Clinical Trial Safety Data Management

An introduction

T V S Sarma

February 19, 2009

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What is Safety Data?
• Safety data refers to the data about…
• Adverse Events / Experiences (AE)
• Adverse Event / Experience
• Serious Adverse Event / Experience (SAE)
• Adverse Drug Reactions (ADR)
• Adverse Drug Reaction (ADR)
• Unexpected ADR
• Serious ADR

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What is safety data management?
It is the process of capturing, management
and reporting of Safety Data.

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Definition of Terms
• Adverse Event / Experience
• Any untoward medical occurrence in a patient
or clinical investigation subject, administered a
pharmaceutical product and which does not
necessarily have to have a causal relationship
with this treatment

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…definition of Terms
• Adverse Drug Reaction
• In case of a pre-approval clinical experience:
a noxious and unintended responses to a medicinal
product related to any dose should be considered
adverse drug reactions
• For marketed medicinal products:
A response to a drug which is noxious and
unintended and which occurs at doses normally used
in man for prophylaxis, diagnosis, or therapy of
disease or for modification of physiological function

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…definition of Terms
Unexpected Adverse Drug Reaction
• An adverse reaction, the nature, intensity or
incidence falls outside the information
provided in
• Investigator's Brochure for an unapproved
investigational medicinal product
• The package insert of a marketed drug.

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…definition of Terms
• Serious Adverse Event and Serious Adverse Drug
Reaction
Any untoward medical occurrence that, at any dose that:
• Results in death
• Is life threatening
• Requires inpatient hospitalization or prolongation of
existing hospitalization
• Results in persistent or significant disability/incapacity, or
• Is a congenital anomaly/birth defect

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Minimum standards
• Ensure compliance with regulations.
• Ensure that the standard of quality supports the utilization of
the data.
• Ensure that conclusions about the safety profile of a
compound can be reliably drawn from the database.
• Ensure that safety risks are identified and reported accurately.
• Ensure that normal ranges are properly linked to laboratory
data. If normal ranges are unavailable, ensure that the
reference ranges used are documented as such. This is
especially crucial when normal ranges are updated frequently.

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Relevant ICH guidelines
• E1: The Extent of Population Exposure to Assess
Clinical Safety for Drugs Intended for Long-Term
Treatment of Non-Life-Threatening Conditions
• E2A, E2B and E2C: Clinical Safety Data
Management guidelines that provide guidance for
definitions and standards for expedited reporting,
data elements for transmission of individual case
safety reports, and for periodic safety update reports
for marketed drugs.
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…Relevant ICH guidelines
• E3: Structure and Content of Clinical Study
Reports
• E5(R1): Ethnic Factors in the Acceptability of
Foreign Clinical Data
• E6(R1): Good Clinical Practice, Consolidated
Guidelines
• E9: Statistical Principles for Clinical Trials

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Safety reporting
• Safety data are reported and examined at various
stages of an investigation and by different assessors.
• IND regulations specify expedited reporting for
serious or alarming adverse events
• Studies generally have Safety Data Management
Boards that review data as they are accumulated
• FDA requires that sponsors provide them with what
they need to meet their obligations to Congress and
to the public
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 Safety reporting:
What Should be Reported?
• Single Cases of Serious, Unexpected ADRs
• Other Observations
• For an "expected," serious ADR, an increase in the rate of
occurrence which is judged to be clinically important.
• A significant hazard to the patient population, such as lack
of efficacy with a medicinal product used in treating life-
threatening disease.
• A major safety finding from a newly completed animal
study (such as carcinogenicity).

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 Reporting Safety Data
Any AE or ADR that is serious or life
threatening or fatal need be
• …reported by Sponsor to regulatory authority
in 15 calendar days
• …reported by investigator to sponsor in 24
hours
• …reported by Investigator to Ethics
committee in 7 days
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 Capture, Management and Reporting
Of Safety Data
These are the points to consider regarding safety data
• Precision
• High Precision
• Moderate Precision
• Low Precision
• Severity
• Dictionaries
• WHOART
• COSTART
• MedDRA
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…Capture, Management and Reporting
Of Safety Data
• Encoding
• Avoid use of adjectives as initial words (e.g., “weeping wound” may
be coded to “crying” or “faint rash” may be coded to “syncope”)
• Avoid use of symbols and abbreviations in the AE text field (symbols
may be interpreted by different individuals differently)
• Avoid inclusion of severity (e.g., “severe headache” in the AE text
box inhibits auto-encoding; severity should be recorded in the
severity box, not the AE text box)
• Ensure AE text has clinical meaning (e.g., “bouncing off the walls”
and “feeling weird” are difficult to interpret)
• Ensure AE text has clear meaning (e.g., “cold feeling” may be
interpreted as “chills” or “flu symptoms”)

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Capture, Management, and Reporting
of Laboratory Data
• One of the most challenging aspects of
managing laboratory data is linking the data to
the appropriate normal range
• In cases where normal ranges are not
available or not obtainable, reference ranges
may be used
• Normalization techniques for laboratory data
are often employed for convenience of
combining data across studies
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 Other Data
• Safety data can have forms other than AEs and laboratory
values. Capture of data from specialty tests (e.g.,
electrocardiograms, electroencephalographs) requires
understanding the common data derived from the test, the
format, precision, and special attributes
• Physical examinations are customary in clinical trials. In a
broad sense, the physical exam is a screening method; if an
unexpected, significant abnormality is detected during a
physical exam, there is generally a specialty test to confirm
the event. The data with greater reliability, then, is the
specialty test

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 …other data
• In considering data capture, free-text
commentary boxes are generally discouraged

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 SAE Data
• Expedited reports are required by regulatory
agencies for certain serious adverse events
• In many companies, the receiving of SAE
reports, computerizing and managing of these
reports is the responsibility of a dedicated
group, which is often separate from the Data
Management group

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 General Safety Data
• The FDA provides specific guidance to industry that reflects thinking
within the Agency about safety data
• the FDA described the concept of clinical domains for a review of the
following systems
• Cardiovascular
• Gastrointestinal
• Hemic and Lymphatic
• Metabolic and endocrine
• Musculoskeletal
• Nervous
• Respiratory
• Dermatological
• Special Senses
• Genitourinary
• Miscellaneous.

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 …general Safety Data
FDA specifies that an NDA be reviewed against
each clinical domain with two key questions
as goals
• Are the safety data adequate to assess the
influence of the product on the clinical domain?
• What do the data indicate about the influence of
the product on the clinical domain?

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 Center effects on safety data
• The investigator as an individual (the bedside
manner, personal biases, peculiar methods of
assessment)
• The environment (equipment, SOPs, staff,
etc.)
• The subject population (those who frequent
the hospital or clinic, VA hospital, university
hospital, country clinic, etc.)
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 Recommended Standard Operating
Procedures
• Coding of adverse events
• Maintenance of coding dictionaries
• Reconciliation of serious AEs in SAE
database with clinical trial database
• Management of AE analysis file
• Management of laboratory data and normal
ranges
• Preparing integrated summaries of safety data
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 Terminology Relevant to Safety Data
Management
• AE: Adverse Event or Adverse Experience
• SAE: Serious Adverse Event/Experience
• ADR: Adverse Drug Reaction
• SADR: Serious Adverse Drug Reaction
• UADR: Unexpected Adverse Drug Reaction
• SUSAR: Suspected Unexpected SAE
• EMEA: European Medical Evaluation Agency
• CDER: Center Drug Evaluation and Research
• CBER: Center for Biologics Evaluation and Research
• CRF: Case Report / Record form

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 …terminology
• FDA: Food and drug Administration
• EAB: Ethical Advisory Board
• IFPMA: International Federation of Pharmaceutical
Manufacturers Association
• ATC: Anatomical Chemical Classification
• PT: Preferred Terms
• SOC: System Organ Class
• HLT: High Level Term
• HLGT: High Level Group Term
• LLT: Low Level Term

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 References
• GCDMP Version 4 Chapter on Safety Data
Management and Reporting
• ICH E2A
• ICH E2B
• ICH E2C

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That will be all

Thank you

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