In this week’s blog, we will provide some basic clarification regarding product intended use, label and off-label promotion and their limitations.
These issues are covered in many separate guideline documents and regulations issued by the FDA and other agencies (e.g. EMA). In addition, these topics are discussed by various regulatory consulting firms in a lengthy and laborious way.
Because we are a consulting firm dedicated to providing full regulatory support to medical device and biotechnology start-up companies, we will try to present this info in a much more simplified way to serve as a useful reminder to the regulatory professional dealing with label and promotion-related tasks.
What is Product Labeling?
Any material used to facilitate the sale of a medical device or drug is considered to be product labeling.
This material may include, but is not limited to labels, brochures, website materials, training, adverts, leaflets provided to physicians, articles in medical journals disseminated by the company or trade show materials.
FDA defines labeling (21 CFR Sec 1.3) as:
(a) Labeling includes all written, printed, or graphic matter accompanying an article at any time while such article is in interstate commerce or held for sale after shipment or delivery in interstate commerce.
(b) Label means any display of written, printed, or graphic matter on the immediate container of any article, or any such matter affixed to any consumer commodity or affixed to or appearing upon a package containing any consumer commodity.
Product labeling is subjected to rigorous appraisal by an FDA reviewer during the market review of a new product.
“During the market review of a new drug or medical device, FDA reviews labeling on the specifics of the drug or device’s risks and benefits as well as the indications and claims the manufacturer can make based on the rigorous series of pre-clinical and clinical trials, so that the drug or device is both safe and effective for all proposed claims. If a manufacturer were to obtain approval for a narrow indication and thereafter market its product for a set of much broader indications, the integrity of the new drug and medical device approval system could be compromised” (C. Frederick Breckner, III, Deputy Assistant Attorney General, U.S. Department of Justice, at FDLI’s Enforcement and Litigation Conference, February 5-6, 2007).
Let us now understand how the regulation defines product intended use.
What is Product Intended Use?
The words intended use(s) as defined in 21 CFR 801.4 (for medical devices) and 21 CFR 201.128 (for drugs) refer to the objective intent of the company (or persons) legally responsible for the labeling of medical devices and drugs, respectively.
“The intent is determined by such persons’ expressions or may be shown by the circumstances surrounding the distribution of the article. This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives. It may be shown by the circumstances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neither labeled nor advertised. The intended use(s) of an article may change after it has been introduced into interstate commerce by its manufacturer.
If, for example, a packer, distributor, or seller intends an article for different uses than those intended by the person from whom he received the devices, such packer, distributor, or seller is required to supply adequate labeling in accordance with the new intended uses.
However, if a manufacturer knows, or has knowledge of facts that would give him notice that a device introduced into interstate commerce by him is to be used for conditions, purposes, or uses other than the ones for which he offers it, he is required to provide adequate labeling for such a device which accords with such other uses to which the article is to be put” (underlined and bolded by the author).
In Action on Smoking and Health v. Harris, 655 F. 2d 236, 239 (D.C. Cir. 1980) it is stated that “it is well established that the ‘intended use’ of a product, within the meaning of the [Food, Drug, and Cosmetic] Act is determined from its label, accompanying labeling, promotional claims, advertising and any other relevant source”.
From this FDA definition, we can learn the following:
- What the intended use (the objective intent) means
- The FDA acknowledges that the intended use of the marketed product may change with time
- If the manufacturer knows in advance that the product will be marketed for off-label use, he is required to provide adequate labeling. If you want to know whether knowledge alone is sufficient to make you responsible – keep reading.
What is Off-label Use?
The terms unapproved new use, unapproved use and off-label use are often used interchangeably and refer to a use of an approved or cleared medical product that is not included in the product’s approved labeling or cleared indications for use statement.
In general, it is acknowledged that physicians may exercise their professional judgment to make individual patient care decisions, which may include the use of the medical products for the uses which are not approved.
An Investment in Knowledge Pays The Best Interest (Benjamin Franklin)
Recently, (January 9, 2017) the FDA issued a rule addressing the circumstances when tobacco products may be regulated as drugs, devices or combination products. The FDA intended to provide clarity for drug and device manufacturers regarding its interpretation and application of its existing definitions of “intended use”.
The rule amends the last sentence of Product Intended Use definitions (21 CFR 801.4 for devices and 21 CFR 201.128 for drugs, see underlined above) to clarify that a manufacturer’s knowledge, alone, that its product is prescribed or used by physicians for an unapproved use is not proof in and of itself that the manufacturer intends such use. Consequently, such knowledge of use would not be sufficient to trigger the obligation to provide adequate labeling for that unapproved use.
The amended language clarifies that a new intended use is created, and a manufacturer is required to provide adequate labeling for such use, only if the totality of the evidence shows that the manufacturer objectively intends for a drug/device to be used for uncleared/unapproved conditions or purposes.
The amended regulations, therefore, specify that manufacturer knowledge may be one source of evidence of intended use, but are not the sole basis of such evidence.
The FDA further clarified that the amended intended use regulations are limited to legally marketed products but not to products that are not legally marketed as medical products for at least one use. The proposed rule’s revision of the drug/device intended use regulations remains in line with the common practice of the FDA.
This is also in compliance with court practice that “off-label speech” could not be used as sole evidence of intended use.
Distributing Scientific and Medical Publications on Unapproved New Uses
In February 2014, the FDA issued a Guidance for Industry – “Distributing Scientific and Medical Publications on Unapproved New Uses — Recommended Practices” which includes many important definitions relating to the practice of off-label use.
This draft guidance recognizes the value that healthcare professionals place on truthful and non-misleading scientific or medical publications regarding unapproved new uses, but also emphasizes that this information is in no way a substitute for the FDA premarket review process “which allows FDA to be proactive, rather than reactive, in protecting the public from unsafe or ineffective medical products.”
So, this guidance defines the rules you should implement when writing and distributing publications which contain off-label use information.
The FDA has previously developed draft guidance – “Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices” that addresses how manufacturers can respond to unsolicited requests for off-label information relating to their FDA-approved or cleared products without such responses being used as evidence of intended use.
This is basically an FDA guidance on how to be “regulatory correct” when it comes to correspondence regarding off-label use.
The detailed review of both these two guidances falls far beyond the scope of this blog but they should be essential reading for professionals in the field.