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Title: Pharmacovigilance


1
Pharmacovigilance
  • Dr. Sunettra Chinnapha
  • MRCGP (UK), Diploma Dermatology (London)
  • Medical Director, GSK Thailand

Vaccinology Course, Miracle Grand, Bangkok, 19th
May 2009
2
Topics
  • Definitions and key stakeholders
  • History of major events in PV
  • Methods used in PV
  • Clinical trials
  • Spontaneous reports
  • Pharmaco-epidemiology
  • Intensive monitoring
  • Database studies
  • PV in vaccines
  • Recent developments
  • Future perspectives
  • References

3
WHO definition
  • The science and activities related to the
  • detection
  • assessment
  • understanding
  • prevention
  • of adverse effects or any other drug-related
    problem.

4
Adverse Event
  • Any untoward medical occurrence in a patient or
    clinical investigation subject, temporally
    associated with the use of a medicinal product,
    whether or not considered related to the
    medicinal product.

5
Serious Adverse Event
  • Fatal
  • Life-Threatening
  • Disabling or incapacitating
  • Hospitalization (new or prolonged)
  • Congenital anomaly
  • Other medically important events (e.g. lab
    abnormalities, etc.)

6
Key stakeholders in PV
  • Patients
  • Health professionals
  • Governments (regulatory authorities)
  • Pharmaceutical companies
  • International Organisations, e.g.
  • CIOMS
  • ICH

Pharmacovigilance Partnership for Patient Safety
7
CIOMS
  • Council for International Organisations of
    Medical Sciences
  • International, non-governmental, non-profit
    organisation
  • Established in 1949 by WHO and UNESCO (United
    Nations Educational, Scientific Cultural
    Organisation)
  • Independent forum to consider and prepare advice
    on contentious issues in bioethics and safety of
    pharmaceuticals for WHO, regulators,
    pharmaceutical industry and others
  • website www.cioms.ch

8
CIOMS Pharmacovigilance Working Groups
  • First working group established in 1986
  • Composition
  • Regulators
  • Company pharmacovigilance specialists
  • Other invited attendees and observers e.g. WHO
    co-ordinating centre
  • CIOMS has no legal jurisdiction and is reliant on
    other bodies for regulatory or legislative
    framework

9
CIOMS Initiatives
  • CIOMS I International Reporting of Adverse
    Drug Reactions (1990)
  • CIOMS I Reporting Form
  • CIOMS II International Reporting of Periodic Drug
    Safety Update Summaries (1992)
  • CIOMS III Guidelines for Preparing Core Clinical
    Safety Information on Drugs (1999)
  • CIOMS IV Benefit/Risk Balance for Marketed
    Drugs Evaluating Safety Signals (1998)
  • CIOMS V Current Challenges in Pharmacovigilance
    Pragmatic Approaches (2001)
  • CIOMS VI Management of Safety Information from
    Clinical Trials (2005)
  • CIOMS VII Development Safety Update Report (2006)

10
Other CIOMS Initiatives
  • Current
  • CIOMS VIII Signal Detection (report to be
    published in 2009)
  • Completed
  • Definitions and Basic Requirements for the Use of
    Terms for Reporting Adverse Drug Reactions (1999)
  • Pharmacogenetics Towards Improving Treatment
    with Medicines (2005)
  • Standardised MedDRA Queries (2004)
  • Joint CIOMS-WHO Working Group on Drug Development
    Research and Pharmacovigilance in Resource-Poor
    Countries (2006)
  • CIOMS/WHO Working Group on Vacccine
    Pharmacovigilance (2007)

11
History of major events in PV (1)
  • 1961 Thalidomide
  • phocomelia in children of mothers who took this
    drug during early pregnancy
  • ? Introduction of PV related regulations
  • 1969 Clioquinol
  • subacute myelo-opticus neuropathy (SMON) in
    Japan
  • ? Discovery of ethnic and genetic influences on
    drug-related risks

12
History of major events in PV (2)
  • 1975 Practolol
  • oculomucocutaneous reaction
  • ? Invention of the Prescription Event
    Monitoring (PEM) in the UK and NZ
  • 1982 Benoxaprofen
  • Liver necrosis in the elderly and unusual
    photosensitivity
  • ? Creation of CIOMS (Council of International
    Organizations of Medical Sciences)

13
History of major events in PV (3)
  • 1990s 3rd generation oral contraceptives
  • more frequent venous thromboembolism compared
    with 2nd generation OCs
  • ? worldwide fostering of pharmaco-epidemiology
  • 2001 Cerivastatin
  • more frequent rhabdomyolysis than other statins
    if combined with gemfibrozil
  • ? Introduction of pharmacovigilance plans

14
History of major events in PV (4)
  • 2002 Hormone replacement therapy (HRT)
  • breast cancer
  • ? Scientific prestige of RCTs over pharmaco-epi
    studies and re- thinking of relevant endpoints in
    long-term therapies
  • 2004 Rofecoxib
  • more frequent myocardial infarction than
    classical NSAIDs
  • ? New concepts for risk/benefit balancing

15
Methods Used in PV
  • Clinical trials
  • Spontaneous reporting
  • (Including published case reports or literature
    reports)
  • Pharmaco-epidemiology studies
  • Intensive monitoring
  • Database studies

16
Clinical Trials
  • Main method to gather information on a drug in
    pre-marketing phase
  • Regulated by internationally accepted standard,
    i.e. ICH-GCP
  • Safety and tolerability, usually 2º endpoint
  • Subject to be informed of risks benefits before
    giving consent
  • Investigators to report SAEs to sponsors within
    24 hrs
  • Sponsors obligations
  • Expedite important safety information to
    investigators, ethics committees and regulatory
    authorities
  • Annual Safety Report (EU)

17
Important definitions
  • SAE Serious Adverse event
  • Fatal, life-threatening, hospitalisation,
    disability/incapacitating, congenital anomaly and
    other medically important event
  • not the same as clinically severe
  • Adverse events
  • Any untoward event
  • Expected and unexpected adverse reactions
  • Reactions not included or more severe or more
    frequent than those listed in the product
    information
  • SUSAR serious, unexpected, suspected adverse
    reaction
  • Expedited reporting required IND Safety Reports
    (US FDA)

18
Clinical Trials Advantages
  • Double-blind randomised controlled trials are
    considered the most rigorous approach to
    determine whether cause-effect relationship
    exists between a treatment and an outcome.

19
Clinical Trials Limitations
  • Duration of trial too short to detect ADRs with a
    long latency
  • Study population do not always correspond to the
    general population
  • Strict inclusion and exclusion criteria
  • Elderly, women of child-bearing age, children,
    ethnic minority groups, are often excluded
  • Relatively small number of subjects compared to
    the whole population
  • Very rare adverse events typically will not be
    discovered in pre-licensure testing
  • Cannot measure efficacy against rare diseases

20
Spontaneous Reporting
  • Primary method of collecting post-marketing
    information on the safety of drugs
  • Enable physicians, pharmacists and patients to
    report suspected ADRs to a pharmacovigilance
    centre
  • Also used by pharmaceutical companies to collect
    information about their drugs

21
Minimum Information of a Single Case ADR Report
  • An identifiable reporter
  • An identifiable patient
  • At least one identifiable drug
  • At least one identifiable suspected ADR
  • Reporters contact details

22
Spontaneous Reporting Advantages
  • Early detection of signals of new, rare and
    serious ADRs
  • A means to monitor all drugs on the market
    throughout their entire life cycle

23
Spontaneous Reporting Limitations
  • Under-reporting
  • Can lead to a false conclusion that a real risk
    is absent
  • Selected reporting
  • May give a false impression of a risk that does
    not exist
  • Not possible to establish cause-effect
    relationships or accurate incidence rates
  • However spontaneous reporting strength is still a
    valuable tool in detecting new safety issues

24
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25
Pharmaco-epidemiology
  • Non-interventional study of the use and the
    effects of drugs in large numbers of people
  • Methodologically, it was defined as
  • the science of what happens anyway
  • (as opposed to experimental clinical
    pharmacology)
  • the science of the denominator
  • (i.e. how to relate events occurring to single
    persons to the underlying exposed population)
  • the science of exposure and outcome
  • (i.e. relating exposure to outcome and vice
    versa)

26
Advantages Disadvantages of Pharmaco-epidemiolog
ical Studies
  • Compared to spontaneous reports
  • ? Provide both numerator and denominator for the
    calculation of ADR frequencies
  • Do not detect extremely rare ADRs and do not
    describe the quality of ADRs in detail
  • Compared to clinical trials (RCTs)
  • ? Permit investigation of ADRs with much lower
    frequency or latency
  • ? Real life conditions
  • Prone to systematic errors (biases)
  • Cannot provide answers to questions related to
    very specific interventions not common in medical
    practice

27
Intensive Monitoring (1)
  • Started in late 1970s early 1980s
  • NZ Intensive Medicine Event Monitoring
  • UK Prescription Event Monitoring (PEM)
  • Use prescription data to identify users of
    certain drug
  • The prescriber of the drug is asked about any AE
    occurring during the use of the drug

28
Intensive Monitoring (2)
  • Opportunities
  • Potential for the conduct of cohort and
    case-control studies
  • Allowing the determination of absolute and
    relative ADR incidences below 1 1000
  • Limitations
  • Number and quality of answers depend on doctors
    compliance
  • Only feasible in countries with a centralised
    system for collection and re-imbursement of
    prescriptions

29
Database Studies
  • Data collected in a reliable and routine fashion
    are needed for pharmaco-epidemiological studies
  • Large automated multipurpose population-based
    databases
  • Administrative data for re-imbursement e.g.
  • Kaiser Permanente (US) 7.5 M patients
  • Saskatchewan (Canada) 1 M citizens
  • Representative doctors e.g.
  • General Practitioners Research Database (GPRD in
    UK) 500 GPs, 4 M patients
  • Regional pharmacies and hospitals e.g.
  • PHARMO in Netherlands 2 M patients

30
Advantages Disadvantages of Database Studies
  • Advantages over field studies
  • Quick and cost effective
  • No bias due to interviewer or recall
  • Disadvantages
  • Missing data necessary to answer special
    questions
  • ( the reason these databases were not
    designed for specific questions)

31
Pharmacovigilance of Vaccines
32
Smallpox vaccine Jenner started it all
33
Vaccines
  • Biological preparation that establishes or
    improves immunity to a particular disease
  • Contains a small amount of a weakened agent
    (virus or microorganism)
  • Stimulates the immune system to recognize the
    agent as foreign, destroys it, and "remember" it,
    so that the immune system can more easily
    recognize and destroy any of these microorganisms
    that it later encounters
  • Stored under optimal temperature to ensure
    potency
  • Prophylactic (vaccines against infection)/Therapeu
    tic (cancer vaccine)

34
Smallpox
NOTE Before vaccination annual mortality was
10-15 of the worlds population
35
Vaccine Preventable Diseases from the
maximum/year to 2000, USA
Source CDC unpublished data. Personal
communication J Ward (UCLA)
36
The Paradox of Concern
Infection
SAE due to vaccines
37
The Paradox of Concern
Infection
SAE due to vaccines
38
Real or Perceived Safety Issues of Vaccines
Hexavalent Vaccines Sudden Infant Death
MMR Autism
Hepatitis B MS
Rotavirus Vaccine Intussusception
Varilrix Sepsis
Adjuvants Autoimmune Disease
39
WHO on Vaccines
  • There is no such thing as a "perfect" vaccine
    which protects everyone who receives it AND is
    entirely safe for everyone.
  • Effective vaccines (i.e. vaccines inducing
    protective immunity) may produce some undesirable
    side effects which are mostly mild and clear up
    quickly.
  • The majority of events thought to be related to
    the administration of a vaccine are actually not
    due to the vaccine itself - many are simply
    coincidental events, others (particularly in
    developing countries) are due to human, or
    programme, error.
  • It is not possible to predict every individual
    who might have a mild or serious reaction to a
    vaccine, although there are a few
    contraindications to some vaccines. By following
    contraindications the risk of serious adverse
    effects can be minimized.

40
Classification of Adverse events following
Immunization
  • Vaccine reaction event caused or precipitated by
    the vaccine when given correctly, caused by the
    inherent properties of the vaccine
  • Programme error event caused by an error in
    vaccine preparation, handling, or administration
  • Coincidental event that happens after
    immunization but not caused by the vaccine - a
    chance or temporal association but not causal
    association
  • Injection reaction event from anxiety about, or
    pain from, the injection itself rather than the
    vaccine
  • Unknown events cause cannot be determined

http//www.who.int/immunization_safety/publication
s/aefi/en/AEFI_WPRO.pdf
41
Programme errors
  • Non-sterile injection
  • infection
  • Incorrect preparation
  • abscess (inadequate shaking)
  • drug effect (use of drug instead of
    vaccine/diluent)
  • Injection in wrong site
  • local reaction/abscess (wrong tissue level)
  • nerve damage
  • Vaccine frozen
  • local reaction
  • lack of efficacy (breakthrough infections)
  • Contraindication ignored
  • avoidable severe reaction

41
42
Mistaking one vial for another
TT
DTP
Insulin vial
42
43
FIXING THE PROBLEM
  • Treat the patient
  • Communicate with patient, parent, health worker
    and community
  • Take corrective action
  • Programme error
  • change in logistics for supplying, storing or
    handling vaccine
  • change in procedures at the health facility
  • training of health workers
  • intensified supervision
  • Coincidental
  • communication so people understand that link is
    just coincidental
  • Vaccine Reaction (if higher rate than expected)
  • -Withdraw specific lot (NRA action)

43
44
Barriers to reporting among health workers
  • Not considering the event as related to
    immunization
  • Not knowing about reporting system and process
  • Lethargy - procrastination, lack of interest or
    time, inability to find report form
  • Fear that the report will lead to personal
    consequences
  • Guilt about having caused harm and being
    responsible for the event
  • Diffidence about reporting an event when not
    confident about the diagnosis

44
45
Temporal or causal AEFIs?
  • The problem if a vaccine is given to every
    infant in a population, every single disease in
    that population will happen after that vaccine
  • for most people, if B happens after A, then A is
    the cause of B
  • it explains why most diseases of unknown
    aetiology have been attributed to vaccination at
    one point in time until association disproven

46
Temporally linked AEFIs
vaccine
AEFI
  • Multiple sclerosis
  • Sudden Infant Death Syndrome
  • Crohns disease
  • Autism
  • Hep B
  • DTP pert.
  • Me/MMR
  • Me/MMR

Adapted from S. Plotkin, Vaccine 2001
47
MMR/autism trend analysis
48
HepB vaccines ..
not the cause of MS!!
  • incidence of MS in France 2-5 cases/100,000
    population
  • investigated frequency in the French population
    vaccinated against HepB 0.65 cases / 100,000
    vaccinees

49
Causally linked AEFIs
vaccine
AEFI
  • anaphylaxis
  • paralysis (VAPP)
  • intussusception
  • aseptic meningitis
  • many injectables
  • Polio Sabin (OPV)
  • Rotashield Rh strain
  • mumps/Urabe Am9

Adapted from S. Plotkin, Vaccine 2001
50
GMPs, GISPs, GMPs
  • good medical practices
  • good immunisation services practices
  • good management practices

first "do no harm principle"
51
Recent development in PV
  • Transparency data open to the public
  • Clinical trial registry
  • Spontaneous report database in CN, NL, UK
  • Risk management plans
  • Proactive post-marketing strategies to prevent or
    minimise risk

52
Future Perspectives in PV
  • Post-marketing surveillance
  • Data collection and evaluation
  • Quality and quantity of reports
  • Real life / real-time databases
  • Research into risk management strategies
  • effective ways to minimise risk / communicate
    benefits risks of medicines
  • Pharmacogenetics
  • Education to health professionals and patients

53
References
  • http//www.who-umc.org/
  • http//www.cioms.ch
  • Beckmann J. Basic pharmacovigilance A two-day
    seminar according to a curriculum of the
    International Society of Pharmacovigilance
    Ha(ISoP). October 27-28, 2005, Bangkok
  • Harmark L and van Grootheest AC.
    Pharmacovigilance methods, recent developments
    and future perspectives. Eur J Clin Pharmacol
    200864743-752
  • Pillans PI. Clinical perspectives in drug safety
    and adverse drug reaction. Expert Rev Clin
    Pharmacol 20081(5)695-705

54
Safety and Pharmacovigilance
Patient safety is always a priority!
55
Thank you
Vaccinology Course, Miracle Grand, Bangkok, 19th
May 2009
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