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PR3145 > Pharmacovigilance > Flashcards

Pharmacovigilance Flashcards

1
Q

How does the Health Products regulation group Safeguard public health?

A

Ensure appropriate technical standards are met
Facilitate recalls, product withdrawals
*Made possible by legislation in place

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2
Q

How does the Health Products regulation group act as a facilitator?

A

Provide access to good quality and efficacious products

Support development of a high quality healthcare system

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3
Q

How does the Health Products regulation group act as an assurer?

A

Instill trust, confidence and credibility of products (home or abroad)

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4
Q

What are the range of health products regulated by HSA?

A 
Investigational drugs
Medical devices
Cosmetics 
Tobacco products 
Therapeutic products (TPs)
Complementary Health products (CAMs)
Advanced therapy products (CTGT)
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5
Q

What are the 3 categories of Therapeutic products (TPs)?

A

POMs
GSL
Prescription only

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6
Q

What are the 3 categories of CAMs?

A

Vitamins, minerals and quasi medicine
Chinese proprietary medicine (CPMs)
Other traditional medicines

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7
Q

What is HSA’s role in tobacco product regulation?

A

Control is on the importers and wholesalers

  • licensing the retailers
  • control of tar and nicotine content
  • also catch the underage (under 21) smokers
  • advertisements of tobacco products regulated (not allowed in SG)
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8
Q

What is HSA’s role in CAMs?

A
  • largely left to the market to import/sell
  • job scope is in ensuring not adulterants, set heavy metal/microbial limit in legislation
  • generally quite a free market (except Chinese proprietary medicines) –> not as intense as therapeutic products but similar –> all dealers have to list products w HSA
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9
Q

How does HSA regulate medical devices?

A
  • relatively tight control, quite similar control to therapeutic products
  • 4 classes of medical devices (A < B < C < D) in terms of tightness of control
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10
Q

What are the possible areas HSA can control in the Pre-market stage?

A

Clinical trials (therapeutic products)
Product registration/listing
Dealers* licensing

*dealers refer to manufacturers, wholesalers, importers, retailers

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11
Q

What are the possible areas HSA can control in the Placing-on-market stage?

A

Storage and distribution
Advertising
Supply and sale

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12
Q

What are the possible areas HSA can control in the Post-market stage?

A

Vigilance
Surveillance
Compliance monitoring
Enforcement

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13
Q

What are the advertisement controls laid out by HSA?

A

SG has tight controls on POMs due to consequences on pt perception
*only a few countries allow adverts for prescription medicines (i.e. US, NZ)

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14
Q

What are the health products subject to Good distribution practices (GDP) in SG?

A
  • GDP control not done for CAM (vitamins and other traditional medicines etc..)
  • GDP done for therapeutic products and medical devices

*GDP control (FYI: Good Distribution Practices (GDP) is a quality system for warehouse and distribution centers dedicated for medicines)

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15
Q

How does HSA approach risk management?

A

Risk based approach titrated according to inherent risks

- More stringent controls for high risk products

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16
Q

What risk level do TPs have?

A

High risk

*milligrams can result in beneficial/adverse effects

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17
Q

What is the level of control for TPs like?

A

TPs: Pre and Post market control
Approved when benefit > risk for intended population and use
- This R/B monitored post marketing (regulatory action can be taken when R/B changes)
- Tolerance for risk higher for drugs that have higher benefit (serious/ life-threatening conditions, cancer drugs, disease with few alternatives)

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18
Q

What is the level of control for Chinese proprietary medicines (CPMs) like?

A

CPMs: Listing process and Post market control

*a listing process –> still called a registration process, albeit a very much reduced one

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19
Q

What is the level of control for Cosmetics like?

A

Cosmetics: Notification Process and Post market control (companies just have to notify HSA what they are bringing in + make declarations i.e. no carcinogens in lipstick)
- dependent on post market controls to pick up poor quality products

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20
Q

What is the level of control for all other health products like (not TPs/CPMs/Cosmetics)?
*includes Traditional medicines, health supplements, homeopathic medicines

A

Others: Post market control

- dependent on post market controls to pick up poor quality products

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21
Q

What was the incident that led to the US Federal Food, Drug and Cosmetic Act (FDC)?
- What does FDC include?

A

16 Nov 1937 Elixir Sulfanilamide Tragedy (Poisonous solvent that was not safely tested)
- FDC included stronger drug safety requirements

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22
Q

What was the incident that led to the 1962 Kefauver-Harris Amendment to the FDC?
- What is the change?

A

Thalidomide Tragedy

  • New drugs had to demonstrate substantial evidence of efficacy and safety for marketed indication
  • Strengthened control on human experimentation
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23
Q

What are some major events in pharmacovigilance?

A

1975 Practolol –> Occulomucocutaneous Reaction –> resulted in Prescription event monitoring (PEM) in UK and NZ

1990 Bovine derived Biologicals –> BSE (prions) –> to reduce risks and use of cattle derived medicines

2004 Rofecoxib (Vioxx) --> MI --> new concepts of risk/risk balancing (MI protection > GI protection)
risk/risk = which risk is greater
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24
Q

How are medicines licensed today?

A

Based on efficacy, safety and quality

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25
Q

How is efficacy usually shown?

A

Randomized trials

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26
Q

How is safety usually shown?

A

Animal testing
Phase 1 trials (human volunteers)
Phase 2 trials (Early trials on clinical pts)
Phase 3 trials (large scale trials)
Post-marketing surveillance/Pharmacovigilance

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27
Q

What kind of safety data do clinical trials provide and why?

A

Phase 2/3 trials pick up more common adverse events esp since the studies are powered for efficacy

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28
Q

Why do we say that for adverse EVENTS, causality is NOT implied?

A

not sure if the drug caused the adverse events

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29
Q

What do we mean when we say that for adverse REACTIONS, causality is ASSUMED?

WHO definition of ADR: A reaction that is _______/harmful & _______ & occurs at doses ________ ________ in man for prophylasis, diagnosis or treatment of disease of the modification of physiological function (excludes ______, drug abuse, ________ errors)
vs

side effect: any _______ effect occurring at doses _________ in humans that is related to the pharmacological properties of the drug; can be _______/______

A

No need to make confirmation that the drug causes the adverse reaction

  • there are varying levels of causality
    i. e. when 10 pts take and 10pts develop adverse events
  1. noxious
  2. unintended
  3. normally used
  4. overdose
  5. medication
  6. unintended
  7. normally used
  8. positive/negative
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30
Q

How can we overcome the fact that individual case assessment in reactions and causality is always problematic?

A

data from across the country can be collated to see if there is indeed causality –> just report it

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31
Q

What is the rule of three used in detecting rare ADR for a required sample size?

A

To pick up an ADR with an incidence of 1 in 100, a corresponding sample size of 300 (3x) is needed
*Statistical reasons, this gives 95% confidence interval

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32
Q

What does the rule of three mean when applied to a clinical trial with 1800 patients where no ADR was found?

A

There is only a 95% confidence that the true frequency of this ADR is less than 1 in 600

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33
Q

What are some limitations of clinical trials?

A
  1. Designed for efficacy
  2. Only detects common ADRs (1 in 100 to 1 in 1,000)
  3. Small* sample size
  4. Short duration (1-3 years)

*By the time drug is marketed, usually only ~3k pts exposed under ICH E1 guidelines

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34
Q

In terms of Cell, tissue and gene therapy products (CTGTP), why is it ok for those clinical trials to only involve a small number of patients?

A

The diseases treated are usually rare

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35
Q

How do vaccine trials differ from usual clinical trials in terms of required sample size and what is the reasoning?

A

Larger numbers are needed (in the range of 40k)

  1. needed to prove efficacy
  2. we are giving vaccines for healthy people –> need more exposure
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36
Q

What are the ICH E1 guidelines to assess clinical safety for drugs meant for chronic illnesses or repeated intermittent use for longer than 6 mths (non-life threatening conditions)?

A
  1. 300-600 patients exposed to drug
  2. 100 pts exposed for minimum of 1 year**
  • *Reasonable assurance that true cumulative one year incidence is no greater than 3%
  • Most ADRs develop within first few months of drug tx (concern that some ADRs develop >6months after tx)
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37
Q

What are 3 groups of drugs that get special considerations under the ICH E1 guidelines?

A

Anti-obesity
Anti-cancer
Anti-diabetics

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38
Q

What is the incidence of ADRs in US/UK/SG?

A

US: 6-7% hospital admissions, 100k annual deaths
UK: 5% hospital admissions, 1/1000 medical inpatient death
SG: 8% hospital admissions

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39
Q

What is the impact of ADRs for patients vs healthy individuals?

A

USD 3.5 billion (to manage 380-450k preventable ADRs)

  • Double: mean length of stay, cost and risk of mortality for patients VS controls
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40
Q

What is pharmacovigilance?

A

Science of collecting, monitoring, researching, assessing and evaluating info from HPs and pts on adverse effects of health products with a view to:

  • Identify new info on hazards
  • Prevent harm to pts
  • esp since R/B profile of a drug can change
  • need to be able to identify the changes to decide on what we can do to reduce harm to patients
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41
Q

Why is pharmacovigilance relevant in SG?

A
  • Biomedical Sci is the 4th economic engine (need PV to create confidence to set up BMS sector)
  • Limitations of clinical trials
  • Genetic/Envt influences
  • Aging population (polypharmacy + susceptible)
  • Increased use of CAMs (perception that it is safer)
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42
Q

Following worldwide drug recall data from the 2000s, what trend can we see?

A

There can be a long delay between launch and withdrawal (up to 24 years) –> usually in 1st 3-5years (period where pharmacovigilance needs to be intensified)

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43
Q

Why are there long delays between withdrawal and launch for certain withdrawn drugs?

A

Initial indications may not cause ADRs, but when used off-label or in combination with certain medications, ADRs can occur (i.e. changes in prescription patterns)

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44
Q

What is the pharmacovigilance framework?

A
  1. Signal/Risk detection (monitoring ADRs to detect risks & change in R/B)
  2. Risk assessment (assessing R/B)
  3. Risk minimization
  4. Risk communication (to optimize safe and effective use)
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45
Q

What are signals?

A
  • An early indicator or warning* of a potential new problem with a drug or drug class
  • Reported info on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously
  • Usually >1 report needed to generate a signal
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46
Q

What are some sources of signals?

A

ADR reports*
Literature report
New epidemiological study
Randomized trials

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47
Q

How are international data involved in risk detection?

A
  1. WHO international drug monitoring program
  2. Environmental scanning (literature, media, other Regulatory Agencies)
  3. International Regulatory Exchanges (ASEAN, AU, NZ CA, Switzerland)
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48
Q

What are the Pre-market data involved risk detection?

A

Clinical trial and animal study data

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49
Q

What are the local data involved in risk detection?

A
  1. HCPs
  2. Autopsy reports, toxicology lab
    3, Active surveillance initiatives (CMIS, Sentinel sites for vaccines, Registries for selected drugs)
    4, Mandatory reporting for drug companies
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50
Q

What are the mandatory reporting measures for drug companies?

A

Serious reports within 15days
Study findings that alter R/B
Periodic safety update reports
Post-marketing studies (PRN in SG)

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51
Q

What percentage of drugs have undetected serious adverse effects prior to approval?

A

50%

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52
Q

What are the advantages of ADR reporting?

A
  • Works for all drugs given to patients throughout drug’s marketed life
  • Relatively Inexpensive
  • Accessible to HCPs
  • Can provide rapid identification of new ADRs
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53
Q

What are the disadvantages of ADR reporting? What are the difficulties of reporting an ADR?

A
  • Low level of reporting
  • Requires HPs to recognize ADRs (complicated by many ADRs mimicking naturally occurring illness + insufficient data*)
  • Data relate to suspected associations only (could be false +ve)
  • Lack of denominator** = no incidence rate (vs clinical trials fixed no of people)
  • i.e. pt secretly takes CAMs w/o knowledge of doctor
    • dont know how many pts took the drug (can estimate based on drug company sales)
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54
Q

What is the qualitative method of signal detection?

A

Case by Case evaluation on:

  • Frequency
  • Nature/type of event
  • Time to onset
  • Duration
  • Rechallenge/dechallenge
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55
Q

What are the quantitative methods of signal detection?

A

Frequentist approach

Bayesian approach

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56
Q

How can signals be confirmed?

A

Hypotheses testing
Epidemiological study

*if signal is very strong, testing and studies may not be necessary prior to taking action

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57
Q

What are the kind of data considered for R/B (Risk-benefit) assessment?

A
  • Efficacy data
  • Safety data
  • Therapeutic alternatives
  • Type of disease (e.g. cancer/terminal illness, more risk can be taken)
  • Impact on population
  • Ability to mitigate risk
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58
Q

What are some likely outcomes when a drug is revaluated to have a favorable R/B analysis? (Risk minimisation & management)

A
  • Enhancement of warnings in package inserts
  • Change in indications (mitigate risk) (1st line –> now 2nd line)
  • New contraindications
  • Post market studies, registries (companies to do further studies)

Rare:

  • Restriction to certain medical disciplines only
  • Restriction of access to certain patients only
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59
Q

What is a black box warning?

A

The sternest warning by the US FDA that a medication can carry while remaining on the market

  • anti-depressants and suicidality
  • FQs and tendinitis/tendon rupture
  • rosiglitazone and increased CV risk

*known adverse effects that regulators want the public to know

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60
Q

What are some likely outcomes when a drug is revaluated to have a UN-favorable R/B analysis?

A

Suspension of sales
Product recall
Withdrawal: ‘Voluntary’ withdrawal if initiated by company

61
Q

What are some avenues that HSA use to conduct risk communication to HPs and public?

Moreover, what is the aim of risk communication?

A 
Dear HCP letters
Public advisories (Website, Press, TV)

Aim:

  • minimise risk & enhance safe use of drugs
  • update and inform intended audience of safety issues in a timely, transparent, and unbiased manner
62
Q

What does pharmacovigilance policy require from the government?

A
  • Establishment of a national drug regulatory agency
  • Establishment of PV systems (including national PV centers)
  • Development of legislation
  • Multidisciplinary collaboration
  • Continual provision of info on ADR to HPs/public
  • Monitoring impact via process indicators and outcome
63
Q

What kind of knowledge must pharmacovigilance staff possess?

A
  • Data collection and verification
  • Interpreting and coding of adverse reaction descriptions
  • Coding of drugs
  • Case causality assessment
  • Signal detection
  • Risk management
  • Risk communication
64
Q

What are some organizations involved in pharmacovigilance?

A
  • WHO and its collaborating centre for International drug monitoring (Uppsala, Sweden)
  • CIOMS (Council of international organizations of medical sciences)
  • ICH (International council for harmonization)
65
Q

What does the WHO Uppsala monitoring centre (UMC) do?

A

looks & coordinates at ADR globally

66
Q

What does CIOMS (Council of international organizations of medical sciences) do?

A

reviews alot of matters relating to regulatory science

- alot of pharmacovigilance topics

67
Q

What does the ICH (International council for harmonization) do?

A

Provide technical requirements for pharmaceuticals

- gold standard that guides RAs on the necessary data for when a company submits data for registration

68
Q

Define Adverse event

A

Medical occurrence temporarily associated with the use of a medicinal product but not necessarily causally related

69
Q

Define Adverse reaction

A

A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for prophylaxis/tx/diagnosis of disease/modifying physiological function

70
Q

Define side effect

A

Unintended effect occurring at normal doses related to the pharmacological properties

71
Q

Define spontaneous reporting

A

Voluntary submission of reports on AE/ADRs by HPs to the national RA (or equivalent) outside of a systemically planned study
*No legal obligation

72
Q

Define mandatory reporting of ADRs

A

Legal obligation to report suspected ADRs

73
Q

What are the minimum information of an individual case safety report (ICSR)?

A
  1. Identifiable reporter
  2. Identifiable patient (age, gender, initials, IC)
  3. At least 1 identifiable drug
  4. At least 1 identifiable suspected ADR
74
Q

What may constitute as serious adverse reactions?

A
  1. Potential to cause death
  2. May threaten a person’s life
  3. Potential for hospitalization/prolonging hospital stay
  4. Potential to cause persistent/significant disability/incapacity
  5. Potential to cause congenital defects/ birth defects
  6. Judged medically important (jeopardizing health or requires medical intervention to prevent the above)

*any one of these will suffice

75
Q

What are listed/labelled/expected ADRs?

A

Adequately described ADR

- In package insert/summary

76
Q

What are unexpected ADRs?

A

ADRs not consistent with product info or drug characteristics

77
Q

What does frequency mean?

A

Prevalence or Incidence, or both

78
Q

What does prevalence mean?

A

Number of cases of an event

  • in a defined population
  • during a given period of time
  • includes old and new
79
Q

What does incidence mean?

A

Number of NEW cases

  • in a defined population
  • during a given period of time
  • i.e. 10 cases per 1000 pts per year
80
Q

What do the terms very common, common, … rare, very rare mean in terms of frequency?

A 
Very common: 1/10 or larger
Common: between 1/10 to 1/100
Uncommon: between 1/100 to 1/1k
Rare: between 1/1k to 1/10k
Very rare: 1/10k or smaller
  • may not always be per patient but sometimes by patient years
  • need to look at terminology
81
Q

What are positive predictive values and what do they allow us to do?

A

Probability the positive result is actually accurate
- enables us to determine what kind of regulatory action i.e. carbamazepine (mandate genetic testing for pt months in advance to starting drug)

82
Q

What are negative predictive values?

A

Probability that a negative result is actually accurate

83
Q

What are cohort studies?

A

Definition. A study design where one or more samples (called cohorts) are followed prospectively and subsequent status evaluations with respect to a disease or outcome are conducted to determine which initial participants exposure characteristics (risk factors) are associated with it.

84
Q

What are case-control studies?

A
  • compare how frequently the exposure to a risk factor is present in each group to determine the relationship between the risk factor and the disease.
  • Retrospective
  • Observational

Case control studies are also known as “retrospective studies” and “case-referent studies.”

85
Q

What are nested case control studies?

A
  • cases and controls are drawn from the population in a fully enumerated cohort.

Usually, the exposure of interest is only measured among the cases and the selected controls.

86
Q

What are case-cohort studies?

A
  • cases are participants who developed the disease of interest
  • controls are identified before the cases develop
  • baseline data can be collected early in the study.
87
Q

What are cross sectional studies?

A
  • looks at data from a population at one specific point in time
  • Participants are selected based on particular variables of interest.
  • Observational in nature and are known as descriptive research
88
Q

What can change an adverse event to an ADR?

A

Suspicion of casual relation

89
Q

What are the 5 Methods of causality assessment?

A
  1. Pharmacological plausibility
  2. Chronology
  3. Synergistic- PK
  4. Synergistic - Broad
  5. Alternative
90
Q

What is considered under pharmacological plausibility for causality assessment?

A
  • chemical nature of the molecule/ class
  • assumable intrinsic activity
  • dosage and duration of tx fitting (i.e. high dose/longer duration = higher possibility)
  • PK (conc at relevant site fitting)
  • Phenomenological plausibility because of previous cases (priniciple of Bayes)
91
Q

What is considered under Chronology for causality assessment?

A

Temporal relationship

  • De-challenge (removal of drug = ADR improvement?)
  • possibly re-challenge (rarely done)
92
Q

What is considered under synergistic - PK for causality assessment?

A

Other drugs/factors (PK related) that could not cause AE alone, but could raise the conc of drug to cause a type A reaction

made possible by synergism
- i.e. serotonin syndrome (triptans + SSRIs)

93
Q

What is considered under synergistic - broad for causality assessment?

A

Other drugs/factors which could alone cause the AE in the same way as the drug under consideration and could also in combi cause the whole quantitative degree of the effect.

94
Q

What is considered under alternative for causality assessment?

A

Other possible causes

  • I.e. other drugs/factors that alone could have caused the AE, and thus exonerate the drug under consideration
    e. g. allergic reactions
95
Q

What are the 3 criteria used for causality classes?

A

WHO-UMC Causality assessment
Naranjo causality assessment
CIOMS/RUCAM* scale for drug induced liver injury (DILI)

*Roussel Uclaf Causality Assessment Method

96
Q

What are 5 causality classes?

A
  1. Certain
  2. Probable
  3. Possible
  4. Unlikely
  5. Unclassified/unassessable
97
Q

What are the factors involved when we say the causality is certain?

A
  • AE pharmacologically clear and plausible
  • Chronologically well fitting challenge/de-challenge or even re-challenge
  • Timing within half an hour
  • Lab data specifically implicating the drug
98
Q

What are the factors involved when we say the causality is probable?

A
  • AE pharmacologically plausible
  • Close temporal/spatial correlation i.e. skin
  • Recovery upon drug withdrawal (no tx)
  • Uncommon clinical phenomenon and reasonable exclusion of other factors
99
Q

What are the factors involved when we say the causality is possible?

A
  • > 1 drug (>1 drug might be involved?)
  • Time relationship unclear
  • Pharmacological causality not excludable
  • Chronologically fitting challenge/de-challenge
  • Alternative causes possible
  • Info on AE unclear/incomplete
100
Q

What are the factors involved when we say the causality is unlikely?

A

Chronologically not fitting (challenge/de-challenge)

Alternative causes possible

101
Q

What are the factors involved when we say the causality is Unclassified/unassessable?

A

Incomplete information

102
Q

How does the RUCAM DILI scoring system work?

A

Higher score = higher causality

103
Q

What are the 2 parameters that RUCAM DILI is based on?

A
  1. Hx of DRUG/CAM ingestion within 12 months of onset illness
  2. Time of onset of reaction in association with intake, and discontinuation
104
Q

How is DILI diagnosed?

A

Hx of drug ingestion (including CAMs) within 12 months:
- Exclusion of viral serology (anti-HAC/anti-HCV IgM - exclude hep A,B,C)

  • Negative metabolic screen (exclude autoimmune disorders)
  • Daily alcohol intake <20g
  • Absence of biliary or focal liver pathology on ultrasound/CT scan
  • Done by excluding all other possible causes
105
Q

What are the 6 local legislation requirements on pharmacovigilance for therapeutic products?

A
  1. Duty to maintain records of defects and adverse effects
  2. Duty to report adverse effects
  3. Duty to report defects
  4. Duty to notify authority concerning recall
  5. Duty to carry out risk management plan
  6. Submission of R/B evaluation report
106
Q

What are the details manufacturers/importers/registrants must note in maintaining records of defects and adverse effects?

A
  • Standard format

- Retention for at least 2 years post expiry

107
Q

What are the details manufacturers/importers/registrants must note in reporting adverse effects?

A
  • Serious adverse reactions (SAR) must be reported
  • Non serious AEs excluded
  • Reported no later than 15 calendar days (ICH E2D)
108
Q

What are the details manufacturers/importers/registrants must note in reporting defects?

A
  • Report within 48h for defects that present serious threat to persons/public health
  • Within 15 days for other cases
109
Q

What are the details manufacturers/importers/registrants must note in product recall?

A
  • 1 calendar day prior to recall
  • Class of recall - timelines (depending on health consequence)
  • Level of recall - extent (wholesale/retail/consumer)
110
Q

What are the details manufacturers/importers/registrants must note in risk management plan?

A

Aims to ensure favorable R/B

  • May be requested upon identification of safety issues pre/post market
  • Risk management measures

*Applicable to new drug applications, biosimilars and others on a case-by-case basis

111
Q

What are the details manufacturers/importers/registrants must note in submitting R/B report?

A
  • In alignment with ICH E2 guidelines
  • For selected TPs with safety concerns
  • 6 month intervals for 1st 2 years, subsequently annually for another 3 years
112
Q

What is risk management to the industry?

A

A continuous process throughout the life cycle of a product to optimize B/R

  • Proactive risk assessment pre/post market
  • Develop and implement tools to minimize risks
  • Continual reassessment of B/R

*Ensure benefits of the products EXCEEDS its risks throughout product life cycle

113
Q

How does SG bridge continuity between Pre/post market assessment?

A
  • Discussion with HSA pre-approval and post-market
  • Adapt plans from reference agencies that are relevant locally
  • Additional items (Letter at product launch, Educational materials)
  • Reports (PBRER*&raquo_space; PSUR**)
  • Provision of sales data
  • Restricted access/use
  • Drug registries
  • Post market clinical studies***
  • PERER: Periodic Benefit-Ratio evaluation report
  • *PSUR: Periodic safety update report
  • **May dissuade companies from marketing product in SG
114
Q

When are risk management plans (RMPs) mandatory for submission to HSA?

A
  • New drug applications
  • Biosimilars
  • On request from HSA (i.e. for generics where local RMPs in place for innovators)

*Using US REMS or EU RMP

115
Q

When are educational materials useful in RMPs?

A

When there are impt safety issues to note

  • i.e. risks involving identified pt groups
  • Serious safety signals from clinical trials/post market experience
  • Impt parameters to monitor regularly
116
Q

What are DHCPLs?

A
  • Highlights Serious side effects doctors need to be aware of
  • Special monitoring required
  • Decoupled from promotional materials
  • Letters need to reach all buyers and potential prescribers

*Different from letter at launch

117
Q

Why is sales data useful?

A

Provides a rough estimate of denominator

  • i.e. small levels of sales but high relative proportion of ADR –> concern
  • High vol of sales but low relative proportion of ADR –> low concern
118
Q

When are restricted use/access schemes implemented?

A

For products with serious potential risks but with important role in tx

  • Special conditions (i.e. trained physician / blood tested pt)
  • For use in specific pts w/o alternatives
  • Restricted by medical discipline
119
Q

What are some key features of restricted access/use schemes?
- Other than selected pt group, supply for registered physicians only

A
  • Physician’s and pharmacist’s undertaking (get them to be aware of ADRs)
  • Pt’s informed consent
  • Company to provide regular sales data and updated physician’s list to HSA
120
Q

How do restricted access schemes affect drugs generally?

A

usually reduces the market usage –> drug companies feel they dont want to market anymore -> discontinue
- tradeoffs in protecting pt

121
Q

What are CAR-T cells?

A

Genetically engineered T Cells that express Chimeric antigen receptors (CAR) on cell surface
- CARs grant the specificity of antibody to cytotoxic T cells

122
Q

What are some new considerations for the use of CAR-T cells?

A
  • may take 2-3 weeks for pt cells to be flown to overseas manufacturing facilities and back
  • considerations on how to store product properly, how to monitor for ADR
  • many unexpected/expected ADRs for these products –> finding how to best monitor the products
  • shift from weight dosing to cell count dosing in future
  • kept under new conditions i.e. -20C (a need for specialised facilities to keep the product)
123
Q

What are some potential side effects of CAR-T cells?

A
  • Neurological toxicity
  • On-target, Off tumor toxicity (off target effects)
  • Anaphylaxis
  • Cytokine release syndrome (too many cytokines released)
  • Insertional oncogenesis (other kinds of cancer in the long run)
124
Q

How will pharmacovigilance change in response to new gene therapies?

A
  • pharmacovigilance will be very tricky, requiring long term monitoring of the safety of the pts
  • impt as we are infusing gene transformed cells into the pt –> we need to know long term safety & long term efficacy
125
Q

From 2010-2019, CPM/CM/HS accounted for <1% of all ADRs. How can we rationalize this data?

A
  • this is not the full picture of adverse reactions from CAM –> alot of under-reporting
  • most CAM adverse events reported by doctors/pharmacists (healthcare professionals) while TCM practitioners largely do not report adverse drug rxn
  • pt normally do not relate adverse events to CAM use (or tell their doctor)
  • but the actual number cannot largely outweigh this %
126
Q

What are 8 causes of ADRs?

A
  1. Inherent drug characteristics
  2. Quality issues
  3. Adulteration
  4. Substitution of ingredients
  5. DDI/ Drug-Food interactions
  6. Long term exposure/High doses
  7. Individual susceptibility
  8. In-use issues
127
Q

How can Inherent drug characteristics cause ADRs?

A
  • Active Ingredient and/or Excipients (formulation) may cause allergic rxn
  • switch brands may cause allergic rxn, lowered efficacy (esp CNS drugs, when switching, branded to generics or generics to branded, pt report lower efficacy)
128
Q

How can Quality issues cause ADRs?

A
  • Contamination with toxic heavy metals
  • Counterfeit, substandard products

*Common in SG

129
Q

What are some examples of DDI/Drug-Food interactions?

A

i. e. triptans + SSRIs –> increased risk of serotonin syndrome
i. e. grapefruit juice + contraceptives/erythromycin/anti-hypertensives

130
Q

How can genetics (individual susceptibility) play a role in ADRs?

A

Alleles can predispose pts to certain conditions

  • i.e. HLA-B*1502 predisposes to severe skin rxn with carbamazepine
  • i.e. HLA-B*5801 predisposes to allopurinol induced serious cutaneous adverse reactions (SCAR)
131
Q

How can in-use issues cause ADRs?

A

i.e. not following administration advice –> even properly formulated products can cause ADR

132
Q

What are some occurrences that likely signify a drug association?

A
  • SJS
  • TEN
  • Agranulocytosis
  • Acute dystonias (Abnormal/ involuntary actions)
  • DILI (if confounders properly excluded)
  • Cushing’s syndrome (if endogenous causes excluded)
133
Q

What needs to be done before we arrive at the diagnosis of ADR?

A

We must exclude all other possible causes

MUST exclude SJS, TEN, Agranulocytosis, Acute dystonia, DILI, and Cushing’s syndrome

134
Q

How can we use the background incidence of SJS-TEN to help detect ADRs?
- 1-6 per million/year

A

Sometimes doctors may view more cases than usual background incidence –> may point to certain triggering factors

135
Q

What are alternative causes for SJS-TEN?

A

Infections (viral/bacterial/fungal)

- but SJS-TEN is essentially drug induced, esp TEN

136
Q

What is the presentation of SJS, TEN and transitional SJS-TEN?

A

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

137
Q

What is the most common cause for drug withdrawals?

A

DILI (drug induced liver injury)

138
Q

What is the common identifiable cause of liver toxicity?

A

Viral disease

139
Q

Recall: How can we diagnose DILI?

A

Hx of drug ingestion (including CAMs) within 12 months:

  • Exclusion of viral serology
  • Negative metabolic screen
  • Daily alcohol intake <20g
  • Absence of biliary or focal liver pathology on ultrasound/CT scan

*Done by excluding all other possible causes

140
Q

What is the drug induced cause for Cushing’s syndrome?

A

Long term exposure of high dose steroids

141
Q

What some non-visual side effects of Cushing’s syndrome?

A
  • Increased BP
  • Reduced immunity
  • Increased blood sugar (can predispose to DM)
  • Bone loss
  • Cataracts
142
Q

What are alternative (non-drug causes) of Cushing’s syndrome?

A
  • Adrenal tumor
  • Pituitary tumor (too much ACTH) –> common
  • Ectopic ACTH producing tumor (i.e. in lung)

*drugs are still the most common cause of Cushing’s

143
Q

What are the permissible heavy metal limits for complementary medicines (CM) dating Sep 2020?

A

Arsenic: 5ppm
Cadmium: 0.3ppm
Lead: 10ppm
Mercury: 0.5ppm

144
Q

What was the key learning point(s) of Endopiles?

A

Heavy metals can be found in alarmingly high quantities in CMs with serious side effects

145
Q

What was the key learning point(s) of Pan Pharmaceuticals?

A

Poor GMP compliance can result in ADRs, product recall and loss of confidence in a country’s pharmaceutical products

146
Q

How is it possible that adulterated CMs appear in SG despite initial listing process?

A
  • Listing process is relatively simple (look at formula, is it sold in China)
  • Look at distributor GDP (not GMP) standards
  • Unscrupulous companies bring in clean batches and adulterate products after approval
147
Q

Why are analogues created for adulterated products?

A
  • avoid detection

(less developed labs have a library of substances that are matched against –> known substance i.e. fenfluramine –> will have its known chromatogram library –> analogues will not match –> some labs will not detect)

148
Q

What was a clinical consequence due to slim 10?

A

Liver toxicity

- also mis-diagnosis of pts with hyper-thyroidism

149
Q

What are the 5 future challenges for HSA?

A
  1. Opportunities in Genomic era
    - genes and association with drug effects
  2. Emergence of CMs
    - people think CAMs more natural, less adverse effects but need to beware unscrupulous manufacturers
  3. Registries for biological products and gene tx
    - esp for these products with long term adverse effects –> registries to track pts
    - altho registries have not been very successful in SG
  4. Forging closer ties with international counterparts
  5. Maximizing IT tools for signal detection and communication

PR3145 (10 decks)

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