PV, S&S Flashcards
Range of Health Products Regulated by HSA
Nearly all medication stuff:
- Investigational drugs
- Medical devices
- Therapeutic products
- Complementary Health Products
- Cosmetics
- Advanced Therapy products
- Tobacco
Health products regulation consist of pre-market and post-market stage. Which stage does PV stand and what are some components of PV in that stage?
Post-market stage
- Vigilance
- Surveillance
- Compliance monitoring
- Enforcement
What products are considered high risk?
Therapeutic products. (Usually the potent ones but with serious AE/SE)
The thalidomide tragedy led to the 1962 Kefauver-Harris amendment to the FD and C. What did the amendment include?
- All drugs to demonstrate substantial evidence of efficacy and safety for its indication
- Strengthened control on experimentation on humans
Name some major events in PV
- Sulfanilamide tragedy caused by DEG in product
- Thalidomide tragedy due to racemic mixture
- Practolol (1975): caused occulomucocutaneous reaction
- Biologicals from bovine materials due to BSE
- Rofecoxib (Vioxx) which increased risk of MI
In which year was PV established in HSA
2000
Medicines are licensed today on the basis of ______, ________ and _______.
Efficacy, safety, quality
How is efficacy shown?
Randomised trials (note: randomised trials are NOT sufficient for safety testing)
What are some tests and ways to ensure safety of a medicine before and after licensing?
- Animal testing
- Phase I CT (human volunteers)
- Phase II CT (early clinical trials)
- Phase III CT (large scale trials)
- Postmarketing surveillance/pharmacovigilance
Describe the rule of three. What is it used for?
- Rule of three is used to determine the sample size required to detect a rare ADR
- If ADR is not detected in CT, can only rule out with 95% confidence that the point estimate for the frequency of that ADR is not higher than 3 in the size of the investigated population
What are some limitations of clinical trials (CTs) in the detection of ADRs?
- Designed to test efficacy. Only can detect common ADRs (1/100 to 1/1000)
- By the time drug is approved and marketed, many patients are already exposed
- Duration of CTs is too short (1-3yrs)
ICH guideline number on Clinical trials
E1
Goals of Pharmacovigilance (PV) according to its definition from HSA
- Identify new info about hazards
2. Prevent harm to patients
The 4 steps in the process of PV
- Signal/risk detection: indicator/warning of potential new problem with drug/class of drug
- Risk assessment: review safety signals for drugs and do risk-benefit analysis (R/B analysis)
- Risk minimisation and management: make changes according to favourable or unfavourable R/B analysis
- Risk communication: Update stakeholders of safety issues in timely, transparent and unbiased manner
In signal and risk detection of the PV frameworks, what are some possible sources of signals?
- ADR reports
- Literature report
- New epidemiological study
- Randomised trial
Data from international organisations or local
In signal and risk detection of the PV frameworks, what are some advantages of ADR reporting?
- Operates for all drugs given to patient
- Operates throughout drug’s life
- Inexpensive to do so
- Accessible to all HCP
- Rapid identification of new ADR
In signal and risk detection of the PV frameworks, what are some disadvantages of ADR reporting?
- Low level of reporting
- ADR recognition complicated by mimicking naturally-occuring illness
- Data collected related to suspected associations only
- Cannot provide incidence rates (no denominator data)
In signal and risk detection of the PV frameworks, what are some channels of reporting ADRs?
- Mail/fax/telephone
- Email to HSA drug safety
- Online reporting
- E-reporting linked to medical records: Critical Medical Info Store (CMIS)
Qualitative methods of signal detection in the PV framework
- Freq
- Nature/Type of Event
- Time to Onset
- Duration
- Rechallenge/Dechallenge
Must action be taken immediately to a signal detection? How are follow-up on Signal Detection carried out?
No. Action taken usually when there are more similar reports. After signals are confirmed, then follow-up on signal detection should be carried out via:
- Hypothesis testing
- Epidemiological Study
In R/B assessment of the PV framework, what are some data used to assess R/B?
- Safety & Efficacy data
- Therapeutic alternatives
- Type of disease
- Impact on population
- Ability to mitigate risks
In risk minimisation and management of the PV framework, what are some actions taken in the case of favourable R/B analysis?
- Enhance warnings in package inserts (E.g. black box warning)
- Change indication to mitigate risk
- New C/I
- Postmarket studies/ registries
- Restrict use to certain medical disciplines
- Restrict of access to certain patients only
In risk minimisation and management of the PV framework, what are some actions taken in the case of unfavourable R/B analysis?
- Suspend sales
- Recall pdt
- Withdraw pdt (“voluntary” if initiated by company)
Name some ways of risk communication in the PV framework.
- Professional letters to HCP
2. Public advisories on websites/press/TV (E.g. Posters, bulletin inserts)
Distinguish between Adverse Event (AE), Adverse Reaction (AR) and Side effect (SE).
AE: Occurrence associated with use of medicinal product, but not causally related
AR: Noxious and unintended response to a drug occurring at doses normally given
SE: Unintended effect at normal dose related to pharmacological properties of a drug (nature of the effect does not matter)
Distinguish between Spontaneous Reporting and mandatory Reporting of ADRs
Spontaneous: Voluntary submission of reports of AE/ADR by HCP to authority
Mandatory: legal obligation to report suspected ADRs
What are the minimum information required in an Individual Case Safety Report (ICSR)
- Identifiable reporter
- Identifiable patient (e.g. age, gender, initials, no need IC)
- At least one identifiable drug
- At least one identifiable suspected ADR
Terms by CIOMS used to describe the frequency of ADR
- Very common: ≥10%
- Common/Frequent: ≥1%, <10%
- Uncommon (infrequent): ≥0.1%, <1%
- Rare: ≥0.01%, <0.1%
- very rare: <0.01%
(steps of tenths)
What is required to determine whether an AE is and ADR?
Suspicion of causal relation
What are the 5 things to consider in causality assessments?
- Pharmacological (e.g. principle of Bayes, chemical nature)
- Chronology: Temporal relation, dechallenge and rechallenge
- Synergistic PK (due to DDI)
- Synergistic (broad factors)
- Alternatives (e.g. allergy)
The five categories of causality assessments
- Certain
- Probable
- Possible (causality pharmacologically not excludable, >1 drug, etc.)
- Unlikely (chrono sequence hardly fitting, can be explained via alternative causes
- Unclassified/Unassessable (due to incomplete info)
What does the CIOMS/RUCAM scale measure and what parameters is it based on?
- Measures causal relationship with drug and DILI (drug induced liver injury)
Params:
- Hx of drug ingestion (incl. CAM) within 12 months of onset
- Time of onset of reaction in association with intake of product and discontinuation of product
The scoring system for CIOMS/RUCAM Scale in diagnosing DILI
- <0: Not related
- 1-2: Unlikely
- 3-5: Possible
- 6-8: Probable
- > 8: Highly Probable
What are the criteria before the diagnosis of DILI is confirmed?
- Exclude viral infection via serology
- Exclude autoimmune disorders/ acute liver injuries
- Daily alcohol <20g
- Absence of biliary/focal liver pathology on ultrasound/CT scan of abdomen
What are the local legislation on PV requirements for therapeutic products (TP)?
- Maintain records of defects and AE (at least 2 yrs after expiry)
- Report serious AE within 15 days
- Report defects (within 48h for serious threats, 15d for others)
- Notify authority of recall (1d prior to start of recall)
- Risk management plan to ensure favourable R/B of TP
- Submit R/B evaluation report per 6 months for 2 yrs, then annually for 3 more years
Purpose of Risk Management by industry
Ensure benefits of product exceeds its risks throughout the product’s life cycle
In Singapore, when is submission of existing RMPs mandatory?
- New Drug Applications
- Biosimilars
- Anything else if requested (e.g. generic products where existing local RMP already in place for innovators)
In Singapore, what are some components of Risk Management Plans by Industry?
- Letter at launch of product (E.g. special monitoring, serious potential SE to be aware)
- Educational materials (E.g. package inserts for both HCP and patient)
- PBRER/PSUR
- Provision of sales data
- Restricted use/access schemes (pdt with serious potential risk, but important role in therapy)
- Drug registries (difficult)
- Post market clinical studies (difficult)
In RMPs by industry, what are some key features of Restricted Access Scheme?
- Patients: selected group, informed consent
- Physician: Undertaking, supply to only Registered personnel
- Pharmacists: Undertaking
- Company: provide regular sales data and updated physician’s list to HSA
List of restricted use/access programs in Singapore
- Restriction on use:
- Tegaserod (discontinued?)
- Aprotinin (discontinued 2015)
- Rosiglitazone (discontinued 2019) - Pregnancy Prevention Program:
- Pomalidomide
- Lenalidomide
- Isotretinoin (teratogenicity concern)
In US, describe the program that controls the use of Thalidomide
Program: Thalomid Risk Evaluation and Mitigation Strategy (REMS)
Includes:
- Pregnancy test
- Proper counselling
- Double protection against pregnancy when taking drug
- Limited qnty dispensed per visit to prevent abuse
- Close monitoring by HCP
Describe the program that controls the use of Thalidomide analogues in Singapore
i-access Program (under pregnancy prevention program)
Before Rx/Dispensing:
- Prescriber to register manually. or via i-access
- Pharmacy or dispensing clinic to register as well
- One-time registration with Celgene required before Rx/dispensing thalidomide analogues
The overview of i-access program in Singapore for
- Women of child bearing potential
- Men/Women of Non-childbearing Potential
- Women of child bearing potential:
- Patient agreement form (1st Rx) + negative pregnancy test
- Prescribing drugs: submit preg test results and Rx form
- Refer patient to i-access registered pharmacy (dispesngin allowed only after Celgene authorise it)
- Max 1 box (21 caps) - Men/Women of non-child bearing potential:
- Same as above, w/o preg test results
- Max 2 boxes (42 caps) dispensed at a time
Briefly describe how are CAR-T cells prepared
- Extract WBC, filter T-cells, cryopreserve
- Reprogram T cells with inactive virus
- Expansion
- Quality check
- Lymphodepleting chemotherapy to help patient’s body accept reprogrammed CAR-T
- Infuse CAR-T
Potential SE of CAR-T Cells
- Neurotoxic
- Attack own cells (On target, off tumour toxicity)
- Allergy/Anaphylaxis
- Cytokine Release Syndrome
- insertional Oncogenesis
