02 AE - SAE- Safety reporting.ppt by wuzhenguang


									Safety Reporting
2004-2005: A “Perfect Storm” of Safety Concerns

                            Risk of suicidal ideation
                             associated with use of
                             antidepressants in children

                            Withdrawal of COX-2
                             analgesics and new
                             warnings about NSAIDs due
                             to increased risk of
                             cardiovascular adverse

                            Withdrawal of Tysabri due to
                             progressive multi-focal
Need for Safety Data Reporting
 Safety Data Management - most challenging aspect of the
  management and reporting of clinical trial data
 In investigative clinical research trials, one of the key
  objectives generally is to investigate, characterize,
  establish, or confirm the safety profile of an investigational
 Reporting of Safety should facilitate to identify the trends
  and salient features of the data, to ensure adequate
  reporting of results that pertain to product effects
 Goal of reporting safety data is to convey information that
  facilitate reliable conclusions to be drawn
Safety Relevant Data

  Adverse Events
  Laboratory data
  Vital signs
   (blood pressure, pulse rate, ECG,
   respiration, temperature, weight)
  Physical examinations + diagnostic
 Aspects of Safety Data Management

 Capture – How to gather the Safety information
  timely and effectively
 Process – how to set up channel of reporting which
  works without fail
 Report – How to report safety data to concern
  authority in expected time frame
 Analysis – How to get meaningful conclusion out
  of reported safety information
    There are 2 issues within the broad subject of
    clinical safety data management :
   Development of standard definitions and
    terminology for key aspects of clinical safety
   Appropriate mechanism for handling expedited
    (rapid) reporting, in the investigational (i.e., pre-
    approval) phase
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
 Ensure that normal ranges are properly linked to lab
  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
   Best Practices
 In order to ensure adequate attention to the collection of safety
  data, develop CRFs with teams of individuals from:
      Monitoring
      Data Management
      Statistics
      Regulatory Affairs
      Medical
 Consider the level of precision that can be attained in the study
  and select the CRF format for collecting AEs appropriate for
  that level. Also consider the level of precision in the analysis, to
  reduce the likelihood of over-interpretation or misinterpretations
    High precision
    Moderate precision
    Low precision
 Define severity, understanding its uses and limitations
Best Practices
  Consider related parameters for compounds with
   potential toxicity in specific body systems
  Examine laboratory data from the perspectives of
   categorical shifts, changes in magnitude for the group,
   individual significant values or changes, and listings
  Consider laboratory normalization techniques when
   combining data across studies or centers where
   varying normal ranges are used
     Ensure proper linkage with the units
     Include clear links for comparators and ensure linkage to the
      appropriate normal range
     In cases where normal ranges are not available or not
      obtainable, references ranges maybe used, which maybe
      derived from normal ranges that are available in the study or
      from a reference book
   Best Practices
 Include data managers and statisticians working together when
  considering computerization, management, reporting, and
  analysis of safety data. These are highly integrated and require
  joint considerations of individual team constituents
 Develop SOPs for data capture, data validation, statistical
  analysis, and reporting of data that include guidelines for this
  team approach
 Document the status and quality of safety data and include this
  documentation with the database
Best Practices
  Apply standards commensurate with the utilization of
   the results residing in the databases when using
   databases for safety reporting (expedited reporting,
   ongoing review by monitoring boards, routine reporting,
   etc.) If important decisions rely on the information,
   know the level of quality and the appropriateness of the
  Time-to-event analyses are only meaningful when the
   timing of the event is reliably known
Players in Monitoring Safety
Definition per ICH GCP

 Adverse Event (AE)
    An AE is any untoward medical occurrence in
   a patient or clinical investigation subject
   administered a pharmaceutical product. It does
   not necessarily have a causal relationship with
   this treatment. An AE can therefore be any
   unfavorable and unintended sign (including an
   abnormal laboratory finding), symptom, or
   disease temporally associated with the use of a
   medicinal (investigational) product.
 Definition per ICH GCP
Adverse Drug Reaction (ADR)
  In the pre-approval clinical experience with a new
 medicinal product or its new usages, particularly as
 the therapeutic dose (s) may not be established, all
 noxious and unintended responses to a medicinal
 product related to any dose should be considered
 adverse drug reactions. The phrase "responses to a
 medicinal product” means that a causal relationship
 between a medicinal product and an adverse event
 is at least a reasonable possibility, I.e., the
 relationship cannot be ruled out.
  Regarding marketed medicinal products: A response
 to a drug that is noxious and unintended and that
 occurs at doses normally used in man for
Adverse Events Classifications
 Seriousness
   Refers to clinical significance of adverse event
   Seriousness is different from severity. Eg.,
    Severe headache
   Any adverse event that
     Results in death
     Is life-threatening
     Requires inpatient hospitalisation or prolongation of
      existing hospitalisation
     Results in persistent or significant
      disability / incapacity
     Is a congenital anomaly / birth defect
Adverse Events Classifications

    Expectedness
      An expected event is one where the
       specificity and severity of the event are
       consistent with the information in the
       investigator brochure or labeling for the
      An unexpected event is one where the
       specificity or severity is not consistent with
       the applicable product information
      Expectedness has nothing to do with
       expected complications of underlying
 Adverse Events Classifications
 Severity
   Mild - The AE does not interfere in a significant
    manner with the patient’s normal functioning level
   Moderate - The AE produces some impairment of
    functioning, but is not hazardous to health
   Severe - The AE produces significant impairment of
    functioning or incapacitation and is a definite hazard
    to the patient’s health (usually corresponding to a
    serious AE)
   Life-threatening - The patient is in immediate danger
    of death unless intervention is done. It does not mean
    that the patient may die at some time in the future
    from the event or may have died if the event had
    been more serious or specific
Adverse Events Classifications
 Causal Relationship
   Related – There is a reasonable possibility that
    the event could have been caused by the drug.
   Not Related - No causal relationship exists
    between the study drug and the event, but an
    obvious alternative cause exists, e.g. the subject’s
    underlying medical condition or concomitant
     Expected               Mild                         Possible
     Unexpected Intensity                                 Probable
                            Moderate    Relationship
                            Severe                       Definite

Not Serious
  Expected                  Mild                       None
  Unexpected    Intensity
                            Moderate    Causal         Possible

                            Severe     Relationship    Probable

Adverse Events Include:

  Exacerbation/worsening of pre-existing
  Increased frequency or intensity of a pre-
   existing episodic event or condition
  Condition diagnosed (manifestation) after
   start of study (medication) even though
   possibly present prior to start of study
Adverse Events do not Include:

   Medical or surgical procedure ( BUT the
    indication leading to the procedure is an AE)
   Pre-existing diseases and condition, which do
    not change
   The disease being studied (lack of efficacy) –
    might be handled differently for different
   Death (death is an outcome, the underlying
    cause is an AE)
Who’s responsibility is it?
 21 CFR 312.64 (Investigator reports) requires
 investigators to report adverse events during clinical
 trials. It states:

 “Safety reports. An investigator shall promptly report
 to the sponsor any adverse effect that may be
 reasonably regarded as caused by, or probably
 caused by, the drug. If the adverse effect is alarming,
 the investigator shall report the adverse effect
Who’s responsibility is it?
  The ICH GCPs also contain a section (4.11) on
  safety reporting. In this section, it states that:

   “All serious adverse events (SAEs) should be
  reported immediately to the sponsor except for
  those that are designated in the protocol or
  investigator brochure as not needing to be
  reported immediately. The initial report should
  be followed by a detailed written report.
   The investigator should comply with regulatory
  requirements for reporting unexpected SAEs to
  regulatory authorities and the IRB”.
               Process Involved

                                            Sponsor sends
Investigator   Sponsor      Sponsor         expedited report
sends SAE to   enters SAE   performs        to health
sponsor        into SAE     medical         authorities,
               database     assessment +    ethics
                            assesses        committees and
                            reportability   investigators
Expedited Reporting
It is the sponsor’s responsibility to report to the
 regulatory agency serious, unexpected, related
 events that are fatal or life threatening, as follows:
    Initial report immediately after awareness of event, by
     telephone and/or facsimile – within 7 calendar days
    Written report detailing all the information about the
     event – within 15 calendar days

Adverse events that are serious, unexpected and
 related to the investigational drug but not fatal or
 life threatening, must be reported by sponsor to
 the regulatory agency within 15 calendar days
 after first awareness of event
                                                 Submit to

              Investigator                      Drug Safety
              documents                         enters SAE
              SAE report                        into Drug
                              SAE form
              form                              Safety
              immediately                       Database

experiences                                                    Reconciliation

               Investigator    Monitor       Data Management
                documents      collects          enters CRF
                 patient’s     CRF                 data in
               data in CRF                    clinical database
SAE Reporting
  Submit as soon as the relevant information is
  Relevant information – explains or clarifies the
   circumstances of the reported adverse event
   experience (i.e. admitting notes, history and
   physical examination, test results, laboratory
   reports, discharge summary, death reports and
   possible autopsy findings)
  Extent of follow-up will depend on sponsor
   specifications, drug relatedness, type of event
   and availability of documentation
SAE Reporting

  Timelines are important
  Investigator/Sponsor must notify IRB/EC
   of all serious adverse events that occur
   at his or her site after the SAE form is
  Investigator must also notify IRB of all
   serious, unexpected, fatal or life-
   threatening adverse events that occur at
   any site (IND safety reports)
The International Conference on Harmonization of
Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) has issued
several guidelines to provide guidance to industry
for how to manage and report clinical trial safety
data. Some of them are:
    E1A
    E2A
    E2B
    E2C
    E3
    E5
    E6
    E9

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