Draft monograph: KPV — 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.
The document should state what a reader ought to do
This submission addresses the draft on KPV from the standpoint of a reader who meets the compound in supply material before meeting it in a journal.
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 absence of a rare harm in the trial set is presented as reassurance
The respondent read the draft on KPV and has confined this submission to one matter.
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 route of administration studied is not the route in which the compound is supplied
Having read the draft monograph on KPV, the respondent puts one point to the committee.
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.
The mechanism section is written with more confidence than the clinical section it precedes
This is a submission on KPV.
The pharmacology section states what the compound does at its receptor in the indicative mood and without hedging. The clinical section then reports that the effect has not been demonstrated in people. A reader who stops after the first section, as many will, takes away a claim the document goes on to withdraw.
The respondent does not propose that the pharmacology be hedged, which would be inaccurate, but that each pharmacology section close with a sentence stating which of the described actions has been shown to produce a clinical effect and which has not.
This point is adjacent to the one made in submission 001 and the respondent puts it in a form the secretariat can act on.
The secretariat accepts the proposal in part. Receptor pharmacology is often well established and hedging it would misdescribe the literature.
Every pharmacology section now closes with a statement identifying which described actions are supported by clinical evidence assessed in §3 and which are not. The pharmacology itself is stated as the sources state it.
The interaction section lists mechanisms rather than interactions
The respondent submits on KPV.
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.
Absence of evidence is presented in a form a reader will take as negative evidence
The draft on KPV was read against the sources cited in it, and this submission arises from that comparison.
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.
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.
Mechanistic claims for a peptide fragment are carried without evidence that the fragment acts as described
This is a submission on the draft for KPV, from a respondent working in peptide chemistry rather than in clinical practice.
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 respondent supports submission 003 so far as it goes and adds the matter set out here.
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.
The document set should be published in translation
The respondent read KPV in draft. The point applies to it and to the series generally.
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.
Registered trials that never reported are absent from the monograph
This submission concerns the draft on KPV. The respondent’s interest is in whether a reader can tell which of the cited work was done in animals, in cell culture, or in people.
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.
A superseded version should remain reachable from the version that replaced it
The respondent notes that the draft on KPV carries no controlled human trial, and submits with that in view.
The respondent states that the draft supersedes an earlier document and that a reader who cited the earlier version has no way to reach it from the new one, which makes it impossible to see what changed.
The respondent asks that every version carry a link both to what it supersedes and to what supersedes it.
The secretariat notes this submission. The corrections and versioning policy already requires bidirectional version links and every superseded document is retained at its own address.
No amendment arises. The requirement is stated in the corrections and versioning policy and the amendment log of this document links to the version it replaced. The respondent is correct that the link was absent from the draft page furnished for consultation, which was a defect of the consultation copy and not of the policy.
The analytical section is longer than the clinical assessment it accompanies
This submission concerns KPV and makes one point.
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.
A purity figure from a certificate is quoted as though it were a content figure
The respondent’s comment on the draft for KPV arises from work with compounds of this class in a laboratory rather than a clinical setting.
The draft quotes a purity percentage from supply documentation in a sentence about how much compound a vial contains. Chromatographic purity is a relative area within what was detected; it is not a mass fraction and it does not bound vial content.
The respondent, an analytical chemist, proposes that purity and content never appear in the same sentence without an explicit statement that they answer different questions.
The secretariat accepts this submission. The conflation is the error the Institute most often corrects in supply documentation, and it appeared in an Institute draft.
Purity and content are now reported in separate rows with separate definitions, and the monograph states that a purity figure sets no bound on content and that a content figure requires a determination against a standard of assigned content.
What happens when the compound is stopped is not addressed
The respondent submits on the draft monograph for KPV. Repair peptides are where the distance between the preclinical literature and the clinical literature is widest, and a monograph earns its place by measuring that distance.
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 respondent has read submission 004 and asks that this submission be considered with it.
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 compound is supplied under names the monograph does not list
The respondent has read the draft covering KPV and makes one submission.
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 respondent has read submission 006 and puts a further matter to the secretariat.
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 document should not describe uses outside the approved indication
The respondent has read KPV and submits on a matter of presentation.
The submission is made on behalf of a marketing-authorisation holder. It states that the draft describes uses of the compound that fall outside the approved indication, that such uses are not supported by the sponsor, and that describing them may be read as legitimising them.
The sponsor asks that the sections concerned be removed, or in the alternative that they carry a prominent statement that the sponsor does not support such use.
The secretariat does not accept this submission. The Institute records what is supplied and what is used, because a reader encountering a compound outside a regulated route is the reader most in need of an assessment of the evidence for it.
The sections remain. Every such section already states the regulatory status of the use described and states that the evidence for it is assessed separately from the evidence for the approved indication. The submission is published in full and identified as an industry submission.
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.