Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
PharmacovigilanceInteraction with the Regulatory Agency
SalvadorSeptember 26, 2006
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Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Post-MarketingEvaluation
CancerCancer
Idiosyncratics eventsIdiosyncratics events
Licencing
Unexpected effects in some patientsUnexpected effects in some patients
ToxicityToxicity
Pre-MarketingEvaluation
Phase I Phase II Phase IIIPhase I Phase II Phase III
Clinical Trials Pharmacovigilance
Drug Safety Knowledge
Time
Drug Safety Knowledge is gained either by experience, learningand perception or through associationand reasoning
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
• More than 130 pharmaceutical products havebeen withdrawn from various markets over thepast 40 years– 1/3 within two years of launch;– 50% within 5 years.
• The most frequent problems are: ADRshepatic, hematological and cardiovascular complications
Source: Management of Safety Information from Clinical Trials. Report of CIOMS Working Group VI. 2005. p. 22
World safety facts about medicinesWorld safety facts about medicines
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Cerivastatin and RhabdomyolysisAugust 2001
Rofecoxib and Cardiovascular effectsOctober 2004
Time
Voluntary withdrawn from the market for safety reasons (e.g)
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Why drug safety issues may not be indentifieduntil the post-marketing periode?
1. The adverse reaction is rare and thereforeundetectable until large number of patientshave been exposed to the drug
2. There is a long latency between starting thedrug and development of the adverse reaction
3. The drug has not been studies in normal clinical practice
Source: Waller PC, Arlett P. Responding to signals. In: Pharmacovigilance. Mann R, Andrews E, editors. Wiley Chicester 2002
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
WHO Pharmacovigilance definition
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The Importance of Pharmacovigilance, WHO 2002
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
The aims of pharmacovigilance in relation to the use of medicines
� improve patient care and safety� improve public health and safety� detect problems related to the use of
medicines and communicate the findings in a timely manner;
� contribute to the assessment of benefit, harm, effectiveness and risk
Source: The safety of medicines in public health programmes: pharmacovigilance anessential tool. WHO, 2006 P. 9
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
The aims of pharmacovigilance in relation to the use of medicines (cont.)
� leading to the prevention of harm and maximization of benefit;
� encourage the safe, rational and more effective (including cost-effective) use of medicines; and
� promote understanding, education and clinical training in pharmacovigilance and its effective communication to the public.
Source: The safety of medicines in public health programmes: pharmacovigilance anessential tool. WHO, 2006 P. 9
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Drug-related problems[Adverse Drug Event and Medication Errors]
(in time of hospitalization)
20 – 72%
Drug permanent disabilities and deaths
7 – 12%Source: T Vira, M Colquhoun, E Etchells. Reconcilable differences: correctingmedication errors at hospital admission and discharge. Qual Saf Health Care2006;15:122–126.
Patient impact of Adverse events
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
How can we get drug safety information?� Spontaneous Reports
- Healthcare professionals- Other
� Literature� The internet� Solicited reports (How do you fill?)� Clinical trial reports� Epidemiology and Observational studies� Disease registries and Regulatory databases� Licensor-license interactions
Source: Current Challenges in Pharmacovigilance: Pragmatic Approaches. Report of CIOMS Working Group V. 2001.
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Standard Regulatory Requirement for Spontaneous Reports
�Serious suspected reactions (15 days)�Non-serious suspected reactions (line-listing
withing PSUR)�SUSAR (7 calendar days)
Source: Current Challenges in Pharmacovigilance: Pragmatic Approaches. Report of CIOMS Working Group V. 2001.
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
There are two principal criteria that control the priority for documenting, validating, evaluating and regulatory-
reporting of ADR cases:
� Seriousness� Expectedness
Source: Current Challenges in Pharmacovigilance: Pragmatic Approaches. Report of CIOMS Working Group V. 2001. p. 109
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Serious Adverse Event or Reaction: Seriousness Standard Criteria
Any untoward medical occurrence that at any dose:
� Results in death� Is life-threatening� Requires inpatient hospitalization or prolongation of
existing hospitalization� Results in persistent or significant disability/incapacity, or� Is a congenital anomaly/birth defect
Source: Management of Safety Information from Clinical Trials. Report of CIOMS Working Group VI. 2005. p. 236
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Unexpected ADR
An adverse reaction, the nature or severity of which is not consistent with the applicable product information
Source: ICH Guideline: E6 Good Clinical Practice
� Listed or unlisted (in association with the Company Core SafetyInformation [CCSI])� Labeled or unlabeled (in connection with official productinformation for marketed medicines, such as package insert, SPC ordata sheets
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Frequency of ADRsIn evaluating clusters of cases as opposed to individual cases, the
newly observed (estimated) frequency of occurrence may be “unexpected” relative to the information in Reference Safety Information (e.g., RSI may state an ADR is “rarely” but new signals say, at least “uncommon”)
< 1/10,000 (<0.01%)Very rare
� 1/10,000 and <1/1000 (� 0.01% and < 0,1%)Rare
� 1/1000 and <1/100 (� 0.1% and < 1%)Uncommon (infrequent)
� 1/100 and <1/10 (� 1% and < 10%)Common (frequent)
� 1/10 (� 10%)Very common
Source: Current Challenges in Pharmacovigilance: Pragmatic Approaches. Report of CIOMS Working Group V. 2001. p. 122
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Signal
A report or reports of an event with an unknown causal relationship to treatment that is recognized as worthy of further exploration and continued surveillance.
Source: Management of Safety Information from Clinical Trials. Report of CIOMS Working Group VI. 2005. p. 237
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
The discovery of an adverse drug effectThe discovery of an adverse drug effect
Signalstrengthening
Signal follow-up
Kno
wle
dge
of th
ead
vers
eef
fect
(%)
timeSinal generation
0 %
100 %
//
//
Signal assessment
Fonte: Meyboom et al. Principles of segnal detection in pharmacovigilance. Drug Saf 1997 17 (6) (376)
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Pharmacovigilance(Hypotesis generation)
Pharmacoepidemiology(Hypotesis testing)
Statistical Evidence
Clinical & pharmacological information
Relation between case reports and epidemiology
Source: A. C. van Grootheest. Improving pharmacovigilance and the role of the pharmacist. P. 68(modified)
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Priority for handling and follow-up ADRs
Source: Current Challenges in Pharmacovigilance: Pragmatic Approaches. Report of CIOMS Working Group V. 2001. p. 128-130
� Serious unexpected and “special interest” cases� Serious expected and non-serious unexpected cases� Non-serious, expected cases
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Different types of reports by Pharmaceutical companies
Source: Current Challenges in Pharmacovigilance: Pragmatic Approaches. Report of CIOMS Working Group V. 2001. p. 146-147
� US NDA- Quarterly- Annual
� ICH PSUR- 6-month- One-year
� Five-year relicensing� Six-year relicensing (for Japan)
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
The Benefit
• Drug´s positive effect on diseasereduction, prevention orelimination
Source: Holden, William L. Benefit-Risk Analysis. A Brief Review and Proposed Quantitative Approaches. Drug Safety2003, 26 (12), 853-862
The Risk
• Negative effectexpressed as unwanted orunanticipatedadverse outcomes
Benefit-risk analysis
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Benefit/risk evaluation and regulatory action
� Indications- Limiting the indications for which the benefits are
insufficient to jusfity use- For which use is associated with a greater risk of the
ADR�Dose
- Reductions in dose- Limitation on duration of treatment (e.g. ADRs
related to cumulative dose)�Contraindications
- Addition of concomitant diseases and/or medications
Source: Davies´s Textbook of Adverse drug reactions. Fifth ed. Chapman & Hall Medical. DM, Davies. p. 25-26
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
�Drug interactions- Addition of concomitant medications which
interact�Pregnancy/lactation
- Addition of new information�Warnings
- Addition of concomitant diseases and/or medication to be carefully weighed against the benefits
�Undesirable effects- Addition of newly recongnized adverse reactions
Benefit/risk evaluation and regulatory action
Source: Davies´s Textbook of Adverse drug reactions. Fifth ed. Chapman & Hall Medical. DM, Davies. p. 25-26
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Food and Drug Administration(e.g)
• Guidance for Industry. GoodPharmacovigilance Practices andPharmacoepidemiologic Assessment (2005)http://www.fda.gov/cber/gdlns/pharmacovig.pdf
• Otherhttp://www.fda.gov/cder/Offices/ODS/regs.htm
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
ICH CLINICAL SAFETY DATA MANAGEMENT
(e.g)• DEFINITIONS AND STANDARDS FOR EXPEDITED
REPORTING E2A (1994 – Step 5)http://www.ich.org/LOB/media/MEDIA436.pdf
• DATA ELEMENTS FOR TRANSMISSION OF INDIVIDUAL CASE SAFETY REPORTS E2B(M) –(2000 - Step 5)http://www.ich.org/LOB/media/MEDIA2217.pdf
• PERIODIC SAFETY UPDATE REPORTS FOR MARKETED DRUGS E2C(R1) – (1996 – Step 5 e Addendun )http://www.ich.org/LOB/media/MEDIA477.pdf
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
ICH POST-APPROVAL SAFETY DATA
MANAGEMENT(e.g)
• DEFINITIONS AND STANDARDS FOR EXPEDITED REPORTING E2D (2003 – Step 5)http://www.ich.org/LOB/media/MEDIA631.pdf
• PHARMACOVIGILANCE PLANNING E2E (2004 –Step 5)http://www.ich.org/LOB/media/MEDIA1195.pdf
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
European Medicines Agency(e.g)
• THE EXPOSURE TO MEDICINAL PRODUCTS DURING PREGNANCY: NEED FOR POST-AUTHORISATION DATA (2006)http://www.emea.eu.int/pdfs/human/phvwp/31366605en.pdf
• VOLUME 9 – PHARMACOVIGILANCE. Medicinal Products for Human use andVeterinary Medicinal Products (2004)http://eudravigilance.emea.eu.int/human/docs/vol9en.pdf
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
• MHRA Statutory Pharmacovigilance Inspection
http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&nodeId=826
(e.g)
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
• Guidelines on the reporting of adverse drug reactionsby drug sponsors (July 2005)http://www.tga.gov.au/docs/html/adrguide.htm
• Australian guideline for pharmacovigilance responsibilities of sponsors of registered medicinesregulated by drug safety and evaluation branch
http://www.tga.gov.au/adr/pharmaco.pdf
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
• CIOMS I - Expedited Reporting of Individual ADRs
• CIOMS 1A - Harmonisation of Data Elements and Fields for ElectronicReporting of Individual ADRs
• CIOMS II - Periodic Safety Updates• CIOMS III - Core Clinical-Safety
Information• CIOMS IV - Benefit-Risk Evaluation
CIOMS -Council for International Organizationsof Medical Sciences
(Publications)
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Management of SafetyInformationfrom Clinical TrialsReport of CIOMS WorkingGroup VI (2005)
PharmacogeneticsTowards improving treatmentwith medicines (2005)
SMQsDevelopment andRational Use of Standardised MedDRAQueries (2004)
Current challenges in pharmacovigilancepragmatic approachesreport of CIOMS WorkingGroup V (2001)
http://www.cioms.ch/
CIOMS -Council for International Organizations of Medical Sciences
(Standardised MedDRA Queries)
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
CIOMS – Working Groupson Drug Safety (in process)
• CIOMS WG VII on Development Safety UpdateReport (DSUR)
• CIOMS WG on Signal Detection: Points to consider
• CIOMS WG on Vaccine Pharmacovigilance• DRUG DEVELOPMENT RESEARCH IN
RESOURCE-LIMITED COUNTRIES. How to succeed in implementation of Good ClinicalPractice Guidelines
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
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Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
PANDRH OPERATING SYSTEM
Pan American Conference
Steering Committee
WG WG
WG WG
WG
WG
Andean Area
MERCOSUR
CARICOMSICA
NAFTA
RegulatorsConsumersAcademiaProfessional Ass Industry
Secretariat
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
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1. GMP (FDA, USA)
2. BE (FDA, USA)
3. GCP (ANMAT, Argentina)
4. D. Counterfeiting (ANVISA, Brazil)
5. D. Classification (MOH, Costa Rica)
6. Drug Approval (Registration) (MOH, Venezuela)
7. Pharmacopoeia (USP)
8. Medicinal Plants (MOH, Jamaica)
9. Pharmacovigilance (INVIMA, Colombia)
10. GLP (ISP, Chile)
11. Drug Promotion(ANVISA, Brazil)
12. Vaccines (MOH, Cuba)
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
PANDH WG/Phv: Mission
To develop and strengthen pharmacovigilance through activities and proposals of harmonized regulatory actions that promote the safe and rational use of drugs as a necessary component of Public Health policies in the Region of the Americas
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
PANDH WG/Phv: Objectives
1. To promote the development and dissemination of knowledge, criteria and methodologies in pharmacovigilance to be used in training activities
2. To review and develop tools to support harmonization in pharmacovigilance
3. To design a system that support the work in network to improveand strengthen exchange communication knowledge and decisionmaking in the area of pharmacovigilance.
4. To foster integration of pharmacovigilance as part of drug policyand public health programs
5. To promote and disseminate research on pharmacovigilance andevaluation of their impact in public health and patient safety
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Brazilian Drug Marketing• 551 Pharmaceutical Companies• 56,138 Community Pharmacies• 40,000 Pharmaceutical Products• 10,000 Drugs• 8,000 Hospitals• More than 180,000,000
inhabitants
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Risk EvaluationTeam N#1
(ATC: C, D, G, H, M, N e R )
Risk EvaluationTeam N#2
(ATC: A, J, B, L, S, V e P )
Pharmacovigilance Unit(CNMM)
Database Team
SentinelHospitals
Regional Pharmacovigilance
Centres
Pro
gram
ms
Wor
king
Gro
ups
ReportingPharmacies
PharmaceuticalCompanies
Alerts andInformation
Risk and Crises Management
Safety and Rational Drug Use promotion
Pharmacists: 12 Physicians: 3 Administrative: 2
Brazilian Drug Monitoring Centre (CNMM) – Pharmacovigilance Unit/NUVIG
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
9 Regional Pharmacovigilance Centres – Brasil
Mato Grosso do Sul (2006)
Santa Catarina(2004)
São Paulo (2001)
Rio de Janeiro (2005)
Bahia(2005)
Goiás(2004)
Ceará (2001)
Mato Grosso(2006)
Paraná(2005)
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Eletronic
Health Professionals ADR Form
Internet on-line form
Internet PDF
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
BrazilianMedication Error
Report Form
Internet PDF
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Assessment of Adverse events:causality (Algorithm or Global Instropection)
- +
0 % 100 %
Probability
unlikely possibly probably definitely
not related
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
North - 17 hospitals
Northeast - 39 hospitals
Middle East - 12 hospitals
Southeast - 77 hospitals
South - 31 hospitals
176 Sentinel Hospitals
Sentinels: 104 ; Collaborators: 72
Hospital Pharmacovigilance
Programme(Since 2001)
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
If you have problems withmedicines?
Look for the Pharmacist
CommunityPharmacies
PharmacovigilanceProgramme(Since 2005)
1655 Reporting
Pharmaciesand
4120 Pharmacists in
(500 reports)
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
Accumulative Reports per Year received by Brazilian Centre for Drug Monitoring
(CNMM)
34 110 3041259
3215
5301
880810236
0
2000
4000
6000
8000
10000
12000
1999 2000 2001 2002 2003 2004 2005 2006*
Rep
orts
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
The knowledge-driven model of decision-making
Source: Design and Implementation of Health Information Systems. WHO, 2000. p. 35 (modified)
Data
Information
Knowledge
Understanding
Judgement
Decision
Sorting/selection
Collection
Analysis
Interpretation
Weghing options
Valuation
Report
Murilo Freitas Dias
INTERACTION WITH THE REGULATORY AGENCY
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