March 2024

Holidays, surgery, sickness: interruption in practice

The convention — resume lower, re-escalate — is not caution. It follows directly from the elimination half-life.

What a month without the drug does to tolerability

The convention — resume lower, re-escalate — is not caution. It follows directly from the elimination half-life.

Diminishing returns, quantified

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

What the GLP-1 receptor actually does when mazdutide binds it

Selectivity, potency and efficacy are three different measurements. The trade routinely reports none of them.

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…

From 0.25 to 2.4: reading a ladder as a series of ratios

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

Gallstones during rapid weight loss: drug, or weight loss?

We give background rates alongside trial rates, because an event occurring during treatment is not thereby caused by it.

The glucagon receptor arm, and why it is the hardest to reason about

Head-to-head data exists for some of these comparisons and not for others. This piece says which.

Custody, condition and the temperature nobody logged

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

Reproducibility, measured rather than assumed

Two years ago we ran an anonymised version of this comparison and promised a named one. This is it, with every method printed in…

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

What the Journal asks when a document arrives unsigned, and what the answers have been.

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…

LAL, kinetic chromogenic, recombinant factor C: three ways to the same figure

Bacterial endotoxin is a heat-stable lipopolysaccharide from the outer membrane of Gram-negative organisms. It survives…

Reading a certificate as a document rather than as a score

The purity figure is the least informative line on a well-constructed certificate and the only line most buyers read.

Why FGP can be entirely straightforward and still tell you nothing about bioburden

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

The named comparison we promised two years ago

Duplicate submissions under different names test within-laboratory repeatability, which is a different quantity from…

Micronutrient monitoring: which panel, how often, and on whose evidence

Micronutrient guidance for this drug class is borrowed almost entirely from post-bariatric surveillance, where the anatomy is…

The three-times-upper-limit convention, and where it came from

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

The dose that got you here and the dose that keeps you here

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

Lean mass is a compartment, not a tissue

The instrument determines the answer more than the drug does, and the trade quotes the answer without naming the instrument.

Why "muscle-sparing" is a marketing term and not a measurement

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

The imaging substudy is an afterthought in the protocol and the centrepiece of the debate

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

Which results are findings and which are consequences of the weight loss

A substantial proportion of the abnormal results generated during rapid weight loss are consequences of the weight loss rather…

Twenty-eight days is a number from somebody else’s product

We set out what is known, what is inferred and what is simply assumed about the fortnight after a vial is opened.

Soft ionisation: the twenty-year-old trick that made peptide identity routine

A brief and unromantic tour of the interface between a liquid sample and a vacuum.

Four ways a peptide comes apart

Deamidation, oxidation, aggregation and hydrolysis account for nearly all of what happens to a peptide over time. Each has a…

Aggregation: the impurity your chromatogram dissolved before it looked

We describe each pathway in enough chemical detail to explain why it is invisible to the method the trade uses, because that is…

Why a dead-clean sterile filter can pass pyrogen straight through

Bacterial endotoxin is a heat-stable lipopolysaccharide from the outer membrane of Gram-negative organisms. It survives…

Low endotoxin recovery: the interference nobody looks for

The masking phenomenon known as low endotoxin recovery means a formulation can return a clean result while containing endotoxin…

A tested vial is evidence about a vial

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

Vitamin D, adiposity, and a volume-of-distribution problem

Reduced intake is a plausible mechanism for deficiency. Reduced absorption is not, and the two are conflated in most of the…

What the trials adjudicated, and how

The features that should prompt urgent assessment, stated once and plainly.

What STEP 4 and SURMOUNT-4 actually established

The dose-response curve in this class flattens near its top. That has direct consequences for whether the final rung is worth…

The advice is mostly reasonable. The certainty is not earned.

A tour of the source literatures, with an assessment of how far each legitimately reaches.

Thiamine and the vomiting patient

What the trials measured, which in the case of micronutrients is very little.

Percentage of loss, absolute kilograms, and the sleight of hand between them

A substudy powered to describe a mean is not a substudy powered to detect a clinically meaningful individual change.

The supply gap as a clinical event

Cost is the modal reason for discontinuation in every dataset we have seen, and it is absent from the clinical literature.

Blind duplicates: what happens when a laboratory does not know it is being watched

Two years ago we ran an anonymised version of this comparison and promised a named one. This is it, with every method printed in…

What SURMOUNT-1 tells us about maintenance, and what it does not

A survey of the maintenance evidence, which is shorter than the survey of the withdrawal evidence.

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

A survey of the maintenance evidence, which is shorter than the survey of the withdrawal evidence.

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

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

The badge is about a sample. The listing is about a product.

The Journal does not treat a badge as evidence and states so wherever it reports one.

SURPASS-3 was built to answer the stopping question, and it did

What was withdrawn, from whom, after how long, and what was measured afterwards.

Why a result on one vial says less than the trade needs it to

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

Gauge, pain and flow rate

Skin thickness at the standard injection sites is approximately two millimetres in adults and varies remarkably little with body…

How a correct calculation becomes a wrong dose

Almost every case involves a change — a new vial, a new syringe size, a new supplier — carried forward with an old number.

HbA1c and its lag: what a result three months old is telling you

HbA1c integrates roughly three months of glycaemia with the most recent weeks weighted most heavily. Almost every misreading of…

D-amino acids are invisible to mass spectrometry, and that is the whole problem

What would be needed to catch each of these, and what it would cost.

Site selection when the tissue has already changed

A rotation scheme that is too complicated will not be followed. We describe the simple ones that are.

Collapse temperature, and the hour of the cycle where shelf life is lost

The physics of the drying cycle explains why some cakes are matte and full-volume and others are glassy discs, and why the…

What happens in solution that does not happen in the cake

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

The reference change value: the number that tells you whether a delta is real

Almost every misreading of a laboratory panel is a misunderstanding of what a reference interval is and how much a result has to…

The impurity hiding underneath the parent peak

The most useful single addition to any purity determination is a second separation under a different pH or on a different…

Why two wavelengths on one run would settle several arguments

Non-chromophoric components — counter-ions, salts, some excipients — contribute mass to the vial and nothing at all to the…

Twelve things a real certificate has, and what their absence means

The header identifies the batch, the table records the tests, and the footer says who is answerable. Two of the three are…

Reflux, early satiety, and the volume the stomach will accept

What scintigraphy and breath-test studies established about emptying rate, and what they did not.

The specification sheet says 500,000. The report says conforms.

Calibration drift is real, unremarkable, and the reason serious laboratories run internal standards.

The template economy: one certificate, many products

A blank certificate with the numbers left editable is an ordinary internal document. Its circulation as a finished record is the…

The interventions with trial support, and the much longer list without

Almost nothing in the standard management repertoire has been tested in a randomised trial in this specific population. We say…

When a template becomes a misrepresentation

A blank certificate with the numbers left editable is an ordinary internal document. Its circulation as a finished record is the…