Pharmacovigilance Flashcards
the objective of health products regulation groups
- safeguard public health:
- ensure appropriate technical standards are met
- facilitate recalls, product withdrawals - facilitate:
- access to safe, good quality, and efficacious health products
- support development of a high quality healthcare system - assure:
- instill trust, confidence and credibility of products at home and abroad
ranges of health products regulated by HSA
- investigational drugs
- med devices
- cosmetics
- therapeutic products
- complementary health products
- advance therapy products (CTGT)
- tobacco
types of complementary health products
- usually OTC
1. Chinese proprietary (most regulated)
2. vitamins, minerals, quasi
3. other traditional meds
types of therapeutic products
- prescription only
- pharmacy only (OTC)
- GSL (OTC)
- pre and post-market control
pre-market stage regulation
- clinical trials
- product registration listing
- dealers license
post-marketing stage regulation
- vigilance
- surveillance
- compliance monitoring
- enforcement
regulations when placing on-market
- storage and distribution
- advertising
- supply and sale
HSA role in risk management
- risk-based approach titrated according to inherent risks (TP more risk than CHP/cosm)
- more stringent controls for high risk products
what products have post-marketing controls
- therapeutic products
- cosmetics
- chinese proprietary medications
- others like traditional meds, health supplements, homeopathic meds
HSA role in risk management for TP
- approve the drug when it assesses that the benefits outweigh its risk for the intended population and use
- tolerance for risk higher for drugs that treat serious and life-threatening disease
- balance benefit/risk continue to be monitored post-marketing (recall action if needed)
reactions and causality of adverse events and reactions
adverse events: causality not implied
adverse reaction: causality assumed
required sample size for detecting a rare ADR
incidence: 1 in 10000
sample size 30000
*rule of three (95% CI)
limitations of clinical trials
- clinical trials designed to test the efficacy and detect common ADR (1 in 100 etc)
- by the time the drug is marketed, usually 1500-3000 pt are exposed (larger numbers for vaccine trials)
- short duration of 1-3 years (some ADR take a while to occur, maybe 6 mths)
- at the point of marketing, not a lot of pt are being trialled and tested
impact of ADRs
ADR doubles the mean length of stay in hospitals, which increases the cost burden and the inherent risk of mortality
process of pharmacovigilance
- signal/risk detection
- risk assessment
- risk minimisation
- risk communication
what are signals
- an early indicator or warning of a potential new problem with a drug, or class
- reported information on possible causal r/s between adverse event and a drug (may be unknown or incompletely documented previously)
- usually more than 1 report is required to generate a signal
- kinda like a hypothesis with data and argument that support it
source of a signal
- ADR reports
- literature report
- new epidemiological study
- randomised trial
sources of signal detection
- international data
2. local data
types of international data
- WHO international drug monitoring programme
- Environmental scanning
- international regulatory exchanges
types of local data
- HCP
- autopsy reports/ toxicology labs
- active surveillance initiatives
- CMIS, sentinel sites (vaccines), registries for selected drugs - mandatory reporting (drug companies)
- serious reports within 15d
- findings from studies after BR ratio
- post-marketing studies
advantages of ADR reporting
- operates for all drugs given to patients
- operates throughout the whole of the drug’s life
- relatively inexpensive to operate
- accessible to all physicians/dentist/pharmacists
- can provide rapid identification of newly identified ADR
disadvantages of ADR reporting
- low level of reporting (~2-4%)
- scheme required HCPs to recognise ADRs, which is complicated by many ADR mimicking naturally-occuring illnesses
- data collected relate to suspected associations only
- unable to provide incidence rate because of lack of denominator data
channels of reporting
- mail, fax, tel
- email HSA
- online reporting (ADR online)
- e-reporting linked to med records (CMIS)
case by case evaluation of the qualitative method of signal detection
- frequency
- nature/ type of event
- time to onset
- duration
- rechallenge/ dechallenge
different approaches of quantitative method of signal dection
- frequentist method:
- Proportional reporting ratio (PRR)
- reporting odds ratio (RORs)
- sequential probability ratio test (SPRT) - Bayesian approaches:
- bayesian confidence propagation neural network information component (BCPNN)
- Multi-item GPS GAMMA Poisson shrinker
- Empirical Bayes Geometric mean (EBGM)
how to confirm signals
- hypothesis testing
2. epidemiological study
what is the use of risk-benefit assessment
- review safety signals receive for drugs and further confirmatory studies
- determine the benefit vs risk profile of the drug through collection and review of relevant data
factors affecting risk-benefit assessment
- efficacy data
- safety data
- therapeutic alternatives
- types of disease
- impact on population
- ability to mitigate risk
a favorable R/B analysis would:
retain product in the market by having:
- enhancement of warnings in package inserts
- change of indications to mitigate new risk
- new contraindications to use
- postmarket studies, registries
- restriction of use to certain medical disciplines only
- restriction of access to certain patients only
effect of an unfavorable R/B analysis
- suspension of sales
- recall of product
- withdrawal of PDT (‘voluntary’ withdrawal if initiated by company)
aim of risk communication
- minimise risk and enhance safe use of drugs
2. update and inform unintended audience of safety issues in a timely, transparent and unbiased manner
spontaneous reporting
voluntary submission of reports on AEs or ADRs by healthcare professionals to the national regulatory authority outside a systematically planned study
mandatory reporting of ADR
is a legal obligation to report suspected ADR
minimum information of an individual case safety report (ICSR)
- an identifiable reporter
- an identifiable patient (age, gender, initials)
- at least 1 identifiable drug
- at least 1 identifiable suspected ADR
serious ADR
- may result in death
- may threaten a life
- result in hospitalisation or prolonged stay
- result in persistent or significant disability/incapacity
- results in congenital anomaly or birth defects
- judged to be medically important even tho the effect might not be immediately life-threatening or results in hospitalisation
causality assessment
- pharmacological plausibility:
- chemical nature of molecule/class
- assumable intrinsic activity
- dosage and duration of therapy fitting
- PK fitting
- phenomenological plausibility because of previous cases - chronology:
- temporal relationship
- dechallenge, possibly rechallenge - synergistic PK
- synergistic (general)
- alternatives
pharmacoepidemiology
- cohort studies
- case-control studies
- nested case-control studies
- case-cohort studies
- cross-sectional studies
several criteria for causality classes
- WHO-UMC causality assessment
- naranjo causality assessment
- CIOMS/RUCAM scale
certain causality class
- AE pharmacologically clear and plausible
- chronologically well fitting challenge/dechallenge, even rechallenge
- timing within hal hour
- lab data specifically implicating that drug
probable causality class
- AE pharmacologically plausible
- Close temporal or spatial correlation (eg. skin)
- recovery upon drug withdrawal (no therapy)
- uncommon clinical phenomenon and reasonable exclusion of other factors
possible causality class
- more than 1 drug
- time relationship unclear
- causality pharmacologically not excludable
- chronologically fitting challenge/dechallenge
- also explainable through alternative causes
- information about the AE incomplete or unclear
unlikely causality class
- chronological sequence (challenge, dechallenge), hardly fitting
- plausible explanation through alternative causes
CIOMS/RUCAM scale scoring system
<=0: relationship with drug excluded 1-2: unlikely 3-5: possible 6-8: probable >8: highly probable
parameters to keep within for CIOMS/RUCAM scale
- history of ingestion of drugs, including complementary medicines, within 12 months of the onset of illness
- time of onset of reaction in association with intake of product, and discontinuation of product
diagnosis of DILI with CIOM/RUCAM scale
- exclusion of viral serology
- -ve metabolic screen
- daily alcohol intake <20g
- absence of biliary of focal liver pathology on ultrasound or CT scan of the abdomen
local legislation on PV requirements for therapeutic products
- duty to maintain record of defects and ADR
(retain records by manu, importers, suppliers, registrants, at lest 2y after exp of TP) - duty to report ADR
(SAR by manu, importers, suppliers, registrants, within 15d) - duty to report defects
(by manu, importers, suppliers, registrants; within 48h, if serious, 15d for other cases) - duty to notify authorities
(notification 1 calendar day prior to intended recall) - duty to carry out risk management plan
(ensure favorable benefit ratio profile of TP) - submission of benefit-risk evaluation report
(6mth intervals for 2 years then annually for next 3 years)
risk management by the industry
continuous process throughout the lifecycle of a product to optimise benefit-risk balance
- proactive risk assessment pre and post market
- develop and implement tools to minimise risk
- continual reassessment of benefit risk balance
*ensure benefits of products exceeds risk throughout the product life cycle
singapore’s risk management plans by the industry
- discussed with HSA pre-approval and post-market
- adapt plans from reference agencies that is relevant to local context
mandatory submission of existing RMPs for:
- new drug applications
- biosimilars
- on request from HSA
educational materials
- physician educational material
- patient medication guide
restricted use/access
- restricted for use in specific groups of patients where there are no suitable alternatives
- restricted for use by certain medical specialities (eg. cardio, infectious)
key features of the restricted access scheme
- physician’s undertaking
- the patient’s informed consent
- pharmacist’s undertaking
- selected group of patients
- provide regular sales Data and updated physicians list to HSA
- supply of product only to physicians who have registered
toxic heavy metals limit for CM
- arsenic: 5ppm
- cadmium 0.3ppm
- lead: 10ppm
- mercury 0.5ppm
future challenges
- opportunities in genomic era
- emergence of complementary medicines
- registries for biological products and gene therapy
- forging closer ties with international counterparts
- maximising IT tools for signal detection and communication
