Draft monograph: Thymosin beta-4 — 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.
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.
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 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.
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.
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.
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 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.
Evidence for one member of the class is presented as evidence for this compound
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.
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.
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 certainty rating for the principal assessed outcome cannot be traced to the contributing trials
The draft states a certainty rating for the principal assessed outcome and lists the contributing trials, but does not state which domain drove the downgrade. A reader who disagrees with the rating cannot tell whether the disagreement concerns risk of bias, imprecision, indirectness or inconsistency.
The respondent proposes that each rating carry its downgrade reasons explicitly, in the same row as the rating, so that a reader can accept the evidence assessment while disputing a single domain judgement.
The secretariat accepts this submission. A rating without its reasoning is an assertion, and the draft asserted rather than showed.
Each assessed outcome now carries its downgrade domains in the summary-of-findings row, with a short statement of the judgement made in each, so that the rating can be checked domain by domain against the contributing trials.
Where the compound is a glucagon-like peptide-1 receptor agonist, the cardiovascular outcome evidence should be an assessed outcome
The respondent states that for compounds in this class the cardiovascular outcome evidence, reported for semaglutide in SELECT in the New England Journal of Medicine in 2023 and for liraglutide in LEADER in the same journal in 2016, is the evidence a prescribing decision most often turns on, and that the draft treats it as background.
The respondent proposes that cardiovascular outcomes be an assessed outcome with its own certainty rating for every compound in the class for which such a trial exists.
The secretariat accepts this submission in part. Cardiovascular outcomes become an assessed outcome where a dedicated outcome trial of the compound exists. The proposal to extend the rating across the class by inference is declined, in line with the treatment of class-level extrapolation elsewhere in the series.
Cardiovascular outcomes are now an assessed outcome with their own certainty rating in every monograph for which a dedicated cardiovascular outcome trial of that compound has reported, and are recorded as not assessed elsewhere.
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 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.
Adverse event frequencies are given without the denominator or the exposure period
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.
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
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