Draft monograph: Semaglutide, oral — 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.
Doses are expressed in units that differ between sections
Having reviewed the draft on Semaglutide, oral, the respondent makes a single submission, on the view that one point put clearly is more use to the secretariat than six put together.
The draft expresses dose in milligrams in one section and in micrograms per kilogram in another, drawn from different sources without conversion. The respondent 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.
Anti-drug antibody data are omitted
The draft on Semaglutide, oral was read in full. The respondent notes at the outset that this class has an unusually deep randomised evidence base, and that a monograph on it is fairly judged against a higher standard than one on a compound with none.
The respondent states that immunogenicity is measured in the development programmes of peptide therapeutics and that the monograph does not report it, leaving a reader unable to judge whether loss of effect over time has an immunological explanation.
The respondent proposes that anti-drug antibody incidence and its relation to effect be reported for every compound in the series.
Submission 001 raises an adjacent matter. The respondent regards the two as separable and addresses only this one.
The secretariat accepts this submission in part. Immunogenicity is reported where a contributing trial reported it. The proposal to report it for every compound is declined because for many compounds in the series no such data exist and a uniformly empty row is not informative.
Anti-drug antibody incidence and any reported association with loss of effect are now reported where measured, and recorded as not measured where the contributing trials did not assess them.
The absence of paediatric evidence is not stated where a reader would look for it
The respondent submits on the draft monograph for Semaglutide, oral. The observation arises from teaching the material rather than from prescribing it.
The population section describes the adult trial populations. Nothing states whether the compound has been studied in anyone under eighteen. For several compounds in this series it has not, and for one or two it has; the document does not let the reader tell which case applies.
The respondent proposes a standing row in the population table recording paediatric evidence as present, absent, or present in a named subpopulation only.
The secretariat accepts this submission. An unstated absence is indistinguishable from an unread section.
The population table now carries a paediatric row in every monograph, and where evidence exists the trials are named.
The monograph should not describe how the compound is supplied outside a regulated route
The draft on Semaglutide, oral is a substantial document and the respondent has confined this submission to one matter.
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 analytical section assumes a reference standard that is not generally available
The respondent read the draft on Semaglutide, oral alongside the approved labelling for the class, and submits on one matter arising.
The draft describes identity and content determinations that require a reference standard of assigned content. For this compound no such standard is in general circulation, and a laboratory following the section as written cannot perform the determination described.
The respondent, employed by a contract analytical laboratory, proposes that the monograph state explicitly where a reference standard is unavailable and what a determination performed without one can still establish.
The secretariat accepts this submission. The section described an ideal case and did not say so.
The analytical section now states whether a reference standard is in general circulation for this compound and, where it is not, states which determinations remain possible and which become qualitative. A content figure obtained without a reference standard is recorded as an estimate against a stated assumption rather than as a determination.
The certainty rating for the principal assessed outcome cannot be traced to the contributing trials
This submission concerns the draft on Semaglutide, oral. The respondent assesses incretin-class evidence for a national body and comments in a personal capacity.
The draft states a certainty rating for the principal assessed outcome and lists the contributing trials, but does not state which domain drove the downgrade. A reader who disagrees with the rating cannot tell whether the disagreement concerns risk of bias, imprecision, indirectness or inconsistency.
The respondent proposes that each rating carry its downgrade reasons explicitly, in the same row as the rating, so that a reader can accept the evidence assessment while disputing a single domain judgement.
The secretariat accepts this submission. A rating without its reasoning is an assertion, and the draft asserted rather than showed.
Each assessed outcome now carries its downgrade domains in the summary-of-findings row, with a short statement of the judgement made in each, so that the rating can be checked domain by domain against the contributing trials.
Open-label extension data are presented alongside randomised data without distinction
The respondent has read the draft monograph on Semaglutide, oral against a caseload in which incretin analogues are prescribed daily.
Long-term figures in the clinical section come from open-label extensions in which every participant received the active compound and those who did not tolerate it had already withdrawn. They are printed in the same table as randomised comparisons and in the same typeface.
The respondent proposes that extension data be presented in a separate table, or at minimum in a separately labelled block, and that the surviving-population problem be stated once where it arises.
The respondent notes submission 005 above and does not repeat the ground it covers.
The secretariat accepts this submission. An extension estimate answers a different question from a randomised one and should not be read as though it answered the same one.
Extension data now appear in a separate table headed as uncontrolled follow-up, with a standing note on differential withdrawal.
Quantitative claims are reproduced without the method that produced them
This submission addresses the draft monograph on Semaglutide, oral. The respondent went through the document twice, once as a specialist and once as a reader arriving without the background.
Several figures in the draft are quoted from sources that determined them by different methods. A figure obtained by one determination and a figure obtained by another are not comparable, and the draft places them in the same sentence without distinguishing them.
The respondent, an analytical chemist, proposes that every quantitative claim carry the method that produced it at the point of use rather than in the reference.
The secretariat accepts this submission. Placing two figures side by side is an implicit claim that they are the same kind of quantity, and in the cases identified they were not.
Every quantitative claim now carries the determination that produced it at the point of use, and figures obtained by non-comparable methods are no longer presented in the same row or sentence.
Where the compound is a glucagon-like peptide-1 receptor agonist, the cardiovascular outcome evidence should be an assessed outcome
This is a submission on the draft covering Semaglutide, oral, from a respondent whose work is with the people taking compounds of this class rather than with the trials that produced them.
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 respondent’s submission overlaps with submission 001 and was prepared without sight of it.
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.
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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