Draft monograph: SS-31 (elamipretide) — submissions
The 16 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
16 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.
Guidance on lyophilised storage is missing
The respondent submits on the draft monograph for SS-31 (elamipretide). 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 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 reproduce the approved labelling rather than paraphrase it
The respondent has read the draft covering SS-31 (elamipretide) 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.
The mechanism section is written with more confidence than the clinical section it precedes
The respondent has read SS-31 (elamipretide) in draft and makes a single submission.
The pharmacology section states what the compound does at its receptor in the indicative mood and without hedging. The clinical section then reports that the effect has not been demonstrated in people. A reader who stops after the first section, as many will, takes away a claim the document goes on to withdraw.
The respondent does not propose that the pharmacology be hedged, which would be inaccurate, but that each pharmacology section close with a sentence stating which of the described actions has been shown to produce a clinical effect and which has not.
The respondent has read submission 001 and puts a further matter to the secretariat.
The secretariat accepts the proposal in part. Receptor pharmacology is often well established and hedging it would misdescribe the literature.
Every pharmacology section now closes with a statement identifying which described actions are supported by clinical evidence assessed in §3 and which are not. The pharmacology itself is stated as the sources state it.
A purity figure from a certificate is quoted as though it were a content figure
This submission concerns the draft on SS-31 (elamipretide). The respondent’s work is with biomarkers of mitochondrial function.
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 respondent has read submission 003 and asks that this submission be considered with it.
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.
A near-isobaric analogue is not distinguished by the identity determination described
The respondent’s comment on the draft for SS-31 (elamipretide) arises from laboratory work with compounds of this class.
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.
Every contributing trial shares one sponsor and the monograph does not say so
The respondent submits on SS-31 (elamipretide), on a matter that is not specific to this draft but is visible in it.
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.
This submission should be read alongside submission 004, which arises on the same draft.
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.
The compound is supplied under names the monograph does not list
The respondent submits on SS-31 (elamipretide). The point would apply equally to any document in the series.
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’s submission overlaps with submission 003 and was prepared without sight of 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.
The pharmacokinetic section does not connect half-life to the dosing schedule
This submission concerns SS-31 (elamipretide) and a convention used across the Institute’s output.
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 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.
A sortable table implies a comparison the underlying data do not support
The respondent read SS-31 (elamipretide) in draft. The point applies to it and to the series generally.
The draft presents a sortable table whose columns are drawn from sources of differing quality. The respondent states that sorting on such a column produces an ordering that looks like a ranking and is not one.
The respondent proposes that sorting be disabled on any column whose values are not commensurable.
The respondent notes submission 007 above and does not repeat the ground it covers.
The secretariat notes this submission and records that the point is correct in principle.
No amendment arises here because every sortable table in the document set already carries a standing statement above it that the ordering is not a ranking and that the values in each column are commensurable only where the column header says so. The proposal to disable sorting was considered and not adopted, because a reader who cannot sort a table generally sorts it elsewhere and without the statement.
The monograph does not tell a reader that two vials of the same compound may not contain the same thing
This submission concerns the draft on SS-31 (elamipretide) and is made from a biochemical standpoint.
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.
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. 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.
Two factual descriptions of the sponsor's programme are inaccurate
Having read the draft monograph on SS-31 (elamipretide), the respondent puts one point to the committee.
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 same concept is given three different names in one document
This is a submission on the draft for SS-31 (elamipretide), from a respondent who assesses evidence of this kind for a hospital formulary.
The draft refers to the same quantity as a response rate, a responder proportion and a categorical outcome in different sections. The respondent, who works in health-technology assessment, states that a reader cannot tell whether the three refer to one thing or to three.
The respondent proposes that the glossary term be used at every occurrence and that the glossary entry be linked at first use in each section rather than only at first use in the document.
The secretariat accepts this submission. The variation was stylistic and its cost to the reader exceeds any benefit.
A single term is now used throughout for each defined concept, and the glossary entry is linked at first use within each section rather than once per document.
Nothing is said about impaired renal or hepatic clearance
This is a submission on SS-31 (elamipretide).
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 respondent notes that submission 010 has already been made and confines this submission to a matter not covered by it.
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 document should not describe uses outside the approved indication
The respondent notes that SS-31 (elamipretide) is supplied for indications remote from those studied, and submits in that context.
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.
Anti-drug antibody data are omitted
The draft on SS-31 (elamipretide) was read from the standpoint of a clinical biochemistry service.
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.
The preclinical section is extensive and the clinical section is not
The respondent read the draft on SS-31 (elamipretide) and has confined this submission to a single matter.
The draft summarises a large animal literature and a small or absent human literature. The respondent states that the resulting document reads as though a great deal is known, when what is known concerns rodents.
The respondent proposes that the preclinical section be reduced to a statement of what has been observed in animals and that the detail be removed entirely.
The respondent’s submission overlaps with submission 015 and was prepared without sight of it.
The secretariat accepts this submission in part. The section is shortened and given a standing statement. The proposal to remove the detail is declined, because a reader encountering claims derived from that literature needs to be able to see what it actually contains.
The preclinical section is reduced in length, placed after the clinical assessment rather than before it, and opens with a standing statement that an effect observed in an animal model is not a clinical outcome and does not support a certainty rating.
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
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