Draft monograph: tirzepatide, version 2 — 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.
Registered trials that never reported are absent from the monograph
The respondent states that the trial list appears to be drawn from published reports, and that registered trials which completed without a report are therefore invisible. The proportion of a programme that never reported is itself a finding about the evidence base.
The respondent proposes that every registered trial of the compound be listed, with its reporting status, whether or not a report exists.
The secretariat accepts this submission. A trial list built from publications reproduces publication bias in the shape of the document.
The trial list now includes every registered trial the Institute identified, with its reporting status stated, and the monograph reports the proportion of registered trials for which no result has been posted or published.
What happens when the compound is stopped is not addressed
The draft assesses the effect of the compound while it is being taken. The respondent, who declares having used a compound in the class under prescription, states that the question a person actually faces is what happens afterwards, and that the monograph is silent on it.
The respondent proposes that the trajectory after discontinuation be an assessed outcome wherever any contributing trial measured it, and a recorded evidence gap wherever none did.
The secretariat accepts this submission. The omission was one of framing rather than of evidence, and the framing followed the trials rather than the decision.
Discontinuation trajectory is now an assessed outcome in every monograph where a contributing trial measured it, and a recorded evidence gap in every monograph where none did, so that its absence is visible rather than silent.
Declared interests should appear on the document rather than on a separate page
The draft links to a central conflicts register. The respondent argues that a reader assessing whether to rely on a particular document should not have to leave it to find out who assessed it and what they declared.
The respondent proposes that the interests of every named contributor to a document be printed on that document.
The secretariat notes this submission and records that the draft already provides for it, which the respondent could reasonably have missed because the provision sits in an appendix.
Every document carries the declared interests of its named contributors in its front matter, and the central register exists so that a reader can see a person across all documents rather than one at a time. No amendment arises; the provision has been moved from the appendix into the body of the methodology document so that it is findable.
The monograph should not describe how the compound is supplied outside a regulated route
The respondent states that describing presentations observed in unregulated supply risks being read as a guide to obtaining them, and asks that the material be removed.
The respondent accepts that the information is accurate and objects to its presence rather than to its content.
The secretariat notes this submission and records the concern as a real one that the draft had already considered.
No amendment arises. The monograph describes what is supplied and names no supplier, price or route of acquisition, and it carries the standing statement that the Institute assesses evidence and does not recommend use. Describing a presentation a reader may already hold is the condition of being useful to that reader.
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.
Doses are expressed in units that differ between sections
The draft expresses dose in milligrams in one section and in micrograms per kilogram in another, drawn from different sources without conversion. The respondent, a hospital pharmacist, states that this is the shape of error that reaches a patient.
The respondent proposes a single unit throughout, with the source unit retained in parentheses where a conversion was performed.
The secretariat accepts this submission. The inconsistency was inherited from the sources and should have been resolved in drafting.
A single dose unit is now used throughout each monograph, with the source unit retained in parentheses wherever a conversion was applied, and every conversion is stated rather than performed silently.
The compound is supplied under names the monograph does not list
The respondent states that the compound is supplied under several trade names, research codes and transliterations, and that a reader holding a label bearing one of them will not find the monograph.
A list of names observed in supply, with the source of each observation, accompanied the submission.
The secretariat accepts this submission. A monograph a reader cannot find is not serving the reader.
The synonym list is extended to include every name the Institute can evidence from a document it holds, each recorded with its source. Names asserted without a supporting document are not added, and the distinction is stated at the head of the list.
Where the compound is a glucagon-like peptide-1 receptor agonist, the cardiovascular outcome evidence should be an assessed outcome
The respondent states that for compounds in this class the cardiovascular outcome evidence, reported for semaglutide in SELECT in the New England Journal of Medicine in 2023 and for liraglutide in LEADER in the same journal in 2016, is the evidence a prescribing decision most often turns on, and that the draft treats it as background.
The respondent proposes that cardiovascular outcomes be an assessed outcome with its own certainty rating for every compound in the class for which such a trial exists.
The secretariat accepts this submission in part. Cardiovascular outcomes become an assessed outcome where a dedicated outcome trial of the compound exists. The proposal to extend the rating across the class by inference is declined, in line with the treatment of class-level extrapolation elsewhere in the series.
Cardiovascular outcomes are now an assessed outcome with their own certainty rating in every monograph for which a dedicated cardiovascular outcome trial of that compound has reported, and are recorded as not assessed elsewhere.
The absence of a rare harm in the trial set is presented as reassurance
The draft states that a specific serious event was not observed in the contributing trials. The respondent states that trials of the size conducted here could not have detected an event at the frequency in question, and that reporting the absence without that arithmetic converts an uninformative result into a reassuring one.
The respondent proposes that the detectable frequency be stated wherever the absence of an event is reported.
The secretariat accepts this submission. The Institute's own framework treats an absent event in an underpowered set as uninformative, and the draft departed from it.
Wherever the monograph reports that an event was not observed, it now states the total exposure and the frequency the contributing trials could have detected, so that the absence is read as the limit of the evidence rather than as a finding.
The population to which the headline estimate applies is not stated with the estimate
The draft carries a headline effect estimate in the abstract without the eligibility criteria of the trials that produced it. The respondent states that the estimate applies to a trial population with specific age, comorbidity and baseline criteria, and that a reader will apply it to whoever is in front of them.
The respondent proposes a one-line population statement adjacent to every headline estimate.
The secretariat accepts this submission. An estimate detached from its population is an estimate of nothing in particular.
Every headline estimate now carries a one-line statement of the population in which it was observed, and the full eligibility criteria are reported in the included-studies table rather than only in the source.
The analytical section is longer than the clinical assessment it accompanies
The respondent, an academic pharmacologist, states that the analytical section occupies more of the monograph than the assessment of clinical effect, and that the proportions imply the Institute considers the analytical question the more important one.
The respondent proposes that the analytical material be moved to the standards series and referenced rather than reproduced.
The secretariat accepts this submission in part. The general analytical material is moved to the standards series and referenced. The compound-specific material stays, because a reader holding a certificate for this compound needs to know what that certificate does and does not establish for this compound.
The analytical section is reduced to compound-specific content and cross-references the relevant standards for the general procedure, which shortens it substantially without removing what is not available elsewhere.
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 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.
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.
The monograph should state what the compound costs
The respondent states that a reader deciding whether to pursue treatment needs to know what it costs, and that omitting price makes the assessment less useful than it could be.
The respondent proposes that a price range be recorded for each compound with the source and date.
The secretariat does not accept this submission. Price varies by jurisdiction, payer, presentation and date to a degree that no single figure could survive, and a stale price is worse than no price.
No price is recorded. The monograph records the presentations available and the regulatory status in each jurisdiction, which are the facts the Institute can verify and maintain. The submission remains published in full.
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.