Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
35th BRAZILIAN CONGRESS OF
35th BRAZILIAN CONGRESS OF
PHARMACEUTICAL MEDICINE
PHARMACEUTICAL MEDICINE
GCP
GCP
inspections
inspections
in Brazil
in
Brazil
:
:
ANVISA
ANVISA´
´
s perspective
s perspective
RICARDO ECCARD DA SILVA Coordination of Researches, Clinical Trials and New Drugs – COPEM General Office of Drugs – GGMED
1
1 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
National
National
Health
Health
Surveillance
Surveillance
Agency
Agency
Anvisa's
Anvisa's
Mandate
Mandate
"To protect and promote the
"To protect and promote the
population`s
population`s
health, ensuring the
health, ensuring the
sanitary safety of products and
sanitary safety of products and
services and taking part in developing
services and taking part in developing
access to it."
access to it."
2
2
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Organization
Organization
Chart
Chart
General Office of Drugs
3
3 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
What
What
we
we
do
do
at
at
COPEM
COPEM
AssessmentAssessmentofofclinicalclinicaltrialtrialprojectsprojects;;
ControlControlofofproductsproductsimportationimportationfor for researchresearch involving
involvinghumanhumanbeingbeing;;
ExpandedExpandedaccessaccessandandcompassionatecompassionateuse;use;
Inspection
Inspection
of
of
clinical
clinical
research
research
sites.
sites.
4
4
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
LAW 6360/76
LAW 6360/76 --SANITARY SURVEILLANCESANITARY SURVEILLANCE
REGULATION FOR BIOMEDICAL
REGULATION FOR BIOMEDICAL
RESEARCH IN HUMAN SUBJECTS
RESEARCH IN HUMAN SUBJECTS
RDC 39/08 Clinical Trial CNS 196/1996 Biomedical Research in Human CNS 292/99 International Cooperation CNS 301/00 Placebo RDC 26/99 Expanded access RDC 305/02 BSE RDC 68/03 BSE R CNS 346/05 CEP-CONEP CNS 251/1997 New Medicines CNS 340/04 Human Genetics RDC 81/08 Importation IN. 04/2009 5 5 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
REGULATORY FRAMEWORK FOR CLINICAL TRIALS REGULATORY FRAMEWORK FOR CLINICAL TRIALS
RDC 39/2008 RDC 39/2008
Approves the RULES FOR THE CONDUCT OF Approves the RULES FOR THE CONDUCT OF
CLINICAL RESEARCH among other provisions.
CLINICAL RESEARCH among other provisions.
Article 5: This rule applies to all clinical research Article 5: This rule applies to all clinical research
with drugs and medical devices (research
with drugs and medical devices (research
involving therapeutic interventions or diagnostic
involving therapeutic interventions or diagnostic
not registered in Brazil) phases I, II and III and it
not registered in Brazil) phases I, II and III and it
may support, in ANVISA, the record or any
may support, in ANVISA, the record or any
change post
change post--marketing, considering the current marketing, considering the current
sanitary standards and for which it requires the
sanitary standards and for which it requires the
assessment of ANVISA and subsequent
assessment of ANVISA and subsequent
issuance of CE (Approval Document).
issuance of CE (Approval Document).
6
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
REGULATORY FRAMEWORK FOR CLINICAL TRIALS REGULATORY FRAMEWORK FOR CLINICAL TRIALS
RDC 39/2008 RDC 39/2008
ArticleArticle66°°. : . :
This rule does not apply to
This rule does not apply to
studies of Bioavailability and
studies of Bioavailability and
Bioequivalence.
Bioequivalence.
7
7 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
REGULATORY FRAMEWORK FOR CLINICAL TRIALS REGULATORY FRAMEWORK FOR CLINICAL TRIALS
RDC 39/2008 RDC 39/2008
Article Article88ºº§§22°°
The ANVISA may, during the conduction of
The ANVISA may, during the conduction of
a clinical research, request more
a clinical research, request more
information to those responsible for its
information to those responsible for its
implementation or monitoring, and conduct
implementation or monitoring, and conduct
inspections at the sites, checking the
inspections at the sites, checking the
degree of adherence to current Brazilian
degree of adherence to current Brazilian
legislation and the Good Clinical Practices
legislation and the Good Clinical Practices
(Document of Americas
(Document of Americas
-
-
Good Clinical
Good Clinical
Practices).
Practices).
8
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Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
REGULATORY FRAMEWORK FOR CLINICAL TRIALS REGULATORY FRAMEWORK FOR CLINICAL TRIALS
RDC 39/2008 RDC 39/2008
Article 14
Article 14
°
°
Penalties: Failure to comply
Penalties: Failure to comply
with the provisions of this resolution leads
with the provisions of this resolution leads
to sanitary violation, the violator shall be
to sanitary violation, the violator shall be
subject to penalties stipulated in Law
subject to penalties stipulated in Law
6.437/77.
6.437/77.
9
9 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br Normative
NormativeStatementStatementNNºº4, 4, MayMay1111th, 2009, 2009
GUIDELINE FOR INSPECTION IN GOOD
GUIDELINE FOR INSPECTION IN GOOD
CLINICAL PRACTICES
CLINICAL PRACTICES
To harmonize
To harmonize andandguideguidethetheproceduresproceduresfor for inspectioninspection
of
ofgoodgoodclinicalclinicalpracticespractices, in , in orderorderto to promotepromote
regulatory
regulatoryactionactionononsanitarysanitarysurveillancesurveillance, to , to ensureensure
a
a unifiedunifiedstandard standard andandsecuritysecurityofofallallpartiesparties involved
involved..
10
10
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br Normative
NormativeStatementStatementNNºº4, 4, MayMay1111th, 2009, 2009
Stages
Stages
of
of
the
the
inspection
inspection
:
:
Communication Communication fromfromthetheinspectioninspectionto to thethe
sponsor
sponsor/ CRO / CRO andandPI PI
OpeningOpeninginterview interview
Interview Interview withwiththethestudystudyteamteam Study Records Review
Other records and site facilities Concluding the inspection
11
11 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Normative
Normative
Statement
Statement
N
N
º
º
4,
4,
May
May
11
11
th, 2009
, 2009
In In routineroutineinspectioninspectionits its notificationnotificationwillwillbebesentsent 15
15 daysdaysin in advanceadvance. .
In In thethecase case ofofcomplaintcomplaintororsuspectedsuspected
irregularities
irregularitiesthetheinspectioninspectionwillwilloccuroccurwithoutwithout
notice
notice..
TheTheinspectionsinspectionswillwillbebedirecteddirectedto to researchresearchandand clinical
clinicaltrialstrials, , therethereis no site is no site certificationcertification..
12
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Normative
Normative
Statement
Statement
N
N
º
º
4,
4,
May
May
11
11
th, 2009
, 2009
Inspection
Inspection
in
in
up
up
to
to
five
five
workdays
workdays
;
;
Inspection
Inspection
Report
Report
;
;
Sponsor
Sponsor
must
must
provide
provide
relevant
relevant
documention
documention
requested
requested
by
by
Anvisa
Anvisa
up
up
to 30
to 30
days
days
;
;
Final
Final
Report
Report
of
of
the
the
inspection
inspection
( ANVISA ).
( ANVISA ).
1313 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br Normative
NormativeStatementStatementNNºº4, 4, MayMay1111th, 2009, 2009
Anvisa'sAnvisa'senforcement in cases of inappropriate enforcement in cases of inappropriate
conduct of Clinical Trials
conduct of Clinical Trials::
temporarytemporaryinterruptioninterruptionofofthetheClinicalClinicalTrial;Trial;
suspensionsuspensionofofInvestigator'sInvestigator'sactivitiesactivities; ;
thethedefinitivedefinitivecancellationcancellationofofclinicalclinicalresearchresearchatat
the
thesite site andand/ / oror
thethedefinitivedefinitivecancellationcancellationofofclinicalclinicalresearchresearchin in all
allsites in sites in BrazilBrazil. .
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14
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Studies
Studies
/Sites
/Sites
Selection
Selection
Studies
Studies
/Sites
/Sites
haven
haven
´
´
t
t
inspected
inspected
by
by
others
others
agencies.
agencies.
Number
Number
of
of
subjects
subjects
included
included
.
.
number
number
of
of
serious
serious
adverse
adverse
events
events
notified
notified
.
.
complexity
complexity
of
of
the
the
study
study
.
.
Requests
Requests
of
of
others
others
Anvisa
Anvisa
´
´
s
s
area
area
, CEP
, CEP
or
or
CONEP.
CONEP.
other
other
criteria
criteria
.
.
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15 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
INSPECTION GUIDELINE
INSPECTION GUIDELINE
A.
A.
Facilities
Facilities
A.1 A.1 ––ReceptionReception
A.2 A.2 --OfficesOffices
A.3 A.3 ––WardWardroomroom
A.4 A.4 ––PharmacyPharmacy
A.5 A.5 ––TechnicalTechnicalFacilitiesFacilities
A.6 A.6 --WasteWasteManagementManagement
A.7 A.7 --ArchiveArchive
B.
B.
Quality
Quality
assurance
assurance
System
System
16
16
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
INSPECTION GUIDELINE
INSPECTION GUIDELINE
DOCUMENTS
DOCUMENTS
C.1
C.1. . Before the Clinical Phase of the Trial
Commences
C.1.1 General C.1.1 General DocumentsDocuments
InformedInformedConsentConsentFormFormsignedsigned;;
Case Case ReportReportFormForm(CRF)(CRF)
EthicalEthicalandandregulatoryregulatoryapprovalsapprovals;;
ListListofofsignatures signatures andandrespectiverespectiveteamteamidentificationidentification
C.1.2 Standard C.1.2 Standard OperatingOperatingProceduresProcedures(SOP) (SOP)
C.1.3 C.1.3 TechnicalTechnicalFacilitiesFacilities
C.1.4 C.1.4 InvestigationalInvestigationalProductProduct(IP)(IP)
17
17 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
INSPECTION GUIDELINE
INSPECTION GUIDELINE
DOCUMENTS
DOCUMENTS
C.2.
C.2.
During the Clinical Conduct of the Trial
C.2.1 General
C.2.1 General DocumentsDocuments+ C.1+ C.1
Source Source documentsdocuments;;
Case Case ReportReportFormForm(CRF)(CRF)
RecruitmentRecruitmentRowRowofofsubjectssubjects; ;
SubjectsSubjectsRowRowincludedincluded
AmendmentsAmendments
ProtocolProtocolViolationsViolations
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Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
INSPECTION GUIDELINE
INSPECTION GUIDELINE
DOCUMENTS
DOCUMENTS
C.3.
C.3. After completion or Termination of
the Trial
C.1 + C.2 C.1 + C.2
C.3.1 General C.3.1 General DocumentsDocuments
StudyStudyFinal Final ReportReport;;
InvestigationalInvestigationalProductProductfinal final destinationdestination;;
MonitoringMonitoringReportReport;;
ProductsProductsaccountabilityaccountability..
19
19 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Classification of inspection
findings
Critical
Critical
"C":
"C":
(critical): Observations classified as
critical may affect the rights, safety or well
being of the subjects, lead to death, life
threatening and/or the quality and integrity
of data (including studies started without
authorization, fraud...)
20
20
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Examples
Examples
Is
Is
There
There
regulatory
regulatory
approval
approval
for
for
the
the
study
study
?
?
Was
Was
there
there
a
a
team
team
training
training
on
on
the
the
protocol
protocol
of
of
the
the
study
study
?
?
Were
Were
changes
changes
/
/
corrections
corrections
in
in
the
the
CRF
CRF
performed
performed
according
according
to
to
Good
Good
Clinical
Clinical
Practice
Practice
? (
? (
dated
dated
,
,
initialed
initialed
and
and
without
without
masking
masking
the
the
original
original
records
records
)?
)?
21
21 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Classification of inspection
findings
Major "M"
Major "M"
Observations
Observations
that
that
may
may
affect
affect
sujects
sujects
health
health
or quality and integrity of data.
or
22
22
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Examples
Examples
Is there evidence that the sponsor monitors the study?
Was the monitoring plan followed? Were adverse events and serious adverse events reported in accordance with regulatory requirements?
Was the monitoring visit dated and recorded?
23
23 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Classification of inspection
findings
Minor
Minor
"Me":
"Me":
Observations
Observations
that
that
aren
aren
´
´
t
t
critical
critical
or
or
major,
major,
but
but
show
show
violations
violations
and
and
/
/
or
or
deficiencies
deficiencies
.
.
24
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Examples
Examples
Are the cleanliness and comfort of the area adequate to attend the research subjects?
Is access to reception appropriate for the type of study population (infants, wheelchair)?
Is there a receptionist trained to have the first contact with potential research subjects?
25
25 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Classification of inspection
findings
Informative
Informative
"INF":
"INF":
Descriptive
Descriptive
Observations
Observations
and
and
/
/
or
or
additional
additional
.
.
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Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Examples
Examples
Is
Is
the
the
receptionist
receptionist
who
who
feeds
feeds
the
the
database
database
with
with
basic
basic
information
information
about
about
the
the
research
research
subject
subject
?
?
Is
Is
the
the
technical
technical
facilities
facilities
located
located
in
in
the
the
research
research
site?
site?
27
27 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Inspections
Inspections
in 2009
in 2009
ThreeThreeinspectionsinspectionshavehavedonedoneuntiluntiloctoberoctober..
CONEP CONEP membermembertogethertogetherwithwithAnvisaAnvisa..
FollowFollow--upupFDA/EMEA FDA/EMEA inspectionsinspections..
TECHNICAL COOPERATION WITH CECMED TECHNICAL COOPERATION WITH CECMED
(CUBA) ON THE GCP INSPECTION
(CUBA) ON THE GCP INSPECTION
PROGRAM.
PROGRAM.
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28
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Inspections
Inspections
in 2009
in 2009
SOME FINDINGSSOME FINDINGS
TheTheofficesofficesroomsroomsdondon´´t t alowalowthetheprivacyprivacyofofthethesujectssujects
to
to getgetthetheinformedinformedconsentconsent..
TheTheresearchresearchsujectssujectsdidndidn´´t t receivereceivea a copycopyofofthethe
informed informedconsentconsent..
TheThedocumentsdocumentsofofcertificationcertification, , calibrationcalibration, , validationvalidation
and
andqualityquality, , guideguideandandSOPSOP’’ssequipmentsequipments//instrumentsinstruments weren
weren´´t t availableavailable..
29
29 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Inspections
Inspections
in 2009
in 2009
SOME FINDINGSSOME FINDINGS
TheTheinvestigationalinvestigationalproductproductwerenweren´´t t storedstoredatatthethe
pharmacy
pharmacy..
ArchiveArchiveroomroomwithoutwithoutmanagement, management, organizationorganization, ,
control
controlandandsafetysafetyofofdocumentsdocuments..
LackLackofofmonitoringmonitoringplanplan..
30
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Inspections
Inspections
in 2009
in 2009
SOME FINDINGSSOME FINDINGS
Some time Some time membersmemberswerenweren´´t t trainedtrainedfor for thethe
protocol
protocol..
LackLackofofSOPSOP’’ssandandits training its training rowsrows..
LackLackofofqualityqualitymanagement system.management system.
LackLackofofinteractioninteractionwithinwithinthetheteamteam..
31
31 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Inspections
Inspections
in 2009
in 2009
MAIN RECOMMENDATIONSMAIN RECOMMENDATIONS
ImplementationImplementationofofqualityqualitymanagement system management system withwith
flowcharts, SOP,
flowcharts, SOP, indicatorsindicators, , qualityqualitymanualsmanuals. . TheTheactivitiesactivities and
andresponsabilitiesresponsabilitiesofofthethequalityqualitymanagement management teamteam members
membersmustmustbebewellwelldefineddefined. .
“The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s)” ((Document of Americas Document of Americas --Good Good Clinical Practices)
Clinical Practices)
32
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Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Inspections
Inspections
in 2009
in 2009
MAIN RECOMMENDATIONSMAIN RECOMMENDATIONS
““The investigational product(s) should be stored
as specified by the sponsor and in accordance with applicable regulatory requirement(s)..””
(
(Document of Americas Document of Americas --Good Clinical Practices)Good Clinical Practices)
““The investigator should ensure that the investigational product(s) are used only in accordance with the approved protocol..””((Document of Americas Document of Americas --Good Clinical Good Clinical Practices)
Practices)
33
33 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Inspections
Inspections
in 2009
in 2009
MAIN RECOMMENDATIONSMAIN RECOMMENDATIONS
““When allowed/required, the investigator/institution may/should assign some or all of the
investigator's/institution’s duties for investigational product(s) accountability at the trial site(s) to an appropriate pharmacist or another appropriate individual who is under the
supervision of the investigator/institution”” ((Document of Document of Americas
Americas --Good Clinical Practices)Good Clinical Practices)
TheThedocumentsdocumentsofofcertificationcertification, , periodicperiodiccalibrationcalibration, ,
validation
validationandandqualityquality, , guideguideandandSOPSOP’’ss equipments
equipments//instrumentsinstrumentsmustmustbebeavailableavailable..
34
34
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Inspections
Inspections
in 2009
in 2009
MAIN RECOMMENDATIONSMAIN RECOMMENDATIONS
“Before participating in the study, the subject or his legally authorized representative should receive a copy of the signed and dated informed consent form and any other written information furnished during the process.”
(
(Document of Americas Document of Americas --Good Clinical Practices)Good Clinical Practices)
“Recording, handling, and storage of all clinical trial information should be appropriate to allow accurate trial reporting, interpretation and verification” ((Document of Document of Americas
Americas --Good Clinical Practices)Good Clinical Practices)
35
35 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Inspections
Inspections
in 2009
in 2009
MAIN RECOMMENDATIONS MAIN RECOMMENDATIONS
“A written monitoring plan should be available”
(Document of Americas Document of Americas --Good Clinical Good Clinical
Practices)
Practices)
“Ensuring that the investigator and the
investigator's trial staff are adequately informed about the trial”(Document of Americas Document of Americas -
-Good Clinical Practices)
Good Clinical Practices)
36
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Inspections
Inspections
in 2009
in 2009
MAIN RECOMMENDATIONSMAIN RECOMMENDATIONS
“Make provision for the maintenance of confidentiality, not only by Inspectors but also by any other person who gain access to confidential information as a result of GCP Compliance Monitoring activities”(Document of Americas Document of Americas
--Good Clinical Practices)Good Clinical Practices)
“The investigator can only delegate duties/activities but not responsibilities; and occasionally, when initiate or conduct the study with no other sponsor, the investigator can also be responsible as sponsor” (Document of Americas -Document of Americas -Good Clinical Practices)
Good Clinical Practices)
37
37 Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Inspections
Inspections
in 2009
in 2009
MAIN RECOMMENDATIONS MAIN RECOMMENDATIONS
“The investigator should ensure that all persons assisting with the trial are adequately informed about the protocol, the investigational product(s), and their trial-related duties and functions”(Document of Americas Document of Americas --Good Clinical Good Clinical Practices)
Practices)
“Training of the study participants should be documented including: the name of the staff persons trained, procedures and dates”(Document of Americas -Document of Americas -Good Good Clinical Practices)
Clinical Practices)
38
38
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Central de atendimento
Central de atendimento
ANVISA
ANVISA
0800 642 9782
0800 642 9782
www.anvisa.gov.br
www.anvisa.gov.br
Thank you for your attention!
39