February 2024

The label says four weeks. The clinic says whatever holds.

What the regulatory dossiers actually contain on dose selection is remarkably thin, and worth knowing before treating the ladder…

The trade has decided the ceiling is arbitrary. The trials disagree.

The ceiling in this class is anatomical: the same receptor populations that suppress appetite provoke nausea, and they saturate…

A supply gap is a pharmacological event

One omitted dose is a labelling question. Four omitted doses is a clinical one. The two are routinely conflated.

Severity grading, and the gap between a grade and an experience

Trial adverse-event tables count episodes reported to a study nurse. They are the best data we have and they systematically…

What the trials counted as intolerance

We set out the questions that distinguish a symptom to manage from a dose to change.

Escalating past the approved maximum, examined honestly

Where the curve flattens, what flattens with it, and what does not.

The escalation table is the thinnest page in the label

The published ladder exists because a protocol needed a single number. Practice has never followed it exactly, and the…

Six words a verification badge would need to mean anything

A badge asserts that something was tested. It does not assert what, when, on whose sample, by what method, or whether the lot on…

The batch number is the only thing connecting the page to the vial

What happens to traceability when bulk material is subdivided, repackaged and relabelled two or three times before sale.

Who signed this, and what did they undertake by signing it

Two signatures — one who performed the work, one who approved its release — are the ordinary regulated convention and are almost…

Who signed this, and what did they undertake by signing it

Somebody has to be answerable for a release document. On most certificates in this market, nobody is named at all.

Oxidation, and the peroxide that came in with the surfactant

The sequence predicts the failure mode. A methionine predicts oxidation; an asparagine followed by a glycine predicts…

Janoshik, Medutest, PeptideMeter, VendorInvestigate: a capability audit

The absence of microbiological capability in this market is a commercial fact with a straightforward explanation, and it is…

Adsorption, and the dose that stayed on the glass

Every degradation pathway accelerates by orders of magnitude on reconstitution, because the solvent that lyophilisation removed…

What the older diet-and-exercise trials found in the hip

The evidence base is one secondary analysis, several small studies and a large amount of extrapolation from bariatric surgery.

Reading HbA1c in the presence of anaemia

The alternatives with shorter windows, what they measure, and why they are rarely ordered.

What the outcome trials measured in the kidney

Asymptomatic pancreatic enzyme elevation is common on treatment and is not pancreatitis. The distinction is clinical, not…

Which results should be repeated before they are investigated

What the pivotal programmes measured and how often, which is a more defensible template than most published monitoring schedules.

Why the bone question is harder than the muscle question

What the Journal would want measured before treating this as settled in either direction.

Seasonal use, holiday use, and the honest state of the evidence

What the exposure arithmetic says about a fortnightly schedule, and where the arithmetic stops being informative.

Bone density during rapid weight loss: what is known, which is less than you would hope

Weight loss reduces bone mineral density at load-bearing sites. Whether that translates into fractures in this population is…

The named comparison we promised two years ago

The Journal submitted split samples from single lots to three assay services, under names unconnected to this publication, and…

Quadrupole, time-of-flight, orbital trap: what each class can and cannot see

Every instrument specification quoted in an advertisement is a best case obtained on a calibration mixture, not on a submitted…

One column, one wavelength, one very large blind spot

The Journal has read several hundred certificates from twenty companies. We set out what the documents actually cover, and what…

In-use stability is a separate study, and almost nobody has done it

An in-use period is established by a dedicated study on a specific formulation in a specific container at a specific…

Sixteen daltons: methionine, and the easiest degradation to find

Deamidation adds 0.98 daltons. On a low-resolution instrument at incretin molecular weights, that is inside the noise.

Set the threshold at a tenth of a per cent and the small impurities vanish

We work through a single chromatogram twice, under two integration conventions, and show where the difference comes from.

Leucine, isoleucine, and a difference no balance can measure

Deamidation adds 0.98 daltons. On a low-resolution instrument at incretin molecular weights, that is inside the noise.

The retest date and the expiry date are not the same document

A retest date says that material should be re-examined before use. An expiry date says it should not be used. The trade uses the…

Randomised withdrawal is the cleanest design in this field and the least discussed

The regain trajectories, arm by arm, with the estimands named.

Two sessions a week, and the evidence behind the prescription

Mass and function are different endpoints and training affects them differently. Most coverage treats them as one.

The ceiling is a tolerability finding, not an efficacy one

Where the curve flattens, what flattens with it, and what does not.

A needle is a single-use instrument

For licensed products the in-use period is established by stability data. For a peptide reconstituted at home there is no such…

What the cagrilintide schedule assumes about a person it has never met

The four-week step exists because four to five weeks is approximately how long a once-weekly drug takes to stop rising at a…

A guide to the results that will resolve themselves

Three different explanations for the same abnormal number, and how to tell them apart.

The arithmetic of a step: what doubling a dose actually asks of you

What the published pharmacokinetics permit, what the labels state, and where the two diverge.

A guide to the results that will resolve themselves

Three different explanations for the same abnormal number, and how to tell them apart.

How a claim degrades between the bench and the listing

Lot-level verification with a public report is a real and achievable thing. It exists in this market, on a minority of listings.

The submitted sample: the weakest link in the whole system

What a laboratory can and cannot know about the provenance, storage history and representativeness of what lands on its bench.

The shortage years, and what they taught about interruption

A supply interruption is a discontinuation with no notice, no taper and no plan. That is a distinct clinical situation.

What a laboratory knows about the material it receives

The condition on arrival is recorded by some services and not others, and it is one of the more informative lines in a report.

What happens when the drug is taken away: three randomised answers

Three randomised withdrawal designs have tested what happens when treatment stops. Their results are consistent and they are…

Side effects, cost, supply, target: four reasons with four trajectories

Real-world persistence figures, with their definitions stated, because the definitions are doing most of the work.

What SURPASS-3 tells us about maintenance, and what it does not

What the labels permit, what clinicians do, and the size of the gap between them.

Who chose the vial that was tested?

The condition on arrival is recorded by some services and not others, and it is one of the more informative lines in a report.

Why the bone question is harder than the muscle question

The evidence base is one secondary analysis, several small studies and a large amount of extrapolation from bariatric surgery.

What a 1 mL syringe does that a 0.3 mL syringe does not

We work through the arithmetic in full, because it is short, and because the errors it prevents are order-of-magnitude errors.

What column temperature does to selectivity

Column chemistry, particle size and pore diameter determine what the separation is capable of before the gradient is even…

A vial can be 99.4 per cent pure and not sterile in the same afternoon

Every certificate circulating in this market answers a question about molecules. Almost none answers a question about organisms,…

Reading the semaglutide composition data without the press release

The composition data comes from imaging substudies enrolling a few score participants at selected sites. It is the best evidence…

The one-quarter rule, and the paper that took it apart

The gap between a defensible recommendation and a confident one is where most of the harm in this subject lives.

What “LC-MS: conforms” tells a reader, which is almost nothing

None of what a checkable identity statement requires is commercially sensitive, and all of it is known to whoever produced the…

The cold chain in this trade is a gel pack and an optimistic estimate

A gel pack has a finite thermal budget, and once it is spent the payload equilibrates with whatever is outside the box. The only…

Escalating past the approved maximum, examined honestly

The ceiling in this class is anatomical: the same receptor populations that suppress appetite provoke nausea, and they saturate…

What the anaesthetists said, and then said again

What endoscopic and ultrasound studies found about residual gastric content, and what the aspiration data does and does not…

The site you keep using is the site that stops working

Repeated injection into the same small area produces lipohypertrophy — thickened, rubbery subcutaneous tissue with blunted and…

Specification and result are two columns, and only one of them is a measurement

Statements of conformity are supposed to rest on a stated decision rule. Almost nothing in this trade states one.

What high resolution actually buys you

Parts per million sound impressive until they are converted into daltons at the molecular weight of the thing being measured.

Accuracy, precision and the tolerance nobody states

Every instrument specification quoted in an advertisement is a best case obtained on a calibration mixture, not on a submitted…

Background rates, and why they matter for attribution

Rapid weight loss by any means raises gallstone risk. Separating that from a direct drug effect requires a comparator, and the…