Issue and Challenges of Regulatory Harmonization in Pharmacovigilance : viewpoint of academia 2012.10.25 Korea Society for Pharmacoepidemiology and Risk Management (KoPERM) Jin-Ho Lee 2012 AHC Pharmacovigilance Workshop, October 25-26, 2012 / Novotel Gangnam Hotel, Seoul
Contents 1 Introduction 2 Academic concerns in 5 RM steps 3 Future perspectives: challenges 2
1. Introduction 3
History of Drug Safety after Thalidomide 1961 - Dr William McBride (Australia) reported 20% increase in foetal abnormalities and significant increase of phocomelia in relation with thalidomide use, later numerous reports from other countries (more than 10,000 cases) 1962 - USA Kefauver-Harris Amendment to the law (requirement to prove safety and efficacy before issuing MA) 1964 - UK started yellow cards system 1965 - European Union issued EC Directive 65/65 1968 - start of WHO Programme for International Drug Monitoring(UMC) 1980s - CIOMS (Council for International Organization of Medical Sciences) ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) 1989 International Society for Pharmacoepidemiology
Pharmacovigilance The science and activities relating to ADR or any other drug-related problem (WHO): - Detection - Assessment - Understanding - Prevention Educated decision for drug therapy by enough information - doctor and patient Risk management: -Risk assessment -Risk confrontation -Risk intervention -Risk communication -RM evaluation - Risk of stop medication ADR concerned about 5
Guidelines for Drug Safety IEA(International Epidemiology Association); Guidelines on Ethics for Epidemiologists 1991 ACE(American College of Epidemiology); Ethics Guidelines 2000 European Epidemiology Federation: Good Epidemiological Practice (GEP) 2004 ISPE(International Society for Pharmacoepidemiology); Guidelines for Good Pharmacoepidemiological Practices (GPP) 2007.4 IEA Guidelines for Proper Conduct of Epidemiological Research 2007.11
Safety Withdrawals, 1997-2001 (FDA)
Safety Concerns Rosiglitazone withdrawal: - Increased risk of MI and death from CV causes - Benefits overweigh its risk within the framework of its approved indications - Constant revision/updating of product information and continued monitoring of ADR Critical evaluation of the current method and mechanisms available for safeguarding the safe use of a drug! 8
Risk Management 5. Risk Management Evaluation measurements of effectiveness of aforementioned activities 1. Risk Assessment estimation and evaluation of risk 4. Risk Communication interactive process of exchanging risk information Risk Management 2. Risk Confrontation determination of acceptable risk level in social context 3. Risk Intervention actions to control risk 9
2. Academic concerns in 5 RM steps 10
Data collection: Data source Data quantity Data analysis(data mining): Data quality: Validation Sentinel production: 1. Risk Assessment Signal detection Signal strengthening Signal validation Hypothesis testing in a formal PE study 11
Sources of drug safety Assessment Premarketing ad hoc Postmarketing Epidemiologic Studies : Case control study Cohort study Phase 4 Studies : Clinical trial Sources Postmarketing(PMS) Product Usage(DUR) Case Reports & Signal detection 12
Limitations in data sources 13
Post-marketing studies Descriptive studies: - Generate hypothesis(starting point for analytical studies) - Describe the occurrence of events(toxicity, efficacy) - Spontaneous reporting, intensive monitoring Analytical studies: - Test hypothesis - Determine association or causal connections btw observed effects and particular drugs - Measure the size of these effects - Case control studies, cohort studies, clinical trials 14
(1) Spontaneous reporting Monitor all drugs on the market through their entire life cycle at a relatively low cost Selective reporting and underreporting; - False positive and false negative conclusion - Easier to detect new signals of ADRs - Limits: cause-effect relationship, incidence rates, risk factors, patterns of use Powerful method in detecting safety issues; - Randomized trial 18% - Comparative observational studies 18% - SRS supported withdrawal 73% - SRS only 36% - Initial detection by SRS 67% 15
Safety Withdrawals, 1995~ (Europe) Drug Safety concern Key evidence Regulatory action Trovofloxacin Hepatotoxicity Spontaneous ADRs Withdrawn Tolcapone Hepatotoxicity Spontaneous ADRs Suspend Cisapride Bupropion QT prolongation; arrhythmia Seizures; drug interaction Spontaneous ADRs Spontaneous ADRs Cerivastatin (2001) Rhabdomyolysis Spontaneous ADRs Withdrawn Hormone Replacement Therapy SSRIs CVS risk, cancer long term Suicidal behavior in children Epidemiological studies Clinical trials Patient registration license subsequently cancelled Posology change, Warnings Warnings and restriction of indication Warnings accompanied by clinical guidance COX2s (2004) CVS risk Clinical trials Warnings and clinical guidance Topical macrolide immunosuppressants Risk of cancer Spontaneous reports Restriction of use, Risk management plan
Data mining in SRS Signal detection: Case-by-case analysis Data mining Data mining: Analysis data from different perspectives and Extract the relevant information Algorithms: determine hidden patterns of associations or unexpected occurrences(i.e. signals) in large databases Methods: N(observed cases) vs N(expected cases): Proportional reporting ratio (PRR) Reporting odd ratios (ROR) Bayesian confidence propagation neural network - WHO Multi-Item Gamma Poisson Shrinker (MGPS) - US FDA Limits: Cannot distinguish between known and new associations Clinical review to analyze these events 17
(2) Intensive monitoring Late 1970s ~ early 1980s New Zealand (Intensive Medicine Monitoring Programme) UK (Prescription Event Monitoring) Prescriber is asked about any adverse event occurring during the use of the drug being monitored (Noninterventional observational cohort design): Provide real world clinical data involving neither inclusion nor exclusion criteria; no selection bias Event monitoring - detect unknown signals Estimation of Incidence of ADR, quantification of the risk of certain ADRs Underreporting: reported event rate not true incidence rate No control group: true background incidence rate not known EC EID 2007: strengthening and rationalizing EU PV 18
(3) Database studies Data collected in a reliable and routine fashion; available for a study to test a hypothesis General Practice Research Database (GPRD) PHARMO Record Linkage System Integration of various health outcome data; Clinical data, social data, administrative data HIPPA (Health Insurance Probability and Accountability Act); bypass personal ID MEMO (The Medical Monitoring Unit) Scotland Tayside 19
System development Proactive monitoring system: - Sentinel Initiative 2008 : public-private partnership - Query a multitude of data sources; as much as possible - EMR, administrative claim databases, registries - Detect new signals and confirm emerging safety issues - Close collaboration with various experts from both public and private institutions - ENCePP (European Network of Centers for Pharmacoepidemiolgy and Pharmacovigilance) - Key goals: - Improving the safety of medicines - Provide a platform for pharmacoepidemiologial research 20
(2011.12.) 31 institutes, 126 million patients data
http://www.encepp.eu (2011) 17 countries, 99 institutes, 20 data sources
2. Risk Confrontation Balance of risk and benefit Safe drug: risk < benefit - not no risk Benefit: Efficacy vs Effectiveness Complicated process by various factors; Medical factors: outcome study Societal factors: pharmacoeconomics Individual factors: Patient Reported Outcome Decision analytic method; Cost Effectiveness Analysis Cost Utility Analysis 23
Theoretical depiction of RM Increasing Risks Acceptable risk for some patients or physicians Maximum acceptable risk for all patients Disapprove Risk Management Zone Approve Acceptable benefits for some patients or physicians Minimum acceptable efficiency for all patients Increasing Benefits 24
3. Risk Intervention Goals Objectives Tools 1. Targeted education and outreach 2. Reminder/prompting system 3. Performance-linked access systems 25
Effectiveness of RM tools(1) Intervention Examples Effectiveness Legislation or national government campaign APAP in the UK Aspirin-Reye's syndrome Childproof packaging Generally good Engineeringbased APAP: blister packs, limited tablet number Childproof packaging Clozapine: lab result linked to Rx dispensing Switch from terfenadine to fexofenadine Generally good 26
Effectiveness of RM tools(2) Intervention Examples Effectiveness Product labeling Dear Health Care Provider letters Bromfenac, cisapride, isotretinoin, pemoline, terfenadine, troglitazone Bromfenac, cisapride, isotretinoin, pemoline, terfenadine, troglitazone Generally poor Generally poor Public advisory meetings Isotretinoin, troglitazone Generally poor Voluntary liver enzyme monitoring Pemoline, troglitazone Generally poor Educational campaigns Cisapride, isotretinoin Generally poor Signed informed consent Isotretinoin Generally poor 27
Legislative developments RM strategy + marketing authorization: - RMP (risk management plan) 2004/27/EC - All new drugs - Following changes in marketing authorization - New safety issues - REMS (risk evaluation and mitigation strategy) 2007 US FDA Amendment Act - Case-by-case basis - Enforce commitments; - Reauthorization procedures - Monetary penalties - Product withdrawals - Improving PV practices (EU) 28
4. Risk Communication Educated decision for drug therapy by enough information - Regulatory science: health professional, public - Risk of stop medication ADR concerned about Concerns: - Journalism and linguistics - Educational engineering Ex) AHRQ CERT (Centers for Education and Research on Therapeutics) 29
Communications: Governments WHO-UMC: 1968 worldwide monitoring system Korea: 1992 member of WHO-UMC. WHO monitoring countries
BRIDGE from Korea to Asia Global Leadership in Pharmacovigilance in APEC Korea is the champion country of Pharmacovigilance by 2020 KFDA will take the lead within the RHSC for organizing activities to promote convergence and will be the primary author of a specifically tailored roadmap for Pharmacovigilance by 2020 Asia Pacific Economy Cooperation has currently comprised of 21 member economies
Communications: Academia
5. RM Evaluation 1. Select evidence-based performance measures 2. Compensate for an evaluation method s limitations 3. Evaluate the effectiveness of tools in addition to RM goals 4. Evaluate RM tools prior to implementation Transparency: Scientific verification Ethical standards 33
3. Future perspectives: challenges 34
Guidance on future of PV General confidence and trust over the world Science underpin the processes 1 Process-oriented best evidence 2 Robust scientific decision-making 3 Effective tools to deliver protection of publichealth 4 Scientific development: pharmacogenetics 5 Near-real time: Identify new safety issues without delay 6 Patients empowerment: salvage system 7 Audit 35
Guidance on future of PV Transparency Erice declaration, Waller and Evans statement - IRB: 1964 World Medical Association - DSMB(Data and Safety Monitoring Board) 1960 US Registration of clinical trial and tracking: full and unbiased reporting Free access of the public to spontaneous reporting system (Canada, Netherland, UK) 36
Thank you! 2012 AHC Pharmacovigilance Workshop 37