PV

Question 1

What products does HSA regulate

Answer 1

1) Investigational products
2) Therapeutic products
3) Medical devices
4) Complementary health products
5) Advanced therapy products
6) Tobacco
7) Cosmetic products

Question 2

Level of regulation of:

1) Therapeutic products
2) Complementary health products
3) Medical devices

Answer 2

Therapeutic products

• Highest level of regulatory control
• Categorized into: Prescription only (POM), Pharmacy only (P), General sales list (GSL)

Complementary health products

• Less tightly controlled
• Limits toxic heavy metals, ensures no adulteration
• TCM - slightly more tightly controlled (dealers must list products)

Medical devices

• Relatively tight control
• 4 classes: A - D (Class A lowest risk)

Question 3

Types of regulation at:

1) Pre-market
2) Placing on market
3) Post-market

Answer 3

Pre-market:

1) Clinical trials
2) Product registration/listing
3) Dealer licensing

Placing on market:

1) Storage & distribution
2) Advertisement
3) Supply & sale

Post-market:

1) Vigilance
2) Surveillance
3) Compliance monitoring
4) Enforcement

Question 4

Types of regulation:

1) Therapeutic products
2) Chinese proprietary medicines
3) Cosmetics
4) Others

Answer 4

Therapeutic products

1) Pre-market controls
- Product approval & registration –> HSA only approves drugs where benefit > risk
- Tolerance for risk is higher for drugs used for severe/life-threatening diseases or if there are no/few alternatives
2) Post-market controls
- Continue monitoring risk-benefit ratio
- Regulatory action taken when risk-benefit ratio changes

Chinese proprietary medicines

1) Listing process
2) Post-market controls

Cosmetics

1) Notification process
2) Post-market controls

Others
1) Post-market controls

Question 5

Major events contributing to development of regulation of medicines

Answer 5

1) Elixir sulfanilamide tragedy
- Poisonous solvent
- Drug not tested safely
- Killed 10 people
- New regulation: Federal Food, Drug & Cosmetic Act (FD&C Act)
• Stronger drug safety requirements

2) Thalidomide tragedy
- Animal tests showed no fetal problems
- Caused > 10,000 birth defects
- New regulation: 1962 Kefauver-Harris Amendment to FD&C Act
• All new drugs to demonstrate substantial evidence of safety & efficacy for its marketed indication, strengthened control on human experimentation

3) Practolol, 1975
- Caused occulomucocutaneous reactions
- New regulation: Prescription Event Monitoring (PEM) in UK, NZ
• Monitor use of drug

4) Biologicals prepared from bovine material, 1990
- Possible prion transmission
- New regulation: Sophisticated concepts to reduce risks & use of cattle-derived materials

5) Rofecoxib, 2004
- Higher risk of MI
- New concepts for risk-risk balancing

Question 6

Licensing of medications

Answer 6

Needs to show:

1) Efficacy
- Randomized trials
2) Safety
- Animal studies
- Human volunteer studies
- Early clinical trials
- Large scale trials
- Post-marketing surveillance / pharmacovigilance

Question 7

Relevance of pharmacovigilance

Answer 7

1) Biomedical sciences: 4th pillar of economic engine
2) Increased use of complementary medicines
3) Limitations of clinical trials
4) Aging population
5) Genetic/Environmental influence

Question 8

Organizations involved in pharmacovigilance

Answer 8

1) WHO & its Collaborative Centre for International Drug Monitoring
2) CIOMS
3) ICH

Question 9

Pharmacovigilance framework

Answer 9

1) Signal / Risk detection
2) Risk assessment
3) Risk minimization
4) Risk communication

Question 10

What are signals

Answer 10

Early warning/indicator of a potential new problem with a drug/class of drugs
A hypothesis with data & evidence
Reported information on a possible causal relationship between an AE & a drug, the relationship being completely unknown/incompletely documented previously
Usually need > 1 report to generate a signal

Question 11

A signal may provide

Answer 11

Additional/New information about beneficial/adverse effects of an intervention or information about already known association of a drug and an adverse drug effect

Question 12

Sources of signal detection

Answer 12

International data:

1) WHO drug monitoring program
2) Environmental scanning
- Literature reports, media reports, information from international regulatory authorities
3) International regulatory exchanges
- WHO, ASEAN
- Australia, NK, US, Canada, Switzerland

Local data:

1) HCP
2) Autopsy reports, toxicology labs
3) Active surveillance initiatives
- CMIS
- Sentinel sites (for vaccines)
- Registries for selected drugs (not used in SG)
4) Mandatory reporting by drug companies
- Serious reports within 15 days
- Findings from studies that alter benefit-risk ratio
- Post-marketing studies
- Periodic safety update reports

Question 13

Signal detection - Qualitative methods

Answer 13

Case-by-case evaluation:

1) Frequency
2) Nature/Type of event
3) Time to onset
4) Duration
5) Rechallenge/Dechallenge

Question 14

Signal detection - Quantitative methods

Answer 14

Frequentist methods:

1) Probability reporting ratio (PRR)
2) Reporting odds ratio (ROR)
3) Sequential probability ratio tests (SPRT)

Bayesian approaches:

1) Bayesian confidence propagation neural network information component (BCPNN) / WHO
2) Empirical Bayes geometric mean (EBGM)
3) Multi-item GPS poisson shrinker

Question 15

Signals need to be confirmed via:

Answer 15

1) Hypothesis testing

2) Epidemiological studies

Question 16

Advantages of ADR reporting

Answer 16

1) Operates for all drugs given to patients
2) Operates throughout the whole of the drug’s life
3) Relatively inexpensive
4) Accessible to all HCPs
5) Rapid identification of newly identified ADRs

Question 17

Disadvantages

Answer 17

1) Low level of reporting
2) Requires HCPs to recognize ADRs
3) Data collected related to suspected associations only –> may have false-negatives
4) Unable to provide incidence rates (no denominator data)

Question 18

Minimum information needed to be included in Individual Case Safety Report (ICSR)

Answer 18

1) Identifiable reporter
2) Identifiable patient (e.g. age, gender, initials)
3) At least one identifiable drug
4) At least one identifiable suspected ADR

Question 19

What is risk-benefit assessment

Answer 19

Scientific assessment to determine risk-benefit profile of a drug through collection & review of relevant data from:

1) Clinical studies
2) Post-market experience

Question 20

What to consider when carrying out risk-benefit assessment

Answer 20

1) Efficacy data
2) Safety data
3) Therapeutic alternatives
4) Type of disease
5) Impact on population
6) Ability to mitigate risks

Question 21

Risk minimization & management in favourable risk-benefit analysis

Answer 21

Retention of product in market, with:

1) Enhancement of warnings in product insert (e.g. black box warnings)
2) Change indications
3) New contraindications
4) Post-market studies, registries
5) Restrict use/access to certain medical disciplines/certain patients only

Question 22

Risk minimization & management in unfavourable risk-benefit analysis

Answer 22

1) Suspension of sales
2) Recall of product
3) Withdrawal of product

Question 23

Purpose of risk communication is to

Answer 23

1) Minimize risk & enhance safe use of drugs

2) Update & inform intended audience of safety issues in a timely, transparent & unbiased manner

Question 24

How to communicate risk

Answer 24

1) Dear Healthcare Professional Letters

2) Public advisories

Question 25

Pharmacovigilance guidelines

Answer 25

1) ICH guidelines
- E2B: Clinical safety data mangement
- E2C (R2): Periodic risk-benefit evaluation report
- E2D: Post-approval safety data
2) EU Good Pharmacovigilance Practice modules
3) REMS (Risk evaluation & mitigation strategy) guidelines from US FDA
4) CIOMS working group reports

Question 26

Local Legislation on Pharmacovigilance Requirements for Therapeutic Products

Answer 26

1) Maintain records on defects & adverse events
- TP Regulation 33
- Records to be maintained by manufacturers, importers, registrants
- Standard format required for reports
- Records must be kept at least 2 years after expiry

2) Report AEs
- TP Regulation 34 (2); Health Products Act Section 42
- Mandatory reporting of all serious adverse reactions (SARs) by manufacturers, importers, suppliers, registrants
- Must report within 15 calender days
- Non-serious AEs exempted

3) Report defects
- TP Regulation 34 (1); Health Products Act Section 42
- Mandatory reporting by manufacturers, importers, suppliers, registrants
- Report within 48h for defects that represent serious threat to person or public health
- Report within 15 days for all other cases

4) Notify authority concerning recall
- TP Regulation 35; Health Product Act Section 44
- Notify at least 1 day prior to start of intended recall
- Class of recall - Timeline
- Level of recall - Extent of recall

5) Carry out risk management plan
- TP Regulation 35
- Applicable to New Drug Application (NDA-1), biosimilar application, others on case-by-case basis
- Describe risk management measures
- May be requested upon identification of safety issues pre-/post-market

6) Submission of risk-benefit evaluation report
- TP Regulation 44
- In alignment with ICH E2C (R2) guidelines on periodic benefit-risk evaluation reports
- Only needed for selected therapeutic products, with identified safety concerns
- Submitted every 6 months for first 2 years, followed by annually for another 3 years

Question 27

Risk management by industry - strategies

Answer 27

1) Letter at launch of product
- Provide information on serious potential side effects, special monitoring
- Decoupled from promotional material
- Needs to reach all buyers & potential prescribers

2) Educational materials
- Educate on risks involving certain patient groups, serious safety signals from clinical studies/post-market experience, important parameters to monitor on regular basis

3) Periodic risk-benefit evaluation report / Periodic safety update report

4) Restricted use/access schemes
- Restrict for use in certain patient groups OR by certain medical specialties
- Product supply restricted by special licensing conditions
- Key features:
• Patient’s informed signed consent
• Pharmacist’s/Physician’s undertaking
• Selected group of patients
• Supply of product only to physicians who have ‘registered’
• Provide regular sales data & updated physician’s list to HSA
- Restriction use: Tegaserod, Aprotinin, Rosiglitazone
- Pharmacy prevention program: Pomalidomide, Lenalidomide, Isotretinoin

5) Drug registries
6) Post-market clinical studies

7) Provision of sales data
- Provide broad categories of buyers
- Currently trying to shift towards electronic medical records