PV Flashcards
Objectives of health products regulation group
Safeguard Public Health
► Ensure appropriate technical standards are met
► Facilitate recalls, product withdrawals
• Facilitate
► Access to safe, good quality, and
efficacious health products
► Support development of a high quality healthcare system
• Assure
► Instill trust, confidence & credibility of products at home & abroad
Practolol caused
Occulomucocutaneous reaction
Rofecoxib (vioxx) caused
MI
Medicines are licensed today on the basis of______
Medicines are licensed today on the basis of efficacy, safety & quality
Clinical Trials designed to:
- Test efficacy
- Detect common ADRs (1 in 100 to 1 in 1,000)
By the time a drug is marketed:
- Usually 1,500 – 3,000 patients are exposed (ICH E1) (larger numbers for vaccine trials)
Short duration:
- 1-3 years
Clinical Trials designed to:
- Test efficacy
- Detect common ADRs (1 in 100 to 1 in 1,000)
By the time a drug is marketed:
- Usually 1,500 – 3,000 patients are exposed (ICH E1) (larger numbers for vaccine trials)
Short duration:
- 1-3 years
Required sample size for detecting a rare ADR
Incidence
Sample size
1 in 100
300
1 in 200
600
1 in 1,000
3,000
1 in 2,000
6,000
1 in 10,000
30,000
PV frame work
1) signal/risk detection
- monitoring ADRs to detect risks and change in R/B profile
2) risk assessment
- assessing risk-benefit profile
3) risk minimization
- minimizing risk by appropriate regulatory actions
4) risk communication
- communicating information to optimize safe and effective use
Source of signal
Source of a Signal: **ADR reports, a literature report, a new epidemiological study, a randomised trial
Serious reports within ___ days
15days
Advantages of ADR reporting
Advantages of ADR Reporting
• Operates for all drugs given to patients
• Operates throughout the whole of the drug’s life
• Relatively inexpensive to operate
• Accessible to all physicians/dentists/pharmacists
• Can provide rapid identification of newly identified adverse drug reactions
Disadvantage of adr reporting
• Low level of reporting
- estimated that 2-4% of all ADRs & <10% of
serious ones are reported
• Scheme requires HCPs to recognise ADRs; recognition is complicated by the many ADRs mimick naturally-occurring illnesses
• Data collected relate to suspected associations only
• Unable to provide incidence rates because of lack of denominator data
Risk minimization and management
Re-evaluate Approval Decisions
- Package Insert Amendments
- RestrictedAccess
- PostmarketStudies,Registries
- Suspension or Withdrawal of a Product (eg Prepulsid®, Lipobay®)
Risk communication aim
Aim:
• To minimise risk & enhance safe use of drugs
• Update and inform intended audience of safety issues in a timely, transparent and unbiased manner
National policy on PV
- Responsibility of governments to ensure provision of good quality, safe and effective drugs and their appropriate use
- Requires establishment of:
- A national drug regulatory agency; and
- A special centre for ADR study, and maintenance of their activities
• Multidisciplinary collaboration involving different departments of the Ministry of Health and other stakeholders, such as pharmaceutical industry, universities, non-governmental organizations and professional associations for education on rational use of drugs and pharmacotherapy monitoring is of great importance
Important activities include:
• Establishment of national pharmacovigilance systems, including
national pharmacovigilance centres
• Development of necessary legislation/regulation for drug monitoring
• Development of national policy and plans of action (including costing, budgeting and financing)
• Undergraduate and continuing education of healthcare providers on safe and effective pharmacotherapy
• Continuously providing information on ADR to professionals and consumers
• Monitoring of the impact through process indicators and outcome
Very common =
> = 1/10
Common (frequent)
> = 1/100 AND <1/10
Uncommon (infrequent)
> = 1/1000 AND <1/100
Rare
> = 1/10000 AND <1/1000
Very rare
<1/10000
Criteria for Causality classes
Certain =
Certain:
- AE pharmacologically clear and plausible
- Chronologically well fitting challenge/dechallenge, possibly even
rechallenge
- Timing within half hour
- Lab data specifically implicating that drug
Criteria for causality classes
Probable
- AE pharmacologically plausible
- Close temporal or spatial correlation (eg skin)
- Recovery upon drug withdrawal (no therapy)
- Uncommon clinical phenomenon and reasonable exclusion of other
factors
Criteria for causality classes
Possible
Possible:
- More than 1 drug
- Time relationship unclear
- Causality pharmacologically not excludable
- Chronically fitting challenge/dechallenge
- Also explainable through alternative causes
- Information about the AE incomplete or unclear
Criteria for causality classes
Unlikely
- Chronological sequence (challenge, dechallenge) hardly fitting
- Plausible explanation through alternative causes
Criteria for causality classes ranking
Certain Probable Possible Unlikely Unclassified / unassessable
Cioms/Rucam drug induced liver injury (DILI)
Scoring system
- 0 or lower: Relationship with the drug excluded
- 1-2: Unlikely
- 3-5: Possible
- 6-8: Probable
- > 8: Highly probable
Based on the following parameters:
• History of ingestion of drugs, including complementary medicines, within 12 months of onset of illness
‐ Time of onset of reaction in association with intake of product; and discontinuation of product
Diagnosis of DILI
• Exclusion of viral serology e.g. anti-HAV IgM, anti-HCV IgM
• -ve metabolic screen (autoimmune disorders or diseases that causes liver injury) e.g. Antinuclear Antibody Test (ANA), ceruloplasmin, antimitochondrial antibody (AMA)
• Daily alcohol intake < 20 g
• Absence of biliary or focal liver pathology on ultrasound or CT scan of abdomen
Diagnosis of DILI
• Exclusion of viral serology e.g. anti-HAV IgM, anti-HCV IgM
• -ve metabolic screen (autoimmune disorders or diseases that causes liver injury) e.g. Antinuclear Antibody Test (ANA), ceruloplasmin, antimitochondrial antibody (AMA)
• Daily alcohol intake < 20 g
• Absence of biliary or focal liver pathology on ultrasound or CT scan of abdomen
Clinical safety data management: data elements for transmission of individual case
reports
E2B
Periodic Benefit Risk Evaluation Report
E2C
Post-approval safety data: definition and stds for expedited reporting
E2D
PV planning
E2E
Mandatory submission of existing RMPs for the following categories of applications:
– New Drug Applications
– Biosimilars
– On Request from HSA
o For example, generic products where existing local RMP is already in place for innovators (e.g. Avandia – restricted access)
Risk management methods
1) Educational Materials
When there are important safety issues to note
– Risks involving identified groups of patients
– Serious safety signals that have arisen from clinical studies or post-market experience
– Important parameters to monitor on regular basis
2) Letters to Healthcare Professionals
• “Letter at Launch” vs Dear Healthcare Professional Letter (DHCPL)
• Serious potential side effects that doctors need to be aware of
• Special monitoring required
• Decoupled from promotional materials
• Letters will need to reach all buyers and potential prescribers
3) Sales Data
Provide Broad Categories of Buyers
- Companies may be required to assist in contacting buyers during investigations or implementing risk mitigation strategies
4) Special Licensing Conditions
• Implemented for products with serious potential risks:
– Identified in specific groups of patients
– Product has important role in therapy
– E.g. of products: Clozapine, Revlimid®
• Product supply is bound by conditions:
– E.g. for patients who have undergone special blood tests, physicians who have undergone special programmes
5) Restricted Access Programme
• Implemented for products with serious potential risks :
– Identified groups of patients with no suitable therapeutic alternatives
– Product still has important role in therapy
– Usually a post-market initiative
6) Letter of acknowledgement/undertaking and/or patient consent form:
• Clozapine – safety concerns with agranulocytoisis
• Natalizumab (Tysabri®, UCB Trading) – safety concern of progressive multifocal leukoencephalopathy (PML)
• Strontium ranelate (Protos, Servier) – physician to acknowledge receipt of letter detailing RMP for Singapore
• Panitumumab (Vectibix®, Amgen) – physician to acknowledge receipt of notification of inferior progression free survival and overall survival observed when Vectibix is used in combination with oxaliplatin based chemotherapy
Occurrence most likely signify a drug association:
Occurrence most likely signify a drug association:
- SJS
- TEN
- Agranulocytosis
- Acute dystonias
‐ Drug-induced liver injury (if confounders properly excluded)
- Cushing’s syndrome (if endogeneous causes excluded)
A diagnosis of an ADR is arrived after excluding all possible causes
