Pharmacovigilance as integral part of hospital Quality Management Systems 1 ARETE-ZOE, LLC 1/21/2018

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Data Collection Implicit Guidance and Control Title 21 CFR Section E2E Pharmacovigilance Planning Article 24 of Regulation (EC) No 726/2004 Article 107 and 107a of Directive 2001/83/EC Electronic submission under ICH-E2B(R3) Good PV Guideline (GVP) Off-label Use in PV (EMA/293194/2016) ICSRs from literature (EMA/161530/2014) Good practice guide medication errors Compliance-driven discipline Over-specialization 3 1/21/2018

Data Collection Unfolding circumstances Treatment guidelines and standards of care Standard and new treatment protocols Off-label use Creative use by patients, abuse and misuse Outside information Unreported Adverse Drug Events Patient experience Interaction with environment Social media hot topics, true or not Reimbursement, pharmaco-economics Availability and real-life use Counterfeit, falsified and substandard drugs 4 1/21/2018

Data Gaps Exposure data not available  Incidence and prevalence unknown Indication typically not collected  Risk:benefit profile of off-label uses  Standard and new treatment protocols Voluntary reporting by physicians in the U.S.  Incomplete picture  Medication errors inconsistently reported  ADR vs. ADE vs. Quality concerns Overdose and abuse  Not subject to expedited reporting, PSUR only Efficacy and comparative efficacy data 5 1/21/2018

Orientation Compliance as the key driver Dominant IT providers define form Signal detection: case review & disproportionality analysis  Human factors affect detection threshold  Organizational culture defines response to safety concerns  Significant uncertainty 6 1/21/2018

Hospital QMS v. PV systems 1/21/2018http://aretezoe.com/ 7 Adverse Drug Reactions Medication Errors Adverse Drug Events Adverse drug reaction: “Harm directly caused by a drug at normal doses” Medication error: “Inappropriate use of a drug that may or may not result in harm” Adverse Drug Events: All harms that occur during medical care that are directly caused by the drug including medication errors, ADRs, allergic reactions and overdoses HRET, 2017 HRET, 2017 and DHHS, 2014DHHS, 2014

Adverse Drug Events Inpatient settings ADEs account for 1 in 3 of all hospital AEs 30% of inpatients experience an ADE Affect 2 million hospital stays each year ADEs / 1,000 hospital discharges Prolong hospital stays by 1.7 to 4.6 days Outpatient settings Over 3.5 million physician office visits 1 million emergency department visits 125,000 hospital admissions Highest risk Elderly Pediatric patients Multiple medications 1/21/2018http://aretezoe.com/ 8 HRET, 2017 HRET, 2017 and DHHS, 2014DHHS, 2014

1/21/2018http://aretezoe.com/ 9 MeasureNumeratorDenominator Target Reduction Departmental Measure Alignment Rate of visits to U.S. hospital EDs for injury from oral anticoagulants Number of visits to U.S. hospital EDs for injury from oral anticoagulants Number of patients receiving dispensed oral anticoagulants in U.S. retail outpatient settings 10%HHS Healthy People 2020Medical Product Safety Objective 5.1Healthy People 2020 Rate of visits to U.S. hospital EDs for injury from insulin Number of visits to U.S. hospital EDs for injury from insulin Number of patients receiving dispensed insulin in U.S. retail outpatient settings 10%HHS Healthy People 2020Medical Product Safety Objective 5.2Healthy People 2020 Rate of visits to U.S. hospital EDs for injury associated with therapeutic use of opioid analgesics Number of visits to U.S. hospital EDs for injury associated with therapeutic use of opioid analgesics Number of patients receiving dispensed opioid analgesics in U.S. retail outpatient settings 10%HHS Healthy People 2020Medical Product Safety Objective 2.3Healthy People 2020 ODPHP (2017). National Targets and Measures - Adverse Drug Events - health.gov. [online] Health.gov. Available at: [Accessed 26 Nov. 2017]. Adverse Drug Events

1/21/2018http://aretezoe.com/ 10 ICSRs: Clinical trials, PMS, PASS, Literature Company databases, monitoring systems Signal detection No action Triage of Outputs & Interpretation Impact Assessment ICSR review Aggregate reports, PSURs NI studies, class analysis ICSR review Aggregate reports, PSURs NI studies, class analysis Data mining algorithms Disproportionality reporting ratios Data mining algorithms Disproportionality reporting ratios Signal evaluation Signal prioritization ICSR review Aggregate analysis Periodic reports NI studies Class analysis

1/21/2018http://aretezoe.com/ 11 Large-sample confidence intervals (CI) for reliability and validity: (a)both estimates from random samples; (b)reliability from a random sample but validity from a selected sample; (c)validity from a random sample but reliability from a selected sample; (d)both estimates from selected samples. Good reliability Poor validity Poor reliability Good average validity Good reliability Good validity

Decide & Act FAERS data EudraVigilance data PRAC reviews Product label updates Box warnings RMP/REMS Product withdrawal /21/2018

13 Level of evidenceNumber (%) of withdrawals All marketed drugs (n = 462) Marketed drugs launched since 1950 (n = 286) Level 1: Systematic reviews6 (1.3)6 (2.1) Level 2: Randomized studies27 (5.8)25 (8.7) Level 3: Non-randomized studies43 (9.3)30 (10.5) Level 4: Case reports330 (71.4)189 (66.1) Level 5: Mechanism-based reasoning56 (12.1)36 (12.6) Levels of evidence used to justify post- marketing withdrawal of medicinal products Onakpoya, I., Heneghan, C. and Aronson, J. (2016). Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature. BMC Medicine, 14(1).

1/21/2018http://aretezoe.com/ 14 Leveson, N: Applying System Engineering to Pharmaceutical Safety The direct effects of an improved information system

Threats to enterprise Compliance Failure Diverse requirements Fluid and changing Accidents Drug shortages Forced improvisation PHI breaches Business sector competition Dominant IT providers Stove-piping & groupthink Failure to innovate Mergers and acquisitions Incompetence & Corruption Local and national interests Off-shoring operations Access to global talent Cultural differences Training Organized crime Civil disruption Natural disaster 1/21/2018http://aretezoe.com/ 15

Summary Gaps in observation: Exposure data, patterns of use Compliance-driven discipline, other threats disregarded Customers other than regulators and sponsors often ignored Dominant IT providers define form, limit innovation PV signal detection relies on disproportionality analysis PV reporting poorly captures patterns of use and trends Level 4 evidence (case reports) used for most withdrawals ADEs routinely monitored as part of QMS Most ADEs attributed to anticoagulants, insulins and opioids Improvement in information environment crucial Future: utilization of real-world data in standard PMS 1/21/2018http://aretezoe.com/ 16

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Deployable in hospitals as COTS platform Analytical outputs provide real-time insight Continuing evaluation of treatment outcomes Utilization of RWD for generation of RWE Data source for observational and large simple trials /21/2018

The Platform can provide valuable insight into actual real- world performance of marketed drugs and devices, procedures and treatment protocols, including accurate real- time evaluation of existing, new and emerging safety concerns and assessment of novel uses and combinations by comparing prescribing information and treatment outcomes utilizing selected information from electronic health records and other real world data /21/2018

Pharmaceutical Industry – Sponsors, CROs PV Compliance, PMS obligations Research, benchmarking of products New indications, combinations, populations, interactions Investors Independent evaluation of product performance Decision support and Verification of industry claims Hospitals and healthcare providers Part of quality of care management systems Measurement of treatment effectiveness Limiting drug-related injury and iatrogenic conditions Insurers and payers Cost-effectiveness of procedures and treatments Reducing costs of avoidable patient casualty Regulators and elected officials New ways of obtaining medical evidence Objective, comprehensive, independent, real-time /21/2018

Patient characteristics Demographics w/o PII Relevant conditions (NAFLD, type-II DM) Relevant PGX biomarkers Admission diagnosis Interventions: Medications and their combinations Standard treatment protocols Duration of treatment Dosing Treatment outcomes Consistent and valid outcome measures Complications, ADEs and ADRs Quality markers 21 The detection of patterns and relationships between interventions and treatment outcomes Structured information Analytical outputs RWE Source 1/21/2018

Point-of-care/real-time Quality of care feedback Treatment protocol/intervention adjustment Learning health system Prospective and retrospective data review 22 RWD source for RWE production – Per protocol analysis – RCTs: PASS, Large simple trials, pragmatic trials – Observational studies – Pharmaco-economic studies – Proper study design paramount 1/21/2018

Major hospitals Academic research centers Public-private partnerships Insurers Institution-based COTS PII do not leave the original institution Analytical outputs shareable/marketable /21/2018

High-quality medical evidence Master Study Protocols to standardize medical evidence and improve its comparability across the sector PII protection No PII sharing outside organization Unique identifier other than patient’s identity Relevance of collected data Valid endpoints and measures Limited number of variables Integral part of hospital QMS Principles of continuing quality improvement Responsive to changing standards in care delivery Designed to provide decision support to physicians /21/2018

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CURRENT SITUATION /21/2018

The Intelligence Cycle Intelligence/evidence production in medicine Gaps and omissions Publication bias, availability of study results Cognitive biases Availability of information at point-of-care Critical appraisal of evidence /21/2018

Boyd cycle Informed decision Real-time feedback loop Information availability at point-of-care Observe: relevant and comprehensive information collection Orient: appraisal of available evidence in appropriate contexts Decide: make a sound and timely decision Act: actions conform to decisions made /21/2018

Evidence from clinical studies RCT: narrow scope, I/E, limited generalizability Very long delay in producing results Uncertainty prolongs inappropriate and harmful use and slows removal of products from the market RWE increases real-time awareness of product true performance for all stakeholders /21/2018

QMS Main quality criteria in healthcare /21/2018

Adverse drug events National ADE action plan Top 4 classes – insulins, oral antidiabetics, anticoagulants, opioids /21/2018

ADR reporting FAERS EudraVigilance National and WHO vigilance systesm Mandatory v. voluntary /21/2018

Signal detection in PV No baseline – no exposure data High noise background /21/2018

RWD to produce RWE /21/2018