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Background and Introduction

The FHIR Adverse Event resource was initially developed under the stewardship of the HL7 BRR Group. The use cases and requirements that underpinned this resource structure definition are primarily driven by clinical trial and regulatory reporting contexts.

Within the clinical community, Adverse Event has three primary scope of uses:

    • Documentation, primarily in electronic medical record system or electronic healthcare record systems, of adverse events (which include near misses) arising from clinical activities or workflow; and supporting clinical care
    • Reporting adverse events arising from clinical activities or workflow within healthcare organisation to meet clinical safety and quality improvement requirements
    • Documentation and reporting of activities relating to the detection, assessment, understanding and prevention of problems/adverse effects or any other medicine-related and biological products (phmarcovigilance and biovigilance)
    • Regulatory reporting requirements including:
      • Reporting clinical trial related adverse events to meet regulatory requirements, where:
        • There may or may not be assertion of causality between the intervention/medication
        • There may not even be an intervention/active drug being administered to the subject

As such, the current FHIR Adverse Event resource design has generally been considered too narrow for the scope of uses described above.  A number of issues have been logged (see relevant section of the 2018-08-30 Patient Care FHIR Conference Call minutes for details) and required to be addressed.

CIMI modelling group has adopted and extended on a set of use cases that cover all the extended scope of uses described above. A logical model covering the expanded scope of use has been developed and balloted.

The Patient Care Workgroup decides to initiate a coordinated and collaborative effort to address issues of the current FHIR Adverse Event design and to harmonise as far as possible with the CIMI logical model while preserving as much as possible background compatibility to minimise implementation disruption

Leadership

  • Elaine Ayres
  • Stephen Chu
  • Russ Leftwich
  • Claude Nanjo
  • Emma Jones
  • Michelle Miller

Definitions

The concept of Adverse Event has different definition/meaning to different organisations and/or professional groups. The following is a collection of Adverse Event definitions discovered through online and literature search.

US Food and Drug Administration (FDA) definition:

Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related

It is worth noting that the FDA acknowledges the concept of Adverse Reaction when elaborating on the concept of Adverse Event:

Life-threatening adverse event or life-threatening suspected adverse reaction. An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death

Unfortunately, the narratives appear to infer that the two concepts (adverse event and adverse reaction) can be treated somewhat anonymously.

Clinical Trial and Science Institute (CTSI) Definition - University of California, San Francisco:

An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug

An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose

Definition from the International Council of Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use

Adverse Event: Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product

Adverse Drug Reaction

    • In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase responses to a medicinal product means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out.
    • Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function

It is also worth noting that the ICH makes a distinction between the two concepts - adverse event (any untoward medical occurrence) and adverse reaction (all noxious and unintended responses)

Definition from Victoria Department of Health (Australia):

An adverse event is an incident that results in harm to the patient

Institute for Healthcare Improvement Definition (quoted by the Agency for Healthcare Research and Quality on: Adverse Event, Near Misses and Errors):

Unintended physical injury resulting from or contributed to by medical care (including the absence of indicated medical treatment), that requires additional monitoring, treatment, or hospitalization, or that results in death

Adverse events may be preventable or non-preventable.

Preventable adverse event is defined as: events resulting from care that fell below the standard expected of physicians in their community. The are avoidable avoidable by any means currently available unless that means was not considered standard care.

WHO Definition of Medical Adverse Event (cited in a 2016 paper: Epidemiology of medical adverse events)

An event that causes patients injuries from medical errors such as misdiagnosis, malpractice, and device dysfunction, rather than as a result of their own diseases

A “near miss event” is defined as an event that could potentially have caused harm but was stopped by inadvertent intervention or immediate correction. 

A “no harm event” is an MAE (medical adverse event) that causes no patient damage (Comment: an example is - a dose of Vitamin C given to a wrong patient; another example is a correct operation, e.g. appendectomy was performed on a patient by a surgeon who was not assigned to be the patient's treating surgeon)

Other definitions

A definition provided by WG members during the 14 March 2019 conference call:

Christy shared her definition of AE:  "Any untoward or unintended sign, symptom, result, disease, or other medical occurrence (including an abnormal laboratory or ECG finding) in a clinical trial participant or associated person with a temporal association with the use of a medical product, procedure or other therapy, or in conjunction with a research study, regardless of causal relationship. EXAMPLE(S): death, back pain, headache, pulmonary embolism, heart attack, car accident."  Nausea would be included in that definition.

Definition from legal perspective:

The broadest use of the term (Adverse Event) is any harm to a patient as a result of medical care or the use of a medical product

Related Concept

Pharmacovigilance

The World Health Organization (WHO) describes pharmacovigilance as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem. This includes:

– collection and evaluation of spontaneous case reports of suspected adverse events
– pharmacoepidemiology studies (ICH 2004).

A presentation from the Australian Therapeutics Goods Administration (TGA) on Pharmacovigilance is available here.

Biovigilance

The science and activities relating to the detection, assessment, understanding and prevention of adverse events or any other problems related to biologicals

Where the meaning of biologicals include:

(1) Subject to subsection (3), a biological is a thing that:
     (a) either:
          (i) comprises, contains or is derived from human cells or human tissues; or
          (ii) is specified under subsection (2); and
     (b) is represented in any way to be, or is, whether because of the way in which it is presented or for
           any other reason, likely to be taken to be:
          (i) for use in the treatment or prevention of a disease, ailment, defect or injury affecting persons;
          or
         (ii) for use in making a medical diagnosis of the condition of a person; or
         (iii) for use in influencing, inhibiting or modifying a physiological process in persons; or
         (iv) for use in testing the susceptibility of persons to a disease or ailment; or
         (v) for use in the replacement or modification of parts of the anatomy in persons.

A presentation from the Australian TGA on Biovigilance is available here.

Adverse Event vs Adverse Reaction - a boundary and relationship discussion

From the definitions about, the concept of Adverse Event has two temporally related components:

  • Untoward medical occurrence and harm (FDA)
  • Untoward medical occurrence and unintended signs, symptoms or disease (ICH)

It is worth noting that the ICH makes a distinction between the two concepts - adverse event (any untoward medical occurrence) and adverse reaction (all noxious and unintended responses)


Based on definitions of the two concepts from various sources, common clinical understanding and analysis of common use cases, the following relationships can be derived:

  • An adverse event may result in harm, which may be evidenced by adverse reactions, or resulting injury 
    • Examples:
      • adverse event = medication administration error; harm = adverse reactions to administered medication
      • adverse event = fall; harm/injury = fracture hip
  • In the cases of near miss event or no harm event, there is no harm
    • In near miss the event was stopped before it can impact on the patient
      • Example: wrong medication administration stopped before given to patient; wrong medical device or implant discovered before implanted into patient
    • In no harm event, there is no resulting adverse reaction; but the untoward (medical) occurrences nonetheless has happened
      • Example: a dose of vitamin D was given to a wrong patient, with no resulting adverse effect
  • Some adverse event had occurred and resulted in harm, but only a temporal relationship with another event (and not causal relationship) can be asserted
    • Example:
      • Event 1 = a patient receiving a clinical trial drug
      • Event 2 = patient had a fall during the day or in the middle of the night
      • Harm caused by Event 2 = fracture hip
    • Until investigation confirms that there is a causal linkage between Event 1 and Event 2, the only relationship that can be asserted is one of temporal
  • Some adverse reactions had happened after a patient was prescribed and taken a medication. The prescribing physician had taken the proper clinical precaution to ensure that the patient had no known previous history of allergy/intolerance or adverse reaction to the medication prescribed. This is a case of adverse reaction. there is no adverse event.
  • Reporting known drug side effects:
    • Example - 
      • Ibrance was initially approved in 2015. It is a kinase inhibitor, approved in combination with an aromatase inhibitor as the first hormonal-based therapy in women who have gone through menopause and in men, or with fulvestrant in patients whose disease progressed following hormonal therapy
      • Ibrance has a set of documented/known adverse/side effects: infections, leukopenia (low levels of white blood cells), fatigue, nausea, stomatitis (inflammation of the mouth and lips), anemia (low levels of red blood cells), hair loss, diarrhea and thrombocytopenia (low levels of thrombocytes, also known as platelets, in the blood). Other common side effects reported are rash, vomiting, decreased appetite, asthenia (abnormal physical weakness or lack of energy) and fever
      • Analysis of real-world data (RWD) from electronic health records (EHRs) as additional supportive data to characterize the use of palbociclib in combination with endocrine therapy (aromatase inhibitor or fulvestrant) in male patients with breast cancer based on observed tumor responses in this rare subset of patients with breast cancer
    • Comment - the use of Adverse Event to report drug adverse/side effects data from EHR appears to be inappropriate

Challenges

If the FHIR AdverseEvent resource remains unchanged structurally, how can it be used to document and report on:

  • Adverse reactions that have temporal or causal relationship(s) with exposure to or administration/intake of substance
    • adverse reactions which may be a condition (e.g. anaphylaxis), or manifested as a collection of signs and symptoms, but are not "conditions" 
  • An adverse event of fall, resulting in harm/injury (fracture hip), and the fall is subsequently determined to be causally linked to another event, e.g. administration of clinical trial drugs
    • Event 1 (e.g. clinical trial drug administration) and event 2 (e.g. fall) which are temporally and possibly causally related
    • Event 2 (e.g. fall) and resultant harm/injury (e.g. fractured hip) and both temporally and causally related
  • Reporting known adverse/side effects of drug for pharmacovigilance 


Scope 

  1. Support clinical documentation
  2. Support documentation and reporting of Adverse incidents and QA within an organization
  3. Support documentation and reporting of pharmacovigilant and biovigilant requirements
  4. Support reporting to regulatory agencies as it relates to clinical trials. 

Note some of this work is being done by IHE Pharmacy. 


Requirements and Use Cases

Resources and References

Past Discussion Meeting Minutes

2018-08-30 Patient Care FHIR Conference Call

Claude demonstrated going to http://cimi.hl7.org/ and then selecting HTML document link, http://cimi.hl7.org/submissions/september_2018/cimi_doc/index.html

BRR Confluence page on Adverse Event Topic:




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