Transcript Slides

Compliance Central with FDA Center
Compliance Directors (Part II)
Mary Malarkey, Director, Office of Compliance and Biologics
Quality, CBER
Enforcement
Litigation and
Compliance
Washington,
DC
December 910, 2015
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 Update
FDLI Enforcement, Litigation and Compliance
Conference
December 9, 2015
Mary Malarkey, Director
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research/FDA
Office of Compliance and
Biologics Quality
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
4
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
5
Rules and Guidance: Update
6
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.”
7
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)).
8
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.”
10
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.
12
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).”
13
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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Same surgical procedure exception
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”
Minimal Manipulation
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
Autologous adipose tissue
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
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
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceCompl
ianceRegulatoryInformation/Guidances/Tissue/UCM469751.pdf
18
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-35810001
• FDA will have a public hearing on April 13, 2016 to obtain
input on all four draft guidances.
19
Some Current Priorities
20
Program Alignment
• With ORA, working through commitments
in FY2015 Biologics Action Plan and
developing FY2016 plan.
http://www.fda.gov/aboutfda/centersoffic
es/ucm392733.htm
• Target areas are specialization, training,
work planning, compliance and
enforcement, and imports
21
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
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
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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: [email protected]
Phone: 301-827-3821
Manufacturers Assistance and Technical Training Branch
(MATTB)
Email: [email protected]
Phone: 301-827-4081
Follow us on Twitter
https://www.twitter.com/fdacber
25
2015 FDLI Enforcement
Conference
Compliance Update
Cynthia Schnedar, J.D.
Director, CDER Office of Compliance
December 9, 2015
Washington, DC
One Quality Voice
• For Drugs
• For Patients
• For Industry
• For Healthcare Professionals
• For Healthcare Purchasers
27
Priorities
CDER reorganization
Program alignment
Implementing legislative authorities
Compliance and enforcement actions
Track & trace
Compounding
28
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 Actions
January to October 2015
January to
October 2015
Import Alerts, 18
Warning Letters,
16
Untitled Letters, 5
Import Alerts, 18
Warning Letters, 16
Untitled Letters, 5
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
• 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.
33
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/GuidanceComplianceRegulatory
Information/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 I: The
Compounding
Quality Act
Title II: Drug
Supply Chain
Security Act
(DSCSA)
Product Tracing
Wholesale
Distributor and
3PL Licensing
and Standards
• 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/falselylabelled/falsified/counterfeit
(SFFC) medicines
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• Recalls
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
Office of Scientific Investigations
(OSI) Activities
• 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 (cont’d)
• 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
FY2014 OSI Warning Letters &
Disqualifications
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5
3
1
1
2
Compliance Central
Center for Devices and Radiological Health
CAPT Sean M. Boyd, MPH, USPHS
Acting Director
Office of Compliance
CDRH Office of Compliance
Division of Manufacturing and
Quality
Bill MacFarland
Deputy Director for Regulatory
Affairs
CDR Kristina Donohue (acting)
Director
CAPT Sean Boyd (acting)
Deputy Director for Medical
Affairs
Kimber Richter, MD
FDLI LEC 12/09/2015
Division of International
Compliance Operations
Carl Fischer
Division of Premarket Labeling
Compliance
Keisha Thomas (acting)
Division of Bioresearch
Monitoring
CAPT Jim Saviola, OD
Division of Analysis and
Program Operations
Ann Ferriter
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/cdrhtr
ansparency/ucm471117.pdf
FDLI LEC 12/09/2015
CY2014 Top 10 Foreign Inspection Locations
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
FDLI LEC 12/09/2015
16
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
QS Subsystem
# of
Observations
Percentage
P&PC
1,197
32%
CAPA
1,148
31%
DES
515
14%
MGMT
497
13%
DOC
383
10%
http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacc
o/cdrh/cdrhtransparency/ucm471117.pdf
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 in 483s and in WLs
QS Subsystem
# of Citations
Percentage
CAPA
262
34%
P&PC
254
33%
DES
121
16%
MGMT
74
10%
DOC
63
8%
http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cdrh/cdrhtr
ansparency/ucm471117.pdf
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
QS Subsystem
# of
Observations
Percentage
P&PC
1,197
32%
CAPA
1,148
31%
DES
515
14%
MGMT
497
13%
DOC
383
10%
http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cdrh/cdrhtr
ansparency/ucm471117.pdf
FDLI LEC 12/09/2015
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/cdrhtr
ansparency/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
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
FDLI LEC 12/09/2015
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, postapproval inspections not affected
• Pilot through December 2016,
implementation in 2017
FDLI LEC 12/09/2015
52
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
53
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
54
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
inventory
FDLI 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/ucm
378185.htm
• Future approach to emphasize patient safety and
product quality
– Shared goal among stakeholders
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/MedicalDeviceQualityandCompliance/ucm
378185.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 characteristic
Impact
of failure
Control
Reference to 820
Reference to QSIT
MDIC CfQ Forum 12082015
63
Critical to Quality Documents
CtQ 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/medicaldevicequal
ityandcompliance/ucm469128.pdf
MDIC CfQ Forum 12082015
65
Contact Information
CAPT Sean Boyd
Acting Director, Office of Compliance
301-796-5895
[email protected]
FDA Center for Devices and Radiological Health
Office of Compliance
White Oak Building 66
10903 New Hampshire Avenue
Silver Spring, MD 20993
66
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