Draft monograph: Pramlintide — submissions
The 15 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
15 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.
Every contributing trial shares one sponsor and the monograph does not say so
Having read the draft on Pramlintide, the respondent submits on a single matter.
The respondent, who has published a systematic review of this literature, states that all of the contributing trials for the principal outcome were conducted by a single sponsor, and that this is a property of the evidence base rather than a criticism of any individual trial.
The respondent proposes that sponsor concentration be recorded as a characteristic of the evidence base in the certainty assessment rather than as a note in the discussion.
The secretariat accepts this submission. Sponsor concentration bears on what an independent replication would add, and the draft recorded it where a reader was least likely to see it.
Sponsor concentration is now stated with the certainty rating, and the monograph records how many independent sponsors contributed evidence to each assessed outcome.
A sortable table implies a comparison the underlying data do not support
The respondent has read Pramlintide in draft and makes a single submission.
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.
Submission 001 raises an adjacent matter. The respondent regards the two as separable and addresses only this one.
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.
Trials are described as terminated where they completed as planned
Having read the draft under consultation, which concerns Pramlintide, the respondent submits as follows.
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 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.
Two factual descriptions of the sponsor's programme are inaccurate
The respondent has read Pramlintide and submits on a matter of presentation.
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.
Storage and reconstitution guidance is given without stating what it rests on
The respondent submits on Pramlintide. The point would apply equally to any document in the series.
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 search date is not on the face of the document
The respondent read the draft monograph on Pramlintide and puts one point to the secretariat.
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.
Local reactions are omitted from the adverse-event table because the trials reported them separately
This submission concerns the draft on Pramlintide. The respondent’s work is with satiation-directed compounds and the observation arises from that.
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 notes submission 003 above and does not repeat the ground it covers.
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.
Regulatory status is stated without naming the jurisdiction
The respondent has read the draft covering Pramlintide and makes one submission.
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 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.
Evidence for one member of the class is presented as evidence for this compound
The respondent’s interest in the draft for Pramlintide is in what a person starting the compound would want to have been told.
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 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.
What happens when the compound is stopped is not addressed
The respondent submits on the draft monograph for Pramlintide. 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 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.
The monograph does not tell a reader that two vials of the same compound may not contain the same thing
The respondent notes that Pramlintide 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 respondent read submission 006 after drafting this one and has not altered it, the two points being distinct.
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.
The analytical section is longer than the clinical assessment it accompanies
The draft on Pramlintide was read by a respondent whose interest is in the distance between what receptor pharmacology predicts and what has been measured in people.
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 respondent supports submission 003 so far as it goes and adds the matter set out here.
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.
The interaction section lists mechanisms rather than interactions
The respondent submits on Pramlintide.
The section describes pathways by which an interaction could occur. It does not say which interactions have been observed, in what setting, or with what consequence. A reader dispensing alongside other therapy cannot act on a mechanism.
The respondent proposes that observed interactions be separated from theoretical ones, and that the theoretical ones be labelled as such.
The secretariat accepts the separation and declines to expand the section beyond the evidence.
The interaction section is now divided into interactions reported in clinical use and interactions predicted from mechanism, with the second labelled as prediction. Where neither exists the section says so in one line rather than being padded.
The document should state what a reader ought to do
This submission concerns the draft on Pramlintide and is made by a respondent who sees this class in a metabolic medicine service.
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 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 route of administration studied is not the route in which the compound is supplied
This submission concerns Pramlintide and makes one point.
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.
This point is adjacent to the one made in submission 014 and the respondent puts it in a form the secretariat can act on.
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.
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.