Preview Pages of a Practical Guide on Pharmacovigilance for Beginners

A Practical Guide on Pharmacovigilance for Beginners

First Edition

A PRACTICAL GUIDE ON

PHARMACOVIGILANCE FOR

BEGINNERS

DR.S.GUNASAKARAN, MBBS, MD R.SATHEESH KUMAR, M.PHARM


A Practical Guide on Pharmacovigilance for Beginners First Edition, 2010

Copyright © Gunasakaran & Satheesh kumar, 2010. All rights reserved. No part of this publication may be reproduced or distributed in any form or by any means (electronic, mechanical, photocopying, recording or otherwise), or stored in a database or retrieval system, without the written permission from the authors. The authors have made a conscientious effort to ensure that the information contained in this book is accurate and in accordance with the accepted standards at the time of publication. However, in this rapidly changing world guidelines and practices are subject to change without prior notification, therefore readers are advised to confirm these as and when required. Rs. 250 (INR) Printed in India Printed at:


PPRREEFFAACCEE

The Authors are pleased to present the First edition of “A Practical Guide on Pharmacovigilance for Beginners”. This book is sketched to provide a concise introduction along with practical applications of pharmacovigilance that medical students, post graduates in pharmacology, pharmacy students and life science graduates can impart during their academics as well as during their industrial exposures. This book is expected to provide basic knowledge about the different aspects concerning adverse event reporting and will be an eye opener for beginners who step into the field of pharmacovigilance. This book details the global and domestic aspects of pharmacovigilance, various drug regulatory bodies guidelines governing the pharmacovigilance, and different reporting systems prevailing among various regulatory agencies along with detailed description of the standard terminologies used in the field of pharmacovigilance. It also covers interesting case scenarios to ignite the minds of bibliomaniacs – the future critiques of this book. Each chapter is thoughtfully developed to help the reader understand the fundamentals of pharmacovigilance. We are greatly honor-bound to our colleagues who showed interests, encouragement & enthusiasm by devoting their precious time in shape the dream into reality. Further suggestions, criticisms and elucidation are always welcome from the students and readers, which may be addressed to the author’s desk at

Dr.S.Gunasakaran, MBBS, MD

Ph : + 91 98413 12609

Email : [email protected]

(Or)

Mr. Satheesh kumar, M.Pharm Ph : + 91 94431 60516

Email : [email protected]


CCoonntteennttss PPaaggee nnoo

1. Standard Terms & Definitions in

Pharmacovigilance………………………………………………………. 3

2. Global perspective of Pharmacovigilance…………………………... 21

3. Domestic perspective of Pharmacovigilance………………………. 29

4. Guidelines and laws governing Pharmacovigilance…………….. 41

5. Global Adverse Event Reporting systems and

Reporting forms………………………………………………………… 59

6. Individual Case Safety Reports…………………………………….. 115

7. Periodic Safety Update Reports……………………………………. 261

8. Answers for Case studies…………………………………………… 267

9. Answers for Exercise based Questions………………………….. 272


AABBBBRREEVVIIAATTIIOONNSS

ABPI Association of the British Pharmaceutical Industry ADE Adverse Drug Event ADE Adverse Drug Experience ADHD Attention Deficit Hyperactivity Disorder ADR Adverse Drug Reaction ADRAC Adverse Drug Reaction Advisory Committee AE Adverse Event AEFI Adverse Events Following Immunization AHFS American Hospital Formulary Service ALT Alanine Transaminase AML Acute Myeloid Leukemia ANC Absolute Neutrophil Count ANDA Abbreviated New Drug Application AR Adverse Reaction ASR Annual Safety Report AST Aspartate Transaminase BID Bis In Die BLA Biologics License Application BNF British National Formulary BP Blood Pressure CBC Complete Blood Count CCDS Company Core Data Sheet CCSI Company Core Safety Information CDC Centre for Disease Control and prevention CDSCO Central Drugs Standard Control Organization CFR Code of Federal Regulations CHM Commission on Human Medicines CIOMS Council of International Organization for Medical sciences CMS Centres for Medicare and medicaid Services CNS Central Nervous System CPS Compendium of Pharmaceuticals and Specalties CRO Contract Research Organization CSI Core Safety Information CT Computerized Tomography CTD Common Technical Document DEG Diethylene glycol DGHS Directorate General of Health Services


DILI Drug Induced Liver Injury DM Diabetes Mellitus DSEB Drug Safety and Evaluation Branch DSUR Developmental Safety Update Report EEA European Economic Area EMEA/EMA European Medicines Agency EU European Union FDA Food and Drug Administration FEI FDA Establishment Identifier GI Gastro-Intestinal HCTER Human Cells and Tissue Establishment Registration HCV Hepatitis C Virus HT Hypertension IB Investigator’s Brochure IBD International Birth Date ICH International Council of Harmonization ICH-GCP International Conference on Harmonization – Good Clinical

Practice ICMR Indian Council of Medical Research ICSR Individual Case Safety Reports ICU Intensive Care Unit ID Identification IND Investigational New Drug IND Investigational New Drug INR International Normalized Ratio IV Intravenous kg Kilogram lb Pound LKM – 2 Liver Kidney Microsomal antibody type 2 MAH Marketing Authorization Holder MAUDE Manufacturer and User Facility Device Experience Database MCHC Mean Corpuscular Hemoglobin Concentration MCV Mean Corpuscular Volume MDR Medical Device Reporting MedDRA Medical Dictionary for Regulatory Activities Mfr Manufacturer MHPD Marketed Health Products Directorate MHRA Medicines and Health related products Regulatory Agency MHRA Medicines and Healthcare products Regulatory Agency MIMS Monthly Index of Medical Specialties


MIS Management Information System mmHg millimeter of mercury MSSO MedDRA Maintenance and Support Service Organization NA Not Applicable NCVIA National Childhood Vaccine Injury Act NDA New Drug Application NDC National Drug Code NPAC National Pharmacovigilance Advisory Committee NPC National Pharmacovigilance Centre NPP National Pharmacovigilance Programme NPPI National Pharmacovigilance Programme of India NYHA New York Heart Association OD Once Daily OEM Original Equipment Manufacturer OMSM Office of Medicines Safety Monitoring OTC Over The Counter PC Personal Computer Phv Pharmacovigilance PI Product information PMA Pre-Market Application PPC Peripheral Pharmacovigilance Centre PSUR Periodic Safety Update Reports PSVT Paroxysmal Supra Ventricular Tachycardia QA Quality Assurance RPC Regional Pharmacovigilance Centre SADRRF Suspected Adverse Drug Reaction Reporting Form SGOT Serum Glutamic Oxaloacetic Transaminase SGPT Serum Glutamic Pyruvic Transaminase SmPC Summary of Product Characteristics SMQs Standardized MedDRA Queries SOP Standard Operating Procedure STN Submission Tracking Number TEN Toxic Epidermal Necrolysis TGA Therapeutic Goods Administration TID Ter In Die UF User Facility UK United Kingdom ULN Upper Limit of Normal UMC Uppsala Monitoring Centre UNESCO United Nation Educational, Scientific and Cultural Organization


UNK Unknown US United States USC United States Code VAERS Vaccine Adverse Event Reporting System WBC White Blood cells WHO World Health Organization WHO-ART World Health Organization Adverse Reaction Terminology ZPC Zonal Pharmacovigilance Centre


his chapter discuss in detail about the various standard terminologies and definitions used in adverse event reporting system and pharmacovigilance. The standard terms are

defined based on various drug regulatory guidelines and modified for better ease of understanding to the readers. The glossary of terms described here covers most of the terminologies which are in use in the field of pharmacovigilance and risk management. Pharmacovigilance WHO defines Pharmacovigilance as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problems.” Pharmacovigilance is the process and science of monitoring the safety of medicines and taking action to reduce risks and increase benefits from medicines. Drug A drug includes any substance or mixture of substances manufactured, sold or represented for use in:

• the diagnosis, treatment, mitigation or prevention of a disease, disorder or

• abnormal physical state, or its symptoms, in human beings or animals,

• restoring, correcting or modifying organic functions in human

beings or animals, or disinfection in premises in which food is manufactured, prepared or kept.

T

STANDARD TERMS AND DEFINITIONS IN PHARMACOVIGILANCE

CHAPTER 1


Adverse Event (or Adverse Experience) Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Adverse Drug Reaction (ADR) In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase "responses to a medicinal product" means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out. Regarding marketed medicinal products, a well-accepted definition of an adverse drug reaction in the post-marketing setting is found in WHO Technical Report 498 [1972] and reads as follows: A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function. Unlisted / Unexpected Adverse Drug Reaction An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved investigational medicinal product and prescribing information / Summary of Product Characteristics (SmPC) for marketed products). Listed / Expected Adverse Drug Reaction An ADR whose nature, severity, specificity, and outcome are consistent with the information in the CCSI.


Challenge Administration of a suspect product by any route. Dechallenge Withdrawal of a suspect product from a patient's therapeutic regimen. Negative Dechallenge Continued presence of an adverse experience after withdrawal of the suspect product. Positive Dechallenge Partial or complete disappearance of an adverse experience after withdrawal of the suspect product. Rechallenge Reintroduction of a suspect product suspected of having caused an adverse experience following a positive dechallenge. Negative Rechallenge Failure of the product, when reintroduced, to produce signs or symptoms similar to those observed when the suspect product was previously introduced. Positive Rechallenge Reoccurrence of similar signs and symptoms upon reintroduction of the suspect product. Serious Adverse Event or Adverse Drug Reaction A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose:

* results in death, * is life-threatening,

The term "life-threatening" in the definition of "serious" refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.

* requires inpatient hospitalisation or prolongation of existing hospitalisation, * results in persistent or significant disability/incapacity, * is a congenital anomaly/birth defect.


egulatory guidelines are adapted by different regulatory agencies to suit to their national needs of reporting adverse events. Assessment of safety will be done based on global detection of

safety signals and necessary steps needs to be taken to curtail the unnecessary risks and hazards to public health and safety due to medicinal products.

The various pharmacovigilance guidelines for different regulatory markets such as United States, European Union, Canada, Australia, etc., are discussed below. Each regulatory agency drafted and implemented their own set of guidelines to fulfill the regional requirements of updating the safety of medicinal products both in the preapproval and post-marketing phases. ICH GUIDELINES The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a unique project that brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration. The purpose is to make recommendations on ways to achieve greater harmonization in the interpretation and application of technical guidelines and requirements for product registration in order to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines. The objective of such harmonization is a more economical use of human, animal and material resources, and the elimination of unnecessary delay in the global development and availability of new medicines whilst maintaining safeguards on quality, safety and efficacy, and

R

REGULATORY GUIDELINES AND LAWS GOVERNING PHARMACOVIGILANCE

CHAPTER 4


multidisciplinary (regulatory) obligations to protect public health. The key concepts of ICH guidelines can be easily remembered as QSEM Q - Quality S - Safety E - Efficacy M – Multidisciplinary. The ICH guidelines which deal with pharmacovigilance are E1, E2A, E2B, E2C, E2D, E2E, E2F, M1 and M4.

S. No. ICH Guidance

Name of the guidance

01 E1 The extent of population exposure to assess clinical safety for drugs intended for long-term treatment of non-life-threatening conditions

02 E2A Clinical Safety Data Management: Definitions and Standards For Expedited reporting

03 E2B Maintenance of the ICH guideline on clinical safety data management : Data elements for transmission of Individual Case Safety Reports

04 E2BM Data Elements for Transmission Of Individual Case Safety Reports

05 E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs

06 E2D Post-approval safety data management: Definitions and standards for expedited reporting

07 E2E Pharmacovigilance Planning 08 E2F Development Safety Update Report 09 M1 Medical Dictionary for Regulatory

Activities 10 M4 The Common Technical Document

Table 2: ICH guidelines related to Pharmacovigilance


Assessment of case report as a Reportable one or Not

There are minimum requirements need to be present in the case reports for reportability such as

1. Identifiable patient 2. Identifiable source 3. Suspect medication(s) 4. An Event or Outcome

Identifiable patient and Identifiable Source:

The identifiablility of the patient and reporter is important to avoid duplication of cases, detection of fraudulent ones, and facilitation of follow-up of appropriate genuine cases. A patient can be identified either by

• Initials/Name • Age/Date of Birth (D.O.B) • Age category • Sex/gender • Patient Identification number

The sources of information can be categorized into primary and secondary source. The primary reporting source(s) of the information is a person/source from which an adverse event report arises. Secondary sources are the one who will transmit the information (e.g., industry to regulatory authority). The identifiable reporting source may be any one of the following

• Consumers • Health care professionals • Lawyers • Care takers • Literature reports • Clinical study reports etc

Suspect Medicinal Product:


A Suspect medicinal product is the one which is suspected at first to be the reason for the reported adverse event. An Event or Outcome: An event or outcome should be present for the case to be reportable to the regulatory authorities. All the above four criteria should be present to make the adverse event as reportable one. In some cases, both the reporting source and identifiable patient will be the same. Exercise 5: Dr. Dinesh called TH manufacturers and stated that 21 year old male patient had rigor after administration of tablet diclofenac manufactured by them, which is also marketed in US. As a Medical affairs executive,

• To which regulatory body will you report this case? (a) DCGI

(b) FDA

(c) Both Exercise 6: Dr. Ramachandran, MD called LEL drug pharmaceuticals and stated that 29 year old female patient had giddiness, vomiting and shortness of breath after administration of codeine cough syrup manufactured by them, which is also marketed in US.

• Which forms need to be filled in this case? (a) MedWatch 3500 (b) MedWatch 3500 A (c) SADRRF (d) Both a and c (e) Both b and c


Case scenarios: Case 1

Check the criteria of identifiable patient in this case. Yes No

1. Name/Initials 2. Patient ID 3. Age /D.O.B 4. Age category 5. Sex

Whether this case report fulfills the criteria of an identifiable patient..?

Yes/No Case 2




Yes/No

A Dermatologist called KA pharmaceuticals and reported that a 21 year old male patient named Johnson had urticaria after intake of Terbinafine tablets.

Dr. Johnson mailed PJ pharmaceuticals that a young man complained of severe abdominal pain after the intake of amoxicillin tablets.


Case 3




Yes/No Case 4




Yes / No

A nurse from Indiana Hosptials reported that a patient identification number of IJN 3421 developed rash, itching and shortness of breath after administration of theophylline injection intravenously.

A pharmacist made a call to ABC Pharma and informed that a female patient reported 3 episodes of vomiting after intake of azithromycin tablets.


AAnnsswweerrss ffoorr ccaassee ssttuuddiieess

Case no Reportability Reportable criteria / Remarks

1 Yes 1,3 2 Yes 4

3 Yes 2 4 Yes 5

5 Yes 3

6 No -

7 Yes 4 8 No - 9 No -

10 Yes 1 11 No No event or outcome

12 No No suspect medication

13 No No identifiable patient

14 Yes 1,2,3,4

15 Yes 1,2,3,4 16 Yes 1,2,3,4

17 No No suspect medication

18 Yes 1,2,3,4

19 Yes 1,2,3,4 20 No No identifiable patient

21 Yes 1,2,3,4 22 Yes 1,2,3,4 23 Yes 1,2,3,4

24 Yes 1,2,3,4 25 No No identifiable patient

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