Draft synthesis: Amylin analogues as monotherapy and in… — 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.
Doses differing several-fold are pooled without examining dose-response
The respondent notes that the review question — What is the effect of an amylin receptor agonist alone and in combination with a glucagon-like peptide-1 receptor agonist on body weight? — is answerable only if the contributing trials measured the same thing, and submits with that in view.
Contributing trials administer doses that differ by a factor of several. The draft pools them and reports one estimate. The respondent states that where a dose-response relationship exists the pooled figure corresponds to no dose that anyone receives.
The respondent proposes that estimates be reported by dose and that dose-response be examined where the data allow.
The secretariat accepts this submission. A pooled estimate across doses is an estimate for an average dose that no protocol specifies.
Estimates are now reported by dose group, a dose-response examination is reported where three or more dose levels contribute, and the pooled across-dose estimate is removed rather than retained alongside.
Analytical surveys are treated as evidence about suppliers when they establish only what was in a sample
The respondent has read the draft synthesis on What is the effect of an amylin receptor agonist alone and in combination with a glucagon-like peptide-1 receptor agonist on body weight? and makes one submission.
Several included surveys purchased material anonymously and analysed it. The respondent states that where the chain from a named supplier to the analysed vial cannot be documented, the result describes a sample and not a supplier.
The respondent proposes that provenance be an explicit eligibility dimension, with surveys reported separately according to whether it could be established.
Submission 001 concerns the same document. The respondent’s point is a different one.
The secretariat accepts this submission. Moderate certainty evidence from the included surveys supports statements about material circulating in a market; it does not support statements about any named supplier's output.
Provenance is now assessed for every included survey and reported as a study characteristic, surveys without establishable provenance are reported separately rather than pooled with those that have it, and no supplier-level inference is drawn from a sample-level result.
The document should not describe uses outside the approved indication
The respondent submits on the draft synthesis addressing What is the effect of an amylin receptor agonist alone and in combination with a glucagon-like peptide-1 receptor agonist on body weight?. This submission concerns the methods rather than the conclusion, on the view that a conclusion is only as good as the search that produced it.
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.
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 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.
An indirect comparison is presented without an assessment of transitivity
The respondent read the draft review of What is the effect of an amylin receptor agonist alone and in combination with a glucagon-like peptide-1 receptor agonist on body weight? and has confined this submission to a single matter.
The draft compares two interventions through a common comparator. The respondent states that the trials contributing to each side differ in background therapy and in baseline severity, and that the resulting estimate assumes a similarity the draft does not test.
The respondent proposes that transitivity be assessed explicitly and reported before any indirect estimate is presented.
The secretariat accepts this submission. An indirect estimate presented without a transitivity assessment invites a reader to treat an assumption as a result.
Transitivity is now assessed against a stated list of effect modifiers and reported before any indirect estimate, and where the assessment fails the contrast is reported as unestimable with the reason rather than estimated with a caveat.
A sponsor trial meeting the eligibility criteria was excluded
Having read the draft synthesis on What is the effect of an amylin receptor agonist alone and in combination with a glucagon-like peptide-1 receptor agonist on body weight?, the respondent puts one point to the committee.
The submission is made on behalf of the sponsor. It identifies a completed trial of the sponsor's compound that meets the stated eligibility criteria and does not appear in the included set, and supplies the trial report and the registry record.
The sponsor asks that the trial be included and the estimate recomputed. No view is expressed on the direction the recomputation should take.
The secretariat accepts this submission in part. The trial does meet the criteria and has been included. The recomputed estimate is materially unchanged, which the response states explicitly so that the outcome of the correction is on the record.
The trial is added to the included set, the estimate and the certainty rating have been recomputed, and the screening record now states why the trial was missed, which was a database indexing gap rather than a screening judgement. The submission is identified as an industry submission.
Regulatory assessment documents were not searched
This submission concerns What is the effect of an amylin receptor agonist alone and in combination with a glucagon-like peptide-1 receptor agonist on body weight? and makes one point.
The respondent states that regulatory assessment reports frequently contain analyses that never appear in journals, and that a search limited to bibliographic databases will miss them.
The respondent proposes that regulatory documents be searched for every review in the series.
The secretariat accepts this submission in part. Regulatory assessment documents are searched. The proposal that they be treated as equivalent to a full study report is declined, because the level of detail varies and is often insufficient for risk-of-bias assessment.
Published regulatory assessment documents are now searched as a named source, are reported as a distinct evidence class in the included-studies table, and contribute to the assessment while being excluded from pooled estimates where risk of bias could not be assessed from the document.
A superseded version should remain reachable from the version that replaced it
The draft review of What is the effect of an amylin receptor agonist alone and in combination with a glucagon-like peptide-1 receptor agonist on body weight? was read against its registered protocol.
The respondent states that the draft supersedes an earlier document and that a reader who cited the earlier version has no way to reach it from the new one, which makes it impossible to see what changed.
The respondent asks that every version carry a link both to what it supersedes and to what supersedes it.
The respondent read submission 006 after drafting this one and has not altered it, the two points being distinct.
The secretariat notes this submission. The corrections and versioning policy already requires bidirectional version links and every superseded document is retained at its own address.
No amendment arises. The requirement is stated in the corrections and versioning policy and the amendment log of this document links to the version it replaced. The respondent is correct that the link was absent from the draft page furnished for consultation, which was a defect of the consultation copy and not of the policy.
The review question is drawn too broadly to be answerable
This submission addresses the draft synthesis on What is the effect of an amylin receptor agonist alone and in combination with a glucagon-like peptide-1 receptor agonist on body weight? from the standpoint of a reader who will use the summary and not the appendices.
The respondent states that the population as registered spans groups in which the intervention would be expected to behave differently, and that a single estimate across them is uninformative.
The respondent proposes that the question be split and the review re-registered.
The respondent supports submission 007 so far as it goes and adds the matter set out here.
The secretariat does not accept this submission. The breadth was registered before screening, the pre-specified subgroups address the variation the respondent identifies, and re-registering after the results are known would convert a pre-specified analysis into a post hoc one.
The question stands as registered. The point is recorded in the limitations, and the assessment committee has noted it for the protocol of the next version of this review, which will be registered before the search is run. The submission remains published in full.
The review does not say when it will be updated or what would trigger an update
The respondent’s comment on the draft review of What is the effect of an amylin receptor agonist alone and in combination with a glucagon-like peptide-1 receptor agonist on body weight? arises from comparing the included set against the respondent’s own knowledge of the field.
The respondent states that a synthesis in a field where trials report frequently is out of date from the day it is published, and that a reader has no way to know whether the version in front of them is current.
The respondent proposes a stated trigger for an update as well as a scheduled review date.
The secretariat accepts this submission. A review date alone tells a reader when the document will be looked at, not whether it should already have been.
Every synthesis now records a scheduled review date and a stated update trigger, being the reporting of a trial that would materially change the contributing evidence, and the registered trials capable of triggering an update are listed by name.
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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