When is off-label marketing considered free speech? And when should such communications, whether they are directed at doctors, insurers or the public be considered in violation of the law or US Food and Drug Administration (FDA) regulations?
FDA on Wednesday attempted to answer these questions and more with the release of two new draft guidance documents and a 63-page memorandum on public health interests and First Amendment considerations related to off-label communications.
The release of the memo and new guidance follows a two-day meeting in November (the comment period on that meeting has been extended until 10 April 2017, according to FDA) on off-label communications in which the agency questioned the need for looser regulations despite recent court decisions that have gone against FDA.
The difficulty of crafting such a wide-reaching policy is at the forefront of Wednesday’s memo, with FDA noting: “Integrating the many substantial interests, some of which are in tension with each other, in a way that best promotes public health and comports with recent First Amendment jurisprudence is a complex task.”
FDA makes clear upfront that its off-label promotion policies are intended to protect public health, noting: “Marketing activities and communications regarding the safety and effectiveness of a medical product for a particular use that are not properly supported by scientific evidence may thus create a false or misleading impression about the safety and efficacy of the medical product for that use, which can lead to prescribing or use decisions that harm patients.”
The agency offers examples of cases when marketing activities have caused such harm, including those linked to drugs from Amgen, Abbott Laboratories, and atypical antipsychotics from Eli Lilly, Pfizer, AstraZeneca, Bristol-Myers Squibb and Boehringer Ingelheim.
For instance, Amgen’s Aranesp (darbepoetin alfa) was approved for the treatment of anemia associated with chronic renal failure and for the treatment of chemotherapy-induced anemia. But Amgen did not win approval for Aranesp as a treatment for anemia caused by cancer. However, the company’s sales representatives later promoted this unapproved use to doctors (and ended up paying more than $750 million to resolve False Claims Act allegations) with “the very same studies that the FDA had rejected as insufficient to support the safety and efficacy of those off-label uses, when Amgen had applied to expand Aranesp’s label to encompass them.”
One of the more in-depth portions of the memo deals with alternative approaches to regulating or restricting off-label communications or uses and the agency’s opinion on these approaches.
In response to a call to eliminate off-label drug uses or communications, or to cap such off-label uses, FDA makes clear that these approaches do not “take into account the public health interests behind allowing health care providers and patients to work to determine the best treatment options for each patient in specific circumstances.”
However, FDA also makes clear that recent studies have found that most unapproved uses for which drugs are prescribed lack adequate evidence of effectiveness, and the risk of adverse events is higher for unapproved versus approved uses and even higher when the unapproved use is not supported by reliable scientific data.
Furthermore, if firms can promote the public use of unevaluated indications, FDA notes that “there may be greater potential for wide-scale public health tragedies, wasted public and private health care dollars, and fraud.”
And if companies can promote drugs more freely off-label thanks to the First Amendment, FDA also explains how incentives to sponsor research into new indications are likely to be diminished.
“The legal requirement to generate appropriate evidence to demonstrate the safety and effectiveness of medical products for each intended use creates the impetus for firms to conduct those studies for subsequent uses of products – studies that no other actor will likely have the motivation and resources to undertake,” the agency says.
New Draft Guidance
In addition to the memo, FDA released one new draft guidance document dealing with the communication of health care economic information (HCEI) to payers, formulary committees and other similar entities, and another draft guidance offering 11 questions and answers on medical product communications consistent with labeling.
On the HCEI front, FDA notes that it understands payors are interested in receiving information from drug and device firms about medical products that are not yet approved by FDA for any use and a part of the draft discusses ways companies can ensure their communications on investigational products are truthful and non-misleading.
In terms of HCEI with respect to approved drugs, which was slightly tweaked by the 21st Century Cures Act, FDA notes that the statute says HCEI shall not be considered false or misleading if, among other things, it “relates to an [approved] indication.”
But the agency offers a look into its interpretation of that clause, noting: “An economic analysis of disease course modification related to use of a drug that is approved only to treat the symptoms of the disease would not be considered related to the approved indication.”
For example, FDA says, if an analysis for a drug indicated for the acute relief of angina discussed the effect of the drug on delaying the worsening of coronary artery disease (disease course modification), “FDA would not consider this to relate to the approved indication. Similarly, an analysis based on prolonging patient survival (disease course modification) for patients with heart failure would not be considered related to an indication for a drug approved only for the treatment of the signs and symptoms of heart failure.”
In the other draft guidance on communications consistent with labeling, FDA reiterates what it explains in the memo, noting, “If a communication alters the benefit-risk profile of a product in a way that may result in increased harm to health, this indicates that the communication is not consistent with the FDA-required labeling.”
For example, if a communication claims that a drug has superior effectiveness compared to another drug, but its drug is reserved for third-line use due to severe risks while the comparator drug is approved for first-line use due to a more favorable overall benefit-risk profile, FDA says “such a communication has the potential to increase harm to the health of patients by suggesting use in a broader patient population (e.g., all patients with the disease/condition instead of just patients for whom first- and second-line therapies are not suitable) than the drug’s benefit-risk profile justifies.”
FDA Memorandum--Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products
Drug and Device Manufacturer Communications With Payors, Formulary Committees, and Similar Entities – Questions and Answers
Medical Product Communications That Are Consistent With the FDA-Required Labeling — Questions and Answers