Presented by:Robert Lindblad, M.D.

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Identifying, Reporting and Resolving
Adverse Events in CTN Trials

• Presented by Robert Lindblad, M.D.
• Blake Apple
• Maria Campanella, B.S.N., R.N., CCRA

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Training Outline

• Bob Lindblad, MD
• Monitoring safety in research studies
• Clinical and regulatory importance
• New regulations and guidelines
• Blake Apple
• Safety Reporting The Site Perspective
• Identifying
• Naming (Verbatims)
• Characterizing
• Reporting
• Maria Campanella, BSN,RN, CCRA
• Responsibility and resources
• MedDRA Coding
• Resolving
• Discussion and guidance
• Closing the data base reconciliation

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Why Monitor Safety?

• HUMAN SUBJECT PROTECTION
• The Declaration of Helsinki
• Concern for the interests of the subjects
• must always prevail over the interests of
• science and society.
• Primum non nocere
• Hippocrates, 460-377 BC

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Why Monitor Safety?

• GUIDELINES and REGULATIONS
• ICH GCP guidelines
• The rights, safety, and well-being of the trial
  subjects are the most important considerations
  and should prevail over interests of science and
  society.
• The Federal Government
• All clinical trials supported or conducted by
  the Federal Government must monitor and protect
  the safety of human subjects.

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Why Monitor Safety

• Not an IND study
• Funded through NIH
• Good Clinical Practice

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Strategy for Reporting
Population
Intervention
RISK
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Strategy for Reporting

• Identify the Risk in the proposed clinical trial
• Tailor the reporting to the identified risk
• Maintain standard Adverse Event language
• Definitions
• Severity grading
• Relationship designation

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New Regulations

• FDA issued new regulations regarding safety
  reporting
• Will impact all clinical trial reporting
• Increased consistency with ICH and GCP guidelines

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Summary

• Why report Safety?
• It is the right thing to do to ensure
  participants well being in a clinical research
  study
• NIDA CTN population meets the definition of a
  vulnerable population

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Safety Event Process Recommendations
Identifying Reviewing
Resolving
AEorSAE
Reporting Verbatims
Discussion Guidance
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Identifying Safety Events
Identifying Reviewing
What is a Safety Event?

• The term Safety Events includes both
• Adverse Events and Serious Adverse Events

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Identifying Safety Events

• What is an Adverse Event (AE)?
• Any reaction, side effect, or untoward event
• that occurs during the course of the clinical
  trial, whether or not the event
• is considered clinically significant
• or related to the intervention.

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Identifying Safety Events

• What is a Serious Adverse Event (SAE)?
• A SAE is an AE that results in
• Death or
• or Is life-threatening
• or Requires admission to an inpatient medical
  facility
• or Prolongs a hospitalization
• or Persistent or significant disability or
  incapacity
• or Is a birth defect or congenital anomaly
• or Requires medical intervention to prevent one
  of the above

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Reporting Safety Events

• WHEN are AEs and SAEs reported?
• Research staff should assess for reportable AEs
  and SAEs at every study visit.
• All reportable AE/SAEs should be entered into the
  EDC system via the Adverse Events CRF as soon as
  the site becomes aware of the event.
• All information related to a reported AE should
  be entered into the EDC system within 7 days of
  the site becoming aware of the event.
• All information related to a reported SAE should
  be entered into the EDC system within 24 hours of
  the site becoming aware of the event.

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Identifying Safety Events
Know your Protocol its all in the details

• The protocol defines the rules for reporting
  adverse events.
• It also defines the notification time frames and
  reporting responsibilities.

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Adverse events can be identified through a
variety of ways

• Direct participant discussions
• Direct observation of the participant (bruises
  etc)
• Family or friends of the participant
• Newspaper articles, as in death announcements
• Confidential discussions with other research
  staff
• Discussions with outside providers, if the
  participant has given consent to do so

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Following up on Unresolved AE/SAEs

• It is easy to forget a certain participant has an
  open AE.

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Identifying Safety Events
Identifying Reviewing

• Safety events are chronically underreported in
  clinical trials
• the participant is not forthcoming with the
  information
• the research staff isnt asking the right
  questions
• the information is hidden in a progress note
  and not recorded appropriately as a safety event
• participants sometimes report AEs in regular
  conversations

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Reporting Safety Events

• WHAT information about an AE/SAE
• needs to be reported
• When a Participant Reports an Event, the RA
  has to figure out
• 1- The name of the event
• 2- The severity of the event
• 3- The relatedness of the event
• 4- If the event is a Serious Adverse Event?
• 5- If the event is a reportable one?
• (To whom, what and when?)

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Reporting Safety Events

• The Biggest Challenge? The Name of the Event
• Knowing how to take everything that you see and
  hear during your assessment and boiling it down
  to
• one, accurate and succinct term
• Avoiding getting caught in the drama of the
  event
• It sounds a lot easier than it is.

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Naming the Events

• The Name of the Event
• The Verbatim the AE description
• Simple
• Accurate
• 2-3 words
• Prefer a diagnosis to symptoms

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Naming the Events

• Examples of AEs that were incorrectly reported
  during other clinical trials

Oops!
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Normally normal after drinking coffee
Naming Safety Events
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Avoid Vague or Ambiguous Medical Terms
Naming Safety Events
AE Term AE Term AE Term
Incorrect Eye problem Borderline cardio reply Liver disturbance
Why? What is the problem? What does reply mean? What is the disturbance?
Correct Eye pain Congestive heart failure Fatty liver
Site action Record diagnosis if obtainable. If diagnosis unobtainable, record one specific sign/symptom per line. Record diagnosis if obtainable. If diagnosis unobtainable, record one specific sign/symptom per line. Record diagnosis if obtainable. If diagnosis unobtainable, record one specific sign/symptom per line.
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HEARS NEW AGE MUSIC WHEN THE FURNACE TURNS ON
Naming Safety Events
Could this be a hallucination?
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LK RTCTL UNSP XTRNDL ORG
Naming Safety Events
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Watch out for Abbreviations and Acronyms
Naming Safety Events
AE Term AE Term
Incorrect CA DM
Why? Could be -Cardiac arrest -Coronary angioplasty Could be Diastolic murmur -Dermatomyositis -Or others
Correct Cancer Diabetes Mellitus
Site action Avoid use of abbreviations or acronyms since they can be ambiguous. Enter each word completely. Avoid use of abbreviations or acronyms since they can be ambiguous. Enter each word completely.
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ABDOMINAL DISCOMFORT SECONDARY TO AIRPLANE FOOD
INGESTION
Naming Safety Events
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Avoid Extraneous Data Keep it simple
Naming Safety Events
AE Term AE Term
Incorrect Vomited several times at midnight after eating spicy food Headache off and on during the evening
Why? Frequency, time and food type unnecessary in AE field Frequency and time unnecessary in AE field
Correct Vomited Headache
Site action If date/time/severity, etc. are needed, fields will be provided. Record the additional data in appropriate fields, not the AE name field. If date/time/severity, etc. are needed, fields will be provided. Record the additional data in appropriate fields, not the AE name field.
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MUSCLE PAIN IN THE BAG
Naming Safety Events
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Where is it?Body Site is Needed for Certain
Conditions
Naming Safety Events
AE Term AE Term AE Term
Incorrect Obstruction Congestion Ulcer
Why? These conditions can occur in multiple locations. These conditions can occur in multiple locations. These conditions can occur in multiple locations.
Correct Bronchial obstruction Venous congestion Ulcer (site unknown)
Site action Record body site/organ for ambiguous medical terms. If body site is unobtainable, document that it is unknown. Record body site/organ for ambiguous medical terms. If body site is unobtainable, document that it is unknown. Record body site/organ for ambiguous medical terms. If body site is unobtainable, document that it is unknown.
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PEES LIKE A CAMEL
Naming Safety Events
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We Need Complete Medical Terminology
Naming Safety Events
AE Term AE Term AE Term AE Term
Incorrect Diabetes Anorexia Cold Sore
Why? Could be mellitus or insipidus Different conditions Feels cold or has an infection Could be a lesion or has sore muscles
Correct Diabetes Insipidus Anorexia nervosa Chest cold Cold soreSore shoulder
Site action Ensure complete medical condition is recorded. Ensure complete medical condition is recorded. Ensure complete medical condition is recorded. Ensure complete medical condition is recorded.
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PATIENT RECENTLY BEGAN NEW JOB WHERE HE WORKS
AROUND CHICKEN WINGS AND BARBECUE SAUCE
Naming Safety Events
Nice Information! But what is The adverse event?
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HEADACHES and SEEING PEOPLE IN ROOM, SEEING
CHICKENS AT WINDOW
Naming Safety Events
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Dont Place Multiple Diagnoses in One Entry
Naming Safety Events
AE Term AE Term
Incorrect Broken finger/Hand abrasions Urinary bladder obstruction with Cystitis
Why? 2 events 2 events
Correct Broken finger Hand abrasions Urinary bladder obstruction Cystitis
Site action Record only one medical diagnosis per line. Record only one medical diagnosis per line.
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Reporting Safety Events
Reporting Safety Events

• Why is the getting the verbatim right
• so important?
• MedDRA Coding
• (Medical Dictionary for Regulatory Activities)

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MedDRA Coding

• MedDRA - the Medical Dictionary for Regulatory
  Activities
• medical terminology used to classify adverse
  event
• coding allows health authorities and the
  biopharmaceutical industry to more readily
  exchange and analyze data related to the safe use
  of medical products.
• MedDRA was developed by the International
  Conference on Harmonisation (ICH)

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MedDRA Coding
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MedDRA Coding

• The structural elements of the MedDRA terminology
  are as follows
• SOC Highest level of the terminology, and
  distinguished by anatomical or physiological
  system, etiology, or purpose
• HLGT Subordinate to SOC, superordinate
  descriptor for one or more HLTs
• HLT Subordinate to HLGT, superordinate
  descriptor for one or more PTs
• PT Represents a single medical concept
• LLT Lowest level of the terminology, related to
  a single PT as a synonym, lexical variant, or
  quasi-synonym (Note All PTs have an identical
  LLT).

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MedDRA Coding
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Reporting Safety Events

• Once youve named the event,
• then you have to characterize it.
• Events are characterized by determining
• the relatedness and severity.

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Reporting Safety Events
Relatedness requires an assessment of temporal
relationships

• The relatedness of the event refers to whether
• the event is thought to have been
• caused by or made worse by the study intervention

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Event Relatedness

• Is the event related to the study intervention
  that the participant has been randomized to?
• NO Unrelated No reasonable temporal sequence and
  if the event can most likely be explained by the
  study participants clinical disease state or by
  other therapies
• YES Possibly A reasonable temporal sequence,
  follows a known response pattern, but could have
  been produced by the study participants clinical
  state or by other therapies
• YES Probably A reasonable temporal sequence,
  follows a known response pattern, cannot be
  reasonably explained by the known characteristics
  of the study participants clinical state or other
  therapies
• YES Definitely A temporal sequence follows a
  known response pattern.

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Reporting Safety Event - Severity

• Grade 1 Mild
• Transient or mild discomfort (less than 48 hours)
  no or minimal medical Intervention/therapy
  required, hospitalization not necessary.
• Grade 2 - Moderate
• Mild to moderate limitation in activity, some
  assistance may be needed no or minimal
  intervention/ therapy required, hospitalization
  possible.
• Grade 3 - Severe
• Marked limitation in activity, some assistance
  usually required medical intervention/ therapy
  required, hospitalization possible.
• Grade 4 - Life-threatening
• Extreme limitation in activity, significant
  medical/ therapy intervention required,
  hospitalization or hospice care probable.
• Grade 5 - Death
• Remember that death is not the SAEthe cause of
  the death is the SAEdeath is the outcome.

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Reporting Safety Events

• Remember that Severe and Serious
• are not the same thing
• Serious events may be Grade 2 (Moderate)
• Grade 3 (Severe) events are NOT always serious

Know your protocol!
Death or or Is life-threatening or Requires
admission to an inpatient medical facility or
Prolongs a hospitalization or Persistent or
significant disability or incapacity or Is a
birth defect or congenital anomaly or Requires
medical intervention to prevent one of the above
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Reporting Safety Events
The reportability of an event in CTN trials
based on TWO things

• Your Protocol

• Your IRB

Protocol
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Reporting Safety Events

• WHO reports AEs and SAEs?
• The participant Study staff
• The study staff EDC Site IRB
• EDC NIDA CTN Safety Office
• NIDA CTN Safety Office Sponsor

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Protocol Reporting Requirements
Reporting Safety Events

• Knowledge of the protocol requirements
• A process
• for eliciting adverse event related information
  from your participants
• for reporting this information to the Medical
  Monitor/Safety Monitor in the appropriate
  timeframes
• for following up and resolving reported events.

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IRB Reporting Requirements
Reporting Safety Events

• Knowledge about how your site IRB(s) reporting
  requirements differ from the protocol
  requirements.
• A process for reporting to the IRB and for
  documenting evidence of this reporting to a
  protocol monitor.

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Consider a Cheat Sheet that will Breakdown what
isReportable for Protocol vs. Reportable for the
IRB
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Resolving Safety Events

• Youve identified, named, characterized and
  reported a safety event according to the protocol
  and your IRB

Now what?
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Resolving Safety Events

• All Adverse Events including deaths reported in a
  Clinical Trial should have
• An outcome
• A resolution date (end date)

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Resolving Safety Events
What is the difference between clinical
resolution and regulatory resolution?

• Clinical resolution
• Events may never be resolved and may be
  chronic or ongoingforever.

• Regulatory resolution
• Events may be resolved when they are medically
  stable or when they are no longer followed within
  the parameters of a clinical trial

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Resolution Outcomes
Ongoing From a clinical standpoint, when an event is not yet resolved and the participant is still enrolled in the trial Events is this category should move to a resolution category as soon as resolution is achieved
Resolved An event is no longer present or when an event is medically stable
Resolved with sequelae The event is no longer active and there may be some residual effects from the event
Resolved by convention From a regulatory standpoint, when no follow up about the event is anticipated and a window of time, defined as 30 days past the study termination date or 30 days past the active study participation date has passed.
Death A death is reported
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Resolving Safety Events

• Resolved by Convention
• AEs/SAEs are to be followed until resolved or
  medically stable or until 30 days have passed
  since study completion.
• If study participant is lost to follow up and
  resolution information about a previously
  reported event is not anticipated, the site
  should make every effort to locate the
  participant in order to resolve the event.
• Once the study participation window ends however,
  attempt to contact a participant for 30 days. If
  no contact made, then the event may be resolved
  by convention.

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Responsibility and Resources

• Any research staff member who comes into contact
  with an individual enrolled in a clinical trial
  has a responsibility to identify and report
  adverse events.

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Know Your Safety Resources

• The Protocol
• The Protocol Manual of Operations and
• CRF Instructions Manual
• The Protocol Safety Monitor
• The Protocol Monitor for your site
• The Protocol Lead Study Team

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Questions?
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Questions?
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Polling Question Review

• Why care about safety events in a CTN clinical
  trial?
• NIH requires safety monitoring.
• What determines the risk in a clinical trial?
• Risk is determined by the intervention and the
  population being studied
• A participant reports they have had a symptoms of
  a cold for the last week. You would
• I would determine the severity of the event and
  then the relatedness, and then determine from the
  protocol whether or not it is reportable
• You hear through the grapevine that a study
  participant has died. What should you do next?
• Always report the death, even if details are
  pending
• A study participant has an ongoing adverse event.
  Despite all efforts the participant is lost to
  follow up. What should you do next?
• Always resolve an event

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Clinical Trials Network Dissemination
Library
National Drug Abuse Treatment
A copy of this presentation will be available
electronically after the meeting from
CTN Dissemination Library
http//ctndisseminationlibrary.org
and
NIDA Livelink
https//livelink.nida.nih.gov