Draft monograph: Tesamorelin — 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.
A superseded version should remain reachable from the version that replaced it
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 The corrections and versioning policy already requires bidirectional version links and every superseded document is retained at its own address.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.
Every contributing trial shares one sponsor and the monograph does not say so
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.
The pharmacokinetic section does not connect half-life to the dosing schedule
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.
The document should state what a reader ought to do
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.
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.
Absence of evidence is presented in a form a reader will take as negative evidence
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.
The document should not describe uses outside the approved indication
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.
Trials are described as terminated where they completed as planned
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.
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 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.
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 recorded evidence gaps omit outcomes a reader would consider material
The evidence-gap section records what has not been studied. The respondent, a practising clinician, states that the list is drawn from the outcomes the trials chose to measure and therefore reproduces the sponsor's outcome selection rather than correcting for it.
The respondent proposes that the gap list be constructed from the outcomes a prescribing decision turns on, and that outcomes measured by no trial appear in it as such.
The secretariat accepts this submission in part. The gap list is reconstructed from the decision-relevant outcome set rather than from the measured set. The proposal that every unmeasured outcome be listed is declined, because an unbounded list of things not studied is not a finding.
The evidence-gap section is now derived from the anchor and decision-relevant outcomes for the indication, and any such outcome measured by no contributing trial is recorded as not measured rather than omitted.
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 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.
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.