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Safety Workshop: Part I Clinical Trial Safety and Safety Monitoring. August 18, 2010 Albert Yoyin, M.D. DAIDS Regulatory Support Center (RSC). Objectives. At the conclusion of this workshop, participants will be able to demonstrate an understanding of:

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safety workshop part i clinical trial safety and safety monitoring

Safety Workshop: Part IClinical Trial Safety and Safety Monitoring

August 18, 2010

Albert Yoyin, M.D.

DAIDS Regulatory Support Center (RSC)


At the conclusion of this workshop, participants will be able to demonstrate an understanding of:

  • Current context regarding safety in clinical trials
  • The concept of safety and safety monitoring and how it relates to clinical trials research
  • Protocol requirements pertaining to areas relevant to safety
  • Key roles and responsibilities related to safety
  • Safety and adverse event terminology
  • Expedited reporting of adverse events

At the conclusion of this workshop, participants will be able to demonstrate an understanding of:

  • Ensuring safety in clinical trials
  • The adverse event life cycle
  • What makes a well-documented adverse event, including a comprehensive narrative
  • How to assess an adverse event case, including causality assessment
regulations federally supported research involving human subjects
Regulations: Federally Supported Research Involving Human Subjects

45 CFR 46: Protection of Human Research Subjects

  • Applies to all research involving human subjects
  • Institution must provide assurance of compliance, such as a Federal Wide Assurance (FWA) on file with the Office for Human Research Protection (OHRP)
  • FWA provides assurance that research is conducted in accordance with the regulations
    • Research reviewed and approved by IRB
    • Subject to continuing review by IRB
regulations non federally supported studies involving human subjects
Regulations: Non-Federally Supported Studies Involving Human Subjects

21 CFR 50: Protection of Human Subjects

  • Clinical investigations regulated by FDA
  • Requirements for informed consent
    • Elements of informed consent
    • Documentation of informed consent
      • Form approved by IRB

21 CFR 56: Institutional Review Boards

  • Clinical investigations regulated by FDA
  • Requirements for IRB review
    • Membership, functions, review procedures, etc
    • Criteria for IRB approval
current safety environment
Current Safety Environment
  • Increasing demands for safety data:
    • All Serious Adverse Events (SAEs); Follow all AEs/SAEs till resolved or stable
    • Additional adverse events of interest (e.g. cancers, MIs, hepatic events)
    • Pregnancy outcomes
    • Food and Drug Administration Amendments Act of 2007 (FDAAA): Provides FDA with additional requirements, authorities, and resources with regard to both pre- and postmarket drug safety
    • Global reporting to EMEA and regulatory agencies of European Union (EU) member states
      • Use of CIOMS form
      • Country of origin of AE
clinical trial continuum from drug development to optimal regimens to treatment strategies
Clinical Trial Continuum: From Drug Development to Optimal Regimens to Treatment Strategies













safety monitoring
Safety Monitoring

Why is safety monitoring

required in all clinical trials?

To Ensure Subject Safety and Study Integrity


Roles and Responsibilities – Site Investigator

Implementing the protocol “as written”

Strict adherence to inclusion

and exclusion criteria

Investigator assures Subject Safety and Study Integrity by:

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
roles and responsibilities research staff
Roles and Responsibilities – Research Staff

Is immediate/emergency intervention needed?



  • Follow site SOP for emergencies
  • Follow site SOP to notify study clinician/physician
  • Record the AE/SAE
  • Record AE and/or SAE per protocol specifications
  • Follow protocol toxicity management section
roles and responsibilities study clinician physician
Roles and Responsibilities – Study Clinician/Physician
  • Subject reports AE
  • Emergency intervention vs.
  • Non-emergency care
  • Study clinician/physician
  • will assess and manage
  • the AE Decide if SAE
  • Research provisions
  • vs.
  • Clinical care
  • Documentation
    • Follow until AE resolution
  • or condition stabilizes
assurance of safety and well being research vs medical roles
Assurance of Safety and Well-Being:Research vs. Medical Roles
  • Emergency intervention vs. Non-emergency care
    • Acute on-site management, as necessary, and per site SOP
    • Referral to care when stable
  • Research provisions vs. Clinical care
    • Provide interventions permitted by the protocol
    • Follow protocol specifications for toxicity management
    • Beyond protocol specifications, refer out for clinical care
clinical role vs research role
Clinical Role vs. Research Role

Balancing Both Roles

  • Balancing Both Roles

Research Role: Study/Data OK

Clinical Role: Subject OK

  • Identification of adverse event
  • Immediate notification necessary? To whom? [per protocol and safety monitoring plans]
  • Complete documentation of adverse event. Follow until resolution/stability including updating records
  • Determine if AE meets criteria for SAE
  • Adhere to reporting requirements
  • Adhere to toxicity management as specified
  • Adhere to stopping rules as specified
  • Is subject in imminent jeopardy?
  • Provide appropriate management commensurate with clinical situation, e.g. toxicity management
  • Provide appropriate referral: emergent care or back to regular care
  • Follow up with subject status

Not Subject’s Primary Clinician

therapeutic misconception
Therapeutic Misconception
  • Subjects think they are receiving proven interventions, per their usual clinical care, despite participating in a research study
    • Informed Consent Process must not be trivialized or relegated to administrative status
    • Check for understanding
    • Time for questions, making decision
  • Physicians think they can provide interventions, per usual practice
    • Strict adherence to protocol provisions for care, toxicity management
    • Decide if subject can continue in study
roles and responsibilities study clinician physician15
Roles and Responsibilities – Study Clinician/Physician
  • Action taken with Study product
  • after AE



Study product:

Dose held, changed,

or discontinued?

Study participation:

Continue, withdraw?

Study product: Per site, per study?

Study status: Safety pause, clinical hold, early termination?

roles and responsibilities study team
Roles and Responsibilities – Study Team

Safety: Ensure safety and well being of subjects at all times

  • Monitor safety across all study sites
  • Review all safety data at specified intervals
  • Discuss need for change(s) driven by safety

Data: Ensure data integrity to assess the risks/safety profile of the study intervention

  • Data capture; especially safety data
  • Be cognizant of expedited reporting requirements for safety data
roles and responsibilities study team vs sponsor rsc
Roles and Responsibilities – Study Team vs. Sponsor/RSC
  • Safety monitoring by study team
    • Acute on-site management and discussion with study team
    • Periodic review by study team and monitoring committees
      • Data generated by Data Management Centers (DMC)
  • Expedited reporting to sponsor/RSC
    • SAE sent to RSC
    • RSC is not part of discussions that occur within study/safety monitoring teams regarding the event
    • The RSC only has information about the event from the SAE Form; site should include relevant information from study team discussions
    • RSC processes event and sends queries to site to obtain additional information
    • All follow-up information should be provided to RSC



Land’s End at Cabo San LucasThe majestic stone arch at the southern tip of Baja,

where the Sea of Cortez meets the Pacific Ocean

ich e documents on safety
ICH: E Documents on Safety

Clinical Safety

  • ICH E1– The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life Threatening Conditions
  • ICH E2A– Clinical Safety Data Management: Definitions and Standards for Expedited Reporting
  • ICH E2B– Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports
  • ICH E2C– Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs
  • ICH E2D– Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting
  • ICH E2E– Pharmacovigilance Planning
  • ICH E2F– Development Safety Update Report

Good Clinical Practice

  • ICH E6 – Good Clinical Practice

adverse event flowchart
Adverse Event Flowchart

To other

To other

Subject Enrolled

Subject Enrolled



AE Reported

AE Reported



To Sponsor

To Sponsor



Record SAE**

Record SAE**

Record AE*

Record AE*









Follow until Resolution

or Stability

Follow until Resolution

or Stability



Update SAE

Update SAE

adverse event
Adverse Event

* Protocol specifications for AE

  • When to collect e.g., study visit
  • Method of collection e.g., in person, telephone call
  • What to collect e.g., all AEs, only certain AEs by body system, only certain AEs by severity
  • What forms to use e.g. AE CRF, study CRFs

** Protocol specifications for SAE

  • Criteria
  • Expedited time frames
  • Reporting form (e.g. SAE)
documentation differences between ae crf and sae form
Documentation Differences Between AE CRF and SAE Form

Record on SAE Form (includes narrative)

Record in source document

Attach additional documentation

Record on AE case report form

Does AE meet SAE criteria?


safety data from clinical trials
Safety Data from Clinical Trials

Obligations to report safety data (IND or Non-IND studies):

  • Data for non-expedited reporting:
    • Recorded on AE CRF, goes to clinical trial database
  • Data for expedited reporting:
    • Recorded on AE CRF and linked to an SAE type form
    • Goes to safety database
    • IND timelines: 24o to sponsor, 7/15 days to FDA, EMEA
    • Post-marketing timelines: depends on sponsor, 15 days to FDA, EMEA
  • Annual/Periodic Reports :
    • Need safety data from clinical and safety database
    • Must be reconciled
adverse event28
Adverse Event

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.


adverse event term
Adverse Event Term
  • The AE should best describe what the subject says (i.e. verbatim description)
  • Can be extracted from medical records
  • Can incorporate medical assessment (including a diagnosis if available)
  • The more accurate the AE term, the more accurate the safety database. The AE terms will be coded using a standard dictionary, e.g. Medical Dictionary for Regulatory Activities (MedDRA); this is NOT site responsibility
ae term examples
AE Term - Examples
  • If “anaphylactic reaction” is associated with “rash, dyspnea, hypotension, and laryngospasm,” report primary AE as “anaphylactic reaction.”
  • If “myocardial infarction” is associated with “chest pain, dyspnea, diaphoresis, ECG changes and jaundice,” report “myocardial infarction” and “jaundice” as separate primary AEs.
serious adverse event sae
Serious Adverse Event (SAE)

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
  • Is a congenital anomaly/birth defect
  • In addition, “…important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the definition above…should also usually be considered serious.”


adverse event vs event outcome
Adverse Event vs. Event Outcome


  • Hospitalization is a consequence and is not usually considered an AE.
    • Example: If the subject was hospitalized due to congestive heart failure, “congestive heart failure” is the primary AE and hospitalization is the outcome.
  • If the only information available is that the study subject was hospitalized, “hospitalization” can be reported.

Hospitalization in the absence of a medical AE is not in itself an AE and does not need to be reported in an expedited time frame, such as:

  • Admission for treatment of a pre-existing condition (can include target disease) not associated with the development of a new AE or with a worsening of the pre-existing condition
  • Diagnostic admission (e.g. for work-up of persistent existing condition such as pre-treatment lab abnormality)
  • Protocol-specified admission (e.g. procedure required by study protocol)
  • Administrative admission (e.g. for yearly physical exam)
  • Social admission (e.g. study subject has no place to sleep)
  • Elective admission (e.g. elective surgery)
  • Describes the intensity of the event
  • Events are graded on a severity scale
    • Mild, Moderate, Severe
    • Numeric Scale e.g. 1 to 5
  • Severity grading must match the clinical picture
    • Presenting AE is Grade 1
    • AE progressed to SAE (hospitalization)
    • The expedited report should have the grade of the SAE, not the AE
seriousness is not the same as severity
Seriousness is NOT the same as Severity



  • Based on outcome of the AE and is a factor in determining reportability (regulatory definition)
  • Based on the intensity of the AE and is not a factor in determining reportability (clinical descriptor)
  • Determined using the SAE criteria
  • Determined using the DAIDS grading table
action taken with drug
Action Taken with Drug
  • Action Taken with Drug:
    • Withdrawn
    • Dose reduced
    • Dose increased
    • Dose not changed
    • Unknown
    • Not applicable > ICH E2B (R3)
  • Refer to protocol
  • Refer to DAERS
  • Outcome of reaction/event at the time of last observation
    • Recovered/resolved
    • Recovering/resolving
    • Not recovered/not resolved
    • Recovered/resolved with sequelae
    • Fatal
    • Unknown > ICH E2B (R3)
  • Outcome of subject in study
    • Remains in Study
    • Withdrawn
    • Lost to follow-up
    • Death
  • Pertains to whether an event is expected or unexpected (on the basis of previous observation, not what might be anticipated from the pharmacological properties of the product)
  • Unexpected: the nature or severity of the adverse event is not consistent with the applicable product information (e.g. Investigator’s Brochure for unapproved product, Package Insert for approved product)
relatedness causality
Relatedness (Causality)
  • No standard international nomenclature
  • Conveys that a “causal relationship” between the study product and the adverse event is “at least a reasonable possibility” [ICH E2A]
    • Facts (evidence) exist to suggest the relationship
    • Information on SAEs generally incomplete when first received
    • Follow-up information actively pursued
  • Judged by:
    • Reporting health professional
    • Sponsor
determination of causality
Determination of Causality
  • Standard determinations include:
    • Is there [Drug Exposure] and [Temporal Association]?
    • Is there [Dechallenge/Rechallenge] or [Dose Adjustments]?
    • Any known association per [Investigator’s Brochure] or [Package Insert]?
    • Is there [Biological Plausibility]?
    • Any other possible [Etiology]?

Determination of Causality

  • ‘May be more art than science’
    • NR: evidence for alternate etiology and/or low or no biologic plausibility
    • R: reasonable possibility; facts or evidence to substantiate relationship, and biologic plausibility
    • Is there evidence to compel change in previous conclusions?
  • Clear-cut case; easy to make a determination
  • Not so clear-cut: use your best judgment based on available information; assure adequacy of information
  • Unless clear-cut case,there’s no absolute right or wrong; give your best judgment; substantiate and follow-up
  • Err on conservative side


  • Comprehensive, stand-alone “medical story”
    • Written in logical time sequence
    • Include key information from supplementary records
    • Include relevant autopsy or post-mortem findings
  • Summarize all relevant clinical and related information, including:
    • Study subject characteristics
    • Therapy details
    • Medical history
    • Clinical course of the event(s)
    • Diagnosis (workup, relevant tests/procedures, lab results)
    • Other information that supports or refutes an AE
    • > ICH E2D
narrative template
Narrative Template
  • This is a [Age]year old [Race][Male/Female]in[Study]who reported [Primary AE]on[Date of AE].Enrolled into study on [Date Enrolled],Study medication was started on [Date], which is [Study Day _/Week _],taken for[Duration].The event occurred during the [Treatment/Follow-up Phase].
  • If fetus: provide [Gestational Age],(or mother’s LMP), at time of event. Also, [Gestational Age/Trimester]at first drug exposure and duration of exposure. If birth, provide details of [Infant Status]at birth. If hospital stay is complicated, provide details of hospital stay.
  • Provide details of the [AE]in chronological order, along with other [Signs/Symptoms].Provide details of [Physical Exam],along with all relevant [Procedures]and[Lab Results].
narrative template44
Narrative Template
  • Provide details of [Treatment]and[Treatment Rationale]on basis of[Findings/Test Result(s)].Describe [Treatment Response].
  • If hospitalization, provide[Dates Hospitalization], describe relevant [Hospital Course], [Diagnostic Work-up], [Procedures/Tests and Results], [Treatment], [Treatment Response].
  • Provide[Discharge Diagnosis], and any[Follow-up Information]. List[Discharge Meds].
  • Provide pertinent[Past Medical Hx], [Family Hx], [Concomitant Meds], [Alcohol/Tobacco/Substance Use]and any previous similar[AEs].
review and assessment of sae
Review and Assessment of SAE
  • Assemble all information available and use medical judgment
  • Standard for each AE:
    • Select [Seriousness Criteria]
    • Grade [Severity] per DAIDS Toxicity Table
    • Specify [Actions Taken on Study Product]
    • Specify [Outcome of SAE]. If Outcome is not resolved at time of evaluation, follow until resolution or stability at each study visit
    • Is it [Expected]?
    • Is it [Related]?

Clinical Case Evaluation

  • Sponsor role: (ICH E2D)
    • Information about the case should be collected from the healthcare professionals who are directly involved in the study subject’s care
    • Clearly identified evaluations by the sponsor are considered appropriate and are required by some regulatory authorities
    • Opportunity to render another opinion; may be in disagreement with; and/or provide another alternative to the diagnosis/assessment given by initial reporter
    • Sponsor makes an assessment of causality (attribution) just as the PI makes an assessment of causality (attribution)
    • If causality (attribution) is different between the sponsor and the investigator, both assessments are reported
site vs sponsor assessment
Site vs. Sponsor Assessment

Site Assessment

Sponsor Assessment

  • Balancing Both Roles
  • Site advantage: has access to subject; may elicit further info, perform PE, obtain tests, labs, records
  • Information from self-report (may lack validation)
  • Know subject best
  • Judgment stands
  • Open to dialog with sponsor
  • Information limited to what was submitted from site
  • May initiate queries to site: incur time and delay
  • Constraint: Must adhere to reporting timelines to FDA
  • MO level: Serious? Unexpected? Related?
  • SPT level: sign-off, agree with Site PI, agree with DAIDS MO. Any critical flaw in reasoning?
  • Open to dialog with Site PI, DAIDS MO