Research · 9 min read
How a New Approved Use Gets onto a Label
A trial result is not an approved use. Federal regulation names the instrument that adds one, lists the eight changes it covers, and says the change may not reach the market before it is approved.
Key takeaways
- Adding an approved use is a separate approval, and the regulations name the paperwork an efficacy supplement.
- That definition covers eight changes at once, including a new indication, a new dose regimen, a new route, a comparative claim and a significantly altered patient population.
- Labeling changes sit in the bucket headed changes requiring supplement submission and approval prior to distribution of the product made using the change.
- Certain safety changes may go on a thirty-day route instead, and so may deleting a false, misleading or unsupported indication; adding one may not.
- Approval is refused where there is a lack of substantial evidence that the drug will have the effect suggested in the proposed labeling, and the statute defines that phrase.
- One adequate and well-controlled investigation plus confirmatory evidence may count as substantial evidence where the Secretary so determines based on relevant science.
- Indications or uses must not be implied or suggested in other sections of the labeling if they are not listed in the indications section.
- Promotional labeling and advertising must be promptly revised to match a labeling change, so promotion follows the label rather than leading it.
Answer first: a new use is a new approval, and the instrument has a name
Approval of a medication is not approval of the medication. It is approval of a product for a stated use, in a stated population, on stated evidence.
Adding a second use is therefore a second decision. The regulations call the paperwork an efficacy supplement, and define it precisely.
An efficacy supplement is a supplement to an approved new drug application that proposes one or more related changes to product labeling from a list of eight. The first entry on that list is to add or modify an indication or claim.
Until such a supplement is approved, the label says what it said before. Everything downstream reads the label, which is why a headline about a trial changes nothing at a pharmacy counter on the day it appears.
The eight changes the same instrument covers
The list is worth reading whole, because it groups things a marketing page treats as unrelated. All eight are the same instrument.
The first four are adding or modifying an indication or claim, revising the dose or dose regimen, providing a new route of administration, and making a comparative efficacy claim naming another drug product. The next two are significantly altering the intended patient population, and changing the marketing status from prescription to over-the-counter use. The seventh covers traditional approval of a product originally approved under the accelerated pathway, or the evidence of effectiveness needed for it. The eighth is incorporating other information based on at least one adequate and well-controlled clinical study.
Four of those are commercial requests in disguise. A wider population, a head-to-head claim, a new route and a new use are the things a market most wants to be able to say.
The regulation puts them in one place and attaches one procedure to all of them. That is the useful fact: the difficulty of getting a new claim onto a label is not specific to the claim.
The timing rule, which is stricter than people assume
The regulation on changes to an approved application sorts them into three buckets by how much notice they need.
The first bucket is headed changes requiring supplement submission and approval prior to distribution of the product made using the change, and the regulation calls these major changes. Its enumerated list includes labeling changes, other than the narrow set the regulation sends elsewhere.
It also names, as a major change, any change to the information required in the Highlights section of a prescribing information document. Two removals and a revision date are the stated exceptions there, and they may be reported in an annual report instead.
There is an expedited route within that bucket rather than around it. A supplement may be marked for expedited review where a delay would impose an extraordinary hardship on the applicant, or where the agency's own review is warranted for public health reasons.
Safety can move faster than effectiveness, and the asymmetry is written down
The second bucket is headed changes requiring supplement submission at least thirty days prior to distribution, and the regulation calls these moderate changes. A supplement in this bucket is labeled with a phrase the regulation prescribes, and distribution may begin not less than thirty days after the agency receives it.
One entry in that bucket is labeling changes to reflect newly acquired information, for a closed list of purposes. The purposes are a closed list. One is to add or strengthen a contraindication, warning, precaution or adverse reaction that meets the labeling standard. A second is to add or strengthen a statement about drug abuse, dependence, psychological effect or overdosage. A third is to add or strengthen an instruction about dosage and administration intended to increase safe use. A fourth is to delete false, misleading, or unsupported indications for use or claims for effectiveness. The last is any change the agency specifically asks to be submitted by this route.
Read the fourth of those. Deleting an unsupported indication is on the faster list. Adding an indication is not on it anywhere.
The agency also keeps a stop. Where it tells the applicant within thirty days that the change actually requires prior approval, or that required information is missing, the product made using the change must not be distributed.
The evidence standard the supplement has to clear
The statute behind all of this lists the grounds for refusing an application, and one of them is written about the label rather than the drug.
Approval is refused where there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have. The statute measures that against the conditions of use prescribed, recommended, or suggested in the proposed labeling. A separate ground covers labeling that is false or misleading in any particular, on a fair evaluation of all material facts.
The statute then defines substantial evidence in the same subsection. It means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved. On the basis of that evidence it must be possible for such experts to conclude, fairly and responsibly, that the drug will have the effect it purports or is represented to have.
One later sentence softens the plural. Where the Secretary determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence are sufficient to establish effectiveness, that may be treated as substantial evidence. The confirmatory evidence may be obtained before or after the investigation.
What the Indications and Usage section is required to contain
The format rules say what that section has to state. It must state that the drug is indicated for the treatment, prevention, mitigation, cure or diagnosis of a recognized disease or condition. A manifestation of one, or the relief of symptoms associated with one, is also permitted.
Several conditional requirements sit under it. Where a drug is used for an indication only in conjunction with a primary mode of therapy, the section must say so. It must state that the drug is indicated as an adjunct to that mode of therapy. The regulation's own examples of a primary mode are diet, surgery, behavior changes and another drug.
Two further conditions trigger a requirement of their own. One is evidence supporting safety and effectiveness only in selected subgroups; the other is an indication approved on a surrogate endpoint. In either case the section must carry a succinct description of the limitations of usefulness of the drug and any uncertainty about anticipated clinical benefits, with a reference to the clinical studies section.
There is also a closing rule that decides what everything else on the label can be read as. All indications listed must be supported by substantial evidence based on adequate and well-controlled studies as the regulations define them, unless the requirement is waived. And indications or uses must not be implied or suggested in other sections of the labeling if they are not included in that section.
One limit belongs beside those requirements. The format rules apply to the products the neighboring scope section describes, which is defined by when an application or efficacy supplement was approved, pending or submitted around a stated date. Older products are sent to a different section.
The clause written for a use everyone already believes in
A quieter paragraph in the same section handles the case where a drug has a reputation the evidence does not carry.
The trigger has two halves. The first is a common belief that a drug may be effective for a certain use, or a common use of it for a condition. The second is that the preponderance of evidence shows the drug is ineffective, or that its therapeutic benefits do not generally outweigh its risks. Where both hold, the agency may require the section to state that there is a lack of evidence that the drug is effective or safe for that use.
That is a labeling requirement aimed at a marketing situation. It exists because a use can spread without any of the machinery described above ever running.
The neighboring paragraph handles the comparative case. Statements comparing the safety or effectiveness of a drug with other agents for the same indication must be supported by substantial evidence from adequate and well-controlled studies, unless the requirement is waived.
The advertising has to follow the label, not the other way round
The same regulation on changes carries a short general obligation that most readers never meet.
The applicant must promptly revise all promotional labeling and advertising to make it consistent with any labeling change implemented under the major and moderate change provisions.
The direction of travel is the point. Promotion is downstream of the label. Nothing about a label changes because a campaign or a press release describes something new.
That is also why a company's own materials are a poor way to learn what a product is approved for. They are supposed to match the label, so the label is the shorter read.
What this means for a page you are reading
A conference presentation, a journal paper, a press release and a regulatory submission are four different things, and only the last of them starts the process described here.
So a claim built on a new result is checkable in one step. Open the prescribing information and see whether the use appears in the indications, because the regulations forbid a use being implied elsewhere on the label if it is not listed there.
A claim that a drug is under review, or that a submission has been filed, is a statement about a process rather than about an approved use. Both are ordinary and lawful things for a company to say, and neither one moves the coverage rules or the paperwork.
Where a use has genuinely been added, the label shows it. The indications section is the shortest document in this whole chain, and it is the only one that had to be approved.
Sources
- 21 CFR 314.3 — DefinitionsThe definition of an efficacy supplement, quoted in the body and in a takeaway: a supplement to an approved new drug application proposing one or more related changes to product labeling from among eight, beginning with adding or modifying an indication or claim, and running through revising the dose or dose regimen, providing a new route of administration, making a comparative efficacy claim naming another drug product, significantly altering the intended patient population, changing marketing status from prescription to over-the-counter use, providing for or providing evidence of effectiveness necessary for traditional approval of a product originally approved under the accelerated pathway, and incorporating other information based on at least one adequate and well-controlled clinical study. Verified against a same-run control at the same path depth on the same host, which returned the host's not-found page carrying none of the quoted text.
- 21 CFR 314.70 — Supplements and other changes to an approved NDAThe three-bucket structure and the timing rules. Paragraph (a)(1), which requires the applicant to notify the agency about each change beyond the variations already provided for, through a supplement or an annual report depending on the type of change. Paragraph (a)(4), quoted for the duty to promptly revise all promotional labeling and advertising to make it consistent with any labeling change implemented under paragraphs (b) and (c). Paragraph (b), headed changes requiring supplement submission and approval prior to distribution of the product made using the change, whose enumerated labeling changes cover changes in labeling other than the narrow set sent elsewhere, and any change to the information required in the Highlights section with two stated exceptions reportable in an annual report; and the expedited-review marking available within that paragraph. Paragraph (c), headed changes requiring supplement submission at least thirty days prior to distribution, its prescribed labeling of a supplement, its rule that distribution may begin not less than thirty days after receipt, and the agency's power within thirty days to require prior approval or to stop distribution for missing information. And paragraph (c)(6)(iii), whose closed list of permitted purposes includes adding or strengthening a contraindication, warning, precaution or adverse reaction, adding or strengthening a statement about drug abuse, dependence, psychological effect or overdosage, adding or strengthening an instruction about dosage and administration intended to increase safe use, and deleting false, misleading, or unsupported indications for use or claims for effectiveness. Verified against a same-run control at the same path depth, which returned the host's not-found page.
- 21 CFR 201.57 — Specific requirements on content and format of labeling for human prescription drug and biological productsThe requirements on the Indications and Usage section, at paragraph (c)(2). The opening requirement that the section state the drug is indicated for the treatment, prevention, mitigation, cure or diagnosis of a recognized disease or condition, of a manifestation of one, or for the relief of symptoms associated with one. The conditional requirement that, where a drug is used for an indication only in conjunction with a primary mode of therapy, with diet, surgery, behavior changes and another drug given as the regulation's own examples, the section state that the drug is indicated as an adjunct to that mode of therapy. The conditional requirement of a succinct description of the limitations of usefulness of the drug and any uncertainty about anticipated clinical benefits, where evidence supports safety and effectiveness only in selected subgroups or where an indication is approved on a surrogate endpoint. The provision permitting the agency to require a statement that there is a lack of evidence that the drug is effective or safe for a use, where there is a common belief or common use but the preponderance of evidence shows the drug ineffective or its benefits not generally outweighing its risks. The requirement that comparative safety or effectiveness statements be supported by substantial evidence from adequate and well-controlled studies unless waived. And the rule that all indications listed be supported by substantial evidence on that basis, together with the sentence that indications or uses must not be implied or suggested in other sections of the labeling if not included in that section. The scope limit stated in the body comes from the neighboring section this one names. Verified against a same-run control at the same path depth, which returned the host's not-found page.
- 21 U.S.C. 355 — New drugsSubsection (d) only. Its refusal ground where there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling, and its separate ground where, on a fair evaluation of all material facts, such labeling is false or misleading in any particular. Its definition of substantial evidence as evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have. And the later sentence permitting data from one adequate and well-controlled clinical investigation and confirmatory evidence, obtained before or after that investigation, to be treated as substantial evidence where the Secretary so determines based on relevant science. Nothing in this article rests on any other subsection of the section. Verified against a same-run control on the same host, which returned the database's document-not-found page carrying none of the quoted text.
Frequently asked questions
A trial just reported a big result. Does that change what the drug is approved for?
Not on its own. A change to labeling that adds an indication falls in the regulation's major change bucket, which requires a supplement to be submitted and approved before the product made using the change is distributed. The regulations define the paperwork as an efficacy supplement and put adding or modifying an indication or claim first on its list of eight covered changes. Until that is approved, the label reads as it did, and everything downstream reads the label.
What is an efficacy supplement?
It is a defined term. The regulations describe it as a supplement to an approved new drug application, proposing one or more related changes to product labeling from a list of eight. The list begins with adding or modifying an indication or claim. It continues with revising the dose or dose regimen, providing a new route of administration, and making a comparative efficacy claim naming another drug product. It then covers significantly altering the intended patient population, and changing marketing status to over-the-counter use. The last two are providing for traditional approval of a product first approved under the accelerated pathway, and incorporating other information based on at least one adequate and well-controlled clinical study.
Why can a warning be added faster than a use?
Because the regulation sorts changes by how much notice they need, and it puts certain labeling changes reflecting newly acquired information in the thirty-day bucket. That list includes adding or strengthening a contraindication, warning, precaution or adverse reaction, and it also includes deleting a false, misleading or unsupported indication. Adding an indication is not on that list. The asymmetry runs in one direction: a claim can be removed on the faster route, and it cannot be added on it.
How much evidence does a new use need?
The statute refuses approval where there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have. The measure is the conditions of use suggested in the proposed labeling. It defines substantial evidence as evidence consisting of adequate and well-controlled investigations, including clinical investigations, by qualified experts. A later sentence permits data from one adequate and well-controlled clinical investigation plus confirmatory evidence to count, where the Secretary so determines based on relevant science.
A label describes a study result I care about. Is that an approved use?
Not by itself, and the regulations address the question directly. All indications listed in the indications section must be supported by substantial evidence based on adequate and well-controlled studies, unless the requirement is waived. And indications or uses must not be implied or suggested in other sections of the labeling if they are not included in that section. A result described in a clinical studies section is evidence the label carries; the approved uses are the ones listed where they belong.
If a company is advertising a new use, has it been approved?
The obligation runs the other way. The regulation requires an applicant to promptly revise all promotional labeling and advertising to make it consistent with any labeling change made under the major and moderate change provisions. Promotion is supposed to follow the label. Reading the indications section takes less time than assessing a campaign, and it is the document the rest of the chain is built on.