Draft monograph: Glutathione — submissions
The 14 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
14 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 monograph should state what the compound costs
This is a submission on the draft for Glutathione, from a respondent who assesses evidence of this kind for a hospital formulary.
The respondent states that a reader deciding whether to pursue treatment needs to know what it costs, and that omitting price makes the assessment less useful than it could be.
The respondent proposes that a price range be recorded for each compound with the source and date.
The secretariat does not accept this submission. Price varies by jurisdiction, payer, presentation and date to a degree that no single figure could survive, and a stale price is worse than no price.
No price is recorded. The monograph records the presentations available and the regulatory status in each jurisdiction, which are the facts the Institute can verify and maintain. The submission remains published in full.
Open-label extension data are presented alongside randomised data without distinction
The respondent submits on Glutathione.
Long-term figures in the clinical section come from open-label extensions in which every participant received the active compound and those who did not tolerate it had already withdrawn. They are printed in the same table as randomised comparisons and in the same typeface.
The respondent proposes that extension data be presented in a separate table, or at minimum in a separately labelled block, and that the surviving-population problem be stated once where it arises.
The respondent has read submission 001 above and makes this submission independently of it.
The secretariat accepts this submission. An extension estimate answers a different question from a randomised one and should not be read as though it answered the same one.
Extension data now appear in a separate table headed as uncontrolled follow-up, with a standing note on differential withdrawal.
The monograph should not describe how the compound is supplied outside a regulated route
This submission concerns Glutathione and makes one point.
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 respondent read submission 002 after drafting this one and has not altered it, the two points being distinct.
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.
What happens when the compound is stopped is not addressed
Having read the draft under consultation, which concerns Glutathione, the respondent submits as follows.
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.
Registered trials that never reported are absent from the monograph
Having read the draft monograph on Glutathione, the respondent puts one point to the committee.
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.
This submission is made by a respondent with a different professional interest in the outcome from the one behind submission 002.
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.
The document set should be published in translation
The respondent submits on Glutathione. The point would apply equally to any document in the series.
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.
Submission 002 concerns the same document. The respondent’s point is a different one.
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 should reproduce the approved labelling rather than paraphrase it
The respondent has read the draft covering Glutathione and makes one submission.
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.
Every contributing trial shares one sponsor and the monograph does not say so
The respondent read the draft on Glutathione and has confined this submission to 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.
Mechanistic claims for a peptide fragment are carried without evidence that the fragment acts as described
This submission concerns the draft on Glutathione and is made from a biochemical standpoint.
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.
A near-isobaric analogue is not distinguished by the identity determination described
This submission concerns the draft on Glutathione. The respondent’s work is with biomarkers of mitochondrial function.
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 certainty rating for the principal assessed outcome cannot be traced to the contributing trials
The respondent submits on the draft monograph for Glutathione. The mechanistic literature for this class is strong and the clinical literature is thin, and a document that does not make that plain will be read as though both were strong.
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.
A purity figure from a certificate is quoted as though it were a content figure
The respondent’s comment on the draft for Glutathione arises from laboratory work with compounds of this class.
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.
Declared interests should appear on the document rather than on a separate page
The respondent notes that Glutathione is supplied for indications remote from those studied, and submits in that context.
The draft links to a central conflicts register. The respondent argues that a reader assessing whether to rely on a particular document should not have to leave it to find out who assessed it and what they declared.
The respondent proposes that the interests of every named contributor to a document be printed on that document.
The respondent supports submission 001 so far as it goes and adds the matter set out here.
The secretariat notes this submission and records that the draft already provides for it, which the respondent could reasonably have missed because the provision sits in an appendix.
Every document carries the declared interests of its named contributors in its front matter, and the central register exists so that a reader can see a person across all documents rather than one at a time. No amendment arises; the provision has been moved from the appendix into the body of the methodology document so that it is findable.
Preclinical findings are reported without the model that produced them
The respondent has read Glutathione in draft and makes a single submission.
The section reports effects on healing, on mitochondrial function or on cognition without stating whether the observation was made in a cell line, in a rodent, or in an isolated tissue, and without stating the dose relative to anything a person would receive.
The respondent proposes that every preclinical statement carry its model and its dose, on the ground that a reader cannot otherwise judge how far the finding travels.
The secretariat accepts this submission. A preclinical claim without its model is not a citation, it is an assertion with a reference attached.
Every preclinical statement in the series now carries the model and, where the source reports it, the dose and the route.
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.