Draft monograph: TB-500 — submissions
The 8 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
8 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
The respondent submits on the draft monograph for TB-500. 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 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 paediatric evidence is not stated where a reader would look for it
The respondent has read the draft covering TB-500 and makes one submission.
The population section describes the adult trial populations. Nothing states whether the compound has been studied in anyone under eighteen. For several compounds in this series it has not, and for one or two it has; the document does not let the reader tell which case applies.
The respondent proposes a standing row in the population table recording paediatric evidence as present, absent, or present in a named subpopulation only.
The secretariat accepts this submission. An unstated absence is indistinguishable from an unread section.
The population table now carries a paediatric row in every monograph, and where evidence exists the trials are named.
The document should not describe uses outside the approved indication
The respondent read the draft on TB-500 and has confined this submission to one matter.
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.
The interaction section lists mechanisms rather than interactions
Having read the draft monograph on TB-500, the respondent puts one point to the committee.
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 respondent’s submission overlaps with submission 002 and was prepared without sight of it.
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.
Open-label extension data are presented alongside randomised data without distinction
This submission concerns the draft on TB-500. 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.
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 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.
Mechanistic claims for a peptide fragment are carried without evidence that the fragment acts as described
The draft on TB-500 was read against the sources cited in it, and this submission arises from that comparison.
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 compound is supplied under names the monograph does not list
This submission addresses the draft on TB-500 from the standpoint of a reader who meets the compound in supply material before meeting it in a journal.
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 asks that this submission be considered with it.
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.
Absence of evidence is presented in a form a reader will take as negative evidence
The respondent notes that the draft on TB-500 carries no controlled human trial, and submits with that in view.
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 respondent has read submission 007 and puts a further matter to the secretariat.
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.
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.