ADVERSE EVENTS and RISK MANAGEMENT

Nora Bucko Nora.Bucko@BiogenIdec.com

Objectives
Introduction Definitions Causality Coding Data Collection Responsibilities Clinical trial reporting timeframes Postmarketing reporting timeframes Case Study Gilenya Risk Management
TM

Introduction

Introduction
Goals of Drug Safety: Minimize harm to patients Understand the medical toxicity of the product Establish benefit/risk ratio

Introduction
A drug is considered safe when its risks have been identified and are judged to be acceptable (when weighed against the potential benefit).

Introduction Continuous Assessment of Risk

Preclinical-single and repeat dose toxicity in animals (mutagenicity, carcinogenicity, reproductive studies) Clinical
Phase I: Safety in humans Phase II and III: Efficacy and Safety Phase IV: Long term safety, safety in special populations (pediatric and geriatric patients)

Definitions

Definitions
Consistent standards and definitions are required in order to:
accurately and effectively analyze safety data meet worldwide regulatory reporting requirements for adverse events during clinical development

Definitions Definitions
Adverse Event: Event any untoward medical occurrence (including significant abnormal laboratory findings), symptom or disease temporally associated with the use of study drug treatment during a clinical study, whether or not considered related to the use of study treatment.

Definitions
Adverse Drug Reaction:
all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions
where responses to a medicinal product means there is a reasonable possibility that the drug caused the event

Definitions
Serious Adverse Event: Any adverse drug experience occurring at any dose that results in any of the following outcomes:
Death Life-threatening adverse drug experience Inpatient hospitalization or prolongation of existing hospitalization

Definitions
Serious Adverse Event
A persistent or significant disability/incapacity A congenital anomaly/birth defect Important events that may not result in the above, but based on medical judgment, they may require medical or surgical intervention to prevent one of the outcomes listed above.

Definitions
Unexpected:
Not identified in investigators brochure or package insert/product labeling Greater in severity or specificity than as described in the Investigators Brochure or Product labeling

Definitions
Causal relationship:
Associated with the use of the drug means there is a reasonable possibility that the experience may have been caused by the drug
21 CFR 312.32

Causality

Causality
How to determine causality:
Is this a known reaction to the drug? Is there a temporal relationship to drug administration? Are there alternative explanations, e.g. procedures, concomitant medications or concomitant diseases?

Causality
Factors to consider:
Positive dechallenge-did symptoms abate (decrease or disappear) on dose reduction or discontinuation of drug? Positive rechallenge-did symptoms recur on readministration of drug?

CODING

Coding
Standard medical terminology with codes needed for:
Adverse event using standard dictionaries, e.g. MEDDRA Drug treatment and concomitant medications Medical History and Procedures

Data Collection

Data Collection Standard Adverse Event

Severity-Mild, Moderate, Severe Dates-onset, resolution or continuing Frequency-single or multiple episodes Relationship: Investigators causalitylikely,definitely, not related, possibly, probably, unlikely Action taken with study drug, treatment required, outcome of event

Clinical Trials

Clinical Trials
Reporting Timeframes Expedited report Serious, Unexpected and Associated
7 Day Phone call or Fax to FDA for Lifethreatening or Fatal Reaction 15 Calendar Day submit IND Safety Report on MedWatch Form to FDA

Clinical Trials
Routine adverse events
Recorded on CRF Annual IND Report Final Study Report Post-Marketing Periodic Report (include all IND reports) from clinical trials

Responsibilities

Sponsor Responsibilities
Submit IND Safety Report to FDA Send Letter to all Investigators using study drug If applicable, update Protocol, Investigator Brochure and Informed Consent Consult clinical experts

Investigator Responsibilities
Immediately report all SAEs to Sponsor/CRO, complete SAE form Inform Institutional Review Board of SAE. Record all adverse events on CRF and in patients medical record (source document) Medically manage patient (consult sponsor, adjust study drug dosage, administer corrective treatment)

CRA Responsibilities
Train site in recognition and reporting of Serious Adverse Events During monitoring visit, if AE or SAE identified, inform coordinator/Investigator Request follow-up information (hospital discharge summaries, autopsy, laboratory reports)

CRA Responsibilities
Discuss safety trends and findings with Investigator and Sponsor Medical Director Review Serious Adverse Event form for accuracy and completion Alert Sponsor Regulatory department if 15 Day IND report is to be filed

FDA Actions
Approve labeling changes Boxed Warnings Dear Doctor letter Request additional investigation and/or clinical trials Clinical Hold Recall

Postmarketing Pharmcovigilance

Postmarketing Pharmacovigilance
Spontaneous reporting system for evaluation of drug safety:
mandatory for manufacturers voluntary for health care professionals in clinical practice
limitations- no control group, no denominator, cannot calculate incidence

Postmarketing Pharmcovigilance
Reporting rates of adverse events are affected by many factors: length of time on market initial rate of sale unexpectedness of events publicity, media, publication solicitation

Postmarketing Pharmcovigilance
Reporting Timeframes:
Expedited reporting (15 days) of serious and unexpected events; causality implied Quarterly periodic reports to FDA for first 3 years of marketing, then yearly Periodic Safety Update (PSUR) to Europe (EMEA)

Periodic Review
Build knowledge base of drug Compile and revise product safety profile Update safety section of Informed Consent Update Product labeling if marketed Update Investigators Brochure if investigational drug

Risk Management
FDA Guidances
Premarketing Risk Assessment Good Pharmacovigilance Practices and Pharmacoepidemiogic Assessment Development and Use of Risk Minimization Action Plans (RiskMAP) ICH Harmonised tripartite guideline ICHE2 Pharmacovigilance planning

Case Study:GILENYA TM

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