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

Judith Sanabria, M.D. Clinical Pharmacology

Biomedical Research Institute of Málaga (IBIMA), Spain

“Challenges of measuring the impact

• f pharmacovigilance processes”

Workshop: measuring the impact of pharmacovigilance activities

5-6 December 2016 European Medicines Agency, London, United Kingdom

Why is it important to measure the impact

• f 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 Is it possible to focus on measuring the impact in certain type of adverse drug reactions (ADRs)…?

Adopted from PRAC strategy on measuring the impact of Pharmacovigilance activities, 2016

Classification of ADRs

Are there specific ADRs that require more attention than

• thers?

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

• thers?

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

Identification of the majority of Type B ADRs

PHASE 3

5000 10000 15000 20000 25000 PHASE 1 PHASE 2 PHASE IV

50 volunteers 250 volunteer

Identification of the majority

• f Type A ADRs

Marketing authorization 2 000 volunteer More than de 3000 Number of Subjects

Death / Tx Acute liver failure Serious injury, hospitalization Detectable slight liver functional loss Just enzyme elevations, mostly adaptation Patent tolerate exposure – no adverse effects occur

Drug-Induced Liver Injury severity (ADR Type B)

3.9-6.7%

Robles-Díaz et al, Gastroenterology, 2014 Chalasani et al, Gastroenterology, 2015

₋ It is responsible for more than 10% of all cases of acute liver failure ₋ DILI is one of the most frequent reason for marketed drug withdrawal and modification of labelling ₋ More than 1,100 medicines, natural products, vitamins, dietary supplements, recreational and illicit compounds have been reported to cause DILI ₋ One of the most common reasons for attrition during drug development and adoption of post-marketing regulatory actions

What are the challenges in measuring the impact of pharmacovigilance processes? (Liver Safety Perspective)

• 1. Risk identification

⁻ Optimal methods to identify DILI ⁻ Diagnosis, causality assessment and predictive models ⁻ At the pharmaceutical industry level ⁻ At the regulatory level ⁻ Access to clinical data

Potential actions

⁻ Systematic protocols to assess DILI: ⁻ Guidance for special populations ⁻ Guidance for biological agents ⁻ Analysis

• f

signals during premarketing clinical trials ⁻ Reach a consensus on terminology and define levels of evidence ⁻ Develop standardized electronic data capture systems

Challenges Part I: Risk Analysis

• 2. Risk Quantification

⁻ DILI incidence ⁻ Drug prescription and dispensing

• 3. Evaluation of Risk/benefit balance

⁻ Type of studies ⁻ Time lag between recognition and adoption

• f

regulatory measures ⁻ Promote well-designed studies ⁻ Combine large clinical trial data sets during drug development ⁻ Identification & Validation

• f

mechanistic-based biomarkers ⁻ Personalized medicine approaches ⁻ Promote research based

• n

international networking and multidisciplinary bridging (ethnicity, pharmaceutical policies..)

What are the challenges in measuring the impact of pharmacovigilance processes? (Liver Safety Perspective)

Challenges Part II: Risk Analysis Potential actions

Impact of the registry on liver safety

5 10 15 20 25 30 35 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Anabolic Steroids Bentazepam Medicinal Herbs RIP+INH+PIZ Nimesulide Tetrabamate Ebrotidine

RIP+NH+PIZ Medical Herbs Ebrotidine Bentazepam Nimesulide Tetrabamate Anabolic Steroids

10 20 30

Amoxicillin/clavulanate Ibuprofen Isoniazid Diclofenac

21 3 3 2 2 2 2

Top individual agents implicated in DILI in Spain (%)

5 10 15 20

Amoxicillin/clavulanate Azathioprine Nitrofurantoin Atorvastatin

16 6 4 4 4 3 2

Iceland (%)

5 10 15

Amoxicillin/clavulanate Isoniazid Nitrofurantoin Sulfamethoxazole/trimet… Minocycline Cefazolin Azithromycin

10 5 5 3 3 2 2

DILIN, US (%)

Bessone et al, Int J Mol Sci 2016 Chalasani et al, Gastroenterology, 2015 Björnsson et al, Gastroenterology, 2013

2 4 6 8 10

Amoxicillin/clavulanate Diclofenac Nimesulide Nitrofurantoin Cyproteron Rifampicin/ isoniazid/… Carbamazepine 10 6 5 5 4 3 2

Latin America (%)

Impact of the registry on liver safety

10 20 30

Amoxicillin/clavulanate Ibuprofen Isoniazid Diclofenac

21 3 3 2 2 2 2

Top individual agents implicated in DILI in Spain (%)

5 10 15 20

Amoxicillin/clavulanate Azathioprine Nitrofurantoin Atorvastatin

16 6 4 4 4 3 2

Iceland (%)

5 10 15

Amoxicillin/clavulanate Isoniazid Nitrofurantoin Sulfamethoxazole/trimet… Minocycline Cefazolin Azithromycin

10 5 5 3 3 2 2

DILIN, US (%)

Bessone et al, Int J Mol Sci 2016 Chalasani et al, Gastroenterology, 2015 Björnsson et al, Gastroenterology, 2013

2 4 6 8 10

Amoxicillin/clavulanate Diclofenac Nimesulide Nitrofurantoin Cyproteron Rifampicin/ isoniazid/… Carbamazepine 10 6 5 5 4 3 2

Latin America (%)

Impact of the registry on liver safety

₋ Registries have the potential to identify signals in a more efficient way – Consequently, adopting regulatory measures in shorter period of time ₋ Registries help detect emergent problems: Autoimmune-DILI and problems related with biological agents. ₋ Registries support confident decision-making for regulatory agencies

How to measure the impact ?

• Measuring the time lag between signal recognition and regulatory measure adopted
• The decrease in the frequency of medication withdrawal in the post-marketing

period