Draft monograph: Teduglutide — submissions
The 7 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
7 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.
Nothing is said about impaired renal or hepatic clearance
The respondent read the draft on Teduglutide alongside the approved labelling for the class, and submits on one matter arising.
The pharmacokinetic section gives clearance and half-life in healthy volunteers or in the trial population. It does not say whether either has been characterised in impaired renal or hepatic function, which is the question a clinician reaches the section with.
The respondent proposes that the pharmacokinetic section state, for each compound, whether a dedicated study in impaired function exists, and where none does, say so rather than leaving the field out.
The secretariat accepts this submission. A missing row and an absent study look the same on the page and are not the same thing.
The pharmacokinetic table now carries renal and hepatic rows in every monograph, populated with the study where one exists and with an explicit statement of absence where none does.
Evidence for one member of the class is presented as evidence for this compound
The draft on Teduglutide is a substantial document and the respondent has confined this submission to one matter.
The draft supports a statement about this compound with a citation to a trial of a different compound in the same class. The respondent states that a class-level inference is a judgement that should be labelled as one rather than presented as direct evidence.
The respondent proposes that any class-level extrapolation be flagged at the point of use and excluded from the certainty rating for the compound itself.
The respondent endorses the general approach taken in submission 001 and asks that it be extended to the matter identified here.
The secretariat accepts this submission. Moderate certainty evidence supports several class-level statements in this area, but a class-level statement is not evidence about a particular member of the class.
Class-level inferences are now labelled at the point of use, are excluded from the certainty rating for the compound, and are reported in a separate subsection stating which compound the underlying evidence concerns.
The search date is not on the face of the document
The draft on Teduglutide 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 draft carries a publication date and a review date but not the date on which the evidence was last searched. Those are three different dates and only the third tells a reader how current the assessment is. A document published in one quarter may rest on a search run two quarters earlier, and nothing on the page allows that gap to be measured.
The respondent proposes that the search date be printed adjacent to every certainty rating rather than in the methods section, on the ground that a reader who acts on a rating is unlikely to have read the methods section first.
The secretariat accepts this submission. The distinction between publication, review and search dates is real and the draft did not make it visible where it mattered.
The search date is now printed adjacent to every certainty rating and is carried in the document metadata, so that the interval between the search and the reading is visible without reference to the methods section.
The monograph should reproduce the approved labelling rather than paraphrase it
The respondent has read the draft monograph on Teduglutide against a caseload in which incretin analogues are prescribed daily.
The submission is made on behalf of the marketing-authorisation holder. It states that the draft paraphrases the approved indication, the posology and the contraindications, and that any paraphrase risks diverging from the authorised text.
The sponsor asks that the authorised wording be reproduced verbatim in each case, and offers the current summary of product characteristics as the source.
The secretariat accepts this submission in part. The authorised indication and the contraindications are reproduced verbatim and attributed. The posology is not, because the monograph reports what the trials administered as well as what the labelling authorises, and the two are frequently different.
The approved indication and contraindications are now reproduced verbatim from the named authorisation with its version and date, and the posology section reports the labelled schedule and the schedules studied side by side, with the source of each stated.
The pharmacokinetic section does not connect half-life to the dosing schedule
This submission addresses the draft monograph on Teduglutide. The respondent went through the document twice, once as a specialist and once as a reader arriving without the background.
The draft reports a half-life and, separately, a dosing interval. The respondent, a clinical pharmacologist, states that the relationship between the two is what determines accumulation and time to steady state, and that the monograph leaves the reader to derive it.
The respondent proposes that time to steady state be stated explicitly, with the assumption from which it was derived.
The secretariat accepts this submission. The derivation is short, it is decision-relevant, and leaving it to the reader invites it to be done wrong.
The pharmacokinetic section now states approximate time to steady state alongside the half-life and dosing interval, with the assumption of first-order elimination stated, and records where the assumption is not supported for this compound.
Adverse event frequencies are given without the denominator or the exposure period
The respondent submits on the draft monograph for Teduglutide. The observation arises from teaching the material rather than from prescribing it.
The draft reports adverse event frequencies as percentages. The respondent states that a percentage without a denominator and without an exposure period cannot be compared with any other figure, including the corresponding figure in the comparator arm.
The respondent proposes that every frequency carry the number of participants and the exposure period over which it was observed.
The respondent has read submission 002 with interest and adds one observation the secretariat may find useful.
The secretariat accepts this submission. A frequency detached from its denominator is a number without a quantity.
Every reported frequency now carries the number of participants, the number of events and the exposure period, and comparator-arm figures are reported alongside rather than in a separate table.
Doses are expressed in units that differ between sections
Having reviewed the draft on Teduglutide, 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.
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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