Enforcement Litigation and Compliance

Washington, DC

December 9-10, 2015

Compliance Central with FDA Center Compliance Directors (Part II)

Mary Malarkey, Director, Office of Compliance and Biologics Quality, CBER

Cynthia Schnedar, Director, Office of Compliance, CDER

CAPT Sean Boyd, Acting Director, Office of Compliance, CDRH

Moderated by John Taylor, Principal Compliance and Regulatory Affairs, Greenleaf Health LLC, and Member, FDLI Board

Compliance Central with FDA Center Compliance Directors (Part II)

Mary Malarkey, Director, Office of Compliance and Biologics Quality, CBER

Cynthia Schnedar, Director, Office of Compliance, CDER

Sean Boyd, Acting Director, Office of Compliance, CDRH

Moderated by John Taylor, Principal Compliance and Regulatory Affairs, Greenleaf

Health LLC, and Member, FDLI Board

CBER Compliance UpdateFDLI Enforcement, Litigation and Compliance

ConferenceDecember 9, 2015

Mary Malarkey, DirectorOffice of Compliance and Biologics Quality

Center for Biologics Evaluation and Research/FDA

Office of Compliance and Biologics Quality

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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

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Rules and Guidance: Update

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Drug Shortages: Final Rule

• “Permanent Discontinuance or Interruption in Manufacturing of Certain Drug or Biological Products.” 7/8/2015

• Effective date: September 8, 2015• Requirements for electronic notification of FDA of

a “permanent discontinuance or an interruption in manufacturing of the product that is likely to lead to a meaningful disruption in supply (or a significant disruption in supply for blood or blood components) of the product in the United States.”

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21 CFR 600.82

• Adds biological drugs to requirements in 506(c) of the Federal Food Drug and Cosmetic Act and amends the regulations

• All applicants with an approved BLA for a covered biological product, other than blood or blood components (§ 600.82(a)(1)).

• Applicants with an approved BLA for blood or blood components, if the applicant is a manufacturer of a significant percentage of the U.S. blood supply (§ 600.82(a)(2)).

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General Safety Test: Final Rule

• “Revocation of General Safety Test Regulations That Are Duplicative of Requirements in Biologics License Applications,” effective date August 3, 2015.

• “For a number of years, FDA has not codified specific test methods as standards for licensed biological products, in part because codifying specific test methods as standards can diminish the ability of the Agency and industry to respond to technological developments.”

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GST - 2

• “The final rule is removing Sec. Sec. 610.11, 610.11a, and 680.3(b), the regulations that require that manufacturers of biological products perform a specified test for general safety of biological products. FDA is taking this action because the existing codified GST regulations are duplicative, outmoded, or are otherwise unnecessary to help ensure the continued safety, purity, and potency of licensed biological products.”

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Draft “Guidance for Industry:Request for Quality Metrics”

• Draft guidance issued on July 27, 2015• Public meeting held August 24, 2015;

questions to stakeholders in the Notice of Availability for the guidance.

• FDA extended comment period to November 27, 2015.

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Applicability to Biologics?

• Scope:– Exemptions include manufacturers of blood

and blood components for transfusion, vaccines, cell therapy products, gene therapy products, allergenic extracts, human cells, tissues, and cellular and tissue based products and non-recombinant versions of plasma derived products.

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Draft Guidance Compounding

• “Mixing, Diluting or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application,” February 13, 2015. Comment period until May 20, 2015.

• “This draft guidance describes the conditions under which FDA does not intend to take action against a state-licensed pharmacy, a Federal facility, or outsourcing facility that mixes, dilutes, or repackages certain biological products without obtaining an approved biologics license application (BLA).”

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Recent HCT/P Draft Guidance Documents

• Provides FDA’s current thinking on certain criteria in 21 CFR 1271.10(a) and the exception in 1271.15(b).

• Industry uses these regulations to determine the need for FDA premarket review and approval

• Alternatively, the Tissue Reference Group and/or submission of a Request for Designation provide informal and formal avenues for FDA input.

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Exception based on the consideration that autologous cells or tissues removed from an individual and implanted into the same individual without intervening processing beyond rinsing, cleansing, or sizing, or certain manufacturing steps, raise no additional risks of contamination and communicable disease transmission beyond that typically associated with surgery.

Explains the regulation and its three parts:•Autologous use•Removed and implanted in same procedure

• Two procedures consisting of more than a single operation are listed – craniectomy , parathyroidectomy

•Remain “such HCT/Ps”

Same surgical procedure exception

Based on the bipartite regulatory definition of ‘minimal manipulation’•For structural tissue, minimal manipulation means that the processing does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement.•For cells or nonstructural tissue, minimal manipulation means that the processing does not alter the relevant biological characteristics of the cells or tissues.

The draft guidance explains•How to determine whether an HCT/P is a structural tissue or a cellular/nonstructural tissue for the purpose of applying the definition•How to determine if it is minimally manipulated

Minimal Manipulation

This draft guidance responds to the numerous inquiries regarding HCT/Ps manufactured from adipose tissues.

It explains•How the four criteria in 1271.10(a) apply to adipose tissue-derived products•How to determine whether adipose tissue that is implanted into the same individual during the same surgical procedure is subject to FDA regulation•How to get more information about the appropriate regulatory considerations

Autologous adipose tissue

Homologous Use

Homologous use is defined as: The repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor (21 CFR 1271.3(c)).

The draft guidance explains:•Key terms•Recommendations for applying the homologous use criterion; provides examples

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http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM469751.pdf

Update on the Draft HCT/P Guidance Documents

•The comment period has been reopened for the three draft guidance documents published in 2014

•The comment period for all 4 draft guidance documents will close on April 29, 2016

•Comments submitted to the docket are available to the public:• Same Surgical Procedure Exception: http://www.regulations.gov/#!

docketDetail;D=FDA-2014-D-1584• Minimal Manipulation: http://www.regulations.gov/#!docketDetail;D=FDA-2014-D-1696• Adipose Tissue: http://www.regulations.gov/#!docketDetail;D=FDA-2014-D-1856• Homologous Use: http://www.regulations.gov/#!documentDetail;D=FDA-2015-D-3581-0001

•FDA will have a public hearing on April 13, 2016 to obtain input on all four draft guidances.

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Some Current Priorities

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Program Alignment

• With ORA, working through commitments in FY2015 Biologics Action Plan and developing FY2016 plan. http://www.fda.gov/aboutfda/centersoffices/ucm392733.htm

• Target areas are specialization, training, work planning, compliance and enforcement, and imports

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Program Alignment -2

• We are aligned in many aspects and are fine tuning to further integrate:– Team Biologics – biological drugs and devices– Biologics Cadre – blood, plasma, 361 HCT/Ps

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• Facilitating the importation and exportation of clinical trial materials for Ebola.

• Part of an intergovernmental working group providing communication channels between all relevant government components: CBP, HHS/BARDA, FDA, CDC, USDA/APHIS, DOT, FWS, DOC/BIS

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Vision for CBER

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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

Public Access to CBER

CBER website:http://www.fda.gov/BiologicsBloodVaccines/default.htm

Phone: 1-800-835-4709 or 301-827-1800

Consumer Affairs Branch (CAB) Email: ocod@fda.hhs.govPhone: 301-827-3821

Manufacturers Assistance and Technical Training Branch (MATTB)Email: industry.biologics@fda.govPhone: 301-827-4081

Follow us on Twitter https://www.twitter.com/fdacber

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2015 FDLI Enforcement Conference

Cynthia Schnedar, J.D.Director, CDER Office of Compliance

December 9, 2015Washington, DC

Compliance Update

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One Quality Voice• For Drugs

• For Patients

• For Industry

• For Healthcare Professionals

• For Healthcare Purchasers

Priorities

CDER reorganization

Program alignment

Implementing legislative authorities

Compliance and enforcement actions

Track & trace

Compounding28

Office of Manufacturing Quality (OMQ) Focus

• Current Good Manufacturing Practices• Mutual reliance / Increase in joint inspections

with international regulatory partners

• Global training

• Data Reliability

OMQ ActionsJanuary to October 2015

Import Alerts, 18

Untitled Letters, 5

Warning Letters, 16

January to October 2015

Import Alerts, 18

Untitled Letters, 5

Warning Letters, 16

CY2014 drug GMP Warning Letters

Manufacturer location

CY2014 drug GMP Warning Letters

Placed on Import Alert (#66-40)

Cited data reliability issue

Foreign 19 8 11

*Domestic 1 N/A 0

* Does not include Warning Letters issued to compounders

Office of Unapproved Drugs and Labeling Compliance (OUDLC)

Focus•Develops and implements policies and strategies to ensure compliance with new drug and labeling requirements of the FD&C Act•Directs inspections and coordinates compliance and enforcement actions regarding:

– Fraudulent drug products– Compounding– OTC drugs– Marketed, unapproved prescription drugs

•Implements the compounding provisions of the Drug Quality and Security Act (DQSA) 32

Compounding Actions

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• Since enactment of the DQSA on November 27, 2013, FDA has completed the following actions:– Conducted approximately 200 inspections of

compounders.– Issued a Form FDA 483 at the conclusion of almost

all of its inspections.– Issued approximately 60 warning letters to

compounders including one warning letter that addressed violations identified at four facilities.

– Issued to state boards of pharmacy approximately 20 letters referring findings from inspections of pharmacies that appeared to operate in accordance with section 503A of the Act.

Compounding Policy• Since enactment of the DQSA, to implement

the new law and clarify its policies regarding compounding and related activities, including repackaging, FDA has issued:– 12 draft guidances, 5 of which were finalized– A draft memorandum of understanding– A proposed rule

• FDA also held three meetings of the Pharmacy Compounding Advisory Committee.

FDA’s Compounding Website

• Keep up to date on developments at:http://www.fda.gov/Drugs/

GuidanceComplianceRegulatoryInformation/Pharmacy Compounding/default.htm

•Site contains links to:• all policy documents including Guidances (final and

draft), • Form FDA 483s and Warning Letters issued, • a list of registered outsourcing facilities, and • questions and answers about what it does and does

not mean to be a registered outsourcing facility

Office of Drug Security, Integrity, and Response (ODSIR) Focus

• Title II - Product tracing (track and trace)

• Regulates internet pharmacies

• Operation Pangea• Counterfeit and foreign

approved drug actions• Indictments /

Prosecutions• Letters to doctors

• APEC Supply Chain Roadmap

• WHO spurious/falsely-labelled/falsified/counterfeit (SFFC) medicines

• Recalls

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Major Reasons for Recalls FY 12-15*

2012 - Impurities/Degradation Products- GMP Deviations- Lack of Assurance of Sterility

2013 - Lack of Assurance of Sterility- Impurities/Degradation Products- Presence of Particulate Matter

2014 - Marketed without an Approved NDA/ANDA- Presence of Particulate Matter

      - Lack of Assurance of Sterility

2015* - Lack of Assurance of Sterility- Presence of Particulate Matter- Impurities/Degradation Products

*=Quarter 4

• Focus– Enforces the following requirements

• BIMO (bioresearch monitoring)• Risk Evaluation and Mitigation Strategies

(REMS)• Post-market adverse drug event reporting• Post-marketing requirements (PMRs)

– International Collaboration

Office of Scientific Investigations (OSI) Activities

• Activities– Engage with UK & EU health authorities to

conduct GCP and bioequivalence inspections

– Collaborate with ICH to modernize clinical trials

– Develop enforcement standards for IRBs and RDRCs

Office of Scientific Investigations (OSI) Activities (cont’d)

FY2014 OSI Warning Letters & Disqualifications

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1 1

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Compliance CentralCenter for Devices and Radiological Health

CAPT Sean M. Boyd, MPH, USPHS

Acting DirectorOffice of Compliance

CDRH Office of Compliance

FDLI LEC 12/09/2015

Medical Device Quality System Data

• Increasing proportion of foreign inspections as foreign manufacturer inventory growing rapidly

http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cdrh/cdrhtransparency/ucm471117.pdf

FDLI LEC 12/09/2015

Country Name Number of Inspections

China 190

Germany 72

Japan 37

Taiwan 29

Switzerland 25

Canada 24

Ireland 23

Korea, Republic of South 23

United Kingdom 23

France 16

CY2014 Top 10 Foreign Inspection Locations

FDLI LEC 12/09/2015

Medical Device Quality System Data

• Production and Process Controls and Corrective and Preventive Action continue to be the most frequently cited QS subsystems on 483s and in WLs

http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cdrh/cdrhtransparency/ucm471117.pdf

FDLI LEC 12/09/2015

QS Subsystem# of

ObservationsPercentage

P&PC 1,197 32%

CAPA 1,148 31%

DES 515 14%

MGMT 497 13%

DOC 383 10%

Medical Device Quality System Data

• Production and Process Controls and Corrective and Preventive Action continue to be the most frequently cited QS subsystems in 483s and in WLs

http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cdrh/cdrhtransparency/ucm471117.pdf

FDLI LEC 12/09/2015

QS Subsystem # of Citations Percentage

CAPA 262 34%

P&PC 254 33%

DES 121 16%

MGMT 74 10%

DOC 63 8%

Medical Device Quality System Data

• Production and Process Controls and Corrective and Preventive Action continue to be the most frequently cited QS subsystems

http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cdrh/cdrhtransparency/ucm471117.pdf

FDLI LEC 12/09/2015

QS Subsystem# of

ObservationsPercentage

P&PC 1,197 32%

CAPA 1,148 31%

DES 515 14%

MGMT 497 13%

DOC 383 10%

Medical Device Quality System Data

• The number of Warning Letters (WL) decreased slightly from 144 in CY2013 to 121 in CY2014

http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cdrh/cdrhtransparency/ucm471117.pdf

FDLI LEC 12/09/2015

Priorities

• Resolve patient safety, product quality, and regulatory violations with appropriate action– Meaningful, Timely

• Use interactive approaches to resolve less significant issues– Proportional, Timely

• Employ comprehensive strategies to address widespread issues– Informed, Proportional, Consistent

FDLI LEC 12/09/2015

Bioresearch Monitoring

• Piloting inspections in non-traditional situations including 510(k)s, de novos, post-approval studies.– Risk based approach– 19 inspections performed annually in FY14 and FY15

for Class II devices related to 510(k) and De Novo submissions

MDSAP

• Single regulatory audit of firm’s quality management system satisfies needs of multiple regulatory jurisdictions

• Substitute for FDA routine surveillance inspections– For-cause, follow-up, pre-approval, post-

approval inspections not affected

• Pilot through December 2016, implementation in 2017

FDLI LEC 12/09/2015

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MDSAP• Many aspects of pilot promising, on-track

– 5 regulatory partners committed to the program (Australia Brazil, Canada, Japan, US)

– 6 third party auditing organizations authorized to conduct audits of medical device manufacturers

– 59 participating manufacturing sites as of December 1, 2015– Health Canada transitioning to MDSAP starting in January 2017

• Evaluating documents, policies and audit/assessment models and reports to validate Pilot Proof of Concept

• Accepting manufacturer and auditing organization feedback to improve MDSAP processes

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Program Alignment• Establish commodity-based and vertically

integrated Regulatory Programs– Delayering/streamlining– Specialization– Training– Workplanning– Compliance and quality policy, enforcement and

engagement– Import operations– Lab optimization

FDLI LEC 12/09/2015

FDLI LEC 12/09/2015

What does this mean?

• Investigators, compliance officers and managers specialized by program

• Increased understanding of technology and manufacturing processes

• Development of team-based approaches and streamlined decision-making

• Shared strategic priorities & program goals• Work planning based on risk and global

inventoryFDLI LEC 12/09/2015

More to Come

• Finalize decisions, organizational models, roll-out individual assignments

• Launch and continue transition activities through FY16

• Stand up the new model in FY17

• Points of contact will change over time

• Continuous Improvement… including evaluating and measuring success

FDLI LEC 12/09/2015

Compliance vs. Quality• Current approach reinforces compliance with

regulatory requirements– Observations of repetitive quality system issues among

major device manufacturers, unrelated to product quality

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/MedicalDeviceQualityandCompliance/ucm378185.htm

• Future approach to emphasize patient safety and product quality– Shared goal among stakeholders

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/MedicalDeviceQualityandCompliance/ucm378185.htm

FDLI LEC 12/09/2015

Case For Quality

• Collaborative interaction among device stakeholders to promote improvement in device quality through a variety of activities relating to quality of the organization, system, product and personnel.

• Both FDA and industry looking at what we need to do to align our approach on quality to the lessons learned from these collaborative activities.

FDLI LEC 12/09/2015

Collaboration

• Medical Device Innovation Consortium– Measures and Metrics– Quality maturity– Data analytics– Competency development

• Adapting industry and FDA practices to shift toward quality focus

FDLI LEC 12/09/2015

Data Sharing• Identifying new metrics and applications for

internal FDA data• Release of application programming interfaces

(API) to allow external use of FDAs public data– Adverse events– Device classification– PMA– Recalls– 510k– Registration and listing

https://open.fda.gov/index.html

MDIC CfQ Forum 12082015 61

Focus on Quality• Critical to Quality Technical Documents

– Lists quality indicators related to product features or manufacturing processes that are essential to the quality of a device

– May be specific to a particular submission, a specific device, or class of devices

– Used to link technical design or process related information to a traditional QSIT inspectional approach, but may be more broadly applied

FDLI LEC 12/09/2015

Example CtQ Indicator

Key characteristicKey characteristic

Impactof failureImpact

of failure

ControlControl

Reference to 820Reference to 820 Reference to QSITReference to QSITMDIC CfQ Forum 12082015 63

Critical to Quality DocumentsCtQ Information Document Who was involved?

Implantable devices with batteries CDRH, Battery Suppliers, OEMs

Implantable spine device CDRH

Semi-constrained knee implants CDRH

Abdominal surgical mesh CDRH

Implantable cardioverter defibrillators CDRH, AdvaMed

Defibrillator leads CDRH, AdvaMed

Neuro embolization devices CDRH, AdvaMed

Infusion pumps CDRH, AdvaMed

Ventilators CDRH, AdvaMed

Catheter coatings CDRH, AdvaMed

MDIC CfQ Forum 12082015 64

Battery Pilot Outcomes• Firm and investigator feedback positive

– Promoted interactions– Clarified expectations– Improved satisfaction– Focused on quality

• Explore further– Differentiating from QSIT inspections– Resource utilization

http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/medicaldevicequalityandcompliance/ucm469128.pdf

MDIC CfQ Forum 12082015 65

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Contact Information

CAPT Sean BoydActing Director, Office of Compliance301-796-5895sean.boyd@fda.hhs.gov

FDA Center for Devices and Radiological HealthOffice of ComplianceWhite Oak Building 6610903 New Hampshire AvenueSilver Spring, MD 20993

Questions?

Compliance Central with FDA Center Compliance Directors (Part II)

Mary Malarkey, Director, Office of Compliance and Biologics Quality, CBER

Cynthia Schnedar, Director, Office of Compliance, CDER

Sean Boyd, Acting Director, Office of Compliance, CDRH