The FDA Drug Label
Part 1: Introduction to the FDA drug label
What is a drug label?
A drug label is a legal document. For prescription drugs, the drug label is lengthy, heavy on the science, and every word must be approved by the FDA. It is printed on thin paper that is folded more often than a road map and typeset in a “don’t read me” font size.
For over-the-counter drugs, the label is much simpler. It must contain specific sections and some of those sections must include specific language. Rather than a multiply folded paper document, the consumer information printed on the box or bottle constitutes an OTC drug’s label.
The FDA neither reviews nor approves OTC drug labels: they are created by manufacturers or distributors on an honor system. For ways in which this can go very wrong, see Mermaid Tears.
A critical element of both prescription and OTC drug labels is the section that specifies the drug product claim. For prescription drugs, the drug product claim states what diseases the drug has been proven to treat, through clinical trials. This section is headed Indications and Usage.
The drug product claim for an OTC drug states what symptoms the drug will alleviate. This information is provided in two sections: Purpose and Uses. Purpose describes how the drug works (eg antihistamine). Uses describe symptoms that are improved (eg runny nose and sneezing), sometimes connected to underlying causes (eg cold or flu).
Allowed OTC drug product claims are specified in a document called an OTC Monograph. Each general category of OTC drug has its own Monograph.
For OTC lubricating eye drops, Monograph M018 for ophthalmic products has the following allowed drug product claims under Uses:
For the temporary relief of burning and irritation due to dryness of the eye.
For the temporary relief of discomfort due to minor irritations of the eye or to exposure to wind or sun.
For use as a protectant against further irritation or to relieve dryness of the eye.
For use as a lubricant to prevent further irritation or to relieve dryness of the eye.
Part 2: On-label vs off-label drug prescribing
What is on-label prescribing?
On-label prescribing (synonym: on-label use) is a term that is applied to prescription drugs. Prescribing a drug on-label means that the patient has the disease specified in the drug Indications and Usage section, and the patient matches the characteristics of the subjects in the original clinical trial which proved that the drug would treat those specific disease(s).
In other words, the patient and the prescription are a match for the drug label.
What is off-label prescribing?
Patients and health care providers might be surprised to learn what constitutes off-label use.
If the clinical trial subjects ranged in age from 20 to 45 years, and the drug is prescribed for someone who is 47 years old, technically this is off-label use.
Numerous drugs are prescribed for children that were never formally investigated in a pediatric clinical trial. These prescriptions - even if dosed appropriately based on weight - are off-label.
Much off-label use involves prescribing a drug for a disease or condition other than that specified in the drug label. The condition may be related: for example, drops which are used on-label to treat open angle glaucoma are also used to treat many other types of glaucoma. Although this is medically rational, since the drug’s clinical trial only enrolled subjects with open angle glaucoma, use in any other type of glaucoma is off-label.
Occasionally the on-label and off-label conditions are extraordinarily different: Avastin (a colon cancer drug) is used to treat macular degeneration.
Who oversees off-label prescribing?
The FDA does not regulate the practice of medicine. Health care providers may prescribe drugs for off-label use without violating any Federal laws or regulations. Read more here.
State entities such as the Boards of Medicine or Optometry do not oversee off-label prescribing. With the recent exception for opiate drugs, State legislatures also avoid telling health care providers how to practice medicine.
A State medical board may receive a complaint about a provider, and that complaint may be related to off-label drug prescribing. However, this does not automatically mean that the medical board will act against the provider if the off-label prescribing was within the standard of care (SOC). The SOC is defined by what a “reasonable and prudent” health care provider would do in the same situation.
Manufacturers love off-label prescribing, because the market for off-label prescribing is often vastly greater than for on-label prescribing.
Part 2A: The OTC label dance - prescription drug product claims
Manufacturers and distributors of OTC eye drops must be extremely careful to avoid making prescription drug product claims.
Imagine every possible claim an OTC eye drop might make, then subtract the allowed claims in the OTC Ophthalmics Monograph.
Everything that is left is a prescription drug product claim.
Either your OTC eye drop drug product claim lives on the list in Monograph M018, or your eye drop is an (unapproved) prescription drug that is being illegally marketed as an OTC drug.
It doesn’t matter what’s in the eye drop or how it works, what matters is how the manufacturer or distributor markets it.
A recent example of claim creep - from an OTC eye drop manufacturer who should know better - is language on the front of the box about “nourishing” the eyes. Even a description of how an ingredient allegedly works, such as “antioxidant,” is a drug product claim. Monograph M018 does not have “nourishing” or “antioxidant” as options under Purpose.
The eye drop I just described is, legally speaking, being marketed as a prescription drug because it is making claims about how it works and what it does, which are beyond the allowed claims set out in Monograph M018.
If this seems backwards to you, it seemed backwards to me for a long time.
Part 2B: The OTC label dance - hiding naughty ingredients in plain site
There is a tiny segment in the Federal Food Drug & Cosmetic Act regarding inactive ingredients in OTC drugs [21 CFR Part 330.1(e)]. These ingredients must be “suitable (and) safe in the amounts administered.” That is it.
This minimalist law allows an eye drop manufacturer to cram all sorts of ingredients onto the drug label, and into the eye drop, if they are classified as inactive. Who does the classifying? The manufacturer.
In some cases, the ingredients are legitimate, such as lubricants that are not listed in the (outdated) Monograph M018. Examples include hyaluronic acid and trehalose. Manufacturers and consumers both know that these ingredients are potentially adding a useful lubricating effect.
However, the latest marketing trend is to add “nutritional” inactive ingredients which sound good but are unnecessary for the symptom-relieving effect of dry eye drops. These include vitamins, amino acids and plant extracts. Possibly such ingredients are safe, if they are free of impurities and do not negatively affect the eye drop in other ways (such as changing the pH). Are they suitable? I would argue not, because - by definition - an inactive ingredient is not doing anything. At all. So why would you add vitamin E to an eye drop if it is doing nothing. At all.
Inactive ingredients are not listed with concentrations on the drug label. In fact, the manufacturer does not have to tell the FDA the concentration of an inactive ingredient in an OTC product. So maybe there are 3 molecules of vitamin E in that 15 mL eye drop bottle. Did you pay extra for it?
Part 3 Ringing the FDA’s doorbell
Irrelevant, market-driven inactive ingredients in OTC eye drops are low on the FDA’s list of concerns. Partly it is not worth the fight, because the FDA would need to argue that a certain ingredient was either not safe (in general, as opposed to a bad batch) or not suitable. The FDA is throwing rocks up hill, and the manufacturer’s attorneys are shooting arrows downhill, well-protected by the lack of clarity - in this context - of “suitable.”
Conversely, drug product claims about inactive ingredients will get the FDA’s attention.
Manufacturers, repeat after me: You cannot state, even by nudge-nudge wink-wink implication, that an inactive ingredient does anything. At all. Under any circumstances. Ever. Doing so immediately converts your inactive ingredient into an active ingredient by law, regardless of where you listed it on the box.
Since the inactive ingredient is actually an active ingredient and because it is not on the list of allowed active ingredients in Monograph M018, ipso facto the eye drop is a prescription eye drop. It is unapproved, and therefore illegal to manufacture, market and sell.