December 8-9, 2014 THE FOOD AND DRUG LAW INSTITUTE’S THE FDLI’S ENFORCEMENT, LITIGATION AND COMPLIANCE CONFERENCE PHARMACEUTICAL AND MEDICAL DEVICE ADVERTISING AND PROMOTION: FIRST AMENDMENT ISSUES AND THE FUTURE OF FDA REGULATION Presented by: Mark C. Levy, Esquire

First Amendment—Post Caronia  United States v. Caronia, CR (2d Cir. December 3, Not appealed to the Supreme Court. “While the FDCA makes it a crime to misbrand or conspire to misbrand a drug, the statute and its accompanying regulations do not expressly prohibit or criminalize off-label promotion.”

First Amendment—Post Caronia  “we construe the FDCA as not criminalizing the simple promotion of a drug's off-label use because such a construction would raise First Amendment concerns. Because we conclude from the record in this case that the government prosecuted Caronia for mere off- label promotion and the district court instructed the jury that it could convict on that theory, we vacate the judgment of conviction.”

First Amendment—Post Caronia  We decline to adopt the government's construction of the FDCA's misbranding provisions to prohibit manufacturer promotion alone as it would unconstitutionally restrict free speech. We construe the misbranding provisions of the FDCA as not prohibiting and criminalizing the truthful off-label promotion of FDA-approved prescription drugs.

First Amendment—Post Caronia  We conclude simply that the government cannot prosecute pharmaceutical manufacturers and their representatives under the FDCA for speech promoting the lawful, off-label use of an FDA- approved drug.  Post-Caronia—United States v. Vascular Solutions Inc. (W.D. Tex.) (Nov. 14, 2014)-- indictment alleging conspiracy to defraud U.S. government, along with distributing adulterated and misbranded medical devices.

First Amendment—Post Caronia—The False Claims Act Statement of interest by the government: United States of America ex rel. Matthew Cestra et al. v. Cephalon, Inc., et al., S.D.N.Y., 10 Civ (SHS) (case transferred to E.D. PA., 08-cv TON) and captioned United States of America ex. rel. Bruce Boise, et al. v. Cephalon, Inc., et al. Recovery of 3.8 billion in 2013 under FCA. Qui Tam—2.9b. Relators share: $345m. 752 filed in FDCA cases, criminal fines—1.3b.

First Amendment—Post Caronia  In responding to a motion to dismiss under Rule 9(b) in non intervened case: The FCA does not prohibit off-label promotion..; rather the FCA prohibits conduct that causes the submission of false claims to the Government for payment.” “…the central question is whether the defendant’s marketing caused the submission of false claims, i.e., claims for off-label uses that are not covered or reimbursable by federal health care programs.” The FCA does not prohibit speech; rather it is a remedy for actions that cause a false claim submission.

First Amendment—Post Caronia  United States of America, ex. Rel. Frank Solis v. Millennium Pharmaceuticals, Inc., Schering- Plough Corp., and Merck & Co., U.S.D.C., E.D. Ca., 2:09-CV-3010-MCE-JFM. Amicus Brief of PhRMa—no allegation that speech allegedly giving rise to false claim was false or misleading. Rather, distribution of reprints of medical studies from reputable journals regarding off label use.

First Amendment—Post Caronia  Government response: Does not matter whether true or false as it is prompting submission for reimbursement ineligible for payment.  Phrma—First Amendment demands a direct causal nexus between speech and claim. The speech at issue in Solis does not urge or instruct others to submit false claims.  Sets the table for another legal battle over the implication of free speech in the context of pharmaceutical marketing.

New DOJ Policy on Qui Tam Review  Leslie Caldwell, Assistant AG for Criminal Div. September 17, Qui Tam cases—stepping up use of FCA as enforcement tool - committing more resources. New review process: all new qui tam complaints shared by Civil Division with Criminal Division upon receipt. Encourage Qui Tam relators/counsel to reach out to criminal authorities when discussing with civil authorities if appropriate.

Citizen Petitions: What is FDA’s response to constitutional limits on it regulatory scheme?  Citizen Petitions of Medical Information Working Group (MIWG)--September 3, Challenge to FDA regulations and policies regarding manufacturers’ communications about off-label uses in light of constitutional limitations. June 6, 2014 Response from FDA.

Questions? Mark C. Levy, Esquire Two Liberty Place, 50 S. 16 th Street, 22 nd Floor Philadelphia, PA (215) |

December 8, 2014 Embracing 21st Century Information Sharing: Defining a New Paradigm for FDA’s Regulation of Healthcare Professionals

Biopharmaceutical Company and Healthcare Professional Information Sharing Patients expect their physicians to receive accurate, data- driven information about the medicines they prescribe. A new paradigm demands regulations that are consistent with 21 st Century information sharing. Sources of information may include: Information in the FDA- approved Prescribing Information (PI) Peer-reviewed medical literature (some information not contained in PI) Information on cost- effectiveness (not in PI) Information on use of medicine based on real world evidence (e.g., health records, payer data) Sub-population analyses (e.g., results based on gender) Medically-accepted, reimbursed alternative uses of approved medicines

FDA-approved Labeling Sources of Information about Medicines for Healthcare Professionals Lectures and CME Social Media Advertising and Promotional Labeling Medical Literature Clinical Practice Guidelines Journal Articles Post-market Safety and Effectiveness Data Analyses from Health Records Cost-effectiveness Information Clinical Trial Data

Calls for Regulatory Reform House Energy and Commerce Committee White Paper on 21 st Century Cures “Communication about how certain treatments are working in certain patients is happening through a multitude of media around the globe. These conversations between and among doctors, patients, researchers, and scientists in academia and industry should be facilitated. This includes the free flow of data, research, and results related to what a therapy or combination of therapies does or does not do well and in what types of patients. We need to harness the power of the Internet and social networks.” E&C call for comments from patients “How do you learn about new treatments and cures? How do you communicate with other patients regarding treatments and cures?” Society for Women’s Health Research “We believe open and transparent communication of important scientifically accurate data is important to advancing medical treatments in the digital age. Access to company data should be established in a way that provides for appropriate communication to health care professionals and patients on medication usage that could improve patients’ health outcomes.” National Organization of Rare Disorders “The government severely restricts what drug companies can say about new research and about off-label uses, thus cutting off information from the most knowledgeable sources. The Congress should seek new policies that permit drug companies to share appropriate information without fear of enforcement action.” 16

Patient and Provider Groups Speak Out The Alliance urges FDA to reconsider some of its proposed language changes, which could potentially chill off-label use of oncology drugs and the dissemination of scientific information about non-approved uses. “ ” - The Ovarian Cancer National Alliance, May 2014 To enhance patient care, physicians must have unrestricted access to truthful, non­‐misleading information about the benefits and risks of all therapies available for treatment, including medically accepted alternative uses of approved prescription drugs, biologics, and/or devices. “ ” - The Alliance of Specialty Medicine, May

Principles for a New Regulatory Paradigm 18 All communications about medicines should be truthful and non-misleading Should apply to companies, government, payers Proactive as well as “unsolicited” Regulation should balance patient benefit and potential risk 1.Approved Uses/Approved Medicines Permit truthful and non-misleading information beyond the approved labeling 2.Medically Accepted Alternative Uses of Approved Medicines Supported by clinical guides/medical compendia/reimbursed by govt./private payers Permit truthful and non-misleading information beyond the approved labeling Specifically disclose that use is not FDA-approved 3.Non-Medically Accepted Alternative Uses of Approved Medicines Limited to Exchange between Scientifically-Trained Professionals 4.Investigational Medicines Limited to Exchange between Scientifically Trained Professionals

19 Disclosures/Disclaimers Preferred Over Restrictions – Disclose limitations of data instead of always requiring “two adequate and well controlled studies ” – Communications should disclose regulatory status of medicine/treatment Recognize the Need to Provide Incentives for Sponsors – Disclosure of regulatory status encourages development of supp. approvals – FDA should explore innovative pathways for supplemental approvals Companies Must be Able to Provide Adequate Directions – For approved and medically accepted alternative uses of approved medicines – Providing needed information should not constitute failure to provide adequate directions for use “Labeling” Should Comport with Statute – Non-physical and oral communications are not labeling Principles for a New Regulatory Paradigm

20 FDA should create clear safe harbors for truthful, non-misleading communication about – approved uses – medically-accepted alternative uses Potential areas for sponsor information sharing to enhance patient care include: – Observational data and “real world evidence” (e.g., registries, EHRs) – Pharmacoeconomic information – Sub-population data and other endpoints (e.g., gender and race) – Retrospective data analyses – Claims supported by less than two adequate, well controlled studies FDA guidance should address appropriate methods to qualify and describe information and data so that trained healthcare professionals may evaluate and assess Areas for Potential Safe Harbors