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 TermsAdverse 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 TermsAdverse 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 TermsAdverse 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 ReactionSerious 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 TermsUnexpected 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 TermsUnexpected 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 TermsUnexpected 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 TermsUnexpected 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 TermsHealthcare 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 SourcesSpontaneous ReportsLiteratureInternetOther Sources
Sources of individual Case Safety Reports Unsolicited SourcesSpontaneous 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 SourcesSpontaneous 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 SourcesLiterature 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 SourcesLiterature 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 SourcesLiterature 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 SourcesInternet 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 SourcesInternet 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 SourcesOther 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 SourcesReports 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 AgreementsMarketing of medicines takes place between two or more companyMay market same product in the same or different counties/regionThis 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 agreementsOne company to be responsible for literature screeningMAH is ultimately responsible for regulatory reportingMinimize the data exchange period between contracting partners and MAH
Sources of individual Case Safety Reports Regulatory Authority SourcesIndividual serious unexpected adverse drug reaction reports (ISUADR) originating from foreign regulatory authority to be expedited reporting to other authorities by MAHDo not report SADR without new information to the originating regulatory authority unless specified by local regulations
Standards for Expedited Reporting What Should be ReportedSerious and unexpected ADRs (15 days)Serious, Expected ADRs (varies among countries) (PSUR)
Standards for Expedited Reporting What Should Not be ReportedNon-Serious and Unexpected ADRsNon-Serious and Expected ADRs Note: These to be reported in the PSUR Note: FDA requires everything
Standards for Expedited Reporting What Should Not be ReportedOther 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 ReportedLack 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 ReportedOverdose 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 ReportingMinimum Criteria for Reporting An identifiable reporter An identifiable patient An adverse reaction Suspect product
Standards for Expedited Reporting Reporting Time FramesAll Serious, Unexpected ADRs No later than 15 calendar days. The date report fulfills minimum criteria considered day 0
Standards for Expedited Reporting Reporting Time FramesAll Serious ADRs Time frames varies among countries depending on source, expectedness and outcome.
Standards for Expedited Reporting Good Case Management PracticesReports to be Authentic Accurate Complete as possible Non duplicative
Standards for Expedited Reporting Assessing Patient and Reporter IdentifiabilityIdentifiability 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 IdentifiabilityIdentifiable 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 NarrativesObjective 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 informationPrioritization of case reports1.Serious and unexpected2.Serious and expected3.Non-serious and unexpected4.Cases might lead to labeling change
Standards for Expedited Reporting Follow-up informationObtain the follow up information via1.Telephone call2.Site visit3.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