Pharmacovigilance- History, Need of PV, ADR reporting, Individual Case Report Forms

1. PHARMACOVIGILANCE

2. It is the pharmacological science relating to the collection, detection,
assessment, monitoring and prevention of Adverse reactions with
Pharmaceutical products
Pharmacovigilance – Drug Safety
Pharmacovigilance

3. Objectives of Pharmacovigilance
To improve patients care and safety
To improve Public health and safety
To contribute to the assessment of benefit,
harm, effectiveness and risk of medicines
To promote understanding clinical
training & effective communication to
health professionals and public

4. Need of Pharmacovigilance

5. History of Pharmacovigilance

6. •In 1848, a year after the Scottish surgeon Sir James Simpson
had discovered that chloroform was a safer and more
powerful anesthetic than ether.
•Hannah Greener a healthy 15 year-old girl from the north of
England became the first recorded fatality directly attributed to
chloroform.
• She required the removal of a second toenail, several months
after she had undergone a successful similar operation with
diethyl ether as the anesthetic.
•Two minutes after the start of the operation she was dead.
•The exact cause has been variously suggested, from an
anesthetic overdose to secondary complications
Hannah’s death

7.  The causes of death was investigated to understand what happened to Hannah, but it was
impossible to identify what killed her.
 As a result of other deaths and alerts raised by the clinicians and the public about the
safety of anesthesia, The Lancet Journal established a commission to take on this
problem.
 The commission exhorted English doctors, including the doctor in colonies, to report
deaths caused by the anesthesia.
 The results were published in The Lancet in 1893.
 The US Federal FDA was formed on June 30, 1906, and it established that drugs must be
pure and free of any contamination.
 Furthermore, in 1911, this organization forbade false therapeutic indications of drugs

8. Sulfanilamide
 During September and October 1937 this drug was responsible for the deaths of more than 100 people
in 15 states, as far east as Virginia and as far west as California. The drug and the deaths led to the
passage of the 1938 Food, Drug, and Cosmetic Act, which increased FDA's authority to regulate
drugs.
 Sulfanilamide- to treat Streptococcal infection
In June 1937 sudden
demand for the drug in
liquid form.
Companies
chief chemist
& pharmacist
found that
sulfanilamide
would dissolve
in diethylene
glycol
they tested it for flavor,
appearance, fragrance and
found it satisfactory and
shipped it all over the
country
New formulation had
not been tested for
toxicity.

9.  At the time the food and drugs law did not require that safety studies be done on new drugs.
 Watkins failed to note one characteristic of the solution.
Diethylene glycol, a chemical normally used as an antifreeze, is a deadly poison.
 October 11 American Medical Association received reports from physicians – that Sulfanilamide was
responsible for number of deaths.
 AMA asked for sample and found diethylene glycol as toxic ingredient and issued warning in newspaper
and radio.
1938 -Federal Food, Drug, and Cosmetic Act- The
New Drug section, added to prevent such tragedies,
gave the United States a new system of drug control
which provided superior protection while stimulating
medical research and progress

10. • In 1938, Douthwaite supposed that acetylsalicylic acid (ASA) could cause melena.
•In 1955, it was proved that ASA can cause GI diseases and therefore it is currently contraindicated in
patients with gastrointestinal ulcers
•In 1961, a big change of European Pharmacovigilance happened following the tragedy of
Thalidomide.
•Dr. McBride, an Australian doctor, wrote a letter to the editor of the Lancet Journal, in which he
suggested a connection between congenital malformation of babies and thalidomide.
•At the same time, during a Pediatric Convention in Germany Dr. Lenz suggested a correlation between
malformations and thalidomide and his suspect was published in a German Journal (Welt am Sonnatag)
•In USA, the tragedy of thalidomide was not observed, because Dr. Kelsey showed strong doubts about
the safety of thalidomide during pregnancy

11. Thalidomide tragedy – Lessons for Drug safety and regulation
•Thalidomide – initially prescribed to pregnant
women as tranquilizer and antiemetic for morning
sickness
•10,00.0 children worldwide are disabled.
•Developed by german pharmaceutical company
Grunenthal in stolberg
•first entered the German market in 1957 as an over-
the-counter remedy

12.  The tragedy of thalidomide brought to light many problems and critical issues, in
particular, the reliability of animal tests, the behavior of the industrial company, and the
importance of monitoring the drugs after their marketing.
 In particular, this tragedy changes the system of Pharmacovigilance, because the
spontaneous reporting of adverse drug reactions became systematic, organized, and
regulated.
 This letter already contained all of the elements needed to generate a spontaneous
reporting and to establish a cause-effect relationship between the adverse event and the
drug

13. McBride’s letter and important elements for generating spontaneous
reporting

14. •In 1964, the “Yellow card” (YC) was structured in the UK.
•YC is a specific form to compile a spontaneous report of drug toxicity.
•In USA (1962), the amendment, requiring safety and efficacy data of drugs before premarketing submission,
was approved.
•In Europe (1965), the disaster of thalidomide stimulated the development of a European legislation with the EC
Directive 65/65.
•In 1966, a pilot study of Boston Collaborative Drug Surveillance Program started.
•It was the first group to conduct epidemiologic researches to quantify the potential adverse effects of drugs.
•In 1968, the WHO Programme for International Drug Monitoring was instituted and ten members participated
in this program (Australia, UK, USA, Germany, Canada, Ireland, Sweden, Denmark, New Zealand, and
Netherlands)
•Many studies of observed adverse drug reactions were conducted between 1968 and 1982

15. •In 1992, the European Society of Pharmacovigilance (ESoP) was funded, turned into the International
Society of Pharmacovigilance (IsoP).
•The aims of this society were to promote Pharmacovigilance, and enhance all aspects of the safe and
proper use of medicines
•In 1995, the European Medicines Agency (EMA) was set up.
•In 2001, EudraVigilance was funded.
•It is the official European database for managing and analyzing information on suspected adverse
reactions to medicines which have been authorized for the market or being studied in European clinical
trials,
•In November 2017, the new EudraVigilance format was launched; in particular, the marketing
authorizations will have extended access to the EudraVigilance database to support the fulfillment of
their Pharmacovigilance obligations

16. Pharmacovigilance in India
1986
ADR monitoring
system for India
(proposed in 12
regional centres)
1997
India joined WHO-
ADR monitoring
programme (3
centres: AIIMS,
KIM, JLN)
2010
Pharmacovigilance
programme of India
2004-2008
National
Pharmacovigilance
programme (2 zonal,
5 Regional, 24
Peripheral) overseen
by CDSCO

17. Terminology
 Adverse Drug Reaction (ADR): An unintended reaction to a drug taken at doses normally used in man
 Adverse Event (AE): Any untoward medical occurrence that may present during treatment with a
medicine but which does not necessarily have a causal relationship with the treatment
 Serious Adverse Event (SAE) : Any AE which is fatal, life threatening, Congenital anomaly, permanently
disabling or which leads to hospitalization
 Suspected Unexpected Serious Adverse Reaction (SUSAR): refer to an adverse event that occurs in a
clinical trial subject, which is assessed by the sponsor and or study investigator as being unexpected,
serious and as having a reasonable possibility of a causal relationship with the study drug.

18. Severity of ADR
 Minor – No need of therapy/hospitalization
 Moderate – Requires drug change
 Severe – Life threatening, Hospitalization
 Lethal – Leads to death

19. Pharmacovigilance process
Detecting and reporting an ADR
ADR form is filled out with patient and reaction
details in prescribed format – forms basis for data
entry
Reporting
Spontaneous Mandatory
•Most common form of
ADR reporting
•Health care
professionals identify and
report any suspected
ADR to national PV
centers/to the
manufacturers
•Manufactures are
required to submit
reports they receive from
health care providers to
the National authority in
the form of PSUR
(Periodic Safety update
Report)
•Regulatory document
prepared by marketing
authorization holder and
submitted to the agency

20. ADR reporting through vigiflow
Vigiflow is a web-based Individual Case Safety Report (ICSR) management system that
is specially designed for use by national centers in WHO programme for international drug
monitoring
Subscription for Vigiflow is free in India
ADR reporting forms
India (Red form), US (MED WATCH Form 3500), and UK (Yellow card
form)
Online Reporting systems:
India – Vigiflow
US – US online reporting
UK – Yellow card online reporting

23. Methods of collecting ADR
Comparative Observational
Studies
Cross sectional Survey
Case Control Study
Cohort Studies
Large Safety trials
Drug utilization studies
Active Surveillance
Site Surveillance (Hospitals,
Pharmacies, nursing homes etc.,)
Focused ADR monitoring of drugs
Prescription event monitoring
Disease registries from public
health record

24. Criteria for ADR and its Reporting to Regulatory
Authority
What to report?
Following events can be reported to the nearest reporting centre or authority
• Life-threatening event or death
• Hospitalization of the patient
• Congenital anomaly
• Lack of efficacy connected with the use of a medical device or drug product.
• All suspected drug interactions
All known or unknown, serious, non-serious, frequent or rare reaction caused due to use of vaccine or drug
must be reported.

25. When to report?
All spontaneous case should be reported within
10 days.
➢ All suspected ADR should be reported as
soon as possible because over reporting is
always better than under reporting.
➢ Death event must be reported as soon as
possible, while all other serious ADR/event
needs to report within 7 days only.
➢ All non-serious cases must be reported
within 30 days.
Who can report?

26. How to report?
Duly filled ADR reporting form needs to
send to the nearest AMC or directly to the NCC.
Dial toll free helpline number-1800 180 3024
to report ADRs.
Mailing the filled ADR reporting form directly
to pvpi@ipcindia.net or
pvpi.ipcindia@gmail.com.
Logging on to the http://www.ipc.gov.in,
http://www.ipc.gov.in/PvPI/pv_home.html for
list of authorized AMCs of India.
PVPI- Pharmacovigilace
programme of India
Where to report?
Various Peripheral, Regional and Zonal centers
have been proposed and established in India
WHO & UMC (Uppsala Monitoring Centre)- is
responsible for the management of WHO program
for International Drug monitoring
Computer software for case report management
is designed to suit the needs of National centers
( Vigiflow)

29. Vigi flow

33. Roles and Responsibilities of In-Charge Personnel at PVPI
➢ The Co-ordinator at PVPI-AMC smooth and effective functioning of AMC.
➢ AMC appoints a technical associate who is responsible for collection, follow up, reporting,
scrutiny, assessment and entry of ADR in to Vigi-Flow database. All the procedure followed as per
SOP and final assessment is performed by NCC.
➢ AMC controller/in-charge %send monthly ADR status reports to NCC.
➢ Making awareness and guiding the HCPs, students, patients about ADR reporting by taking
lectures, advertisement though email, telephone, pamphlet and newsletter
➢ Feedback collection and communication to the HCPs is an additional duty of AMC coordinator.

34. Work Flow of PV activity

35. Signal Detection
What Is A Signal
Information that arises from one or multiple sources (including observations and experiments), which suggests
a new potentially causal association, or a new aspect of a known association, between an intervention and an
event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify
verificatory action”.
Signal Detection
Signal detection in PV involves looking at the adverse reaction data for patterns that suggest new safety
information.

36. Process for managing signals
Signal detection
Validation and Confirmation
Analysis
Prioritization
Assessment
Recommending action

37. Causality Assessment
 Causality assessment of ADRs is a method used for estimating the strength of relationship between
drug exposure and occurrence of adverse reaction.
 It is an essential part of ADR report and important task conducted by National pharmacological
programme in each country.
 Many regulatory authorities assess spontaneous ADR reports, where causality assessment can help in
signal detection and risk–benefit decisions regarding medicines.

38. Criteria for establishing causality
a) assessment of strength of the association,
b) consistency of the association,
c) specificity,
d) temporal relationship,
e) biological gradient (dose response),
f) biological plausibility,
g) coherence,
h) experimental evidence and
i) reasoning by analogy.
These elements of assessing strength of relationship between exposure (drugs) and
outcome (adverse reaction) are used widely in ADR CATs

39. Causality assessment Methods

40. Causality assessment scale

41. Naranjo algorithm
 Naranjo Scale is a questionnaire for determining the likelihood of whether an ADR is actually
due to the drug rather than the result of other factors.
 Probability is assigned via a score termed definite, probable, possible or doubtful. Values
obtained from this algorithm are sometimes used in peer reviews to verify the validity of author's
conclusions regarding adverse drug reactions.

42. Naranjo algorithm questionnaire

43. Individual Case Safety Report (ICSR)
 Individual Case Safety Report is a document in a specific format for the reporting of one or several
suspected AR to a medicinal product that occur in a single patient at a specific point of time.
 A WHO global individual case safety report database (VigiBase) is maintained and developed on behalf
of the WHO by the UMC.
VigiBase
 VigiBase is the single largest drug safety data repository in the world.
 Vigibase is used to obtain the information about a safety profile of a medicinal product.
 These data are used by pharmaceutical industries, academic institutions and regulatory authorities for
statistical signal detection, updating periodic reports, ICSR comparisons with company databases and
studying the reporting patterns.
 The data is collected from each of its 110 member states. About a hundred thousand ICSRs are added
each year.

44. Adverse event reporting
 One of the fundamental principles of adverse event reporting is the determination of what
constitutes an ICSR. During the triage phase of a potential adverse event report, it is important
to determine if the “four elements” of a valid ICSR are present:
 an identifiable patient
 an identifiable reporter (called the “verbatim”)
 a suspect drug
 an adverse event

45. ICSR format is precise, exact and includes:
 References for administration and identification purposes, including where the report came from and
who received it
 All information from primary sources
 Characteristics of the patient concerned
 Description of the relevant events
 Results of clinical tests and procedures
 Characteristics of the medicinal product in question
 Narrative style summary of the case
 Any further relevant supporting information

46. It is expected that each ICSR should be:
 Validated before reporting
 Submitted within extremely strict and rapid timescales
 Rapidly re-submitted as new or updated information becomes available which has an
impact on the original submission
 You also need to be sure that detailed Safety Data Exchange Agreements (SDEAs)
exist regarding relevant information exchanges (including information from periodic
Literature Searching) with any of your contractors. SDEAs must be formulated to
ensure compliance with the interim and final arrangements.

47. The processing of individual case safety
reports (ICSRs) originating from various
sources:
•Post-marketing non-solicited/Spontaneous
reports
•Clinical reports
•Special reports (Medico-legal and Literature)
•Related sources
Case Processing

48. Regulatory Reporting Timelines For ICSRs
 ICSR reporting timelines primarily vary based on the seriousness of an event and the nature of the reporter
Events Regulatory
Authority
Principal
Investigator
Ethics committee
Non-serious AE 90 Calendar days 90 Calendar days Periodic Reporting
SAE and SAR 15 calendar days
and follow up with
regular Periodic
reports
15 calendar days 15 calendar days
SUSAR (LT/Fatal) 7 calendar days 15 calendar days 7 calendar days
SUSAR( Non-
fatal)
15 calendar days 15 calendar days

49. Aggregate Reporting
Also known as Periodic
Reporting, plays a key role in
the safety assessment of drugs
Aggregate reporting involves
the compilation of safety data
for a drug over a prolonged
period of time (months or
years) and submit the findings to
regulators worldwide.
Aggregate report examines and summarize all existing safety
experience with a medicinal product
Report includes risk assessment of SAEs and ADRs, pregnancy
reports, overdose and lack of efficacy reports.
It is submitted to regulators as long as the medicine is marketed
anywhere in the world and enables understanding of risk benefit
profile of product over a period of time.

50. Examples of Aggregate Reports
Post marketing Reports
Periodic Safety Update Reports
(PSURs)
Periodic Adverse (Drug)
Experience Reports (US),
Development Safety Update
Reports (DSURs),
Integrated Summaries of Safety
(US), or
Clinical Summaries of Safety (EU)
Pre marketing Reports
NDAAnnual Reports
IND annual Reports
Clinical Study Reports (CSR)

51. PV regulation in India