1 Adverse Events: Documenting, Recording, and Reporting Developed by Center for Cancer Research, National Cancer Institute, NIH Endorsed by the CTN SIG Leadership Group
2 Introduction Monitoring of adverse events (AEs) is critical to the patient s safety (i.e., human subjects protection) and data integrity. This module will provide an overview of AEs, including assessment, documentation, recording, and reporting. At the conclusion of this module, you will be able to Define what constitutes an AE. Discuss how the Common Terminology Criteria for Adverse Events (CTCAE) is used for assessing AEs. Describe the elements required to document AEs. Define serious and unexpected AEs and how to report these types of events to various regulatory/oversight groups. Discuss the purpose and processing of an Investigational New Drug (IND) Safety Report (ISR). Define what an unanticipated problem is and learn how to report an unanticipated problem to your IRB.
3 Adverse Events It is important to note that multiple clinical terms have been used to convey an Adverse Event (AE) including: toxicity side effect acute or late effect complication all essentially pointing to a change possibly caused by treatment However, all of the terms above imply that an intervention caused the event which is not the definition of an AE. 3
4 Adverse Event: ICH GCP and OHRP Definition An adverse event (AE), as defined by Good Clinical Practice, is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease having been absent at baseline, or, if present at baseline, appears to worsen AND is temporally associated with medical treatment or procedure, REGARDLESS of the attribution (i.e., relationship of event to medical treatment or procedure). Adverse Event: FDA Definition FDA defines an adverse events as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.
5 Purposes of Adverse Event Monitoring The purposes of AE surveillance, especially those events related to the study intervention, include: Identifying events that may have immediate effect on the safety of the patient Informing regulators, investigators, and others of new and important information about events that occur on a clinical trial Providing a summary of adverse experiences in order to develop the drug or regimen toxicity profile
6 Challenges in Oncology Trials In oncology clinical trials, many challenges exist when trying to assess an AE, its severity, cause (i.e., attribution), and the need for regulatory reporting: Protocols are complex and often involve multiple drugs and/or therapeutic modalities. A patient s prior therapies can affect the occurrence and/or severity of an AE. Many patients with cancer have complex presentation of their disease with many baseline signs and symptoms. Concurrent medical conditions and/or medications can affect the occurrence and/or severity of an AE.
7 ASSESSMENT Assessing adverse events is done by the PI or designee (member of the research team) and includes determining the following: Severity of even) Attribution of the event This assessment + expectedness of the event helps in determining the timeliness for reporting of event to the IRB, Sponsor, or other regulatory/ oversight groups. The next several pages will first address the severity assessment in oncology clinical trials followed with attribution assessment.
8 Severity Assessment The tool used to determine the severity of an AE in oncology clinical trials is the Common Terminology Criteria for Adverse Events (CTCAE) The Cancer Therapy Evaluation Program (CTEP) of NCI developed the original Common Toxicity Criteria (CTC) in 1983 to aid in the recognition and grading severity of adverse effects of chemotherapy Fundamentally intended to be an agreed upon terminology for the designation, reporting and grading of AEs that occur in oncology research
9 Purposes of the CTCAE Enable recognition and provide severity grading of AEs Standardize AE reporting across groups/sites Monitor safety data Provide regulatory reporting Define protocol parameters related to: eligibility dose-limiting toxicities/maximum tolerated dose dose modifications
10 Versions of CTCAE Since CTC version 1.0, the tool has been expanded, adapted internationally by the oncology community, renamed, and harmonized with the international medical regulatory dictionary. In May 2009, CTCAE version 4.0 was harmonized with the international community (i.e., MedDRA). Details on the evolution of CTCAE help provide an understanding of its use. You may have protocols that are using both version 3.0 and 4.0. KNOW YOUR PROTOCOL.
11 How to Read the CTCAE The CTCAE is set up in a table format using the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC). SOCs are listed alphabetically. CTCAE term is a MedDRA Lowest Level Term (LLT). Within each SOC, AEs are listed and accompanied by descriptions of severity: grades 1 5 Each SOC has an Other, specify options for reporting text terms not listed in CTCAE. Semicolon indicates or within the description of the grade. Em dash ( ) indicates a grade is not available. The next pages provide examples of CTCAE table for 2 SOCs.
12 Example SOC:Blood and lymphatic system disorders Grade Adverse Event Anemia Hemoglobin (Hgb) <LLN g/dl; <LLN mmol/l; < LLN g/l Hgb < g/dl; < mmol/l; <100-80g/L Hgb < g/dl; < mmol/l; <80-65 g/l; transfusion indicated Life-threatening consequences; urgent intervention indicated Death Definition: A disorder characterized by an reduction in the amount of hemoglobin in 100 ml of blood. Signs and symptoms of anemia may nclude pallor of the skin and mucous membranes, shortness of breath, palpitations of the heart, soft systolic murmurs, lethargy, and fatigability.
13 Example SOC: Gastrointestinal disorders Grade Adverse Event Diarrhea Increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline Increase of 4-6 stools per day over baseline; moderate increase in ostomy output compared to baseline Increase of >=7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL Definition: A disorder characterized by frequent and watery bowel movements. Life-threatening consequences; urgent intervention indicated Death Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.
14 How to Access CTCAE All versions of CTCAE are found on CTEP s website: pplications/ctc.htm CTCAE will continue to be harmonized with MedDRA: MedDRA versions are released bi-annually, with a major release in March and a minor release in September. It is estimated that a new version of CTCAE will occur every two years in March to coincide with alternating major releases of MedDRA. Major MedDRA releases may result in changes at the PT/LLT level and hierarchical groupings, causing changes in CTCAE. CTCAE terms are largely stable MedDRA LLTs, and although a rare term may become non-current, CTCAE MedDRA LLTs will not be deleted. Every CTCAE update will be harmonized with the latest version of MedDRA.
15 Attribution or Relatedness Once the severity of the event is established, the next step is to find the cause, or attribution, of the event. Is the event related to the study agents, the patient s cancer, or an underlying preexisting condition? It is important to identify what the AE is related to and NOT merely what it is not related to Information assists regulatory/oversight groups to assess safety and protect human subjects
16 Determining Attribution Determining the attribution is done by the investigator with input from the research team. There is an art to assigning an attribution for an AE. The following are some questions for the research team to consider: What do we already know about the drug/therapy, or classification of drug? What is the temporal relationship of the AE to the study therapy? Does the AE improve or disappear when drug/therapy is stopped? If rechallenged with the drug/therapy, does the AE reappear? At the same severity? At the same time point? Is the AE a result of existing cancer signs and symptoms? Is the AE a worsening of baseline symptom(s)? Is the AE a result of an underlying concurrent medical condition(s) or concurrent medication(s)? Two approaches can be used when assigning attribution to an AE. One uses two options and the other uses five.
17 Attributions: Approach 1 When having two options, the choices are typically: Related: reasonable causal relationship between the AE and Not related: no reasonable causal relationship between the AE and
18 Attributions: Approach 2 When having five options, the choices are: Definite clearly related to Probable likely related to Possible may be related to Unlikely doubtfully related to Unrelated clearly not related to
19 Fill in the Blank for Approach 1 & 2 The trick is filling in the blank for either approach. Is the AE related to the IND agent, the commercial agent, the radiation therapy or surgery, the research, or the patient s cancer, or are more than one of these the cause of the AE? IRB is looking for relatedness to the research FDA is looking for relatedness to the IND agent A sponsor may do either Teasing out the attribution to research versus IND agent will assist in assessing the need to report the AE to regulatory groups
20 AE Documentation All adverse events must be documented in the patient s medical record. Before documenting AEs, the research team must understand how AEs should be collected. In order to prevent bias collection of AEs, patients should not be questioned regarding specific events that might be anticipated while on the study. Ideally, AEs should be spontaneously reported or elicited from a subject: During open-ended questioning During examination During evaluation.
21 AE Documentation Collection of AE information begins at the initiation of study intervention (drug/procedure). AE information should also be collected from the start of a placebo lead-in period or other observational period intended to establish a baseline status for the patient. AEs should be followed to resolution or stabilization. Follow-up also is required for AEs that cause interruption or discontinuation of the study drug, or those that are present at the end of study treatment as appropriate.
22 AE Progress Note All AEs should be documented in the patient s medical record, including any workup or treatment needed. A good progress note documenting an AE will contain both good clinical practice documentation and good clinical research practice documentation including: Date the AE began (Note: It also may be important to time the AE, especially with infusion reactions.) Treatment for the AE (e.g., no treatment needed, further testing to diagnosis event, hospitalization, dose reduction, holding of study intervention) Description of the event in enough detail that a CTCAE term and grade can be assigned as part of data management activities Attribution of the AE (Note: May need to tease out if there is more than one therapy or drug given.) Date the AE resolved If an ongoing AE worsens or improves in its severity or its relationship to the study drug changes, documentation should be collected as above.
23 Recording Adverse Events Recording of AEs (i.e., data abstraction) onto a case report form (CRF) is dependent on the protocol. For some protocols, such as phase 1 studies, all AEs will be recorded. For others, maybe only grade 2 5 events will be recorded. The protocol should clearly outline what types of AEs will be recorded. Although CRFs vary, some common elements will always be recorded: Date the AE began Treatment for the AE Description and severity/grade of the AE Attribution of the AE Date the AE resolved Other fields also may appear on CRF see the CRF instruction manual for completion instructions. If an ongoing AE worsens or improves in its severity or its relationship to the study drug changes, a new AE entry for the event should be entered on the CRF. Always refer to the protocol and the CRF completion manual for specifics of AE collection and data abstraction.
24 Reporting Adverse Events to Regulatory Oversight Groups There are two types of mechanisms used when reporting AEs to regulatory groups (i.e., IRB, FDA): Routine Expedited
25 Routine AE Reporting: IRB Routine reporting of AEs occurs at the time of continuing review. At a minimum there needs to be a brief statement that there have been no unanticipated problems and that adverse events have occurred at the expected frequency and level of severity as documented in the research protocol, the informed consent document, and investigator s brochure Some IRBs may require a summary report of AEs that have occurred on the protocol since the previous continuing review and allows this to be done in a table format. Know your IRB s policy.
26 Routine AE Reporting: FDA FDA will be informed by the Sponsor in a summary fashion of AEs in the annual report required for all INDs.
27 Routine AE Reporting: IBC & OBA Protocol using recombinant DNA will require additional oversight by an Institutional Biosafety committee (IBC) and the Office of Biotechnology Activities (OBA) OBA will be informed in a summary fashion of AEs in the annual report that is required for all recombinant DNA studies. Know your IBC s policy on routine AE reporting.
28 Routine AE Reporting: Sponsor Sponsor will be informed of a routine AE via the AE CRF. Per FDA regulations, the investigator must record (i.e.,,enter onto a CRF) nonserious adverse events and report them to the sponsor according to the timetable for reporting specified in the protocol.
29 Expedited Adverse Events Subset of adverse events that are reported to regulatory/oversight groups (i.e.: IRB, Sponsor, FDA, IBC, OBA) in an expedited manner Often referred to by many aliases including: Serious Adverse Event Serious Adverse Experience Expedited Adverse Event Adverse Drug Reaction
30 Expedited Adverse Events It is important to understand the following definitions: Suspected adverse reaction Serious adverse event Unexpected adverse event Definitions + attribution will drive the expedited reporting requirements for regulatory groups The next few pages will provide the definitions needed for serious and unexpected events.
31 Suspected Adverse Reaction (SAR) Any AE for which there is a reasonable possibility that the drug caused the AE Reasonable possibility means there is evidence to suggest a causal relationship between the drug and AE
32 Serious Adverse Event (SAE) (21 CFR 312, ICH GCP, OHRP Guidance). Any adverse event occurring at any dose that results in any of the following outcomes: Death Life-threatening adverse drug experience Inpatient hospitalization or prolongation of existing hospitalization persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions Congenital anomaly/birth defect OR.
33 ...Serious Adverse Event (SAE) (21 CFR 312, ICH GCP, OHRP Guidance) Important medical events (IME) that may not result: in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, they may: jeopardize the patient/subject AND may require medical or surgical intervention to prevent one of the outcomes above
34 Unexpected Adverse Event Regulations and guidances don t define an expected event, but rather define when an event is unexpected. When assessing an AE to determine if the event will need expedited reporting, the PI/research team should ask the question is the event unexpected?. The next 2 slides provide the regulatory oversight groups definitions for unexpected.
35 FDA Definition: Unexpected AE An adverse event (AE) or suspected adverse reaction (SAR) is considered unexpected if any of the following occur: Not listed in the investigator brochure (IB) Note: IB should be used to write the protocol and informed consent document Not listed at the specificity or severity that has been observed If IB is not required or available, not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended.
36 OHRP & ICH GCP Definition: Unexpected AE OHRP Guidance: Adverse event that is not described in terms of nature, severity, or frequency given: the research procedures that are described in the protocolrelated documents, such as the IRB-approved research protocol and informed consent document; and the characteristics of the subject population being studied; ICH GCP: 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 product or package insert/summary of product characteristics for an approved product).
37 Reminder Serious vs. Severe Serious is based on outcome and is a factor in determining reportability e.g.: subject hospitalized as result of event Severity refers to the intensity of the experience e.g.: CTCAE grade 3 events which may or may not also be serious
38 Expedited Reporting Requirements Events to be reported in an expedited manner to various regulatory groups must be defined in the protocol including the time line for reporting. Each regulatory group will have their own form to be used for reporting. This is often referred to as the SAE form.
39 IRB Expedited Reporting Requirements Know what your IRB wants reported in an expedited manner. This may be based on severity and/or seriousness. Know the timeline for reporting to your IRB and what form is to be used.
40 FDA Expedited AE Reporting: IND Safety Reports (ISR) Sponsor is to notify FDA and all participating investigators of potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days An ISR results in a safety-related change in the protocol, informed consent, IB (excluding routine updates of these documents), or other aspects of the overall conduct of the clinical investigation.
41 FDA Expedited AE Reporting: IND Safety Reports (ISR) ISR includes: All serious and unexpected suspected adverse reaction Findings from other studies Findings from animal or in vitro testing Increased rate of occurrence of serious suspected adverse reactions The next several slides will provide further definitions of the above types of adverse events that result in an IND safety report.
42 FDA Reporting: Serious and unexpected SAR Sponsor must report any SAR that is both serious + unexpected Also report an AE as a SAR only if there is evidence to suggest a causal relationship between the drug and the AE, such as: Single occurrence of an event that is uncommon and known to be strongly associated with drug exposure One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug Aggregate analysis of specific events observed in a clinical trial that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group known consequences of the underlying disease or condition under investigation other events that commonly occur in the study population independent of drug therapy
43 FDA Reporting: Findings From Other Studies Sponsor must also report expeditiously any findings from clinical, epidemiological, or pooled analysis of multiple studies or any findings from animal or in vitro testing that suggest a significant risk in humans exposed to the drug Reports are required for studies from any source, regardless of whether they are conducted under the IND or by the sponsor
44 FDA Reporting: Findings From Animal/In Vitro Testing Sponsor must report any findings from animal or in vitro testing, whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug, such as reports of mutagenicity, teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or near the expected human exposure.
45 FDA Reporting: Increased Occurrence of Serious SARs Sponsor must report any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.
46 Formats of Submission an ISR Narrative overall findings or pooled analyses from published and unpublished in vitro, animal, epidemiological, or clinical studies FDA Form 3500a Council for International Organizations of Medical Sciences (CIOMS) I Form which is used with international studies Electronic format that FDA can process, review, and archive Safety Reporting Portal (SRP) pending for drugs/biologics
47 FDA Reporting: Unexpected Fatal or Life- Threatening SAR Reports Sponsor must notify FDA of any unexpected fatal or life-threatening SAR as soon as possible but in no case later than 7 calendar days after the sponsor's initial receipt of the information
48 FDA Reporting: ISR & 7-day report Follow-up Upon request from FDA, sponsor must submit any additional data or information that the agency deems necessary, as soon as possible, but in no case later than 15 calendar days after receiving the request
49 What To Do With An ISR. PI reviews the ISR PI sends to AI(s), CTN(s) PI assesses need to amend protocol/consent ISR submitted to IRB per local IRB policy All ISRs placed in regulatory binder including IRB review/ comments PI amends protocol/consent as needed
50 .What To Do With An ISR PI/CTN informs currently enrolled patients immediately (i.e.: by phone) of new potential risk and DOCUMENTS conversation and patient s willingness to continue on study in medical record Re-consent patient as guided by IRB
51 Expedited AE Reporting: IBC & OBA Some studies may have yet another reporting group: IBC and OBA OBA Reporting requirements are the same as the FDA: 7- day and 15-day. Form is available from OBA s website Some studies may be registered for electronic submission via GemCRIS Know expedited reporting process for your IBC.
52 Expedited AE Reporting: : Sponsor Sponsors may cast a broader net when defining adverse events that are to be reported to them in an expedited manner. These definitions may not be the same as the IRB or FDA. You will need to familiarize yourself with all your sponsors requirements and their report forms.
53 Investigator Safety Report to Sponsor per FDA Part An investigator must immediately report to the sponsor any serious adverse event, whether or not considered drug related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility that the drug caused the event.
54 Investigator Safety Report to Sponsor per FDA Part Study endpoints that are serious adverse events (e.g., allcause mortality) must be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the drug and the event (e.g., death from anaphylaxis). In that case, the investigator must immediately report the event to the sponsor. The investigator must record non-serious adverse events and report them to the sponsor according to the timetable for reporting specified in the protocol.
55 Words of Caution FDA/OBA are looking for an attribution as it relates to an investigational drug/product IRB is looking for an attribution as it relates to the research Sponsors may use either one or a combination This means that an event that is to be reported to a Sponsor may not necessarily be reported to the IRB or FDA.
56 Though expedited report forms may be different, they all have similar key components
57 Key Information Reporter information Subject demographics Study agent (date(s) given, dose, route of administration) Event Attribution Narrative summary Investigator signature
58 The Narrative Summary Most important part Very likely that the recipient of the form does not know anything about the subject and their history Provides the background information necessary to assess the event and support the Investigator s attribution
59 The Narrative Summary: What to include Description of the event: Information that helps to describe the event(s) Information that puts the event in perspective (Relevant subject history) Underlying medical conditions Prior surgeries or procedures Family history Recent events that may be a contributing factor Concomitant medications sponsor specific e.g., subject medical history, other medical conditions etc.
60 Supporting Documentation Related source documentation should accompany the report When needed to explain the experience When needed to support the differential diagnosis Sponsor specific not always necessary Click here for examples
61 What To Do If Only Limited Information Is Available Contact treating physician/institution and document all conversations in medical record Submit what you have: most recent clinical evaluation, baseline history and physical Provide plan for obtaining information Provide a summary of the event and treatment to date When additional information becomes available amend the report
62 Expedited AE Follow-up Reporting As a general rule, follow-up is required when: there is a change in the cause/or relatedness of the experience new information on a death becomes available requested by the regulatory/oversight group As a general rule, follow-up report is not required when: the AE resolves resolved date will be noted on the adverse event case report form
63 Reminders Expedited events are a subset of adverse events All information captured on an expedited event form MUST be present in the source documents & be found on the adverse event case report form
64 Reminders Some events that initially appear to meet expedited reporting requirements may be excluded from expedited reporting as per the protocol. The protocol trumps all other reporting requirements. All expedited report forms and any response information from the regulatory/oversight group is to be placed in the regulatory binder.
65 Unanticipated Problem (UP) In addition to adverse event reporting, OHRP and FDA require that unanticipated problems be reported to the IRB. OHRP 45 CFR (b)(5) written procedures for ensuring prompt reporting to IRB, appropriate institution officials (i) any unanticipated problems involving risks to subjects or others FDA 21 CFR (b) Follow written procedure for ensuring prompt reporting to the IRB, appropriate institutional officials, and FDA of (1) any unanticipated problems involving risks to human subjects or others;. 21 CFR The investigator shall also assure that he or she will promptly report to the IRB and all unanticipated problems involving risk to human subjects or others
66 Unanticipated Problem: Definition An incident, experience, or outcome that meets all of the following criteria: Nature, severity, or frequency is unexpected for the subject population or research activities as described in the current IRB approved protocol, supporting documents, and the IC document(s) Related or possibly related to participation in the research Suggests the research may place the subject or others at a greater risk of harm than previously recognized physical, psychological, economic, or social harm
67 OHRP Application Guidance Documents Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events, January 15, FDA Guidance for Clinical Investigators, Sponsors, and IRBs Adverse Event Reporting to IRBs Improving Human Subject Protection, January Guidances/UCM pdf
68 Unanticipated Problem Reporting There is a subset of adverse events that also meet the criteria for being an unanticipated problem and some unanticipated problems that are not adverse events. The diagram below, found in OHRP s guidance document, illustrates this concept. Reporting to OHRP is done by the IRB or the institution s human subject protection office.
69 FDA: Adverse Events that are Unanticipated Problems IND Safety Report (15-day) Serious and unexpected suspected adverse reaction Findings from other studies Findings from animal or in vitro testing Increased rate of occurrence of serious suspected adverse reactions FDA 7-day reporting of unexpected fatal or lifethreatening SARs Change to protocol and IC document is an Unanticipated Problem
70 Protocol Deviation/Violation that is an Unanticipated Problem In addition to adverse events, there are protocol deviations/violations that also may meet the criteria to be an unanticipated problem and reportable to the IRB. Examples include: Malfunctioning infusion pump results in drug being given over 15 minutes versus 1 hour as specified in protocol but subject doesn t have any AEs Ineligible subject who receives protocol intervention w/o any AEs Subject received more drug (10-times) than per protocol but suffers no adverse events
71 Unanticipated Problem that is not an AE or Deviation/Violation There are also unanticipated problems that occur that are neither an AE or protocol deviation/violation. Examples: Individually identifiable sensitive information stored on laptop computer without encryption, and the laptop computer is stolen Product contamination with no AEs experienced by subjects Staff member becomes ill due to odor from IV bag of investigational product but patient with no AEs Subject becomes incarcerated during the course of the research
72 OHRP Guidance: Content of an UP Report Appropriate identifying information for the research protocol, such as the title, investigator s name, and the IRB project number Detailed description of the adverse event, incident, experience, or outcome Explanation of the basis for determining that the adverse event, incident, experience, or outcome represents an unanticipated problem Description of any changes to the protocol or other corrective actions that have been taken or are proposed in response to the unanticipated problem
73 Correction Action Plan for an Revise protocol: Unanticipated Problem Modify inclusion or exclusion criteria to mitigate the newly identified risks Implement additional procedures for monitoring subjects Suspend enrollment of new subjects Terminate the research Informed consent Revise the IC document Provide additional information about newly recognized risks to previously enrolled subjects Inform enrolled subjects Increase monitoring activities Encrypt laptops, no identifiable information on laptop Provide training/re-training Submit ORS and work with appropriate institutional officials
74 Reporting to IRB Know the process and forms/database used by your IRB(s) for unanticipated problem reporting.
75 Resources Code of Federal Regulations, Food and Drugs, 21 CFR 312: IND Application Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events Guidelines for Good Clinical Practice. International Conference on Harmonisation (ICH).
76 Resources OHRP (2007) Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events FDA (2009) Guidance for Clinical Investigators, Sponsors, and IRBs Adverse Event Reporting to IRBs Improving Human Subject Protection Guidances/UCM pdf OHRP Video on unanticipated problems
77 Module Evaluation The CTN SIG would greatly appreciate your feedback on this learning module. Please complete the evaluation form and fax to Elizabeth Ness at
Reporting of Adverse Events and Unanticipated Problems Policy date: 12/2011 Purpose The purpose of this policy is to ensure that the review, reporting and analysis of adverse events and unanticipated problems
ST. MICHAEL S HOSPITAL Guidelines for Reporting Serious Adverse Events / Unanticipated Problems to the SMH Research Ethics Board (REB) July 09, 2014 1. Introduction The St. Michael s Hospital (SMH) REB
Make copies of the blank SAE report form as needed. Retain originals with confirmation of all information faxed to DMID Pharmacovigilance Group Clinical Research Operations and Management Support (CROMS
Clinical and Translational Science Institute / CTSI at the University of California, San Francisco Welcome to Online Training for Clinical Research Coordinators Adverse Events in Clinical Trials: Definitions
Office for Human Research Protections (OHRP) Department of Health and Human Services (HHS) Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events
IOWA STATE UNIVERSITY Institutional Review Board Reporting Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others Introduction This policy details the Institutional Review Board
Laurie Shaker-Irwin, Ph.D., M.S. Co-Leader, Regulatory Knowledge and Research Ethics UCLA Clinical and Translational Science Institute Understand the protocol completely Recognize institutional polices
Clinical Research Definitions and Procedures Steven Hirschfeld MD PhD Associate Director for Clinical Research National Institute of Child Health and Human Development U.S. DEPARTMENT OF HEALTH AND HUMAN
Data Management in Clinical Trials Introduction to the Principles and Practice of Clinical Research February 19, 2013 Diane St. Germain, RN, MS Nurse Consultant Division of Cancer Prevention National Cancer
PHARMACY AND POISONS ORDINANCE (Cap. 138) APPLICATION FOR A CLINICAL TRIAL/MEDICINAL TEST CERTIFICATE PART A: TRIAL INFORMATION A1. Title of Clinical Trial (as stated in proposed Protocol) Protocol No.
Roles & Responsibilities of the Sponsor Developed by Center for Cancer Research, National Cancer Institute, NIH Endorsed by the CTN SIG Leadership Group Objectives Funding for clinical research comes from
University of Maryland Greenebaum Cancer Center UMGCC Standard Operating Procedure Title: Data & Safety Monitoring Plan Effective Date: October 2015 Procedure No: DSM001 University of Maryland Greenebaum
Clinical Trial Protocol Development Developed by Center for Cancer Research, National Cancer Institute Endorsed by the CTN SIG Leadership Group Objectives The clinical trial protocol is the heart of any
Causality Assessment in Practice Pharmaceutical Industry Perspective Lachlan MacGregor Senior Safety Scientist F. Hoffmann-La Roche Ltd., Basel Disclaimer: The opinions expressed in this presentation are
Guidance for Industry Determining the Extent of Safety Data Collection Needed in Late Stage Premarket and Postapproval Clinical Investigations DRAFT GUIDANCE This guidance document is being distributed
Clinical Trials and Safety Surveillance of Drugs in Development Hoda Eid, M.Sc., Ph.D. Manager, ADR Unit Office of Clinical Trials Therapeutic Products Directorate email@example.com Overview Clinical
Guidance for Industry and Investigators Safety Reporting Requirements for INDs and BA/BE Studies U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and
9.0 Protocol Violations, Deviations, and Exceptions 9.1 Definitions Protocol deviation(s): means a minor or administrative departure from the IRBapproved protocol procedures (e.g., the protocol, informed
European Medicines Agency June 1995 CPMP/ICH/377/95 ICH Topic E 2 A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting Step 5 NOTE FOR GUIDANCE ON CLINICAL SAFETY DATA MANAGEMENT:
EUROPEAN COMMISSION DG Internal Market, Industry, Entrepreneurship and SMEs Consumer, Environmental and Health Technologies Health technology and Cosmetics MEDDEV 2.7/3 revision 3 May 2015 GUIDELINES ON
Guidance for Pharmaceutical Industry Adverse Drug Reaction Reporting Requirements Drug Office Department of Health February 2015 Guidance for Pharmaceutical Industry ADR Reporting Requirements (02/2015)
703 1 of 11 POLICY The Beaumont Research Coordinating Center (BRCC) will provide advice to clinical trial investigators on protocol development, content and format. Upon request, the BRCC will review a
Guidance for Industry Cancer Drug and Biological Products Clinical Data in Marketing Applications U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE POST-APPROVAL SAFETY DATA MANAGEMENT: DEFINITIONS
The following definitions are provided as a resource to supplement the information provided in the Medicine Safety Education section of the Pfizer.com Web site; they are not intended as a comprehensive
Data Management & Case Report Form Development in Clinical Trials Introduction to the Principles and Practice of Clinical Research February 3, 2015 Marge Good, RN, MPH, OCN Nurse Consultant Division of
CDISC Data Standards Can Facilitate Composition of Adverse Event Narratives Anisa Scott, Ph.D. and Richard C. Zink, Ph.D. JMP Life Sciences SAS Institute, Inc. firstname.lastname@example.org Copyright 2010 SAS Institute
Guidance for Clinical Investigators, Sponsors, and IRBs Adverse Event Reporting to IRBs Improving Human Subject Protection U.S. Department of Health and Human Services Office of the Commissioner (OC) Center
Issues: Regulatory Obligations Post-marketing Adverse Event Reporting; MDRs and Safety Reports Martha A. Feldman, RAC Drug & Device Development Co., Inc. Topics for today Post-approval requirements for
Investigator Responsibilities Standard Operating Procedure Office of Health and Medical Research Queensland Health SOP reference: 010 Version number: 1 Effective date: 01 June 2010 Review due: May 2011
Compliance Programs in Academic Medical Centers Kenneth L. Dretchen, PhD Director of Regulatory Affair Chair, Department of Pharmacology Sheila Cohen Zimmet, RN, JD Director, Research Assurance and Compliance
: I. PURPOSE The purpose of this policy is to establish procedures for the proper control, storage, use and handling of investigational drugs and biologics to ensure that adequate safeguards are in place
THE STUDY PROTOCOL The study protocol is a written document detailing how a clinical trial is conducted. The elements of a protocol include: 1. Trial design and organization; 2. Study objectives; 3. Background
FDA Audit Guidelines University of Miami Office of the Vice Provost for Research FDA Audit Guidelines Contents INTRODUCTION 3 VICE PROVOST FOR RESEARCH ROLE IN FDA AUDITS 3 PRE-AUDIT REVIEW 3 INSPECTION
Clinical and Translational Science Institute / CTSI at the University of California, San Francisco Welcome to Online Training for Clinical Research Coordinators ROLE OF THE RESEARCH COORDINATOR Study Start-up
Welcome! This document contains three (3) series of Case Study examples that will demonstrate all four OHSU reporting categories (#1 4) as well as examples of events that are considered not reportable.
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE DEVELOPMENT SAFETY UPDATE REPORT E2F Current Step
Quality Monitoring Checklist Instructions: For each task below, the Quality Monitor indicates in the appropriate column if the Monitor accomplished the task by using the following codes Yes No N/A = Monitor
Clinical Investigators Handbook for UNIVERSITY OF MARYLAND MARLENE AND STEWART GREENEBAUM CANCER CENTER 22 S. Greene Street, Baltimore, MD 21201 http://www.umgcc.org Version: January 2016 (Note: Attachments
Quality Management in Clinical Research Julie Doherty MSN, RN Director, Regulatory Compliance Office of Academic Affairs Human Research Protections Office University of Maryland Baltimore March 17, 2016
Principal Investigator Responsibilities for Education and Social/Behavioral Researchers Introduction The purpose of this module is to provide a basic understanding of the responsibilities of the principal
MedDRA in clinical trials industry SFDA ICH MedDRA Workshop, Beijing, 13 14 May 2011 Christina Winter, MD, FFPM Medical director GlaxoSmithKline R&D / ICH MedDRA Management Board 2011 ICH International
Application Guide 2015 Global Awards in Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) Research A Competitive Grants Program Supported by Pfizer www.aspireresearch.org Table of Contents THE ASPIRE
v. 5.13.13 12.0 Investigator Responsibilities 12.1 Policy Investigators are ultimately responsible for the conduct of research. Research must be conducted according to the signed Investigator statement,
Medical Dictionary for Regulatory Activities (MedDRA) Update International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Topics MedDRA as an ICH
Study Start-Up SS-204.01 STANDARD OPERATING PROCEDURE FOR Site Initiation Visit (SIV) Approval: Nancy Paris, MS, FACHE President and CEO 08 March 2012 (Signature and Date) Approval: Frederick M. Schnell,
Guidance for IRBs, Clinical Investigators, and Sponsors Considerations When Transferring Clinical Investigation Oversight to Another IRB U.S. Department of Health and Human Services Food and Drug Administration
A.P. Chen, MD Director, Developmental Therapeutics Clinic Division of Cancer Treatment and Diagnosis National Cancer Institute Click to view Biosketch and Presentation Abstract or page down to review presentation
Page 1 of 14 Purpose: To establish policy with respect to the emergency use of unapproved drugs and biologics. Definitions: 1. IRB approval means the determination of the IRB that the research has been
Howard University Institutional Review Board Application (Protocol) for IRB Review (A-1) Funded and/or Drugs and/or Devices and/or Greater than Minimal Risk Research Section One: Application Information
The Trans-Tasman Early Warning System Processes in Australia and New Zealand Version 1.0 May 2013 About Medsafe Medsafe is the New Zealand Medicines and Medical Devices Safety Authority and is responsible
Pre-Questions Mastering Clinical Research July 29, 2015 1. To be compliant with SOP 2.1 Obtaining Informed Consent for greater than minimal risk interventional clinical trial, which Licensed Professional
NOTE: THIS GUIDANCE SUPERSEDES OHRP S JANUARY 15, 2007 GUIDANCE ENTITILED GUIDANCE ON CONTINUING REVIEW. CLICK HERE FOR THE JANUARY 15, 2007 GUIDANCE. Office for Human Research Protections Department of
History of CBUs First CBU transplant done in 1988 10-CBA providing access to unlicensed cord blood units Using the NMDP IND to access unlicensed cord blood units Amy Hays, Sr. Clinical Research Specialist,
Ethical Issues in the Statistical Analysis of Clinical Research Data Roger J. Lewis, MD, PhD Department of Emergency Medicine Harbor-UCLA Medical Center Torrance, California Introduction Types of data-centered
PROTOCOL DEVIATIONS 229 1 of 7 PURPOSE The purpose of this policy is to define protocol deviations and the subsequent actions required by the Principal Investigator (PI) once a protocol deviation occurs
Awad Mohamed Ahmed, MD Professor of Medicine, University of Bahr Elghazal, Khartoum, Sudan For correspondence Professor Awad Mohamed Ahmed E-mail: email@example.com Tel.: +249 912344936 Abstract Randomized
Tip Sheet 11: Following the Guideline of the International Conference on Harmonization Good Clinical Practice (E6) Related Accreditation Elements: I.1.D., I.1.F., I-2, I.7.B., II.2.E., II.2.F., II.4.A.,
1 2 20 February 2012 EMA/876333/2011 3 4 Guideline on good pharmacovigilance practices (GVP) Annex I - Definitions Draft finalised by the Agency in collaboration with Member States 7 February 2012 Definitions
Managing Risk in Clinical Research Dr Martha J Wrigley R&D Manager Senior Visiting Fellow University of Surrey Aim of the session To explore the risks associated with clinical research and understand how
Vol. 5, No. 12, December 2009 Can You Handle the Truth? A New Standard for Medical Device Adverse Event Classification By Nancy J. Stark Adverse events are defined and managed differently in the device
A Phase 2 Study of (Avonex ) in Ulcerative Colitis - Study Results - ClinicalTrials.gov A Phase 2 Study of (Avonex ) in Ulcerative Colitis This study has been completed. Sponsor: Biogen Idec Information
Guideline for Industry The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for Longterm Treatment of Non-Life- Threatening Conditions ICH-E1A March 1995 GUIDELINE FOR INDUSTRY
Effective Date: 09/12/06, 08/02/10, 3/2/11 Title: 1.0 OBJECTIVE: 1.1 This SOP describes the methods and policies for: Handling investigational drug Dispensing investigational drug 1.2. This procedure applies
Classifying Adverse Events From Clinical Trials Bernard LaSalle, Richard Bradshaw University of Utah, Biomedical Informatics, Salt Lake City, UT USA firstname.lastname@example.org Abstract The use of adverse
Regulations & Requirements for Conducting Clinical Trials on Drugs Version 1.0 Date issued Date of implementation 08/07/2015 08/07/2015 1 [SFDA Regulations & Requirements for Conducting Clinical Trials
Guidance for Industry IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment of Cancer U.S. Department of Health and Human Services Food and Drug Administration Center
Research Study Protocol Template (For clinical trials) Instructions This protocol template is a tool to facilitate the development of a research study protocol specifically designed for the investigator
UNIVERSITY OF TENNESSEE HEALTH SCIENCE CENTER INSTITUTIONAL REVIEW BOARD EMERGENCY MEDICINE RESEARCH EXEMPTION FROM INFORMED CONSENT REQUIREMENTS I. PURPOSE This document outlines the procedures for University
Office for Human Research Protections (OHRP) Department of Health and Human Services (HHS) Guidance on Withdrawal of Subjects from Research: Data Retention and Other Related Issues This guidance represents
Non-Compliance Kelley O Donoghue, MPH, CIP Director Office for Human Subject Protection (OHSP) September 18, 2012 The Principal Investigator (PI) The Principal Investigator (PI) is the individual who has
CLINICAL DATA MONITORING PLAN (CDMoP) PROTOCOL #  [TITLE] CONTRACT RESEARCH ORGANIZATION SPONSOR [NAME] [ADDRESS] 1 TABLE OF CONTENTS 1. Purpose 3 2. References 3 3. Study Roles and Responsibilities
Paper PH-07 Developing a Complete Picture of Patient Safety in Clinical Trials Richard C. Zink, JMP Life Sciences, SAS Institute, Cary, NC, United States Russell D. Wolfinger, JMP Life Sciences, SAS Institute,
Expanded Access Programs Richard Klein Office of Special Health issues Food and Drug Administration Expanded Access Programs (EAPs) What is expanded access? History Legislative background General principles
Training Guide February, 2015 PRODUCED BY CAPITAL TECHNOLOGY INFORMATION SERVICES, INC. The Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP- AERS) Training Guide was prepared for:
DHHS/NIH/OD/OIR/OHSRP 1/2/2015 The audience for this course is Principal Investigators (PIs), investigators and Research Coordinators (RCs) serving on the study team of human clinical studies and trials.
JDRF Scientific Guidelines for applicants Version/Date 002/Aug 2015 Version history 001/Jul 2011 Contents Introduction... 2 JDRF clinical terms of award... 3 Nonexempt human subject s research... 3 Full
Challenges in the Regulation of Pediatric Clinical Trials Wilson W. Bryan, M.D. FDA / CBER / OCTGT email@example.com National Institutes of Health Recombinant DNA Advisory Committee (RAC) Meeting
Yale Cancer Center Data and Safety Monitoring Committee Charter Purpose/Mission The purpose of the Yale Cancer Center (YCC) Data and Safety Monitoring Committee (DSMC) is to provide ongoing data and safety
Monitoring & Auditing of Clinical Trials Sponsored by Center for Cancer Research National Cancer Institute Objectives Guidelines suggest that following the good clinical research practice of monitoring/auditing
Essential Documents for the Conduct of a Clinical Trial Debra Dykhuis Associate Director RSO Introduction Rationale for choosing this topic AHC movement toward setting GCP (Good Clinical Practice) guidelines
abcd Clinical Study for Public Disclosure This clinical study synopsis is provided in line with s Policy on Transparency and Publication of Clinical Study Data. The synopsis which is part of the clinical
Clinical Trials Reporting Program (CTRP) and Clinicaltrials.gov (CT.gov) Helpful tips and guidance Objectives NCI s Clinical Trials Reporting Program (CTRP) Overview CTRP What is it? CTRP is an NCI mandated
Comprehensive Study Documents List (Biomedical Studies) Investigators conducting human subjects research must maintain study documents in adherence to federal and state regulations, USC policies, and good
Use of MedDRA in CTCAE and in the Biopharmaceutical Industry Ann Setser, BSN, MEd MedDRA MSSO MedDRA is a registered trademark of the International Federation of Pharmaceutical Manufacturers and Associations
Principal Investigator and Sub Investigator Responsibilities I. Purpose To define the roles and responsibilities of Principal Investigators conducting research at GRU. II. Definition The term Principal
U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA s website for reference purposes only. It was current when produced, but is no longer maintained
Considerations for Waivers of Informed Consent and Authorization Contents: Waiver of Informed Consent... 1 Office for Human Research Protections (OHRP) regulations... 1 Government projects... 1 All other