Industry Seeks More Off-label Use Dissemination Freedom
Pharmaceutical Research and Manufacturers of America (PhRMA) says that as a first step in dealing with off-label information dissemination, FDA should create a clear safe harbor for manufacturer communications concerning new medicines and off-label uses of approved medicines with payers and other population health decision makers, “a highly sophisticated segment of the health care system, and one with a particular economic interest to be discerning in its review of information.” PhRMA’s comments were presented 11/9 by Covington & Burling partner Michael Labson during an FDA public hearing to obtain input on issues related to off-label communications by manufacturers, packers, and distributors. FDA says it is engaged in a “comprehensive review of its regulations and policies governing firms’ communications about unapproved uses of approved/cleared medical products,” and the input will inform its policy development in this area.
“A second step,” according to PhRMA, “would involve the creation of a clear safe harbor regarding the communication to health care professionals of real world evidence — evidence based on actual patient use of approved medicines in medical practice – as well as other clinical trial information about patient treatment options. A third step would involve the creation of a safe harbor to protect communication to health care professionals regarding medically accepted unapproved uses of FDA-approved medicines, including in particular, uses recognized by national medical associations and compendia services.”
To help companies comply with any new guidelines FDA establishes, PhRMA proposed that FDA implement an optional preclearance process such as the one that FDA agreed to through its litigation settlement agreement with Amarin (see earlier story). This review process could be adopted to the existing advisory comment process or as a separate process. “However structured, it is critical that the process provide timely feedback so that there is not undue delay in the review of proposed communications,” the group said. “The review would include a key focus on whether information is presented in a way that is truthful and non-misleading, including that there is appropriate contextual information and disclosures provided.”
AdvaMed believes a “balanced and rational agency policy regarding scientific exchange and importantly a tailored policy for medical devices will further the public health by fostering the full exchange of scientific information to healthcare professionals, payers, and other key stakeholders without diminishing FDA’s regulatory purpose of protecting the public health.” The group told the agency that the “chilling impact” of a one-size-fits-all policy or single factor approach could have a particularly harmful impact on truthful and non-misleading communications about medical devices.
AdvaMed said its members support sound guidance by FDA that “recognizes the particular characteristics and regulatory framework for medical technologies. Attention should be given to consider the attributes that differentiate them from other treatments in development and use in the healthcare system. Medical devices are often multifaceted with various technical features, components, and accessories. Accordingly, the design, use and understanding of these instruments is often complex, driving the need for engagement with the healthcare community through the lifecycle of the medical device.”
The device group noted that manufacturers are often requested to provide technical support on the use of their devices to help ensure a healthcare provider’s safe and effective use. “Providing current, scientifically appropriate information about the use of a device, which may include off-label use information, to provide technical support or other customer-facing resources is important to facilitating safe and effective use of the device in real-world, real-time scenarios,” it said. AdvaMed also encouraged unrestricted communications with payers about products for which a premarket submission has been made. “These discussions allow payers to conduct the in depth independent scientific and economic analyses that they perform in order to determine what products and procedures they will cover,” it told FDA.
Presenting the views of the Medical Information Working Group (MIWG), Kellie Combs (Ropes & Gray) and Coleen Klasmeier (Sidley Austin) complained that FDA promised in 2014 to issue guidance on unsolicited requests, scientific exchange, payer communications, and clinical practice guidelines, adding that the public hearing appears to be another delay tactic. The group said scientific exchange is one of the most important activities on which industry needs guidance. “Robust scientific exchange is critical because prescribers must make treatment decisions for their patients based on a range of information, including information that is not contained in the product labeling,” Klasmeier told the hearing. “FDA has never clearly delineated when a communication qualifies as scientific exchange, or what FDA contends is subject to regulation as advertising or labeling. This lack of clarity chills manufacturers from sharing important medical and scientific information about their products and raises serious questions under the Constitution.”
The MIWG has also proposed that FDA confirm the legal definition of labeling in a new guidance. “Currently, manufacturers do not have clear guidance as to the types of communications that are within the key statutory definition, and the lack of clarity undermines the ability of payors, practitioners, and patients to receive high-quality information,” Klasmeier said. And, the group urged FDA to amend the regulatory definitions of “intended use” so that FDA would no longer be able to point to a manufacturer’s mere knowledge that its product is being used off-label to support a misbranding action under the statutory “adequate directions” provision.
Meanwhile, Public Citizen told FDA it should strongly limit – not extend – off-label marketing practices because it endangers patients. Research, the group said, shows 80% of off-label uses “lack sufficient evidence of effectiveness and are associated with a more than 50% increase in side effects” compared to approved uses. “The FDA would be reckless to weaken rules and allow the pharmaceutical and medical device industry to promote products for which they are not proven to be safe and effective,” said Sidney Wolfe, founder and senior adviser of Public Citizen’s Health Research Group. “Opening the door to the promotion of potentially dangerous products undermines the entire FDA approval process. The FDA needs to slam this door shut.”
The existing legal restrictions on marketing drugs and devices for unapproved uses “reflect the fact that assurances by manufacturers that claims of safety and effectiveness are well-supported are no substitute for the FDA’s rigorous, independent evaluation of the evidence, Public Citizen told the hearing. The group discouraged the agency from allowing dissemination of peer-reviewed medical literature. “Peer-reviewed scientific and medical journals vary significantly in their credibility and rigor,” Public Citizen said. “But even among the most respected journals, the peer-review process suffers from shortcomings that can permit fraudulent or otherwise misleading articles to find their way into publication. Unlike the rigorous FDA review process for drugs and high-risk medical devices, the peer-review process for scientific and medical journals generally is not well equipped to uncover the wide range of problems that can undermine the integrity of clinical trial data, including outright fraud, flawed study design, failure to adhere to protocol-specified procedures, poorly conducted statistical analyses, and incomplete reporting of key data.”