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Pharmacovigilance overview
- 2. •What is pharmacovigilance •Pharmacovigilance center in India •History of Pharmacovigilance •Who reports •What to report •How it is categorized •Reporting methods •Reporting timings •Flow of data •Methods to assessment( scales/ algorithms) •Data mining/ software used •MedDRA •Discussion •conclusion
- 3. The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem a • Hippocrates’ admonition. • “First, do no harm” Humanitarian concerns Check if drugs on the market fulfill their intended role in society i.e. if resources spent on drugs produce optimal results in terms of benefits Economical concerns Why pharmacovigilance? World Health Organisation
- 4. Drugs withdrawn from Market due to severe ADR Drug ADR Company Year Rofecoxib Myocardial infarction Merck 2004 Cerivastatin Rhabdomyolysis Bayer 2001 Cisapride Cardiac arrythmia J&J 2000 Astemizole Cardiac arrythmia J&J 1999 Bromfenac Liver toxicity Wyeth 1998
- 5. WHO ALL ARE INVOLVED Regulatory authorities Animal owner Veteran Drug company Social service personal Doctor/ dentist/ health professional Consumer
- 6. The problem of ADRs Account for 5% of all hospital admissions. Occur in 10-20% of hospital inpatients. Cause death in 0.1% of medical and 0.01% of surgical inpatients. Adversely effect patients quality of life. Cause patients to lose confidence in their doctors. Increase costs of patients care.
- 7. What to report: ADVERSE EVENT-1 Any unfavorable, unintended sign, symptom, illness or experience (untoward medical occurrence) that develops or worsens in a subject during the period of observation (defined by protocol) « Adverse event » does not imply causal relationship with the study medication • Abnormal results of diagnostic procedures, including laboratory findings considered by investigator to be of clinical relevance, are considered to be adverse events
- 8. ADVERSE DRUG REACTION “A noxious and unintended response at doses normally used for prophylaxis, diagnosis, or therapy of diseases, or for the modification of physiological function.” All ADRs are AEs……. but all AEs are NOT ADRs
- 9. SAE results in death is life threatening requires inpatient hospitalisation or prolongation of existing hospitalisation results in persistent or significant disability/incapacity is a congenital anomaly/birth defect is important medical event
- 10. WHAT IS NOT AN AE/SAE? Surgical Procedures They are therapeutic measures of a condition requiring surgery They are not AEs/SAEs per se; The condition for which the surgery is performed, may be an AE/SAE which has to be reported Surgical procedures planned prior to randomization and conditions leading to these measures are not adverse events (medical history) An Unexpected ADR An ADR whose nature, intensity or incidence falls outside the information provided in • the Investigator’s Brochure • the Package Insert or Product Monograph of a marketed drug
- 11. Adverse Event Intensity Seriousness Expectedness •Mild •Moderate • Severe •Serious •Non serious •Expected •Unexpected •Related •Un-related Relatedness DIMENSIONS OF AN ADVERSE EVENT
- 12. OUTCOME OF AN AE & FOLLOW UPS Complete recovery Ongoing Recovered with sequelae Unknown Death
- 13. CAUSAL ASSESSMENT – WHO ALGORITHM •Certain •Probable •Possible •Unlikely •Unclassifiable REPORTING METHOD & SYSTEM Medwatch Yellow Card ADR form
- 14. THE MINIMUM CRITERIA FOR A VALID ADR REPORT* Identifiable patient A suspect drug An adverse event Identifiable Reporter ICH / CIOMS (Centre for international organization of Medical Science) group V working recommend
- 15. ADR FORM I. Reaction Information II. Suspect Drug III. Concomitant Drugs & History IV. Manufacture’s Information
- 16. LAWS, REGULATIONS AND GUIDELINES Schedule Y requirements ICH guidelines International regulations (US FDA)
- 17. 12/17/2015 17 Adv.Event DCGI Sponsor within 14 calendar days SeriousNon -Serious Record in CRF Record in CRF SUSAR / U.SAE Report EXPEDITEDLY Global Team HQ PIs / ECs DSMB EC immediately / within 24 hours/ within 7 calendar days Safety Review Safety Profile Update
- 18. CURRENT US FDA REGULATIONS Safety reporting requirements are specified in Title 21, Code of Federal Regulations: Part 310.305 Old Drugs (marketed pre-1938) Part 312.302 Safety reporting from INDs Part 314.80 Marketed drugs Part 314.98 Generic drugs Part 600.80 Therapeutic Biologic products
- 19. ICH-GCP GUIDELINES - III E2A Expedited clinical safety reporting E2B Safety reporting data elements spec’s E2B(M) Data Elements for Electronic submission E2C & E2C Addendum – PSURs E2D Post-marketing expedited reporting standard E2E Pharmacovigilance planning
- 20. The post marketing surveillance may comprise of one of the following; Phase IV Clinical Trials PMS Studies Observation al Studies Registries Prescription Event Monitoring Spontaneou s reporting
- 21. AIMS OF POST MARKETING SURVEILLANCE Expose more patients to confirm and better understand safety of new molecule (delayed effects, prolonged use effects. Evaluation in unexposed population (children, pregnant women, nursing mothers, elderly, immuno-suppressed) Identification of risk groups Occurrence of rare and serious ADRs Assessment of costs of ADRs to various sectors of the society
- 22. SPONTANEOUS REPORT “An unsolicited communication to a company, regulatory authority or other organization that describes an adverse drug reaction in a patient given one or more medicinal products and which does not derive from a study or any organized data collection scheme is called “Spontaneous Report”. Strengths Cornerstone of ‘PV’ Cheap & Easy Encompass all clinical settings Life-time span Detection of rare ADRs Weaknesses Underreporting Quality of reporting No denominator Subject to bias Delayed effects go undetected
- 23. Its a formal, structured update of the worldwide safety experience for a registered medicinal product (per ICH E2C standards), prepared for submission to regulatory authorities at defined times post-authorization PSUR- PERIODIC SAFETY UPDATE REPORTS
- 24. PERIODIC SAFETY UPDATE REPORTS • New safety information from appropriate sources. 1 • Data to patient exposure. • Summarizes the market authorization status in different countries. • Create periodically the opportunity for an overall safety re- evaluation. • Indicate whether changes should be made to product information.
- 25. REPORTING TIMINGS Schedule Y (Indian) EU Requirements US Requirements o Only ‘New Drug’ o Six Monthly – first 2 years o Annual – subsequent 2 years o To be submitted within 30 calendar days o Even if not marketed o Six Monthly – first 2 years o Annual – subsequent 2 years o At the first renewal, and then o 5-yearly at renewal thereafter o One PSUR for each active substance o To be submitted within 60 days of last data lock o Pre-Approval PSUR – 4 months after application o Post Approval for each approved NDA/ANDA/BLA o Quarterly– for first 3 years o Then annual interval / on request o Within 30 days of the close of quarter o Annual reports within 60 days
- 26. THE FLOW Data Evaluation Database Signal Detection & Evaluation R / B Evaluation Decision MakingCommunication Data Collection
- 27. PV SOFTWARES & DATABASE 1. Intranet / Internet based 2. Restricted Access 3. Level privileges 4. MedDRA / WHO integrated 5. Company Product Library 6. Time bound process 7. QBS 8. Signal generation 9. Report generation 10.Electronic submissions 1. ArgusAERS (US FDA) 2. Eudravigilance (EMEA) 3. ARIS global 4. Clint race 5. Oracle
- 28. MedDRA MedDRA is a clinically-validated international medical terminology used by regulatory authorities and the regulated biopharmaceutical industry. The terminology is used through the entire regulatory process, from pre-marketing to post-marketing, and for data entry, retrieval, evaluation, and presentation.” Med DRA: medical Dictionary for Regulatory Activities
- 30. MedDRA - Structure SOC – System Organ class HLGT – High Level Group Term HLT – High Level Term PT – Preferred Term LLT - Low Level Term
- 31. The Gains from PV Database • Patient’s safety & care • Dissemination of information to all concerned • Regulatory compliance • Detection of new safety issues • Changes in design / documents • Ongoing safety review • Regulatory actions
- 32. ADR detection Subjective report Objective report patient complaint Direct observation of event abnormal findings physical exam Laboratory test Diagnostic procedure
- 33. NARANJO's ALGORITHM Question Yes No Don't know Are there previous conclusion reports on this reaction? +1 0 0 Did the adverse event appear after the suspect drug was administered? +2 -1 0 Did the AR improve when the drug was discontinued or a specific antagonist was administered? +1 0 0 Did the AR reappear when drug was re administered? +2 -1 0 Are there alternate causes [other than the drug] that could solely have caused the reaction? -1 +2 0 Did the reaction reappear when a placebo was given? -1 +1 0
- 34. NARANJO's ALGORITHM Question Yes No Don’t know Was the drug detected in the blood [or other fluids] in a concentration known to be toxic? +1 0 0 Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 0 0 Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1 0 0 Was the adverse event confirmed by objective evidence? +1 0 0
- 36. Other methods Irey’s method Karch and Lasanga’s Method Blanc et al’s method Kramer et al’s method FDA(Jones Method) Emmanuel and Sacchetti’s method The French Method Stephen’s personal scoring method Venulet et al’s method Spanish quantitative imputation scale
- 37. Methods of assessment Expert judgment/global introspection Algorithms Probabilistic methods (Bayesian approaches) Three broad categories
- 38. Methods of assessment Expert judgments(global introspection): They are individual assessments based on previous knowledge and experience in the field. Algorithms : Are sets of specific questions with associated scores for calculating the likelihood of a cause-effect relationship. Bayesian approaches: use specific findings in a case to transform the prior estimate of probability into a posterior estimate of probability of drug causation
- 40. Drawbacks
- 41. Which method to use? Naranjo WHO Widely used
- 42. WHO v/s Naranjo