MEDICAL EVALUATION OF ADVERSE EVENTS IN PHARMACOVIGILANCE

Global perspective of pharmacovigilance :The WHO defines pharmacovigilance as the science and
activities relating to the detection, assessment, understanding and prevention of adverse effects or any other
drug-related problem .safety issues need to be carefully addressed in a coherent way, because information is
gathered from different sources (pre-marketing trials, post-approval safety studies, spontaneous reports,
etc.)and from different parts of the world(e.g. FDA-AERS,Vigibase,Eudravigilance)according to different
standards. Consistency in collection of safety data is mandatory to reduce bias and facilitate analysis
/interpretation in a global perspective. Currently, the global pharmacovigilance program is coordinated by
Uppasala monitoring centre (UMC), Sweden, with active coordination and cooperation from the member
countries.
Single case processing: This area entails the processing of individual case safety report (ICMR), which
refers to the format and content for the reporting of one or several suspected adverse reactions in relation to a
medicinal product that occurs in a single patient at a specific point of time. A valid ICSR should include at
least one identifiable reporter, one single identifiable patient, at least one suspect adverse reaction and at
least one suspect medicinal product.

The following flow chart shows the flow of the process occurs to process ICSR.

Sources for ICSR collections: The safety data related to company drug need to be collected by the
pharmaceutical company as per the regulations. The following will be the sources for the collection of safety
data:

1. Spontaneous source
2. Clinical sources
3. Literature sources
 4. Health authority etc. 
All these adverse events are collected by the company affiliate personnel and sent to ICSR processing
centers.

Processing of ICSRs: All these serious adverse events or adverse events collected from various sources are
sent by the company affiliates to the processing centers by uploading the SAE forms in to the software like
ARISg or ARGUS. At the processing centers following actions are taken by the drug safety associates.

1.) Initiations/ Case booking: After the receipt of the SAE forms, the drug safety associates checks for the
duplicates ICSRs.
Validity of ICSRFirst the validity of ICSR will be checked for the following four criteria’s:
1. Report
2. Patient
3. Adverse event
4. Suspect drug
2.) Case Coding / Case processing: After the case initiation, the case come in data entry / coding workflow.
The following information need to be added to the ICSR.
AE source and Reporter details
 The source of AE should be captured i.e. clinical, spontaneous etc.
 The reporter details such as name, address, phone number etc. details should be added.
 If the reporter is consumer (non-health care profession such as patient, patient’s relative without
knowledge of medical etc), the case should be considered as non-medically confirmed and the protect
confidentiality should be marked in database. This is done to protect the details of the reporter as per
regulations.
 The medically significant flag should be marked that either yes or no depending upon the reporter.
For consumer or non-healthcare professionals, it should be No. For health care professionals such as
doctors, nurse etc, it should be marked as Yes.

Patient details Patient identifiable information will be captured such as initials, Other relevant identifier
(clinical investigation number, for example), gender, age and/or date of birth, weight and height
Suspected Medicinal Product(s)The brand name as reported, International Non-Proprietary Name (INN),
batch number indication(s) for which suspect medicinal product was prescribed or tested, dosage form and
strength, daily dose and regimen (specify units – e.g., mg, ml, mg/kg), route of administration, starting date
and time of day, stopping date and time, or duration of treatment should be captured.

Tools used for Data Entry

Software: Adverse Reaction Information System Global (ARISg), Adverse Reaction Gathering Universal
System (ARGUS)
Dictionaries for Drug: WHO DD – All other non-company concomitant drugs and past drugs were selected
from this dictionary’s (Company product dictionary) – A suspect company product should be selected from
CPD. The CPD contain the information regarding the licensee number and other details which were not in
WHODD.
3.) Quality Review:
1. Quality review team checks the quality of the ICSR prior to submitting to
regulatory authority.

2. All the SUSAR and late cases undergo quality review. Non-serious cases will also
go under quality review depending upon the sponsor’s decision or operating
procedures.
3. Quality review team fixes errors which occurred during data entry and ensures all
the queries are resolved before moving this to next workflow.
4. Once, QC check done, the ICSR will be sent to next workflow i.e. Medical review
4.) Medical Review: Medical reviewer will ensure that all the medical aspects will be addressed properly
before sending the ICSR for regulatory submission. Following aspects will be seen during medical review.
1. Adverse event capture
2. Sequencing of AEs
3. Confirmation of coding
4. Reviews of concurrent conditions, medical history
5. Company causality assessment
6. Identification of potential safety signals
ICSR submission: After medical review, the case has been sent for the submission to various stake holders
includes;
1.Regulatory authority
2.Licensee partner
3.Investigators and institutional review boards

Regulatory perspectives of narrative writing

Narrative writing is an important part of Pharmacovigilance and in-patient safety as well. A narrative is a
brief summary of specific events experienced by patients, during the course of a clinical trial/treatment.
Narrative writing involves multiple activities such as generation of patient profiles, review of data sources,
and identification of events for which narratives are required.it provide a concise summary of
identified/specific adverse events (AEs) occurring in a patient to conclude causal relationship between the
drug and event.

Objective: The objective of the narrative is to summarize all relevant clinical and related information,
including patient characteristics, therapy details, prior medical history, clinical course of the event(s),
laboratory evidence and any other information that supports or refuses a diagnosis for an ADR. The
information should be presented in a logical time sequence.

Regulatory Perspectives: The ICH guideline (E2B) on data elements and specifications for electronic
reporting of individual ADR cases states that company narratives are required for all serious
reactions. Narratives are expected to be submitted for all cases reported expeditiously to any regulatory
authority, but are useful and should be made available when needed for other types of reports and purposes. 

As per International Conference on Harmonisation (ICH) E3, a patient narrative should describe:
 The nature, intensity and outcome of the event
 Clinical course leading to the event
 Timing of study drug administration
 Relevant laboratory measures
 Counter measures
 Action taken with the study drug in relation to the event
 All this information is extracted from the source files (e.g. Council for International
Organisations of Medical Sciences [CIOMS] form.
Flow of Narrative:
 Report type and reporter information
 Patient demographics
 Patient medical history and concomitant medication information
 Suspect product information timing and conditions surrounding the onset of the reaction(s) 
 Clinical course of the events, with an indication of timing of event corresponding to drug
administration
Standard narrative template: 
This initial [serious/non-serious] [spontaneous/literature] report, which originated from [country] was
received by [Marketing Partner’s Name] on [date DD MMM YYYY]. Information has been received from a
[reporter] concerning a [age] year old [male/female]. The patient’s medical history of [history, including the
duration of concurrent illness, age at diagnosis, date of diagnosis or onset date not reported]. Concomitant
therapy included [generic name of relevant concomitant drugs with/without indication if appropriate. Or
provide a general statement such as subject was also receiving multiple concomitant medications, with or
without indications (for example, he/she was taking multiple medications for pain, hypertension and
depression).

Follow-up Information:
When relevant new information becomes available, a follow-up narrative may need to be written depending
on the amount and importance of the information. There are three options for incorporating the new
information: 

1. Prepare an entirely new narrative

2. Add new information in a separate additional paragraph
3. Highlight in some way (e.g., bold or underline) the newly added follow-up material interspersed
within the original narrative. 
The Working Group’s preference is as follows: Every effort should be made to blend the follow-up details
into the original narrative, as usual in chronological order, to avoid repetition and
contradictions.Example:Follow-up information received on [DD-MMM-YYYY] from [source] (or Source
Data Verification received on…., or Data Correction Made on…., etc): (Briefly describe additions,
corrections)

Case narratives from clinical trial data

Patient narratives are written for deaths, serious adverse events (SAEs), or adverse events of special clinical
interest (eg, AEs associated with the mechanism of action being studied, laboratory results of special
interest, regulatory requirements etc.) and those leading to permanent component of clinical study reports
and pharmacovigilance activities like post marketing safety reports.

Clinical narrative template:

 Protocol/studyID; XXXX
 Study title/study description: post-marketing surveillance of DRUG mg(ingredient)to evaluate its
safety and efficacy
 Screening number/randomization no: XXX-XX-XXX
 Patient ID/subject ID: XXXX-XXXX
 This case was reported by an investigator on DD-MMM-YYYY
 This case reefers to a XX-year-old female/male patient who had liver foundation test (LFT)elevation
during drug therapy.
 The patient’s relevant medical history included:
 The patient’s concomitant medications included
 The patient’s laboratory data on (therapy)
 The patient was administered with
 About AE/SAE
 The patient’s laboratory data on (post therapy)
 Action taken with respect to drug was no change and patient was recovered from the event LFT
elevation on DD-MMM-YYYY
 The reporter assessed the causality between the medication and the event LFT elevation as possibly
related

Case narrative from spontaneous reporting

The initial spontaneous case was reported by a physician via sales representative via partner, on XX-XXX-
XXXX.This case refers to a XX-year-old male/female patient who experienced increased alkaline phosphate
levels following therapy with Dug(ingredient). The patient’s medical history was not reported. Current
condition included crohn’s disease. The patient’s concomitant medications were not reported. The patient
commenced therapy with drug (unspecified dose) weekly via IV route indicated for crohn’s disease on since
an unspecified date in XXX-XXXX.The reporter assessed the case to be non-serious and the causality
between the medication and the event was not reported.

 Narrative should be precise and concise.

  Double check spell mistakes, spaces, format, flow of narrative in a agreed chronology
 Do not repeat the information
 Abbreviations should be expanded and globally accepted
 Avoid short forms in narratives
 Do not change the meaning of narrative by adding own supportive words/conclusion
 The verbatim should be written as it is presented in source document. Use quotation marks to present
strange verbatim terms.
 Use paragraphs to present narrative in style and logical format.

Case narrative from literature reporting

This is a report from literature which described anti-TNF, infliximab and adalimumab, can be effective in
eosinophilic bowel disease. A report of eight paediatric cases.

Abstract: Eosinophilic enterocolitis(EEC) is an emerging distinct inflammatory bowel disease of unknown

etiology.There are no published data on the effect of infliximab or adalimumab for the treatment of
refractory cases.Methods:A report of all paediatric EEC cases treated with anti-TNF,identified after an open
international call.Results:we describe here the first eight children with refractory EEC who were treated with
infliximab (75% males; mean age at diagnosis 8.6+/-4.03)range 1.6-14 yrs,mean age at infliximab treatment
11.7+/-4.4(range 4.2-16 yrs.).Allergic and infectious causes of EEC were excluded in all cases. Rapid and
complete clinical remission was documented in 6(75%) children following the induction infusions ;3(38%)
with endoscopic remission,2(25%) with endoscopic improvement and one unknown. Four of the six
responders had secondary loss of response and switched to adalimumab, three of whom with sustained
remission using high doses. overall, the six responders were followed for a median of 7 years (range4-12;
IQR6.4-8.8 years) without evidence of developing crohn’s disease or ulcerative colitis. The only case with
macroscopic findings on endoscopy was a primary non- responder. This file represents a patient a patient no
1 of 8. Description regarding patient no:1The reporting physician considered the event serious (Medically
significant).

Conclusion: Infliximab and adalimumab may be effective cases of refractory idiopathic EEC.

Quality assessment of case narratives

Adverse drug reaction (ADR)probability scale was developed in 1991 by Naranjo and co-workers from the
university of Toronto and is often referred to as the Naranjo scale. The scale was also designed for use in
controlled trials and registration studies of new medications, rather than in routine clinical practise.
Nevertheless, it is simple to apply and widely used. Many publications on drug induced liver injury mention
results of applying the ADR probability scale. The ADR probability scale consists of 10 questions that are
answered as either yes, no, or do not know. Different point values (-1,0, +1 or +2) are assigned to each
answer. A simplified version of the 10 questions provided below.

 Are there previous conclusive reports of this reactions?

 Did the adverse event appear after the drug was given?
 Did the adverse reaction improve when the drug was discontinued?
 Did the adverse event reappear upon readministering the drug?
 Were there other possible causes for the reaction?
 Did the adverse reaction reappear upon administration of placebo?
 Was the drug detected in the blood or other fluids in toxic concentrations?
 Was the reactions worsened upon increasing the dose?
 Did the patient have a similar reaction to the drug or a related agent in the past?
 Was the adverse event confirmed by any other objective evidence?

The actual ADR probability scale form and instructions on how it is complicated are provided below. Total
scores range from -4 to +13: the reaction is considered definite if the score is 9 or higher, probable if 5 to 8,
possible if 1 to 4, and doubtful if 0 or less. While this sale includes all of the usual features that are important
in assessing causality, the scale is not weighted for the most critical elements in judging the likelihood of
drug induced liver injury, such as specific time to onset, criteria for time of recovery, and the list of critical
diagnosis to exclude, making the scale of limited use in assessing hepatotoxicity. The Naranjo scale also
relies upon testing for drug levels, which is rarely helpful in idiosyncratic drug induced liver disease. Finally
the scale was designed for use in clinical trials, and points are subtracted if the reaction reappears with the
administration of placebo, which does not apply to the usual case of drug induced liver disease .Direct
comparisons to RUCAM system have shown that the ADR probability scale is easier to apply, but has less
sensitivity and specificity in assigning causality to cases of drug induced liver injury.

Naranjo algorithm, or adverse drug reaction probability scale, is a method by which to assess whether there
is acausal relationship between an identified untoward clinical event and adrug using a simple using a simple
questionnaire to assign probability scores.

Score Interpretation of scores

Total score DefiniteThe reaction (1) followed a reasonable temporal sequence after
>/=9 a drug or in which a toxic drug level had been established in body fluids
or tissues, (2) followed a recognised response to the suspected drug, and
(3) was confirmed by improvement on withdrawing the drug and
reappeared on new exposure.

Total score Probablethe reaction (1) followed a reasonable temporal sequence after
5-10 a drug, (2) followed a recognised response to the suspected drug, (3) was
confirmed by withdrawal but not by exposure to the drug, and (4) could
not be reasonably explained by the known characteristics of the patient’s
clinical state.

Total score 1-4 PossibleThe reaction (1) followed a temporal sequence after a drug, (2)
possibly followed a recognized pattern to the suspected drug. And (3)
could be explained by characteristics of the patient’s disease.

Total score Doubtfulthe reaction was likely related to factors other than a drug.
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