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Drug Safety Surveillance Process Overview:
®
MedDRA Application and Challenges From Clinical Trials to Post-Authorisation
Amarilys Vega, M.D, M.P.H., Sonja Brajovic, M.D., Jung Lee, R.Ph, Mark Vieder, R.Ph., Bane Bradic, M.D.
PSI International, Inc., USA
Objective: To describe the application of and challenges encountered in the use of the Medical Dictionary for Regulatory Activities
terminology (MedDRA® ) in the drug safety surveillance process including the FDA and EMEA perspectives.
Data Collection, Entry, and Storage
Collect, enter, and store in database all safety data
• Data collection must be complete and detailed to facilitate clinical interpretation, MedDRA® coding, and data
retrieval and analysis
• Information technology tools are necessary throughout the different phases of the Drug Safety Surveillance
process
Data Coding and Coding Quality Control
Develop and implement coding and quality control guidelines
MedDRA® Coding Guidelines and coding practices have great impact on:
 Data accuracy, consistency, and uniformity
 Data reconciliation, retrieval, and analysis
 Post-authorisation pharmacovigilance efforts
Example of an Adverse Event Narrative
2-3 weeks after starting Suspect drug, patient is fatigued, with no appetite, blood pressure 95/65 mmHg.
Diagnosed with ARF and hyperkalemia, due to pre-renal azotemia. Physician suspects known drug
interaction with patient’s on-going therapy. Patient’s medical history: hypertension, no prior renal
insufficiency.
Organisation’s Specific Coding Guidelines
Based on the ICH endorsed MedDRA® Term Selection: Points to Consider document and the
organisation’s specific objectives
1.
2.
3.
Coding by Organisation B
MedDRA 8.1
Coding by Organisation A
MedDRA 8.1
LLT Azotemia prerenal
1.
PT
Acute prerenal failure
SOC Renal
LLT Known drug-drug
2.
interaction medication error
PT
Labelled drug-drug
interaction medication error 3.
SOC Injury
LLT Blood pressure decreased
PT
Blood pressure decreased
SOC Investigation
Coding by Organisation C
before MedDRA 8.0
LLT
PT
SOC
LLT
PT
SOC
LLT
Acute renal failure
Renal failure acute
Renal
Hyperkalemia
Hyperkalaemia
Metabolism
Known drug-drug
interaction medication error
PT
Labelled drug-drug interaction
medication error
SOC: Injury
1.
2.
3.
LLT
PT
SOC
LLT
PT
SOC
LLT
PT
SOC
Acute renal failure
Renal failure acute
Renal
Blood pressure low
Hypotension
Vascular
Drug interaction
Drug interaction
General
Compare all available safety data for potential safety signals (i.e., data mining)
Clinical Trials
Data
MedDRA®
Conversion
Coded in other
Terminologies or in Different
versions of MedDRA®
MedDRA® Coded
+
Clinical Trials
Data
+
Organization’s
Postmarketing
Safety Data
USA Food and Drug Administration
Adverse Event Reporting System
(AERS)
FDA AERS is a computerized
information database designed to
support the FDA's post-marketing
safety surveillance program for all
approved drug and therapeutic
biologic products.
AERS replaced the Spontaneous
Reporting System in November
1997, with all legacy data converted
to MedDRA®. FDA AERS is a passive
surveillance system which collects
spontaneous adverse event data
submitted by manufacturers,
consumers and health professionals.
FDA Coding guidelines are
developed based on ICH endorsed
MedDRA® Term Selection: Points to
Consider document and FDA’s
coding principles. The goal is to
capture medical concepts described
in the narrative and classify them
into accurate MedDRA® terms.
Coding guidelines and practices are
regularly reevaluated and modified
according to FDA’s needs and
requirements, and according to
ICH-endorsed guidance.
MedDRA® coding accuracy is
monitored by a continuous quality
assurance process.
The use of MedDRA® is
discretionary under FDA’s
jurisdiction with exception to
electronic data submission.
European Medicines Agency (EMEA)
EudraVigilance System
Eudravigilance, the European data
processing network and
management system, launched in
December 2001 and developed
according to internationally agreed
standards, enables the electronic
data exchange and supports the
EMEA’s drug safety surveillance
program.
The EudraVigilance system supports
the electronic transmission of
Individual Case Safety Reports
(ICSRs)/Suspected Unexpected
Serious Adverse Reactions (SUSARs)
between the EMEA and national
Competent Authorities, marketing
authorisation holders (MAH),
applicants and sponsors of clinical
trials.
EudraVigilance supports the
Pharmacovigilance activities in the
pre- and post- authorisation phase
and contains two reporting modules:
• The EudraVigilance PostAuthorisation module (EVPM)
designed for post-authorisation
ICSRs
• The EudraVigilance Clinical Trial
module (EVCTM) designed for preauthorisation SUSARs
The use of MedDRA® is mandatory
under EMEA’s jurisdiction for both
clinical trials SUSARs and postauthorisation ICSRs.
• Safety data collected during clinical trials is incorporated into the product’s
approved label.
• Regulatory reviewers monitor products’ safety profiles. They search for
safety signals by reviewing reported data, case reports found in medical
literature, and data from other passive and active surveillance systems.
Most of this data is coded in MedDRA®.
• One of the tools employed by the reviewers to identify safety signals is data
mining. In-depth knowledge of MedDRA® is required for effective data
mining.
• Safety data collected along with drug class safety data will characterize the
initial safety profile of the product in development.
• Product label will reflect safety concerns identified thus far
• The terminology used in product label is not standardized (level of
MedDRA® hierarchy varies)
Safety Signal Generation
Clinical Trials
Data
Regulatory authorities monitor medicinal product safety, provide the
best available tools for storing and analyzing safety reports and take
action necessary to improve public health.
Other Sources of
Safety Data
Compare data from these sources and determine which combination of MedDRA® terms suggest a potential safety signal for a particular product
Safety Signal Evaluation
Drug Safety review:
• Create a case definition using MedDRA® terms which describe the clinical
Descriptive Epidemiology
Describe and summarize all available information pertaining to the adverse event of interest and the suspect product
and product definitions. Add literature cases to case series.
• Evaluate raw data from individual case reports and extract all relevant case
Other Sources
of Safety Data
Data Retrieval
suspect product.
• Create a case series by retrieving from reported data all cases fulfilling case
Create a “Case Definition”
Using MedDRA® Terms
Organisation’s
Safety Data
process of interest and create a search group containing all names for the
data stratifying information as necessary.
(i.e., medical literature, WHO)
• Provide a clinical assessment of the findings based on the nature of the
disease under treatment and adverse event characteristics.
Case 1
Case 2
Case 3
Case 4
Case n
• Address safety concerns identified during clinical trials by further data
collection through experimental studies.
Clinical assessment
Summarize
all case
information
Enhance
dataset
by abstracting
additional
information
Obtain
disease
Natural
history
data
Obtain
adverse
event’s typical
characteristics
data
• Scientists from within the regulatory and other organisations conduct
experimental and observational studies (large population-based databases).
• Use of MedDRA® depends on the characteristics of the study database and
When possible, code in MedDRA®
the existence of terminology bridges between MedDRA® and study
Analytic Epidemiology
Verify identified safety signals by means of observational and/or experimental epidemiological studies
Identify cases of interest
in large external
databases
(other standard
terminologies are bridged
to MedDRA® )
database’s particular terminology (ICD, SNOMED, etc.).
• Residual safety concerns addressed by further data collection through
Phase IV commitments: Experimental studies, post-marketing epidemiologic
Observational
Studies
Experimental
Studies
Descriptive
Epidemiology
Studies
Verify
Safety
Signal
studies, and other risk management strategies.
In-depth analysis
Actions
Assess clinical relevance of safety signal and take the necessary steps to improve drug safety
Regulatory actions:
• Develop product-specific Risk Management Strategy
• Assess safety issue’s impact on patient support and disease management programs
• Assess impact on product marketing
Regulatory authorities provide:
• Continuous assessment of new safety data and its impact on patient safety.
• Drug safety surveillance process guidelines.
• MedDRA® terminology improvement recommendations.
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