We’ve blogged a number of times about the illogical, and often downright counterproductive, nature of the FDA’s position that regulated manufacturers are generally banned from providing the medical community (or the public) with truthful information about the off-label uses of their products. Even information about the risks of off-label uses cannot be included on a product’s labeling unless the FDA requires it.
A new draft FDA guidance demonstrates how strange these results can be. This draft guidance, entitled “Informed Consent Information Sheet, Guidance for IRBs, Clinical Investigators, and Sponsors,” is located here on the FDA’s website. It came out in July. Like the title says, it concerns the informed consent obligations of persons involved in FDA-regulated clinical trials. As with most other medical practice, the attending physician (in clinical trials, the “investigator”) has primary responsibility for providing patients (“subjects” in trials) with the information necessary to obtain their informed consent. The Draft Guidance discusses this information in detail.
The interesting part, from our perspective, has to do with “alternative procedures or treatments.” Here the FDA advises “consent forms must disclose appropriate alternatives to entering the clinical investigation, if any, that might be advantageous to the subject.” Part III(B)(4) (sorry about this, but the FDA’s online documents aren’t paginated). That’s pretty standard. Viable alternative treatments are part of most, if not all, states’ informed consent common law. When discussing alternatives, “a description of any reasonably foreseeable risks or discomforts and potential benefits associated with these alternatives must be disclosed.” Id.
According to the FDA, the informed consent disclosure “must include a description of the current medically recognized standard of care.” Id. We’ve pointed out in the past that, in many instances, the medical standard of care includes off-label use. Notably, in the new draft guidance, the FDA recognizes this fact as well:
Standard of care may include uses or treatment regimens that are not included in a product’s approved labeling (or, in the case of a medical device cleared under the 510(k) process, in the product’s statement of intended uses).
Id. For this proposition, the draft guidance cites an earlier finalized guidance:
As FDA has recognized in prior guidance, “[O]ff-label uses or treatment regimens may be important and may even constitute medically recognized standard of care.” FDA Guidance, “Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices.”
So the FDA recognizes that investigators in regulated clinical trials have to provide informed consent information to trial subjects about off-label use where that treatment represents the medical standard of care. Trouble is, what’s the most logical source for this information? The manufacturer of the product being used off label. After all, the manufacturer is the primary entity with the obligation under the FDA’s regulatory scheme to report adverse events, and the FDA’s adverse event reporting regulations don’t really distinguish between on- and off-label uses – manufacturers report about both. After a fashion, the FDA also recognizes that logic. In discussing the informed consent role of manufacturers (“sponsors,” in clinical-trial-speak), the new draft guidance observes:
Sponsors often provide clinical investigators with a model consent form that may be adapted by the clinical investigator to meet local needs. When the consent form is submitted to FDA for review, FDA’s comments are generally directed to the sponsor. . . . [T]he sponsor should work closely with the clinical investigator to make certain the modified consent form is reviewed and approved.
Draft Guidance at Part III(C).
But in the case of a standard-of-care off-label use one of two things has to happen: (1) the off-label use is of the sponsor/manufacturer’s own product, or (2) the off-label use is of a different, competing manufacturer’s product. It’s either one or the other. If the first option is applicable – as will be the case when the sponsor is attempting to bring the off-label use onto the label (something FDA encourages) – then the sponsor/manufacturer could be in trouble. Providing the investigator/physicians with proposed informed consent forms accurately describing off-label use is what the FDA calls, in other contexts, “promotion” of off-label use. The FDA claims that’s illegal. So do all these plaintiffs we write about frequently seeking to follow in the FDA’s footsteps.
The draft guidance, of course, recites that it doesn’t “establish legally enforceable responsibilities.” Id. at Part I. That means that, if it wants, the FDA might come along and try to prosecute manufacturer/sponsors for providing physician/investigators with the very information that this draft guidance states should be provided. Or private plaintiffs might improperly purport to enforce the FDCA concerning off-label promotion.
Don’t laugh. It’s already happened. We’ve already seen plaintiffs allege that clinical trials are merely ruses for off-label promotion.
And if option two – the standard-of-care off-label use is of a competing product − is applicable, then the results verge on the downright perverse. The FDA’s regulations don’t prohibit the off-label promotion of a competing product. After all, in the jerry-rigged regulatory scheme by which the FDA professes to ban manufacturer dissemination of truthful information about off-label uses, the manufacturer is only obligated to provide “adequate directions for use” about its own product, not somebody else’s. So a manufacturer can “promote” the off-label use of a different company’s product.
What’s the incentive for it to do so? Is there anything in the FDCA that requires a manufacturer to provide “fair balance” about a product it doesn’t make? Why would it want to present the off-label use of a competing product as the “standard of care” at all? Beyond that, what information is a manufacturer going to have about the risk profile of competing products’ off-label uses. A manufacturer doesn’t receive adverse event reports about products it doesn’t make. Even if it received one by accident, the FDA’s reporting requirements relate only to products for which it is the NDA/ANDA/PMA/§510k holder.
So the practical result of the new informed consent draft guidance is that sponsors are expected to help investigators with informed consent forms, and investigators are required to provide patients with information about off-label uses when they are the standard of care. Owing to the FDA’s outdated off-label promotion positions, however, a sponsor is open to persecution/prosecution for off-label promotion when it does what this draft guidance envisions with respect to the products it knows most about – those being its own. It has no incentive, and is likely to be providing incomplete information, to the extent that this guidance relates to off-label uses of competing products.
The FDA is tying itself in knots with respect to its increasingly untenable position about truthful off-label promotion. We suppose it will continue to do so until the First Amendment finally forcibly ejects the Agency from those positions.
In our opinion, that can’t happen soon enough.