introduction to pharmacovigilance system in taiwan …
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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
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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
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““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
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� 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
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PHARMACOVIGILANCE IN WESTERN COUNTRY
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� 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
PHARMACOEPIDEMIOLOGY 4.Ed, edited by BRIAN L. STROM
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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
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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
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PHARMACOEPIDEMIOLOGY 4.Ed, edited by BRIAN L. STROM
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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
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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.
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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
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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….
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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
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PUBLIC ADVERTISING
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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
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CAST INTO OPERATION
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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
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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
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• 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
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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
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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
Further Investigation
For future reference
ADR Query, Analysis
Communication Letter
Yes
No
TFDA
ADR Team
Safety Communication
Yes
NoFor future reference
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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
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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.
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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)
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ADR REPORTING-STATISTICS
77,000 Cases
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ADR REPORTING-STATISTICS
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ADR REPORTING-STATISTICS
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ADR REPORTING-STATISTICS
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ADR REPORTING-STATISTICS
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TOOL-ADR REPORT SUMMARY
� General description of analysis
� Case descriptive
� Statistical signal
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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
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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
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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
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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
INT J TUBERC LUNG DIS 17(12):1590–1595
TAIWAN RHEUMATOLOGY ASSOCIATION GUIDEANCE
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OUR WORKS IN 2013
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• 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
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