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PR3145 Compliance & Good Practices in Pharmacy > L08-L10 Pharmacovigilance > Flashcards

L08-L10 Pharmacovigilance Flashcards

1
Q

What are the objectives of establishing the Health Products Regulation Group within HSA?

A

1) Safeguard public health
- Ensure appropriate technical standards (quality, safety & efficacy) are met
- Facilitate recalls, product withdrawals

2) Facilitate
- Access to safe, good quality and efficacious health products
- Support development of a high quality healthcare system

3) Assure
- Instill trust, confidence and credibility of products at home and abroad

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2
Q

List the range of products regulated by HSA.

A 
Investigational drugs
Medical devices
Cosmetics
Therapeutic products
Complementary health products
Tobacco products
Advanced therapy products (e.g. CTGT products)
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3
Q

Which categories of health products are subjected to the highest level of control by HSA?

A

1) Therapeutic products
- POM
- POME
- P-only (OTC)
- GSL

2) Medical devices
- Class A has the lowest risk
- Class D has the highest risk

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4
Q

Which category of complementary health products has a higher level of regulatory control, as compared to its peers?

A

Chinese proprietary medicines

- Required to list products with HSA

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5
Q

Explain the role of HSA in the risk management framework in ensuring the safe & effective use of quality drugs in Singapore.

A

1) Risk-based approach titrated according to inherent risks
- High risk: Therapeutic products
- Low risk: Complementary health products, cosmetics

2) More stringent controls adopted for high risk products
- Therapeutic products: Pre- & post-market controls
- CPMs: Listing process (reduced registration controls) & post-market controls
- Cosmetics: Notification process & post-market controls
- Others: Post-market controls

3) Approval of therapeutic products by HSA only occurs when benefits outweighs risks for intended population & use
- Tolerance for risk is higher for drugs that treat serious & life-threatening diseases or diseases w/ few or no alternative Tx options
- Balance of benefit/risk ratio continues to be monitored post-marketing; regulatory action taken when benefit/risk ratio changes
- NO PRODUCT IS RISK-FREE!

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6
Q

List the various crises & the year of occurrence that influenced the development of the pharmacovigilance framework.

A

1) Sulfanilamide tragedy (1937)
- Led to US FDA Food, Drug & Cosmetic Act to establish safety requirements

2) Thalidomide tragedy (1950s)
- Led to development of congenital abnormalities in babies & taken off the market in 1961
- Led to 1962 Kefauver-Harris Amendment to US FDA Food, Drug & Cosmetic Act to establish efficacy and clinical trial requirements

3) Practolol (1975)
- Resulted in “Prescription Event Monitoring (PEM)” program in UK & NZ

4) Biologicals prepared from bovine material (1990)
- Resulted in sophisticated concept to reduce risks & use of cattle-derived medicines

5) Rofecoxib (2004)
- Caused MI more frequently than classical NSAIDs w/ higher GI toxicity
- Resulted in comparison of risks between medications i.e. risk/risk balancing

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7
Q

Define ‘adverse drug reaction’.

A

WHO definition:
Reaction that is noxious/harmful and unintended and occurs at doses normally used in man for prophylaxis, diagnosis or treatment of disease of the modification of physiological function
- Exclude overdose, drug abuse & medication errors

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8
Q

Define ‘side effect’.

A

Any unintended effect occurring at doses normally used in humans that is related to pharmacological properties of drug
- Can refer to positive or negative effect

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9
Q

Differentiate between ‘adverse events’ & ‘adverse reactions’.

A

AE: Causality not implied.
ADR: Causality assumed; i.e. this event would NOT have happened if the drug had not been taken

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10
Q

Calculate the true frequency of clozapine-induced agranulocytosis occurring, when WBC counts were performed for 2100 participants in a randomised clinical trial, with a confidence interval of 95%.

A

True frequency of ADR (i.e. agranulocytosis) <= 1/700

Rule of Three:
For statistical reasons, in the event that a given ADR was not detected in clinical trial w/ population of certain size, it is only possible to rule out w/ 95% CI that point estimate for frequency of ADR is NOT higher than 3 times the size of the investigated population.

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11
Q

What are some limitations of conducting clinical trials to detect serious, rare ADR?

A

1) Clinical trial is usually designed to test efficacy & detect common ADR, BUT NOT serious, rare ADR!

2) Cumulative sample size exposed to drug, before the drug is marketed, is usually 1500-3000 patients, which is too small to pick out serious, rare ADR!
- Less for CTGT products; more for vaccine trials

3) Too short a duration of 1-3 years to pick out serious, rare ADR
4) Concerns that some ADRs may occur after Tx for > 6 months

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12
Q

Define ‘pharmacovigilance’.

A

Science of collecting, monitoring, researching, assessing and evaluating information from healthcare providers and patients on the adverse effect of medicines, biological products, herbal and traditional medicines, with a view to identifying new information about hazards and preventing harm to patients.

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13
Q

Explain the relevance of pharmacovigilance.

A

1) Circumvent limitations of clinical trials
2) Determine genetic/environmental influences
3) Biomedical sciences form the 4th pllar of economic engine, thus the need to monitor for ADR of medicinal products.
4) Ageing population encourages polypharmacy and diminished hepatic/renal functions increases risk of ADR occurring.
5) Increasing use of complementary medicines

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14
Q

List the steps of the pharmacovigilance framework.

A

1) Signal / risk detection
- Monitoring ADRs to detect risks & changes in risk/benefit profiles

2) Risk assessment
- Assessing risk/benefit profile

3) Risk minimization
- Minimising risk by appropriate regulatory actions

4) Risk communication
- Communicating information to optimise safe and effective use

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15
Q

Describe how signal detection works in the pharmacovigilance framework.

A

1) Early indicator or warning of a potential new problem with a drug, or class of drug
- Reported info on possible causal relationship between adverse event and drug
- Relationship being unknown or incompletely documented previously
- Usually > 1 report required to generate signal

2) Hypothesis w/ data & arguments that support it from one or more sources

3) Evidence in signal is NOT conclusive & is ONLY an early indication
- May change substantially over time as more data accumulates
- Further investigation may or may not lead to conclusion that product caused event

4) May provide additional or new information about adverse or beneficial effects of an intervention, or information about an already-known association of a drug w/ an adverse drug effect
- e.g. range of severity, postulating MOA, indicating at-risk group, suspected dose range, pharmaceutical group-effect or lack of effect etc.

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16
Q

__% of approved drugs have serious adverse effects undetected prior to approval.

A

50%

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17
Q

Which local data source is less successful in Singapore in identifying potential signals in the pharmacovigilance framework?

A

Registries for selected drugs

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18
Q

Name some sources of potential signals captured in pharmacovigilance.

A

1) Pre-market (i.e. clinical trials)
2) Post-market
3) International data
- WHO International Drug Monitoring Programme
- Environmental scanning (e.g. literature, media reports, info from other regulatory agencies)
- International regulatory exchanges
4) Local data
- HCP
- Autopsy reports and toxicology labs
- Active surveillance initiatives (e.g. Critical Medication Information Store - CMIS, sentinel sites, registries for selected drugs)
- Mandatory reporting by SG law of drug companies

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19
Q

What are some advantages of ADR reporting?

A

Operates for all drugs given to patients
Operates throughout entirety of drug’s lifespan
Relatively inexpensive to operate (vs clinical trials)
Accessible to all physicians/dentists/pharmacists
Can provide rapid identification of newly identified ADR

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20
Q

What are some disadvantages of ADR reporting?

A

Low level of reporting worldwide
Schemes require HCPs to recognise ADRs
- Recognition complicated by many ADRs mimicking naturally-occurring illnesses
Data collected relate to suspected associations only
Unable to provide incidence rates because of lack of denominator data
- i.e. unable to know fully how many people are exposed to drug
- Clinical trials are more accurate

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21
Q

What criteria should be captured during signal detection when using a qualitative method?

A 
Frequency
Nature / type of event
Time to onset
Duration
Attempts to rechallenge / dechallenge
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22
Q

List the available methods used for quantitative signal detection in pharmacovigilance.

A

1) Frequentist methods
- Proportional reporting ratio (PRR)
- Reporting odds ratio (RRR)
- Sequential probability ratio tests (SPRT)

2) Bayesian approaches
- Applied to signal detection and clinical trials
- Bayesian Confidence Propagation Neural Network information component (BCPNN) / WHO
- Multi-item GPS Gamma Poisson Shrinker
- Empirical Bayes Geometric Mean (EBGM)

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23
Q

Describe what is done in the risk assessment step of the pharmacovigilance framework.

A
  • Review safety signals received for drugs & conduct further confirmatory studies/data
  • Determine benefit vs risk profile of drug thru collection & review of relevant data
  • Scientific assessment using clinical studies data, post-marketing experience & balancing pros and cons of product in local context on efficacy, safety, therapeutic alternatives available, disease type, impact on population and ability to mitigate risks
24
Q

What are some management strategies adopted if a favourable risk/benefit analysis was concluded for a particular drug, despite acknowledging the new risk of an associated rare, serious ADR?

A

Enhancement of warnings in package inserts
Change of indications to mitigate new risks
New contraindications to use
Post-market studies, registries
Restriction of use to certain medical disciplines only
Restriction of access to certain patients only

25
Q

An unfavourable risk/benefit analysis of a drug after conducting pharmacovigilance studies may result in ___.

A

Suspension of sales
Recall of products
Withdrawal of products
- Voluntary if initiated by company

26
Q

Name the international organisations involved in pharmacovigilance.

A

1) World Health Organisation (WHO) and its Collaborating Centre for International Drug Monitoring at Uppsala, Sweden
- i.e. Uppsala Monitoring Centre (UMC): special arm/collaborative centre of WHO that looks at ADR globally

2) Council of International Organisations of Medical Sciences (CIOMS)
3) International Council of Harmonisation (ICH)

27
Q

Define ‘spontaneous reporting’.

A

Voluntary submission of reports on AEs or ADRs by healthcare professionals (HCPs) to the national regulatory authority (or any relevant set up) outside a systematically planned study.

28
Q

What are all the minimum required information to file an individual case safety report (ICSR)?

A

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

29
Q

Explain what a “serious adverse reaction” is, as defined by the Health Products (Therapeutic Products) Regulation 2016, Reg 34 (5)?

A

Adverse reaction that:

  • may results in a person’s death
  • may threatens a person’s life
  • results in person being hospitalised or prolong a person’s existing stay in hospital
  • results in a person’s persistent or significant disability or incapacity
  • results in a congenital anomaly or birth defect
  • is judged to be medically important even though the effect might not immediately life-threatening or result in death or hospitalisation, but may jeopardise the person’s health or require intervention to prevent the person’s death or one of the other outcomes mentioned.
30
Q

Differentiate what an expected ADR & an unexpected ADR is.

A

Expected ADR:

  • Already adequately described in terms of kind, specificity and intensity
  • Found in package insert of product or summary of product characteristics

Unexpected ADR:
- Not consistent with applicable product information or characteristics of drug

31
Q

Differentiate between ‘prevalence’ & ‘incidence’.

A

Prevalence: No. of cases of an event in a defined population during a given period of time
- Includes both old & new cases (i.e. lifetime)

Incidence: No. of new cases of an event in a defined population during a given period of time
- ONLY include new cases (i.e. 10 cases per 1000 patients per year)

Frequency: Both prevalence & incidence

32
Q

Based on CIOMS’ definition, identify the appropriate terminology used to define the true frequency of ADR occurrences.

A

Very common: At least 1/10
Common (frequent): At least 1/100 and less than 1/10
Uncommon (infrequent): At least 1/1,000 and less than 1/100
Rare: At least 1/10,000 and less than 1/1,000
Very rare: Less than 1/10,000

33
Q

What study designs are commonly adopted when conducting pharmacoepidemiological studies of prevalence / incidence of ADR occurrences?

A

Observational studies:

  • Cohort studies
  • Case-control studies
  • Nested case-control studies
  • Case-cohort studies
  • Cross-sectional studies
34
Q

What are the criteria used to assess the causality of an ADR to a drug based on multiple ICSR reported?

A

Adverse event (AE) + suspicion of causal relation = ADR

1) Pharmacological plausibility:
- Chemical nature of molecule/class (e.g. toxicophores)
- Assumable intrinsic activity
- Dosage & duration of therapy fitting
- Pharmacokinetics (conc. at relevant sites) fitting
- Phenomenological plausibility because of previous cases (Principle of Bayes)

2) Chronology:
- Temporal relationship (i.e. timing between factor and outcome)
- Evidence of causality confirmed with de-challenge, followed up with re-challenge
- However, re-challenge is only attempted in exceptional circumstances.

3) Synergistic-PK:
- Other drugs/factors which alone could NOT cause AE BUT could raise the concentration of victim drug under consideration & enable it to cause Type A reaction

4) Synergistic (in a broad sense):
- Other drugs/factors which alone COULD cause AE in the same way as drug under consideration BUT in combination cause an increased quantitative degree of effect (e.g. serotonin syndrome)

5) Alternative:
- Other drugs/factors which alone and specifically also may have caused the AE and thus could completely exonerate the drug under consideration (e.g allergic/hypersensitivity reaction = Type B/D reaction)

35
Q

List the type of causality assessment framework available to classify ADRs.

A

1) WHO-UMC causality assessment
2) Naranjo causality assessment (checklist)
3) CIOMS/RUCAM scale for drug-induced liver injury (DILI)
- RUCAM = Roussel Uclaf Causality Assessment Method

36
Q

Describe how an ADR identified to be associated to a drug is classified based on causality assessment frameworks.

A

1) Certain
- AE pharmacologically clear & plausible
- Chronologically well-fitting with challenge/de-challenge, possibly even with re-challenge
- Timing of ADR occur w/in half an hour
- Lab data specifically implicating that drug

2) Probable
- AE pharmacological plausible
- Close temporal or spatial correlation
- Recovery upon drug withdrawal w/o therapy
- Uncommon clinical phenomenon and reasonable exclusion of other factors

3) Possible
- More than 1 drug involved
- Temporal relationship is unclear
- Causality pharmacologically not excludable
- Chronologically fitting with challenge/de-challenge
- Also explainable thru alternative causes
- Information about AE incomplete/unclear

4) Unlikely
- Chronological sequence (challenge/de-challenge) hardly fitting
- Plausible explanation thru alternative causes

5) Unclassifiable/Unassessable
- Full information NOT given

37
Q

The diagnosis of drug-induced liver injury (DILI) is usually a diagnosis of inclusion. True or false?

A

False!

DILI is a diagnosis of EXCLUSION!

38
Q

What are the parameters used to determine the presence of DILI?

A

DILI is a diagnosis of EXCLUSION based on following parameters:

1) Hx of ingestion of drug, including complementary medicines w/in 12 months of onset of DILI
- Time of onset of ADR in association to intake of product
- Discontinuation of product

2) Exclusion of viral serology
- Hep A & Hep B especially
- i.e. anti-HAV IgM, anti-HCV IgM absent

3) Negative metabolic screening results
- Exclusion of other cases, such as autoimmune disorders or metabolic diseases that cause liver injury
- i.e. antinuclear antibody test (ANA), ceruloplasmin, anitmitochondrial antibody (AMA)

4) Daily EtOH intake < 20g (more common overseas)
5) Absence of biliary or focal liver pathology on ultrasound or CT scan of abdomen

39
Q

Describe the scoring system of the CIOMS/RUCAM scale of DILI.

A 
0 or lower: Relationship w/ drug excluded
1 to 2: Unlikely
3 to 5: Possible
6 to 8: Probable
> 8: Highly probable
40
Q

What forms are available to perform spontaneous reporting to HSA on possible ADR causality with a particular medical product?

A

1) Yellow Form
2) Form for Chinese Traditional Medicine Practitioners
3) Blue Form (Vaccines) - usually more batch related
4) Critical Medical Information Store (CMIS) electronic form

41
Q

Summarise the pharmacovigilance requirements pharma manufacturers, importers & registrants are legally bound to do in Singapore, in accordance with the Health Products Act.

A

1) Duty to maintain records of defects & adverse effects
2) Duty to report adverse effects
3) Duty to report defects
4) Duty to notify HSA concerning recalls
5) Duty to carry our risk management plan
6) Duty to submit risk-benefit evaluation report

42
Q

Describe, in full, the pharmacovigilance requirements pharma manufacturers, importers & registrants are legally bound to do in Singapore, in accordance with the Health Products Act.

A

1) Duty to maintain records of defects & adverse effects
- Records to be retained, in a standardised format, for at least 2 years after expiry date of therapeutic products

2) Duty to report adverse effects
- Mandatory reporting for serious ADR NO later than 15 calendar days, aligned with ICH E2D guidance
- Non-serious AEs exempted

3) Duty to report defects
- To report w/in 48h for defects that represents serious threat to persons or public health
- To report w/in 15 calendar days for all other cases

4) Duty to notify HSA concerning recalls
- Notification to HSA to be 1 calendar day prior to start of intended recall
- Extent/level of recall: (lowest) wholesale < retail < consumer (highest)

5) Duty to carry our risk management plan
- To ensure favourable risk-benefit profile of therapeutic products
- May be requested upon identification of safety issues pre-/post-marketing
- Describes risk management measures (e.g. educational materials, Dear HCP letters, restricted access prog.)
- Applicable to new drug applications, biosimilar applications, others on case-by-case basis

6) Duty to submit risk-benefit evaluation report
- Only for selected therapeutic products w/ identified safety concerns
- Submitted at 6-monthly intervals for first 2 years, then annually for another 3 years

43
Q

Explain how the risk minimisation step of the pharmacovigilance framework is implemented by industries.

A

Continuous process throughout life cycle of product to optimise benefit-risk balance

  • Requires proactive risk assessment pre- and post-market
  • Develop and implement tools to minimise risks
  • Continual reassessment of benefit-risk balance
  • To ensure benefits of product exceeds its risks throughout product life cycle
44
Q

What are some steps Singapore has implemented to bridge continuity in pre- and post-market assessment of medical products?

A

1) HSA has adapted international plans from reference agencies that is relevant to local context & added additional managements where applicable.

2) May contain one or more of the following:
- Letter at launch of product vs Dear HCP Letter
- Educational materials
- Periodic Benefit-Risk Evaluation Report (PBRER) / Periodic Safety Update Report (PSUR)
- Provision of sales data
- Restricted use / access schemes
- Drug registries (not successful due to small population)
- Post-market clinical studies

45
Q

When will education materials be included as part of the risk communication strategy?

A

When there are important safety issues to note:

  • Risks involving identified groups of patients (e.g. renal/hepatic impairment, pregnant/lactating mothers, elderly vs children etc.)
  • Serious safety signs raised by clinical studies or post-market experience
  • Important parameters to monitor on regular basis

Includes physician educational materials & patient medication guide.

46
Q

Differentiate the purpose of sending ‘Dear Healthcare Professional Letters’ from the purpose of sending educational letters at launch of product.

A

Dear HCP Letters raise serious potential side effects HCP should be aware of & require special monitoring

  • Decoupled from promotional materials i.e. letter at launch
  • Dear HCP letters will need to reach ALL buyers & potential prescribers.
47
Q

What are some sales data pharma companies have provided to HSA as part of pharmacovigilance efforts?

A 
Total no. of units sold annually
No. of units sold to:
- Public hospitals
- Private hospitals
- GPs
- Specialists
- Pharmacists
48
Q

What are some causes behind the occurrence of ADRs?

A

1) Inherent drug characteristics
- Pharmacological effect of API resulting in expected SE OR
- Unexpected SE due to intrinsic / extrinsic contaminants

2) Quality problems
- Contamination w/ toxic heavy metals
- Counterfeits, sub-standard products

3) Adulteration
- Largest problem w/ complementary products
- Potent medicinal ingredients or its analogues

4) Substitution of ingredients
5) DDI/FDI
6) Long-term exposure or high doses

7) Individual susceptibility (Genetics)
- e.g. HLA-B1502 for carbamazepine
- e.g. HLA-B5801 for allopurinol

8) In-use issues (e.g. non-adherence)

49
Q

Name the ADR occurrences that most likely signify a drug association to this ADR.

A

1) SJS/TEN
2) Agranulocytosis
3) Acute dystonia
4) DILI if confounders are properly excluded
5) Cushing’s syndrome

Diagnosis of ADR arrived for the above are after excluding all possible causes.

50
Q

Differentiate between SJS & TEN.

A

SJS: epidermal detachment in < 10% of total BSA
TEN: epidermal detachment in > 30% of total BSA
Transitional SJS-TEN: epidermal detachment in 10-30% of total BSA

51
Q

Describe the clinical presentation of SJS/TEN.

A

1) Severe mucosal erosions (eyes, oropharynx, genitalia, anus)
- e.g. ulcers all around oral cavity

2) Widespread erythematous macules
- e.g. blisters all over face & body

3) Epidermal detachment
4) Unbearable pain & mentally draining

52
Q

Briefly describe what Cushing’s syndrome is.

A

Hormonal disorder resulting from long-term exposure of high doses of steroids.

53
Q

Describe the clinical presentation of Cushing’s syndrome.

A

1) Weight gain, increased appetite, insomnia occur quickly

2) “Cushing” appearance after weeks to months
- Moon face, buffalo hump
- Truncal weight gain, skin thinning
- Purplish striae

3) Thinner limb extremities (i.e. “lemon on a stick” appearance)

4) Other effects include:
- Increased BP (strain on heart & vascular system)
- Increased BG (may lead to diabetes)
- Decreased immunity (increased risk of infections)
- Bone loss
- Cataracts

54
Q

What are some possible causes of Cushing’s syndrome?

A

1) Adrenal tumour
2) Cushing Disease (i.e. pituitary tumour resulting in excess ACTH - common pathological cause)
3) Ectopic ACTH-producing tumour (e.g. lung tumour)
4) Exogenous source (most common cause)

55
Q

What are the allowable limits of heavy metals in Chinese proprietary medicines, in accordance with the Medicines Act?

A 
Arsenic = 5 ppm
Cadmium = 0.3 ppm
Lead = 10 ppm
Mercury = 0.5 ppm

PR3145 Compliance & Good Practices in Pharmacy (5 decks)

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