introduction to pharmacovigilance system in taiwan …

INTRODUCTION TO PHARMACOVIGILANCE SYSTEM IN TAIWAN-2014PRESENTED BY CLIFF W.M. KE(柯韋名) MSc IN CLINICAL PHARMACY

SPECIALIST IN CEO’S OFFICE, TDRF

ICPE 2014, TAIPEI, TAIWAN CLIFF KE 1

OUTLINE

� Drug-injury relief scheme & ADR report system

� Taiwan’s Story, what brings both system together?

� How do we practice everyday?

� SRS report processing

� NHI database data application

� What we have done based on current resource?

� Take TNF-alpha RMP as an example



““We already walked too far, down to we had forgotten We already walked too far, down to we had forgotten

why embarked.why embarked.””

Kahlil Gibran, Lebanese poet, 1883-1931

PHARMACOVIGILANCE IN WESTERN COUNTRY

4

� During 1950s

� Rapid expansion of antibiotics due to explosive knowledge grew in chemistry during WWII

� Inadequate testing humans in pre-marketing trials

� Within 6 month after chloramphenicol approval (1949)

� Literature reports in EU and USA suggesting the association of fatal aplastic anemia with chloramphenicol use

� In late June 1952

� FDA ordered the staff in all 16 district offices to contact every hospital, medical school, and clinic in cities with populations of 100,000 or more to collect information on any cases of aplastic anemia or other blood dyscrasias attributed to chloramphenicol.

� Within four days of field contacts, additional 217 cases identified

PHARMACOEPIDEMIOLOGY 4.Ed, edited by BRIAN L. STROM

ICPE 2014, TAIPEI, TAIWAN CLIFF KE

PHARMACOVIGILANCE IN WESTERN COUNTRY

5

� In response

� American Medical Association established a Committee on Blood Dyscrasias (1954)

� Source of over 7,000 hospitals and 250,000 physicians

� Expand to “Registry on Adverse Reactions” in 1961

� Discontinued in 1971 due to FDA SRS working

� FDA, spontaneous reporting system

� Pilot in 1956

� American Society of Hospital Pharmacists, National association of medical records librarians, and AMA

� Began with 6 hospitals and by 1965 had grown to over 200 teaching hospitals which reported to the FDA on a monthly basis.

� Computerized in 1967



JUST AROUND THE CORNER

� A new drug with specific effectiveness in nausea and vomiting of pregnancy, Mornidine eliminates the ordeal of morning sickness.

� With its selective action on the vomiting center, or the medullary chemoreceptor “trigger zone,” Mornidine possess the advantages of the phenothiazine drugs without unwanted tranquilizing activity.

�� Withdrawn from the market for Withdrawn from the market for causing hepatic lesions in patients on causing hepatic lesions in patients on July 17, 1969July 17, 1969


http://theunnecesarean.com/blog/2010/6/17/mornidine-now-she-can-cook-breakfast-again.html#sthash.EDddePkZ.dpbs

Canadian Medical Association Journal on July 1, 1959

THALIDOMIDE DISASTER

� Thalidomide, launched by Grünenthal on 1 October 1957

� Tranquilizer and painkiller

� Insomnia, coughs, colds and headaches

� In the late 1950s and early 1960s, more than

10,000 children in 46 countries were born 10,000 children in 46 countries were born

withwith deformitiesdeformities such as phocomeliasuch as phocomelia

� The Australian obstetrician William McBride and the German pediatrician Widukind Lenz suspected a link between birth defects and the drug, and this was proved by Lenz in proved by Lenz in

19611961

7



KEFAUVER HARRIS AMENDMENT, 1962

�� Proof of the effectiveness and safety of their drugs before apprProof of the effectiveness and safety of their drugs before approvaloval

� In the form of “adequate and well-controlled investigations”- Phased study

� Remove 600 medicines that approved between 1938-1962

�� Adverse drug reactionsAdverse drug reactions were required to be reported to the FDAwere required to be reported to the FDA

� Monitor pharmaceutical advertising

� Ensure all drug had readable generic name

� Failing part

� Overhauling patent & indication, compulsive licensing

�� Eliminate meEliminate me--too drug unless it proved to be superior than comparator, too drug unless it proved to be superior than comparator, comparative effectiveness


N Engl J Med, 2012. 367(16): p. 1481-3.

THALIDOMIDE IN TAIWAN(沙利竇邁度)

� MAH is “大日本製藥株式會社” and marketed by “順裕貿易有限公司”

� This product is also suspended in Sept. 6th, 1962

� Dr.吳基福� ophthalmologist, owner of newspaper”台灣時報”, legislator

� In 1974, as a legislator, he questioned the administration did nothing on the thalidomide victims and mobilized all mobilized all 台灣時報台灣時報 journalists to investigate journalists to investigate further information.further information.

�� JDJD李聖隆李聖隆 is responsible for negotiation withis responsible for negotiation with大日本製藥株式會社大日本製藥株式會社�� 239 victims was reported, and 33 cases confirmed associated with239 victims was reported, and 33 cases confirmed associated with

thalidomidethalidomide

�� MAH paid 183.5million JPY, ~= 2.385 million NTD, in 1976.MAH paid 183.5million JPY, ~= 2.385 million NTD, in 1976.


http://blog.yam.com/lawpaper/article/38663931http://blog.nownews.com/article.php?bid=20807&tid=2170541https://sites.google.com/site/makehistory0809/people/ji-fuA study on the Drug product Liability and Risk Management, 陳弘文 2012, Thesis

““History, despite its wrentching pain, cannot be unlived, but if History, despite its wrentching pain, cannot be unlived, but if

faced with courage, need not be lived again.faced with courage, need not be lived again.””

Maya Angelou, African-American author, poet, dancer, actress and singer, 1928-2014


Quoted from https://www.youtube.com/watch?v=bJSKxUfK3cA#t=194

SOME MINDSET OF TAIWANESE ON MEDICATION

� Something that approved by government is 100% safe and good

� Drug, food, accreditation ,etc.

�� Concept of Concept of ““Benefit risk balancingBenefit risk balancing””, , ““unpredictability nature both on unpredictability nature both on

efficacy and safetyefficacy and safety”” are not wildly acceptedare not wildly accepted

� If something goes wrong after WHATEVER intervention, the WHATEVER intervention must be the culprit, no matter what concurrent or underlying situation is.

� There must be someone must be someone fully responsible to the wrong/unexpectedness.

� Victim is always perusing justice in terms of apology from manufacture , improvement of process or product quality, or etc….


TERBINAFINE

� Market in Taiwan in 1992 by Novartis

� A non-azole, non-polyene antimycotics

� Indication: Onychomycosis, Tinea captitis, serious and general skin fungal infection failure after local therapy.

� Treatment course:

� Tinea pedis: 2-6weaks, Tinea captitis: 6-12 weaks


PUBLIC ADVERTISING


1994/5/271994/5/27

1994/3/31994/3/3

1. Grand breaking achievement2. Endorsed by Doctor in famous medical center3. How wonderful his/her experience on this new

medication compared with other now standard4. No OBIVIOUS risk5. Maybe you should pay by yourself ☺

MEDIA STROM COMING,POSITION OF STAKEHOLDERS

� Legislator

� Inadequate governments on drug

� Addition cases of victim is scattering and no one take care of them, information is hidden

� False advertising

� Victim family

� In deep sorrow of lost their family

� Financial problem

� Pharma

� Illegal prescription drug acquisition

� Appropriate document of liver injury on package insert

� Severity of description and PI edition are arguable.

� Administrative

�� Enhance the law enforcement on prescription drug Enhance the law enforcement on prescription drug leakageleakage

� The GLOBAL data use to evaluate the safety show green light

� No SAE observed 3 years after drug approval

� But how to monitor it??ICPE 2014, TAIPEI, TAIWAN CLIFF KE 14

1997/7/41997/7/4

Case Zero:•Male 40yro, HBV carrier

••Direct access terbinafine without prescription from pharmacyDirect access terbinafine without prescription from pharmacy•Tinea pedis•N/V on D47, admitted•Expired 11weeks after of treatment

ICPE 2014, TAIPEI, TAIWAN CLIFF KE15

CAST INTO OPERATION


1997/7/51997/7/5

ONE MORE PUNCH

� Itraconazole associated fetal liver injury

� Overwhelming public attention on drug safety

� Petition on ensuring drug safety, especially in terms of liver injury


1997/7/161997/7/16

INVESTIGATION RESULT

� No single definite liver injury case is attributed to terbinafine or itraconazole

� Concomitant medication(including herb drugs) , underlying disease status are not available in most of case

� The description in package insert is not clear, suggest revising it.

� No further restriction on this medication


• Gov is actively in organize a no-fault drug hazard relief scheme to comfort victim and family in a timely manner.

• MAH is welling to donate a fund• Some detail negotiation took place and

consensus was made in this interval

Drug-injury Relief

ADR reporting system

DOH initiate a pilot project to est. a ADR reporting system, leaded by Arnold Chan

Case Zero, Case Zero,

Lamisil eventLamisil event

• Novartis refuse to pay for the injury.

• Family & Congressmen revealed it to Media for public empathy

July 4July 4thth, ,

19971997

Aug,1996


Immediate operation Immediate operation

of ADR reporting of ADR reporting

• Collaborate with 12 medical center

• Doctor could directly call for reporting Lamisil associated case

July 16July 16thth

Itraconazole Itraconazole

eventevent

Aug 9Aug 9thth

Official ingestion completed

Official Official

ingestion ingestion

completedcompleted

What we did AFTER media storm?

June 10June 10thth,,19981998

Draw up a essential principle in compensating drug hazard relief

Draw up a Draw up a

essential principle essential principle

in compensating in compensating

drug hazard reliefdrug hazard relief

May 31May 31stst

20002000

“Drug Hazard Relief Law”sign into law

““Drug Drug

Hazard Hazard

Relief LawRelief Law””

sign into lawsign into law

Jan 12Jan 12thth,,19991999

“Direction of Drug Hazard Relief”enforced

““Direction of Direction of

Drug Hazard Drug Hazard

ReliefRelief””

enforcedenforced

Sept 20Sept 20thth

20012001

Establish TDRF

Establish Establish

TDRFTDRF

April 21April 21stst

19991999

First Case Compensated(aspirin injection associated anaphylaxis)

First Case CompensatedFirst Case Compensated

(aspirin injection associated anaphylaxis)(aspirin injection associated anaphylaxis)

May 4May 4thth

20122012

Amendment to compensate off-label use injury

Amendment to Amendment to

compensate offcompensate off--

label use injurylabel use injury

Upgrade to National ADR reporting scale

Jan 1Jan 1stst ,,19981998

• Run as academic project host by Taiwan Society of Health-System Pharamcist(TSHP)

• 4 district local centers

• Still project-based• Report serious ADR is mandatory to MAH and

HCPs in 2004.• Centralized data collection and analysis in 2005• New generation e-reporting portal in 2013

Operate under TDRF

Jan 1Jan 1stst ,,20032003

WHAT/HOW WE ARE DOING WITH SRS DATA?FROM CASE REVIEW TO CLINICAL PRACTICE CHANGING


SRS: spontaneous reporting system

ADR REPORT PROCESSING PROCESS

Reporting Data

• From HCP and MAH etc• Spontaneous reports,

Literature and AEFI etc

Case Approval

• Check the integrity of reports(minimum requirement)

• Reject case as needed

ADRDatabase

Reviewers

Case Established

Online,Mail

•• Coding(drug and event)Coding(drug and event)

•• WHO ATCWHO ATC

•• MEDDRAMEDDRA• Evaluate the causality

• WHO Causality• Check the importance of reports

• Expectedness• Clinical impact(empirical)ICPE 2014, TAIPEI, TAIWAN CLIFF KE 21

INTERNATIONAL NEWS MONITORING

Search all website

Pharmacist

Safety Information

• Check marketing status• Any associated information

collected• Any action taken by TFDA

Mail

Further Investigation

For future reference

ADR Query, Analysis

Communication Letter

Yes

No

TFDA

ADR Team

Safety Communication

Yes

NoFor future reference


LIST OF WEBSITES

U.S. FDA Medwatch -What’s New http://www.fda.gov/Safety/MedWatch/default

U.K. MHRA -What’ New http:/ www.mhra.gov.uk/index.htmlHealth Canada-Latest Advisories, Warnings and Recalls http://www.hc-sc.gc.ca/dhp-mps/medeff/index-eng.php

Australian TGA-TGA advisories http://www.tga.gov.au/safety/alerts-current.htm

European Medicines Agency-What’s New http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/landing/

Swiss Agency for Therapeutic Products-Communications regarding the safety of medicines

http://www.swissmedic.ch/index.html?lang=en

社團法人醫藥品醫機器總合機構(日本PMDA)-医薬品安対策通知

http://www.info.pmda.go.jp/iyaku/iyaku.html

日本厚生勞動省(MHLW)-医薬品等安全性関連情報 http://www1.mhlw.go.jp/kinkyu/iyaku_j/iyaku_j.html

社團法人醫藥品醫療機器總合機構(日本PMDA)-医薬品・医療機器等安全性情報

http://www.info.pmda.go.jp/iyaku_anzen/anzen2011.html

Reuters-Health News Healthcare http://www.reuters.com/news/health?type=healthNews

http://www.reuters.com/sectors/healthcare

Yahoo-健康-醫療衛生新聞 http://tw.news.yahoo.com/disease/中央通訊社(CNA)-生活醫藥新聞 http://www2.cna.com.tw/List/aHEL-1.aspx


UnexpectedOr

Expected yetClinical meaningful*

DEATH CASE EVALUATION PROCESS

Reviewers

Coding

Sufficient content

Yes

No

AmendmentSufficient For future reference

Causality

UnclassifiedUnclassifiable

InsufficientNo more info

Can’t be r/o

No

Yes

Literature review

Internal Meeting**

AdvisoryCommittee

*Expected:

1.Documented on CCIS or package insert

2.Well-known ADR by HCP

3.Pharmacologically explainable

4.Complication from ADR

Clinical meaningful:

•Based on the reviewer or committee member’s opinion and judgment, the

signal identified should communicate with HCP.

**Internal meeting

•A prepare meeting for AC meeting, participated by all reviewers and 2

committee member(MD) is hold bimonthly. All death case was briefly

presented and check the completeness of material.


COMMUNICATION

ADR TeamCDE TEAM

Relief Team

1. Compassionated use drug associated ADR

2. Daily International drug safety summary

1. Proactively forward NDA cases with RMP

2. Response to safety information while the drug was under review

• Proactively forward drug relief case series with concern.

• Join pre-conference meeting

• Review drug-relief material(summary of medical records)


ADR REPORTING-STATISTICS

77,000 Cases


TOOL-ADR REPORT SUMMARY

� General description of analysis

� Case descriptive

� Statistical signal


TOOL- NATIONAL HEALTH INSURANCE DATABASE

� Analysis using pattern of given drug

� 1. how many prescription?(number, avg prescription days per prescription, by products)

� 2. how many user?(distribution of gender, age)

� 3. Product distribution

� 4. Doc Specialty, Clinic

� 5. Geological distribution of prescrptions

� How the drug was used

� Treatment episode number, average length of treatment, total exposure days

� The diagnosis code pattern at that prescription with given drug


Drug Safety AC

Signal Manage

Extracting data

Triage for further action

NoYes

Data miningStriking Case

News Inquiry

Detection

Data flow

Refine/Assess

Drug relief/prelicensure

Reviewers

Safety Info Check List

Prioritization

Cross RefPackage Insert

News

Compassionated use

Reference Data

Summary Report

NHI

As needed

ADR DB

CaseReview

QuerySRS

PSURPrimary

Literatures

PharmacoEpi

Higher Priority Cross Ref

1. DME/TME2. Monitoring drug3. Our interest

Primary Rule

Periodic Project

Reviewers

Further Monitoring

ActionICPE 2014, TAIPEI, TAIWAN CLIFF KE 34

ACHIEVEMENT FROM SIGNAL DETECTION, EVALUATION AND RISK MINIMIZATION


ADRSTATISTICAL SIGNAL DETECTION

Drug-event combination N PRR 95%CI EBGM EB05

Tuberculosis

adalimumab 21 1281.70 683.49 2403.48 424.94 207.06

etanercept 8 142.57 66.24 306.83 144.45 54.66

ribavirin 2 10.51 2.53 43.62 11.02 0.70

peginterferon alfa-2a 2 6.59 1.59 27.41 7.13 0.60

rituximab 1 6.78 0.93 49.34 - -

erythropoietin 1 15.12 2.09 109.39 - -

sirolimus 1 43.30 6.09 307.91 - -

prednisolone 1 8.50 1.17 61.73 - -

paliperidone 1 12.35 1.70 89.54 - -

Data as of: 2011/1/1

36

ESTIMATED IMPACT

adalimumab etanercept

2008 Syringes Patients Syringes Patients

OPD 314 183 5458 1052

Inpatient 0 0 15 15

Total 314 183 5473 1067

2009

OPD 750 469 7026 1414

Inpatient 0 0 0 0

Total 750 469 7026 1414

健保百萬人抽樣檔: 年度藥品處方數量及人數

推估每治療人年通報事件比率 YR 2009

CT:300 events/ 100,000 PYOBS:

1490 events/100,000PY

adalimumab* etanercept**

Reported Event 10 1

Diagnosis confirmed case 8 0

Sampled syringes used(per million population) 750 7026

Estimated total syringes distributed in TW(*20,*24) 15000 18000 140520 168624

Estimated patient treatment year 535.71 642.86 5855 7026

Estimated events per 100 pateint treatment year base on

Reported Events 1.87 1.56 0.02 0.01

Diagnosis confirmed cases 1.49 1.24 0.00 0.00

*From the PSUR, 28syringes/ yr was assumed

** We assumed 24 syringes/ yr was prescribed

CONCLUSION OF OBSERVATION

Incidence of general pop.

Incidence of ADA user

Ratio

USA, EU region

31-48 270 6.75

TW 84 660-1240 7.8-14.7

� adalimumab使用於台灣族群可能具有較高產生結核病的風險� 台灣adalimumab使用者:660-1240個案

每十萬治療人年� 全球臨床試驗adalimumab使用者: 130-

300個案每十萬人年� 台灣整體結核病發生率: 84個案每十

萬人年)

� adalimumab使用者診斷出發生結核病的時間跨距有較快速的趨勢(adalimumab: 46.4±36.7 wks, Q1-Q3: 15.5-74 wks; etanercept: 106.5±76 wks, Q1-Q3: 53-157.8 wks, p=0.062)

Reporting rate=X incidence!!Reporting rate=X incidence!!

TIME TABLE OF TNF-ALPHA&TB RISK

� Jan 11, 2011: Signal detected

� Feb 11, 2011: Signal refinement report completed

� June 15, 2011: AC recommend RMP and further research.

� Aug 1, 2011: Get authorization from BNHI and start study design and data analysis

� Jan 6, 2012: Frist Draft of analysis report

� April 2, 2012: TNF-alpha RMP started

� July 23, 2012: Chinese's edition analysis result & recommendation send to TFDA

� March 1, 2013: Taiwan Rheumatology Association issue a guidance on screen and management of TB/HBV in TNF-alpha users

INT J TUBERC LUNG DIS 17(12):1590–1595

TAIWAN RHEUMATOLOGY ASSOCIATION GUIDEANCE


OUR WORKS IN 2013


• 291 messages collected• 186 from Regulators• 57 from international press• 58 from domestic press

• 47 communication posts to public

• 291 messages collected• 186 from Regulators• 57 from international press• 58 from domestic press

• 47 communication posts to public

• Evaluation initiated from regular (death case, mentoring drug) or on demand (news, inquiry) bases.

• 52 Report submitted to Drug Safety AC.

• 18 package insert change• 5 indication restrictions• 2 withdraw/RMP• 3 public communication

• Evaluation initiated from regular regular (death case, mentoring drug) or on on

demand demand (news, inquiry) bases.• 52 Report submitted to Drug Safety

AC.• 18 package insert change• 5 indication restrictions• 2 withdraw/RMP• 3 public communication

• 8 conferences with HCPs• 8 invited speech and appealing to

students(public health, pharmacy), medical community, and general public

• 4 issues of Drug Safety Newsletter

• 8 conferences with HCPs• 8 invited speech and appealing to

students(public health, pharmacy), medical community, and general public

• 4 issues of Drug Safety Newsletter

CONCLUSION

� 15 years after Lamisil Event, the drug hazard relief scheme drug hazard relief scheme and postpost--marketing drug safety monitoring marketing drug safety monitoring keep operating and evolving to meet the expectation of public

�� Easy of provisions on offEasy of provisions on off--label use label use in hazard relief

� By 2013, 12 cases with off-label use of medication, i.e allopurinol for hyperurecemia, sulfasalazine for ankylosing spondylitis and others, have been paid

�� Involving fields of vaccine Involving fields of vaccine (influenza, from 2009) and medical deviceand medical device(2014) safety monitoringsafety monitoring

�� Developing inDeveloping in--house capacity in designing and executing house capacity in designing and executing pharmacoepidemiology study pharmacoepidemiology study

� A quicker peek and clarify of drug safety issue

�� Increasing the transparency of drug safety decisionIncreasing the transparency of drug safety decision--makingmaking

� Publish the reference study/reports in a concise manner

� Actively communicate the concern behind a decision, lesion from TNF-alpha blocker RMPICPE 2014, TAIPEI, TAIWAN CLIFF KE 44

THE ENDTHANKS FOR YOUR ATTENTION


introduction to pharmacovigilance system in taiwan …

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