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ICH - E2D Pharmacovigilance and Drug Safety - Pharmaceuticals
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Post-Approval Safety Data Management: Definitions and Standards for Expedited
Reporting
ICH-E2D
Professor Peivand Pirouzi 2010
Definition and Terminology Basic Terms
Adverse Event (AE) (or Adverse 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.
Any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Definition and Terminology Basic Terms
Adverse Drug Reaction (ADR) All noxious and unintended responses to a
medicinal product. “responses to a medicinal product” means that a
causal relationship between a medicinal product and an adverse event is at least a reasonable possibility.
Definition and Terminology Basic Terms
Adverse Drug Reaction (ADR) A reaction in contrast to an event is characterized
by the fact that a causal relationship between the drug and the occurrence is suspected. “if an event is spontaneously reported, even if the
relationship is unknown or unstated, it meets the definition of an adverse drug reaction.
Definition and Terminology Serious Adverse Event or Adverse Drug Reaction
Serious adverse event / ADR (experience) Results in death. Is life-threatening, Requires inpatient hospitalization or prolongation of
existing hospitalization Results in persistent or significant
disability/incapacity, Is a congenital anomaly/birth defect.
Definition and Terminology Basic Terms
Unexpected Adverse Drug Reaction If AE is not consistent with the term or description
used in the product labeling (Package Insert or summary of Product Characteristics) If uncertain whether an ADR is expected or
unexpected, the ADR should be treated as unexpected. ADR with fatal outcome should be unexpected unless
the local /regional product labeling states that the ADR might be associated with a fatal outcome.
Definition and Terminology Basic Terms
Unexpected Adverse Drug Reaction Drug Class ADRs considers expected if the event is
in the local /regional product labeling of the specific drug.
Definition and Terminology Basic Terms
Unexpected Adverse Drug Reaction “Listed or unlisted” terms describe the
expectedness of ADRs in association with the Development Core Safety Information (DSCI) in an Investigator’s Brochure.
Definition and Terminology Basic Terms
Unexpected Adverse Drug Reaction Labeled or unlabeled (Expected or unexpected)
are terms should be used in connection with official product information for marketed medicines such as US Package insert, an EU SPC or other country data sheets.
Definition and Terminology Basic Terms
Healthcare Professional (HP) A medically – qualified person such as physician,
dentist, pharmacist, nurse, coroner or as otherwise specified by local regulations.
Consumer A person who is not a healthcare professional
such as a patient, lawyer, friend, or relative of a patient.
Sources of individual Case Safety Reports Unsolicited Sources
Spontaneous Reports Literature
Internet
Other Sources
Sources of individual Case Safety Reports Unsolicited Sources
Spontaneous Reports A communication by HP or consumer to a company,
Regulatory Authority or other organization. Describes one or more adverse drug reactions
A patient was given one or more medicinal products Not reported from a study or any organized data
collection scheme
Sources of individual Case Safety Reports Unsolicited Sources
Spontaneous Reports e.g. healthcare professional letter publication in the press Questioning of HP by company representatives Consumer adverse reaction reports
Note: If reports received from consumers which do
not qualify for regulatory reporting, the cases should be retained.
Sources of individual Case Safety Reports Unsolicited Sources
Literature Reports MAH regularly should review the reference
databases or literatures. Frequency of the literature searches depends to
local requirements or at least every two weeks.
Sources of individual Case Safety Reports Unsolicited Sources
Literature ADR Reports Identifiable patient Report source (a copy of article to sent if
requested) Expedited reporting time clock starts as soon as
minimum criteria is available If product source not specified, the MAH should
assume that the product is its product. (the report should indicate that the specific brand was not identified).
Sources of individual Case Safety Reports Unsolicited Sources
Literature Reports If multiple products are in the literature, a report
should be submitted only by the applicant whose product is suspected. Suspected product which is identified by the
article’s author
Sources of individual Case Safety Reports Unsolicited Sources
Internet report If MAH become aware of an ADR on a website and
is not managed by MAH, the MAH should review and determine the reportability of the ADR.
Sources of individual Case Safety Reports Unsolicited Sources
Internet report Unsolicited cases should be handled as
spontaneous reports Verify the reporter refer to existence of a real
person (verify the patient and reporter exist) e.g. report from email
Sources of individual Case Safety Reports Unsolicited Sources
Other Sources A non medical sources e.g. the lay press or other
media Should be handled as a spontaneous report
For reportability, the same criteria should be
applied as for other reports
Sources of individual Case Safety Reports Solicited Sources
Reports Derived from Organized Data Collection Systems Clinical Trials Registries Post approval named patient use programs SAP) Other patient support and disease management
programs Surveys of patients or healthcare providers
Sources of individual Case Safety Reports Solicited Sources
Reports Derived from Organized Data Collection Systems Should not be considered as spontaneous reports.
Should be classified as study reports. Should have causality assessment by HP or MAH.
Sources of individual Case Safety Reports Contractual Agreements
Marketing of medicines takes place between two or more company
May market same product in the same or different counties/region
This can be a complex issue Define in the agreements, the processes for exchange
of safety information, including timelines and regulatory reporting Process to be in place to avoid duplicate of the
reporting
Sources of individual Case Safety Reports Contractual Agreements (cont.d)
Safety personnel to be involved in development of any agreements One company to be responsible for literature
screening MAH is ultimately responsible for regulatory reporting
Minimize the data exchange period between
contracting partners and MAH
Sources of individual Case Safety Reports Regulatory Authority Sources
Individual serious unexpected adverse drug reaction reports (ISUADR) originating from foreign regulatory authority to be expedited reporting to other authorities by MAH Do not report SADR without new information
to the originating regulatory authority unless specified by local regulations
Standards for Expedited Reporting What Should be Reported
Serious and unexpected ADRs (15 days) Serious, Expected ADRs (varies among
countries) (PSUR)
Standards for Expedited Reporting What Should Not be Reported
Non-Serious and Unexpected ADRs Non-Serious and Expected ADRs
Note: These to be reported in the PSUR Note: FDA requires everything
Standards for Expedited Reporting What Should Not be Reported
Other observations Any observation that could change the risk benefit
evaluation of the product to be communicated to RA in accordance with local regulation as soon as possible
E.g. lack of efficacy with a drug used in a serious disease.
Standards for Expedited Reporting What Should Not be Reported
Lack of Efficacy Evidence of lack of efficacy should be discussed in
the PSUR
Medicinal Products used for the treatment of life-threatening/serious diseases, vaccines and contraceptives, the lack of efficacy report should be considered for expedited reporting.
Standards for Expedited Reporting What Should Not be Reported
Overdose Collect any information on overdose Reports with no associated adverse outcome not
to be reported as Adverse Reactions. SADR are consider subject to expedited reporting,
unless specified by local regulation. Follow up to ensure the information is as
complete as possible with regard to symptoms, treatment and outcome.
Standards for Expedited Reporting Minimum Criteria for Reporting
Minimum Criteria for Reporting An identifiable reporter
An identifiable patient
An adverse reaction
Suspect product
Standards for Expedited Reporting Reporting Time Frames
All Serious, Unexpected ADRs No later than 15 calendar days. The date report fulfills minimum criteria
considered day 0
Standards for Expedited Reporting Reporting Time Frames
All Serious ADRs Time frames varies among countries depending on
source, expectedness and outcome.
Standards for Expedited Reporting Good Case Management Practices
Reports to be Authentic
Accurate
Complete as possible
Non duplicative
Standards for Expedited Reporting Assessing Patient and Reporter Identifiability
Identifiability Verify the existence of a patient and a reporter Apply local data privacy laws Prevent duplication of the report
Identifiable Patient Age or age category (adolescent, adult, elderly) Gender Initials Date of Birth Name Patient identification number
Standards for Expedited Reporting Assessing Patient and Reporter Identifiability
Identifiable Reporter All parties providing the information should be
identifiable
Standards for Expedited Reporting The Role of Narratives
Objective of Narratives Summarize all relevant clinical information Patient characteristics Therapy details Medical history Clinical course of the events Diagnosis Outcome Laboratory evidence Any other information supports or refutes an ADR
Standards for Expedited Reporting The Role of Narratives
Objective of Narratives Avoid abbreviations and acronyms (except of
laboratory parameters and units) Summarize the autopsy or post-mortem finding Reflect the Terms e.g. adverse event, ADRs,
indication and medical conditions in appropriate data field
Standards for Expedited Reporting Clinical Case Evaluation
Medical Review Ensure correct interpretations of medical information Review for the quality and completeness Is a diagnosis possible? Have the relevant diagnostic procedures been
performed? Were alternative causes of the reactions (s)
considered? What additional information is needed? Use the verbatim term is used by the reporter
Standards for Expedited Reporting Follow-up information
Prioritization of case reports 1.Serious and unexpected 2.Serious and expected 3.Non-serious and unexpected 4.Cases might lead to labeling change
Standards for Expedited Reporting Follow-up information
Obtain the follow up information via 1.Telephone call 2.Site visit 3.Written request (make specific questions by
questioners or specific form) Note: if information refused by the reporter, a
regulatory authority might be able to help in obtaining follow up data
Standards for Expedited Reporting How to Report
CIOMS-I It’s important that certain basic data elements be included with any
expedited report, whether in a tabular or narrative presentation. MedDRA to be used for coding medical information
Links: Canada Guide book:
http://www.hc-sc.gc.ca/dhp-mps/medeff/report-declaration/ar-ei_form-eng.php
CIOMS Form: http://www.hc-sc.gc.ca/dhp-mps/medeff/report-declaration/ar-
ei_form-eng.php