The label box that says a claim is only possibly effective

A grading vocabulary written into a regulation

Most arguments about whether a medicine works are conducted in ordinary language. There is a formal vocabulary for it, written into a labeling regulation, and it has six terms.

The regulation describes a review of labeling claims for drugs marketed under new drug and antibiotic procedures "between 1938 and 1962".

It records that the resulting evaluations used six categories: "effective," "probably effective," "possibly effective," "ineffective," "ineffective as a fixed combination," and "effective but".

The regulation also records the reviewers' verdict on what they were looking at. It states that "the quality of the evidence of efficacy, as well as the quality of the labeling claims, is poor."

The report the section describes was, by its own account, applicable to more than eighty percent of the drugs marketed at that time. That is a statement about the market of the period, and this article does not convert it into a claim about any current one.

Why a grade had to appear on the label

The reasoning behind the requirement is the interesting part, because it is an argument about disclosure rather than about efficacy.

Take a claim an expert panel classified as less than effective, on a label that keeps making it. The regulation concludes that failing to disclose that classification "is a failure to disclose facts that are material in light of the representations made and causes the drug to be misbranded".

The second limb is broader still. A classification other than effective "establishes that there is a material weight of opinion among qualified experts contrary to the representation made or suggested in the labeling". Failing to reveal that makes the labeling misleading.

That is a general principle stated in a specific context. A known, qualified body of expert disagreement with a claim is itself a material fact.

The regulation also notes the practical problem it was solving. Delays had been encountered in bringing the panels' conclusions to the attention of prescribers.

What the box has to look like

Once an implementation notice publishes on a prescription drug, package labeling, promotional labeling and advertisements must carry an appropriate qualification of every claim evaluated as other than effective, if those claims are still being made.

The presentation is prescribed rather than left to design. The qualifying information "shall be at least of the same size and color and degree of prominence as other printing in the labeling and shall be presented in a prominent box".

Two formats are permitted. The boxed statement may replace the indications section entirely, listing the indications under the headings effective, probably effective and possibly effective.

Or the effective indications may sit outside the box, with the box immediately following and listing the probably and possibly effective ones.

Both formats end with the same sentence, which is the one a reader should notice. "Final classification of the less-than-effective indications requires further investigation."

Where the agency's own classification differs from the expert panel's but is still other than effective, the qualifying statement refers to the agency's classification instead.

Where the classification becomes effective, whether through revised wording or adequate data, the qualification is no longer needed.

The same grade follows the advertisement

The requirement does not stop at the carton and the insert. Advertising carries a parallel obligation, with the same format, language and emphasis.

The boxed statement appears in or next to the brief summary information. It "shall have prominence at least equal to that provided for other information presented in the brief summary", with comparable type size, captions and color.

On a single page advertisement, a less-than-effective indication in the promotional message must be keyed to the box by an asterisk or equivalent.

On a multiple page advertisement, an asterisk goes after the most prominent mention of the indication on each page, or after the first mention where prominence does not vary.

The asterisk points to a footnote whose wording is supplied. "This drug has been evaluated as probably effective (or possibly effective whichever is appropriate) for this indication", followed by a pointer to the brief summary or prescribing information.

So the grade travels with the promotion rather than staying in the technical documents.

This is not the boxed warning

Two different boxes can appear on a drug label and they answer different questions.

The safety boxed warning, covered elsewhere on this site, concerns risk. It exists to tell prescribers about serious or life-threatening hazards.

This box concerns efficacy. It exists to tell prescribers that a stated indication has not been established to the effective standard, and that its final classification is still open.

A drug can have neither, either or both, and their presence answers unrelated questions.

The distinction is worth keeping because the visual convention is identical. A prominent box on a label is a signal that something has been formally graded, and reading the heading tells you which axis was graded.

The deadline machinery, which is how these things actually move

The section also carries its own transition rules, and they show how a labeling change is forced through in practice.

For new drugs and antibiotics, supplements providing the revised labeling had to be submitted under the ordinary supplement provisions within ninety days after publication of the implementation notice in the Federal Register.

The revised labeling then had to be put into use as soon as possible, and no later than the end of the period allowed for submitting those supplements.

That pattern, a notice, a fixed window for filing, and a hard stop on using the old labeling, is the standard shape of a compelled labeling change.

It is worth recognizing because the same shape appears whenever a class of products is required to change what it says about itself.

Why an old rule is still worth reading

The obvious objection to this section is its age, and the obvious answer is that the reasoning outlived the exercise.

It puts three ideas in regulatory language that are otherwise argued informally.

That a claim can be graded rather than simply asserted or denied, using categories between effective and ineffective.

That expert disagreement with a claim is a material fact which must be disclosed alongside the claim, not weighed privately by the seller.

And that a qualification must be as prominent as the claim it qualifies, in the labeling and in the advertising, keyed to the specific indication rather than buried.

Those three ideas map onto how any evidence claim should be read, including claims about compounds that were never in this review at all.

Two limits belong here. Only this section was read, in full. No implementation notice was retrieved and no drug was looked up, so nothing here says how many products carry such a box today, or which ones.

Sources

Each document below is named as it names itself, with the date printed on that document rather than the day it was read.

1. Title 21 Code of Federal Regulations section 201.200, Disclosure of drug efficacy study evaluations in labeling and advertising, read in full — Electronic Code of Federal Regulations, Office of the Federal Register, March 1990