A

Project Report

ON

Pharmacovigilance Data Management and Case processing

Subject: Project Work Paper Code: BP813PW

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., Principal & Dean,

BBDU 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 & 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
to Mrs. 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 1-3

2. Data management in pharmacovigilance 4

3. Data quality management in pharmacovigilance 5

4. Data collected for pharmacovigilance 6

5. Data management in clinical research 6-10

6. Case processing 10-16

7. Case narative 17-22

8. Pharmacovigilance and risk management 22-24

9. Role of case processor 24-27

10. Case processing significance 28

11. Book-in and registraion 29

12. References 30-31

0
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.[1]

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 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. [2]

1
 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, assessment of drug-related

mortality, abuse and misuse of health products, and adverse interactions of medicines with chemicals and

other drugs.

2
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. [3]

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.

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. [4]

3
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 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.[5]

4
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. [6]

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 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. [7]

5
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.[8]

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 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.[9]

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.

6
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. [10]

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
7
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.

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.

8
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 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

9
Guide for Human Clinical Trials (SDTMIG) and the Clinical Data Acquisition Standards Harmonization

(CDASH) standards, available free of cost from the CDISC website (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.[11]

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

 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

10
 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.

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.[12]

11
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.

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

12
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, 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

13
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.

(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,

14
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 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.[13]

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.

15
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 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. [14]

16
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 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 processes involved. Functionally, it also requires knowledge about the

17
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 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.

18
  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

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
19
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 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.

20
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.

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

21
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 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.[15]

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.

22
 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.

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

23
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. [16]

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.

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

24
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. [17]

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.

25
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

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.
26
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.

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. [18]

27
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

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

do their 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.[19]

28
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.[20]

29
 Reference

1.Friedman M. Lawrence, Furberg D. Curt, DeMets L. David;” FUNDAMENTALS OF CLINICAL

TRIALS”; Third Edition; published by Springer International; Page No.2

2.Tripathi K.D.; “ESSENTIALS OF MEDICAL PHARMACOLOGY”; 8TH EDITION; published by

Jaypee Brothers Medical; Publishers(P) Ltd.; Page no. 74

3.Schneiderman MA: Mouse to man: statistical problems in bringing a drug to clinical trial, Proceedings of

the Fifth Berkeley Symposium on Mathematical Statistics and Probability, Univ of California 4:855-

866,1967

4.Storer BE: Design and analysis of phase 1 clinical trials, Biometrics 45:925-937,1989.

5.” Clinical Trial Delays: America‟s Patient Recruitment Dilemma,” Drug development-

technology.com(2012),https://www.drugdevelopmenttechnology.com/features/featureclinical-trial-patient-

recruitment [accessed March 20,2013]

6.National Commission for the Protection of Human Subjects of Biomedical and Behavioural Research: The

Belmont Report: ethical principles and guidelines for the protection of human subjects of research, Fed

Regist 44:23192-23197,1979.

7.Davies LG: Observer variation in reports on electrocardiograms, Br Heart J 20: 153-161, 1958.

8.Dent NJ: European good laboratory and clinical practices: their relevance to clinical pathology

laboratories, Qual Assurance: Good Prac, Regul , Law 1: 82-89, 1991.

9.Feinstein AR, Gelfman NA, Yesner R et al: Observer variability in the histopathologic diagnosis of lung

cancer, Am Rev Respir Dis 101: 671-684,1970.

10. Ferris FL, Ederer F: External monitoring in multi clinic trials: applications from ophthalmologic studies,

Clin Pharmacol Ther 25: 720-723.1979.

30
11.Furberg CD, Byington RP, Craven T: Lessons learned from clinical trials with ultrasound endpoints, J

Intern Med 236:575-580,1994.

12.Koran LM: The reliability of clinical methods, data and judgements. Part 1, N Engl J Med 293:642-

646,1975.

13.Procock SJ: Clinical trials. A practical approach, Chichester, 1983, John Wiley & Sons.

14.Quality assurance of clinical data: Discussion, Clin Pharmacol Ther 25:726-727,1979.

15.Shapiro MF, Charrow RP: Scientific misconduct in investigational drug trials, N Engl J Med 312:731-

736, 1985.

16.Shapiro MF, Charrow RP: The role of data audits in detecting scientific misconduct, JAMA 261: 2505-

2511,1989.

17.Weiss RB, Vogelzang NJ, Peterson BA et al: A successful system data audits for clinical trials,

Circulation 87(suppl II)9: II38-II47, 1993.

18.Wright P, Haybittle J: Design of forms for clinical trials, BMJ 2:529-530,590-592, 650-651,1979.

19.Neaton JD, Duchene AG, Svendsen KH, Wentworth D: An examination of the efficacy of some quality

assurance methods commonly employed in clinical trials, Stat Med 9: 115-124,1990.

20.Byar DP, Simon RM, Friedward WT et al: Randomised clinical trials: perspectives on some recent ideas,

N Engl J Med 295: 74-80, 1976.

31