Draft monograph: LL-37 — submissions
The 6 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
6 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 not describe how the compound is supplied outside a regulated route
The respondent has read the draft covering LL-37 and makes one submission.
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.
The document should state what a reader ought to do
Having read the draft monograph on LL-37, the respondent puts one point to the committee.
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.
Anti-drug antibody data are omitted
The respondent’s comment on the draft for LL-37 arises from the differences in regulatory status between jurisdictions, which for this class are wider than usual.
The respondent states that immunogenicity is measured in the development programmes of peptide therapeutics and that the monograph does not report it, leaving a reader unable to judge whether loss of effect over time has an immunological explanation.
The respondent proposes that anti-drug antibody incidence and its relation to effect be reported for every compound in the series.
The secretariat accepts this submission in part. Immunogenicity is reported where a contributing trial reported it. The proposal to report it for every compound is declined because for many compounds in the series no such data exist and a uniformly empty row is not informative.
Anti-drug antibody incidence and any reported association with loss of effect are now reported where measured, and recorded as not measured where the contributing trials did not assess them.
Nothing is said about impaired renal or hepatic clearance
The respondent read the draft on LL-37 and has confined this submission to one matter.
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.
The monograph does not tell a reader that two vials of the same compound may not contain the same thing
The respondent notes that this class is supplied in an injectable presentation, and submits with that in view.
The analytical section describes what a determination measures and the supply section describes what suppliers document. Neither says that the quantity of peptide in two vials bearing the same label may differ by more than the difference between two doses in the trial schedule.
The respondent proposes an explicit statement, in §8, that a purity figure describes the lot it was measured on and nothing else, and that the practical consequence is that a dose calculated from a label is an estimate.
The secretariat accepts this submission. It is the single most consequential thing a reader of this series can be told and it was distributed across three sections rather than stated once.
A standing paragraph now appears at the head of §8 in every monograph, stating that a determination applies to the lot measured and that a label mass is not a determination.
Quantitative claims are reproduced without the method that produced them
The respondent submits on the draft monograph for LL-37. An immune modulator supplied outside a regulated route needs a document that is explicit about what the material actually is.
Several figures in the draft are quoted from sources that determined them by different methods. A figure obtained by one determination and a figure obtained by another are not comparable, and the draft places them in the same sentence without distinguishing them.
The respondent, an analytical chemist, proposes that every quantitative claim carry the method that produced it at the point of use rather than in the reference.
The secretariat accepts this submission. Placing two figures side by side is an implicit claim that they are the same kind of quantity, and in the cases identified they were not.
Every quantitative claim now carries the determination that produced it at the point of use, and figures obtained by non-comparable methods are no longer presented in the same row or sentence.
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.