Proposed Inclusion/Exclusion Criteria for the “Important ...



Proposed Inclusion/Exclusion Criteria for the “Important Medical Events” List

Background

Proposed inclusion/exclusion criteria for the “Important Medical Events” (IME) list were developed during review of the current list for maintenance related to MedDRA Version 12.1. They have been updated to MedDRA v14.1.

The criteria – and the proposed additions and deletions to the upversioned list – were based on the official ICH definition of seriousness and of an “important medical event” as noted below:

A serious adverse event (experience) or reaction is

any untoward medical occurrence that at any dose:

* results in death,

* is life-threatening,

* requires inpatient hospitalisation or prolongation of existing hospitalisation,

* results in persistent or significant disability/incapacity, or

* is a congenital anomaly/birth defect. It is recommended that reconsideration of this criterion be made relative to inclusion of terms on the IME list. Not all congenital anomalies have clinical consequence and can be considered even normal variants.

[NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.]

Medical and scientific judgment should be exercised in deciding whether

expedited reporting is appropriate in other situations, such as 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. These should also usually be considered serious.

Examples of such events are intensive treatment in an emergency room

or at home for allergic bronchospasm; blood dyscrasias or convulsions

that do not result in hospitalization; or development of drug dependency

or drug abuse.

Inclusion/exclusion criteria are proposed for the overall IME list as well as for specific MedDRA System Organ Classes.

Core Serious (CS) and Extended Serious (ES)

For the purpose of maintenance of the IME list, the MSSO proposes the following functional criteria for dividing the IME List PTs into “Core Serious” (CS) and “Extended Serious” (ES) terms:

Core serious

Such PTs fit precisely the definition of an IME, that is, “may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent” death, hospitalization/prolongation of hospitalization, or disability.

Example: PT Stroke in evolution

Extended serious

Such PTs do not precisely fit the definition and are sometimes rather broad (e.g., terms for “disorders” of vital organs). Although the term in isolation may not represent a clear cut IME, it could be envisioned that – with additional clinical information and medical circumstances (medical history, age of patient, etc.) available to the recipient of the report – the event may be or evolve into an IME.

Example: PT Anaemia

Overall Criteria

Included

• Generally, all infarct/infarction terms

• Generally, all ischemic/ischemia terms

• Generally, all necrosis/necrotic terms

• Generally, all gangrene/gangrenous terms

• Generally, all hemorrhage/bleed terms except those which are medically insignificant (e.g., PT Vessel puncture site haemorrhage). In particular, terms related to internal organ hemorrhage/bleed terms are included.

• Generally, all toxicity/intoxication terms

• Obstruction/obstructive and perforation terms, generally of gastrointestinal, respiratory and urinary systems as well as the ductal systems of significant organs

• Ulcer terms, generally of gastrointestinal, respiratory and urinary systems

• Terms for failure or insufficiency of life-sustaining organ systems (see note regarding reproductive terms)

• Terms for vascular occlusions that threaten the function and viability of critical organs

• Terms for vascular ruptures and ruptures or hollow or solid organs that may lead to a scenario consistent with the definition of an IME

• Terms for fistulas between organs or structures where significant compromise of organ function or other significant consequences (e.g., hemorrhage) could result (e.g., PT Aorto-oesophageal fistula)

• “Stenosis/stenotic” terms where compromise of organ function could result in an IME (e.g., PT Pyloric stenosis)

• Terms for arterial thromboses and other vascular thromboses where significant compromise of organ function or other significant consequences could result

• Generally, all embolic/embolism terms, aneurysm, vascular dissection terms

• “Mass” terms only for vital organs (e.g., PT Adrenal mass) or in situations where further work up/intervention is essential (e.g., PT Abdominal mass). Note that for MedDRA, “mass” does not automatically connote neoplasia.

• Generally, all dysplasia terms

Excluded

• Terms for non-specific “disorder”, “anomaly”, and other categorizations referring broadly to an organ system (e.g. PT Skin disorder). In these instances, there is nothing inherent in the term to suggest that it fulfills the ICH definition of an IME. Exceptions are made for certain disorder terms (e.g., PT Foetal heart rate disorder) where the term relates to a specific vital function and/or organ

• Generally, all “lesion” terms unless the finding automatically implies an IME, such as for PT Precancerous mucosal lesion and nervous system lesions

• Haematoma terms in general are excluded because they can be small and/or incidental and not fulfilling the ICH definition of an IME. However, a few exceptions are made for anatomic sites where any haematoma is of potential clinical consequence (e.g., PT Extradural haematoma)

• Some terms for reproductive disorders are difficult to assess (e.g., PT Fallopian tube obstruction). In many instances, although they may impair fertility or cause some functional disturbance, the majority (with a few exceptions, e.g., PT Ectopic pregnancy) do not threaten the patient’s life or otherwise fulfill the ICH definition of an IME.

• Terms for cysts, unless qualified as malignant or unless the finding implies that neoplasia is definitely present (e.g., PT Pituitary cyst)

• All polyp terms; by MedDRA convention, unless qualified by the word “malignant”, all polyps are classified as benign

• “Pain” and discomfort terms as pain and discomfort are symptoms, and in and of themselves, do not fit the ICH definition of an IME

• Terms for nonspecific inflammation and induration of non-vital organs and tissues (e.g., PT Connective tissue inflammation)

• Terms for biologic and demographic characteristics or risk factors (e.g., PT Genetic polymorphism, PT Familial risk factor)

SOC Blood and lymphatic system disorders

Included

• Terms for bone marrow depressions and cytopenias or processes (e.g., necrosis) that lead to these events

• Most terms for anemias

• Terms for hemophilias and other forms of clotting factor deficiencies and coagulation disorders; also, non-specific factor deficiencies and related findings

• Terms related to hemolysis

Excluded

• Nonspecific blood/hematologic terms that cover a broad range of possible events (e.g., PT Blood disorders) are excluded.

• Laboratory and radiologic related terms (although not a specific investigation term) that – in isolation – cannot be interpreted as an important medical event outside of other context (e.g., PT Haemoglobinaemia)

SOC Cardiac disorders

Included

• All term for arrhythmias except those which are a risk factor and are not inherently serious (e.g. PT Chronotropic incompetence), and except those which are trivial and on their own do not lead to more significant consequences (e.g., PT Extrasystoles)

• All terms for cardiac valve disorders

• All terms for endocardial disorders

• Terms for all forms of cardiac failure

• Terms for all forms of cardiomyopathy

• Terms for all forms of atrial and ventricular disorders and conditions such as dilatation, fibrosis, hypertrophy, dysfunction, rupture, aneurysm, dyskinesias (both hyper- and hypokinesis).

• Terms for myocardial disorders (which includes papillary muscle) including inflammations, infarctions, ischaemia, fibrosis, hypertrophy, dysfunction, rupture, aneurysm, dyskinesias (both hyper- and hypokinesis), haemorrhage, oedema and abnormal deposits such as amyloidosis

• Terms for all pericardial disorders inflammations, deposits, (consider ES) and haemorrhage (consider CS), etc.

Excluded

• Arrhythmia terms that represent a risk factor and are not inherently serious or fulfill the ICH definition of an IME (e.g., PT Chronotropic incompetence)

• Terms for trivial arrhythmias that do not lead to more significant consequences (PT Extrasystoles)

SOC Congenital, familial and genetic disorders

Excluded

• Because the ICH definition of seriousness includes “congenital anomaly or birth defect”, most terms in SOC Congenital, familial and genetic disorders would fulfill this definition. However, there are some terms in SOC Congenital, familial and genetic disorders that are trivial conditions – or even normal variants – which do not fit the overall definition of an IME (e.g., PT Birth mark, PT Accessory spleen, PT Persistent left superior vena cava). These are excluded

• Terms for gene carrier state (e.g., PT Cystic fibrosis carrier) in which the affected patient is disease free

• Terms for broad, nonspecific concepts that – by themselves – do not fit the ICH definition of an IME (e.g., PT Hamartoma, PT Hereditary disorder)

SOC Ear and labyrinth disorders

Included

• Terms for all forms of deafness

• Terms for most forms of inner ear pathology

SOC Endocrine disorders

Excluded

• Terms for simple enlargement of an endocrine organ (e.g., PT Parathyroid gland enlargement). This is a nonspecific, usually radiologic finding that does not itself indicate disease nor does it fit the ICH definition of an IME

SOC Eye disorders

Included

• Terms for all forms of blindness

• Terms for keratitis

• Terms for retinopathy

• Terms for glaucoma

• Terms for cataracts

SOC Gastrointestinal disorder

Included

• Terms for all perforations, hemorrhages, ulcers and obstructions except for those conditions occurring at less significant sites such as PT Mouth ulceration

SOC General disorders and administration site conditions

Excluded

• Product quality terms

• “Discomfort” terms

• Most injection, infusion, vaccination, and other administration “site” terms except those involving necrosis, ulcer and other forms of significant tissue injury

SOC Hepatobiliary disorders

Included

• Terms for biliary obstruction and its consequences (e.g., PT Cholangitis sclerosing)

• Terms for hepatic fibrosis, necrosis, failure and other processes (hemorrhage, infiltrations) that fit the ICH definition of an IME

• Generally, all hepatitis terms

• Terms for portal and hepatic vascular disorders

SOC Immune system disorders

Included

• Transplant rejection terms

• Generally, terms for all forms of immunodeficiency

SOC Infections and infestations

Included

• Most terms in this SOC generally fit the definition of an IME (see Excluded)

• All bacteremia, fungemia, sepsis/septicemia, and toxemia terms

• Generally, all abscess terms

• Generally, all cellulitis terms

• Encephalitis terms

Excluded

• Terms for nonsignificant infections such as the common cold (PT Nasopharyngitis), fungal nail infection (PT Onychomycosis), etc.

• Terms that represent modes of infection transmission (e.g., PT Indirect infection transmission) as these are not events but a disease mechanism

• Unqualified “inflammatory” terms (e.g., PT Cystitis, PT Rhinitis) unless related to a vital organ function

SOC Injury, poisoning and procedural complications

Included

• Although in isolation, most medication error terms do not fulfill the criteria for an IME, they are designated as ES to recognize the regulatory significance of such events

• Most nerve injury terms, particularly of specific nerves

• Most organ or anatomic site injury terms (e.g., PT Eye injury)

• Most trauma/traumatic terms unless representing a trivial injury

Excluded

• Most device-related terms except those that imply a direct injury or complication to a patient that would fulfill the definition of an IME (e.g., PT Implantable defibrillator malfunction). Note that some LLTs such as LLT Cardiac pacemaker malfunction are linked to PTs (PT Device malfunction) that would otherwise not qualify as an IME. Therefore, PTs such as PT Device malfunction are included on the list

• “Scar” terms because these do not fit the ICH definition of an IME. (They are evidence of past injury, and treatment will not alter their course)

• Nonspecific “complication” terms (e.g., PT Vascular access complication) unless it implies that a vital organ or structure is threatened

SOC Investigations

Included

• Terms that represent measured parameters that do not need additional contextual information to fulfill the criteria for an IME. (e.g., PT Apgar score low. In this case, no additional clinical information is needed to fit the definition of an IME)

• Most CSF test terms (with qualifiers) due to the clinical significance of any abnormality of the CSF

Excluded

• Generally, most terms in this SOC are excluded, especially those that are measured parameters, analytes, etc. An isolated finding of an increased or decreased measured parameter (e.g., PT Blood magnesium increased) does not fit the ICH criteria for an IME; additional information needs to be provided to put the investigational finding in the context of a disorder or diagnosis

• Unqualified test terms (e.g., PT Angioscopy)

SOC Metabolism and nutrition disorders

Included

• Terms for acid-base disorders

• Terms for clinical conditions associated with altered levels of metabolites (e.g., PT Hyperlactacidaemia) if they fit the ICH definition of an IME

SOC Musculoskeletal and connective tissue disorders

Included

• Terms for most types of fractures except trivial ones (e.g., PT Greenstick fracture)

SOC Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Included

• Terms for all malignant neoplasms, including metastatic conditions

• Terms for premalignant conditions with a very high likelihood of progression to malignancy (e.g., PT Myeloproliferative disorder)

• Terms for almost all CNS tumors, even if biologically benign because their clinical consequences may be significant (increased intracranial pressure, focal deficits, seizures, etc.)

Excluded

• Terms for benign and unspecified neoplasms except those that would interfere with organ function to the degree that they fulfill the criteria of an IME (e.g., PT Cardiac myxoma)

• Terms for neoplasms in remission (e.g., PT Acute leukaemia in remission)

SOC Nervous system disorders

Included

• Terms for all forms of coma, dementia, seizures, encephalitis, encephalopathy, and peripheral and other neuropathies

• Terms for forms of mental retardation except PT Borderline mental impairment and PT Mild mental retardation. Individuals with these conditions can be gainfully employed and can live independently

Excluded

• Terms for a variety of neurologic findings (e.g., PT Coordination abnormal, PT Cerebral ventricle dilatation). By themselves, such terms do not fit the ICH definition of an IME. It would only be useful in the context of other reported information, some of which (e.g., report of a cerebral infarct) would fit the definition of an IME

SOC Pregnancy, puerperium and perinatal conditions

Included

• Most abortion terms

• Terms – includling placental and umbilical cord terms – which imply a threat to the health or viability of the fetus

SOC Psychiatric disorders

Included

• Terms for depressions and forms of psychoses and their prominent symptoms (e.g., types of delusions)

• Autism terms and terms for related conditions

Excluded

• Nonspecific terms such as PT Affective disorder

• Terms for most personality disorders

• Terms for phobias unless a specific phobia could endanger a patient

• Terms for nonspecific symptoms (e.g., PT Terminal insomnia) which, by themselves, do not fit the ICH definition of an IME

SOC Renal and urinary disorders

Included

• Terms for glomerular disorders and other forms of nephropathies

• Terms for obstructive urinary tract disorders

Excluded

• Terms for nonsignificant anomalies such as solitary kidney

• Nonspecific terms referring to metabolites or other substances in the urine as these cannot be interpreted as a specific disease state without other clinical findings (e.g., Albuminuria)

SOC Reproductive system and breast disorders

Included

• Terms for ruptures, hemorrhages, and other lesions of reproductive organs that fit the ICH definition of an IME (e.g., PT Ovarian haemorrhage)

• Terms for or related to infertility (e.g., PT Hypospermia)

Excluded

• Terms for or related to sexual dysfunctions

SOC Respiratory, thoracic and mediastinal disorders

Included

• Terms for forms of asthma, pneumonia, pulmonary vascular disorders, neonatal respiratory disorders, and laryngeal and pharyngeal disorders that impair respiratory function or otherwise fit the definition of IME

Excluded

• Terms for minor upper respiratory conditions that do not fit the definition of an IME (PT Paranasal sinus mucosal hypertrophy)

• Terms for nonspecific disorders and findings (e.g., PT Respiratory tract inflammation)

SOC Skin and subcutaneous tissue disorders

Included

• Generally, terms for bullous, ulcerative or necrotic skin conditions that fit the ICH definition of an IME (e.g., PT Toxic epidermal necrolysis)

Excluded

• Common and/or benign skin findings that do not fit the ICH definition of an IME (e.g., PT Spider naevus)

SOC Social circumstances

Included

• Terms that could potentially be reported as AEs/ADRs and that would fit the ICH definition of an IME. Mainly these are terms related to lifestyle issues (e.g., PT Substance abuser)

SOC Surgical and medical procedures

Included

• Any term that implies an IME has occurred (e.g., PT Malignant breast lump removal)

Excluded

• Terms where the procedure may occur without the setting of an IME (e.g., PT Vitamin supplementation)

• Most dental and gingival procedure terms

• Most cosmetic surgery procedure terms

• Terms for immunizations

• Terms for prophylaxis and prevention since these are typically used to code indications, not adverse events

SOC Vascular disorders

Included

• Terms for forms of hypertension (except malignant forms) could be considered for ES in most cases

• Terms for arterial thromboses and other vascular thromboses where significant compromise of organ function or other significant consequences could result

• Generally, all embolic/embolism terms, aneurysm terms, vascular dissection terms, and arteriosclerosis terms, especially for vital organs (often in other SOCs)

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