Pharmacovigilance Safety data management by ToufiqS

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•Historical Development •Why we need ? •What is Pharmacovigilance? •What is safety datamanagement •PV jargons •Classification of AEs • What, Who, When of data collection • Forms & guidelines • Compilation of database • Analysis & Action Plan

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1961 - thalidomide disaster 1968 – WHO pilot research project for international drug monitoring 1971 – WHO meeting advocate establishment of national centers for drug monitoring provide guidelines identify the contribution that national centers might take to the international system

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1984 – international society of pharmacoepidemiology 1992 – european society of pharmacovigilance 2002 – WHO pharmacovigilance 2004 – national pharmacovigilance advisory committee (NHAC) with DGHS as chairman and drug controller general of india as member secretary 24 peripheral centers, 6 regional centers and 2 zonal centers

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Illegal sale of medicines and drugs of abuse over internet Increasing self medication practices Widespread manufacture and sale of counterfeit and substandard medicines Increasing use of traditional medicines outside the confines of traditional culture of use Increasing use medicines of different systems with potential for drug interactions

Pharmacovigilance Defined
This is the science of collecting, monitoring, researching and evaluating data on the effects of medicinal drugs, biological products, herbals, and traditional medicines with a view to identifying new information about adverse reactions and preventing harm to patients” [ Viewpoint – UMC publication]

Pharmacovigilance Defined (II)

“Study of clinical drug safety &

Benefit to Risk Analysis".
* Drug Safety Assessment By G.Gilbert

2 areas of activities
Marketed products - PMS Products in Clinical development



Monitoring of drug safety after introducing into the market through various systems Need 1.To assess risk benefit ratio 2.To confirm safety and efficacy 3.To detect less common adverse effects

Monitoring of drug safety when the trial is in conduct phase and Need 1.To assess risk benefit ratio 2.To confirm safety and efficacy 3.To detect less common adverse effects

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Improvement in patient care and safety in relation to use of medicines and interventions. Improvement of public health and safety. Assessment of benefit, harm, effectiveness and risk of medicines. Encouragement of safe rational and more cost effective use of medicines Increase public awareness through communication Education and clinical training in pharacovigilance Empowerment and involvement of practitioners, patients and public





WHO – collaborating center for international drug monitoring is Uppsala monitoring centre provides activities and events in PV CIOMS – council for international organizations of medical sciences-safety information communication between regulators and industries. ICH – international conference on harmonization discusses scientific and technical aspects of product registration. WHO-ART – WHO adverse reaction terminology for coding clinical information to drug therapy.

Why Learn Pharmacovigilance ? Annually Over 2 Mio serious ADRs 100,000 Deaths

ADRs being 4th leading cause of death
350,000 hospital admissions

Cost Associated With ADR !!!
Annual 177.6 Billion $ Greater than total costs of CV or diabetic care. Mean length of stay, cost & mortality for ADR patients are DOUBLE than that for control patients

The PV – Jargons

•Serious AE/ADR


•Expectedness / Labeled

The Adverse Event
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 unfavourable 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 event » does not imply causal relationship with the study medication/ drug.

The Adverse Drug Reaction

Any Adverse Event
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 products" 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.

Serious ADR or Serious AE
Any ADR or AE which fits into Criteria for Seriousness :  results in death,  is life threatening,  requires inpatient hospitalisation or

prolongation of existing hospitalisation,
 results in persistent or significant


 is a congenital anomaly/birth defect
 is important medical event (Cancer)

Definitions & Basic Concepts
Adverse Event





•Mild •Moderate • Severe

•Non Serious






•Life Threatening

Definitions & Basic Concepts
•The difference between

Seriousness & Severity

Seriousness serves as a guide for defining regulatory reporting obligations. Severity describes the intensity of the event, and may be of relatively minor medical significance.

Definitions & Basic Concepts An Unexpected ADR :
An ADR whose nature, intensity or incidence falls outside the information provided in the Investigator’s Brohcure the Package Insert or Product Monograph of a marketed drug




Definitions & Basic Concepts

the AE may be associated with the study medication?”

“ Is there a reasonable possibility that

Attributing ‘Cause-Effect’ relationship

De-challenge & Re-challenge

Investigator should always enter his assessment of causal relationship on ADR form


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Certain : proven on dechallenge and rechallenge Probable : dechallenge confirms.cannot rechallenge Possible : can be explained by concurrent disease or other drugs Unlikely : not documented in literature Unclassified : additional data is awaited so not documented Unclassifiable : additional data has come but not fit into any categories


An event – •It is serious •The causal relationship is established •It is unexpected i.e. not mentioned any where These are called triple “Y” cases

Non -Serious Serious

Record in CRF


Record in CRF Report EXPEDITEDLY


Global Study team
YYY cases Affiliates All PIs

Regulators Lic


& ECs
Safety Reporting. 12 July 2005 15


•Pre-Approval • Preclinical studies • Clinical Studies • Literature • Spontaneous reports

•Post Approval • Phase IV studies • PMS study •P.E.studies • Ep.databases • Literature •S.Reports

•Laws & Regulations • Sch Y • Guidelines • E2A • E2B • Protocols • CRFs • Misc Forms

•AEs • Lab Values • PK • Test reports [ ECG/EEG/ Venograms] • Physical examinations [ vital signs] • QOL • Pharmacogenetics

• CRFs • Paper • Electronic • SAE forms – expedited reporting • Lab Reports • Misc Forms • Autopsy Reports

•Recording during protocol defined visit • In patients – recording & reporting is simpler • OPD patients • SAEs through phone calls / doctors • Ask for hospital records •Eliciting a response • Questioning • Check list • Patient’s log book

•Abnormal Lab Reports • Test done in central labs • Abnormal values implying safety concerns • Well defined procedures • Lab – Doctors to be trained & sensitized • Difficult subjects • Infants / Coma / Alzheimer’s • Legal representatives / Proxy

◦ Time period defined in protocol ◦ From IC – to last FU visit ◦ from Randomization, if there is gap bet IC &

randomization ◦ Last FU visit >> 5 half lives ◦ Exceptions (long half life – bis phosphonates) ◦ AEs prior to randomization >> Medical history

Period of Observation

Informed Consent signed

Treatment start

Treatment end

Run In period = Screening phase

Active treatment period
Routine procedures collect adverse events

Follow up period

Screening Visit

End of Observation For AEs

Period of observation for AE collection is specified in each protocol

◦ Sponsor [SM / Monitor / Auditor]
 Protocol, CRF, FU reports  Monitor – a critical role

◦ Investigator [PI / Co-Inv /TMs]
 Direct contact with patients  Unspecified medically IMP events

◦ Regulator [DCGI / FDA /EMEA/] ◦ Others [ECs/IRBs / DSMBs]

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Identifiable patient A suspect drug An adverse event Identifiable reporter

MedWatch is the Food and Drug Administration‟s reporting system for adverse events, founded in 1993. An adverse event is any undesirable experience associated with the use of a medical product. The MedWatch system collects reports of adverse reactions and quality problems, primarily with drugs and medical devices, but also for other FDA-regulated products (e.g., dietary supplements, cosmetics, medical foods, and infant formulas). Voluntary reporting by healthcare professionals, consumers, and patients is conducted on a single, one-page reporting form (Form FDA 3500). Reporting can be conducted online, by phone 1-800-FDA-1088, or by submitting the MedWatch 3500 form by mail or fax 1-800-FDA0178.
The MedWatch system is intended to detect safety hazard signals for medical products. If a signal is detected, FDA can issue medical product safety alerts or order product recalls, withdrawals, or labeling changes to protect the public health. Important safety information is disseminated to the medical community and the general public via the MedWatch web site and the MedWatch E-list.”



The Yellow Card Scheme is vital in helping the MHRA monitor the safety of the medicines that are on the market. Before a medicine is granted a license so that it can be made available in the United Kingdom, it must pass strict tests and checks to ensure that it is acceptably safe and effective. All effective medicines, however, can cause side effects (also known as adverse drug reactions), which can range from being minor to being very serious. For a medicine to be granted a licence, the expected benefits of the medicine must outweigh the possible risks of the medicine causing adverse effects in patients. Sometimes, it is difficult to tell whether a possible side effect is due to a medicine, or something else. Even if it is only a suspicion that a medicine or combination of medicines has caused a side effect, we ask patients and health professionals to send us a Yellow Card. Yellow Card reports that we receive on suspected side effects are evaluated, together with additional sources of information such as clinical trial data, medical literature or data from international medicines regulators, in order to identify previously unidentified safety issues or side effects. Information gathered from Yellow Card reports made by patients and health professionals is continually assessed at the MHRA by a team of medicine safety experts made up of doctors, pharmacists and scientists who study the benefits and risks of medicines. If a new side effect is identified, information is carefully considered in the context of the overall side effect profile for the medicine, and how the side effect profile compares with other medicines used to treat the same condition. The MHRA takes action, whenever necessary, to ensure that medicines are used in a way that minimizes risk, while maximizing patient benefit. In assessing the safety of medicines, the MHRA is advised by the Commission on Human Medicines (CHM), which is the Governments independent scientific advisory body on medicines safety. The CHM is made up of experts from a range of health professionals and includes lay representatives.



The Council for International Organizations of Medical Sciences (CIOMS) is an international, non-governmental, non-profit organization established jointly by WHO and UNESCO in 1949. There is currently only one internationally recognized reporting form for submission of ADR case information to national pharmacovigilance centres, the so called CIOMS-I form. It was developed in 1990 to allow marketing authorization holders (MAH) to submit ADR information to regulators using one and the same format in all countries. The form was not designed for soliciting case information from health professionals and would most probably not work for that purpose. The WHO reporting form, developed in 1968 and revised in 1981 for submission of case information from national pharmacovigilance centres to the WHO database is international in scope but is not useful for collection of original data from health professionals. Since 2001 it is no longer accepted as a paper form within the WHO Programme, only as a format for electronic submissions.

Adverse Events Reporting Forms
The Data Elements Required by CIOMS I Form
I. Reaction Information II. Suspect Drug

III. Concomitant Drugs & History

IV. Mnufactur’g Information

Adverse Events Reporting Forms
The Data Elements Required by CIOMS I Form
IReaction Information Patient’s Initial Country DOB /Age Sex Reaction Onset Description of event Seriousness criteria

Adverse Events Reporting Forms
The Data Elements Required by CIOMS I Form
II . Suspect Drug Name of drug Dose Route Indication/s Therapy dates/ duration De-challenge / Re-challenge

Adverse Events Reporting Forms
The Data Elements Required by CIOMS I Form
III . Concomitant Drugs & History Concomitant drugs Dates Relevant history

Adverse Events Reporting Forms
The Data Elements Required by CIOMS I Form
IV. Manufact’ing Information Name & Address Control No Reporting &date of report Source of report Type of report

The Comparative Features of International Forms

Yellow Card


Does not include devices & quality problems Includes devices & quality problems Elicits response on self medication Asks for laboratory data

Differenciates between reporter & clinician Does not differenciate De-challenge / Rechallenge missing De-challenge / Rechallenge explored

Outcome of AE included

Outcome of AE missing
Absence of causality assessment

ICH Guidelines

ICH – E2A  Clinical Safety Data Management (CSDM) – Definitions / Std for expedited reporting ICH – E2B  Data elements for transmission of ICSR ICH – E2C  CSDM - PSUR (Marketed Products ) Format & Process ICH – E2D  Post Authorization SDM - Definitions / Std for expedited reporting





ICH – M2  Electronic standard for transfer of regulatory Information ( ICH E 2B.M)

Unsuspected adverse event is communicated from 1.Sponsor to regulatory authorities within 14 days 2. Investigator to sponsor within 24 hours 3. Investigator to ethics committee within 7 days

Some Practical Tips - 1

Have a fool proof reporting system,


Provide templates / Charts
Study specific file, reporting matrix

 Simplified

 Mock exercise during site initiation  Dedicated 24x7 faxline / Mailbox

Some Practical Tips -2
F L O Investigator Study Monitor
immediately or within 24 hours


Sponsor’s PV Incharge / SM Fax No: +91 00 00000000
immediately or within 24 hours

Global HQ

Some Practical Tips -3
1 – Call <<The Hotline<< as soon as you come to know of a SAE
2 – FAX the SAE report immediately within 24 hrs to +91 00 0000 00000
3 – Sponsor to acknowledge receipt of the fax

4 – Send by courier the completed SAE form to PV office
5 – Send SAE log at the end of every week (Mon – Fri)

6 – Send the EC acknowledgement for the SAE

>> Mr.XYZ<<

Pharmacovigilance Incharge Telephone during business hours: +91 00 12345678 Mobile:

1234567890  Fax 24 hours a day: +91 12 34567890  Email:




A “Follow-Up” report is a MUST for all those SAEs, which are „Ongoing‟ at the time of reporting The same „SAE‟ form to be used to report a „Follow-Up‟ Fax within 24 hours, after the FU information comes to be known.

Responsibilities of Investigators
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Understand the Protocol requirements Training of his team members

Provision of necessary resources & infrastructure Monitor, capture & documents ALL AEs Report  Prescribed Format  Accurately / Legible  Adherence to timelines  Disseminate to concerned parties
Medical care, in case of an AE Follow up the AEs to resolution Respond to queries Archival

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Responsibilities of Sponsor…

SOP  Protocol  Process  Timelines Training  Study team  Investigators team Resources / Infrastructure Compilation / Evaluation Dissemination  Information (AEs / Safety Updates/ PSURs)  All concerned parties (Regulators / INV/Ecs/Etc


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Safety Data Management

Clinical Database

Safety Database

Efficacy + Safety During CTs

Safety During CTs + Marketing





AE at Investigator’s site AEM CRF

Clinical database

Safety database

Safety data management Reconciliation i.e. Data cleaning



Thank you

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