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| Question | Answer |
| What kind of adverse events must be reported within specified time frames to Health Canada and the FDA? | Adverse events that are serious, unexpected and associated with the use of a drug. |
| A serious adverse event (experience) or reaction is | any untoward medical occurrence that at any dose: 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 |
| The term "life-threatening" in the definition of "serious" refers to | an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. |
| Important medical events that may not result in death, be life-threatening, or require hospitlization may be considered a serious adverse drug experience when | based upon appropriate medical judgement, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in the definition of a serious adverse event. |
| An unexpected adverse event is defined as | An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved investigational medicinal product). For example, under this definition, cerebral thromboembolism and cerebral vasculitis would be considered unexpected (greater specificity) if the IB listed only stroke |
| Unexpected (as used in the definition of SUSAR's) | refers to any adverse event that is not in the IB or current sponsor's protocol, even if it might be reasonably anticipated based on a product's pharmacological properties. |
| An event is said to be associated with the use of the product when there exists | a reasonable possibility that the event could have been caused by the product. |
| What are the categories of causality? | In 2005, the Council for International Organizations of Medical Sciences (CIOMS) VI working group recommended a binary causality assessment of Related or not Related. However, research sponsors could aslo provide categories for evaluating the relationship b/w the AE and the test pdt. e.g. definitely related, probably related, .....etc |
| When an AE occurs that meets the criteria for an SAE, and it is also both unexpected and associated with the IP, HC and FDA requires investigators to | report the event to the sponsor in an expedited manner. |
| Under CTA or IND submissions: Will the sponsor require expedited reporting of all SAEs from investigators, independent of the investigator's assessment of causality? | Most sponsors also require expedited reporting of all SAEs from investigators, independent of the investigator's assessment of casuality (related to the use of the IP). This allows sponsors to assess all SAEs and observe trends across investigative sites. |
| Under CTA or IND submissions: Do HC or FDA directives/guidances specify how to resolve differences b/w the investigator and sponsor assessments of causality? | No. The sponsor may "upgrade" an investigator's determination of causality (for example, changing it from "not related" to "related"), but most sponsors are conservative when it comes to reporting SAEs and will not downgrade an investigator's assessment. More typically, they will report the event to the agency and note their disagreement in the report. |
| What is the industry standard for reporting of SAEs by the site to the sponsor? | The industry std is to report all SAEs within 24 hours of their identification. If the event is life-threatening or fatal, the event should be reported immediately. |
| Where are the SAE reporting requirements described? | The sponsor should spell out clearly in the protocol what the reporting requirements are. |
| Expedited reporting to regulatory agencies is not required for events that are either: | Serious but expected Not reasonably related to the IP (hey man, this second one seems very tricky!) These events still might need to be reported to the sponsor and to the REB, according to local requirements. The sponsor will outline in the protocol the criteria and process for reporting all AEs, including those that are serious. |
| Since all SAEs are still adverse events, they must be recorded on | the relevant case report form (CRF) page unless otherwise directed by the sponsor. |
| What is expanded reporting of SAEs? | Sponsors typically also require expanded reporting of SAEs on a separate CRF page/form. |
| Who provides the forms for SAE reporting? | Sponsors may provide their own forms or use the CIOMS I form or Form FDA 3500A, which is the MedWatch Mandatory Reporting Form. |
| What kind of information is gathered regarding an SAE? | Demographic data Product Information Other treatments Details of the suspected adverse event Treatment of event Outcome Details of person submitting the report Administrative and sponsor information |
| What demographic data and patient details are to be included in the SAE Reports? | Initials Age/DOB Sex Height Weight Study Identifier number (privacy rules may limit use of identifiers) |
| What Product information needs to be included in SAE reports? | Brand name International Nonproprietary names batch no dosage form and strength daily dose and regimen route of administration start and stop dates total cumulative dose and /or duration of treatment indication for use |
| What information regarding "Other treatments" needs to be included in SAE reports? | The same information as for the suspected pdt for each concomitant drug (prescription, OTC, supplements) that the subject was taking |
| What Details of the suspected adverse event need to be included in the SAE reports? | Full description, including event (body site), severity, signs, symptoms. A specific diagnosis should be provided for the reaction. Include seriousness criteria, onset date/time of reaction, stop date/time or duration, dechallenge (withdrawal) and rechallenge data. Other observations and relevant information to aid in assessment of event include medical history, allergy history, substance abuse history, family history, history of current disease. |
| What information regarding the Treatment of the event, needs to be included in SAE Reports? | Steps taken to treat the event including withdrawal of the suspect product, interventions taken, drugs given, tests conducted and results, other treatment given. |
| What information regarding the Outcome needs to be included in SAE Reports? | Recovery or after effects. If death is the outcome, cause of death, and autopsy or post-mortem findings if available. |
| What Details of the person submitting the report need to be included in the SAE Report? | Name, address, telephone number, profession (What about privacy in this case? Does this matter?) |
| What Administrative and sponsor information needs to be included in the SAE report? | To be submitted by sponsor: source of report, date report received, country in which event occurred, type of report (initial or follow-up), name and address of sponsor/manufacturer, name /address of contact person, IND/IDE CTA or CTX number, manufacturer's identification number for the case. |
| What are SUSARs? | Suspected Unexpected Severe Adverse Reactions. Sponsors are required to report SAEs that are unexpected and associated with the use of an IP to regulatory agencies within specific time periods. These reports are called SUSARs in Canada. |
| What are IND Safety Reports? | Sponsors are required to report SAEs that are unexpected and associated with the use of an IP to regulatory agencies within specific time periods. |
| Once a sponsor files a SUSAR in Canada or an IND Safety Report with the FDA, what notifications need to be sent out and to whom? | The sponsor must notify all investigators participating in clinical trials of the investigational agent. |
| Once the sponsor notifies the investigator about a SUSAR, what does the investigator need to do? | Investigators should then notify their REB or IRB. Certain events will require modification of the ICF and notification to research participants. |
| Unexpected SAEs associated with the drug but not fatal or life-threatening must be reported by the Sponsor to the regulatories within | 15 calendar days. |
| Unexpected SAEs associated with the drug but not fatal or life-threatening must be reported by the Sponsor to investigators within | 15 calendar days |
| Unexpected SAEs associated with the drug and fatal or life-threatening must be reported by the Sponsor to the regulatories within | ASAP, but within 7 calendar days (fax or phone acceptable) followed by a complete written report within 8 calendar days (total 15 calendar days) |
| Unexpected SAEs associated with the drug and fatal or life-threatening must be reported by the Sponsor to the investigators within | 15 calendar days |
| When is an event considered to be an Adverse Drug Reaction? | Once an event has been definitively linked to the use of a given agent, the event is then considered to be an adverse drug reaction (ADR). |
| When can new ADRs be discovered? | New ADRs can be discovered during clinical development, or they can be previously reported events that have changed in specificity or severity. |
| Does the FDA define ADRs? | NO |
| Where are ADRs defined? | ICH Guidelines, Section E2A, Clinical Safety Data Management |
| Regarding marketed medicinal products, a definition of an adverse drug reaction in the post-marketing setting is found in | WHO Technical Report 498: 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. |
| Why is the term side effect not used any more - and should not be regarded as synonymous with adverse event or adverse reaction? | The old term "side effect" has been used in various ways in the past, usually to describe negative (unfavorable) effects, but also positive (favorable) effects. It is recommended that this term no longer be used and particularly should not be regarded as synonymous with adverse event or adverse reaction |
| Name some of the programs established to gather AE information on marketed products. | CIOMS form submitted to the Marketed Health Product Division (MHPD) at HC. MedWatch (estd by FDA) MedEffect (Canada) VAERS AdEERS (for NCI-sponsored Investigational agents) |
| Do sponsors need to submit periodic summary reports of AEs to the regulatories? | Sponsors need to submit periodic summary reports of AEs to the FDA. This is not required in Canada. |
| What is a narrative and where would you find more information about how to write one? | The objective of the narrative is to summarize all relevant clinical and related information, including patient characteristics, therapy details, medical history, clinical course of the event(s), diagnosis, and ADR(s) including the outcome, laboratory evidence (including normal ranges), and any other information that supports or refutes an ADR. ICH E2D "Role of the narrative" Also course notes for CR-022 contain more info and a template for a narrative |
| Comparison of site versus sponsor assessment of SAE. | Refer to CR-022 notes |
| DCF | Data Clarification form |
| FWA | Federal Wide Assurance |
| OHRP | Office of Human Research Protection |
| Investigator assures Subject Safety and Study Integrity by | Implementing the protocol “as written” Strict adherence to inclusion and exclusion criteria Continued adherence throughout study duration Monitoring subject status, i.e. subject wellbeing, minimization of risk, toxicity management, etc Monitoring safety data collection: •Study database •Safety database |
| At the site, if immediate/emergency intervention is needed for an AE then: | •Follow site SOP for emergencies •Follow site SOP to notify study clinician/physician •Record the AE/SAE |
| At the site, if no immediate/emergency intervention is needed for the AE then: | •Record AE and/or SAE per protocol specifications •Follow protocol toxicity management section |
| Comparison of clinical role versus research role | Refer to CR-022 notes Most important difference is rigorous documentation. |
| What action may be taken/may happen with study product/study after an adverse event? | Dose held, changed or continued? Participant: Withdraw or continue? Safety pause, clinical hold or study termination? Changes made per site, per study? |
| DMC | Data management centers |
| RSC | Probably stands for Regulatory Support Centre or Research Support Centre |
| What is the study team? What is the RSC? | CR-022 notes |
| For information on Safety refer to | ICH E documents (from CR-022 notes) Why not S documents? Try and understand this. |
| MedDRA | Medical Dictionary for Regulatory Activities |
| MSSO | MedDRA Maintenance and Support Services Organization |
| What is MedDRA? | MedDRA or Medical Dictionary for Regulatory Activities is a clinically validated international medical terminology dictionary (and thesaurus) used by regulatory authorities in the pharmaceutical industry during the regulatory process, from pre-marketing to post-marketing activities, and for data entry, retrieval, evaluation, and presentation. In addition, it is the adverse event classification dictionary endorsed by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). (Wikipedia definition) |
| What is a thesaurus? | a book that lists words in groups of synonyms and related concepts MedDRA is a dictionary and a thesaurus? In general usage, a thesaurus is a reference work that lists words grouped together according to similarity of meaning (containing synonyms and sometimes antonyms), in contrast to a dictionary, which provides definitions for words, and generally lists them in alphabetical order. |
| SOC | System Organ Class |
| HLGT | High-Level Group Terms |
| MedDRA is managed by | the MSSO (Maintenance and Support Services Organization) |
| Who holds the intellectual property rights (ownership) of MedDRA? | The International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) is the Trustee of the International Conference on Harmonisation (ICH) Steering Committee and holds the intellectual property rights (ownership) of MedDRA. |
| Who acts as the MSSO? | The ICH has contracted Northrop Grumman to act as the MSSO. |
| What is the MedDRA pricing for regulators and the industry? | MedDRA is free for regulators and priced according to company revenue for industry. |
| The Japanese counterpart for MSSO is called | JMO |
| Why, how and by whom is MedDRA updated? | The MSSO updates MedDRA according to subscriber change requests, for example to add a new medical concept that is yet to be in MedDRA or to change an existing concept. The decisions are made by international medical officers on how to map the terminology within the grouping categories according to a general consensus based on language considerations internationally. |
| How many versions of MedDRA are released in a year, how often and by whom? | The MSSO releases updated MedDRA versions twice a year - in March and September. The March release is the main annual release and contains changes at the HLT level and above along with LLT and PT changes. The September release typically contains changes only at the LLT and PT level. |
| Scope of MedDRA - What is included/in? | Medical conditions Indications Investigations (tests, results) Medical and surgical procedures Medical, social, family history Medication errors Product quality issues Device-related issues Pharmacogenetic terms Toxicologic issues Standardized queries |
| Scope of MedDRA - What is excluded/out? | Frequency qualifiers Numerical values for results Severity descriptors Not an equipment, device, diagnostic product dictionary Clinical trial study design terms Patient demographic terms Not a drug dictionary |
| For information on problems with coding in MedDRA and use by regulatory agencies | Refer to CR-022 notes |
| Are death, hospitalization and disability considered to be adverse events? | No. They are outcomes. |
| What is soft coding? | “Soft Coding” –Selecting a term which is both less specific and less severe than another MedDRA term is “soft coding” –Example: “Liver failure” coded as hepatotoxicity or increased LFTs –Example: “Aplastic anemia” coded as unspecified anemia –Example: “Rash subsequently diagnosed as Stevens Johnson syndrome” coded as rash |
| Why is accuracy in coding important? | Accuracy is important in preventing dilution of safety signals or generating false signals |
| Why is inaccurate AE term submission by sites risky? | Inaccurate AE term submission by sites puts subject and sponsor at risk |
| MedDRA was developed by | ICH Expert Working Group |
| What code is assigned to each MedDRA term? | Each MedDRA term is assigned an 8-digit numeric code (using universal 8 digit code, for example headache is coded to LLT headache with LLT code of 10019211 |
| Where is MedDRA applied? Give examples. | Clinical trial databases (adverse events, medical & social history, investigations, etc.) Investigator’s Brochures, Core Safety Information, Safety summaries Clinical Study Reports Individual Case Safety Reports Periodic Safety Update Reports Product Labeling |
| AE term selection by site suggestions and sources of error? | Refer to notes CR-022. (slide 168) |
| What are study agents in adverse event reporting and where will they be specified? | Study agent(s) – drugs biological agents,combination of drugs and biological agents or devices (approved or investigational) defined in the protocol for which expedited reporting is required • Study agents will be specified in the protocol |
| What is the protocol specified reporting period? | Protocol specified/defined reporting period: from enrollment to end of trial follow-up for that participant. |
| After the protocol-defined AE reporting period, is anything reported by the site to the sponsor? | After the protocol-defined AE reporting period, unless otherwise noted, only SUSARs will be reported to Sponsor if the study staff becomes aware of the events on a passive basis (from publicly available information) |
| What are clinically significant anomalies (congenital anomalies/birth defects) and how does one qualify them for reporting purposes? | An isolated finding of polydactyly or Mongolian spot in an infant with no other findings would not be reported, but polydactyly or Mongolian spot occurring with a major cardiac defect would be included in the SAE report of the major cardiac defect |
| List some examples of important medical events that may be considered as SAEs. | Events considered as important medical events can meet SAE criteria • Examples: – Intensive treatment in an emergency room or at home for allergic bronchospasm – Blood dyscrasias or convulsions that do not result in hospitalization – Development of drug dependency or drug abuse |
| AEs are assessed for | Seriousness Severity Relationship Expectedness |
| Who's responsible for the AE assessment at the site? | Study physician listed on the 1572/ Investigator of Record (IoR) Agreement is responsible for the assessment of AEs |
| How would you look for a primary adverse event in a subject during the study? | Q. Is there an adverse event? Q. If there are associated symptoms, what is the primary AE? Report only one primary AE per report. Q. How many primary AEs are there? Events that are not clearly associated with the primary AE should be reported as separate events. Report only one primary AE per report |
| How many AEs may be included in one report? | Report only one primary AE per report. |
| Is death in and of itself an AE term? | Death in and of itself is not an AE term; it is an outcome of the AE. |
| When the term is "Death Unknown cause" then relationship cannot be | "NR" because we can't assess the relationship. |
| Can death be an expected outcome? | Death is never an expected outcome; unless it is a known consequence of the disease and person is at that stage. |
| How do you determine whether primary AE meets the criteria for an SAE? | Use ICH-SAE definition provided in Manual v2.0 Select appropriate SAE criteria |
| What is seriousness of an adverse event based upon? | seriousness is based upon the outcome of the AE |
| Is severity a factor in determining reportability? | no |
| How is severity of an adverse event determined? | Using the AE grading table. Refer slides 203 and 204 for example. |
| Grading abnormal laboratory values associated with a clinical AE: – When lab values fall between two grades choose | the higher grade. |
| Potentially life-threatening would be categorized as what grade of severity? | Grade 4 and not Grade 5. Potentially life-threatening means at risk of death should the event occur in a more severe form. This is not the same as immediately life-threatening. |
| Event led to hospitalization, but graded as “Grade 1” or “Grade 2”. Grade the SAE, and not the | initial AE (initial AE had progressed to level of SAE) |
| When a SAE is assessed as “not related” to study agent(s), does an explanation for the SAE need to be given? | When an SAE is assessed as “not related” to study agent(s), an alternate etiology, diagnosis, or explanation for the SAE should be provided |
| When might the relationship assessment of any AE be reviewed again? | If new information becomes available, the relationship assessment of any AE should be reviewed again and updated, as required |
| When the study agent is a fixed dose combination agent, an assessment of attribution (for SAE) will be made for | each component and the combination agent as a whole. |
| Could expectedness be based on what might be anticipated from the pharmacological properties of the study agent? | Expected AEs are events that have been previously observed with use of the study agent(s). It is not based on what might be anticipated from the pharmacological properties of the study agent |
| For the SAE, reporting category, who determines expectedness? | Sponsor to determine expectedness. |
| For SUSARs, reporting category of expectedness is determined by whom? | Site physician and Sponsor to determine expectedness |
| What kind of adverse events require expedited reporting? | SAEs and SUSARs. |
| For expedited reports, queries sent by the sponsor to the site need a response from the site within | 1 business day |
| Who is a medical officer? | A scientific or medical officer residing in Canada, representing the sponsor, who is responsible for providing an attestation with respect to the Clinical Trial Application/Amendment at the time of filing, as outlined in Appendix 3 of the Drug Submission Application Form (HC/SC 3011). |
| Once the expedited report is sent by the site to the sponsor, who determines as to whether the expedited report meets regulatory safety reporting requirements? | Medical officer |
| SAE Reporting Category flowchart | Slides: 218-219 Does the AE, following study agent exposure, meet any of the 6 criteria for SAE? Is there a reasonable possibility that the AE may be related to the IP? Is the AE unexpected? If yes to all the questions, then report. No to any, then don't report. |
| Do you need to report an SAE occurring before exposure to a study agent? | No. |
| What kind of AEs are reportable on new/initial reports? | • New AE • Recurrent AE: only if the initial AE has resolved, is now reoccurring, and meets expedited reporting criteria to Sponsor • Pre-existing condition with increase in severity |
| What are the criteria used to determine reporting days? | A reporting day starts at 12:00 AM (midnight) and ends at 11:59 PM local time • A day is counted as a reporting day regardless of the time of day that awareness occurred. The day a site indicates that site personnel became aware of an SAE that meets reporting criteria shall count as day 1 if that day occurs on a reporting day (i.e., Monday through Friday). If that day occurs on a non-reporting day (i.e., Saturday or Sunday), then the next reporting day shall count as day 1 • Monday through Friday count as reporting days • Saturday and Sunday are not considered reporting days • Any holiday (U.S. or in-country/local) that occurs on a Monday through Friday counts as a reporting day |
| Who reviews and verifies the completed report for accuracy and completeness at the site? | A site physician investigator or subinvestigator listed on the 1572 or the IoR Agreement must: – Review and verify the completed report for accuracy and completeness – Sign the report This physician makes the site’s final assessment of the relationship to study agent(s) |
| In the rare event that site physician(s) are not available for signature of the expedited reports | The sites may submit without signature to meet the reporting timeframe • However, the signature and any necessary corrections or additions must be submitted within the next three reporting days. The IoR or designee is responsible for designating at least one other physician who can perform the assessment and signature so as to provide uninterrupted coverage of monitoring AEs that will require expedited reporting |
| When presented with a case or data that need to be evaluated for expediting reporting, how would you proceed? | Structure as: Objective Ask the relevant questions Review the case/data and organize it systematically Identify missing info/Narrative |
| What are the most important objectives when studying a case for adverse event reporting? | To review a case and be able to identify symptoms and symptom clusters. To decide which AEs are reportable to Health Canada in an expedited time frame. To complete an expedited safety reporting form. To determine if available information is adequate. Construct a comprehensive narrative. To perform an assessment of the case. |
| What initial questions do you need to ask to fulfill the objectives for adverse event reporting? | What are the symptoms? How are the symptoms clustered? Which terms/conditions will you use for the symptom cluster? What is the primary AE and it's clinically associated events? How many primary AE's are there? How many primary AEs are reportable? What relevant info is missing from the narrative of the AE? |
| To review a case and assess causality: | Based solely on the information provided: – Is there [Drug Exposure] and [Temporal Association] – Is there [Dechallenge/Rechallenge] or [Dose Adjustments] – Is there known association per [Package Insert] – Is there [Biological Plausibility] – Is there any other possible [Etiology] |
| Questions to be asked as a follow up for/to causality cases? | • Assess for causality: Related or Not Related – Use algorithm, provide rationale • What is the Primary AE? Is it reportable? • Which SAE criteria? Severity grade? Is it expected? • Outcome of SAE? Action taken? • Argue for R or argue for NR • How would you assure subject well-being? |
| ALCOA | Attributable, Legible, Contemporaneous, Original, Accurate (US-FDA key requirements for good documentation) |
| I | Investigator of Record |
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