Draft synthesis: The consequences of a wholly… — submissions
The 10 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
10 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.
Point estimates are given without an interval
The respondent notes that the review question — What is known about the direction and magnitude of the difference between sponsor-conducted and independently conducted trials, and how should an… — is answerable only if the contributing trials measured the same thing, and submits with that in view.
Several estimates in the draft appear as single figures. The respondent states that a point estimate without an interval invites a precision the underlying data do not support, and that the effect is worst where the estimate is drawn from a small contributing set.
The respondent proposes that no point estimate appear anywhere in the document set without its interval, including in summary tables and in the abstract.
The secretariat accepts this submission in part. Intervals are added wherever the source reports one. The proposal is declined for figures the source published without an interval, because the Institute will not compute an interval a source did not report.
Every estimate now carries its interval where the source reported one, and where it did not, the estimate is annotated as reported without an interval rather than left to appear as a precise figure.
The search strategy as published cannot be re-run
The respondent read the draft review of What is known about the direction and magnitude of the difference between sponsor-conducted and independently conducted trials, and how should an… and has confined this submission to a single matter.
The strategy is described in prose rather than reproduced as executed. The respondent, an information specialist, attempted to reconstruct it and obtained a different yield, which may reflect the reconstruction or the original.
The respondent proposes that the strategy be published line by line as run in each database, with the interface, the date and the number of records retrieved at each line.
This point is adjacent to the one made in submission 001 and the respondent puts it in a form the secretariat can act on.
The secretariat accepts this submission. A strategy that cannot be re-run cannot be checked, and a review whose search cannot be checked rests on an assertion.
The full line-by-line strategy for each database is now published with the interface, the run date and the yield at each line, and the total retrieved is reconciled against the screening flow.
The document should not describe uses outside the approved indication
The draft review of What is known about the direction and magnitude of the difference between sponsor-conducted and independently conducted trials, and how should an… was read against its registered protocol.
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.
Declared interests should appear on the document rather than on a separate page
The respondent has read the draft synthesis on What is known about the direction and magnitude of the difference between sponsor-conducted and independently conducted trials, and how should an… and makes one submission.
The draft links to a central conflicts register. The respondent argues that a reader assessing whether to rely on a particular document should not have to leave it to find out who assessed it and what they declared.
The respondent proposes that the interests of every named contributor to a document be printed on that document.
The secretariat notes this submission and records that the draft already provides for it, which the respondent could reasonably have missed because the provision sits in an appendix.
Every document carries the declared interests of its named contributors in its front matter, and the central register exists so that a reader can see a person across all documents rather than one at a time. No amendment arises; the provision has been moved from the appendix into the body of the methodology document so that it is findable.
Registered trials that never reported are not counted anywhere in the review
The respondent submits on the draft synthesis addressing What is known about the direction and magnitude of the difference between sponsor-conducted and independently conducted trials, and how should an…. 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 respondent states that the screening flow accounts for records retrieved and excluded but does not record registered trials identified with no posted result, which are neither included nor excluded and simply disappear.
The respondent proposes that they be counted and reported as a category, with the proportion of the registered evidence base they represent.
The respondent supports submission 003 so far as it goes and adds the matter set out here.
The secretariat accepts this submission. A review that cannot say how much of the evidence base is unreported cannot say how much weight its own estimate deserves.
Registered trials without posted results are now identified, counted and reported as a distinct category in the screening flow, with the proportion of registered participants they represent stated in the limitations.
Overlapping primary studies across included reviews are counted more than once
This is a submission on the draft review of What is known about the direction and magnitude of the difference between sponsor-conducted and independently conducted trials, and how should an…, made from a statistical standpoint.
The draft is an overview of reviews and several included reviews share primary studies. The respondent states that the overview reports the total number of participants across reviews as though the sets were disjoint.
The respondent proposes that overlap be assessed and reported, and that no total be given without correcting for it.
The secretariat accepts this submission. An inflated participant total overstates the evidence base by an amount the reader cannot see.
Overlap between included reviews is now assessed at primary-study level and reported in a citation matrix, and participant totals are reported for the union of primary studies rather than as a sum across reviews.
The choice of effect measure is not justified and changes the appearance of the result
The respondent’s comment on the draft review of What is known about the direction and magnitude of the difference between sponsor-conducted and independently conducted trials, and how should an… arises from comparing the included set against the respondent’s own knowledge of the field.
The draft reports relative effects for benefits and absolute effects for harms. The respondent states that the combination makes the finding look larger than the uniform presentation would, and that the choice should be justified or made uniform.
The respondent proposes that both relative and absolute effects be reported for every outcome.
The secretariat accepts this submission in part. Both measures are reported for every outcome where the baseline risk needed for the absolute effect can be stated. Where it cannot, the relative effect is reported alone with the reason.
Every outcome now reports the relative effect and, where an assumed baseline risk can be stated and sourced, the corresponding absolute effect, with the baseline risk and its source given in the same row.
The axis of the forest plot exaggerates a small difference
This submission addresses the draft synthesis on What is known about the direction and magnitude of the difference between sponsor-conducted and independently conducted trials, and how should an… from the standpoint of a reader who will use the summary and not the appendices.
The plot is drawn on an axis spanning a narrow range, so an effect of no clinical consequence occupies most of the width of the figure. A reader who takes the visual impression rather than the number will overstate the finding.
The respondent proposes that a minimally important difference be marked on every forest plot where one has been established for the outcome.
The secretariat accepts the proposal where a minimally important difference exists and declines to invent one where it does not.
Forest plots now carry a marked minimally important difference wherever a published one exists for the outcome, with its source cited. Where none exists the figure says so beneath the axis.
Risk-of-bias judgements are reported as an overall rating without the domains
This submission concerns the draft review of What is known about the direction and magnitude of the difference between sponsor-conducted and independently conducted trials, and how should an…. The respondent has conducted reviews on adjacent questions and the observation arises from that experience.
The draft reports a single overall risk-of-bias judgement per study. The respondent states that the overall judgement conceals which domain drove it, and that a reader assessing whether the concern applies to their question needs the domain.
The respondent proposes a domain-level table with the supporting quotation for each judgement.
The secretariat accepts this submission. The overall judgement is a summary of the domains and publishing only the summary makes it uncheckable.
Risk of bias is now reported at domain level for every included study, with the text on which each judgement was based quoted and referenced, and the overall judgement derived from the domains rather than asserted alongside them.
Two included studies do not meet the registered eligibility criteria
Having read the draft synthesis on What is known about the direction and magnitude of the difference between sponsor-conducted and independently conducted trials, and how should an…, the respondent puts one point to the committee.
The respondent identifies two studies in the included set whose duration falls below the minimum stated in the protocol, and one excluded study that appears to meet every criterion.
The respondent proposes that the three be reassessed and that the outcome of the reassessment be recorded whichever way it goes.
The secretariat accepts this submission in part. On reassessment, one of the two included studies does fall below the minimum duration and has been removed. The second reports a duration that met the criterion in the protocol version registered at the time. The excluded study was excluded for a reason not clearly recorded, which was a documentation failure.
One study has been removed from the included set and the estimate recomputed, the exclusion reason for the third study has been corrected in the excluded-studies table, and the screening decisions are now recorded against the protocol version in force at the time of screening.
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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