Pharmacovigilance is defined as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems. Periodic safety update reports (PSURs) are used as a tool to monitor the ongoing safety of medicines in the market and provide a critical analysis of the risk-benefit balance of a product over time based on new safety information and cumulative data. The preparation, submission and assessment of PSURs are guided by various international standards and regulations to ensure the safe, rational and effective use of medicines.

2. NO MEDICINAL PRODUCT IS ENTIRELY (OR)
ABSOUTEY SAFE FOR LPEOPLE, IN ALL PLACES, AT
ALL TIME.
PV CAN CHARACTERISE THE RISK

3. PHARMACOVIGIANCE
PHARMAKON (GREEK) = DRUG
VIGILARE (LATIN) = TO WATCH

4.  PV IS DEFINED AS SCIENCE AND ACTIVITIES
REATING TO THE DETECTION, ASSESSMENT,
UNDERSTANDING PREVENTION OF ADVERSE
EFFECTS (OR) ANY OTHER DRUG RELATED
PROBLEM

5. Pre – authorisaton pv :-
Analysis of safety information usually obtained from pre
clinical and clinical studies collected before the
marketing authorisation of the drug.
Post – Authorisaton pv :
Analysis of safety information usually obtained from
spontaneous case reports, literature publications,
safety studies collected after the marketing
authorisation of the drug.

6. AIMS :
 To improve patient care and safety in relation to the
use of medicines.
 To contribute to the assessment of benefit, harm,
effectiveness and risk of medicines, encouraging their
safe, rationale and more effectivfe including cost
effective use.
 To promote understanding, education and cinical
trainin g in PV antd its effective commuunication to
the heath professionas and the public.
 Early detection of unknown safety problems.
 Identification of risk factors.

7.  Preventing patients from being affected
unnecessarily.
Communicating information.

8.  Insufficient evidence of safety from clinical trials.
 Medicines are supposed to save lives.
 To keep products on the market.
 To protect patients from unnecessary harm.
 To reduce healthcare expenses.
 Promoting rational use medicines and adherence.

9. PV MARKET SIZE WAS VAUED AT USA 3.9 BILLION
DOLLARS IN 2017 AND IS EXPECTED TO WITNESS
GROWTH OF AROUND 10.7% CAGR FROM 2018 TO
2024.

11. “The farther back you look the farther forward you
can see” - Winston Churchill

12. In 1785:- English physician William Withering
published his extensive work on adverse effects
associated with digitalis treatment (First systemic
paper on ADRs)
In 1789:- Wouter van, Professor of Medicine at Leiden
University sounded a warning that a second ailment
may be added to the first as a consequence of
treatment Need for watch on the patients after
treatment

13. 1820 :- U.S. Pharmacopeia with first list of standard drugs.
Jan 29, 1848 , (150 years ago, on ):- 15-year-old Hannah Greener
from northeast England, had general anesthesia Chloroform
before treatment of an in growing toenail. Chloroform, had only
been introduced into clinical practice a year earlier by James
Simpson was claimed to produce less nausea. Hannah Greener
died possibly due to ventricular fibrillation. The Lancet set up a
commission, which invited doctors to report anesthesia-related
deaths.
In 1893 - Publication of chloroform related death in England on
The Lancet journal for the first time. Onwards, safety of drug
became the global concern.

14. Pre thalidomide era 1905 - American Medical Association
(AMA) for drug approval.
1906 - The original Food and Drug Act was established to
impose quality criteria for drug manufacturing.
1937 - Sulfanilamide disaster. Sulfanilamide ( Prontosil ),
used since 1932 for treatment of streptococcal infections,
was launched as a syrup, containing diethylene glycol as
solvent. Although tested regarding aspect, taste and odor,
its safety was not evaluated before launching. It was
responsible for the death of 105 individuals (34 children
and 71 adults) and diethylene glycol was incriminated.

15. 1938:- Food Drug and Cosmetic Act, Manufacturers would have to show
scientific evidences of the safety of the drugs.
1941 – Sulfathiazole tragedy:- Nearly 300 deaths from the use of
sulfathiazole tainted with Phenobarbital. FDA introduced good
manufacturing practices (GMPs).
1950: Chloramphenicol : Syndrome of gray baby.
1951- Durham-Humphrey Amendment regarding safety of drugs.
1952 - FDA reveals that chloramphenicol caused nearly 180 deaths.
1953: Phenacetin : Nephrotoxicity.
1954 - FDA started a voluntary program of drug reaction reporting
engaged the American Society of Hospital Pharmacists, the American
Association of Medical Record Librarians, and later the American
Medical Association.

16. Thalidomide disaster 1957:- Thalidomide was prescribed as an allegedly harmless
treatment for morning sickness and nausea. Safety was supported by testing in
300 patients without major ADRs A blockbuster drug in European countries for
the morning sickness. Increased congenital abnormality phocomelia started in
the countries where thalidomide was available (Not in USA due to stronger
safety regulations and resist by Frances Kathleen Oldham Kelsey)
1961- Thalidomide disaster was disclosed with a letter (case report) in the Lancet
by W. McBride, the Australian doctor
Story of Frances Kathleen Oldham Kelsey:
Story of Frances Kathleen Oldham Kelsey Dr. Frances Kathleen Oldham Kelsey a
pharmacologist in USFDA Prevented the entry of Thalidomide into USA
market Insisted for further studies despite its approval in UK and Europe In
1962- She received Presidents award for the distinguished Federal Civilian
Services from President John F Kennedy In 2010- FDA honored Kelsey by
naming one of their annual awards after her name

17. December 1961- Pharmacovigilance (PV) was officially introduced.
In 1962- the Kefauver-Harris amendment was approved, requiring scientific evidences of
efficacy and safety before tests in humans.
In 1963- Committee on the safety of Drugs (CSD) was formed in UK.
In 1964- Yellow Card System (prepaid card) by the CSD of UK.
1964-1965 – National ADR reporting system came into picture in UK, Australia, Newzeland
Canada, West Germany, Swedan.
In 1968- WHO’s Programme for International Drug Monitoring was started. Initially a pilot
project in 10 countries with established national reporting systems for ADRs.
In 1968- The UK Medicines act was enforced.
In 1970- CSD was replaced by Committee on Safety of Medicine
1970- CSM was again replaced by Commission on Human Medicines

18. 1971- An international database (international monitoring
system) was established by WHO at Geneva.
1972 - Over-the-Counter Drug Review for safety, effectiveness
and appropriate labelling of drugs sold without
prescription.
In 1974- The term PV proposed by French group of
pharmacologists.
1978 - The base for international monitoring system was
moved to Uppsala, Sweden Since then Uppsala Monitoring
Centre (UMC) has been managing the primary aspects of
expanding worldwide Pharmacovigilance network of more
than 130 countries.

19. 1983- The UK Committee on Safety of Medicines set up
the Grahame-Smith Working Party, which made 29
recommendations, most of them to address the
problem of under-reporting of suspected ADRs.
1990- Establishment of International Conference on
Harmonization of Technical Requirements for the
Registration of Pharmaceuticals for Human Use (ICH),
a collaborative initiative between the EU, Japan and
the United States with observers from WHO, EFTA
and Canada. ICH harmonization

20. 1993 - FDA launches MedWatch to collect reports on
problems with drugs and other medical products.
1997 - India joined the WHO Pharmacovigilance
programme.
1998 - FDA introduces the Adverse Event Reporting
System (AERS), a computerized database designed to
store and study safety reports.
1999: Revised MedWatch , MedDRA.

21. 2001: Post marketing safety reporting guidelines by FDA
In 2002 , WHO “The importance of Pharmacovigilance”
regarding implementation of Pharmacovigilance program
at International level
2003: 2004 - FDA to monitor risk post approval
2005: Final risk management guidelines from WHO Specifies
how to perform signal detection, risk assessment and risk
mitigation, Launch of NPvP
2007: FDA Amendment Act
2008 : Amendment in EU
2010: Launch of PvPI
2010: European PV legislation passed
2012 : European PV legislation effective
2014 : Good Pharmacovigilance Practice for Medicines (Dec
14)

22. Uppsala Monitoring Centre:
 Uppsala Monitoring Centre 1971 - WHO Collaborating
Centre for International Drug Monitoring, Geneva.
 1978 - Moved to Uppsala after agreement between
Sweden and WHO Non-profit foundation with
international administrative board WHO
Headquarters responsible for policy Self-financing
Global Pharmacovigilance.

23.  Activities are carried out following WHO policy and in
close liasion with headquarters in Geneva. They include
 Collecting, assessing and communicating information from
member countries about the benefits ,harms effectiveness
and risks of medicines.
 Analyzing VigiBase data and identifying signals of
potential safety problems.
 Collaborating with member countries in the development
and practice of pharmacovigilance through consulting and
training.
 Pursuing research in all aspects of the science and pracctice
of PV.

24.  In the year 1986, a formal ADR monitoring system
consisting of 12 regional centers, each covering a
population of 50 million was introduced in INDIA.
(Nothing much happened when)
 In the year 1992 India joined the WHO ADR
monitoring programme based in Uppsala Swedan.
(Unsuccessful)
 From 1 January 2005, the WHO sponsored and World
Bank funded National programme for India was made
operational.

25.  The PvPI was initiated by the Ggovernment of INDIA
in july 2010 with AIIMS, New Delhi as NCC for
monitoring ADR in the country.
 The NCC was shifted from AIIMS , New Delhi as NCC
for monitoring ADR.
 The NCC was shifted from AIIMS, New Delhi to IPC,
Ghaziabad on 15th April 2011.
 In India, PvPI is closely working with CDSCO, drug
regulatory authority of India.

28.  A primary objective of NCC-PvPI is to promote the
safest use of medicines through contributing to
appropriate education in pharmacovigilance and
training activities across the country.
 NCC is committed to communicate the findings of
PvPI to stakeholders and public with respect to
importance of ADRs and reporting them, information
about benefit-harm and effectiveness-risk, rational use
of medicines, etc. A variety of methods for PvPI
communication is used by NCC as follows :

29. Website
 The websites of CDSCO (www.cdsco.nic.in) and NCC (www.ipc.gov.in) are
important tools for communication to the stakeholders and public seeking
specific information. PvPI documents on these websites can be searched by
navigating from the home page. Examples of documents on these websites
include list of AMCs, how, what, and where to report ADRs, newsletters,
training module, guidance document, etc.
Media
 Since medicines safety communications with healthcare professionals,
patients, and the general public must be focused on joint responsibility for safe
and rational therapy, NCC communicates the findings in national newspapers,
electronic media, etc., on regular basis.
Newsletter
 PvPI Newsletter is unique among healthcare professionals because it focuses
on the ADRs-related informations. Three issues per year guides how to take a
leading role in monitoring, reporting, and preventing ADRs. It is available in a
convenient electronic format and printed version is circulated to AMCs,
corporate hospitals, academic institutions, health departments, etc.

30. Android Mobile Application for Adverse Drug Reaction
Reporting
 In developing countries such as India, under-reporting
of ADR remains serious concern. In India, IT is
becoming a great facilitator for promoting public
health. India is cementing its place IT sector through
mobile connections to reach every individual
 Android Mobile Application for Adverse Drug
Reaction Reporting
 In developing countries such as India, under-reporting
of ADR remains serious concern. In India, IT is
becoming a great facilitator for promoting public
health. India is cementing its place IT sector through
mobile connections to reach every individual.

31.  NCC-PvPI in technical collaboration with NSCB
Medical College, Jabalpur, developed a mobile
application for the healthcare professionals to promote
easy and instant reporting of ADR. This facility was
launched by Secretary Health, MoHFW, Government
of India, on May 22, 2015.

32.  Periodic safety update reports (PSURs) are a tool to
monitor the safety of ongoing medicines in the
market. In India, marketing authorization holders
(MAHs) are required to prepare PSURs and to submit
them to CDSCO twice in a year for 2 years and
annually for another 2 years.

35. Periodic safety update report (PSUR) is now known as
the Periodic Benefit-Risk Evaluation Report (PBRER)
A Periodic Safety Update Report is a
pharmacovigilance document intended to provide an
evaluation of the risk-benefit balance of a medicinal
product at defined time points post-authorisation.

36.  To present a comprehensive and critical analysis of the
risk-benefit balance of the product taking into account
new or emerging safety information in the context of
cumulative information on risk and benefits.
This evaluation should ascertain whether further
investigations need to be carried out and whether
changes should be made to the product information or
marketing authorisation.

37.  Data from clinical and non-clinical studies.
 Spontaneous reports (e.g. on the marketing
authorisation holder’s safety database).
 Product usage data and drug utilisation information.
 Observational studies.
 Scientific literature.

38. In July 2012, as per new European Legislation, 16 Good
Pharmacovigilance Practices (GVP) modules came
into effect by replacing Vol 9A guidelines. GVP module
VII provides the guidance for the preparation,
submission and assessment of PSURs.

39. Pharmaceutical companies need to establish and demonstrate the benefit and risk
of the medicinal product for marketing authorization.
Regulators assess the information which is available in the form of new drug
application (NDA) at a specific moment regarding benefits and risks and
product is authorized if benefits are more as compared to the risks.
This balance is valid at a given point of time but may change later once the drug is
in the market due to exposure of a large number of patients, concomitant
medications and diseases, long term exposure, confounding factors, and
uncontrolled conditions.
For example, the percentage of benefit is 90% and risk is 15%, when first
submitted.
These percentages might be changed when 4th PSUR will be submitted (benefit,
80% and risk 50%).
Thus, there have been many drugs which were initially found to be very successful
in a number of patients, but unfortunately were later found to have serious side
effects, resulting in their withdrawal from the market .
Thus, to enhance patient safety and public health, the periodic re-examination of
the benefit- risk balance is needed to ensure that the balance remains in
favorable condition. This periodic reexamination is performed in a document
called a periodic safety update report (PSUR).

40.  PSUR submissions are not required for all medicinal
products, but the need for PSURs is determined using
a risk-based approach. Certain products authorized
under certain legal basis are exempted to submit
PSURs routinely (Article10.1 generic, Article 10a well-
established use, Article 14 homeopathic and Article 16
traditional herbal medicinal products). For such
products, PSURs shall be submitted only where there
is a condition in the marketing authorisation or when
requested by a competent authority.

41. 1986 - CIOMS set up its first Working Group on
pharmacovigilance, a Working Group on International
Reporting of Adverse Drug Reactions to explore means
of coordinating and standardizing international
adverse drug reporting by pharmaceutical
manufacturers to regulatory authorities. Its agenda
was limited to post-marketing reporting of adverse
drug reactions occurring in one country and which the
pharmaceutical industry should report to regulatory
authorities in other countries where the drug is also
marketed.

42.  In 1992 the CIOMS Working Group II report
“International Reporting of Periodic Drug-Safety
Update Summaries” was published. Since then more
than ten Working Groups, including the recent two
Working Groups dealing with vaccine safety have
completed their work creating an extremely valuable
set of pharmacovigilance guidance documents.
 The impact of CIOMS Working Groups on Global
development pharmacovigilance has been substantial.
Several ICH guidelines, such as E2A, E2C, E2D and
E2F, were based on the work of CIOMS Working
Groups.

43.  2003 – Addendum to ICH E2C (R1) published.
 2012 – ICH guideline E2C (R2) on periodic benefit risk
evaluation report.
 2013 – GVP module VII – Periodic safety Update
report.
 2016 – Mandatory use of PSUR

44.  Like other regulators, DCGI also recommends a single
PSUR for all dosage forms, formulations, and
indications for one active substance. Within a single
PSUR, data for different dosage forms, indications or
populations should be provided separately. License
holders are expected to include succinct summary
information along with the critical evaluation of the
safety profile of a marketed drug in the light of new
changes during post-authorization period. A PSUR
should also mention whether further investigations
need to be carried out and what changes need to be
made in the package insert.

45.  Format of PSUR provided in the Schedule Y is similar
to that of ICH E2C format, although it does not
elaborately guide the contents of the data to be
incorporated under each and every heading. For all
practical purposes, a PSUR prepared in accordance
with ICH E2C format should be acceptable to DCGI.

46.  Like other major regulatory authorities, Indian regulations
also require that PSURs should contain the relevant clinical
and non-clinical safety data only for the period of report
(interval data). Although it is not specified in Schedule Y,
as per ICH E2C requirements, PSURs submitted to DCGI
contain cumulative data on the regulatory status
information on authorization applications and renewals, as
well as data on serious, unlisted adverse reactions.
 Periodic safety update reports due for a period must be
submitted within 30 calendar days for the last day of the
reporting period. As there is no guidance available on the
data lock, generally pharmaceutical companies follow the
recommendations from ICH E2C for the data lock.

47.  Schedule Y further states that if the marketing of a new drug is
delayed after obtaining the approval to market, such data may
be submitted on a deferred basis beginning from the time the
new drug is marketed. This is in sharp contrast to EU
regulations, where a pharmaceutical company is required to
meet pharmacovigilance obligations of all the products for
which it holds marketing authorization, irrespective of the
marketing status of the products.
 As there is limited guidance available in Schedule Y as well as
the protocol published by the NPP, it is very important for the
pharmacovigilance team of an Indian pharmaceutical company
to consult the guidance documents available from ICH, US
FDA, and EMEA so as to develop well laid down procedures
for optimally carrying out the pharmacovigilance of new as
well as generic drugs.

48.  DSURs are new, internationally-harmonized, safety documents
(which became mandatory in European Union member states in
September 2011) covering the safety summary of medicinal
products during their development or clinical trial phase.
 The new DSUR (defined in guideline ICH E2F) is based heavily
on the PSUR format already used for updating the safety record
of drugs in their marketing phase. The new DSUR format
replaces the previous European Union ASR (Annual Safety
Report) and the United States IND Annual Report.
 Sponsors are required to submit a DSUR within one year of the
Development International Birth Date (DIBD – the date of first
authorisation of a clinical trial in any country worldwide) and
provide annual DSUR submissions until all open clinical studies
have ended (the final clinical study is completed and its study
report has been submitted).

49.  The concept of a Development Safety Update Report (DSUR)
was first introduced by the CIOMS VI working group and taken
forward by the CIOMS VII working group. In 2008, the ICH
published a draft guideline E2F (step 2) on DSUR, which has
recently been updated (step 4, August 2010), incorporating
background, objective and scope of DSUR and providing
guidance on DSUR contents.
 Since CDSCO does not require DSUR, for Indian pharmaceutical
companies undertaking global trial for a locally developed drug,
Indian regulators will not have real-time update of the drug’s
developing safety profile, while foreign regulators (such as ICH
countries) having requirement of DSUR will have this
information. This underscores the relevance of DSUR to Indian
pharmaceutical companies undertaking indigenous drug
development. With the global focus on DSUR, Schedule Y needs
to be revised incorporating similar provision of providing
cumulative safety updates to the regulators during clinical
development phase.

50. ADVERSE EVENT :
Any untoward medical occurrence in a patient or clinical
investigation subject administered a pharmaceutical
product and which does not necessarily have a casual
relationship with this treatment. An AE can therefore be
any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease
temporally associated with the use of a medicinal
(investigational) product.

51.  A response to a drug that is noxious and unintended
and occurs at doses normally used in man for the
prophylaxis, diagnosis, or therapy of disease or for
modification of physiological function (WHO)

52. TYPE A (AUGMENTED):
Features :
 Common
 Related to the pharmacologic action of the drug –
exaggerated pharmacologic response
 Predictable
 Low mortality.
Examples :
Dry mouth with tricyclic antidepressants, respiratory
depression with opioids, bleeding with warfarin, serotonin
syndrome with SSRIs, digoxin toxicity.
Management :
Reduce dose or withhold drug Consider effects of
concomitant therapy

53. Features :
Not related to the pharmacologic action of the drug
Unpredictable
High mortality
Examples :
Immunologic reactions: anaphylaxis to penicillin .
Idiosyncratic reactions: malignant hyperthermia with
general anesthetics .
Management
Withhold and avoid in future .

54. Features :
Uncommon
Related to the cumulative dose
Examples :
Hypothalamic-pituitary-adrenal axis suppression by
corticosteroids.
 Osteonecrosis of the jaw with bisphosphonates.
Management
Reduce dose or withhold
withdrawal may have to be prolonged

55. Features
 Uncommon .
 Usually dose related .
 Occurs or becomes apparent sometime after use of the
drug .
Examples
 Carcinogenesis
 Tardive dyskinesia
 Teratogenesis Leucopenia with lomustine
Management
Often intractable

56. FEATURES
Uncommon
Occurs soon after withdrawal of the drug
EXAMPLES
Withdrawal syndrome with opiates or benzodiazepines
(e.g., insomnia, anxiety)
MANAGEMENT
Reintroduce drug and withdraw slowly

57. 1.Very Common :-
Incidence : > 10 % (1 in 10 ppl)
EX : Drowsiness associated with carbamazepine.
2.Common ADR :-
Incidence : >1-10 and <1 in 100
EX : Fluid retention with carbamazepine
3.Uncommon ADR :-
Incidence : 0.1 – 1.0 % (>1 in 100 ,<1 in 1000)
Ex : Diarrhea associated with carbamazepine.

58. 4.Rare ADR :-
Incidence : >1 in 1000 , <1 in 10000
Ex : Depression associated with carbamazepine.
5.Very Rare
Incidence : 1 in 10000
Ex : Arrhythmia associated with carbamazepine.

59.  Mild (minor) : does not require any therapy /may not
notice.
 Moderate : Required change in drug therapy.
 Severe (major) : capable of damaging any organ / life
threating, hospitalization, disability (significant,
persistent or permanent, congenital anomaly, required
intervention to prevent permanent impairment or
damage

60. SAE is short for Serious Adverse Event. An SAE is any untoward medical
occurrence in a patient or trial subject, which does not have a causal
relationship with the treatment, and:
 is fatal, and/or
 is life-threatening for the subject, and/or
 makes hospital admission or an extension of the admission necessary,
and/or
 causes persistent or significant invalidity or work disability, and/or
 manifests itself in a congenital abnormality or malformation, and/or
 could, according to the person that carries out the research, have
developed to a serious undesired medical event, but was however
prevented due to premature interference.

61. An SAE that occurs during research with a medical
device may be a SADE. SADE is the abbreviation for
Serious Adverse Device Effect.

62. • Sometimes, during a clinical trial for a certain drug, a
subject may experience serious adverse reactions.
• These reactions may or may not be dose-related, but
they are not consistent with current information on
the drug, so they are considered a "suspected
unexpected serious adverse reaction," or SUSAR.

63. TIMELINES FOR REPORTING SUSAR’s :
Reporting SUSARs is mandatory for clinical
investigators. A report must be submitted to the
national competent authority within 15 days of
occurrence. In cases of death or life-threatening issues,
the time frame shortens to seven days.
INVESTIGATOR TO SPONSOR – 24 HOURS

64.  One conspicuously missing element in amended Schedule Y is the definition
and standards for expedited reporting. By Schedule Y norm, any “unexpected
and serious” adverse events can be reported to CDSCO and other investigators
within 14 calendar days.There is no requirement to prioritize reporting of
events that are suspected of having a causal association; neither is there any
provision to differentiate reporting time lines for unexpected deaths or life-
threatening events that are suspected to be due to study medication. This is in
contrast to both ICH E2A and 21 CFR 312.32, which mandate reporting of fatal
or life-threatening suspected unexpected serious adverse reactions (SUSAR) to
regulators within 7 calendar days, while other SUSARs can be reported in 15
days time.
 Moreover, Schedule Y is silent on safety reporting requirements from foreign
sites for multinational trials. For example, since Schedule Y does not feature
the term “SUSAR” and does not specify expedited reporting requirements for
SUSARs, in the event of SUSARs occurring at a foreign site, the procedure and
timeframe for reporting to Indian regulators and sites remains undefined.
Conversely, for a multinational study being conducted in an Indian site, the
sponsor will report any life-threatening or fatal SUSAR originating from Indian
site to US FDA following the 7 working days expedited reporting norm.[3]
However, since CDSCO does not specify or mandate such expedited reporting
timeline, the event can be reported to CDSCO anytime within the 14 days
timeframe. This means, the USFDA will have knowledge of the event occurring
in India and might raise safety alerts for the site while the Indian regulators are
not even aware of it.

65. Types of Reports :
1. Solicited Reports
2. Unsolicited Reports

66. Solicited reports are reports derived from organized
data collection systems, which include clinical trials,
post-approval named patient use programs, other
patient support and disease management programs,
surveys of patients or healthcare providers, or
information gathering on efficacy or patient
compliance. Adverse event reports obtained from any
of these should NOT be considered spontaneous.

67. 1. Spontaneous Reports : A spontaneous report is an
unsolicited communication by healthcare
professionals or consumers to a company, regulatory
authority or other organization (e.g. WHO, Regional
Centers, Poison Control Center) that describes one or
more adverse drug reactions in a patient who was
given one or more medicinal products and that does
not derive from a study or any organized data
collection scheme.

68. 2. Literature : The Marketing Authorisation Holder (MAH) is
expected to regularly screen the worldwide scientific
literature, by accessing widely used systematic literature
reviews or reference databases.
3. Internet : MAHs are not expected to screen external
websites for ADR information. However, if an MAH
becomes aware of an adverse reaction on a website that it
does not manage, the MAH should review the adverse
reaction and determine whether it should be reported.
Unsolicited cases from the Internet should be handled as
spontaneous reports.
4 Other Sources If MAHs become aware of a case report from
non-medical sources, it should be handled as a
spontaneous report.

69. Unsolicited Reports would be of the following:
 A spontaneous report is an unsolicited communication
by healthcare professionals or consumers to a company,
regulatory authority or other organization (e.g. WHO,
Regional Centers, Poison Control Center) that describes
one or more adverse drug reactions in a patient who was
given one or more medicinal products and that does not
derive from a study or any organized data collection
scheme. Stimulated reporting may occur in certain
situations, such as a notification by a “Dear Healthcare
Professional” letter, a publication in the press, or
questioning of healthcare professionals by company
representatives. These reports should be considered
spontaneous.

70.  The purpose of expedited reporting is to make
regulators, investigators, and other appropriate people
aware of new, important information on serious
reactions. Therefore, such reporting will generally
involve events previously unobserved or
undocumented, and a guideline is needed on how to
define an event as "unexpected" or "expected"
(expected/unexpected from the perspective of
previously observed, not on the basis of what might be
anticipated from the pharmacological properties of a
medicinal product).

71.  The following documents or circumstances will be used to
determine whether an adverse event/reaction is expected:
1. For a medicinal product not yet approved for marketing
in a country, a company's Investigator's Brochure will serve
as the source document in that country.
 2. Reports which add significant information on specificity
or severity of a known, already documented serious ADR
constitute unexpected events. For example, an event more
specific or more severe than described in the Investigator's
Brochure would be considered "unexpected." Specific
examples would be (a) acute renal failure as a labeled ADR
with a subsequent new report of interstitial nephritis and
(b) hepatitis with a first report of fulminant hepatitis

72. What Should be Reported?
1. Single Cases of Serious, Unexpected ADRs

73. All ADRs that are both serious and unexpected are subject to
expedited reporting. This applies to reports from
spontaneous sources and from any type of clinical or
epidemiological investigation, independent of design or
purpose. It also applies to cases not reported directly to a
sponsor or manufacturer (for example, those found in
regulatory authority generated ADR registries or in
publications). The source of a report (investigation,
spontaneous, other) should always be specified. Expedited
reporting of reactions that are serious but expected will
ordinarily be inappropriate. Expedited reporting is also
inappropriate for serious events from clinical investigations
that are considered not related to study product, whether
the event is expected or not. Similarly, nonserious adverse
reactions, whether expected or not, will ordinarily not be
subject to expedited reporting.