Draft monograph: AOD-9604 — submissions
The 17 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
17 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.
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.
A near-isobaric analogue is not distinguished by the identity determination described
The identity determination described in the draft resolves the compound from unrelated substances but would not distinguish it from a closely related analogue whose mass differs by approximately one dalton.
The respondent proposes that the monograph state the resolution required for that discrimination, and state that a nominal-mass instrument reporting an integer mass has not made it.
The secretariat accepts this submission. The point is decisive where one member of a near-isobaric pair is an approved medicine and the other is not.
The analytical section now states the resolving power required to discriminate the pair, names the pair explicitly, and records that an identity claim made below that resolution is not conformant with the identity standard.
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.
Point estimates are given without an interval
Several estimates in the draft appear as single figures. The respondent states that a point estimate without an interval invites a precision the underlying data do not support, and that the effect is worst where the estimate is drawn from a small contributing set.
The respondent proposes that no point estimate appear anywhere in the document set without its interval, including in summary tables and in the abstract.
The secretariat accepts this submission in part. Intervals are added wherever the source reports one. The proposal is declined for figures the source published without an interval, because the Institute will not compute an interval a source did not report.
Every estimate now carries its interval where the source reported one, and where it did not, the estimate is annotated as reported without an interval rather than left to appear as a precise figure.
The preclinical section is extensive and the clinical section is not
The draft summarises a large animal literature and a small or absent human literature. The respondent states that the resulting document reads as though a great deal is known, when what is known concerns rodents.
The respondent proposes that the preclinical section be reduced to a statement of what has been observed in animals and that the detail be removed entirely.
The secretariat accepts this submission in part. The section is shortened and given a standing statement. The proposal to remove the detail is declined, because a reader encountering claims derived from that literature needs to be able to see what it actually contains.
The preclinical section is reduced in length, placed after the clinical assessment rather than before it, and opens with a standing statement that an effect observed in an animal model is not a clinical outcome and does not support a certainty rating.
The search date is not on the face of the document
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.
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.
Anti-drug antibody data are omitted
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.
A sortable table implies a comparison the underlying data do not support
The draft presents a sortable table whose columns are drawn from sources of differing quality. The respondent states that sorting on such a column produces an ordering that looks like a ranking and is not one.
The respondent proposes that sorting be disabled on any column whose values are not commensurable.
The secretariat notes this submission and records that the point is correct in principle.
No amendment arises here because every sortable table in the document set already carries a standing statement above it that the ordering is not a ranking and that the values in each column are commensurable only where the column header says so. The proposal to disable sorting was considered and not adopted, because a reader who cannot sort a table generally sorts it elsewhere and without the statement.
Guidance on lyophilised storage is missing
The respondent asks that the monograph state storage conditions for lyophilised material as well as for reconstituted solution, since the two differ and the former governs the longer part of the shelf life.
The respondent states that the omission is the more consequential because lyophilised material is what is generally received.
The secretariat notes this submission. The draft addresses lyophilised storage, in the presentation section rather than in the section on in-use handling, which is where the respondent looked.
No amendment to content arises. The two storage statements have been brought together under a single heading so that a reader looking for either finds both.
Storage and reconstitution guidance is given without stating what it rests on
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 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 monograph does not tell a reader that a stated mass may be substantially counter-ion and water
The draft quotes vial contents in milligrams without stating whether the figure refers to peptide content or to total solids. For an acetate or trifluoroacetate salt of a peptide, the difference between the two can exceed a fifth of the stated mass.
The respondent, an analytical chemist, states that this is the single most consequential misreading in the field and that a monograph that does not address it directly is leaving the reader to discover it.
The secretariat accepts this submission. Moderate certainty evidence from published analytical surveys suggests that content and total solids are routinely conflated in supply documentation, and the draft did not warn the reader.
The monograph now states, at the point where vial contents are first mentioned, that a mass figure is uninterpretable unless it states whether it is peptide content or total solids, and cross-references the content standard in the analytical series.
The document set should be published in translation
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 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.
The monograph should reproduce the approved labelling rather than paraphrase it
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.
Effect estimates are given without naming the comparator
Several estimates in the draft state an effect without stating what it was measured against. An estimate against placebo and an estimate against an active comparator are not the same quantity and the draft presents them in one column.
The respondent proposes that the comparator be part of every outcome row rather than a footnote, and that estimates against different comparators never share a column.
The secretariat accepts this submission. A footnoted comparator is a comparator a reader will not carry into the next row.
The comparator is now stated in every outcome row, and estimates against different comparators are reported in separate tables with the comparator named in the table caption.
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.