Workshop: measuring the impact of pharmacovigilance activities 5-6 - PowerPoint PPT Presentation

Workshop: measuring the impact of pharmacovigilance activities 5-6 December 2016 European Medicines Agency, London, United Kingdom “Challenges of measuring the impact of pharmacovigilance processes” Judith Sanabria, M.D. Clinical Pharmacology Biomedical Research Institute of Málaga (IBIMA), Spain

Why is it important to measure the impact of pharmacovigilance processes? ₋ To review of the benefits and risks of individual medicines : effectiveness of risk minimisation ₋ Determine what activities are successful ₋ Enablers and barriers for generating positive impacts Adopted from PRAC strategy on measuring the impact of Pharmacovigilance activities, 2016 Is it possible to focus on measuring the impact in certain type of adverse drug reactions (ADRs)…?

Classification of ADRs Are there specific ADRs that require more attention than others? TYPE A (AUGMENTED) TYPE B (BIZARRE) Exaggerated pharmacological effects Not related with the pharmacological effects Predictable Unpredictable Dose-related Dose effect is unclearly defined High incidence and morbility rates Relatively low Incidence and morbility rates Low mortality rates High mortality rates Usually reproducible in animals Lack of animal models Detected in phase I-III clinical trials Detected in postmarketing studies Adopted from Classification of Rawlins and Thompson

Classification of ADRs Are there specific ADRs that require more attention than others? Identification of TYPE A (AUGMENTED) TYPE B (BIZARRE) the majority of 25000 Type B ADRs Identification of the majority Exaggerated pharmacological effects Not related with the pharmacological of Type A ADRs effects Number of Subjects 20000 Predictable Unpredictable Marketing Dose-related 15000 Dose effect is unclearly defined authorization 10000 High incidence and morbility rates Relatively low Incidence and morbility rates Low mortality rates 5000 High mortality rates Usually reproducible in animals Lack of animal models 0 PHASE 2 PHASE 1 PHASE 3 PHASE IV Detected in phase I-III clinical trials Detected in postmarketing studies 50 volunteers 250 volunteer 2 000 volunteer More than de 3000 Adopted from Classification of Rawlins and Thompson

Drug-Induced Liver Injury severity (ADR Type B) ₋ It is responsible for more than 10% of all cases of acute 3.9-6.7% Robles-Díaz et al , Gastroenterology, 2014 liver failure Chalasani et al , Gastroenterology, 2015 Death / Tx ₋ DILI is one of the most frequent reason for marketed Acute liver failure drug withdrawal and modification of labelling Serious injury, hospitalization ₋ More than 1,100 medicines, natural products, vitamins, Detectable slight liver functional loss dietary supplements, recreational and illicit compounds have been reported to cause DILI Just enzyme elevations, mostly adaptation ₋ One of the most common reasons for attrition during Patent tolerate exposure – no adverse effects occur drug development and adoption of post-marketing regulatory actions

What are the challenges in measuring the impact of pharmacovigilance processes? (Liver Safety Perspective) Potential actions Challenges Part I: Risk Analysis 1. Risk identification ⁻ Systematic protocols to assess DILI: ⁻ Optimal methods to identify DILI ⁻ Guidance for special populations ⁻ Diagnosis, causality assessment ⁻ Guidance for biological agents and predictive models ⁻ Analysis of signals during ⁻ At the pharmaceutical industry premarketing clinical trials level ⁻ Reach a consensus on terminology ⁻ At the regulatory level and define levels of evidence ⁻ Access to clinical data ⁻ Develop standardized electronic data capture systems

What are the challenges in measuring the impact of pharmacovigilance processes? (Liver Safety Perspective) Challenges Part II: Risk Analysis Potential actions ⁻ Promote well-designed studies 2. Risk Quantification ⁻ Combine large clinical trial data ⁻ DILI incidence sets during drug development ⁻ Drug prescription and dispensing ⁻ Identification & Validation of mechanistic-based biomarkers 3. Evaluation of Risk/benefit balance ⁻ Personalized medicine approaches ⁻ Type of studies ⁻ Promote research based on ⁻ Time lag between recognition international networking and and adoption of regulatory multidisciplinary bridging (ethnicity, measures pharmaceutical policies..)

Impact of the registry on liver safety 35 Anabolic Steroids Bentazepam Medicinal Herbs RIP+INH+PIZ Nimesulide Tetrabamate Ebrotidine 30 Medical Herbs 25 RIP+NH+PIZ 20 Ebrotidine 15 Anabolic Steroids 10 Nimesulide Tetrabamate 5 Bentazepam 0 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Impact of the registry on liver safety Latin America (%) Top individual agents implicated in DILI in Spain (%) 2 Carbamazepine 3 Rifampicin/ isoniazid/… 2 Diclofenac 2 4 Cyproteron 2 Isoniazid 5 2 Nitrofurantoin 3 Ibuprofen 5 Nimesulide 3 21 6 Diclofenac Amoxicillin/clavulanate 10 Amoxicillin/clavulanate 0 10 20 30 2 4 6 8 10 DILIN, US (%) Iceland (%) 2 Azithromycin 2 Atorvastatin 2 Cefazolin 3 3 4 Minocycline Nitrofurantoin 3 4 Sulfamethoxazole/trimet… 5 4 Nitrofurantoin Azathioprine 5 6 Isoniazid 10 16 Amoxicillin/clavulanate Amoxicillin/clavulanate 0 5 10 15 20 0 5 10 15 Bessone et al, Int J Mol Sci 2016 Chalasani et al, Gastroenterology, 2015 Björnsson et al, Gastroenterology, 2013

Impact of the registry on liver safety ₋ Registries have the potential to identify signals in a more efficient way Latin America (%) Top individual agents implicated – Consequently, adopting regulatory measures in shorter period of time in DILI in Spain (%) 2 Carbamazepine ₋ Registries help detect emergent problems: Autoimmune-DILI and problems related with 3 Rifampicin/ isoniazid/… 2 Diclofenac biological agents. 2 4 Cyproteron 2 Isoniazid 5 2 Nitrofurantoin ₋ Registries support confident decision-making for regulatory agencies 3 Ibuprofen 5 Nimesulide 3 21 6 Diclofenac Amoxicillin/clavulanate 10 Amoxicillin/clavulanate 0 10 20 30 2 4 6 8 10 DILIN, US (%) Iceland (%) How to measure the impact ? 2 Azithromycin 2 Atorvastatin 2 Cefazolin 3 3 - Measuring the time lag between signal recognition and regulatory measure adopted 4 Minocycline Nitrofurantoin 3 4 Sulfamethoxazole/trimet… 5 4 Nitrofurantoin Azathioprine - The decrease in the frequency of medication withdrawal in the post-marketing 5 6 Isoniazid 10 16 period Amoxicillin/clavulanate Amoxicillin/clavulanate 0 5 10 15 20 0 5 10 15 Bessone et al, Int J Mol Sci 2016 Chalasani et al, Gastroenterology, 2015 Björnsson et al, Gastroenterology, 2013