Pharmacovigilance and Drug Development

• FIFARMA focuses on Good Pharmacovigilance Practices

Life cycle of medicines

• Discovery Basic Research takes 4 to 5 years and has an average of 10,000 compounds
• Pre-clinical Development takes 6 to 8 years with a range of 30-250 compounds
• Clinical Development Phases I, II, III, IV take 1 to 2 years using 5 compounds
• Registration and Marketing take 1 to 2 years using only 1 medicine

Clinical drug development Stages

• Stage I: 20-50 healthy volunteers are used for preliminary data collection
• Stage II: 150-350 patients are used to define safety and dosage recommendations
• Stage III: 250-4000 patients in more heterogeneous groups are used to determine short-term safety and efficiency
• Stage IV: Post-approval studies are conducted on selected safety issues

Concept of Pharmacovigilance

• The WHO defines it as science and activities relating to the detection, assessment, understanding, and prevention of adverse effects, and any other medicine/vaccine related problem

Pharmacovigilance Objectives

• Ensure the care and safety of patients in relation to the use of medicines and all medical interventions
• Improve public health and safety in the use of medicines
• Detect problems related to medication use and communicate findings in a timely manner
• Contribute to the evaluation of the benefits, harms, effectiveness and risks of medicines
• Encourage the use of medicines in a safe, rational and more efficient manner
• Promote understanding, education and clinical training in pharmacovigilance

Methodology of Pharmacovigilance

• Spontaneous notification system: identifies and detects suspected adverse reactions by healthcare professionals, done via the WHO International Pharmacovigilance Program
• Procedimientos de farmacovigilancia intensiva: systematic collection of data on harmful effects induced by drugs
  • Divided into drug-centered, and patient-centered systems
• Epidemiological studies test hypotheses to find causality between adverse reactions to drugs, including: cohort studies, and case and control studies

General Principles

• Good Pharmacovigilance Practices are a quality standard for monitoring the safety of medicines
  • This ensures the veracity of the data collected
  • This ensures the confidentiality of reporters and patients
  • This ensures use of uniform criteria for evaluation of notifications and generation of signals or alerts

General information regarding Pharmacovigilance system:

• It is necessary to implement quality management methods to comply and improve practices
• The quality system shall include organizational structure, responsibilities, procedures, processes, resource management, compliance and record keeping

Procedures for practices clarify and unify information on:

• Which events are notifiable
• Who should notify an observation of suspected drug-related problems
• How to fill out notification forms
• Guidelines for the submission and collection of information
• Guidance for the evaluation, follow-up and processing of case notifications to the corresponding institutions
• How to analyze information and possible courses of action
• Good communication practices
• How measure progress of the monitoring system

Countries with manuals for Pharmacovigilance Practice,

• Argentina
• Peru
• PAHO

Pharmacovigilance Center

• The development from initial state to effective organization requires time, vision, dedication, competence and continuity

Documentation is essential for the quality assurance system and good pharmacovigilance practices.

• Notifications can generate signals and their quality is decisive for an appropriate assessment of causality between the drug and the adverse events
• Documented items would include handbooks, notifications, and procedures

Ensure good pharmacovigilance practices and documentation with these characteristics:

• Designed, developed, reviewed and distributed according to its functionality
• Approved, signed and dated
• Unambiguous wording
• Clear and legible documents
• Periodic review and updating

Handbooks

Quality

• Describes the objectives, means and procedures for quality assurance.

Procedures

• It brings together in an orderly and logical manner the standard operating procedures used in the operation and describes the interrelationship between them.

Procedures of documentation of a quality assurance system are defined as:

• Detailed, written instructions for achieving uniformity
• Form the basis for internal or external audits.
• They should describe collection/transmission of safety information, administrative activities, and notification evaluation/reporting

Procedures are identified with:

• Name of procedure
• Name and signature of author/approver
• Code and date of editing
• Name and signature of QC
• Related procedures
• Target staff

Computerized systems should be:

• Validated
• Regular backups
• List of authorized personnel
• Ensure traceability of information
• Periodic quality controls

Management of notifications

• Evaluates notifications from health professionals
• Requests complementary information when they are not physicians
• Contacts the health professionals when it comes from the patient

Minimum information to be considered valid (NPDR):

• Data from patient
• Description of the adverse event
• Suspect drug data
• Notifier data

Complete notification information should include:

• Concomitant Medications
• Risk factors
• Event Diagnostics
• Clinical evolution and results
• Determinations from laboratories
• Exposure and re-exposure information
• Any other relevant information
• Procedures should be made to encourage notification.

Coding and Processing Systems include

• Manual: use when there are few cases
• Computerized including a hierarchical finding of drugs allowing classification by generic component, trade name and therapeutic category, and reactions classified adverse reactions.

Form of sending notifications:

• Mail, fax and telephone
• E-mail or Internet: use systematic processing (e-Reporting/E2B)

Improve notification by:

• Facilitate access to reporting media, like forms, e-mail or a website
• Acknowledge receipt of notification -Provide feedback to notificators
• Stimulate participation of the centers' personnel in scientific meetings or educational courses
• Collaborate with local pharmacovigilance or drug committees and professional associations
• Integrate pharmacovigilance in the development of clinical pharmacy and clinical pharmacology in the country

Codification should:

• Coding categories and terminologies adopted in international regulatory forums
• Be established in the corresponding manual.
• Control data quality to detect systematic errors in data entry and coding
• Allow protection of the identity of both the notificator, patient, and the event
• Ensure the completeness, accuracy, fiability, consistency and confidentiality of all information
• Record the date of receipt and assign an identification number to each notification
• Adverse reaction terminology for drugs should be WHO or MedDRA.

Database review should be:

• Local databases - and those of each institution should be linked to those compiling regional and global information
• Documents related to the same notification of a suspected adverse reaction should be kept in the same file
• Ensure the security and confidentiality of the informatio

Points used in Evaluation of Notifications:

• Quality of information
• Codification
• Determine importance: new medicine? Unknown reaction? Serious reaction?
• Identification of duplicated notifications
• Causality assessment: temporal relationship, medical or pharmacological plausibility and probability or exclusion of other causes

Evaluation of Causality factors:

• Is there an alternative explanation for the observed reaction?
• Were other medications not cited on the notification card administered?
• Is it certain that the patient took the medication as directed?
• Had the patient previously taken this drug or another analog?
• How many cases of this new reaction have been notified to the regional center, national center or UMC?
• Is there a temporal relationship between taking the drug and the occurrence of the adverse reaction?
• Take into consideration that in some countries algorithm for causality assessment. Such as the Naranjo Algorithm - WHO Algorithm - FDA Algorithm - FDA Algorithm

Sponsor Pharmacovigilance in Clinical Trials should:

• Be Responsible for the continuous evaluation of the safety of the products under investigation
• Promptly notify interested institutions and investigators and the regulatory authority of findings that could adversely affect the safety of subjects under study
• Notify all serious and unexpected adverse drug reactions, along with all periodic safety updates and reports

Local Regulation in Clinical Trials:

• Establish in detail the deadlines for notification
• Notifications of clinical studies should be handled or identified separately from those of marketed products