Draft synthesis: The consequences of a wholly… — submissions
The 10 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
10 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.
Results at materially different follow-up durations are pooled
Contributing trials report the outcome at durations ranging across more than a year. The draft pools them into a single estimate. The respondent states that a mean at one duration and a mean at another are not estimates of the same quantity when the effect is still changing.
The respondent proposes that estimates be reported by duration band.
The secretariat accepts this submission. Pooling across durations assumes a plateau the contributing trials do not demonstrate.
Estimates are now reported by duration band, with the number of contributing trials and participants in each band stated, and no estimate is pooled across bands.
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.
The search strategy as published cannot be re-run
The strategy is described in prose rather than reproduced as executed. The respondent, an information specialist, attempted to reconstruct it and obtained a different yield, which may reflect the reconstruction or the original.
The respondent proposes that the strategy be published line by line as run in each database, with the interface, the date and the number of records retrieved at each line.
The secretariat accepts this submission. A strategy that cannot be re-run cannot be checked, and a review whose search cannot be checked rests on an assertion.
The full line-by-line strategy for each database is now published with the interface, the run date and the yield at each line, and the total retrieved is reconciled against the screening flow.
A sortable table implies a comparison the underlying data do not support
The draft presents a sortable table whose columns are drawn from sources of differing quality. The respondent states that sorting on such a column produces an ordering that looks like a ranking and is not one.
The respondent proposes that sorting be disabled on any column whose values are not commensurable.
The secretariat notes this submission and records that the point is correct in principle.
No amendment arises here because every sortable table in the document set already carries a standing statement above it that the ordering is not a ranking and that the values in each column are commensurable only where the column header says so. The proposal to disable sorting was considered and not adopted, because a reader who cannot sort a table generally sorts it elsewhere and without the statement.
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 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.
The document should not describe uses outside the approved indication
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.
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.
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.
The document is unreadable without specialist training
The respondent, a trustee of a patient organisation, states that the draft is written for a reader who already understands certainty grading, and that the people most affected by the subject matter will not reach the assessment at all.
The respondent proposes a plain-language summary at the head of every document, written to the same standard of accuracy as the document itself and not as a promotional abstract.
The secretariat accepts this submission in part. A plain-language summary is added. The proposal that it replace the technical abstract is declined, because the abstract is the part of the document other assessors read and cite.
Every document now opens with a plain-language summary of not more than 150 words, placed above the technical abstract and carrying the same certainty language, so that the two cannot diverge.
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.