"This training has been funded in whole or in part with Federal funds from the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, under Contract No.HHSN271200522081C."

2010 Web Seminar Series

Produced by Liz Buttrey, NIDA CTN CCC Training Office

Presented by: Robert Lindblad, M.D.Blake AppleMaria Campanella, B.S.N., R.N., CCRA

Identifying, Reporting and Resolving

Adverse Events in CTN TrialsAdverse Events in CTN Trials

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

2

Clinical and Regulatory Importance of Monitoring Safety in Research Studies

3

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

4

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.

5

Why Monitor Safety

Not an IND study Funded through NIH Good Clinical Practice

6

Strategy for Reporting

RISK

PopulationIntervention

7

Strategy for Reporting

Identify the Risk in the proposed clinical trial Tailor the reporting to the identified risk Maintain standard Adverse Event language

DefinitionsSeverity gradingRelationship designation

8

New Regulations

FDA issued new regulations regarding safety reporting

Will impact all clinical trial reporting Increased consistency with ICH and GCP

guidelines

9

Summary

Why report Safety?

It is the right thing to do to ensure participant’s well being in a clinical research study

NIDA CTN population meets the definition of a vulnerable population

10

AEor

SAE

Identifying

&

Reviewing

Reporting & Verbatims

Resolving

Discussion & Guidance

Safety Event Process Recommendations

11

Identifying Safety Events:

The term Safety Events includes both

Adverse Events and Serious Adverse Events

Identifying & Reviewing

What is a “Safety Event”?

12

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.

13

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

14

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.

15

So, what Challenges

you?

16

Identifying Safety Events

The protocol defines the rules for reporting adverse events.

It also defines the notification time frames and reporting responsibilities.

Know your Protocolit’s all in the details

17

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

18

Following up on Unresolved AE/SAE’s

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

19

Identifying Safety Events:

Safety events are chronically underreported in clinical trials the participant is not forthcoming

with the information the research staff isn’t 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

Identifying & Reviewing

20

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 event2- The severity of the event3- The relatedness of the event4- If the event is a Serious Adverse Event?5- If the event is a ‘reportable’ one? (To whom, what and when?)

21

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.22

Naming the Events

The Name of the Event

The Verbatim = the AE description

Simple Accurate 2-3 words Prefer a diagnosis to

symptoms

HINT!

It doesn’t mean to write down verbatim what the participant says.

23

Examples of AE’s that were incorrectly reported during other clinical trials

Oops!

24

Naming the Events

Normally normal after drinking coffee

Naming Safety Events

HINT!

Enter Verbatims that make sense.

25

Avoid Vague or Ambiguous Medical Terms

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.

26

Naming Safety Events

HEARS NEW AGE MUSIC WHEN THE FURNACE TURNS ON

Could this be a hallucination?

27

Naming Safety Events

“LK RTCTL UNSP XTRNDL ORG”

HINT!

No acronyms or

abbreviations

28

Naming Safety Events

Watch out for Abbreviations and Acronyms

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.

29

Naming Safety Events

“ABDOMINAL DISCOMFORT SECONDARY TO AIRPLANE FOOD INGESTION”

HINT!

Stick to the facts. Do not need qualifiers.

How about Abdominal discomfort.

30

Naming Safety Events

Avoid Extraneous Data Keep it simple

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.

31

Naming Safety Events

“MUSCLE PAIN IN THE BAG”

HINT!

Watch for typos!

They can change the meaning.

How about

Back pain.

32

Naming Safety Events

Where is it?Body Site is Needed for Certain Conditions

AE Term AE Term AE Term

Incorrect Obstruction Congestion Ulcer

Why? 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.

33

Naming Safety Events

PEES LIKE A CAMEL

How aboutExcessive Urination.

34

Naming Safety Events

We Need Complete Medical Terminology

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 sore”“Sore shoulder”

Site action

Ensure complete medical condition is recorded.

35

Naming Safety Events

“PATIENT RECENTLY BEGAN NEW JOB WHERE HE WORKS AROUND CHICKEN WINGS AND BARBECUE SAUCE”

Nice Information!But what is

The adverse event?

36

Naming Safety Events

“HEADACHES and SEEING PEOPLE IN ROOM, SEEING CHICKENS AT WINDOW”

HINT!

Enter only one event per CRF.

37

Naming Safety Events

Don’t Place Multiple Diagnoses in One Entry

AE Term AE Term

Incorrect Broken finger/Hand abrasions

Urinary bladder obstruction with Cystitis

Why? 2 events 2 events

Correct 1. Broken finger

2. Hand abrasions

1. Urinary bladder obstruction

2. Cystitis

Site action

Record only one medical diagnosis per line.

38

Naming Safety Events

Reporting Safety Events

Why is the getting the verbatim right

so important?

MedDRA Coding(Medical Dictionary for Regulatory Activities)

39

Reporting Safety Events

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)

40

41

MedDRA Coding

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).

42

MedDRA Coding

43

Once you’ve named the event, then you have to characterize it.

Events are characterized by determining the relatedness and severity.

Reporting Safety Events

44

Reporting Safety Events

The relatedness of the event refers to whether

the event is thought to have been caused by or made worse by the study

intervention

Relatedness requires an assessment of temporal relationships

45

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 participant’s 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 participant’s 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.

46

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 SAE…the cause of the death is the SAE…death is the

outcome.47

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

48

Death or or Is life-threatening or Requires admission to an inpatient medical facility or Prolongs a hospitalizationor Persistent or significant disability or incapacityor Is a birth defect or congenital anomaly or Requires medical intervention to prevent one of the above

Know your protocol!

Reporting Safety Events

Your Protocol Your IRBProtocolProtocol

HINT!Your site specific IRB requirements

may differ from protocol reporting

requirements

The reportability of an event in CTN trials based on TWO things:

49

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

50

Protocol Reporting Requirements

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.

Reporting Safety Events

51

IRB Reporting Requirements

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.

Reporting Safety Events

52

53

Consider a Cheat Sheet that will Breakdown what is

Reportable for Protocol vs. Reportable for the IRB

54

Resolving Safety Events

You’ve identified, named, characterized and reported a safety event according to the

protocol and your IRB… Now

what?

55

Resolving Safety Events

All Adverse Events including deaths reported in a Clinical Trial should have:An outcome

A resolution date (end date)

56

Resolving Safety Events

Clinical resolution

Events may never be ‘resolved’ and

may be chronic or ongoing…forever.

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

What is the difference between clinical resolution and regulatory resolution?

57

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

58

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.

59

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.60

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

61

Questions?

62

Questions?

63

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

64

Clinical Trials Network ∙ Dissemination Library

National Drug Abuse Treatment

A copy of this presentation will be available

electronically after the meeting from:

http://ctndisseminationlibrary.org

CTN Dissemination Library

https://livelink.nida.nih.gov

NIDA Livelink

and

65