Pharmacovigilance And Pharmacogenetics Flashcards
What is pharmacovigilacne
- Identification, assessment and subsequent prevention of adverse drug reactions whilst optimising benefits
- Responsibility lies with prescribers, patients and carers (pharma, MHRA..)
- The most common clinical adverse event is a drug reaction
- ~6.5% of hospital admissions in the UK related to an ADR
- Circa £530 million cost
- Don’t want to labour the financial implications but consider the extended clinical significance
What are adrs a result of and what classifies them as serious
• Evidence suggests that the vast majority of ADRs are as a result of well profiled therapeutics where the ADRs are well defined and preventable (7/10)
• Most serious ADRs are of importance to morbidity and mortality (relatively rare – would not reach market)
• Through regulation, data is collected about all ADRs for active medicines
• ONE key focus is to identify those that are classed as serious: Fatal
Life-threatening
Prolonged hospitalisation
Long term disability
Congenital abnormalities
- along with medical judgement
What are adrs
• Unintended and noxious
• Attributable to therapeutic given within the normal recommended
human range
• Differs from and adverse event where causality has not been confirmed
• ADRs are easier to identify and confirm in RCT situation (if big enough)
What are type a reactions
Type A (augmented) reactions generally: Dose-related
Predictable from pharmacology Common
Reversible
Manageable with dose adjustment
Warfarin – bleeding, nitrates – headache, hypoglycaemia – oral antidiabetic agents
What are type b reactions
Type B (bizarre) generally:
Not dose-related
Uncommon
Unpredictable
Serious/irreversible
Indicative that the drug needs to be stopped
Anaphylaxis with penicillin, agranulocytosis with clozapine, thrombocytopenia
• Other sub classifications have been proposed: Chronic, Delayed End of use
Describe risk management with the example of the cocp scare
• Oral contraceptives – late 1960’s through spontaneous ADR reporting COCP increased risk of VTE
dose was reduced (reduced risk of VTE) without compromising efficacy
• When the risk became public - “pill scare” helpfully reported by some media → ↓ in OCs without alternative contraception → ↑ induced abortion
• Further scares identified including MI and breast cancer which again resulted in ↓ OC use
• Pregnancy is much riskier (VTE incidence among others) than use of OCs
• Poor communication of the investigations of 2G and 3G COCP have also influenced PV and how to communicate findings
Describe a study design with rt as an example
• Hormone replacement therapy
• Baseline risk of VTE, cancers and CVD is greater so more feasible to
study clinically
• Observational studies had suggested a reduced risk of CVD including MI and stroke – Pharma promoted this (1980’s and 90’s)
• Woman using HRT may be healthier – confounding factors
• Large randomised trials eventually carried out which showed that
actually there was an increased risk of CVD risk
• Complexity of the risks made and still makes it difficult to communicate (although no serious consequence of stopping HRT abruptly cf. COCP)
How is adr detected
Number of patients required to be 95% (p<0.05) sure of detecting an ADR depends on predicted incidence
Relative risk in context of baseline risk
Baseline risk
Relative risk
S
What is dots
Dose relatedness - toxic, collateral, hyper-susceptibility
Time relatedness - independent vs dependant
Susceptibility - age, gender, etc
• Osteoporosis due to corticosteroids – Collateral, late, age and sex Dosage used in therapeutic range, several months of treatment, females and older people
• Anaphylaxis due to penicillin – hyper-susceptibility, first dose, requires previous sensitisation
Very low, sub therapeutic levels, within minutes of taking first dose
What are the nature and mechanisms of adrs
• Usually mimic disease or syndrome that occur naturally
• Importantly, may have non therapeutic causes (causality)
• Some syndromes causality solely due to therapeutic agents (so far)
Diethylstilboestrol prevent premature labour – vaginal cancer in those exposed in utero
Fibrosing colonopathy – large doses of pancreatic enzymes used in treating children with CF
Whar are moas for. An adr
Broadly four MOA for an ADR Exaggerated response (bleeding warfarin)
Desired pharmacological effect at alternative/additional site (GTN – headache)
Additional/secondary pharmacological effect (QT length) Triggering an immunological response (anaphylaxis)
What are the limitations of pre-marketing clinical studies and adrs
Evaluating the safety and secondly the efficacy of a new therapeutic
• Small number of patients
• Limited by age and possibly gender
• Selected following precise diagnoses
• Short, well defined duration
• Specialist doctors and continuous follow-up
• Concomitant therapeutics usually excluded
Describe teh spontaneous reporting o adrs
• …..Developed in response to the thalidomide tragedy
• Primarily producing a signal that creates further questions
• False positives and negatives – further analysis
• Number of ADRs reported annually through the MHRA ~ doubled cf. 2007
• Pharmaceutical companies, the published literature (pre-clinical)
• Yellow card scheme in place to report:
recently introduced products – all suspected ADRs inc. minor ones, all reactions to vaccines
Established products – serious or unusual suspected reactions (life threatening, disabling or prolonging hospitalisation
What are. The rods and cons of reporting adrs
- Simplicity – all drugs all of the time
- Timely and theoretically inexpensive to administer
- Detects both common and rare reactions
- Accessible by all health care professionals (patients and carers too)
- Inevitable and unquantifiable under-reporting
- Positive bias – serious, unrecognised or new drugs (good)
- Duplication
- Effect of publicity
- Incomplete poor quality data
- Other methods include Cohort, Case Control studies, Systematic Reviews (see Prof. Holland Dr Hsu and Dr Owen’s lectures)
How can reporting be improved
- Responsibility of all of you…..
- Being aware and interested
- Implementing suggested guidance and monitoring in high risk situations
- Integrated approach including multidisciplinary teams
- MUR and CMR
- Targeting and collecting data from under reporting areas – hospitals and particularly oncology – understand why this is so?
- Global approach – large data sets and sharing, particularly for serious but rare ADRs
- REPORTING OF TRIAL DATA, TIMELY AND COMPREHENSIVELY – GOOD OR BAD
