The Regulatory Affairs Professionals Society (RAPS) held its annual conference, the RAPS Regulatory Convergence, from September 17-20 in San Jose, CA. Clarivate Analytics Medical/Regulatory Writer Meg Egan Auderset attended; she wrote the following based on a session called The Changing Landscape of Off-Label Promotion.
Recent legal decisions about the off-label promotion of FDA-approved drug products suggest a shift in what had been a straightforward approach by the agency, according to presenters at this RAPS 2016 Convergence session. While off-label use of products “is extremely common” and most often legal, off-label promotion was “strictly forbidden” until recently, according to consultant Dale Cooke of PhillyCooke Consulting.
Cooke stressed the difference between the two. Off-label use refers to the use of a drug for an unapproved purpose: to treat a disease or condition not included in its FDA-approved indication. Once the FDA approves a product, healthcare providers may prescribe it for unapproved uses when they deem such use medically appropriate for a patient. Prescribers write approximately 20% of all prescriptions for off-label uses, Cooke said; in arenas such as oncology, that percentage can be much higher and, in some cases, off-label use constitutes standard-of-care treatment.
In contrast, a manufacturer engaging in off-label promotion is encouraging the off-label use of a product. Off-label promotion is said to violate the misbranding provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act), the law that authorizes the FDA to regulate drug promotion by pharmaceutical companies. Penalties for off-label promotion have typically begun with an Untitled Letter or a Warning Letter that is posted on the FDA website, but the range of potential sanctions has extended to criminal charges and financial penalties under the False Claims Act.
The FDA distinguishes between promoting off-label use of a product and disseminating information about off-label uses. As explained by Cooke, disseminating off-label information does not suggest encouragement, while off-label promotion does.
Disseminating Reprinted Published Information on Off-Label Uses
The FDA has recognized that “truthful and non-misleading” information on a product’s unapproved uses can be valuable to providers when making treatment decisions for patients. The agency reiterated this stance in draft industry guidance revised in 2014, Guidance for Industry: Distributing Scientific and Medical Publications on Unapproved New Uses – Recommended Practices. The document presents “recommended practices” for drug and device manufacturers to follow when distributing scientific or medical journal articles, reference texts, or clinical practice guidelines to healthcare professionals.
Cooke discussed “high-level do’s and don’ts” from the guidance, including:
- Disseminated materials should concern adequate, well-controlled investigations. They should be current, peer-reviewed, independently available, and published by an independent organization(s) of experts with a full-disclosure policy for conflicts of interest.
- Materials should be unabridged and should be accompanied by a comprehensive bibliography, contrary results, and an FDA-approved product label. They should not highlight or “flag” content.
- Materials from scientific and medical publications should be disseminated separately from promotional content.
- Materials should not be false or misleading. They should not be edited or influenced by anyone with financial ties to the product manufacturer, nor specially funded by the manufacturer. They should not be written, edited, or excerpted specifically for the manufacturer.
- “A big sticker” permanently affixed to the materials should state that the uses described are neither FDA-approved nor cleared, and should note any risks related to the unapproved use. It should list study funders and authors who have financial connections to the manufacturer.
- Materials unacceptable for dissemination include letters to the editor, publication abstracts, reports of trials enrolling healthy volunteers, and publications with little or no data to support their conclusions.
Responding to Unsolicited Requests for Off-Label Information
Cooke also distinguished between solicited and unsolicited requests for off-label information, stressing that the FDA forbids sponsors from soliciting requests. According to draft FDA guidance from 2011, Responding to Unsolicited Requests for Off-Label Information about Prescription Drugs and Medical Devices, “solicited requests may be considered evidence of a firm’s intent that a drug or medical device be used for a use other than that specifically approved or cleared by FDA.” Requests that are “prompted in any way” by the manufacturer are considered solicited, Cooke said. He offered several examples, including:
- Presenting data on off-label uses at promotional events and asking whether anyone in the audience has questions.
- Encouraging users of a product to post videos on YouTube showing “how you use our product.”
- Using Twitter to announce the results of studies on off-label uses and implying that such use is safe and effective.
- Sending information about off-label uses to consumers and encouraging them to write about the uses in public forums.
To clarify what constitutes an unsolicited request, Cooke presented the “classic case” of a pediatrician contacting a manufacturer with questions about pediatric dosing of a product indicated for adults. Should it be based on the child’s weight? On the child’s age? The 2011 draft guidance also distinguishes between non-public unsolicited requests, which are “directed privately to a firm,” and unsolicited requests that occur in a public forum, such as a listserv or live presentation.
Recommendations for responding to unsolicited requests generally advise restraint. For example, a company’s response to a non-public unsolicited request for off-label information about a product “should be scientific in nature,” “truthful, non-misleading, accurate, and balanced,” and “tailored to answer only the specific question(s) asked,” according to the 2011 guidance. The response should be accompanied by:
- The FDA-approved product labeling.
- A “prominent statement” that the FDA has not approved or cleared the product as safe and effective for the relevant off-label use.
- A “prominent statement” of the approved indication.
- A “prominent statement” listing safety information, including boxed warnings.
- A complete list of references for the information disseminated.
In contrast, a public response to a public unsolicited request for off-label information should include only the company’s contact information. Companies should maintain records about their responses to requests, Cooke said.
Recent Case Law
In May 2015, Amarin Corporation plc filed a lawsuit proactively challenging FDA restrictions on the dissemination of information about off-label use. Amarin Pharma, Inc v FDA concerned Vascepa (icosapent ethyl), a prescription drug approved in 2012 to reduce triglyceride levels in adults with severe hypertriglyceridemia—that is, triglyceride levels ≥500 mg/dL. As explained by attorney Alan Minsk, a partner at Arnall Golden Gregory LLP, Amarin filed the suit after receiving a Complete Response Letter from the FDA in April 2015. The FDA denied a supplemental application by Amarin to expand the Vascepa indication to include the reduction of triglyceride levels in adults with mixed dyslipidemia and triglyceride levels ranging from 200 to 499 mg/dL.
According to Amarin, when the FDA denied the supplemental application, it also warned the company against marketing Vascepa for the proposed supplemental use, stating that such promotion could violate the misbranding provisions of the FD&C Act. In the words of the Amarin complaint, filed in May 2015, the lawsuit was a “First Amendment challenge to FDA regulations that prohibit Amarin, a pharmaceutical company, from making completely truthful and non-misleading statements about its product to sophisticated healthcare professionals.”
“Amarin Pharmaceuticals basically preemptively sued the agency” to defend its right to disseminate “truthful and non-misleading” information, including clinical trial data supporting Vascepa’s off-label use, Minsk said. Amarin won the lawsuit in August 2015, and the FDA subsequently settled.
“Because the information was accurate, and they had substantiating information, the court said, ‘FDA, leave them alone,’” Minsk said. The case “holds FDA’s feet to the fire,” he said, since the agency is bound to the court’s declaration that Amarin may engage in truthful and non-misleading speech to promote Vascepa’s off-label use.
The Amarin case followed United States v Caronia, a 2012 case in which an appeals court vacated the conviction of a pharmaceutical sales representative who had been found guilty of promoting a drug for off-label use. The sales rep’s off-label promotion consisted only of truthful, non-misleading speech and, in its ruling, the appeals court asserted that the misbranding provisions of the FD&C Act do not prohibit or criminalize “the truthful off-label promotion of FDA-approved prescription drugs” if that off-label use is legal.
Minsk stressed that the Amarin settlement is fact-specific and does not resolve the question of what exactly “truthful and not misleading” means and who, ultimately, makes that decision. What type of scientific substantiation is required to support an off-label claim? How much? To date, there is no clear guidance from the FDA on the matter, Minsk said. If the FDA disagrees with another company’s assertion that off-label claims are truthful and not misleading, that company will have to decide whether those claims are worth risking an FDA enforcement letter and/or potential litigation, Minsk said.
In the absence of formal FDA guidance, Minsk offered several recommendations to companies, including:
- Remember that false speech is never protected.
- Distribute only high-quality scientific data, such as data from randomized controlled trials, and ensure that the studies support promotional claims: that they are “designed appropriately, adequately powered, statistically significant, and clinically relevant.” Minsk cautioned against data based solely on uncontrolled studies, open-label studies, observational studies, and testimonials.
- Ensure that data are representative of the complete study data set, not “cherry-picked.”
- Pay attention to previous FDA feedback on data. If the agency has already indicated that data are weak, do not use them to support promotional claims.
- Use internal promotional review committees to assess whether promotional materials meet FDA requirements.
- Keep up with scientific developments. Materials on off-label uses must be “truthful and not misleading” when they are released—and they must remain so.
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