Pharmacovigilance Notes

UT5: Pharmacologie Clinique - Pharmacovigilance

Introduction

Pharmacovigilance (PV) is crucial for monitoring the safety of medications after they are released to the market. This set of notes will cover the definition, history, objectives, scope, actors, organization, and methodology of PV.

Historical context

• 1959: Thalidomide scandal.
• 1971-1977: Distilbene® (diethylstilbestrol) affair.
• 1975: Bismuth salts issue.
• 1963: WHO encouraged member states to report adverse drug reactions.
• 1968: Creation of the WHO Drug Monitoring Center in Washington (later Geneva in 1970 and Uppsala in Sweden in 1978).
• 1972: In France, creation of hospital PV centers, followed by the CNPV in 1972, and CRPV in 1982.
• In Algeria: Decree n° 98-192 of June 3, 1998, concerning the establishment, organization, and operation of the CNPM.

Definition of Pharmacovigilance

Pharmacovigilance is defined as the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problem, according to the WHO. It involves:

• Signaling
• Evaluation
• Study
• Implementation of actions

Objectives of Pharmacovigilance

• Early detection of new adverse drug reactions (ADRs).
• Establishing the frequency of ADRs.
• Identifying risk factors.
• Understanding the mechanisms and studying the consequences of ADRs.
• Implementing necessary corrective measures.

Scope of Application

PV applies to:

• Medications and healthcare products for human use with a Market Authorization (AMM) or under ATU (Temporary Authorization for Use):
  • Pharmaceutical specialties
  • Magistral and hospital preparations
  • Officinal preparations
  • Immunological medications (allergens, vaccines, serum, etc.)
  • Gene therapy products
  • Radiopharmaceuticals
  • Homeopathic medications
  • Certain dietary products

Related vigilance:

• Materiovigilance: Medical devices
• Hemovigilance: Labile blood products
• Biovigilance: Organs for transplantation
• Reactovigilance: Reagents
• Cosmetovigilance: Cosmetic products

Application of the PV System

PV applies to:

• Normal Use
• Pregnancy and breastfeeding
• Intoxication
• Dependence, tolerance, or resistance
• Drug interactions
• Misuse
• Therapeutic errors and failures
• Poor quality or counterfeiting
• Poor information

Actors in Pharmacovigilance

• Pharmaceutical Industry
• Ministry of Health (Norms, procedures, authorization, withdrawal, control, inspection).
• WHO/UMC (Uppsala)
• Patients (Report adverse effects).
• Healthcare Professionals (Notify adverse effects).
• Pharmacovigilance Centers (Monitor the impact, evaluate risk, alert, and inform).

Organization of PV and Methodology

The PV system is organized with:

• Minister
• National PV Commission
• Technical Committee
• CRPV (Regional Pharmacovigilance Centers)
• EMEA (European Medicines Agency)
• Industry

Role of the Technical Committee & National Commission

• Technical Committee: Analyzes collected information, monitors/investigates, evaluates risk, and issues opinions/proposes measures.
• National Commission: Makes decisions based on the committee's proposals.

Methodology for Signal Detection

Notification

Voluntary reporting of an adverse event that may be related to one or more medications. Reporting to a pharmacovigilance structure. Example: CRPV.

Recueil Orienté (Oriented Collection)

Structured surveys based on specific objectives, focusing on a particular medication, pathology, or population.

Data Collection and Notification

• Notifiers: Doctors, Pharmacists, Dentists, Midwives, Pharmaceutical Industry.
• Reportable Information: Any serious adverse reaction, unexpected effect, or relevant effect outside these definitions.
• Reporting Time: Immediately for serious or unexpected effects, no specific deadline for others.
• Reporting Methods: Declaration forms, email, or phone. CNPM uses a yellow form.

Types of Adverse Effects

Serious Adverse Effect (EI Grave)

• Lethal
• Life-threatening
• Causes significant or lasting disability or incapacity
• Causes or prolongs hospitalization
• Congenital anomaly or malformation

Expected Adverse Effect (EI Attendu - Type A)

• Listed in the Summary of Product Characteristics (RCP).
• Related to pharmacological properties.
• Dose-dependent.
• Impacted by pharmacokinetics and interactions.

Unexpected Adverse Effect (EI Inattendu - Type B)

• Not mentioned in the RCP.
• Unpredictable.
• Not dose-related.
• Rare.
• May reveal risk factors.

Essential Information for Reporting

• Notifier Identification
• Patient Identification
• Medication Information
• Description of the Adverse Effect

All information is sent to the Regional Pharmacovigilance Center (CRPV).

PV activities

• The PV follow-up: specific monitoring of the product's tolerance profile put on the market, during the first years, or even during its entire market life
• The PV survey: re-evaluate the risk of a drug or product following an alert (national or international)

Steps in a Pharmacovigilance Investigation

1. Designation of a rapporteur is responsible for conducting the investigation among the CRPVs.
2. Delimitation of the investigation:
   • Identification of notifications to the basis of the signal and determination of the urgent character of the signal (if the signal seems to pose serious and immediate risks to the population of sick people aimed at, preventive measures can be taken Immediately) determination of the duration of the investigation and the extent of the field ofInvestigation
3. Validation of the signal
4. Documentary research
5. Imputation (corresponding to the case-by-case analysis of the causal link between taking a drug and the occurrence of an undesirable effect
6. Analysis and Conclusion
7. Structure of the final report
8. Government consultation / Industry
9. Measures taken by the Agency:
   • «Voluntary» measure in agreement with the Industry, «compulsory» in disagreement with the Industry.

Causality Assessment (Imputabilité)

• The probability of a cause-and-effect relationship between drug administration and the adverse effect.
• Useful information elements:
  • Semiological criteria.
  • Chronological and evolutionary criteria.
  • Other: history of the same nature with the same drug or a related drug, frequency and notoriety of the accident.

Intrinsic and Extrinsic Imputability

• Intrinsic Imputability: Information available in the evaluated clinical case (Score d'informativité).
• Extrinsic Imputability: Bibliographic knowledge.

Level of Informativity

For each pair IE / drug

• a = Time of onset of adverse effect compared to the period of exposure to the drug
• b = Notion of stopping or continuing the drug or changing the dose
  • If a and b are informed = NI 2
  • If a or (exclusive) b is informed = NI 1
  • If neither a nor b is informed = NI 0

Chronological Criteria:

Administration of the drug => Time of onset of the effect => Re-administration of the drug => Evolution of the effect

• Imputabilité intrinsèque
  • Suggestive R(+) R(0) R(-)
  • Compatible R(+) R(0) R(-)
  • Incompatible R(+) R(0) R(-)
• Evolution of the effect:
  • << Suggestive >>: Regression of the effect when the drug is stopped with or without symptomatic treatment (with sufficient hindsight and taking into account the pharmacokinetic or pharmacodynamic characteristics of the drug) or when the dose is reduced for a dose-dependent effect.
  • << Non conclusive >>
    • Irreversible injuries or death
    • Unknown evolution
    • Insufficient fall after stopping the drug
    • Persistence of the effect and drug not stopped
    • Persistence of the effect after single administration
  • <>
    • Absence of regression of reversible-type manifestations despite stopping with sufficient hindsight.
    • Complete regression despite continuing the drug.

Examples of Onset Time for Cutaneous Reactions

Semiological Criteria

Score table to follow in the next entries

Bibliographic Data Analysis

• B4: Expected effect: effect whose nature, severity, intensity and evolution correspond to the information described in the summary of product characteristics (RCP)
• B3: Effect referenced or widely published with this drug in reference books (Martindale: the extra pharmacopoeia, Meyler’s side effects of drugs) and/or databases (Embase, Excerpta Medica, Medline…)
• B2: Effect published once or twice in a scientific journal or in a database (with a relatively different semiology or published with another drug in the same pharmacological and/or chemical class or purely experimental data)
• B1: Effect not published in accordance with the definitions of B3 or B2.

Risk Evaluation

Evaluation of Risk and Proposed Measures

Possible Measures Following Risk Evaluation

• Modify the Marketing Authorization (AMM) by adding a contraindication, an adverse effect, a warning, or a precaution for use.
• List the substance as a poisonous substance or change its listing.
• Restrict prescription and use.
• Re-evaluate the benefit/risk ratio.
• Suspend or withdraw the Marketing Authorization.

Example: COX-2 Inhibitors

• AINS: Selective COX-2 inhibitor
• Treatment: Osteoarthritis, acute pain, dysmenorrhea.
• Effects: Increased risk of heart attack
• FDA Study: 27,785 deaths.
• APPROVE Study: 2600 patients, compared to a placebo, duration: 3 years.
• Market Withdrawal: 2004

Conclusion

Pharmacovigilance aims to:

• Reduce the consequences and costs associated with medications.
• Improve clinical practice.
• Promote rational drug use.
• Participate in research and training.

Mathematical Expressions

While the transcript doesn't provide specific equations, here are some general examples of how mathematical expressions would be represented in LaTeX:

• Basic arithmetic: (2 + 2 = 4)
• Square root: (\sqrt{9} = 3)
• A more complex equation: (E = mc^2)