This is a significant topic for discussion in ICSR.
Many ICSRs could have multiple special safety scenarios-apart from routine adverse events and adverse drug reactions. The following scenarios in ICSR case handling need to be considered as “Special” while processing.
Below topics would be covered under special safety scenario concepts for ICSR-case processing.
Drug Exposure in Special Populations
The main objective for conducting clinical trial studies for a drug is evaluation of its “Efficacy” and “Safety”. Even though, an investigation drug is having good safety profile with minimal efficacy or No efficacy, there is no point of bringing it into market.
Similarly, a medicinal product after entering the market, both the safety and efficacy monitoring is required for continuous benefit risk profile assessment.
Now, we will see the difference between ‘efficacy’ and ‘effectiveness’
Efficacy: The extent of drug’s action or work for the intended indication in a clinical trial settings-The ideal circumstances which included highly selected, homogeneous population with several exclusion criteria.
Effectiveness: The extent of drug’s action or work for the intended indication in a everyday real world settings in heterogeneous population with no exclusion criteria.
Adverse events pertaining to drug performance:
Lack of Drug Efficacy: When we receive an ICSR from clinical trial source with lack of drug efficacy in a patient. This special situation would be captured as adverse event in event tab of safety database.
Lack of Drug effect/Drug Ineffectiveness: This adverse event can be originated for drug performance issues from the post-marketing sources.
Key Points to consider:
ICSRs with Lack of efficacy/effect (LOE) with no associated adverse event are not considered for valid submissions to regulatory authority. These ICSRs would be databased in the company’s safety database for further evaluations in aggregate reports and for signal evaluations purposes.
ICSRs with LOE can be considered serious and valid for submission to regulatory authority in the following scenarios-
- Drug intended for the patient suffering from life-threatening disease
- Drug intended for Contraception
- Drug’s LOE leading to the patient’s/subject’s worsening of current disease (causing serious conditions like hospitalization, prolonged hospitalization etc.,)
The below special safety topics would be covered under Drug Usage.
Drug Misuse: (Intentional Inappropriate use)
The situations where the medicinal product is intentionally and inappropriately used not in accordance with the terms of the marketing authorization. [OR] The use of a medicinal product for a purpose not consistent with legal or medical guidelines.
Examples: Administration of drugs more than the prescribed amount, usage of drugs (non-OTC ones) without proper medical prescription etc.,
Drug Abuse: The persistent or sporadic, intentional excessive use of a medicinal product, which is accompanied by harmful physical or psychological effects.
Examples: The most commonly used drugs with abusive potential (which can lead to excessive use for psychological effect) are opioid pain relievers, medicine used to treat attention deficit hyperactivity disorder, anxiety medicine and OTC drugs containing dextromethorphan (in cough and cold medicines).
Drug Abuse often follows the Drug Misuse.
Drug Dependence: A strong desire or sense of compulsion to take a drug substance, a difficulty in controlling its use, the presence of a physiological withdrawal state, tolerance of the use of the drug, neglect of alternative pleasures and interests and persistent use of the drug, despite harm to oneself and others.
Drug dependence usually followed by consistent drug abuse (persistent use of drugs with abuse potential).
Drug Withdrawal: The Syndromes (physical and mental symptoms) that occur after cessation or reduction of a drug intake which caused the dependence.
The characteristics of the withdrawal syndromes depends on the type of drug involved for abuse/dependence.
Drug overdose: The administration of a medicinal product’s quantity given per administration or cumulatively, which is above the maximum recommended dose according to the authorized product information.
Drug overdose can be:
–Intentional (excessive administration of drug for attaining therapeutic benefit by patient or prescriber/excessive intake of drugs by patient in an attempt to suicide).
–Accidental (unintentional excessive usage of drug more than the recommended dose).
Medication error: An unintended/unintentional failure in the drug treatment process which has potential to cause harm to the patient.
Medication errors can occur at different stages as described below:
- Prescription: If a medical prescription is written in an indecipherable way, which has potential for misunderstanding by the dispenser/pharmacist. This might lead to dispensing wrong medicines other than intended.
- Dispensing: Dispensing incorrect medication, dosage strength and form, miscalculations of dose, failure to counsel to patient on usage of drug, lack of knowledge and conscious attention (dispensing chlorpromazine instead of chlorpropamide, Amsat instead of Amset, Adcon instead of Adcom, Benzol instead of Benzole), use of outdated medicines for dispensing.
- Storage: Improper storage (Not in accordance with the label instructions for the medicine) at pharmacy store level and at consumer level at home.
- Preparation and Administration: Errors might occur due to lack of proper skill which included inappropriate use of diluents for injections formulations, incorrect infusion rates, incomplete delivery of container contents, spillage of medicine while preparation, not following instructions specified in the label, communication failure during the patient management, wrong route of administration, irrational use of antibiotics etc.,
Medication errors pose a major burden for public health physically (adverse reaction experiences), mentally (lack of belief in system) and financially (increased cost burden due to additional adverse events associated with medication errors, followed by hospitalization costs).
Off-label use: The intentional medicinal product use for a medical purpose which not in accordance with the terms of the marketing authorization.
Off-label use means an ‘un-approved use of drug’ which can be classified into following categories.
- Based on therapeutic indication: If any medicinal product is used for an indication which is not in accordance with the product label (not an authorized indication), then it would be an off-label use (with respect to therapeutic benefit).
- Based on Route of administration (ROA): Administration of a medicinal product intravenously (Unapproved ROA) instead of orally (Approved ROA) can be considered as off-label use.
- Based on altered doses: Using medicinal product with a dose which is not approved by regulatory authority can fall under off-label use.
- Based on type of population exposure: Use of medicinal product (which was approved for use only in adult patients) for a geriatric patient could classified as off-label use.
Occupation exposure: The exposure of medicinal product because of one’s professional or non-professional occupation.
Complaints on medicinal product can be received while processing an ICSR case.
The possible types of complaints pertaining to medicinal product are listed below:
Appearance: when the product is damaged, and it is appearing different than the original one.
Odour: Unpleasant odour of a tablet, syrup sometimes which is not acceptable to consume by patient.
Color: Change in the color of tablet or capsules inside the packaging which might lead to confusion, wrong administration, and a totally bad patient (consumer) experience.
Taste: Change in the taste of oral medicament which causes unpleasant experience for patient.
Labeling: Improper labelling for a medicinal product could lead to potential medication errors, and undesirable adverse event outcomes.
Drug Exposure in special populations
Let us look into each category of special populations
- Drug exposure in Pregnancy: The exposure of medicinal product ‘before pregnancy’ (especially for medicines with long half-life), ‘during pregnancy’, and ‘after pregnancy’.
There are several medicinal products which are contraindicated for pregnant women due to their teratogenic potential (The ability of medicine to cross through placenta and act on developing tissues of embryo or foetus which might cause potential safety concerns, congenital deformities, or death). And the safety profile of some medicines was not yet established for use in pregnant women.
The safety information of these medicines which are indicated for pregnant women is paramount for early detection of potential safety hazards and early identification of teratogenic potential of a medicine.
The possibility of exposure of drug to embryo or foetus could be in two ways-
- Maternal exposure: Mother is taking the drug and could cross the trans-placental membrane to reach out to embryo or foetus.
- Paternal exposure: Impregnation of drug molecules from Father’s Tran seminal fluid to mother through conception.
The following activities are obligatory tasks for a marketing authorization holder, whenever the company’s medicinal product is being exposure to embryo or foetus in pregnant women.
- Targeted monitoring for adverse drug reactions
- Proactive Follow ups for the collection of updated information
- Follow up for pregnancy outcome
- Follow up for the child development after birth.
- Reasonable attempts should be made for all follow ups.
ICSRs with maternal or paternal drug exposure scenarios associated with abnormal safety concerns should be considered serious for further reporting to regulatory authorities.
The possible abnormal safety concerns are listed here:
- Congenital anomalies or developmental delay in the foetus or the child
- Reports of miscarriage (spontaneous abortion) and foetal death
- Reports of suspected serious adverse reactions in the neonate
No regulatory submissions to health authorities are required for normal pregnancy exposure ICSRs (other than the above possible scenarios). However, these ICSRs should be databased normally in the company’s drug safety database for further evaluation in periodic safety update reports (PSURs).
- Drug exposure in Breastfeeding:
The exposure of medicinal product to infant via breast milk should be monitored for potential adverse reactions in infant or baby.
The suspected adverse reactions in infant followed by exposure to breast milk of women using company’s medicinal product should be reported to respective health authority as part of regulatory obligation.
- Drug exposure in paediatric or elderly population:
These categories of populations are considered “special” due to differences in various factors like varying levels of drug metabolizing enzymes, immunity, different physiological conditions affecting the pharmacokinetic and pharmacodynamic parameters of a medicinal product etc., Hence the susceptibility of occurrence of adverse drug reactions could be higher compared to adult populations.
The safety profile of medicines are not established in these special populations under clinical trial settings which restrict these group of populations.
Marketing authorization holders are obliged to monitor for exposure of the company’s medicinal product to paediatric (children of age less than 18) or geriatric (elderly population of age more than 65). ICSRs with these exposures associated with any serious adverse reactions are reported to regulatory authority.
Pediatric and Geriatric ICSRs with no associated adverse events are databased in company’s safety database for further evaluation in aggregate reports and signal evaluation.