What Does "Off-Label" Mean?

Off-label means using an approved medicine in a way that its approval does not cover. The medicine itself has been assessed by a regulator and allowed onto the market, but only for particular uses. Prescribe it for a different condition, a different age group, by a different route or at a different strength, and that particular use is off-label. The decision to do it rests with the prescriber, not with the regulator.

That is not the same as unapproved. An unapproved product is one that has never been through a regulator's assessment for any use at all. The two words sound similar and are often mixed up, and the difference between them is most of what this article is about.

What is the "label"?

When a regulator approves a medicine, it does not simply say yes. It says yes to something specific. The approval comes with an official document, called the label in the United States and the summary of product characteristics in Europe, which sets out exactly what the medicine is for, in whom, by what route, in what amounts and with what warnings. Everything in that document has been backed by evidence the regulator has examined, usually from large trials.

Think of the label as a surveyed road. The regulator has checked this particular route: these travellers, this destination, this speed. The vehicle is sound, and the route is known. Off-label use takes the same sound vehicle along a road nobody officially surveyed. The road might be perfectly good. Many drivers may have used it for years. But the surveyor never checked it, so the official map says nothing about it either way.

The FDA puts it plainly. Once a medicine is approved, healthcare providers generally may prescribe it for an unapproved use when they judge that it is medically appropriate, but in that case the agency has not determined that the medicine is safe and effective for that use 1.

What counts as off-label?

More than people expect. It is not only a matter of treating a different illness. The European Medicines Agency defines off-label use as situations where a medicine is intentionally used for a medical purpose not in accordance with the terms of its marketing authorisation, meaning its official approval, and gives examples that fall into four groups 2.

• A different condition. The medicine is approved for one illness and used for another.
• A different group of people. It is approved for adults and given to a child, for example.
• A different route. It is approved as a tablet and given another way.
• A different amount or timing. It is approved at one strength or schedule and used at another.

Two details in that definition matter. The word intentionally separates off-label use from mistakes, which regulators count separately as medication errors. The words medical purpose separate it from misuse, which has no medical purpose at all. And the reference point is the approval in the country where the medicine is used 2, which means the same prescription can be on-label in one country and off-label in the next, simply because the two regulators approved slightly different things.

Who decides?

Two different people decide two different things, and keeping them apart clears up most of the confusion.

The regulator decides whether a product may be sold, what it is approved for, and what its maker may say about it. That last part is strict. Companies are not allowed to promote their medicines for off-label uses, and some have paid very large settlements for doing so 4. A company cannot advertise its way around the evidence it never submitted.

The prescriber decides how to treat the person in front of them. In the United States, the FDA regulates medicines but does not regulate the practice of medicine 4, so a doctor may choose an approved medicine for an unapproved use when they judge it appropriate 1. In Europe, the rules on prescribing sit mainly with each country, but the principle is broadly similar. The prescriber carries the professional responsibility for that choice, and is expected to be able to justify it from the evidence.

So off-label is not a gap in the rules. It is a deliberate division of labour. The regulator checks products. Professionals, working under their own codes and oversight, make judgements about patients.

Why does off-label use exist at all?

Because getting a new use onto a label is expensive, and nobody is obliged to pay for it.

Adding a use to a label normally means running new trials and submitting them to the regulator. A company will do that when it expects to earn the money back. Once a medicine is old and cheap and made by many companies, nobody has much reason to fund a large trial for a new use, even if doctors have gathered good evidence for it in the medical literature. The use becomes standard practice while staying off the label for good.

Children are the biggest example. For a long time they were routinely left out of trials, so many medicines were only ever approved for adults. Treating a sick child often meant using a medicine off-label or not at all. One review describes off-label use in almost four out of five hospitalised children 4. Doctors were not being reckless. The trials simply had not been done.

The same review lists other long-standing examples, such as older antidepressants used for nerve pain, which became ordinary practice without ever becoming a labelled use in many places 4. The FDA's own patient guidance notes the commonest reasons in plain terms: there may be no approved medicine for a person's condition, or the approved ones may already have been tried without success 1.

How good is the evidence behind off-label use?

It varies enormously, and that is the honest heart of the matter.

A well-known study looked at prescriptions for 160 commonly used medicines across the United States. About 21 per cent of the prescriptions were for off-label uses. The researchers then checked each off-label use against the published evidence, and found that 73 per cent of them had little or no scientific support 3. So off-label covers a whole range, from uses that are better studied than some labelled ones, to uses resting on little more than a plausible idea.

Off-label use can also go badly wrong, and history has a clear case. In the 1990s, two appetite suppressants, each approved on its own, became widely prescribed together as a pair, a combination the regulator had never assessed. In 1997, doctors reported heart valve damage in people who had taken the combination 5, and one of the two drugs was withdrawn from the market that same year. Off-label use is only as sound as the evidence underneath it.

Is off-label the same as unapproved?

No, and this is the distinction worth carrying away. Off-label only exists in relation to a label. The medicine has been assessed, its manufacturing has been inspected, its quality is controlled, and its known harms are written down. What has not been assessed is one particular use of it.

An unapproved product has none of that. Nobody official has examined whether it is what it says it is, whether it is made consistently, or what it does in people. There is no label to step off, because there is no label.

The third row deserves a word. A compound being tested in a registered trial is unapproved too, but it is not unexamined. Every step is watched: an ethics committee approved the plan, a regulator was told, participants gave informed consent, and everything that happens is recorded. That is the route by which unapproved things become approved ones, and it is described step by step in the article on phases of testing.

This matters on a site about research peptides, because the phrase off-label is sometimes borrowed for compounds that have never been approved for any use. That borrowing does not work. A compound with no approval has no label, so nothing about using it is off-label. It is simply unapproved, and the protections that come with an approved medicine — checked quality, known harms, a professional answerable for the decision — are not there.

What to ask when you read "used off-label"

When you meet the phrase in a news story or an article, three questions will usually tell you what it means in that case.

1. Approved for what? Find out what the medicine's actual label covers, so you know how far the off-label use departs from it.
2. On what evidence? A use backed by several good trials that nobody bothered to submit is very different from a use backed by one small study or a theory.
3. Is there a label at all? If the product was never approved for anything, the word off-label is being used loosely, and the correct word is unapproved.

Off-label is a useful word with a narrow meaning. It says that a regulator checked the medicine but not this use of it, and that a professional took responsibility for the gap. Held to that meaning, it stops being confusing, and it stops being stretched to cover things it was never meant to describe.