FDA Perspective - High Prority Topics & Future Directions
Transcript of FDA Perspective - High Prority Topics & Future Directions
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FDA Perspective:FDA Perspective:High Priority Topics &High Priority Topics &
Future DirectionsFuture Directions
GPhA 2007 Fall Technical ConferenceGPhA 2007 Fall Technical Conference
October 10, 2007October 10, 2007
Deborah M. Autor, Esq.Deborah M. Autor, Esq.DirectorDirector
CDER Office of ComplianceCDER Office of Compliance
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OverviewOverview CDER OC Mission and VisionCDER OC Mission and Vision
FDA Modernization: Drug Quality for the 21FDA Modernization: Drug Quality for the 21stst CenturyCentury
Trends: Recalls, Manufacturing Sites and InspectionsTrends: Recalls, Manufacturing Sites and Inspections
Foreign InspectionsForeign Inspections
Raw Material ControlRaw Material Control FDAFDAs Pharmaceutical Ingredients Pharmaceutical Ingredient
Safety Task ForceSafety Task Force
Bioequivalence InspectionsBioequivalence Inspections Postmarketing Adverse Drug Experience (ADE)Postmarketing Adverse Drug Experience (ADE)
ReportingReporting
Marketed Unapproved Drugs InitiativeMarketed Unapproved Drugs Initiative
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MissionMission
Mission (purpose) of t he CDER Off iceMission (purpose) of t he CDER Off ice
of Complianceof Compliance::
To promote and protect public healthTo promote and protect public health
through strategies and actions thatthrough strategies and actions that
minimize consumer exposure to unsafe,minimize consumer exposure to unsafe,ineffective, and poor quality drugs.ineffective, and poor quality drugs.
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VisionVision
Vision (ambit ion) of t he CDER Off ice ofVision (ambit ion) of t he CDER Off ice ofComplianceCompliance::
Through excellence in riskThrough excellence in risk-- and scienceand science--based policy, surveillance, andbased policy, surveillance, andenforcement, we prevent consumerenforcement, we prevent consumer
exposure to unnecessary risk from drugsexposure to unnecessary risk from drugsthroughout their lifecycle.throughout their lifecycle.
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FDA Modernization:Drug Quality
for the 21st Century
FDA Modernization:FDA Modernization:
Drug QualityDrug Quality
for the 21for the 21stst CenturyCentury
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FDAFDAs Quality System Guidances Quality System Guidance
Result of the CGMP for the 21st CenturyResult of the CGMP for the 21st CenturyInitiativeInitiativefinalized August 2006finalized August 2006
Encourages the use of modern qualityEncourages the use of modern quality
management system for science basedmanagement system for science basedmanufacturingmanufacturing
Emphasizes self management of changeEmphasizes self management of change
Consistent with overall efforts to reduceConsistent with overall efforts to reducemanufacturing supplementsmanufacturing supplements -- 314.70 revisions314.70 revisions
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Pharmaceut ical Quali t yPharmaceut ical Quali t ySystems I CH Q10Systems I CH Q10
Three new letters to learn as we approach theThree new letters to learn as we approach theDesired State for pharmaceutical manufacturingDesired State for pharmaceutical manufacturing
in the 21in the 21stst Century:Century:
PQSPQSHow did we get here? Are there challenges ahead?How did we get here? Are there challenges ahead?
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I CH Qualit y VisionI CH Qualit y Vision -- 20032003 A new vision for ensuring product qualityA new vision for ensuring product quality
(Brussels, July 2003(Brussels, July 2003))
A harmonized pharmaceutical qualityA harmonized pharmaceutical quality systemsystemapplicable across theapplicable across the li fe cycleli fe cycleof the productof the productemphasizing anemphasizing an integratedintegratedapproach toapproach to qualityqualityr isk management and sciencer isk management and science
New ICH guidelines (high level guidelines,New ICH guidelines (high level guidelines,more visionary, less prescriptive, flexiblemore visionary, less prescriptive, flexibleregulatory approaches)regulatory approaches)
Pharmaceutical Development (Q8)Pharmaceutical Development (Q8) Quality Risk Management (Q9)Quality Risk Management (Q9)
Pharmaceutical Quality Systems (PQS) (Q10)Pharmaceutical Quality Systems (PQS) (Q10)
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I CH Qualit y VisionI CH Qualit y Vision PrePre--2003: quantitative guidance2003: quantitative guidance
PostPost--2003: strategic guidance2003: strategic guidance
Q8/Q9/Q10Q8/Q9/Q10
ExistingExisting GMPGMPss
Quality by Design
(PharmaceuticalDevelopment)
Quality Risk
Management
The Regulatory
Quality System
Quality
Systems
Quality
Systems
(Q10)
For companies with :1. Good design and
control strategies
2. Good Risk
Management strategies
3. Good Quality Systems
Quality Risk
Management
(Q9)
Quality
by Design
(Q8)
Reduced regulatory
burden:
Reduction of
submissions onchanges/variations
Inspection of quality
systems
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Pharmaceutical
Development
Technology
TransferManufacturing Discontinuation
GMP
Management Responsibilities
Process Performance & Product Quality monitoring
CAPA
Change Management
Management reviewPQS elements
Quality risk Management
Knowledge ManagementEnablers
ICH Q10 PQSICH Q10 PQSICH Q10 PQS
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Elements of a Robust Qualit y SystemElements of a Robust Qualit y System
1.1. ScienceScience--basedbasedapproachesapproaches
2. Decisions based on2. Decisions based on understanding productunderstanding products intended uses intended use
3. Proper identification and control of areas of3. Proper identification and control of areas ofpotentialpotential
process weaknessprocess weakness(including raw materials)(including raw materials)
4.4. Responsive deviation and investigation systemsResponsive deviation and investigation systemsthat lead tothat lead to
timely remediationtimely remediation
5. Sound methods for5. Sound methods for assessing riskassessing risk
6.6. WellWell--defined and designed processes and products,defined and designed processes and products, fromfrom
development through entire product life cycle.development through entire product life cycle.
7.7. Systems for careful analysesSystems for careful analysesof product qualityof product quality
8. Supportive management (philosophically and financially)8. Supportive management (philosophically and financially)
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Integration: CDER and ORAIntegration: CDER and ORA How do we more formally transfer our knowledge from
Qbd and Qbr from CDER (Review, Compliance) toORA? Create a knowledge transfer from Center toORA. Similar to technology transfer from R&D to
commercial
Final critical aspect of implementing desired state will berealized by new continuity between CDER and ORA
Inspectional role:
Follow-up on key areas suggested by Center Verify process implementation and state of control Assess lifecycle improvements Ensure adequate change control
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TrendsTrends
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Drug RecallsDrug Recalls
977 Recalls in FY 2007 (through 9/21)977 Recalls in FY 2007 (through 9/21)
Drug Recalls
178 162 145 187 168 130 169 128 103
100246
179236
154138
316
188
860
4
1615
15
2016
17
45
14
0
250
500
750
1000
1997 1999 2001 2002 2003 2004 2005 2006 2007
Fiscal Year
Numb
er
Class III Class II Class I
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Drug RecallsDrug RecallsAdjusted to account for multipleAdjusted to account for multiple--recall incidentsrecall incidents
Drug Recalls
178 162 145 187 168 130 169 128 103
100246
179236
154138
217188 189
4
1615
15
2016
922 14
0
250
500
750
1000
1997 1999 2001 2002 2003 2004 2005 2006 2007
Fiscal Year
Num
ber
Class III Class II Class I
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Establishment Evaluation RequestsEstablishment Evaluation Requests(EERs)(EERs)
The FD&C Act provides that FDA may notapprove an NDA or an ANDA if the facilities andcontrols used for the manufacture of the drugare inadequate.
The Office of Compliance serves a role forforeign establishments, similar to a district office
The site must be evaluated by Office ofThe site must be evaluated by Office of
Compliance with field input prior to approval viaCompliance with field input prior to approval viaproductproduct--specific PAI or based upon recent CGMPspecific PAI or based upon recent CGMPhistoryhistory
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Establishment Evaluation RequestsEstablishment Evaluation Requests(EERs)(EERs)
A recent look on a given day this summer in ourdata base found 231 generic foreignfacilities pending an inspection.
How will this challenge be met? Will the abilityto complete timely inspections become a limitingfactor in an already challenging generic drugapproval queue?
Up-to-date CGMP surveillance inspection resultscan help.
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EERs Submitted for NDAs and ANDAsEERs Submitted for NDAs and ANDAs
(Originals and Supplements)(Originals and Supplements)October 1, 2002October 1, 2002September 31, 2006September 31, 2006
34473569
27462622
3606
25852552
1928
1488
1856
0
500
1000
1500
2000
2500
3000
3500
4000
FY 02 FY 03 FY 04 FY 05 FY 06
Domestic Foreign
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Foreign InspectionsForeign Inspections
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Foreign Inspections by CountryForeign Inspections by Countryin FY 2007in FY 2007**
Switzerland
5%
Spain
5%
Japan
4%
China
4%
Others
31%
India22%
France
9%
Germany
7%
Canada
7%Italy
6%
*FY 2007 data current as of 9/25/07
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Foreign Inspection in FY 2007Foreign Inspection in FY 2007** bybyFirm TypeFirm Type
API
51%
Dosage
31%
Both
API/Dosage
7%Control Lab
10%
Others
1%
*FY 2007 data current as of 9/25/07
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FY 2007FY 2007** Inspections byInspections byType of InspectionType of Inspection
185
70
15
6 4
020
406080100
120140
160180200
P
reapproval/
Surveillance
P
reapproval
S
urveillance
F
orCause
T
herapeutic
Drug
*FY 2007 data ,
current as of 9/25/07
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Foreign InspectionsForeign InspectionsFiscal YearFiscal Yearss 20042004 -- 20072007**
33
27
32
31
87
57
61
70
20
24
25
25
104
137
135
140
0 50 100 150
FY 07
FY 06
FY 05
FY 04
API
DosageAPI/Dosage
Others
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Inspections in China and IndiaInspections in China and IndiaFY 2004FY 2004 FY2007*FY2007*
18
36
13
33
16
34
11
82
010
20
30
40
50
60
70
80
90
FY04
FY05
FY06
FY07
CHINA
INDIA
*FY 2007 data current as of 9/25/07
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Inspections in ChinaInspections in ChinaFY 2004FY 2004 -- 20072007**
18
13
16
11
0 5 10 15 20
FY 04
FY 05
FY 06
FY 07
*FY 2007 data current as of 9/25/07
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Inspections in China by Firm TypeInspections in China by Firm TypeFiscal YearFiscal Yearss 200420042007*2007*
1616
11
00
1515
FY 06FY 06
111113131818TotalTotal
000000Dosage ManufacturerDosage Manufacturer
110011API/Dosage ManufacturerAPI/Dosage Manufacturer
101013131717API ManufacturerAPI Manufacturer
FY 07*FY 07*FY 05FY 05FY 04FY 04FIRM TYPEFIRM TYPE
*FY 07 data current as of 9/25/2007
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Type of Manufacturing Facilities inType of Manufacturing Facilities inChinaChina
Intermediate
1%
Control Testing
Lab
2%
Dosage
1%
API/Dosage
4%
API
92%
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Common GMP Deficiencies inCommon GMP Deficiencies inChina FY 2006China FY 2006
Others
22%
Lab Controls
9%
Analytical
Methods
Validation
13%
Lab
Records/Reports
17%
Lack/Inadequate
SOPs
17%
Production
Records/Reports
22%
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Top Five Deficiencies in ChinaTop Five Deficiencies in ChinaFY 2007FY 2007**
3
2
2
2
2
0 1 2 3 4
Laboratory Controls
Analytical Method
ValidationProduction
Records/Reports
QA Systems
Equipment
Design/Qualification
*FY 2007 data current as of 9/25/07
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Inspections in IndiaInspections in IndiaFY 2004FY 2004 -- 20072007**
62
32
30
36
0 10 20 30 40 50 60 70
FY 07
FY06
FY 05
FY04
*FY 2007 data current as of 9/25/07
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Inspections in IndiaInspections in IndiaFiscal Year 2004Fiscal Year 2004 -- 20072007**
3434
11
1111
66
1616
FY 06FY 06
626233333636TotalsTotals
663333Contract LabContract Lab
14147766Dosage ManufacturerDosage Manufacturer
882222API/DosageAPI/Dosage
ManufacturerManufacturer
414121212525API ManufacturerAPI Manufacturer
FY 07FY 07FY 05FY 05FY 04FY 04FIRM TYPEFIRM TYPE
*FY 07 data current as of 9/25/2007
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Type of Manufacturing Facilities inType of Manufacturing Facilities inIndiaIndia
API
66%
Intermediate
1%
Control Testing
Lab9%
Dosage
19%
API/Dosage5%
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Common GMP Deficiencies inCommon GMP Deficiencies inIndia FY 2006India FY 2006
Others31%
QA Systems
4%
Equipment Design/
Qualification
4%
Stability Program
4%
Lab Records/Reports
6%
Failure/OOS
Investigations
4%
Equipment
Cleaning/Maintenanc
e, Cleaning
Validation
7%Lack/Inadequate
SOPs
9%
Process Validation
Study/Protocol
9%
Lab Controls
9%
Production
Records/Reports
13%
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Top Five GMP Deficiencies in IndiaTop Five GMP Deficiencies in IndiaFY 2007FY 2007**
14
11
10
9
8
0 5 10 15
Equipment
Cleaning/Maintenance,
Cleaning Validation
Lack of/Inadequated
SOPs
Equipment Design/
Qualification
Laboratory
Records/Reports
Laboratory Controls
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Raw Material ControlRaw Material ControlRaw Material Control
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DEG ContaminationDEG ContaminationDEG Contamination Scope of the Problem: Recurrent DEG poisoningScope of the Problem: Recurrent DEG poisoning
worldwide (resulting in hundreds of deaths)worldwide (resulting in hundreds of deaths)
20062006PanamaPanama
19951995--19961996HaitiHaiti
19901990--19981998Argentina, Bangladesh, India, andArgentina, Bangladesh, India, and
NigeriaNigeria 19371937United States (Elixir Sulfanilamide)United States (Elixir Sulfanilamide)
FDA issued guidance in May 2007FDA issued guidance in May 2007
to recommendto recommend
testing and other controls to avoid DEG contamination:testing and other controls to avoid DEG contamination:
Guidance for Industry: Testing of Glycerin forGuidance for Industry: Testing of Glycerin forDiethylene GlycolDiethylene Glycol
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Guidance on Testing Glycerinfor DEG
Guidance on Testing GlycerinGuidance on Testing Glycerinfor DEGfor DEG
Drug product manufacturers should:Drug product manufacturers should: Perform a specific identity test and a limit of detection testPerform a specific identity test and a limit of detection test
for DEG (the USP limit for DEG is 0.1%)for DEG (the USP limit for DEG is 0.1%)
Test all containers of all lotsTest all containers of all lots Use the identity tests described in the USP GlycerinUse the identity tests described in the USP Glycerin
Monograph, including the limit test for DEG, orMonograph, including the limit test for DEG, or
Use an equivalent test, such as the thinUse an equivalent test, such as the thin--layerlayerchromatography method published in the Journal ofchromatography method published in the Journal ofAOAC International Vol. 81, No. 1, 1998AOAC International Vol. 81, No. 1, 1998
Guidance on Testing GlycerinGuidance on Testing GlycerinGuidance on Testing Glycerin
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Guidance on Testing Glycerin
for DEG
Guidance on Testing GlycerinGuidance on Testing Glycerin
for DEGfor DEGHow you can prevent use of DEG-contaminated glycerin: Drug product manufacturers should know the supply chain for
glycerin including the component manufacturer and any
distributors. Identify reliable suppliers & know the actual source.
Manufacturers should ensure proper testing of glycerin forDEG and should make personnel aware of the importance of
testing and the potential hazards if testing is not done. Repackers, and others who distribute and prepare glycerin for use
in drug products, should test glycerin used, sold for use, orintended for use in drug products.
Pharmacies that use glycerin in compounding drug productsshould either test the glycerin for DEG content or ensure that suchtesting was properly done by a reliable supplier.
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FDAs Pharmaceut icalIngredient
Safety Task Force
FDAFDAs Pharmaceut icals Pharmaceut icalIngredientIngredient
Safety Task ForceSafety Task Force
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Pharmaceutical Ingredient SafetyPharmaceutical Ingredient SafetyTask ForceTask Force
DEG/glycerin incidents point out potential risksDEG/glycerin incidents point out potential riskswithin global supply chain for ingredientswithin global supply chain for ingredients
should take measures to anticipate and preventshould take measures to anticipate and prevent
similar occurrences with other imported ingredientssimilar occurrences with other imported ingredients
FDA formed task force in midFDA formed task force in mid--20072007
developed recommended action itemsdeveloped recommended action items
recommendations seem to be aligned withrecommendations seem to be aligned with PresidentPresidentss
Interagency Task ForceInteragency Task Force initial recommendationsinitial recommendations
regarding import safety publicized this monthregarding import safety publicized this month
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FDAFDAs Pharmaceutical Ingredients Pharmaceutical Ingredient
Safety Task ForceSafety Task Force
Task Force convened by CDERTask Force convened by CDERs Office ofs Office of
Compliance in May 2007 to: (cont.)Compliance in May 2007 to: (cont.)
define proactive steps to address risks posed bydefine proactive steps to address risks posed bysourcing poor quality, adulterated andsourcing poor quality, adulterated andmisbranded pharmaceutical raw materialsmisbranded pharmaceutical raw materials
and propose other specific ways to enhanceand propose other specific ways to enhance
FDAFDAs oversight of pharmaceutical ingredients oversight of pharmaceutical ingredientsafetysafety
f
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What can drug manufacturers do toWhat can drug manufacturers do to
prevent similar occurrence with anyprevent similar occurrence with anypharmaceutical ingredient?pharmaceutical ingredient?
Apply quality systems approach to monitor ingredient supplyApply quality systems approach to monitor ingredient supplychain integritychain integrity
Establish a robust supplier qualification program (e.g. audits,Establish a robust supplier qualification program (e.g. audits, qualityquality
agreements, appropriate ongoing QC of incoming lots)agreements, appropriate ongoing QC of incoming lots)
Only do business with trustworthy sourcesOnly do business with trustworthy sources
Verify each ingredient shipment comes from approvedVerify each ingredient shipment comes from approved
suppliers/manufacturerssuppliers/manufacturers
Verify shipments came through expected routes and were notVerify shipments came through expected routes and were notdiverted or tampered withdiverted or tampered with
Isolate ingredients that are suspected of being nonIsolate ingredients that are suspected of being non--genuine orgenuine or
mishandled or perhaps adulteratedmishandled or perhaps adulterated
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Bioequivalence (BE)
Inspections
Bioequivalence (BE)Bioequivalence (BE)
InspectionsInspections
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Bioequivalence (BE) InspectionsBioequivalence (BE) Inspections
Verify the quality and integrity ofVerify the quality and integrity ofin vivoin vivoandand in vitroin vitrobiopharmaceutics databiopharmaceutics data in vivoin vivostudiesstudies
pharmacokinetic BE studiespharmacokinetic BE studies
focus on 3 components: clinical, analytical, and statisticalfocus on 3 components: clinical, analytical, and statistical
clinical endpoint BE studiesclinical endpoint BE studies multimulti--site studies involving numerous clinicalsite studies involving numerous clinical
investigatorsinvestigators
in vitroin vitrostudiesstudies e.g., study nasal spray drug products for locale.g., study nasal spray drug products for local
actionaction
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BE Program FocusBE Program Focus
Audit studies pivotal to approval decisionsAudit studies pivotal to approval decisions generic and innovator drug productsgeneric and innovator drug products
PEPFAR applicationsPEPFAR applications
expedited review processexpedited review process many studies conducted outside U.S.many studies conducted outside U.S.
Address CDER reviewer concerns aboutAddress CDER reviewer concerns about
data integrity and study conductdata integrity and study conduct Investigate complaintsInvestigate complaints
allegations of improper study conduct, fraudallegations of improper study conduct, fraud
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Inspectional OversightInspectional Oversight
BE program monitors studies from multipleBE program monitors studies from multiplesourcessources
contract research organizations (CROs)contract research organizations (CROs)
sponsor facilitiessponsor facilities
clinical investigatorsclinical investigators
academic laboratoriesacademic laboratories
sites within and outside the U.S.sites within and outside the U.S.
inspections in India increasinginspections in India increasing
FY02, no BE inspections in IndiaFY02, no BE inspections in India
Since FY05, ~50 BE inspections in IndiaSince FY05, ~50 BE inspections in India
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Problem of Unreliable DataProblem of Unreliable Data
Some applications contain unreliable dataSome applications contain unreliable data failure to assure proper dosingfailure to assure proper dosing
study sample contamination not investigatedstudy sample contamination not investigated
failure to assure data accuracyfailure to assure data accuracy
failure to demonstrate accurate analytical methodsfailure to demonstrate accurate analytical methods
ConsequencesConsequences
FDA rejection of unreliable dataFDA rejection of unreliable data
unfavorable application outcomeunfavorable application outcome
can affect multiple applicationscan affect multiple applications
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For exampleFor examplerecent actionrecent action
Global CRO that conducts pharmacokineticGlobal CRO that conducts pharmacokineticstudies for many pharmaceutical companiesstudies for many pharmaceutical companies
Studies over a 4Studies over a 4--year period from 2 sites wereyear period from 2 sites werenot reliablenot reliable
These studies now must be audited or repeated,These studies now must be audited or repeated,or specimens must be reor specimens must be re--analyzedanalyzed
FDA notified affected sponsorsFDA notified affected sponsors
CDER will monitor followCDER will monitor follow--up to ensure thatup to ensure thatapprovals and pending applications reflect validapprovals and pending applications reflect validdatadata
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Inspectional FindingsInspectional Findings
Examples of deficiencies for generic BEExamples of deficiencies for generic BEstudies includestudies include
failure to follow protocols and SOPsfailure to follow protocols and SOPs
dosing and reserve sample issuesdosing and reserve sample issues method not adequately validatedmethod not adequately validated
inappropriate analytical run acceptanceinappropriate analytical run acceptance
inadequate record keepinginadequate record keeping
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Goal: Data Quality and IntegrityGoal: Data Quality and Integrity
Adherence to FDA regulations andAdherence to FDA regulations andguidance is keyguidance is key
Thoroughly planned and carefullyThoroughly planned and carefully
executed studies provide the bestexecuted studies provide the bestchance for successchance for success
DonDont ignore problemst ignore problems followfollow--up investigations are critical toup investigations are critical to
assure suitable study conclusionsassure suitable study conclusions
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Postmarketing Adverse
Drug Experience (ADE)Reporting
Postmarketing AdversePostmarketing Adverse
Drug Experience (ADE)Drug Experience (ADE)ReportingReporting
Postmarketing Adverse DrugPostmarketing Adverse Drug
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Postmarketing Adverse DrugPostmarketing Adverse Drug
Experience (ADE) ReportingExperience (ADE) Reporting FDA monitors ADE data reporting byFDA monitors ADE data reporting by
Rx & OTC firms:Rx & OTC firms: NDA/ANDA holdersNDA/ANDA holders
Manufacturers, packers, and distributors whoseManufacturers, packers, and distributors whose
names appear on drug labelsnames appear on drug labels Affiliates, marketing partners, and contractorsAffiliates, marketing partners, and contractors
Compliance assessed through riskCompliance assessed through risk--basedbased
inspections and surveillance ofinspections and surveillance ofsubmissionssubmissions
Postmarketing ADE ReportingPostmarketing ADE Reporting
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Postmarketing ADE ReportingPostmarketing ADE Reporting
(cont.)(cont.) New FD&C Act requirements for adverseNew FD&C Act requirements for adverse
event reporting:event reporting: Unapproved OTC and Dietary SupplementsUnapproved OTC and Dietary Supplements
Manufacturers, packers, and distributors whoseManufacturers, packers, and distributors whose
names appear on drug labelsnames appear on drug labels Contact information on labelContact information on label
All serious events reported within 15 daysAll serious events reported within 15 days
Guidance soon, effective December 23, 2007Guidance soon, effective December 23, 2007
Monitoring for compliance begins inMonitoring for compliance begins in
FY2008.FY2008.
Postmarketing ADE ReportingPostmarketing ADE Reporting
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5555
Postmarketing ADE Reportingg p g
(cont.)(cont.) FDA reviews:FDA reviews:
SubmissionsSubmissions Complete, Accurate, TimelyComplete, Accurate, Timely Postmarketing ADE dataPostmarketing ADE data
Initial and followup individual event reportsInitial and followup individual event reports
Periodic summary reportsPeriodic summary reports
Pharmacovigilance: Surveillance,Pharmacovigilance: Surveillance,Receipt, Evaluation, & ReportingReceipt, Evaluation, & Reporting Written proceduresWritten procedures
Actual performanceActual performance
Internal QC/QA and Corrective ActionsInternal QC/QA and Corrective Actions
Postmarketing ADE ReportingPostmarketing ADE Reporting
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5656
44
4946
49
66
57
26
33
22 2329
45
38
22
3 2
711
5 5
00
10
20
30
40
50
60
70
2001 2002 2003 2004 2005 2006 First Half
2007NAI VAI OAI
Postmarketing ADE ReportingPostmarketing ADE Reporting
ADE FY01ADE FY01-- FY06 inspect ional f indings:FY06 inspect ional f indings:
Postmarketing ADE ReportingPostmarketing ADE Reporting
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5757
30
19
9
5 4 3
30
1816
5 4 5
42
1916
4 3 2
0
5
10
15
20
25
30
35
40
45
Late
Reporting
Written
Procedures
Non-
Reporting
No
Followup
Incomplete
Inaccurate
Other
2004 2005 2006
Postmarketing ADE ReportingPostmarketing ADE Reporting
Cit ed Def iciencies by Category/ Year:Cit ed Def iciencies by Category/ Year:
P t k ti ADE R tiPostmarketing ADE Reporting
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5858
Postmarketing ADE ReportingPostmarketing ADE Reporting
(cont.)(cont.)
Generic Firms should anticipateGeneric Firms should anticipatereceiving increased postmarket ADEreceiving increased postmarket ADEdata and subsequent FDA monitoring.data and subsequent FDA monitoring.
Regulatory Actions vsRegulatory Actions vs
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5959
Regulatory Actions vs.Regulatory Actions vs.
Corrective ActionsCorrective Actions
Regulatory Action: Legal authority toRegulatory Action: Legal authority toact to remove the risk by terminating aact to remove the risk by terminating aperformance which creates a risk, soperformance which creates a risk, sothat the harmful outcome of thethat the harmful outcome of the
process is not produced. This mayprocess is not produced. This maystop, but may not correctstop, but may not correctnoncompliance.noncompliance.
Regulatory Actions vsRegulatory Actions vs
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6060
Regulatory Actions vs.Regulatory Actions vs.
Corrective ActionsCorrective Actions
Corrective Actions: Identification andCorrective Actions: Identification andreduction of risk by modifying thereduction of risk by modifying theperformance that may create a risk, soperformance that may create a risk, sothat the beneficial outcome of thethat the beneficial outcome of the
process can continue to be obtained.process can continue to be obtained. Improve the process to improve theImprove the process to improve the
productproduct
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6161
Quality ImprovementQuality Improvement
Development and Implementation ofDevelopment and Implementation ofCorporate Quality Assurance andCorporate Quality Assurance andCorrective Action can prevent nonCorrective Action can prevent non--compliance.compliance.
Development and Implementation ofDevelopment and Implementation ofQuality Assurance and CorrectiveQuality Assurance and CorrectiveActions can avert subsequentActions can avert subsequentregulatory action.regulatory action.
Regulatory Meetings
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6262
Regulatory MeetingsRegulatory Meetings
A meeting requested by FDA management toA meeting requested by FDA management to
inform responsible individuals or firms aboutinform responsible individuals or firms about
how products, practices, processes, or otherhow products, practices, processes, or other
activities violate the lawactivities violate the law
A tool to obtain prompt voluntary complianceA tool to obtain prompt voluntary compliance
As a followAs a follow--up to a Warning Letter (WL) when firmsup to a Warning Letter (WL) when firms
have not corrected all significant violationshave not corrected all significant violations
To achieve voluntary correction more quickly thanTo achieve voluntary correction more quickly than
through written communication or legal remediesthrough written communication or legal remedies In conjunction with a WL to emphasize theIn conjunction with a WL to emphasize the
significance of violationssignificance of violations
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6363
Marketed UnapprovedMarketed Unapproved
Drugs InitiativeDrugs Initiative
Marketed Unapproved DrugsMarketed Unapproved Drugs
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Marketed Unapproved DrugsMarketed Unapproved Drugs
InitiativeInitiative
Improve the safety and effectiveness ofImprove the safety and effectiveness of
the nationthe nations drugss drugs Encourage companies to comply with theEncourage companies to comply with the
drug approval process, while minimizingdrug approval process, while minimizing
disruption to the marketplacedisruption to the marketplace
Provide notice that any product that isProvide notice that any product that is
being marketed illegally without approvalbeing marketed illegally without approvalis subject to FDA enforcement at any timeis subject to FDA enforcement at any time
Marketed Unapproved DrugsMarketed Unapproved Drugs
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Initiative (cont.)Initiative (cont.) June 2006June 2006Compliance Policy Guide onCompliance Policy Guide on
marketed unapproved drugs explainsmarketed unapproved drugs explainsFDAFDAs risks risk--based enforcementbased enforcement Drugs with potential safety risksDrugs with potential safety risks
Drugs that lack evidence of effectivenessDrugs that lack evidence of effectiveness
Fraudulent drugsFraudulent drugs Unapproved drugs that directly compete with anUnapproved drugs that directly compete with an
approved drugapproved drug
Drugs from firms that otherwise violate the ActDrugs from firms that otherwise violate the Act((e.g.e.g., GMP or ADE reporting violations), GMP or ADE reporting violations)
Drugs with formulation changes made as aDrugs with formulation changes made as apretext to avoid enforcementpretext to avoid enforcement
Marketed Unapproved DrugsMarketed Unapproved Drugs
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Initiative (cont.)Initiative (cont.)ClassClass--Wide Actions:Wide Actions:
HydrocodoneHydrocodone Drug Products (SeptemberDrug Products (September2007)2007)
TimedTimed--ReleaseRelease GuaifenesinGuaifenesin Drug ProductsDrug Products(May 2007)(May 2007)
Suppository Products ContainingSuppository Products ContainingTrimethobenzamideTrimethobenzamide (April 2007)(April 2007)
ErgotamineErgotamine Drug ProductsDrug Products Warning LettersWarning Letters
(March 2007)(March 2007) Quinine SulfateQuinine Sulfate Drug ProductsDrug Products (December(December
2006)2006)
CarbinoxamineCarbinoxamine Drug ProductsDrug Products (June 2006)(June 2006)
Marketed Unapproved DrugsMarketed Unapproved Drugs
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Marketed Unapproved DrugsMarketed Unapproved Drugs
Initiative (cont.)Initiative (cont.)Enforcement ActionsEnforcement Actions -- Specific FirmsSpecific Firms
Syntho/ I ntermaxSyntho/ I ntermax GMP violations and unapproved drugsGMP violations and unapproved drugs
Consent decreeConsent decree
Pharmakon LabsPharmakon Labs
GMP violations and unapproved drugsGMP violations and unapproved drugs
CourtCourt--ordered injunctionordered injunction
PharmaFabPharmaFab
GMP violations and unapproved drugs (longGMP violations and unapproved drugs (longhistory of poor manufacturing practices withhistory of poor manufacturing practices withrepeated failure to institute appropriate correctiverepeated failure to institute appropriate correctiveaction)action)
Consent decreeConsent decree
Marketed Unapproved DrugsMarketed Unapproved Drugs
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pp g
Initiative (cont.)Initiative (cont.) EducationEducation
Comprehensive information available on FDAComprehensive information available on FDAss
Unapproved Drugs web siteUnapproved Drugs web sitehttp://www.fda.gov/cder/drug/unapproved_drugs/default.htmhttp://www.fda.gov/cder/drug/unapproved_drugs/default.htm
Marketed Unapproved Drugs WorkshopMarketed Unapproved Drugs Workshop
(January 2007), Docket # 2003D(January 2007), Docket # 2003D--04780478 Educated firms (especially small firms) on how to obtainEducated firms (especially small firms) on how to obtain
approval for their unapproved productsapproval for their unapproved products
Responded to frequently asked questionsResponded to frequently asked questions Participants from more than 150 companiesParticipants from more than 150 companies
We hope that education and incentives will reduce theWe hope that education and incentives will reduce the
need for enforcementneed for enforcement
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SummarySummary Risk-Based
Strategic
Maximizing our impact on the public health
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