Draft monograph: NAD+ (nicotinamide adenine dinucleotide) — submissions
The 9 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
9 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
This submission concerns NAD+ (nicotinamide adenine dinucleotide) and a convention used across the Institute’s output.
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.
A near-isobaric analogue is not distinguished by the identity determination described
Having read the draft monograph on NAD+ (nicotinamide adenine dinucleotide), the respondent puts one point to the committee.
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
This submission concerns NAD+ (nicotinamide adenine dinucleotide) and makes one point.
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.
The monograph should reproduce the approved labelling rather than paraphrase it
The respondent submits on NAD+ (nicotinamide adenine dinucleotide), on a matter that is not specific to this draft but is visible in it.
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.
Local reactions are omitted from the adverse-event table because the trials reported them separately
The respondent has read NAD+ (nicotinamide adenine dinucleotide) and submits on a matter of presentation.
Injection-site reactions are reported in the source trials in a table of their own and do not appear in the systemic adverse-event table the monograph reproduces. The result is that the most common adverse experience of a subcutaneously administered compound is absent from the monograph’s adverse-event section.
The respondent proposes that local reactions be carried in the same table as systemic events, with the reporting convention of the source trial recorded in a footnote.
The secretariat accepts this submission. The omission arose from following the source tables and it produced a misleading total.
Local reactions are now carried in the adverse-event table wherever the source trials report them, footnoted with the convention each trial used.
The document set should be published in translation
The respondent read the draft on NAD+ (nicotinamide adenine dinucleotide) and has confined this submission to a single matter.
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.
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 mechanism section is written with more confidence than the clinical section it precedes
The respondent notes that NAD+ (nicotinamide adenine dinucleotide) is supplied for indications remote from those studied, and submits in that context.
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 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.
The absence of a rare harm in the trial set is presented as reassurance
The respondent submits on the draft monograph for NAD+ (nicotinamide adenine dinucleotide). 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 that a specific serious event was not observed in the contributing trials. The respondent states that trials of the size conducted here could not have detected an event at the frequency in question, and that reporting the absence without that arithmetic converts an uninformative result into a reassuring one.
The respondent proposes that the detectable frequency be stated wherever the absence of an event is reported.
The respondent notes submission 002 above and does not repeat the ground it covers.
The secretariat accepts this submission. The Institute's own framework treats an absent event in an underpowered set as uninformative, and the draft departed from it.
Wherever the monograph reports that an event was not observed, it now states the total exposure and the frequency the contributing trials could have detected, so that the absence is read as the limit of the evidence rather than as a finding.
The monograph does not tell a reader that a stated mass may be substantially counter-ion and water
The respondent has read the draft covering NAD+ (nicotinamide adenine dinucleotide) and makes one submission.
The draft quotes vial contents in milligrams without stating whether the figure refers to peptide content or to total solids. For an acetate or trifluoroacetate salt of a peptide, the difference between the two can exceed a fifth of the stated mass.
The respondent, an analytical chemist, states that this is the single most consequential misreading in the field and that a monograph that does not address it directly is leaving the reader to discover it.
The secretariat accepts this submission. Moderate certainty evidence from published analytical surveys suggests that content and total solids are routinely conflated in supply documentation, and the draft did not warn the reader.
The monograph now states, at the point where vial contents are first mentioned, that a mass figure is uninterpretable unless it states whether it is peptide content or total solids, and cross-references the content standard in the analytical series.
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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