Draft synthesis: Percentage weight change as a surrogate… — submissions
The 9 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
9 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.
Two included studies do not meet the registered eligibility criteria
This submission concerns the draft review of To what extent does a change in body weight predict a change in the clinical outcomes for which weight reduction is undertaken?. The respondent has conducted reviews on adjacent questions and the observation arises from that experience.
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 sponsor trial meeting the eligibility criteria was excluded
This submission addresses the draft synthesis on To what extent does a change in body weight predict a change in the clinical outcomes for which weight reduction is undertaken? from the standpoint of a reader who will use the summary and not the appendices.
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 respondent read submission 001 after drafting this one and has not altered it, the two points being distinct.
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 document should not describe uses outside the approved indication
The respondent read the draft review of To what extent does a change in body weight predict a change in the clinical outcomes for which weight reduction is undertaken? and has confined this submission to a single matter.
The submission is made on behalf of a marketing-authorisation holder. It states that the draft describes uses of the compound that fall outside the approved indication, that such uses are not supported by the sponsor, and that describing them may be read as legitimising them.
The sponsor asks that the sections concerned be removed, or in the alternative that they carry a prominent statement that the sponsor does not support such use.
The secretariat does not accept this submission. The Institute records what is supplied and what is used, because a reader encountering a compound outside a regulated route is the reader most in need of an assessment of the evidence for it.
The sections remain. Every such section already states the regulatory status of the use described and states that the evidence for it is assessed separately from the evidence for the approved indication. The submission is published in full and identified as an industry submission.
The same concept is given three different names in one document
The respondent submits on the draft synthesis addressing To what extent does a change in body weight predict a change in the clinical outcomes for which weight reduction is undertaken?. This submission concerns the methods rather than the conclusion, on the view that a conclusion is only as good as the search that produced it.
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.
Overlapping primary studies across included reviews are counted more than once
The respondent’s comment on the draft review of To what extent does a change in body weight predict a change in the clinical outcomes for which weight reduction is undertaken? arises from comparing the included set against the respondent’s own knowledge of the field.
The draft is an overview of reviews and several included reviews share primary studies. The respondent states that the overview reports the total number of participants across reviews as though the sets were disjoint.
The respondent proposes that overlap be assessed and reported, and that no total be given without correcting for it.
The secretariat accepts this submission. An inflated participant total overstates the evidence base by an amount the reader cannot see.
Overlap between included reviews is now assessed at primary-study level and reported in a citation matrix, and participant totals are reported for the union of primary studies rather than as a sum across reviews.
Crossover trials are pooled with parallel-group trials without adjustment
The respondent has read the draft synthesis on To what extent does a change in body weight predict a change in the clinical outcomes for which weight reduction is undertaken? and makes one submission.
The analysis combines parallel-group and crossover designs by taking the first-period result from the crossovers, which discards half the data, or by taking the paired result, which is not comparable with an unpaired one. The methods do not say which was done.
The respondent proposes that the handling be stated and, where crossover data are used, that a sensitivity analysis excluding them be reported.
The secretariat accepts the requirement to state the handling and declines to require a sensitivity analysis in every case.
The methods section now states the handling of every non-parallel design. A sensitivity analysis is reported where crossover trials contribute more than a fifth of the weight.
Efficacy outcomes are rated for certainty and harms are not
The respondent notes that the review question — To what extent does a change in body weight predict a change in the clinical outcomes for which weight reduction is undertaken? — is answerable only if the contributing trials measured the same thing, and submits with that in view.
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.
Submission 001 concerns the same document. The respondent’s point is a different one.
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.
Intention-to-treat and efficacy-estimand results are combined without distinction
This is a submission on the draft review of To what extent does a change in body weight predict a change in the clinical outcomes for which weight reduction is undertaken?, made from a statistical standpoint.
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.
This submission is made by a respondent with a different professional interest in the outcome from the one behind submission 005.
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.
Doses differing several-fold are pooled without examining dose-response
The draft review of To what extent does a change in body weight predict a change in the clinical outcomes for which weight reduction is undertaken? was read against its registered protocol.
Contributing trials administer doses that differ by a factor of several. The draft pools them and reports one estimate. The respondent states that where a dose-response relationship exists the pooled figure corresponds to no dose that anyone receives.
The respondent proposes that estimates be reported by dose and that dose-response be examined where the data allow.
The secretariat accepts this submission. A pooled estimate across doses is an estimate for an average dose that no protocol specifies.
Estimates are now reported by dose group, a dose-response examination is reported where three or more dose levels contribute, and the pooled across-dose estimate is removed rather than retained alongside.
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
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