Preventing Fraud—7.Post-Market Surveillance and Pharmacovigilance: Continuous Monitoring and Safety

7. Post-Market Surveillance and Pharmacovigilance: Continuous Monitoring and Safety

Pharmacovigilance is defined by the World Health Organization (WHO) as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem.” It’s an ongoing process that begins before a drug is approved (with safety data from clinical trials) and continues throughout the entire time the drug is on the market.

7.A. Adverse Event Reporting Systems :

·         Purpose (Revisited): To collect and analyze reports of adverse events (AEs) associated with drugs and other medical products. This is the cornerstone of pharmacovigilance.

·         Types of Reporting (Expanded):

o    Spontaneous Reporting: Healthcare professionals, patients, and consumers voluntarily report AEs to the pharmaceutical company or regulatory authority. This is the most common source of AE reports.

§  Healthcare Professionals (HCPs): HCPs (doctors, pharmacists, nurses, etc.) are often legally required to report certain types of AEs (e.g., serious AEs, unexpected AEs).

§  Patients and Consumers: Patients and consumers can report AEs directly to the pharmaceutical company or to regulatory agencies (e.g., through the FDA’s MedWatch program in the US). Direct patient reporting is increasingly encouraged.

§  Limitations of Spontaneous Reporting:

§  Underreporting: A significant proportion of AEs are never reported.

§  Reporting Bias: Certain types of AEs are more likely to be reported than others (e.g., serious AEs, AEs associated with new drugs).

§  Incomplete Information: Spontaneous reports may be incomplete or lack critical information.

§  Difficulty Assessing Causality: It can be difficult to determine whether an AE was actually caused by the drug based on a spontaneous report alone.

o    Solicited Reporting: AEs are collected through specific programs, such as:

§  Post-Marketing Studies: Studies specifically designed to collect safety data after a drug has been approved.

§  Patient Registries: Databases that collect information about patients who are taking a particular drug or have a particular condition.

§  Patient Support Programs: Programs that provide support to patients taking a particular drug.

§  Advantages of Solicited Reporting:

§  More complete information.

§  Can target specific populations or AEs.

§  Can provide more accurate estimates of AE incidence rates.

o    Literature Reports: Identifying reports of AEs in the published scientific literature (journals, conference proceedings, etc.). Pharmaceutical companies are required to regularly review the scientific literature for AE reports related to their products.

o    Social Media and Internet Monitoring: Increasingly, companies and regulators are monitoring social media and other online sources for potential AE reports. This is a challenging area due to the volume and unstructured nature of the data.

§  Social Listening Tools: Software tools that can be used to track online conversations and identify potential AE reports.

§  Challenges:

§  Privacy Concerns: Respecting patient privacy.

§  Data Quality: The information may be unreliable or incomplete.

§  Volume of Data: The sheer volume of data can be overwhelming.

§  Distinguishing Between Real AEs and Noise: Separating genuine AE reports from casual mentions or complaints.

o    Active Surveillance: Proactively seeking out information about adverse events, rather than relying on passive reporting systems.

§  Sentinel System (US): The FDA’s Sentinel System uses electronic health data from multiple sources to actively monitor the safety of medical products.

§  Other Active Surveillance Systems: Other countries and organizations have similar active surveillance systems.

·         Reporting Pathways (Expanded):

o    Pharmaceutical Companies: Companies are legally required to collect and report AEs to regulatory authorities. They have pharmacovigilance departments responsible for this.

§  Qualified Person for Pharmacovigilance (QPPV) (EU): In the EU, each company must have a designated QPPV who is responsible for the company’s pharmacovigilance system.

o    Regulatory Authorities:

§  FDA (US): The FDA’s MedWatch program receives AE reports from healthcare professionals, patients, consumers, and manufacturers. The FDA Adverse Event Reporting System (FAERS) is the database that contains these reports.

§  EMA (Europe): The EudraVigilance database collects AE reports from EU member states and pharmaceutical companies.

§  Other Regulatory Agencies: Each country has its own regulatory agency responsible for pharmacovigilance.

o    Healthcare Professionals: HCPs can report AEs directly to the pharmaceutical company or to the regulatory authority.

o    Patients and Consumers: Patients and consumers can report AEs directly to the pharmaceutical company or to the regulatory authority.

·         Data Elements (Expanded): AE reports should include as much information as possible, including:

o    Patient Information:

§  Age (or age group)

§  Sex

§  Weight

§  Medical history (including pre-existing conditions)

§  Other medications being taken (concomitant medications)

§  Allergies

o    Drug Information:

§  Name of the drug (brand name and generic name)

§  Dose

§  Route of administration

§  Frequency of administration

§  Start date and stop date of treatment

§  Indication for use (why the drug was prescribed)

§  Batch/lot number

o    Description of the Adverse Event:

§  Detailed description of the event

§  Onset date (when the event started)

§  Severity of the event

§  Seriousness of the event (see below)

§  Actions taken (e.g., drug stopped, dose reduced, treatment given)

§  Outcome of the event (e.g., recovered, recovering, not recovered, fatal)

o    Reporter Information:

§  Name and contact information of the reporter

§  Reporter type (e.g., physician, pharmacist, patient)

o    Causality Assessment (See Below)

·         Seriousness Criteria (Important): An AE is considered serious if it meets any of the following criteria:

o    Results in death.

o    Is life-threatening.

o    Requires inpatient hospitalization or prolongation of existing hospitalization.

o    Results in persistent or significant disability/incapacity.

o    Is a congenital anomaly/birth defect.

o    Is medically significant (requires intervention to prevent one of the above outcomes).

·         Expedited Reporting Requirements: Pharmaceutical companies are required to report certain types of AEs to regulatory authorities within specific timeframes.

o    15-Day Reports (US): Serious and unexpected AEs must be reported to the FDA within 15 calendar days of the company becoming aware of the event.

o    7-Day Reports (US): In some cases (e.g. certain post-marketing studies) serious, unexpected, fatal or life-threatening events may require expedited reporting.

o    Periodic Safety Update Reports (PSURs) / Periodic Benefit-Risk Evaluation Reports (PBRERs): Companies must submit periodic reports to regulatory authorities summarizing all AEs received during a specific period. The frequency of these reports varies depending on the drug and the regulatory authority. The PBRER is the ICH-harmonized format.

·         Causality Assessment: Assessing the likelihood that the drug caused the adverse event. This is often a complex judgment based on factors such as:

o    Temporal Relationship: Did the event occur after the drug was started?

o    Dechallenge: Did the event improve when the drug was stopped?

o    Rechallenge: Did the event recur when the drug was re-started? (Rechallenge is often not ethical or feasible).

o    Alternative Explanations: Could the event be explained by other factors, such as the patient’s underlying medical condition or other medications?

o    Known Pharmacology: Is the event consistent with the known pharmacology of the drug?

o    Previous Reports: Have there been previous reports of similar events with the drug?

o    Causality Assessment Scales: Various scales are used to categorize causality (e.g., WHO-UMC causality categories: certain, probable, possible, unlikely, conditional/unclassified, unassessable/unclassifiable).

·         Coding of Adverse Events:

o    MedDRA (Medical Dictionary for Regulatory Activities): The internationally standardized medical terminology used to code adverse events. MedDRA is a hierarchical terminology, with different levels of specificity.

§  Purpose: To facilitate consistent coding and analysis of AE data across different studies and countries.

§  Structure: MedDRA is organized into five levels:

§  System Organ Class (SOC)

§  High Level Group Term (HLGT)

§  High Level Term (HLT)

§  Preferred Term (PT)

§  Lowest Level Term (LLT)

§  Example:

§  SOC: Cardiac Disorders

§  HLGT: Cardiac Arrhythmias

§  HLT: Supraventricular Arrhythmias

§  PT: Atrial Fibrillation

§  LLT: Atrial Fibrillation, paroxysmal

7.B. Signal Detection and Risk Assessment :

·         Signal Detection (Revisited): The process of identifying potential safety signals from AE reports and other data sources. A signal is defined as information that suggests a new potentially causal association, or a new aspect of a known association, between an intervention (e.g., a drug) and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify further action to verify.

·         Methods (Expanded):

o    Quantitative Methods:

§  Disproportionality Analysis: Statistical methods to identify AEs that are reported more frequently for a particular drug than would be expected based on the overall reporting frequency for that AE.

§  Proportional Reporting Ratio (PRR): A measure of the relative frequency of an AE for a specific drug compared to all other drugs in the database.

§  Reporting Odds Ratio (ROR): Another measure of disproportionality.

§  Bayesian Methods: More sophisticated statistical methods that incorporate prior knowledge and uncertainty.

§  Limitations of Disproportionality Analysis:

§  Reporting Bias: Can be affected by reporting bias.

§  Confounding: May not account for confounding factors.

§  Does Not Prove Causality: Disproportionality does not prove that the drug caused the AE.

o    Qualitative Methods:

§  Case-by-Case Review: Review of individual AE reports by pharmacovigilance professionals and medical experts. This is essential for identifying potential signals, especially for rare or unusual events.

§  Case Series Review: Review of a group of similar AE reports.

o    Data Mining: Using data mining techniques to analyze large databases of AE reports (e.g., FAERS, EudraVigilance) to identify potential signals.

§  Machine Learning: Using machine learning algorithms to identify patterns in AE data.

o    Expert Review: Review of signals by experts in pharmacovigilance and relevant medical specialties.

o    Other Data Sources:

§  Clinical Trial Data: Reviewing safety data from clinical trials.

§  Epidemiological Studies: Conducting epidemiological studies to investigate potential associations between drugs and AEs.

§  Prescription Data: Analyzing prescription data to identify potential patterns of drug use that may be associated with AEs.

§  Electronic Health Records (EHRs): Using EHR data to identify potential signals.

§  Social Media: (As described above).

·         Signal Validation: Once a signal is detected, it must be validated to determine whether it represents a true safety concern. This is a critical step.

o    Process:

§  Reviewing Additional Data: Reviewing additional data sources (e.g., clinical trial data, epidemiological studies, literature reports).

§  Collecting More Data: Collecting more data, if necessary (e.g., through targeted surveillance).

§  Expert Consultation: Consulting with external experts.

§  Causality Assessment: Assessing the likelihood that the drug caused the AE.

§  Risk Assessment (See Below): Assessing the overall risk associated with the signal.

o    Outcomes:

§  Confirmed Signal: The signal is confirmed as a true safety concern.

§  Refuted Signal: The signal is determined not to be a true safety concern.

§  Further Investigation Needed: More data or analysis is needed to determine whether the signal is valid.

·         Risk Assessment (Expanded): Evaluating the potential risks associated with a drug, based on the available evidence. This includes:

o    Severity of the Risk: How serious is the adverse event? (e.g., mild, moderate, severe, life-threatening, fatal).

o    Frequency of the Risk: How often does the adverse event occur? (e.g., very common, common, uncommon, rare, very rare).

o    Predictability of the Risk: Can the risk be predicted based on factors such as patient characteristics, dose, or duration of treatment?

o    Reversibility of the Risk: Is the adverse event reversible when the drug is stopped?

o    Preventability of the Risk: Can the risk be prevented or mitigated through measures such as dose adjustments, monitoring, or patient education?

o    Impact on Public Health: What is the overall impact of the risk on public health?

o    Benefit-Risk Balance: Weighing the benefits of the drug against its risks. This is a critical judgment.

o    Risk Factors: Identifying factors that increase the risk of the adverse event.

7.C. Risk Management Plans (RMPs) and Risk Evaluation and Mitigation Strategies (REMS) :

·         Purpose: To proactively manage the known and potential risks of a drug and to ensure that the benefits of the drug outweigh its risks.

·         Risk Management Plans (RMPs) (EU):

o    Requirement: RMPs are required for all new drugs in the European Union.

o    Contents:

§  Safety Specification: A summary of the known and potential risks of the drug.

§  Pharmacovigilance Plan: A plan for monitoring the safety of the drug after it is approved. This includes routine pharmacovigilance activities (e.g., AE reporting, signal detection) and may include additional activities, such as post-authorization safety studies (PASS).

§  Risk Minimization Measures: Measures to minimize the risks of the drug. These can include:

§  Routine Risk Minimization Measures: Measures that are part of the standard product information, such as:

§  Product labeling (summary of product characteristics (SmPC) for healthcare professionals, package leaflet for patients).

§  Restrictions on use (e.g., contraindications, warnings and precautions).

§  Additional Risk Minimization Measures: Measures that go beyond the standard product information, such as:

§  Educational materials for healthcare professionals and patients.

§  Controlled distribution systems.

§  Pregnancy prevention programs.

§  Evaluation of Effectiveness: A plan for evaluating the effectiveness of the risk minimization measures.

o    Living Document: The RMP is a “living document” that is updated throughout the lifecycle of the drug as new safety information becomes available.

·         Risk Evaluation and Mitigation Strategies (REMS) (US):

o    Requirement: The FDA can require a REMS for certain drugs with serious safety concerns. A REMS is not required for all drugs.

o    Purpose: To ensure that the benefits of a drug outweigh its risks when there are specific, serious risks that need to be managed beyond standard labeling.

o    Elements: A REMS can include one or more of the following elements:

§  Medication Guide: Patient-friendly information about the drug’s risks that must be dispensed with each prescription.

§  Communication Plan: A plan to communicate risk information to healthcare professionals (e.g., “Dear Healthcare Professional” letters, websites, educational materials).

§  Elements to Assure Safe Use (ETASU): More restrictive measures that are designed to ensure that the drug is used safely. ETASU can include:

§  Prescriber Training and Certification: Requiring healthcare professionals to have special training or certification to prescribe the drug.

§  Pharmacy Certification: Restricting dispensing of the drug to certified pharmacies.

§  Patient Enrollment: Requiring patients to enroll in a registry or monitoring program.

§  Laboratory Testing: Requiring patients to undergo specific laboratory tests before or during treatment.

§  Restricted Distribution: Restricting distribution of the drug to certain healthcare settings (e.g., hospitals).

§  Implementation System: A system for implementing and monitoring the REMS.

§  Timetable for Submission of Assessments: A schedule for assessing whether the REMS is meeting its goals.

o    Examples of Drugs with REMS: Opioid analgesics, isotretinoin (for severe acne), clozapine (for schizophrenia).

·         Differences Between RMPs and REMS:

o    RMPs are required for all new medicines in the EU, while REMS are only required for certain drugs in the US with identified serious risks.

o    RMPs are generally broader in scope, encompassing routine pharmacovigilance and risk minimization.

o    REMS tend to focus on specific, serious risks and often include more restrictive measures (ETASU).

7.D. Post-Market Studies and Surveillance :

·         Purpose (Revisited): To gather additional information about a drug’s safety and efficacy after it has been approved, particularly in real-world settings and over longer periods of time.

·         Types of Studies (Expanded):

o    Phase IV Clinical Trials: Studies conducted after a drug has been approved. These can be:

§  Interventional Studies: Studies where the investigator assigns patients to specific treatments (similar to pre-approval clinical trials).

§  Non-Interventional Studies (Observational Studies): Studies that observe patients in real-world settings, without intervening in their treatment.

o    Observational Studies (Expanded):

§  Cohort Studies: Follow a group of patients (a cohort) over time to see who develops a particular outcome (e.g., an adverse event).

§  Prospective Cohort Studies: Patients are enrolled before the outcome of interest occurs.

§  Retrospective Cohort Studies: Patients are identified after the outcome of interest has occurred, and data is collected from existing records.

§  Case-Control Studies: Compare patients who have a particular outcome (cases) to patients who do not have the outcome (controls) to identify factors that may be associated with the outcome.

§  Cross-Sectional Studies: Collect data from a population at a single point in time.

§  Advantages of Observational Studies:

§  Can study larger and more diverse populations than clinical trials.

§  Can study longer-term effects.

§  Can study rare events.

§  Can reflect real-world use of the drug.

§  Limitations of Observational Studies:

§  Confounding: Difficult to control for confounding factors (factors that are associated with both the drug and the outcome).

§  Bias: Susceptible to various types of bias.

§  Cannot Prove Causality: Observational studies can only show associations, not prove causality.

o    Registries: Databases that collect information about patients who are taking a particular drug or have a particular condition.

§  Purpose: To track long-term outcomes, identify rare events, and assess the effectiveness of treatments in real-world settings.

§  Types:

§  Product Registries: Collect information about patients taking a specific drug.

§  Disease Registries: Collect information about patients with a specific disease.

o    Active Surveillance (Detailed Above): Proactively seeking out safety data.

·         Regulatory Requirements: Regulatory agencies may require companies to conduct post-market studies as a condition of approval or to address specific safety concerns.

o    Post-Authorization Safety Studies (PASS) (EU): Studies that are required by the EMA as a condition of marketing authorization.

o    Postmarketing Requirements (PMRs) (US): Studies and clinical trials that sponsors are required to conduct after approval.

o    Postmarketing Commitments (PMCs) (US): Studies or clinical trials that a sponsor has agreed to conduct, but are not legally required.

7.E. Communication of Safety Information to Healthcare Professionals and Patients :

·         Importance (Revisited): Timely and effective communication of new safety information is essential to protect public health.

·         Methods (Expanded):

o    “Dear Healthcare Professional” Letters (DHCP Letters): Letters sent directly to healthcare professionals to inform them of important new safety information, such as:

§  New warnings or precautions.

§  Changes to the dosage or administration of the drug.

§  New contraindications.

§  New adverse reactions.

§  Product recalls.

§  These are often required by regulatory agencies.

o    Product Labeling Updates: Updating the drug’s prescribing information (package insert) to reflect new safety information. This is a critical mechanism for communicating safety information.

§  Summary of Product Characteristics (SmPC) (EU): The equivalent of the prescribing information in Europe.

§  Package Leaflet (EU): Patient-friendly information that is included with the drug packaging.

§  Medication Guides (US): Patient-friendly information about specific drugs with serious risks (required for some drugs as part of a REMS).

o    Public Health Alerts: Issuing public health alerts or advisories to inform the public about serious safety concerns. This is typically done by regulatory agencies.

o    Websites and Social Media: Using websites and social media to communicate safety information to healthcare professionals and patients.

o    Medical Journals and Conferences: Publishing safety information in medical journals and presenting it at scientific conferences.

o    Continuing Medical Education (CME): Providing CME programs for healthcare professionals on drug safety.

o    Direct Patient Communication: In some cases, companies may communicate directly with patients about safety concerns (e.g., through letters, phone calls, or websites). This is often done in the context of a product recall or a REMS.

o    Risk Communication Plans: Developing comprehensive plans for communicating safety information to different audiences.

·         Principles (Expanded):

o    Accuracy: Information must be accurate and based on the best available scientific evidence.

o    Clarity: Information must be clear, concise, and understandable to the target audience (healthcare professionals vs. patients).

o    Timeliness: Information must be communicated in a timely manner, especially for serious safety concerns.

o    Transparency: The source of the information and any potential conflicts of interest should be disclosed.

o    Objectivity: Information should be presented objectively, without minimizing or exaggerating risks.

o    Accessibility: Information should be readily accessible to those who need it.

o    Targeted Communication: Tailoring the communication to the specific audience (healthcare professionals vs. patients) and using appropriate channels.

o    Completeness: Providing all relevant information, including the nature of the risk, the frequency of the risk, and any actions that should be taken.

o    Consistency: Providing consistent messages across different communication channels.

7.F. Product Recalls and Withdrawals :

·         Recall (Revisited): The removal of a drug product from the market due to a safety concern or a violation of regulations. Recalls can be voluntary (initiated by the company) or mandatory (ordered by a regulatory agency).

·         Withdrawal (Revisited): The permanent removal of a drug product from the market, usually due to a serious safety concern.

·         Reasons for Recalls/Withdrawals (Expanded):

o    Manufacturing Defects: Problems with the manufacturing process that could affect the quality, safety, or efficacy of the drug.

§  Contamination (microbial, chemical, or particulate).

§  Incorrect ingredients or dosages.

§  Subpotent or superpotent product.

§  Defective packaging.

o    Labeling Errors: Incorrect or misleading information on the product label.

o    Unexpected Adverse Events: Serious adverse events that were not identified during clinical trials.

o    Failure to Meet Specifications: The product does not meet its pre-defined quality specifications.

o    Stability Issues: The product degrades or loses potency faster than expected.

·         Classification of Recalls (FDA – Expanded):

o    Class I: A situation in which there is a reasonable probability that the use of or exposure to a violative product will cause serious adverse health consequences or death. This is the most serious type of recall.

o    Class II: A situation in which use of or exposure to a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote.

o    Class III: A situation in which use of or exposure to a violative product is not likely to cause adverse health consequences.

·         Recall Procedures (Expanded): Companies must have detailed, written procedures in place for conducting product recalls. These procedures should cover:

o    Decision-Making: A clear process for deciding whether to initiate a recall.

o    Notification of Regulatory Authorities: Promptly notifying the relevant regulatory agency (e.g., FDA, EMA) of the recall.

§  Required Information: Providing the regulatory agency with detailed information about the recall, including:

§  The product name and description.

§  The reason for the recall.

§  The batch/lot numbers affected.

§  The distribution of the product.

§  The level of the recall (e.g., wholesale, retail, consumer).

§  The company’s recall strategy.

o    Notification of Distributors and Customers: Promptly notifying distributors, wholesalers, pharmacies, hospitals, and other customers who may have received the recalled product.

§  Recall Notices: Issuing recall notices that provide clear instructions on what to do with the recalled product.

§  Multiple Channels: Using multiple channels to communicate the recall (e.g., letters, phone calls, emails, websites, social media).

o    Retrieval of the Recalled Product: Implementing procedures for retrieving the recalled product from the market.

§  Return Instructions: Providing clear instructions on how to return the recalled product.

§  Reimbursement: Providing reimbursement for the returned product.

o    Investigation: Thoroughly investigating the cause of the recall.

§  Root Cause Analysis: Identifying the root cause of the problem.

o    Corrective and Preventive Actions (CAPA): Implementing corrective and preventive actions to prevent the problem from recurring.

o    Documentation: Maintaining detailed records of all aspects of the recall, including:

§  The decision-making process.

§  Notifications to regulatory authorities and customers.

§  Retrieval of the recalled product.

§  The investigation.

§  Corrective and preventive actions.

o    Effectiveness Checks: Verifying the effectiveness of the recall (i.e., ensuring that the recalled product has been removed from the market).

o    Public Notification: In some cases, particularly for Class I recalls, public notification may be necessary (e.g., through press releases, public service announcements).

·         Mock Recalls: Companies should conduct periodic mock recalls to test their recall procedures and ensure that they are effective.

7.G. Global Collaboration and Information Sharing :

·         Importance (Revisited): Pharmacovigilance is a global effort. Adverse events can occur anywhere in the world, and information sharing is essential for identifying and managing safety concerns.

·         International Organizations (Expanded):

o    World Health Organization (WHO):

§  WHO Programme for International Drug Monitoring: Collects and analyzes AE reports from countries around the world. The Uppsala Monitoring Centre (UMC) in Sweden is the collaborating center for this program.

§  VigiBase: The WHO’s global database of individual case safety reports (ICSRs).

o    International Council for Harmonisation (ICH): Develops guidelines for pharmacovigilance, including guidelines on:

§  AE reporting (E2A, E2B, E2D)

§  Risk management (E2E)

§  Periodic benefit-risk evaluation reports (PBRERs) (E2C)

§  Clinical safety data management (E2F)

o    Council for International Organizations of Medical Sciences (CIOMS): CIOMS working groups develop guidance on various aspects of pharmacovigilance.

·         Information Sharing (Expanded): Regulatory agencies and pharmaceutical companies share information about adverse events and safety concerns through various mechanisms, including:

o    Databases: Sharing data through databases such as EudraVigilance (EMA), VigiBase (WHO), and FAERS (FDA).

o    Rapid Alert Systems: Systems for rapidly communicating urgent safety information (e.g., new serious adverse events, product recalls).

o    Joint Inspections and Audits: Regulatory agencies conducting joint inspections and audits of pharmaceutical companies.

o    Conferences and Meetings: Sharing information and best practices at international conferences and meetings.

o    Bilateral Agreements: Agreements between regulatory agencies in different countries to share information.

o    Information Exchange Standards: Using standardized formats for exchanging pharmacovigilance data (e.g., E2B format for ICSRs).

Pharmacovigilance is a continuous, evolving, and essential process for ensuring the safe use of medicines. It requires a robust system for collecting and analyzing AE reports, detecting and validating safety signals, assessing risks, implementing risk minimization measures, and communicating safety information to healthcare professionals and patients. Global collaboration and information sharing are crucial for effective pharmacovigilance. The ultimate goal is to protect public health by minimizing the risks associated with medicines while maximizing their benefits.