Draft monograph: Cagrilintide — 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.
Adverse event frequencies are given without the denominator or the exposure period
This submission concerns the draft on Cagrilintide. The respondent’s work is with satiation-directed compounds and the observation arises from that.
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 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.
What happens to weight after the compound is stopped is not in the assessed outcomes
This is a submission on the draft monograph for Cagrilintide, made from a clinical rather than an analytical 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.
This submission should be read alongside submission 001, which arises on the same draft.
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.
Point estimates are given without an interval
This submission concerns Cagrilintide and makes one point.
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 absence of a rare harm in the trial set is presented as reassurance
The respondent submits on Cagrilintide, on a matter that is not specific to this draft but is visible in it.
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 compound is supplied under names the monograph does not list
The respondent’s interest in the draft for Cagrilintide is in what a person starting the compound would want to have been told.
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.
The monograph does not tell a reader that two vials of the same compound may not contain the same thing
The respondent notes that Cagrilintide is frequently supplied in combination while this draft assesses it alone, and submits in that context.
The analytical section describes what a determination measures and the supply section describes what suppliers document. Neither says that the quantity of peptide in two vials bearing the same label may differ by more than the difference between two doses in the trial schedule.
The respondent proposes an explicit statement, in §8, that a purity figure describes the lot it was measured on and nothing else, and that the practical consequence is that a dose calculated from a label is an estimate.
The secretariat accepts this submission. It is the single most consequential thing a reader of this series can be told and it was distributed across three sections rather than stated once.
A standing paragraph now appears at the head of §8 in every monograph, stating that a determination applies to the lot measured and that a label mass is not a determination.
Trials are described as terminated where they completed as planned
Having read the draft on Cagrilintide, the respondent submits on a single matter.
The respondent states that the draft uses the word terminated for trials stopped at pre-specified interim analyses, for trials stopped for futility and for trials closed for commercial reasons, and that these are three different facts.
The respondent proposes that the status vocabulary be fixed and defined in the glossary.
The respondent has read submission 003 and puts a further matter to the secretariat.
The secretariat accepts this submission in part. The vocabulary is fixed and defined. The proposal to distinguish commercial closure from futility in every case is accepted only where the Institute holds a document stating the reason.
Trial status now uses a fixed vocabulary defined in the glossary, and where the reason for stopping is not evidenced by a document the Institute holds, the status is recorded as stopped with the reason not established rather than assigned.
The document should state what a reader ought to do
The draft on Cagrilintide was read by a respondent whose interest is in the distance between what receptor pharmacology predicts and what has been measured in people.
The draft assesses evidence and stops. The respondent, a practising clinician, states that a reader arriving at the document with a decision to make is left to convert an assessment into an action without help, and proposes that each document close with a recommendation.
The respondent argues that other evidence bodies issue recommendations and that declining to do so transfers the difficult part of the work to the reader.
The respondent has read submission 002 and asks that this submission be considered with it.
The secretariat does not accept this submission, and records that the point is a reasonable one rather than a misunderstanding.
The Institute assesses evidence and does not issue recommendations, because a recommendation embeds values and a resource context that the Institute does not hold and cannot state. That constitutional limit is published on the methodology page and is not varied by consultation. The submission remains published in full.
The analytical section is longer than the clinical assessment it accompanies
The respondent submits on the draft monograph for Cagrilintide. The amylin class sits at an earlier stage of evidence than the incretin class, and a document about it should be readable as such.
The respondent 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.
References should carry a persistent identifier for every cited source
The respondent has read Cagrilintide in draft and makes a single submission.
Several references in the draft carry a journal, a year and a volume but no persistent identifier. The respondent 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.
Absence of evidence is presented in a form a reader will take as negative evidence
The respondent has read the draft covering Cagrilintide and makes one submission.
Where the Institute has identified no study, the draft states that no evidence was found. In several places that sentence sits immediately after a paragraph describing an adverse outcome, and the juxtaposition invites the reading that the compound was studied and found wanting.
The respondent proposes a standing formulation, used identically wherever the situation arises, distinguishing an outcome that was studied and not demonstrated from an outcome that has not been studied at all.
Submission 008 raises an adjacent matter. The respondent regards the two as separable and addresses only this one.
The secretariat accepts this submission. The two states are different, they support different decisions, and the draft rendered them in language a reader could not reliably separate.
A standing formulation has been adopted and is applied wherever an evidence gap is recorded, distinguishing an outcome assessed and not demonstrated from an outcome not assessed. The formulation is identical at every occurrence so that it can be recognised at a glance.
A near-isobaric analogue is not distinguished by the identity determination described
Having read the draft under consultation, which concerns Cagrilintide, the respondent submits as follows.
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.
Anti-drug antibody data are omitted
The respondent read the draft monograph on Cagrilintide and puts one point to the secretariat.
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.
Regulatory status is stated without naming the jurisdiction
This is a submission on Cagrilintide.
The draft states that the compound is approved, or not approved, without saying by whom. The respondent, employed by a health-technology assessment body, states that approval status differs between jurisdictions for several compounds in the series and that an unqualified statement will be wrong somewhere.
The respondent proposes that every status statement name the authority and carry the date on which the status was checked.
The respondent supports submission 005 so far as it goes and adds the matter set out here.
The secretariat accepts this submission. An unattributed status statement is a claim the Institute cannot support.
Every regulatory status statement now names the authority, states the date on which the status was verified, and is recorded per jurisdiction rather than as a single global assertion.
The route of administration studied is not the route in which the compound is supplied
The respondent read Cagrilintide in draft. The point applies to it and to the series generally.
The clinical section describes findings obtained by one route and the supply section describes presentations intended for another. A reader moving between the two sections will carry the effect estimate across the change without noticing that it has been carried, because nothing on the page marks the transition.
The respondent proposes that where the studied route and the supplied presentation differ, the difference be stated in the assessed-outcome table itself rather than in the supply section, on the ground that a reader consults the outcome table and does not always reach §8.
The secretariat accepts this submission. The route by which an estimate was generated is a condition of the estimate and belongs beside it.
The assessed-outcome table now carries the studied route in every row, and a standing note appears wherever the supplied presentation differs from it.
Nothing is said about impaired renal or hepatic clearance
This submission concerns Cagrilintide and a convention used across the Institute’s output.
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.
Submission 003 concerns the same document. The respondent’s point is a different one.
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.
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.