Draft monograph: Hexarelin — submissions
The 7 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
7 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 interaction section lists mechanisms rather than interactions
The respondent notes that Hexarelin is supplied for indications that no trial in the draft addresses, and submits in that context.
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 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.
Evidence for one member of the class is presented as evidence for this compound
Having read the draft monograph on Hexarelin, the respondent puts one point to the committee.
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.
Submission 001 concerns the same document. The respondent’s point is a different one.
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.
A purity figure from a certificate is quoted as though it were a content figure
The respondent has read the draft covering Hexarelin and makes one submission.
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.
This point is adjacent to the one made in submission 002 and the respondent puts it in a form the secretariat can act on.
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.
Trials are described as terminated where they completed as planned
The respondent’s comment on the draft for Hexarelin arises from the anti-doping literature, in which this class is well represented and clinically it is not.
The respondent states that the draft uses the word terminated for trials stopped at pre-specified interim analyses, for trials stopped for futility and for trials closed for commercial reasons, and that these are three different facts.
The respondent proposes that the status vocabulary be fixed and defined in the glossary.
The secretariat accepts this submission in part. The vocabulary is fixed and defined. The proposal to distinguish commercial closure from futility in every case is accepted only where the Institute holds a document stating the reason.
Trial status now uses a fixed vocabulary defined in the glossary, and where the reason for stopping is not evidenced by a document the Institute holds, the status is recorded as stopped with the reason not established rather than assigned.
The search date is not on the face of the document
The respondent submits on the draft monograph for Hexarelin. Growth-hormone-axis compounds are supplied widely and studied narrowly, and a document about one should make that asymmetry visible.
The draft carries a publication date and a review date but not the date on which the evidence was last searched. Those are three different dates and only the third tells a reader how current the assessment is. A document published in one quarter may rest on a search run two quarters earlier, and nothing on the page allows that gap to be measured.
The respondent proposes that the search date be printed adjacent to every certainty rating rather than in the methods section, on the ground that a reader who acts on a rating is unlikely to have read the methods section first.
The secretariat accepts this submission. The distinction between publication, review and search dates is real and the draft did not make it visible where it mattered.
The search date is now printed adjacent to every certainty rating and is carried in the document metadata, so that the interval between the search and the reading is visible without reference to the methods section.
Guidance on lyophilised storage is missing
The respondent read the draft on Hexarelin and has confined this submission to a single matter.
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 pharmacokinetic section does not connect half-life to the dosing schedule
This submission concerns the draft on Hexarelin. The respondent works in an endocrine service in which compounds of this class are assessed.
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 read submission 002 after drafting this one and has not altered it, the two points being distinct.
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.
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.