Pharmacovigilance

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Pharmacovigilance

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

Vaccinology Course, Miracle Grand, Bangkok, 19th
May 2009
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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

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WHO definition

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

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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.

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Serious Adverse Event

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

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Key stakeholders in PV

• Patients
• Health professionals
• Governments (regulatory authorities)
• Pharmaceutical companies
• International Organisations, e.g.
• CIOMS
• ICH

Pharmacovigilance Partnership for Patient Safety
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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

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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

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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)

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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)

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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

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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)

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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

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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

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Methods Used in PV

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

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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)

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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)

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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.

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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

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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

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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

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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

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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

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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)

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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

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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

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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

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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

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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)

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Pharmacovigilance of Vaccines
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Smallpox vaccine Jenner started it all
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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)

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Smallpox
NOTE Before vaccination annual mortality was
10-15 of the worlds population
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Vaccine Preventable Diseases from the
maximum/year to 2000, USA
Source CDC unpublished data. Personal
communication J Ward (UCLA)
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The Paradox of Concern
Infection
SAE due to vaccines
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The Paradox of Concern
Infection
SAE due to vaccines
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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
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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.

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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
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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

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Mistaking one vial for another
TT
DTP
Insulin vial
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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)

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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

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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

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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
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MMR/autism trend analysis
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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

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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
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GMPs, GISPs, GMPs

• good medical practices
• good immunisation services practices
• good management practices

first "do no harm principle"
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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

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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

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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

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