Interaction with the Regulatory Agency Pharmacovigilancesbmf.org.br/pdf_eventos/dia/murilofreitas_26sep.pdf · INTERACTION WITH THE REGULATORY AGENCY Pharmacovigilance ... Davies´s

Murilo Freitas Dias

INTERACTION WITH THE REGULATORY AGENCY

PharmacovigilanceInteraction with the Regulatory Agency

SalvadorSeptember 26, 2006

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Murilo Freitas Dias


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


• More than 130 pharmaceutical products havebeen withdrawn from various markets over thepast 40 years– 1/3 within two years of launch;– 50% within 5 years.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


Cerivastatin and RhabdomyolysisAugust 2001

Rofecoxib and Cardiovascular effectsOctober 2004

Time

Voluntary withdrawn from the market for safety reasons (e.g)

Murilo Freitas Dias


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


WHO Pharmacovigilance definition

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The Importance of Pharmacovigilance, WHO 2002

Murilo Freitas Dias


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


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


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


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


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


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


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


Murilo Freitas Dias


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


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


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.


Murilo Freitas Dias


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


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


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


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


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


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


�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


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


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


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


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


• MHRA Statutory Pharmacovigilance Inspection

http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&nodeId=826

(e.g)

Murilo Freitas Dias


• 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


• 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


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


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


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Murilo Freitas Dias


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


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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


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


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


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


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


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


Eletronic

Health Professionals ADR Form

Internet on-line form

Internet PDF

Murilo Freitas Dias


BrazilianMedication Error

Report Form

Internet PDF

Murilo Freitas Dias


Assessment of Adverse events:causality (Algorithm or Global Instropection)

- +

0 % 100 %

Probability

unlikely possibly probably definitely

not related

Murilo Freitas Dias


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


If you have problems withmedicines?

Look for the Pharmacist

CommunityPharmacies

PharmacovigilanceProgramme(Since 2005)

1655 Reporting

Pharmaciesand

4120 Pharmacists in

(500 reports)

Murilo Freitas Dias


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


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


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Documents

Interaction with the Regulatory Agency Pharmacovigilancesbmf.org.br/pdf_eventos/dia/murilofreitas_26sep.pdf · INTERACTION WITH THE REGULATORY AGENCY Pharmacovigilance ... Davies´s