LEC 7 Pharmacovigilance l

Question 1

Range of therapeutic products regulated by HSA (7)

Answer 1

1. Investigational drugs / Clinical trials drugs
2. Therapeutic products
3. Medical devices
4. CPM
5. Cosmetics
6. Advanced therapy products (CTGT)
7. Tobacco products

Question 2

Health product regulation (pre-market) (3)

Answer 2

1. Clinical trials
2. Product registration/listing
3. Dealers licensing

Question 3

Health product regulation (post-marketing) (4)

Answer 3

1. Vigilance
2. Surveillance
3. Compliance monitoring
   - to GDP/GMP
4. Enforcement

Question 4

Health product regulation (placing on market) (3)

Answer 4

1. Storage and distribution
2. Advertising
3. Supply and sale

Question 5

How are the levels of risks assessed? (2)

Answer 5

Titrate risk based on :

1. Types of health product & its inherent risks (CPM vs Therapeutic products)
   - therapeutic products have higher risks
2. Treatment for diseases
   - treatment for more serious diseases means higher risk tolerance

Question 6

Controls on products (high risk vs low risk)

Answer 6

More stringent control for high risks products

Question 7

HSA approval of drug use into the market

Answer 7

Benefits outweigh the risks for the intended population and use

Question 8

Are all product risk-free?

Answer 8

No

Question 9

Efficacy vs Effectiveness

Answer 9

Efficacy

• under controlled conditions
• shown in clinical trials

Effectiveness
- under clinical conditions

Question 10

Adverse Drug Reaction (WHO definition)

Answer 10

A reaction that is

• noxious/harmful
• unintended
• occurs at doses normally used in man for prophylaxis, diagnosis or treatment of disease of the modification of physiological function (normal therapeutic doses)
• excludes overdosage, drug abuse and medication errors

Question 11

Side effects

Answer 11

Any unintended effect occurring at doses normally used in humans that is related to the pharmacological properties of the drug
- can be positive or negative side effects
eg discovery of new SE can lead to the off-label use of the drug

Question 12

ADR vs SE (2)

Answer 12

ADR

• negative reactions
• may or may not be related to pharmacological properties

SE

• can be positive or negative reactions
• related to pharmacological properties

Question 13

Adverse Events vs Adverse Reactions

Answer 13

Adverse Events
- causality not implied

Adverse Reactions
- causality assumed

Question 14

Rule of Three

Answer 14

• 95% confidence
• point estimate for the frequency of that ADR is not higher than 3 in the size of the investigated population

eg clinical trial sample size = 1,800 (no ADR)
- there is 95% confidence that the true frequency of the ADR is less than 1/600

Question 15

Limitations of clinical trials (5)

Answer 15

1. Mainly test efficacy only
2. Detect common ADR only (1/100 to 1/1,000)
3. Detect short term ADR
4. Small number of exposed patients (1,500-3,000)
5. Short duration (1-3y)

Question 16

Pharmacovigilance

Answer 16

• is the science of collecting, monitoring, researching, assessing and evaluating information
• from healthcare providers and patients
• on the adverse effects
• of health products
• with a view to :
  1. Identifying new information about hazards
  2. Preventing harm to patients

Question 17

Pharmacovigilance framework (4)

Answer 17

1. Signal/Risk detection
2. Risk assessment
   - assess benefit/risk profile
3. Risk minimisation
   - implement appropriate regulatory actions
   - maintain product in market > remove product in market
4. Risk communication

Question 18

What are ‘signals’ (3)

- what does it provide?

Answer 18

• an early indicator or warning of a potential new problem with a drug or class of drug
• more than 1 report to generate a signal
• new ADR or additional info about known ADR

Question 19

Source of a signal (4)

Answer 19

1. International Data
2. Local Data
3. Pre-market Data
4. Post-market Data

Question 20

Can liver toxicity be a signal of paracetamol?

Answer 20

No because it is not a new problem with paracetamol.

It is already known that paracetamol can cause liver toxicity

Question 21

International data (3)

Answer 21

1. WHO International Drug Monitoring Programme
2. Environmental Scanning
   - literature
   - media reports
   - information from other regulatory agencies
3. International Regulatory Exchanges

Question 22

Local data (4)

Answer 22

1. Healthcare Professionals
2. Autopsy Reports & Toxicology Lab
3. Active Surveillance Initiatives
   - CMIS
   - Sentinel Sites (vaccines)
   - Registries for selected drugs
4. Mandatory Reporting (Drug companies)
   - serious reports within 15 days

Question 23

Advantages of ADR reporting (5)

Answer 23

1. Operates for all drugs given to patients
2. Operates throughout the whole lifespan of the drug
3. Relatively inexpensive to operate
4. Accessible to all healthcare providers
5. Can provide rapid identification of newly identified adverse drug reactions

Question 24

Disadvantages of ADR reporting (4)

Answer 24

1. Low level of reporting
   - 2-4% of all ADR
   - <10% of serious ADR are reported
2. Schemes requires HCPs to recognise ADR
   - recognition is complicated by many ADR mimic naturally-occurring illnesses
3. Data collected relate to suspected association only
   - not confirmed causality
4. Unable to provide incidence rate
   - only the frequency / prevalence
   - due to the lack of denominator

Question 25

Given the limitations of ADR reporting, is ADR reporting still important?

Answer 25

Yes. | It is the only way of monitoring the safety of a drug throughout its marketed life

Question 26

Is ADR reporting confidential?

Answer 26

Yes. | Any information related to the identities of the reporter and the patient will be kept confidential

Question 27

Channels of ADR reporting (6)

Answer 27

1. Phone 2. Fax 3. Mail 4. Email 5. Online reporting 6. E-reporting linked to medical records - Critical Medical Information Store (CMIS)

Question 28

Methods of assessing Signal detection (2)

Answer 28

1. Qualitative methods | 2. Quantitative methods

Question 29

Qualitative methods of signal detection (5)

Answer 29

Case by case basis 1. Frequency 2. Nature/Type of event 3. Time of onset 4. Duration 5. Rechallenge/Dechallenge

Question 30

Quantitative methods of signal detection

Answer 30

1. Frequentist method | 2. Bayesian approaches

Question 31

Follow up on signal detection (2) | To confirm causality

Answer 31

1. Hypothesis testing | 2. Epidemiological study

Question 32

Steps for conducting Risk/Benefit assessment (2)

Answer 32

1. Review safety signals and further confirmatory studies/data 2. Determine the benefit vs risk profile - efficacy data - safety data - therapeutic alternatives - type of disease - impact on population - ability to mitigate risks

Question 33

Risk minimisation & management classes (2)

Answer 33

1. Retention of product in market (favourable) | 2. Removal of product in market (unfavourable)

Question 34

(( favourable )) Risk minimisation & management if product is retained in market - more common (4) - less common (3)

Answer 34

More common : - enhancement of warnings in package insert - change of indications to mitigate new risk - new contraindications to use - postmarket studies and registries Less common : - restriction of use to certain medical disciplines - restriction of access to certain patients only eg when treatment resistant - black box warning (sternest warning)

Question 35

Risk minimisation & management if product is removed from market (3)

Answer 35

- suspension of sales - recall of product - withdrawal of product (or voluntary withdrawal)

Question 36

Risk communication aim (1)

Answer 36

- to minimise risk and enhance safe use of drugs by updating and informing intended audience of safety issues in a timely, transparent and unbiased manner

Question 37

Risk communication methods

Answer 37

- Dear Healthcare Professionals Letters - Public advisories - Posters

Question 38

Impact of ADR (3)

Answer 38

1. Increase length of hospital stays 2. Increase costs 3. Risks of mortality

Question 39

Relevance / Importance of pharmacovigilance (4)

Answer 39

1. Clinical trials limitations 2. Genetic & environmental influence 3. Ageing population (polypharmacy, comorbidities) 4. Rising use of Complementary Proprietary Medicines (CPM)