FDA Issues Draft Guidance on Communicating New Risk Information about an Approved Drug Product - Comment Opportunity

This post was written by Jillian W. Riley.

On June 6, 2014, the US Food and Drug Administration (FDA) issued a draft guidance addressing the distribution of new risk information to health care providers (HCPs) and health care entities (HCEs). The draft guidance defines “new risk information” as “information that becomes available after a drug is marketed that rebuts or mitigates information about a risk already identified in the approved labeling or otherwise refines risk information in the approved labeling in a way that does not indicate great seriousness of the risk.” The draft guidance is not intended to address risk information that is newly identified, but that which was not available at the time FDA approved the labeling. Acknowledging the evolving nature of a drug’s safety profile, the draft guidance is aimed at helping sponsors better communicate “new risk information” in order to allow HCPs and HCEs make the best decision for each patient.

Through the guidance, FDA lays out criteria for determining the appropriate circumstances under which to distribute “new risk information” to HCPs and HCEs. FDA does not intend to object to the distribution of new risk information as long as the distribution is consistent with the criteria established in the draft guidance.

The criteria are broken into two categories, those governing the data source and those governing the distribution. Both criteria categories must be met in order for a drug company to distribute new risk information that rebuts, mitigates, or refines risk information in the approved labeling.

Data source criteria include the following:

  • The study or analysis should meet accepted design and other methodologic standards and be sufficiently well-designed and informative;
  • If the data rebuts a prior determination about a causal connection between the drug and an adverse event, the study or analysis should be at least as persuasive as the data it is rebutting;
  • The conclusions should give appropriate weight and consideration to all relevant information in the safety database, including contrary or otherwise consistent findings; and
  • The study or analysis should be published in an independent, peer-reviewed journal.

Distribution criteria include the following:

  • The reprint or digital copy should be accompanied by a cover sheet that clearly and prominently discloses:
    • The study design, critical findings, and significant methodology
    • That the information is NOT consistent with certain risk information in the approved labeling
    • That FDA has not reviewed the data; and
    • Any financial interests or affiliations between the study author(s) and the drug company;
  • The reprint or digital copy should be accompanied by the approved product labeling;
  • The reprint or digital copy should be separate from any promotional material; and
  • Any statements made by a drug company representative to a HCP or HCE concerning the reprint should be consistent with the content and the disclosure information.

Comments on the draft guidance should be submitted by August 20, 2014.

Hundreds of Drugs and Biologics Face Labeling Changes under New FDA Plan

This post was written by Jennifer Pike.

In a notice published in the Federal Register on May 7, 2014, the U.S. Food and Drug Administration (“FDA”) announced its intent to incentivize manufacturers to voluntarily update their prescription drug and biologics labels by using a government contractor.

FDA’s announcement stems from a January 2006 final rule in which FDA established revised content and format requirements for prescription drugs and biologics (the “Physician Labeling Rule” or “PLR”). The PLR required drugs and biologics approved after June 30, 2001 to adopt the new labels. A detailed implementation schedule under the PLR, which only resulted in only 15% of all drug and biologics being labeled in the PLR format, expired in November 2013. Therefore, moving forward, the only products which will be labeled in the PLR format will be new drugs and biologics and drugs that are voluntarily updated. To address this lack of labeling conversion, on February 6, 2013, FDA proposed the Prescription Drug Labeling Improvement and Enhancement Initiative. As part of the initiative, and as explained in detail in FDA’s notice, FDA plans to use a government contractor to provide PLR conversion resources and services, including preparation of draft PLR format labeling, in hopes of facilitating voluntary conversion.

The number of drugs and biologics affected by FDA’s initiative is staggering. FDA estimates that 375 manufacturers will be contacted over a 5 year period regarding 750 products. FDA will select the products for labeling conversion based on criteria that would maximize the benefit to public health, including volume of prescriptions, clinical relevance, and risk-based  considerations. Beyond the 750 products selected for PLR conversion, FDA further estimates that over 1,800 generic products will require labeling updates to reflect changes made to the corresponding brand-name products.

FDA is seeking public comment on its collection of information related to the initiative. Comments should be submitted in writing, or electronically at www.regulations.gov, on or before July 7, 2014.

Will Physician Payment Sunshine Act Data Usher in a New Era of False Claims Act Litigation?

This post was authored by Scot Hasselman, Elizabeth Carder-Thompson, Katie Pawlitz and Jillian Riley.

While attention has been focused on Medicare physician payment data released by CMS yesterday, upcoming Sunshine Act data will shine a new spotlight on financial relationships between physicians and pharmaceutical and medical device companies – with potential FCA implications.

Last week marked the deadline for pharmaceutical and medical device manufacturers and group purchasing organizations (GPOs) to register with and submit aggregate 2013 payment and investment interest data to the Centers for Medicare & Medicaid Services (CMS) on certain financial relationships between themselves and physicians and teaching hospitals, as required by the Physician Payment Sunshine Act.1 In May, manufacturers and GPOs will be required to submit to CMS detailed 2013 payment data. With some exceptions, CMS will be making these data public by September 1, 2014. While the publicly available data are intended to provide more transparency for patients – to allow them to have a better understanding of the financial relationships between physicians and pharmaceutical and medical device companies – patients will certainly not be the only group interested in this public information. The Department of Health and Human Services (HHS) Office of the Inspector General (OIG), Department of Justice (DOJ), and relators’ attorneys will likely utilize these data to initiate investigations and support complaints under the federal False Claims Act (FCA). As with the recent release of the 2012 Medicare Part B Physician Fee Schedule data, members of the media will likely make inferences about certain financial relationships.

The U.S. government recovered $3.8 billion in settlements and judgments from civil cases involving fraud against the government in the fiscal year ending Sept. 30, 2013.2 Fiscal 2014 looks to be a record-breaking year, with ever-increasing civil settlements by major pharmaceutical companies.3

As the reporting deadlines approach, it is worth considering an interesting, and largely unknown, potential implication of the public availability of these data: How will it affect future FCA litigation? The publically available Sunshine Act data could become relevant to FCA litigation in a variety of ways; two in particular are discussed below.

Anti-Kickback Statute Violations

The data could give rise to suspicions of violations of the federal Anti-kickback Statute (AKS). The AKS makes it a criminal offense to knowingly and willfully offer or pay remuneration to induce the referral of, or arrange for the provisions of, federal health care program business.4 In other words, the law prohibits any person or entity from giving, receiving – or offering to give or receive – anything of value in return for or to induce referrals for businesses covered by Medicare, Medicaid, or any other federally funded health care program. Violators of the AKS face imprisonment, criminal, and civil fines, as well as exclusion from federal health care programs.5

It is easy to see how publishing information regarding payments from pharmaceutical and medical device manufacturers to physicians and teaching hospitals could implicate the AKS, and by extension, the FCA. The Patient Protection and Affordable Care Act (ACA) made explicit that violations of the AKS are also violations of the FCA.6 Any payment from a pharmaceutical or medical device manufacturer to a physician who prescribes a product manufactured by the company providing the payment could be viewed as potentially inappropriate remuneration intended to influence prescribing behavior.

Off-Label Promotion

Publically available information reported as a result of the Sunshine Act may also have off-label promotion implications. Notably, reports to CMS must include the name of the drug or the type of device that forms the basis of the payment.7 Tying the payment to a particular drug or type of device could raise suspicions of off-label promotion. A pharmaceutical or medical device manufacturer that promotes its products for uses for which the product has not yet been approved by the United States Food and Drug Administration (FDA), i.e., off-label uses, is at risk of FCA liability. A false claim can arise when a manufacturer promotes a product for off-label, non-covered uses (that is, for a use that both has not been approved by FDA and is not covered by the federal health care programs). Payments going to physicians who specialize in an area that is outside the scope of a pharmaceutical or medical device’s approved indication could necessarily raise suspicions that the manufacturer is promoting the product for unapproved uses.

Potential Limits

Besides the risk of government identifying potential issues for further investigation and prosecution as a result of reported Sunshine Act data, private parties may also mine the publically available data. One substantial impediment to relators’ attorneys using Physician Sunshine Payment data in FCA litigation is the limitation that publicly available data cannot form the basis of a whistleblower claim.8 This is known as the public disclosure bar, although the effectiveness of this defense has been diminished with recent FCA amendments.

That said, the Sunshine Act data, even if not the basis of a claim, could nonetheless impact the litigation in many ways. For example, it could provide additional evidence for the government to review in reaching its decision whether to intervene in a qui tam action. Both OIG and DOJ could review the data before it is publicly available to assist in the determination that a given matter warrants intervention. Additionally, the publicly available data – beyond providing flavor in support of an FCA claim and assisting with meeting the heightened pleading standard associated with fraud allegations9 – could be a potential mine for plaintiff attorneys to locate areas of focus. Relators’ attorneys will no doubt track the data to ascertain potential problem drugs or companies about which they can then dedicate efforts to uncovering fraud and abuse in the federal health care system.

Going Forward

It remains to be seen how all of these risks will play out going forward. Courts will have to decide how these new data will fit into FCA litigation. OIG and DOJ will have to determine how much to rely on the new information. And relators’ attorneys will need to make decisions about how many resources to dedicate to mining the Sunshine Act data.

One potential consequence that we are already starting to see occur is that pharmaceutical and medical device manufacturers may halt or limit payments to physicians, and/or that physicians themselves will be reluctant to accept such payments, e.g., for research, for expenses associated with training on a device, and the like. Companies may decide to do so for a variety of reasons, including avoiding the administrative burdens associated with tracking and reporting such payments for purposes of the Sunshine Act, fear of FCA litigation, or for public relations reasons. Many physicians simply do not want their names publicized. It remains to be seen how these trends will evolve.

1 42 C.F.R. § 403.908(a).
2 DOJ Press Release, available at: http://www.justice.gov/opa/pr/2013/December/13-civ-1352.html. 3 See, e.g., DOJ Press Release, available at: http://www.justice.gov/opa/pr/2013/November/13-ag-1170.html.
4 42 U.S.C. § 1320a-7.
5 Id.
6 42 U.S.C. § 1320a-7b(g). Note that manufacturers may submit “assumptions documents” as part of Sunshine reporting. Although CMS stated in the preamble to the Sunshine regulations its belief that the contents of such documents “should not be made public,” it acknowledged that it could provide access to the documents during an audit or investigation by other HHS divisions, the Office of Inspector General, or the Department of Justice.
7 42 C.F.R. 403.94(c)(8).
8 31 U.S.C. § 3730(e)(4).
9 Fed. R. Civ. P. Rule 9(b).

FDA To Hold Workshop on Accessible Standardized Medical Device Labeling (April 29-30)

On April 29 and 30, 2013, the Food and Drug Administration (FDA) is hosting a public workshop on “Accessible Standardized Medical Device Labeling."  The purpose of the event is to discuss the need for medical device labeling to be delivered in a clear, concise, and readily accessible format so that patients, caregivers, and healthcare providers may use device labeling as efficiently and effectively as possible. This public workshop aims to engage stakeholders in active discussion with FDA and to encourage public comments regarding standard content and format for medical device labeling and the use of a repository containing medical device labeling. FDA also is accepting written or electronic comments related to the public workshop; comments will be accepted until April 12, 2013.

OIG Examines Dietary Supplement Claims, Registration with FDA

The OIG has released two reports focusing on dietary supplements, one examining labeling claims and the other reviewing the FDA’s ability to identify and contact manufacturers in a public health emergency. In the first report, “Dietary Supplements: Structure/Function Claims Fail to Meet Federal Requirements,” the OIG analyzed structure/function claims for a sample of 127 dietary supplements marketed for weight loss or immune system support. The OIG concluded that substantiation documents for the sampled supplements generally were inconsistent with FDA guidance on competent and reliable scientific evidence. Among other findings, 20% of the supplements included prohibited disease claims on their labels and 7% lacked the required disclaimer. The OIG recommends that FDA seek explicit statutory authority to review substantiation for structure/function claims to determine whether they are truthful and not misleading. The OIG also recommend that FDA make improvements to the notification system for these claims and expand market surveillance to enforce the use of disclaimers for structure/function claims and to detect disease claims. In the second report, “Dietary Supplements: Companies May Be Difficult To Locate in an Emergency,” the OIG assessed the FDA’s ability to identify and contact manufacturers in a food emergency, again based on a sample of 127 weight loss and immune support dietary supplements. Out of a subset of 79 companies that the OIG interviewed and were required to register with the FDA, only 72% registered as required, and almost three-quarters of those registrations failed to provide complete and accurate information. In addition, 20% of dietary supplement labels in the sample did not provide the required contact information. The OIG recommends that FDA: (1) improve the accuracy of registry information; (2) seek authority to impose civil monetary penalties on companies that do not comply with registration requirements, and (3) educate industry about registration and labeling requirements. 

FDA Small Entity Compliance Guidance: Toll Free Number Labeling for Drugs

This post was written by Erin Janssen.

The FDA has published a Small Entity Compliance Guide entitled "Toll-Free Number Labeling and Related Requirements for Over-the-Counter and Prescription Drugs Marketed With Approved Applications." This guidance is intended to help small businesses understand and comply with the requirements of the October 28, 2008 final rule on labeling of drugs with a toll-free number for adverse event reporting. The guidance describes certain requirements of the final rule in plain language and provides answers to common questions on how to comply with the rule.

FDA Issues Final Guidance on Risk Labeling for Prescription Drugs and Biological Products

This post was written by Erin Janssen and Areta Kupchyk

On October 12, 2011 the FDA announced the availability of guidance for the industry entitled Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products--Content and Format.” This guidance is intended to assist applicants and reviewers in drafting the “Warnings and Precautions, Contraindications, and Boxed Warning” sections of labeling for human prescription drug and biological products. The recommendations in the guidance are designed to ensure that the labeling is clear, useful, informative, and to the extent possible, consistent in content and format. The guidance provides recommendations on how to determine which adverse reactions are significant enough to warrant inclusion in the "Warnings And Precautions" section; how to decide what situations warrant a "Contraindication," and when to include a "Boxed Warning." The guidance also provides recommendations on how to organize each section and what information to include when describing warnings and precautions, in situations when the use of the product is contraindicated, and in a boxed warning.

FDA Meeting on Patient Medication Information for Prescription Drugs

This post was written by Paul Sheives.

FDA announced a two-day public hearing to be held on September 27-28, 2010 to seek public input on a new framework for the development and distribution of patient medication information (PMI) to be provided to patients with prescription drug products. FDA is considering the use of a single, standardized document with consistent format and content. FDA seeks input on processes and procedures for standardizing PMI using a quality system approach for monitoring the development and distribution of PMI. Registration for the meeting closes September 13, 2010. FDA is accepting written comments on the issue until October 29, 2010. 

FDA Guidance on Label Comprehension Studies for Over-the-Counter (OTC) Drugs

This post was written by Paul Sheives and Areta Kupchyk.

FDA has issued a guidance document entitled “Label Comprehension Studies for Nonprescription Drug Products“ to provide recommendations to industry on conducting label comprehension studies for OTC drug products. The guidance discusses situations where FDA might require a label comprehension study, and provides guidance on the design and conduct of such studies, including the preparation of final reports and various statistical issues inherent to these studies.

FDA Experimental Study of Patient Information Prototypes

This post was written by Paul Sheives.

FDA seeks public comment on a study being conducted by the agency that is designed to test different ways of presenting information about prescription drugs to patients. Specifically, FDA seeks to determine, based on different prototype testing, whether consumers are able to comprehend serious warnings, directions for use, drug indications and uses, contraindications, and side effects in the prototype. The deadline for submission of comments is July 6, 2010.

FDA Meeting on the Development of Drug/Biological Names, Labels and Packaging.

This post was written by Paul Sheives.

FDA will hold a public meeting entitled“Developing Guidance on Naming, Labeling, and Packaging Practices to Reduce Medication Errors” on June 24-25, 2010 in Bethesda, Maryland. The meeting is intended to seek input from interested parties about the design of drug and therapeutic biologic container labels, carton labeling, and product packaging, and practices to develop proprietary names to reduce medication errors. Based on the information received at the meeting, and through the submission of written comments, FDA will develop a draft guidance for industry on this subject. Written comments are due by June 23, 2010.

FDA Guidance on Use of Patient-Reported Outcome Measures to Support Labeling Claims

The FDA has released final guidance for industry entitled "Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims." The document describes how FDA reviews and evaluates patient-reported outcome (PRO) instruments (i.e., a questionnaire plus supporting information and documentation) used to measure treatment benefit in medical product clinical trials. It also provides recommendations on how sponsors can use study results measured by PRO instruments to support claims in approved medical product labeling.

FDA Guidance Documents

This post was written by Paul Sheives.

FDA recently released two guidance documents (one in draft form) concerning hematopoietic reconstitution for specified indications as hematopoietic progenitor cells, cord (HPC-C), which provide information to manufacturers seeking licensure and potential sponsors for Investigational New Drugs Applications (INDs). FDA announced that it no longer intends to exercise enforcement discretion regarding IND and Biologics License Application (BLA) requirements for these products. The final guidance document is entitled “Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications,” and the draft guidance is entitled “Investigational New Drug Applications (INDs) for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications.” Other recent FDA guidance documents include the following:

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