A

Project Report

ON

Pharmacovigilance Data Management and Case processing

Subject: Project Work Paper Code: BP812PW

Submitted By

UTKARSH RAI

Roll no: 1180781091

B. Pharm, VIIIth Sem

Under supervision of Submitted to

Mrs. Amrita Dubey Prof. (Dr.) Rajiv Gupta

Assistant Prof., BBDU Principal & Dean, Pharmacy, BBDU

School of Pharmacy

Babu Banarasi Das University, Lucknow

2021-2022
 DECLARATION

I hereby declare that the Project Entitled in the Partial Fulfilment of Course Curriculum of
the Degree of Bachelor of Pharmacy from Babu Banarasi das University, Lucknow.

The work done by me is my own piece of work and authentic to the best of my knowledge
under the supervision of Mrs. Amrita Dubey.

Place –Lucknow Name – Utkarsh Rai

Date - Roll No- 1180781091

 ACKNOWLEDGEMENT

In the accomplishment of this project successfully, many people have best owned upon me
their blessings and the heart pledged support, this time I am utilizing to thank all the people
who have been concerned with this project.

I express my profound gratitude to Prof.(Dr.)Rajiv Gupta principal &and Dean of

Pharmacy for organizing requirement for project and made all possible arrangement for
smooth flow of the project.

Though, I addressed several difficulties in coordinating the activities of the project but I am
highly indebted toMrs. Amrita Dubey, for her guidance and constant supervision, as well as
for providing necessary information regarding the project and also for his support in
completing the project.

I would also like to express my gratitude towards my parents and subject teacher for their
kind co-operation and encouragement as they helped me a lot in completion of this project.

At last, I end up by thanking all who helped me in finalizing the project within the limited
time frame.

Place- BBD University Name- Utkarsh Rai

Date - Roll no- 1180781091

S. No Content Page no

1. Introduction 2-5

2. Data management in pharmacovigilance 5-6

3. Data quality management in pharmacovigilance 6-7

4. Data collected for pharmacovigilance 7-8

5. Data management in clinical research 8-12

5.1. Tools For Clinical data management
5.2. Regulation, guidelines and standards in CDM
6. Case processing 12-19
6.1. Review and finalization of study document
6.2. Basic step in Pharmacovigilance case
processing
6.3. Safety Data management
6.4. The steps in safety data management
6.4.1. Data collection and verification
6.4.2. Data entry
6.4.3. Data validation
6.4.4. Discrepancy management
7. Case narrative 19-26
7.1. Coding of adverse reactions
7.2. Coding of drugs
7.3. Causality assessment
8. Pharmacovigilance and risk management 26-28

9. Role of case processor 28-32

9.1. Case Reciept mailbox management
9.2. Validity assessment
9.3. Triage
9.4. Coding the adverse events and drugs
9.5 Causality assessment

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 9.6. Expectedness assessment
9.7 Case narrative
9.8. Self quality check
10. Case processing significance 32-33

11. Book –in and registration 33

12. Conclusion 34

13. Reference 35-37

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1. INTRODUCTION

All medicines and vaccines undergo rigorous testing for safety and efficacy through clinical

trials before they are authorized for use. However, the clinical trial process involves studying

these products in a relatively small number of selected individuals for a short period of time.

Certain side effects may only emerge once these products have been used by a heterogeneous

population, including people with other concurrent diseases, and over a long period of time.

Pharmacovigilance has been defined as the process of identifying and responding to drug

safety issues and has grown considerably as a discipline over the past 10 to 15 years. The

number of individual reports of possible adverse drug reactions (ADRs) can be considerable,

for key marketed products often more than 1000 case reports a year are received worldwide

from health care professionals and other sources.

The aims of pharmacovigilance within the industry are essentially the same as those of

regulatory agencies; that is to protect patients from unnecessary harm by identifying

previously unrecognized drug hazards, elucidating pre-disposing factors, refuting false safety

signals and quantifying risk in relation to benefit.

Although now seen as a discipline in its own right, pharmacovigilance is related to a number

of scientific disciplines, the most important being clinical medicine, clinical and pre-clinical

pharmacology, immunology, toxicology and epidemiology.

The identification and analysis of the safety characteristics of medicines falls into two distinct

stages. During the first stage, before marketing, the main methodology is experimental with

clinical trials comparing the new treatment to placebo or existing.

Pharmacovigilance refers to the science and activities relating to the detection, assessment,

understanding, and prevention of adverse effects and other drug-related safety

problems.Related to this general definition, the underlying objectives of pharmacovigilance

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are to prevent harm from adverse reactions in humans that arise from the use of health

products within or outside the terms of marketing authorization and in relation to the life

cycle of these health products.

Fig.1. Key goals of pharmacovigilance

The main goal of pharmacovigilance is thus to promote the safe and effective use of health

products, in particular by providing timely information about the safety of health products to

patients, health-care professionals, and the public. Pharmacovigilance is therefore an activity

contributing to the protection of patients and maintaining public health.

Many other issues are also of relevance to pharmacovigilance-related activities and include

medication errors, lack of efficacy reports, off-label use, acute and chronic poisoning,

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assessment of drug-related mortality, abuse and misuse of health products, and adverse

interactions of medicines with chemicals and other drugs.

The pharmacovigilance approach can be clinical, epidemiological, experimental (e.g., to

reproduce an adverse effect in animals to better understand the mechanism involved for

human protection), or diagnostic (e.g., imputable methods).

The ultimate goal of pharmacovigilance is to accurately characterize and optimize the

benefit/risk ratio of a health product throughout its life cycle.

Pharmacovigilance is defined as the activities involved in the detection, assessment,

understanding, and prevention of adverse effects or any other drug related problems. All

drugs have the capacity to cause adverse effects and no drug is completely safe. Medication

safety is of particular concern for dermatologists, as most treatment indications involve

diseases that are not life-threatening and are often chronic, requiring years of medical

therapy. Although skin diseases can create substantial morbidity, physicians, regulatory

agencies, and society generally have less tolerance for risk when treating skin diseases. This

chapter reviews the eight key principles related to interpreting information related to drug

safety. Knowledge of these principles is fundamental to making informed treatment decisions

and to aid in the discussion of risk with patients.

Pharmacovigilance is more than spontaneous reporting alone, and the evaluation of marketed

medicines is more than just pharmacovigilance. The positioning of a drug usually takes place

during the years following introduction, when worldwide experience has accumulated.

Originally a modest appendix of drug regulation, pharmacovigilance has become a major

activity. The provision of the information needed for the evaluation of the benefits and risks

of drugs is in the first place a scientific challenge.

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Pharmacovigilance, and more generally the study of the benefits and risks of drugs, plays a

major role in pharmacotherapies decision-making, be it individual, regional, national or

international. In addition, pharmacovigilance is becoming a scientific discipline in its own

right.

2.Data Management in Pharmacovigilance

The World Health Organization (WHO) defines pharmacovigilance as the science and

activities relating to the detection,

evaluation, understanding, and prevention of adverse reactions to medicines or any other

medicine-related problems. In 1893, The Lancet first reported an established drug safety

reporting system for suspected adverse drug reactions (ADRs). Since then, the definition and

scope of pharmacovigilance have evolved as a systems approach. Pharmacovigilance is a

highly sensitive field as it involves monitoring of the safety of medicines and taking action to

reduce risk and increase benefit. The pharmacovigilance data management starts with the

data collection and, it is imperative to address the report origin, triage cases, enter

information in drug safety database, make medical assessment, request report follow-up

information and mode for regulatory submissions. All these stages require a high and

complex degree of technical skill and judgment to ensure that accurate conclusions and right

decisions are made during the establishment of benefit-risk profile for a product. A poor

pharmacovigilance data management not only jeopardizes patient safety, it also increases the

risk of investing in the development of wrong product which causes a huge loss to a

pharmaceutical company. Therefore, it is very important to establish a robust

pharmacovigilance data management system which complies with the stringent regulatory

guidelines, global pharmaceutical norms and ultimately safeguard the pharmacovigilance end

users, the patient. An ideal model would be implementation of business management

software (e.g., Microsoft Dynamics NAV/SAP ERP) for better data management, process

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harmonization, enhanced data security and reduction in delay due to high manual

dependence.

The pharmacovigilance data processing cycle starts with data collection and, in computerized

systems, data entry; the next step is data storage and maintenance; followed by data selection,

retrieval and manipulation. The resulting data output is analyzed and assessed. Finally,

conclusions are drawn and decisions made.

3.Data Quality Management in Pharmacovigilance

Pharmacovigilance relies on information gathered from the collection of individual case

safety reports and other pharmacoepidemiologic data. Even given the inherent limitations of

spontaneous reports, the usefulness of this data source can be improved with good data

quality management. Although under-reporting cannot be remedied this way, the negative

impact of incomplete reports, which is another serious problem in pharmacovigilance, can be

reduced. Quality management consists of quality planning, quality control, quality assurance

and quality improvements. The pharmacovigilance data processing cycle starts with data

collection and, in computerized systems, data entry; the next step is data storage and

maintenance; followed by data selection, retrieval and manipulation. The resulting data

output is analyzed and assessed. Finally, conclusions are drawn and decisions made. The

increased knowledge feeds back into the data processing cycle. Focusing on the first three

steps of the data processing cycle, the different quality dimensions associated with these steps

are described in this review, together with examples relevant to pharmacovigilance data.

Functioning, well documented, and transparent quality management systems will benefit not

only those involved in data collection,

Clinical data management (CDM) is a critical process in clinical research, which leads to

generation of high-quality, reliable, and statistically sound data from clinical trials. Clinical

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data management ensures collection, integration and availability of data at appropriate quality

and cost. It also supports the conduct, management and analysis of studies across the

spectrum of clinical research as defined by the National Institutes of Health (NIH). The

ultimate goal of CDM is to ensure that conclusions drawn from research are well supported

by the data. Achieving this goal protects public health and confidence in marketed

therapeutics.

4.Data collected for Pharmacovigilance

Pharmacovigilance is an important process for pharmaceutical firms and other regulatory

bodies since it allows them to monitor the safety of a drug. It is usually done after a drug has

gone through all the phases of clinical trials and has been approved for use by the public.

One of the ways of collecting data for pharmacovigilance purposes is by providing a portal

for drug users to provide information about their experiences with the drugs. This could be in

the form of a special website that is easily accessible and easy to use. It may be difficult to

convince all drug users to log negative experiences of the drugs on the online portal, but the

data collected from the few who do can be valuable.

It is usually done after a drug has gone through all the phases of clinical trials and has been

approved for use by the public. One of the ways of collecting data for pharmacovigilance

purposes is by providing a portal for drug users to provide information about their

experiences with the drugs.

Input from primary care physicians can also be used for pharmacovigilance purposes. When

the doctors prescribe such medication, they usually have the responsibility of following up

their patients to monitor their progress. If a side effect is noted and attributed to the drug in

question, this can be brought to the attention of the party doing pharmacovigilance. For this

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to be effective, the primary care physicians will need to be sensitized on the need for this

information, what to look out for and how to log the information.

Pharmacovigilance data can also be collected directly from patients who are receiving the

drugs from hospital. This is particularly effective for IV medication, which needs to be

provided within a hospital for safety purposes. An individual can then be delegated to collect

data regarding the side effects that the patients have had as a result of using the drug.

5.Data management in clinical research

Clinical trial is intended to find answers to the research question by means of generating data

for proving or disproving a hypothesis. The quality of data generated plays an important role

in the outcome of the study. Clinical data management is a relevant and important part of a

clinical trial. All researchers try their hands on CDM activities during their research work,

knowingly or unknowingly. Without identifying the technical phases, we undertake some of

the processes involved in CDM during our research work. This article highlights the

processes involved in CDM and gives the reader an overview of how data is managed in

clinical trials.

CDM is the process of collection, cleaning, and management of subject data in compliance

with regulatory standards. The primary objective of CDM processes is to provide high-

quality data by keeping the number of errors and missing data as low as possible and gather

maximum data for analysis. To meet this objective, best practices are adopted to ensure that

data are complete, reliable, and processed correctly. This has been facilitated by the use of

software applications that maintain an audit trail and provide easy identification and

resolution of data discrepancies. Sophisticated innovations have enabled CDM to handle

large trials and ensure the data quality even in complex trials.

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High-quality data should be absolutely accurate and suitable for statistical analysis. These

should meet the protocol-specified parameters and comply with the protocol requirements.

This implies that in case of a deviation, not meeting the protocol-specifications, we may think

of excluding the patient from the final database. It should be borne in mind that in some

situations, regulatory authorities may be interested in looking at such data. Similarly, missing

data is also a matter of concern for clinical researchers.

5.1.Tools for Clinical Data Management

Many software tools are available for data management, and these are called Clinical Data

Management Systems (CDMS). In multicentric trials, a CDMS has become essential to

handle the huge amount of data. Most of the CDMS used in pharmaceutical companies are

commercial, but a few open-source tools are available as well. Commonly used CDM tools

are ORACLE CLINICAL, CLINTRIAL, MACRO, RAVE, and eClinical Suite. In terms of

functionality, these software tools are more or less similar and there is no significant

advantage of one system over the other. These software tools are expensive and need

sophisticated Information Technology infrastructure to function. Additionally, some

multinational pharmaceutical giants use custom-made CDMS tools to suit their operational

needs and procedures. Among the open-source tools, the most prominent ones are

OpenClinica, openCDMS, TrialDB, and PhOSCo. These CDM software are available free of

cost and are as good as their commercial counterparts in terms of functionality. These open-

source software can be downloaded from their respective websites.

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 Fig.2. Tools For CDM

In regulatory submission studies, maintaining an audit trail of data management activities is

of paramount importance. These CDM tools ensure the audit trail and help in the

management of discrepancies. According to the roles and responsibilities (explained later),

multiple user IDs can be created with access limitation to data entry, medical coding,

database designing, or quality check. This ensures that each user can access only the

respective functionalities allotted to that user ID and cannot make any other change in the

database. For responsibilities where changes are permitted to be made in the data, the

software will record the change made, the user ID that made the change and the time and date

of change, for audit purposes (audit trail). During a regulatory audit, the auditors can verify

the discrepancy management process; the changes made and can confirm that no

unauthorized or false changes were made.

5.2. Regulation, guidelines and standards in CDM

Akin to other areas in clinical research, CDM has guidelines and standards that must be

followed. Since the pharmaceutical industry relies on the electronically captured data for the

evaluation of medicines, there is a need to follow good practices in CDM and maintain

standards in electronic data capture. These electronic records have to comply with a Code of

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Federal Regulations (CFR), 21 CFR Part 11. This regulation is applicable to records in

electronic format that are created, modified, maintained, archived, retrieved, or transmitted.

This demands the use of validated systems to ensure accuracy, reliability, and consistency of

data with the use of secure, computer-generated, time-stamped audit trails to independently

record the date and time of operator entries and actions that create, modify, or delete

electronic records.[3] Adequate procedures and controls should be put in place to ensure the

integrity, authenticity, and confidentiality of data. If data have to be submitted to regulatory

authorities, it should be entered and processed in 21 CFR part 11-compliant systems. Most of

the CDM systems available are like this and pharmaceutical companies as well as contract

research organizations ensure this compliance.

Society for Clinical Data Management (SCDM) publishes the Good Clinical Data

Management Practices (GCDMP) guidelines, a document providing the standards of good

practice within CDM. GCDMP was initially published in September 2000 and has undergone

several revisions thereafter. The July 2009 version is the currently followed GCDMP

document. GCDMP provides guidance on the accepted practices in CDM that are consistent

with regulatory practices. Addressed in 20 chapters, it covers the CDM process by

highlighting the minimum standards and best practices.

Clinical Data Interchange Standards Consortium (CDISC), a multidisciplinary non-profit

organization, has developed standards to support acquisition, exchange, submission, and

archival of clinical research data and metadata. Metadata is the data of the data entered. This

includes data about the individual who made the entry or a change in the clinical data, the

date and time of entry/change and details of the changes that have been made. Among the

standards, two important ones are the Study Data Tabulation Model Implementation Guide

for Human Clinical Trials (SDTMIG) and the Clinical Data Acquisition Standards

Harmonization (CDASH) standards, available free of cost from the CDISC website

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(www.cdisc.org). The SDTMIG standard [4] describes the details of model and standard

terminologies for the data and serves as a guide to the organization. CDASH v 1.1[5] defines

the basic standards for the collection of data in a clinical trial and enlists the basic data

information needed from a clinical, regulatory, and scientific perspective.

6.Case Processing

 In pharmacovigilance, case processing is a fundamental activity. It provides data for the

analysis of adverse effects that allows to detect new safety concerns and to periodically

assess the benefit to risk ratio associated with the use of a pharmaceutical product. The

precision and quality of safety data processing, also from the medical point of view, is

crucial for ensuring correct analysis and undertaking corrective actions in timely manner,

which in turn helps to safeguard the health of the patients and allows safe use of the

drug.

Fig-3. Case Processing

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 The CDM process, like a clinical trial, begins with the end in mind. This means that the

whole process is designed keeping the deliverable in view. As a clinical trial is designed

to answer the research question, the CDM process is designed to deliver an error-free,

valid, and statistically sound database. To meet this objective, the CDM process starts

early, even before the finalization of the study protocoll.

6.1.Review and finalization of study documents

The protocol is reviewed from a database designing perspective, for clarity and consistency.

During this review, the CDM personnel will identify the data items to be collected and the

frequency of collection with respect to the visit schedule. A Case Report Form (CRF) is

designed by the CDM team, as this is the first step in translating the protocol-specific

activities into data being generated. The data fields should be clearly defined and be

consistent throughout. The type of data to be entered should be evident from the

CRF.Similarly, the units in which measurements have to be made should also be mentioned

next to the data field. The CRF should be concise, self-explanatory, and user-friendly (unless

you are the one entering data into the CRF). Along with the CRF, the filling instructions

(called CRF Completion Guidelines) should also be provided to study investigators for error-

free data acquisition. CRF annotation is done wherein the variable is named according to the

SDTMIG or the conventions followed internally. Annotations are coded terms used in CDM

tools to indicate the variables in the study. In questions with discrete value options (like the

variable gender having values male and female as responses), all possible options will be

coded appropriately.

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Based on these, a Data Management Plan (DMP) is developed. DMP document is a road map

to handle the data under foreseeable circumstances and describes the CDM activities to be

followed in the trial. The DMP describes the database design, data entry and data tracking

guidelines, quality control measures, SAE reconciliation guidelines, discrepancy

management, data transfer/extraction, and database locking guidelines. Along with the DMP,

a Data Validation Plan (DVP) containing all edit-checks to be performed and the calculations

for derived variables are also prepared. The edit check programs in the DVP help in cleaning

up the data by identifying the discrepancies.

6.2.Basic steps in Pharmacovigilance Case Processing

 Pharmacovigilance comprises of-

 Safety data management

 Signal detection for any new altered safety issue

 Signal evaluation and making decisions with regard to safety issues.

Actions, including regulatory, to protect public health Informing all concerned parties or

stakeholders

6.3.Safety Data Management

A Serious Adverse Event for a molecule could be generated during the preregistration or post

marketing phase. They could occur during clinical trials or be reported spontaneously by a

patient, caregiver, relation, doctor, nurse or pharmacist. Another regulatory body or a license

company could also be the informant. It could be received on phone, mail, fax, journals,

newspapers or the latest social media.

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 Fig-4. Safety Data Management

Unexpected adverse events could arise anytime in the life of a product. These could put the

user to serious risk and could curtail the life of the product. As part of the risk management

plan, safety data is gathered throughout the life of a product. Consequently, every company

that markets even a handful of products across many countries, gathers thousands of reports

per year. The only way to manage this load is using latest software and automation.

6.4.The steps in safety data management are-

6.4.1.Data collection and verification

 Coding of adverse reaction descriptions

 Coding of drugs

 Case causality assessment

 Timely reporting to authorities

Every safety management software has a facility to identify and delete duplicates. Certain

characteristics of a case (sex, age or date of birth, dates of drug exposure, clinical trial code,

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country, etc.) may be used to identify duplicate reporting. This action is of significance for

further processing of the case. The duplicate could actually be follow up information that

could alter the seriousness and hence reporting timeline of the case. Missed out duplicates

could send misleading information to signal detection systems.

Fig.5. Data Collection and Verification

Data collection is done using the CRF that may exist in the form of a paper or an electronic

version. The traditional method is to employ paper CRFs to collect the data responses, which

are translated to the database by means of data entry done in-house. These paper CRFs are

filled up by the investigator according to the completion guidelines. In the e-CRF-based

CDM, the investigator or a designee will be logging into the CDM system and entering the

data directly at the site. In e-CRF method, chances of errors are less, and the resolution of

discrepancies happens faster. Since pharmaceutical companies try to reduce the time taken

for drug development processes by enhancing the speed of processes involved, many

pharmaceutical companies are opting for e-CRF options (also called remote data entry).

(Medicine) the principle or practice of sorting casualties in battle or disaster or other patients

into categories of priority for treatment.

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(Government, Politics & Diplomacy) the principle or practice of allocating limited resources,

as of food or foreign aid, on a basis of expediency rather than according to moral principles

or the needs of the recipients.

Triage in safety means prioritizing the case for reporting to authorities. An oversimplification

of triage would be to report deaths and life-threatening unexpected reports in 7 days and other

adverse reactions in 15 days as there are also other occasions where expedited reporting is

required.

6.4.2.Data Entry

A seemingly repetitive and inconsequential step in the process but something that forms the

basis of good reporting. The quality of data entry affects the further processing of the case.

Details of the four pillars of a valid case have to be reported meticulously. Patient

information has to follow the HIPPA code for confidentiality. Reporter information has to

clear and detailed enough to be able to contact the person if necessary. Drug identifiers like

name, formulation and dose have to be captured correctly. Event report has to be detailed

enough for the evaluator to decide on the cause of the adverse event. This would include

chronological description of the event or events, nature, localization, severity, characteristics

of the event, results of investigations and tests, start date, course and outcome, concomitant

medications and other risk factors.

Data entry takes place according to the guidelines prepared along with the DMP. This is

applicable only in the case of paper CRF retrieved from the sites. Usually, double data entry

is performed wherein the data is entered by two operators separately.[8] The second pass

entry (entry made by the second person) helps in verification and reconciliation by

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identifying the transcription errors and discrepancies caused by illegible data. Moreover,

double data entry helps in getting a cleaner database compared to a single data entry. Earlier

studies have shown that double data entry ensures better consistency with paper CRF as

denoted by a lesser error rate.

6.4.3.Data Validation

Data validation is the process of testing the validity of data in accordance with the protocol

specifications. Edit check programs are written to identify the discrepancies in the entered

data, which are embedded in the database, to ensure data validity. These programs are written

according to the logic condition mentioned in the DVP. These edit check programs are

initially tested with dummy data containing discrepancies. Discrepancy is defined as a data

point that fails to pass a validation check. Discrepancy may be due to inconsistent data,

missing data, range checks, and deviations from the protocol. In e-CRF based studies, data

validation process will be run frequently for identifying discrepancies. These discrepancies

will be resolved by investigators after logging into the system. Ongoing quality control of

data processing is undertaken at regular intervals during the course of CDM. For example, if

the inclusion criteria specify that the age of the patient should be between 18 and 65 years

(both inclusive), an edit program will be written for two conditions viz. age <18 and >65. If

for any patient, the condition becomes TRUE, a discrepancy will be generated. These

discrepancies will be highlighted in the system and Data Clarification Forms (DCFs) can be

generated. DCFs are documents containing queries pertaining to the discrepancies identified.

6.4.4.Discrepancy Management

This is also called query resolution. Discrepancy management includes reviewing

discrepancies, investigating the reason, and resolving them with documentary proof or

eclaring them as irresolvable. Discrepancy management helps in cleaning the data and

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gathers enough evidence for the deviations observed in data. Almost all CDMS have a

discrepancy database where all discrepancies will be recorded and stored with audit trail.

Based on the types identified, discrepancies are either flagged to the investigator for

clarification or closed in-house by Self-Evident Corrections (SEC) without sending DCF to

the site. The most common SECs are obvious spelling errors. For discrepancies that require

clarifications from the investigator, DCFs will be sent to the site. The CDM tools help in the

creation and printing of DCFs. Investigators will write the resolution or explain the

circumstances that led to the discrepancy in data. When a resolution is provided by the

investigator, the same will be updated in the database. In case of e-CRFs, the investigator can

access the discrepancies flagged to him and will be able to provide the resolutions online.

Figure 2 illustrates the flow of discrepancy management.

The CDM team reviews all discrepancies at regular intervals to ensure that they have been

resolved. The resolved data discrepancies are recorded as ‘closed’. This means that those

validation failures are no longer considered to be active, and future data validation attempts

on the same data will not create a discrepancy for same data point. But closure of

discrepancies is not always possible. In some cases, the investigator will not be able to

provide a resolution for the discrepancy. Such discrepancies will be considered as

‘irresolvable’ and will be updated in the discrepancy database.

Discrepancy management is the most critical activity in the CDM process. Being the vital

activity in cleaning up the data, utmost attention must be observed while handling the

discrepancies.

7.Case narrative

Provides summary of events to readers who do not have access to original data sets. During

the course of safety data management, it is seen and used by various groups like case

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reviewers to decide seriousness, upgrade etc., affiliate companies to triage for their countries,

during preparation of PSURs and other summary reports and also by regulatory authorities.

One should ensure completeness, chronology and sufficient detail in a narrative so that the

reader is able to come to a conclusion.

7.1.Coding of adverse reactions

This step ensures that everyone is talking the same language and the data can be shared

internationally, most commonly used system is the MedDRA (Medical Dictionary for

Regulatory Activities). Use of MedDRA has lead to a global standardization across

regulatory agencies, across companies & across countries. This step usually needs oversight

by a medically qualified person.

7.2.Coding of drugs

Both the suspect drug and concomitant medication have to be coded. The principle is again to

be talking the same language across countries, companies and regulatory bodies. Most

common dictionary is the WHO Drug Dictionary enhanced. This is provided as a product by

the Upsala Monitoring centre of the WHO. Entries are updated 4 times a year. The majority

of entries refer to prescription-only products, but some over-the-counter (OTC) preparations

are included. The dictionary also covers biotech and blood products, diagnostic substances

and contrast media. For chemical and therapeutic groupings, the WHO drug record number

system and ATC classifications are considered.

Medical coding helps in identifying and properly classifying the medical terminologies

associated with the clinical trial for classification of events, medical dictionaries available

online are used. Technically, this activity needs the knowledge of medical terminology,

understanding of disease entities, drugs used, and a basic knowledge of the pathological

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processes involved. Functionally, it also requires knowledge about the structure of electronic

medical dictionaries and the hierarchy of classifications available in them. Adverse events

occurring during the study, prior to and concomitantly administered medications and pre- or

co-existing illnesses are coded using the available medical dictionaries. Commonly, Medical

Dictionary for Regulatory Activities (MedDRA) is used for the coding of adverse events as

well as other illnesses and World Health Organization–Drug Dictionary Enhanced (WHO-

DDE) is used for coding the medications. These dictionaries contain the respective

classifications of adverse events and drugs in proper classes. Other dictionaries are also

available for use in data management (eg, WHO-ART is a dictionary that deals with adverse

reactions terminology). Some pharmaceutical companies utilize customized dictionaries to

suit their needs and meet their standard operating procedures.

Medical coding helps in classifying reported medical terms on the CRF to standard dictionary

terms in order to achieve data consistency and avoid unnecessary duplication. For example,

the investigators may use different terms for the same adverse event, but it is important to

code all of them to a single standard code and maintain uniformity in the process. The right

coding and classification of adverse events and medication is crucial as an incorrect coding

may lead to masking of safety issues or highlight the wrong safety concerns related to the

drug.

7.3.Causality assessment

 Non spontaneous case reports usually indicate whether an adverse drug reaction is

suspected due to the administered drug. In these circumstances and even otherwise, a

causality assessment is required to be conducted. Various approaches have been

developed for the structured determination of the likelihood of a causal relationship

21
 between drug exposure and adverse events. These systems are largely based on

following considerations:

 The chronology or association in time (or place) between drug administration and

event.

 Current knowledge of nature and frequency of adverse reactions due to the suspect

molecule; or the pharmacology.

 Medical or pharmacological plausibility based on signs and symptoms, laboratory

tests, pathological findings, mechanism of action Likelihood or exclusion of other

causes for the same adverse events; often the disease condition or concomitant

medication. Timely reporting to authorities:

 This is the end goal for which all the above has to be done in a timely manner. The

reporting could be by sending data back to the sponsor or by a click of a button based

on the software used. The latter will provide an extra couple of days for case

processing Safety data management is the most basic step in pharmacovigilance. This

is often outsourced so that internal company resources can focus on the domain

related, mentally stimulating activities like signal detection, regulatory responses,

information to stakeholders

22
 Fig-6. Clinical Data Management

management and output production, but, ultimately, also the pharmacovigilance end users,

the patients.

Risk assessment during clinical product development needs to be conducted in a thorough

and rigorous manner. However, it is impossible to identify all safety concerns during

controlled clinical trials. Once a product is marketed, there is generally a large increase in the

number of patients exposed, including those with comorbid conditions and those being

treated with concomitant medications. Therefore, post marketing safety data collection and

clinical risk assessment based on observational data are critical for evaluating and

characterizing a product’s risk profile and for making informed decisions on risk

minimization. Information science promises to deliver effective e-clinical or e-health

solutions to realize several core benefits: time savings, high quality, cost reductions, and

23
increased efficiencies with safer and more efficacious medicines. The development and use

of standard-based pharmacovigilance

Fig.7. Data Processing

system with integration connection to electronic medical records, electronic health records,

and clinical data management system holds promise as a tool for enabling early drug safety

detections, data mining, results interpretation, assisting in safety decision making, and

clinical collaborations among clinical partners or different functional groups.

The availability of a publicly accessible global safety database updated on a frequent basis

would further enhance detection and communication about safety issues. Due to recent high-

profile drug safety problems, the pharmaceutical industry is faced with greater regulatory

enforcement and increased accountability demands for the protection and welfare of patients.

This changing climate requires biopharmaceutical companies to take a more proactive

approach in dealing with drug safety and pharmacovigilance.

24
Clinical Data Management (CDM) is an important phase in clinical research, which leads to

generation of high-quality, reliable, and statistically sound data from clinical trials.CDM

assures collection, integration and availability of data at appropriate quality and cost. Clinical

Data Management supports the conduct, management and analysis of studies across the

spectrum of clinical research. Pharmacovigilance (PV) is also known as Drug Safety, is the

pharmacological science relating to the collection, detection, assessment, monitoring, and

prevention of adverse effects with pharmaceutical products. As such, pharmacovigilance

mainly focuses on adverse drug reactions (ADRs), which are defined as any response to a

drug which is noxious and unintended, including lack of efficacy

The Primary aim and scope of the course is to make the candidates employable as Manager,

Medical Advisor, Pharmacovigilance Specialist/Expert/Scientist, CDM Specialist, CDM Data

Analyst, Clinical Data Coordinator, Clinical Data Manager, etc. in BPOs, Pharmaceutical

companies, Contract Research Organizations (CROs), Support Staffs for Clinical Data

Management and Biostatistics services to various clients involved with Clinical Research etc.

The Program also serves as a sound introduction to CDM and PV domain for other potential

players in the industry such as medical practitioners, pharmaceutical scientists etc.

In the wake of recent drug withdrawals, to regain the trust of patients, health care providers

and regulators demand that biopharmaceutical or medical device firms show a demonstrated

commitment to safety that goes beyond mere compliance. In today’s world,

pharmacovigilance pushes new boundaries and it is no longer sufficient to simply report

adverse events along with efficacy and quality requirements. Regulators are demanding

proactive surveillance programs that include comprehensive risk management plans and

signal detection/analysis throughout a clinical product’s lifecycle. Organizations that take the

lead in developing a more proactive and long-term approach to manage the safety of their

products recognize that success requires a continuous, consistent process from preclinical

25
research onward. This is achieved through developing a good clinical safety practice that

shows the company was aware of and acted on every safety issue as it developed for a

product or device. In this review, we seek to clarify some of the issues that are central to

current discussions about pharmacovigilance, focusing on topics critical to biopharmaceutical

or medical device companies with marketed products in human use. This paper is prepared

from industry perspectives to present and analyze benefits, advantages, challenges and risks

associated with pharmacovigilance based on systematic overview.

8.Pharmacovigilance and risk management

Biosimilars cannot be authorized based on the same requirements that apply to generic

medicines. Despite the fact that the biosimilar and reference drug can show similar efficacy,

the biosimilar may exhibit different safety profile in terms of nature, seriousness or incidence

of adverse reactions. However, the data from pre-authorization clinical studies normally are

insufficient to identify all potential differences. Therefore, clinical safety of similar biological

medicinal products must be monitored closely on an ongoing basis during the post-approval

phase including continued risk–benefit assessment.

26
 Fig.8. Risk Management Plan

The biosimilar applicant must provide the European Medicines Agency (EMEA) with a risk

management plan (EU-RMP) and pharmacovigilance programme with its application,

including a description of the potential safety issues associated with the similar biological

medicinal product that may be a result of differences in the manufacturing process from the

reference biologic. The most critical safety concern relating to biopharmaceuticals (including

biosimilars) is immunogenicity.

Risk management applies scientifically based methodologies to identify, assess, communicate

and minimize risk throughout a drug’s life cycle so as to establish and maintain a favourable

benefit–risk profile in patients. The risk management plan for biosimilars should focus on

heightens the pharmacovigilance measures, identify immunogenicity risk and implement

special post-marketing surveillance.

27
Although International Non-proprietary Names (INNs) served as a useful tool in worldwide

pharmacovigilance, for biologicals they should not be relied upon as the only means of

product identification. Biologic

Data management is a vital part of PV as there is continuous generation of patient safety data.

Adverse event information can be generated from various modes, for example, clinical trials,

post marketing programs, spontaneous reports, and literature or legal reports. This

information needs to be collected and reported to the regulatory authorities for analysis. The

role of a case processor is to monitor and track all serious adverse events, serious and

medically significant adverse drug reactions (ADRs), and other medical-related product

information followed by timely processing and reporting of such information in accordance

with the company and regulatory reporting timelines. The case processor usually has an

educational background in one of the life sciences (e.g., nursing, pharmacy, or other allied

health professionals); it is also advantageous to have a working knowledge of medical

terminologies. This article describes the activities a case processor performs every day,

during PV data management.

9.Role of case processor

The role of a case processor is to monitor and track all serious adverse events, serious and

medically significant adverse drug reactions (ADRs), and other medical-related product

information followed by timely processing and reporting of such information in accordance

with the company and regulatory reporting. In some organizations, an associate is expected to

work on various activities. In others, the associate works in specific team, for example., case

receipt team, triage team, data entry team, and quality control team. Below is the process

flowchart of the steps required in case processing.

28
9.1.Case receipt Mailbox management

The first thing a case processor will do is to check the email after logging in to the system.

This allows the case processor to check the number of cases that have been assigned and also

allows the associate to go through any feedback or other communication from the

stakeholders.

Once the assigned cases are identified, the case processor starts working on them.

9.2.Validity assessment

After receiving the source document (via email, fax, or phone), the case processor will look

for the minimum information which is required for a valid safety report, i.e., an identifiable

patient, an identifiable reporter, an adverse event/reaction, and a suspect or interacting drug.

9.3.Triage

Under this step, the case processor prioritizes all the incoming reports as per the receipt date,

seriousness, causality, and expectedness assessment in the triage step. Once the cases are

triaged, they can be processed as per the priority assigned to each case.

This is done to ensure that cases which need expedited reporting can be processed and

submitted to the regulatory authorities within timelines.

Standard regulatory timelines are as follows:

As per the International Council for Harmonization of Technical Requirements for

Registration of Pharmaceuticals for Human Use E2A guideline, fatal or life-threatening

unexpected ADRs should be notified to regulatory agencies within 7 days and all other

serious, unexpected ADRs within 15 days.

29
9.4.Coding the adverse events and drugs

This step involves coding of the adverse events in the Medical Dictionary for Regulatory

Activities (MedDRA). MedDRA is a single standardized international medical dictionary

which can be used for regulatory communication and evaluation of data pertaining to

medicinal products for human use.

The case processor can auto code the event term (auto code: when the term has an exact

match in MedDRA) or code it manually if the exact match is not available in MedDRA. The

principle is to be talking the same language across countries, companies, and regulatory

bodies.

9.5.Causality assessment

A causality assessment is the relationship between the drug treatment and the occurrence of

an adverse event. The case processor enters the reporter’s causality assessment (whether

event is related to the drug: yes/no/not reported) in this section.

If the reporter has not provided the causality assessment, the case processor can also assess

the case causality. Various approaches have been developed for the structured determination

of the likelihood of a causal relationship between drug exposure and adverse events. The case

processor can apply the systems which are largely based on the following considerations:

The chronology or association in time (or place) between drug administration and the event

Current knowledge of nature and frequency of adverse reactions due to the suspect molecule,

or the pharmacology of the drug

Medical or confounders based on signs and symptoms, laboratory tests, pathological findings

and mechanism of action

30
Likelihood or exclusion of other causes for the same adverse events, often the disease

condition or concomitant medication.

9.6.Expectedness assessment

The case processor goes through the reference safety documents to check whether the ADR

which is reported is listed/expected in the reference safety information (RSI) document or

not. The RSI is a list of medical terms detailing the Serious Adverse Reactions (SARs) that

are expected for the investigational medicinal products (IMP) and is used by investigators as

a reference point when assessing a SAR to determine whether it is a SUSAR. Various

sections of the RSI need to be carefully checked, especially the undesirable effect section. An

“unexpected” adverse reaction is one, the nature/severity/specificity/outcome of which is not

consistent with the information in the relevant source documents.

9.7.Case narrative

The case processor describes the story of the entire case in this section. The case processor

can use predefined templates for writing narratives as per the customer requirements. The

associate provides a summary of the events to the readers, ensure completeness, chronology,

and sufficient detail in a narrative so that the reader can come to a conclusion. The inputs

given by the medical reviewers can also be incorporated in the safety narrative of the case.

9.8.Self-quality check

The associate does a self-quality check for the case before the case is pushed to the next

workflow. The associate ensures the completeness and accuracy of the information entered

into the database for all the cases. This is a very crucial step, especially when the associate is

working on Suspected Unexpected Serious Adverse Reaction or fatal cases.

31
The associate will also draft queries for the missing information in the case. These queries

are sent to the reporter, and once the reply is received, the data is updated in the case. The

case processor will also ensure proper follow-up with the reporter if there is no response after

sending the first query. Follow-up activities involve contacting the reporter via mail, fax, or

phone. Apart from all these activities, the case processor is also expected to take part in audit

meetings, training refreshers, ensuring training compliance, and maintaining up-to-date

knowledge of global drug safety regulations.

10.Case processing significance

For the case processor, every case is different, even within the same study. In fatal cases, the

case processor will have to check many things such as the cause of death and autopsy details,

whereas in other scenarios, the processor will have to check adverse events of special

interests and important medical events and report the same to the stakeholders. The case

processor should ensure that there are no grammatical/spelling errors in the case, while

routing it to thenext workflow. The case processor shares the best practices, which help other

associates to

Fig.9. Case Processing Significance

32
next workflow. The case processor shares the best practices, which help other associates to

dotheir job efficiently. It may seem that the case processor’s job could become mundane

after a few months; however, for a case processor, every day and every case is a new

experience. There is continuous learning from each and every case which will have new

information, thereby increasing the learning curve. This experience will also help the

processor in future scenarios.

11.Book-in and registration

Once the case processor has completed duplicate search for a case in database, there are two

ways of processing a case.

They are as follows:

 Upon positive duplicate search, i.e., when the processor finds a case in the database,

the processor can add a follow-up to the existing case and process the information

 Upon negative duplicate search, i.e., when the processor does not find any case in the

database, the case processor will create a new case to process the information.

33
 12.CONCLUSION

Pharmacovigilance data management has evolved in response to the ever-increasing demand

from pharmaceutical companies to fast-track the drug development process and from the

regulatory authorities to put the quality systems in place to ensure generation of high-quality

data for accurate drug evaluation. To meet the expectations, there is a gradual shift from the

paper-based to the electronic systems of data management. Developments on the

technological front have positively impacted the CDM process and systems, thereby leading

to encouraging results on speed and quality of data being generated. At the same time,

Pharmacovigilance data management professionals should ensure the standards for

improving data quality. Pharmacovigilance data management, being a speciality in itself,

should be evaluated by means of the systems and processes being implemented and the

standards being followed. The biggest challenge from the regulatory perspective would be

the standardization of data management process across organizations, and development of

regulations to define the procedures to be followed and the data standards. From the industry

perspective, the biggest hurdle would be the planning and implementation of data

management systems in a changing operational environment where the rapid pace of

technology development outdates the existing infrastructure. In spite of these,

Pharmacovigilance data management is evolving to become a standard-based clinical

research entity, by striking a balance between the expectations from and constraints in the

existing systems, driven by technological developments and business demands.

34
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