Draft synthesis: Oral compared with injectable presentations… — submissions
The 15 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
15 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.
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.
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 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 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.
Risk-of-bias judgements are reported as an overall rating without the domains
The draft reports a single overall risk-of-bias judgement per study. The respondent states that the overall judgement conceals which domain drove it, and that a reader assessing whether the concern applies to their question needs the domain.
The respondent proposes a domain-level table with the supporting quotation for each judgement.
The secretariat accepts this submission. The overall judgement is a summary of the domains and publishing only the summary makes it uncheckable.
Risk of bias is now reported at domain level for every included study, with the text on which each judgement was based quoted and referenced, and the overall judgement derived from the domains rather than asserted alongside them.
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.
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.
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.
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.
Subgroup findings are reported that were not registered in the protocol
The draft reports differences between subgroups that do not appear in the registered protocol. The respondent states that unregistered subgroup analysis is hypothesis-generating and that the draft presents it in the same form as the pre-specified results.
The respondent proposes that unregistered analyses be removed.
The secretariat accepts this submission in part. The analyses are retained and relabelled rather than removed, because removing an analysis that was conducted leaves no record that it was.
Every subgroup analysis is now labelled as pre-specified or post hoc against the registered protocol, post hoc analyses are reported in a separate subsection without a certainty rating, and the protocol version against which the labelling was made is stated.
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 conclusion is stated more strongly than the certainty rating supports
The draft rates the anchor outcome at low certainty and then states in the conclusion that the intervention is effective. The respondent states that the two sentences cannot both be true as written.
The respondent proposes that conclusion language be tied mechanically to the certainty rating, so that a low rating cannot produce an unqualified claim.
The secretariat accepts this submission. The mismatch is the failure mode the certainty framework exists to prevent.
Conclusion wording is now drawn from a fixed set of formulations tied to the certainty rating, so that a low certainty rating produces a statement that the evidence may suggest an effect and that the estimate is likely to change with further research.
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.
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.
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.