ich - e2d pharmacovigilance and drug safety - professor peivand pirouzi

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