Draft monograph: amycretin — submissions
The 16 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
16 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 absence of a rare harm in the trial set is presented as reassurance
The respondent notes that a reader will arrive at the draft on Amycretin with the single agents in mind, and submits in that context.
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.
Storage and reconstitution guidance is given without stating what it rests on
This is a submission on the draft for Amycretin, from a respondent whose work is with fixed-ratio products.
The draft states storage conditions and a period of use after reconstitution. The respondent asks what evidence supports the period, and states that in the absence of a stability study on this presentation the figure is a convention rather than a finding.
The respondent proposes that any in-use period be accompanied by the stability evidence that produced it, or removed.
The secretariat accepts this submission in part. The period is retained where a stability study on a comparable presentation exists and is cited. Where no such study exists the figure is removed rather than annotated, because an annotated figure is still a figure a reader will use.
In-use periods now appear only where supported by a cited stability determination on a stated presentation, and elsewhere the monograph records that no in-use stability evidence was identified for this presentation.
The analytical section assumes a reference standard that is not generally available
The respondent has read Amycretin and submits on a matter of presentation.
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.
This submission is made in the same spirit as submission 002 and on a different aspect of the draft.
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 indication table mixes approved indications with uses for which the compound is merely supplied
This submission concerns Amycretin and a convention used across the Institute’s output.
The indication table lists indications in a single sequence. Some are approved by a competent authority, some are the subject of trials that have not reported, and some are uses observed in supply with no trial evidence at all.
The respondent states that the three categories should not share a table without being distinguished in it.
The respondent’s submission overlaps with submission 001 and was prepared without sight of it.
The secretariat accepts this submission. A shared table is an implicit claim of comparable standing.
The indication table now carries a status column with three values, approved, under investigation and supplied without trial evidence, and the value is stated for every row. Rows in the third category also state that no certainty rating is assigned because there is no evidence base to rate.
Registered trials that never reported are absent from the monograph
Having read the draft under consultation, which concerns Amycretin, the respondent submits as follows.
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.
The monograph should state what the compound costs
This submission concerns Amycretin and makes one point.
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.
Local reactions are omitted from the adverse-event table because the trials reported them separately
The respondent read the draft on Amycretin and has confined this submission to one matter.
Injection-site reactions are reported in the source trials in a table of their own and do not appear in the systemic adverse-event table the monograph reproduces. The result is that the most common adverse experience of a subcutaneously administered compound is absent from the monograph’s adverse-event section.
The respondent proposes that local reactions be carried in the same table as systemic events, with the reporting convention of the source trial recorded in a footnote.
The respondent has read submission 002 and asks that this submission be considered with it.
The secretariat accepts this submission. The omission arose from following the source tables and it produced a misleading total.
Local reactions are now carried in the adverse-event table wherever the source trials report them, footnoted with the convention each trial used.
The monograph should reproduce the approved labelling rather than paraphrase it
The respondent submits on Amycretin. The point would apply equally to any document in the series.
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.
Anti-drug antibody data are omitted
Having read the draft monograph on Amycretin, the respondent puts one point to the committee.
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.
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.
What happens to weight after the compound is stopped is not in the assessed outcomes
This submission addresses the draft on Amycretin and is made from a clinical pharmacology standpoint.
Several trials in the evidence base ran a withdrawal period and reported what happened. That evidence is the single most useful thing a person considering the compound could be told, and it appears in the monograph only as a sentence in the discussion.
The respondent proposes that post-withdrawal trajectory be an assessed outcome in its own right for every compound where a withdrawal period was studied, with its own certainty rating.
The respondent supports submission 004 so far as it goes and adds the matter set out here.
The secretariat accepts this submission. The evidence exists, it is directly relevant, and it was not being assessed.
Post-withdrawal trajectory is now an assessed outcome wherever a withdrawal period was studied, rated on the same scale as the others. Where no withdrawal period was studied the outcome is recorded as not assessed.
Mechanistic claims for a peptide fragment are carried without evidence that the fragment acts as described
The respondent submits on Amycretin.
The respondent states that the draft repeats a mechanistic account originating in supply documentation rather than in the primary literature, and that the account attributes activity to a fragment on the basis of the activity of the parent molecule.
The respondent proposes that any mechanistic claim be traceable to a primary source and removed where it is not.
The secretariat accepts this submission. A mechanism repeated from marketing material has no evidential status regardless of how widely it is repeated.
Mechanistic claims not traceable to a primary source are removed, and those retained carry their source and a statement of whether the underlying work was conducted in vitro, in animals or in humans.
Doses are expressed in units that differ between sections
The respondent submits on the draft monograph for Amycretin. A document about a combination has to keep separate what is known about the combination from what is known about each component.
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 respondent notes that submission 009 has already been made and confines this submission to a matter not covered by it.
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 document set should be published in translation
The respondent submits on Amycretin, on a matter that is not specific to this draft but is visible in it.
The respondent notes that the assessments concern compounds supplied internationally and that publishing only in English restricts access to the assessment to readers who work in it.
The respondent proposes machine translation of the document set as an interim measure, with human review of the certainty language.
The secretariat does not accept this submission, and records that the underlying point is sound and that the proposed remedy is the difficulty.
A translation whose certainty language has drifted is a different assessment carrying the Institute's name, and the Institute cannot review translations it does not have the capacity to review. The documents remain in English. The submission is published in full because the access problem it identifies is real and unresolved.
The document is unreadable without specialist training
The respondent has read the draft covering Amycretin and makes one submission.
The respondent 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.
The same concept is given three different names in one document
This submission concerns the draft on Amycretin. The respondent’s interest is in whether the evidence cited was generated with the combination or with its parts.
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.
The pharmacokinetic section does not connect half-life to the dosing schedule
The respondent’s comment on the draft for Amycretin arises from reading it beside the monographs for the single agents.
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.
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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