CBER Compliance Update FDLI Enforcement, Litigation and Compliance Conference December 8, 2014 Mary Malarkey, Director Office of Compliance and Biologics Quality Center for Biologics Evaluation and Research

Office of Compliance and Biologics Quality 2 OCBQ – Director, Mary Malarkey OCBQ - Deputy Director – Mark Schwartz Division of Case Management DCM Director, Bob Sausville Division of Inspections and Surveillance DIS Director, Gill Conley Division of Manufacturing and Product Quality DMPQ Director, Jay Eltermann DMPQ Deputy Director – Laurie Norwood Division of Biological Standards and Quality Control DBSQC Director - Dr. Bill McCormick

OCBQ’s mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review and inspection, and post-market review, surveillance, inspection, outreach and compliance 3

Current OCBQ Priorities Continued FDASIA and DQSA Implementation –2 nd anniversary of enactment of FDASIA (July 9, 2014) –FDASIA PDUFA V – focus on “lessons learned” Titles VII Drug Supply Chain and Title X Drug Shortages –DQSA DSCSA illegitimate and suspect product notification provision Engaged with CDER on Quality Metrics 4

DSCSA Beginning on January 1, 2015, a trading partner who determines that a product in its possession or control is an illegitimate product must notify the Food and Drug Administration (FDA or Agency) and certain immediate trading partners under section 582 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360eee), as added by the Drug Supply Chain Security Act (DSCSA). Trading partner - manufacturers, repackagers, wholesale distributors, or dispensers

Current OCBQ Priorities - 2 Program Alignment –Working with other agency components to address Dr. Hamburg’s decisions for implementation, communicated by memorandum on February 3, Other quality initiatives –Working with other agency components to update quality guidance and implement standards for quality (e.g., Council on Pharmaceutical Quality) Preparedness activities –Centers for Innovation and Advanced Development in Manufacturing –Ebola International –Mutual Reliance Initiative

Current OCBQ Priorities - 3 OCBQ Move to the White Oak Campus. –OCBQ moved May 16 – August 25, 2014 – lot release laboratories relocated last. –Pause for lot release sample submission until September 2, 2014; no effect on lot release protocols or release of products What’s next? –Increasing filling and lyophilization capacity for production of reagents and standards for the other Essential Regulatory Laboratories, manufacturers and other global partners. plianceRegulatoryInformation/ucm htm 7

White Oak Campus Map 8

United States v. Regenerative Sciences, LLC and Christopher Centeno, et al. The complaint for the injunction was filed August 6, 2010, by the Justice Department on behalf of the FDA in the U.S. District Court for the District of Columbia, against Regenerative Sciences and three of its employees, Christopher J. Centeno, M.D., John R. Schultz, M.D., and Michelle R. Cheever. The injunction the government requested would permanently prevent the company and cited individuals from adulterating and misbranding the cultured cell product (or any other drug) while the product, or one or more of its components, is held for sale after shipment in interstate commerce. Regenerative Sciences agreed to cease production of the cultured cell product while the case is pending. 9

US vs Regenerative Sciences LLC - 2 On July 23, 2012, United States District Judge Rosemary Collyer granted summary judgment for the government and issued a permanent injunction prohibiting the defendants, from distributing adulterated or misbranded drugs or causing them to become adulterated or misbranded after shipment of one or more of their components in interstate commerce. The product at issue is an autologous cultured cell product that was subject to more than minimal manipulation during manufacturing and that was promoted as a treatment for a variety of orthopedic conditions. The court held that this product is a “drug” under the Federal Food, Drug, and Cosmetic Act and rejected the defendants' argument that it falls within the "practice of medicine" and thus outside the scope of the Act. 10

US vs Regenerative Sciences LLC -3 The court also held that the Act's interstate commerce requirement was satisfied because its components were shipped in interstate commerce. The court also dismissed the eight counterclaims filed by the defendants, which challenged, under various theories, FDA's authority to regulate the autologous cell products and FDA's regulations for human cellular and tissue based products. Regenerative appealed the decision and on February 4, 2014, the DC Federal Circuit Court of Appeals ruled in the Agency’s favor 11

Vision for CBER CBER uses sound science and regulatory expertise to:  Protect and improve public and individual health in the US and, where feasible, globally  Facilitate development, approval of and access to safe and effective products and promising new technologies  Strengthen CBER as a preeminent regulatory organization for biologics INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTH 12

Public Access to CBER CBER website: Phone: or Consumer Affairs Branch (CAB) Phone: Manufacturers Assistance and Technical Training Branch (MATTB) Phone: Follow us on Twitter 13

Compliance Central with FDA Center Compliance Directors (Part II) Steve Silverman, Director CDRH Office of Compliance December 8, 2014

The Office of Compliance has reorganized. From: Office of Compliance Division of Risk Management Operations Division of Enforcement A Division of Enforcement B Division of Bioresearch Monitoring

The Office of Compliance has reorganized. To: Office of Compliance Division of Analysis and Program Operations Division of Manufacturing and Quality Division of Premarket and Labeling Compliance Division of International Compliance Operations Division of Bioresearch Monitoring

17 The Case for Quality Support and ownership of quality go beyond quality/compliance unitsSupport and ownership of quality go beyond quality/compliance units A culture of quality yields benefits.A culture of quality yields benefits. Recent trends highlight the importance of quality.Recent trends highlight the importance of quality. “Understanding Barriers to Medical Device Quality”“Understanding Barriers to Medical Device Quality” bacco/CDRH/CDRHReports/UCM pdf bacco/CDRH/CDRHReports/UCM pdf October 31, 2011 webcast:October 31, 2011 webcast:

18 The Case for Quality Implementation Plan Initiative 1: Focus on Quality Initiative 2: Enhanced Transparency Initiative 3: Stakeholder Engagement

Case for Quality Activities Engage industry and other stakeholders in national venues Engage industry and FDA districts in local venues Partner with industry and other stakeholders to develop collaborative forums and trustful engagements Stakeholder Engagement Data Transparency Provide relevant device quality data Gather and assess stakeholder data needs Develop a framework for delivering releasable information Activities Sub-Initiative Focus on Quality Develop, implement, and assess a pilot that changes engagement during an inspection Assess internal/external incentives and measures Benchmark with other quality performance models

Case for Quality: Implantable Device Pilot Implantable battery-containing devicesImplantable battery-containing devices Inspections focused on factors that affect device qualityInspections focused on factors that affect device quality Prioritized Form FDA-483sPrioritized Form FDA-483s Does the pilot improve quality and resource allocation?Does the pilot improve quality and resource allocation?

Industry Engagement Process Interview/ Assess Evaluate/ Modify PilotAnalyze Spin Off Update Program Successful pilots can be expanded.

Case for Quality: Maturity Model

FDLI’s Enforcement, Compliance, and Litigation Conference Center for Tobacco Products Office of Compliance and Enforcement 2014 Update Ann Simoneau, Director CTP Office of Compliance and Enforcement December 8, 2014

24 Compliance and Enforcement Report Office of Compliance and Enforcement (OCE) created a comprehensive report covering 2009 through September 30, 2013 Report includes several charts and graphs representing the advisory (WL) and enforcement activities of the office Report available on the CTP website Plan to update periodically

Regulations and Guidances Final Rule Tobacco Products, User Fees, Requirements for the Submission of Data Needed to Calculate User Fees for Domestic Manufacturers and Importers of Tobacco Products 07/10/14 Proposed Rule Deeming Tobacco Products To Be Subject to the Federal Food, Drug, and Cosmetic Act, as Amended by the Family Smoking Prevention and Tobacco Control Act 04/25/14 Proposed Rule National Environmental Policy Act; Environmental Assessments for Tobacco Products; Categorical Exclusions 01/23/14 Guidance Establishing That a Tobacco Product Was Commercially Marketed in the United States as of February 15, /29/14 Guidance Requirements for the Submission of Data Needed to Calculate User Fees for Domestic Manufacturers and Importers of Tobacco Products 07/16/14 Draft Guidance Substantial Equivalence Reports: Manufacturer Requests for Extensions or to Change the Predicate Tobacco Product 07/15/14 Guidance Civil Money Penalties for Tobacco Retailers - Responses to Frequently Asked Questions06/26/14 Guidance Registration and Product Listing for Owners and Operators of Domestic Tobacco Product Establishments 04/07/14 Draft Guidance Enforcement Policy for Certain (Provisional) Tobacco Products that FDA Finds Not Substantially Equivalent 02/25/14

Deeming (Proposed Rule) On April 24, 2014, FDA proposed a new rule that would extend CTP’s authority to cover additional tobacco products. Products that would be “deemed” to be subject to FDA regulation are those that meet the statutory definition of a tobacco product, including: Electronic Cigarettes (e ‐ cigarettes) Cigars Pipe Tobacco Nicotine Gels Waterpipe (Hookah) Tobacco Dissolvables not already under the FDA’s authority

Retailer Enforcement FY 14 Results Contracts with 55 jurisdictions Contracts with tribes Over 124,000 inspections completed Over 8,100 Warning Letters Over 1,070 CMP’s issued Sale to minor violation rate for FY 14 was 11.4%

Internet Surveillance Issued WLs to online retailers –Sale of tobacco products to minors Minors were able to purchase regulated tobacco products from their websites –Modified risk tobacco product violations –Flavored cigarette violations –Smokeless tobacco product warning statement violations

“Provisional” Tobacco Products Found Not Substantially Equivalent (NSE) Misbranded and adulterated NSE tobacco products webpage Letters to regulated industry Draft Guidance – Enforcement Policy for Retailers Ongoing surveillance and inspections Notifications to retailers

User Fees Domestic manufacturers and importers of regulated tobacco products Currently applies to cigarettes, snuff, chewing tobacco, and roll-your-own tobacco Warning Letter for failure to pay user fees – King Mountain Tobacco Company, Inc. Import Alert – Lit Distributor, Inc. & DK Distributors, Inc.

Compliance Webinars TitleDate Other Media Notifications9/23/2014 Draft Guidance – Substantial Equivalence Reports: Manufacturer Requests for Extensions or to Change the Predicate Tobacco Product 8/6/2014 FDA’s Proposed Regulation – “Deeming Tobacco Products To Be Subject to the Food, Drug, and Cosmetic Act, as Amended by the Family Smoking Prevention and Tobacco Control Act; Regulations on the Sale and Distribution of Tobacco Products and Required Warning Statements for Tobacco Products” 5/29/2014 Electronic Establishment Registration and Product Listing4/7/2014 Guidance for Industry on Compliance with Regulations Restricting the Sale and Distribution of Cigarettes and Smokeless Tobacco To Protect Children and Adolescents 12/9/13