A Designation Is a Starting Gun, Not a Finish Line

There is a word that turns up in compound histories and gets read as an achievement when it is nothing of the kind.

The word is designated. As in orphan designation, granted by a regulator for work on a rare disease. It looks like a milestone reached. It is closer to a milestone being set.

Thymosin alpha-1 happens to be an unusually clean way to see the difference, because it holds both kinds of thing at once, and the records say plainly which is which.

What a designation actually is

An orphan designation is an incentive. Regulators grant it to encourage development work on diseases too rare for that work to make commercial sense on its own. The point of granting it is to get a program started.

It is awarded at the beginning. Nothing has been demonstrated at the moment it is given, because the studies that would demonstrate anything have not been run yet.

So a designation tells you a program began. It tells you nothing whatsoever about how the program turned out.

The approvals, which are real

Start with what this compound genuinely holds, because it is more than most.

It has a national marketing authorization in Italy. The European Medicines Agency states in its own words that thymalfasin "is authorised in Italy, where it is used to enhance the immune response stimulated by the influenza virus vaccine".

The sponsor's annual filing records that in China it is approved for hepatitis B and as an immune system enhancer. The same filing notes that the Chinese import license has to be renewed every five years. That is the sort of administrative detail that only exists around a product actually on a market.

Those are marketing authorizations. Very few compounds in a research catalogue hold one anywhere in the world, and this one holds two.

The designations, which are a different object

Now the other column.

FDA has granted four orphan designations for thymalfasin. Chronic active hepatitis B in 1991. DiGeorge anomaly with immune defects in 1998. Hepatocellular carcinoma in 2000. Malignant melanoma in 2006.

Every one of those four records carries a status field, and every one of those fields reads not approved for the orphan indication. The register is not being coy about it.

The European Union holds a designation too, EU/3/02/110, for hepatocellular carcinoma, designated on 30 July 2002. And the EU register settles the question in a single sentence printed on its own page: "An orphan designation is not a marketing authorisation."

FDA, separately, states that no drug products containing this compound are approved in the United States.

Why four designations and no approval is not four failures

This is the reading the piece exists to head off, because it is the natural one and it is wrong.

Line up four designations against no US approval and it looks like a scoreboard. Four attempts, four misses. It is not a scoreboard, because a designation is not a result. It is the thing handed over before the attempt, precisely to make the attempt happen.

The EU record makes the point most cleanly. No EU-wide authorization followed that designation, and none was ever refused or withdrawn either. Nothing was rejected. There is no adverse decision anywhere in that file. A designation and an authorization are not the same kind of object, and one does not automatically progress into the other.

Four designations means four development programs received the incentive that designations exist to give. That is what the record says. Anything beyond that has to come from somewhere else.

Even the sponsor writes it that way

A small corroborating detail, and the kind that is easy to miss.

The sponsor's own annual report lists its designations in melanoma, chronic hepatitis B and hepatocellular carcinoma. When the same document turns to FDA approval, it speaks of it only as a future conditional.

The company holding the designations does not describe them as approvals. It describes them as designations, and approval as something that might happen later. That is the correct usage, written by the party with the most incentive to blur it.

The number that circulates without a source

One more piece of vocabulary hygiene while we are here, briefly.

The sponsor's filing says the product "is approved in over 30 countries". FDA reviewed that same claim and wrote that it "is unable to independently verify these claims of approval in all the specified countries". The widely repeated figure of 35 countries appears in neither document.

That is not an accusation about the sponsor's count. It is a note about where the number people quote is not from.

What to do with the word next time

The useful part of this is portable, which is why it is worth 900 words on one compound.

When you meet designated in a compound's history, read it as a date on which something started. Ask what happened afterwards, because the designation itself will not tell you, and the register that granted it will often say so in as many words if you look.

Compounds that made it all the way through use different vocabulary. Authorized. Approved. With a jurisdiction attached and a body that granted it. This one has both sorts of entry in its file at the same time, which makes it a good place to learn the difference. Our full write-up sets out every one of those records with its citation.