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10 Spontaneous Reporting Systems

235

Fig. 10.2 CIOMS I Form for reporting of ICSR (cioms.ch/cioms-i-form)

236

J. Petracek and M. Fialova

3 Origins ofSpontaneous

Reporting Systems

While the history of pharmacovigilance is as old as the human civilisation, the spontaneous reporting system is a relatively recent component. Various players developed multiple versions of spontaneous reporting in response to the thalidomide tragedy in the 1960s.

Chemie Grünenthal developed thalidomide in Germany shortly after the Second World War. It rst entered the German market in 1957 as a sedative and mild hypnotic, available even without a prescription. It was widely marketed for morning sickness in pregnancy with great commercial success. By 1960, thalidomide was sold in 46 countries [2].

In 1961, Dr. WG McBride, based in Australia, sent a letter to Lancet (Fig.10.3) announcing his observation ‘that the incidence of multiple severe abnormalities in babies delivered of women who were given the drug thalidomide (‘Distaval’) during pregnancy as an anti-emetic or as a sedative, to be almost 20%, asking whether anybody else has observed similar abnormalities’ [3].

At the same time, during a Paediatric Convention in Germany, Dr. Lenz suggested a correlation between malformations and thalido-

mide. His suspicion was published in a German Journal (Welt am Sonntag) [4].

Chemie Grünenthal formally withdrew the drug on 26 November 1961 in Germany and other European countries. In the USA, the drug was never approved thanks to the very cautious assessor at US FDA—although this was not because of concerns about birth defects [5]. Nevertheless, it took many years for thalidomide to be eventually removed from the market worldwide, as it was marketed under various names, by many pharma companies, and in developing countries. More than 10,000 babies have been born with phocomelia and other anomalies, affecting millions of people, including families, caregivers, and many communities.

At the time, there was no single place where the suspicions of adverse effects of medicines could be reported. It took many years before the observations of individual physicians were put together and an association could be hypothesised.

The legal amendment in the United States of America (USA) (1962) required drug safety and efcacy data before marketing approval was passed. Since then, the safety data must include teratogenicity tests in different animals [6]. In 1964, the United Kingdom(UK) introduced the

THALIDOMIDE AND CONGENITAL

SIR,

Congenital abnormalities are present in approximately 1.5% of babies. In recent months I have oberved that the incidence of multiple severe abnormalities in babies delivered of women who were given the drug thalidomide (“ Distaval ”) during pregnancy, as an antiemetic or as a sedative, to be almost 20%. These abnormalities are present in structures developed from mesenchyme–i.e., the bones and musculature of the gut. Bony development seems to be affected in a very striking manner, resulting in polydactyly, syndactyly, and failure of development of long bones (abnormally short femora and radii). Have any of your readers seen similar abnormalities in babies delivered of women who have taken this drug

Confluence of data

Fig. 10.3 McBride’s letter and important elements forming spontaneous reporting [3]

during pregnancy?

Hurstville, New South Wales.

ABNORMALITIES

W. G. McBRIDE.

ADR

Risk group

Increased frequency

10 Spontaneous Reporting Systems

237

‘Yellow Card’ system. The Yellow Card is a specic form for collecting a spontaneous report of suspected ADRs [7].

In Europe (1965), the disaster of thalidomide stimulated the development of European legislation with the EC Directive 65/65. It established the foundations of pharmacovigilance and development ofADR reporting systems.

In 1966, a pilot study of the Boston Collaborative Drug Surveillance Program started [8]. It was the rst group to conduct epidemiologic research to quantify the potential adverse effects of drugs. Paper-based in-hospital monitoring and early utilisation of computers played an essential role in developing and applying methods in drug epidemiology, broadly informing the design of pharmacovigilance systems.

In 1968, the World Health Organization (WHO) established a Programme for International Drug Monitoring. Ten member states initially piloted the programme (Australia, Canada, Czechoslovakia, Federal Republic of Germany, Ireland, Netherlands, New Zealand, Sweden, the UK, and the USA). Today, over 170 members contribute to one central database of ICSRs—VigiBase [9].

4 National andGlobal

Spontaneous Reporting Systems

The organisation of spontaneous reporting systems varies around the world. Health professionals, and sometimes patients or consumers, may send reports of adverse experiences to one or more specied locations. These locations can be the drug regulatory authority, an academic or hospital-based pharmacovigilance centre, or the drug manufacturer.

Member states of the WHO Programme for International Drug Monitoring share information with the Uppsala Monitoring Centre (UMC)that operates the programme for WHO.All the reports are available in VigiBase, the world’s richest source of pharmacovigilance data. Regulatory authorities may access VigiBase fully. Selected services and datasets are also available to other interested parties.

5 Types of Individual Case

Safety Reports

5.1 Adverse Events andAdverse Drug Reactions

The level of suspicion for the causal relationship between the exposure to the medicinal product and the described adverse experience determines whether the ICSR would be considered an AEor an ADR.

While there are many local variations of denitions of AEs and ADRs, the ICH guidelines is a good source of denitions for global applications.

An adverse event (AE) is any untoward medical

occurrence in a patient administered a medicinal

product and which does not necessarily have to

have a causal relationship with this treatment. An

adverse event can therefore be any unfavourable

and unintended sign (for example, an abnormal

laboratory nding), symptom, or disease tempo-

rally associated with the use of a medicinal prod-

uct, whether or not considered related to this

medicinal product. (ICH E2D)

Adverse Drug Reaction is a noxious and unin-

tended response to a medicinal product related to

any dose. The phrase "response to a medicinal

product" means a causal relationship between a

medicinal product and an adverse event is at least

possible. (ICH E2D)

In contrast to an AE, an ADR is characterised by a suspected causal relationship between the drug and the occurrence. In many countries, the term ‘suspected adverse drug reaction’ is used to further stress the uncertainty around causality to protect reporting parties from potential legal consequences associated with communication about this information. Thus, communicating about suspected ADRs does not mean the parties acknowledge the causal relationship.

5.2 Special Situations

Special situations are observations that provide valuable safety information about the medicinal product while not meeting thedenition of anAE or ADR.They are the third category of ICSRs,

238

Special situations

Ov Of Dr

Dr Medication err

Lac Lac Ef

Pr Occupational e Dr

Use of medicinal pr in a paediatr population

Use of medicinal pr dur br

Discontinued pr

Unusual f Ef ne

Administration, Health Canada- Drug regulatory agency of Canadian government

J. Petracek and M. Fialova

other than ADRs and AEs, that may be reported via spontaneous systems. However, in some regions (e.g. EEA) they should be reported only in case they are related to an ADR.

between regions. Globally, they include the following concepts:

• Overdose

• Off-label use

• Drug abuse

• Drug misuse

• Medication errors

• Lack of efcacy

• Use of product in pregnancy or breast-feeding

• Occupational exposure

situations according to different terms of reference [10].

Fig. 10.4 Overview of special situations according to different terms of reference (example fromiViReg system, 2023) [10]

All spontaneous reporting systems must acknowledge reports of special situations and be able to process them accordingly.

Denition of special situations may vary

5.3 Implied Causality of

Spontaneous Individual Case Safety Reports

Aspontaneous reporter’s motivation to share an ICSR is not solicited but related to some suspicion that an event is related. As the effort to report is not insignicant, the pharmacovigilance regulatory environment acknowledges this effort by considering all spontaneously reported ICSRs as having some level ofimplied causality.

Therefore, all spontaneously reported ICSRs

Figure 10.4 provides an overview of special

GVP MedDRA FDAHealth Canada

erdose

f-label use

ug abuse

ug misuse

ors

k of Efficacy (LOE)/ k of Therapeutic

ficacy

egnancy

xposure

ug addiction

oduct

ic or elderly

oduct

ing pregnancy or

eastfeeding

oduct quality issues

oducts

ailure to

ficacy (only applies to

w drugs)

GVP-Good Pharmacovigilance Practice, MedDRA- Medical Dictionary for Regulatory Activities, FDA- Food and Drug

are classied as reports of suspected ADRs. While pharmaceutical companies and regulatory authorities may provide their own causality

10 Spontaneous Reporting Systems

239

assessment of the reported cases, they cannot dispute the implied causality of spontaneous reports to distribute the report further.

5.4 Individual Case Safety ReportsLinked withProduct Quality Defects or Falsied Medicines

Should an ICSR be connected with a product quality complaint, the marketing authorisation holder(MAH) shall investigate whether the product met the approved quality criteria. If not, the ICSR is marked as related to product quality and shall not be used in pharmacovigilance assessment.

Pharmacovigilance systems are primarily designed for the situation where medicinal products are of good quality, and still, an adverse experience is observed. If the adverse experience is explainable by substandard quality or exposure to a falsied medicine, then product manufacturing quality departments shall attend to the issue immediately.

6 Sources of Spontaneous

Individual Case Safety Reports

6.1 Healthcare Professional

Reports andConsumer (Patient) Reports

Spontaneous ICSRs originate at the point of medical care. Healthcare professionals or patients may report them via various channels. These include traditional paper reports via post, fax, email, web, or mobile phone applications. Many countries have designed their forms in ofcial languages, mostly based on the CIOMS form (Fig.10.2).

While some spontaneous reporting systems were once restricted only to reports from healthcare professionals, there has been growing recog-

nition of the importance of patient reports. Many systems now accept patient-generated reports. For example, Italy, Denmark, Netherlands, and Sweden have accepted patient reports since the early 2000s, while Australia has accepted them since 1964. The USA, which has accepted consumer ICSRs since 1969, developed the MedWatch programme in 1993 to facilitate AE reporting from patients and healthcare professionals [11]. Nonetheless, even in 2012, some countries with highly developed regulatory systems were not actively collecting patient reports. Of the50 countries with developed drug regulatory systems surveyed in 2013, 44 had direct patient reporting systems, 17 of which were started onlyin 2012 or 2013 [12].

There is no internationally recognised denition of a ‘patient report’. ICH E2D denes a ‘consumer’ as ‘a person who is not a healthcare

professional such as a patient, lawyer, friend, or relative of a patient’ and notes that ‘consumers’

can submit AE reports. There is growing evidence that patient reports are a valuable source of information. They often contain more details than reports generated by healthcare professionals and can serve to complement those reports [13].

A study of the UK’s Yellow Card system, which allows spontaneous reporting by healthcare practitioners and patients, found that reports generated by patients had a higher median number of suspected ADRs per report. They also had a higher median word count, more detailed information about symptoms, and more description of the emotional and social impact of the AE [14].

A study comparing AE reports submitted by patients and those submitted by healthcare professionals to the Dutch National Pharmacovigilance Centre, Lareb, found that patient reports were comparable to those from health professionals for causality analysis [15]. Similarly, a UMC–Lareb collaboration assessed the contribution of patient reports to global signal detection in VigiBase. It concluded that patient reports provide unique information valuable in

240

J. Petracek and M. Fialova

signal assessment and recommended their inclusion in signal detection processes [16]. Publications also show thatin at least one pharmaceutical company’s AE database, signals were detected earlier when patient reports were included than when only reports from healthcare providers were included [17].

Given the potential importance of patient reporting, efforts have been made to encourage and simplify it. In 2012, WHOpublished a guide for countries to use in setting up a reporting system for the general public, which recommends that a patient reporting system ideally be established in an existing spontaneous reporting system. The patient reporting form may be a dedicated one or the same form used by health professionals, but it should be understandable by a layperson. Education of the public on the importance of patient reporting and training of pharmacovigilance staff in assessing patient reports is recommended.

A discussion on the active involvement of patients in medication safety is elaborated in Chap. 12.

6.1.1 Reporting from Clinical Practice

Process of reporting ADRs in clinical practice may vary signicantly and needs to consider local requirements. Many countries have set up local pharmacovigilance centres, often teaching hospitals coordinating the local efforts. All leading physicians should ensure juniors are well trained in differential diagnoses that include ADRs as potential cause of the patient’s condition. When a suspicion is raised, the reporting should be as easy as possible, with procedural and technical support given to healthcare professionals. In addition to the physicians, other healthcare professionals whoactively involve in the spontaneous reporting are pharmacists, nurses, and dentists. Clinical pharmacists and clinical pharmacologists are the professionals who usually initiate and coordinateADR reporting programmes within the hospital setup, and the same supports the national pharmacovigilance activities.

Culture inuences the willingness to talk about ADRs and sharing experience about them. Open and transparent culture leads to much higher likelihood of clinicians sharing the information and learning from it.

Pharmaceutical industry has a very signicant role in continuous education including pharmacotherapy. It should be performed observing high standards of ethics, as cited in many internal and external documents, including guidance from the WHO [18].

6.2 Individual Case Safety

Reports from Social Media

Social media includes a wide, and constantly changing, range of computer-based technologies that allow the creation [18] and sharing of information, ideas, photographs, and other messages via electronic communication. User-generated content is a dening feature of social media. This content can be made available to others via computer-based networks that connect one user with the other users or groups to form social networks. Given the widespread use of the internet and social media for health-related topics, there is interest in whether social media can be a source of drug safety signals or otherwise shed light on ADRs [19].

Because social media posts describe individual experiences, they can also describe adverse reactions to medicines. The use of social media for pharmacovigilance presents both opportunities and challenges. With an estimated 2.5 billion social media users worldwide, including in parts of the world where formal pharmacovigilance programmes are not highly developed, social media can be a source of patient- and consumer- generated information about AEs. The ability to tap into this potential source of information is especially relevant, given the growing importance of, and attention to, patient- and consumer- generated reports in pharmacovigilance.

The use of social media for pharmacovigilance is an area of active research to address these

10 Spontaneous Reporting Systems

241

challenges. Current research focuses on using natural language processing and other techniques, such as supervised machine learningand large language model (LLM) on identifying drug-related AEs in social media. One of the biggest challenges in this regard is the distinction of drug mentions associated with an AE from those with no association with an AE [20].

Another area of research is determining the utility of social media in pharmacovigilance. In 2014, the Innovative Medicines Initiative (IMI), a public–private partnership between the European Union and the European Federation for Pharmaceutical Industries and Associations, launched WEB-RADR: Recognising Adverse Drug Reactions to develop new technology tools to facilitate the detection and analysis of potential ADRs in social media sites. It also aimed to create a mobile phone app for reporting suspected ADRs to regulatory authorities in the European Union (in the context of traditional AE reporting). One of several planned outgrowths of these efforts is establishing a regulatory framework for social media mining for ADRs.

7 Quality of Individual Case

Safety Reports

The quality of reports in pharmacovigilance varies signicantly. Despite standardisation, differences in training, national healthcare cultures, languages, tools, technologies, pharmacovigilance practices, and many other factors inuence the quality of reports. Poor quality reportsmay lead to awed data analysis and delays or fails to detect signals of potential harm. A commonly used phrase to describe this problem is ‘rubbish in, rubbish out’.

Reporting clinicians should provide as muchrelevant information for the proper assessment of the case that may be available to them. There is very low threshold of reporting enabling a maximum of initial reports to be captured. The initial reports are then followed up to collect as much relevant information as possible (Sect. 7.2), with a focus on those of a more serious nature.

7.1 Validity of Individual Case Safety Reports

The rst crucial qualitative requirement is a socalled report’s validity. Only valid reports are exchanged between the parties in the national and global pharmacovigilance system. Invalid reports are stored by the rst receiver, who must attempt follow-up to validate the ICSR.

Four minimum criteria are required for ICSR

validation:

1. One or more identiable reporter

2. One single identiable patient

3. One or more suspected substance/medicinal

product

4. One or more suspected adverse reaction

7.2 Follow-Up of Individual Case Safety Reports

Follow-up means contacting the reporter for further information about the case. The rst receiving party usually performs a follow-up of a spontaneous ICSR. Typically, follow-up questions are prepared for the telephone, email, or letter conversation with the reporter.

All invalid ICSRs must be followed up until validated or until further attempts are considered futile. Most authorities and pharmaceutical companies perform between zero and three attempts to follow up on spontaneous ICSRs, based on their internal prioritisation system.

8 Processing of Spontaneous

Individual Case Safety Reports

Both industry and regulatory authorities have developed advanced systems for processing ICSRs from any source, including spontaneous reports. As technology progresses and the industry prepares for technological changes, the harmonisation of case processing approaches has reached a new level of maturity.

242

Redaction

ocessing

J. Petracek and M. Fialova

As clinicians are often interested in the fate of their reports, a high-level description of the process may be helpful for a better understanding of modern spontaneous reporting systems and what they serve to.

8.1 Case Intake

The rst step of case processing is case intake. It is typically designed to meet the local requirements and adjust to local conditions based on culture, language, and technology.

Case intake should be able to process any ICSR from any source, acknowledge receipt, meet local distribution requirements, and prepare the received piece of information for case processing in the central pharmacovigilance database system. An example of the process developed by one of the industry consortiums (Transcelerate, see www.transceleratebiopharmainc.com) is provided in Fig.10.5.

8.2 Case Processing

ICSRs from case intake are processed in the central safety systems of regulatory authorities and MAHs. The technological solution varies among the pharmacovigilance players signicantly. However, a signicant level of harmonisation has been achieved. Nowadays, case processing usually encompasses a set of steps (Transcelerate, see www.transcelerate-

biopharmainc.com) depicted in the owchart in

Fig.10.6.

8.3 Case Reporting

Processed cases are further distributed as per reporting requirements. Typically, the pharmaceutical industry must report to regulatory authorities. Regulators then report to the global WHO database (VigiBase). Competent authorities also make the ICSRs available to MAHto download and process in their system. This way,

Data Sources

Data

Acquisition

Acknowledgement of receipt

Prepare and

Send to Global Site

Fig. 10.5 Case intake owchart (developed by Transcelerate)

Inputs (e.g., spontaneous report, clinical trials, literature)

Case

Validation

Local

Structuring

Complete intake form

Local

Tracking

Entry into local system

Local

Submissions

Duplicate

Check

Alert Case

of Interest