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.
Every contributing trial shares one sponsor and the monograph does not say so
The respondent submits on the draft monograph for Thymosin beta-4. 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 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.
Doses are expressed in units that differ between sections
The respondent has read the draft covering Thymosin beta-4 and makes one submission.
The draft expresses dose in milligrams in one section and in micrograms per kilogram in another, drawn from different sources without conversion. The respondent states that this is the shape of error that reaches a patient.
The respondent proposes a single unit throughout, with the source unit retained in parentheses where a conversion was performed.
The secretariat accepts this submission. The inconsistency was inherited from the sources and should have been resolved in drafting.
A single dose unit is now used throughout each monograph, with the source unit retained in parentheses wherever a conversion was applied, and every conversion is stated rather than performed silently.
The certainty rating for the principal assessed outcome cannot be traced to the contributing trials
This submission concerns the draft on Thymosin beta-4. 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 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.
Absence of evidence is presented in a form a reader will take as negative evidence
Having read the draft monograph on Thymosin beta-4, the respondent puts one point to the committee.
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.
Regulatory status is stated without naming the jurisdiction
The respondent has read Thymosin beta-4 in draft and makes a single 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 respondent endorses the general approach taken in submission 003 and asks that it be extended to the matter identified 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 recorded evidence gaps omit outcomes a reader would consider material
The respondent notes that the draft on Thymosin beta-4 carries no controlled human trial, and submits with that in view.
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 respondent notes that submission 005 has already been made and confines this submission to a matter not covered by it.
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 monograph should reproduce the approved labelling rather than paraphrase it
The respondent submits on Thymosin beta-4. The point would apply equally to any document in the series.
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 should carry a persistent identifier for every cited source
This submission addresses the draft on Thymosin beta-4 from the standpoint of a reader who meets the compound in supply material before meeting it in a journal.
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.
Mechanistic claims for a peptide fragment are carried without evidence that the fragment acts as described
The respondent’s comment on the draft for Thymosin beta-4 arises from work with compounds of this class in a laboratory rather than a clinical setting.
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 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 supply section does not record that endotoxin is not determined
The respondent read the draft on Thymosin beta-4 and has confined this submission to one matter.
The compound is supplied as a lyophilisate intended for reconstitution and injection. The supply section lists the determinations that certificates carry and does not state that endotoxin is not among them, which is the determination whose absence has the most direct consequence for that presentation.
The respondent proposes an explicit line in §8 for every compound supplied in an injectable presentation, stating whether endotoxin is determined and, where it is not, what that means.
The secretariat accepts this submission. The omission was an artefact of listing what is present rather than what is absent.
Section 8 now carries an explicit endotoxin line for every compound supplied in an injectable presentation, and states plainly that an undetermined attribute is undetermined rather than acceptable.
Two factual descriptions of the sponsor's programme are inaccurate
Having read the draft under consultation, which concerns Thymosin beta-4, the respondent submits as follows.
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.
The pharmacokinetic section does not connect half-life to the dosing schedule
This submission concerns Thymosin beta-4 and makes one point.
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 respondent has read submission 002 above and makes this submission independently of it.
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.
Nothing is said about impaired renal or hepatic clearance
The draft on Thymosin beta-4 was read against the sources cited in it, and this submission arises from that comparison.
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.
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.
Guidance on lyophilised storage is missing
The respondent submits on Thymosin beta-4.
The respondent asks that the monograph state storage conditions for lyophilised material as well as for reconstituted solution, since the two differ and the former governs the longer part of the shelf life.
The respondent states that the omission is the more consequential because lyophilised material is what is generally received.
The secretariat notes this submission. The draft addresses lyophilised storage, in the presentation section rather than in the section on in-use handling, which is where the respondent looked.
No amendment to content arises. The two storage statements have been brought together under a single heading so that a reader looking for either finds both.
The monograph should not describe how the compound is supplied outside a regulated route
The respondent read Thymosin beta-4 in draft. The point applies to it and to the series generally.
The respondent states that describing presentations observed in unregulated supply risks being read as a guide to obtaining them, and asks that the material be removed.
The respondent accepts that the information is accurate and objects to its presence rather than to its content.
The secretariat notes this submission and records the concern as a real one that the draft had already considered.
No amendment arises. The monograph describes what is supplied and names no supplier, price or route of acquisition, and it carries the standing statement that the Institute assesses evidence and does not recommend use. Describing a presentation a reader may already hold is the condition of being useful to that reader.
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.