Pharmacovigilance has its own unique terminology that is important to understand. Most of the following terms are specific to drug safety, although some are used by other disciplines within the pharmaceutical sciences as well.
Adverse event (AE):
“Any untoward medical occurrence in a patient or clinical-trial subject administered a medicinal product and which does not necessarily have to have a causal relationship with this treatment”.
An adverse event can therefore be any unfavourable and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Adverse drug reaction (ADR), Suspected adverse (drug) reaction:
“A response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, correction or modification of physiological function”.
Response in this context means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility.
Examples:
1. Abortion, miscarriage or uterine hemorrhage associated with misoprostol (Cytotec), a Labor-inducing drug (this is a case where the adverse effect has been used legally and illegally for performing abortions).
2. Addiction with many sedatives and analgesics such as diazepam, morphine,etc.
3. Birth defects associated with Thalidomide and Accutane.
4. Bleeding of the intestine associated with aspirin therapy.
5. Cardiovascular disease associated withCOX-2 inhibitors (i.e. Vioxx).
6. Deafness and kidney failure associated with gentamicin (an antibiotic).
7. Death, following sedation in children using propofol (Diprivan).
Serious Adverse Events (SAEs): are defined as any untoward medical occurrence(s) that at any dose results in death, hospitalisation or prolongation of existing hospitalisation, persistent or significant disability/incapacity or a congenital anomaly or birth defect. These events must be reported immediately to the sponsor. Serious Adverse Events (SARs) are serious adverse events but causally related to investigational medicinal products.
Suspected Serious Adverse reactions (SSARs): are any adverse reactions considered consistent with information available about an Investigational medicinal Product (IMP). They must be reviewed at regular intervals to see if the profile of any IMP has changed and a record made of this.
Suspected Unexpected Serious Adverse Reactions (SUSARs): are any serious events suspected to be caused by a medicinal product, but which are not consistent with information about the medicinal product (these are the most serious of events and are subject to expedited reporting procedures)
Dechallenge: The withdrawal of a drug from a patient; the point at which the continuity, reduction or disappearance of adverse effects may be observed.
Rechallenge: The point at which a drug is again given to a patient after its previous withdrawal
Side effects: Unwanted but often unavoidable, pharmacodynamic effects that occur at therapeutic doses. Predicted from the pharmacological profile of a drug and known to occur in a given percentage of drug recipients
Examples:
- Side effect based on therapeutic effect:
Atropine (preanaesthetic)-dryness of mouth
Acetazolamide (diuretic-bicarbonate excretion) -Acidosis
Drug intolerance: Appearance of characteristic toxic effects of a drug in an individual at therapeutic doses. Intolerance can happen in individuals with a low threshold
E.g: Triflupromazine (single dose) can cause Muscular dystonias in
some individuals
Idiosyncrasy: Defined as genetically determined abnormal reactivity to a chemical
- It is certain Bizarre drug effects due to peculiarities of an individual for
which no definite genotype has been described, are also included. - Drug interacts with some unique feature of the individual, not found
in majority subjects, and produces the uncharacteristic reaction. - Examples:
• Barbiturates can cause excitement and mental confusion in some individuals
• Quinine can cause cramps, diarrhea, asthma, vascular collapse in some individuals - Chloramphenicol can cause Aplastic anemia in rare individuals
Drug allergy/Drug hypersensitivity: Immunologically mediated reaction producing stereotype symptoms, unrelated to the pharmacodynamic profile of the drug. Generally occur even with much smaller doses
- Types of drug allergy:
- Type I: Immediate, anaphylactic (IgE) • E.g:Penicillins – Anaphylaxis
- Type II: Cytotoxic antibody (IgG, IgM)
• E.g: Methyldopa – hemolytic anemia
- Type III: Serum sickness (IgG, IgM)
• Antigen-antibody complex
• E.g: Procainamide-induced lupus
- Type IV: Delayed hypersensitivity (T cell) • E.g: Contact dermatitis
Photosensitivity: Cutaneous reaction resulting from drug induced sensitization of the skin to UV radiation. The reactions are of two types
• Phototoxic: Drug or its metabolite accumulates in the skin, absorbs light and undergoes a photochemical reaction resulting in local tissue damage (sunburn-like, i.e., erythema, edema, blistering, hyper pigmentation)
Example: Tetracyclines (esp. Demeclocycline), and Tar products, Nalidixic acid, Fluoroquinolones, Sulfones etc
• Photo allergic: Drug or its metabolite induces a cell mediated immune response which on exposure to light (longer wave length) produces a papular or eczematous contact dermatitis like picture.
Example: Sulfonamides, Sulfonylureas, Griseofulvin, Chloroquine, Chlorpromazine
Drug dependence: Drugs capable of altering mood and feelings are liable to repetitive use to derive euphoria, withdrawal from reality, social adjustment, etc.
- Psychological dependence: Individual believes that optimal state of well being is achieved only through the actions of the drug.
Example: Opioids, Cocaine.
- Physical dependence: Altered physiological state produced by repeated administration of a drug which necessitates the continued presence of the drug to maintain physiological equilibrium. Discontinuation of the drug results in a characteristic withdrawal (abstinence) syndrome.
Example: Opioids, Barbiturates, Alcohol, Benzodiazepines
Drug abuse: Use of a drug by self medication in a manner and amount, that deviates from the approved medical and social patterns in a given culture at a given time. Drug abuse refers to any use of an illicit drug.
Drug addiction: Compulsive drug use characterized by overwhelming involvement with the use of a drug.
Drug habituation: Less intensive involvement with the drug, withdrawal produces only mild discomfort. Habituation and addiction imply different degrees of psychological dependence.
Drug misuse: Situations where the medicinal product is intentionally and inappropriately used not in accordance with the terms of the marketing authorisation.
Drug withdrawal reactions: Sudden interruption of therapy with certain drugs result in adverse consequences, mostly in the form of worsening of the clinical condition for which the drug was being used.
Examples:
– Corticosteroid can cause Adrenal insufficiency
– β-blockers can cause worsening of angina, precipitation of MI
– Clonidine can cause severe HTN, restlessness, sympathetic over activity
Teratogenicity: Capacity of a drug to cause foetal abnormalities when administered to the pregnant mother.
Drugs can affect the foetus at 3 stages:
1. Fertilization and implantation (Conception to 17 days): failure of pregnancy which often goes unnoticed.
2. Organogenesis(18 days to 55 days): most vulnerable period, deformities are produced.
3. Growth and development (> 56 days): developmental and functional abnormalities can occur.
Examples:
- Thalidomide – Phocomelia, multiple defects
- Anticancer drugs – Cleft palate, hydrocephalus, multiple defects
- ACE inhibitors – Hypoplasia of organs (lungs, kidney)
Mutagenecity and Carcinogenicity:
- Capacity of a drug to cause genetic defects and cancer respectively.
- Chemical carcinogenesis generally takes several (10-40) years to develop.
Examples: - Anticancer drugs,
- Radio-isotypes,
- Estrogens,
- Tobacco.
Drug induced disease:
- Also called Iatrogenic(Physician induced) diseases.
- Functional disturbances caused by drugs which persist even after
the offending drug has been withdrawn and largely eliminated
Examples: - Salicylates, Corticosteroids – Peptic ulcer
- Phenothiazines, other antipsychotics – Parkinsonism
Medication error: A medication error is an unintended failure in the drug treatment process that leads to, or has the potential to lead to, harm to the patient. A failure in the drug treatment process does not refer to lack of efficacy of the drug, rather to human or process mediated failures.
Off-label use: Situations where a medicinal product is intentionally used for a medical purpose not in accordance with the terms of the marketing authorisation.
Examples include the intentional use of a product in situations other than the ones described in the authorised product information, such as:
- Medicine used for disease or medical condition that it is not approved to treat
- Medicine administration through different route or method of administration
- Medicine used with different dose (posology)
- Medicine used in different group of patients (population)
Overdose: Administration of a quantity of a medicinal product given per administration or cumulatively which is above the maximum recommended dose according to the authorised product information. Clinical judgement should always be applied.
Causal relationship: Causal assessment is determined based on temporal relationship,alternative explanations, and (if possible) dechallenge and rechallenge. According to the WHO, the causal relationship between an adverse event and a suspected drug can be:
- certain
- probable/likely
- possible
- unlikely
- conditional/unclassified
- unassessable/unclassifiable.
Important medical event (IME): The EudraVigilance Expert Working Group has co-ordinated the development of an important medical event (IME) terms list based on the Medical Dictionary for Regulatory Activities (MedDRA). This IME list aims to facilitate the classification of suspected adverse reactions, the analysis of aggregated data and the assessment of ICSRs in the framework of the day-to-day pharmacovigilance activities.
Identified risk: An untoward occurrence for which there is adequate evidence of an association with the medicinal product of interest.
Potential risk: An untoward occurrence for which there is some basis for suspicion of an association with the medicinal product of interest but where this association has not been confirmed.
Important risk: An identified risk or potential risk that could have an impact on the risk-benefit balance of the product or have implications for public health.
Risk-benefit balance: An evaluation of the positive therapeutic effects of the medicinal product in relation to the risks, i.e. any risk relating to the quality, safety or efficacy of the medicinal product as regards patients’ health or public health
Safety concern: An important identified risk, important potential risk or missing information
Signal: Information arising from one or multiple sources, including observations and experiments, which suggests a new potentially causal association, or a new aspect of a known association between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify further investigation
CCDS: Company Core Data Sheet: The CCDS is a document that reflects the full company’s knowledge and data evaluation for a medicinal product
CCSI: Company Core Safety Information: The CCSI is the safety information contained in the CCDS
DLP: Data Lock point: The DLP represents the cut-off date for data and analyses presented in a document.
DSUR: Development Safety Update Report: Comprehensive, thoughtful annual review and evaluation of pertinent safety information collected during the reporting period related to a drug under investigation, whether or not it is marketed
IB: Investigator ́s Brochure: The IB is a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects.
International Birth Date: The date of the first marketing authorisation for any product containing the active substance granted to any company in any country in the world
Periodic Safety Update Report (PSUR) / Periodic Benefit-Risk Evaluation Report (PBRER): Pharmacovigilance document intended to provide an evaluation of the risk-benefit balance of a medicinal product for submission by marketing authorisation holders at defined time points during the post-authorisation phase
Risk management system: The RMS covers the entire life-cycle of a medicinal product.
Risk Management Plan: A set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicinal products, including the assessment of the effectiveness of those activities and interventions. The RMP is a dynamic, stand-alone document that should be updated throughout the life-cycle of the medicinal product to reflect the increasing knowledge on risks and benefits and the post-marketing experience with the product.
Summary of Product Characteristics: The SmPC is the basis of information for the healthcare professional on how to use the medicine. Its information is updated throughout the life-cycle of the product as new data emerge. The SmPC is a legal document approved as part of the marketing authorisation of a medicinal product in the European Union.
Sources of Adverse event reporting: Theinformation about adverse event collected from different sources. Below are types of reports –
- Spontaneous / Voluntary reports
- Clinical trials and Post marketing studies
- Regulatory reports
- License partner reports
- Literature reports
In next post we will learn about each type of report in detail..
Very informative.. easy to understand with examples