.
Efficacy outcomes are rated for certainty and harms are not
The draft assigns certainty ratings to the efficacy outcomes and reports harms narratively without ratings. The respondent states that the asymmetry implies harms are less amenable to assessment when they are simply less well measured.
The respondent proposes that harms carry certainty ratings on the same scale, with the reasons for downgrading stated.
The secretariat accepts this submission. Rating one side of the balance and not the other produces a document that cannot be used to weigh them.
Every reported harm now carries a certainty rating on the same scale as the efficacy outcomes, with the downgrade reasons stated, and discontinuation for adverse events appears in the summary of findings rather than in an annex.
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.
Two included studies do not meet the registered eligibility criteria
The respondent identifies two studies in the included set whose duration falls below the minimum stated in the protocol, and one excluded study that appears to meet every criterion.
The respondent proposes that the three be reassessed and that the outcome of the reassessment be recorded whichever way it goes.
The secretariat accepts this submission in part. On reassessment, one of the two included studies does fall below the minimum duration and has been removed. The second reports a duration that met the criterion in the protocol version registered at the time. The excluded study was excluded for a reason not clearly recorded, which was a documentation failure.
One study has been removed from the included set and the estimate recomputed, the exclusion reason for the third study has been corrected in the excluded-studies table, and the screening decisions are now recorded against the protocol version in force at the time of screening.
A surrogate outcome is used as the anchor without validation evidence
The anchor outcome in the draft is a surrogate. The respondent states that the relationship between the surrogate and the outcome a decision turns on is itself an evidential question, and that the draft assumes it.
The respondent proposes that no surrogate serve as an anchor.
The secretariat accepts this submission in part. The anchor is retained where the surrogate is the only outcome the contributing trials measured, and the validation question is addressed rather than assumed.
Where the anchor is a surrogate, the synthesis now states the evidence for the surrogate relationship, rates it separately, and downgrades the anchor rating for indirectness accordingly rather than carrying the surrogate as though it were the outcome of interest.
Registered trials that never reported are not counted anywhere in the review
The respondent states that the screening flow accounts for records retrieved and excluded but does not record registered trials identified with no posted result, which are neither included nor excluded and simply disappear.
The respondent proposes that they be counted and reported as a category, with the proportion of the registered evidence base they represent.
The secretariat accepts this submission. A review that cannot say how much of the evidence base is unreported cannot say how much weight its own estimate deserves.
Registered trials without posted results are now identified, counted and reported as a distinct category in the screening flow, with the proportion of registered participants they represent stated in the limitations.
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.
Intention-to-treat and efficacy-estimand results are combined without distinction
Several contributing trials report both a treatment-policy result and an efficacy result that censors at discontinuation. The draft draws from whichever is reported first in each paper.
The respondent, a trial statistician, states that the two answer different questions, that the difference is substantial where discontinuation is common, and that a synthesis should choose one and say which.
The secretariat accepts this submission. Mixing estimands within a single pooled estimate is a defect of the synthesis rather than of the trials.
The treatment-policy estimand is used throughout as the primary analysis, the efficacy estimand is reported as a secondary analysis where available, and the estimand used is stated in every row of the summary of findings.
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.