2. THE SPONTANEOUS REPORTING
SYSTEM
Passive surveillance system:
Health professionals are encouraged to
report adverse reactions which they believe
to be drug-related directly to
the regulatory authority or
the company marketing the suspected
product on a voluntary basis
3. The spontaneous reporting
system
The spontaneous 1.data acquisition
reporting system process 2.data assessment
3.data interpretation
1. Data acquisition
which depends largely on the input
of information derived from reports
submitted by the health professionals
who have encountered what they
suspect is an ADR
4. The spontaneous reporting
system
1.data acquisition
2.data assessment
3.data interpretation
The spontaneous
reporting system
processes:-
2. data assessment
which involves assessment of
the individual case reports and
assessment of pooled data
obtained from various sources
such as the international database
of the WHO
5. The spontaneous
reporting system
1.data acquisition
The spontaneous 2.data assessment
3.data interpretation
reporting system
processes:-
3. data interpretation
based on the available data and
the assessments made, a signal
related to the adverse reaction
may be generated
6. India – ‘Suspected Adverse Drug
Reaction Reporting Form’
UK – ‘Yellow Card’, since 1964
Australia – ‘Blue Card’ , since 1964
US – ‘Med Watch’
Form FDA 3500 – voluntary reporting
Form FDA 3500A - mandatory reporting
7. Spontaneous reporting - UK
Lincencing authority: Ministers, including Sect., of state for
health .
Authority’s key function: control of medicines by the UK
Medicines and Healthcare Products Regulatory Agency
(MHRA) formed on 1st April 2003 from merger of Medicines
Control Agency (MCA) and Medical Devices Agency (MDA).
Key functions: safety, quality and efficacy of medicines and
safeguard public health.
The vigilance and risk management of medicines of MHRA:
monitoring safety of all licensed medicines in UK,
investigates possible hazards and takes appropriate action
to minimise risk and maximise benefits to users.
8. Introduction of yellow card scheme
Introduced in 1964 (Sir Derrick Dunlop) after
thalidomide tragedy
Spontaneous reports of suspected adverse drug
reactions.
Acts as an early warning system to identify ADRs
and risk factors
Over 600,000 confidential reports have been
received in UK
Doctors, dentists, pharmacists, coroners, nurses,
midwifes, health visitors
Non-medical prescribers
and now patients
MHRA can detect duplicate reports
11. Weakness of yellow cards
all spontaneous reporting Schemes have a
number of limitations: under-reporting
under-reporting: may lead to under-
estimation of the significance of a
particular reaction.
Factors influencing reporting:
i. Seriousness of the reaction
ii. Whether the reaction is labelled
iii.length of time a drug has been on the
market
iv.promotion or publicity about the medicine
or the reaction
12. Evidence suggesting under reporting:
a. reporting may vary between different
groups of doctors, with hospital doctors
reporting less frequently than general
practitioners
b. lack of time uncertainty as to whether the
reaction was caused by a drug
c. Breaching patient confidentiality
13. survey in 1984: Only 16% of doctors who
were eligible to report suspected ADRs to
the Scheme had actually submitted a
Yellow Card between 1972 and 1980.
More recent figures are more encouraging;
an analysis of the reporters of Yellow
Cards submitted between 1992 and 1995
showed that around one-third of practising
doctors submitted a report during this 4-
year period.
14. Since 1964, over 500,000 reports have
been received by the MHRA and the CSM.
It is voluntary for health professionals but
pharmaceutical companies have legal
obligations to report ADRs to the MHRA.
the annual number of reports has risen
significantly since the introduction of the
Scheme, with notable increases in
reporting in the mid-1970s and again in
1986.
15.
16. Reasons for increase in reporting
a. introduction of the CSM(committee on safety of
medicines) drug safety bulletin Current
Problems in Pharmacovigilance
b. the inclusion of a yellow page in
prescription pads used by GPs
c. increased availability of Yellow Cards to
doctors
d. inclusion in the British National Formulary
(BNF)
17. There was a slight decrease in the no. of
reporting in mid-late 1990s.
Due to following reasons: computerised
practice systems, increasing demand on
doctor’s time, confusion b/w AE & ADR and
uncertainty about how the patient’s info
was being used.
In 2000, 33 000 reports were received due
to the large no. of ADRs of vaccine for
meningitis C.
18. RECENT INITIATIVES TO ENHANCE THE
SCHEME
A number of initiatives have been undertaken:
I. Initiatives aimed at increasing the general
reporting base,
II.those aimed at increasing reporting in particular
areas where under-reporting is of particular
concern,
III.those aimed at facilitation of reporting.
19. WIDENING THE YELLOW CARD
REPORTING BASE
Pharmacist Reporting: For many years,
pharmacists have been recognised as reporters to
national spontaneous reporting Schemes in a
number of countries.
A pilot Scheme for hospital pharmacist reporting
conducted by the Northern RMC(Regional monitoring
centres), showed that, in comparison with hospital
doctors, hospital pharmacists submitted a higher
proportion of reports
20. Several studies and surveys conducted in this
regard showed that the no. of reporting was
clearly increased due to participation of hospital
pharmacists.
A pilot study of community pharmacist reporting
was conducted by four RMCs: community
pharmacists submitted reports which were
comparable to those received from GPs, with
regard to both the quality of the reports and the
seriousness of reactions reported
Community pharmacists submitted a higher
proportion of reports for herbal products
compared with GPs
21. nationwide reporting by community pharmacists
was introduced in November 1999.
the introduction of supplementary prescribing in
April 2003 has changed the role pharmacists.
Both hospital and community pharmacists are
nowadays important contributors to the Yellow
Card Scheme and in 2004, over 3000 ADR reports
originated from pharmacists, representing 17% of
all ADR reports
22. Nurse Reporting:
the introduction of independent nurse prescribing
from the Nurse Prescribers’ Formulary for
district nurses and health visitors and the Nurse
Prescribers’ Extended Formulary (NPEF) enabled
prescription by the nurses.
During the UK campaign to vaccinate children
against meningitis C, school nurses were the main
body of health professionals administering the
vaccine.
the CSM subsequently recommended that nurses
should be allowed to report suspected ADRs for
meningitis C vaccine
23. An evaluation of nurse reporting by the
MHRA suggested that nurses report
similar levels of serious reactions to other
health professionals
As a result, the Scheme was extended to
all nurses, midwives and health visitors in
October 2002.
In 2004, over 2000 ADR reports were
received from nurses comprising 11% of all
health professionals who reported
24. SPECIALIST THERAPEUTIC AREAS
in such areas, an approach has been taken to
target existing reporting groups to improve the
reporting of reactions relevant to these areas.
recent initiatives aimed at improving reporting of
ADRs in three areas of particular interest: drugs
used in the treatment of human immunodeficiency
virus (HIV)/Acquired Immunodeficiency Syndrome
(AIDS), ADRs in children, and those associated
with herbal products, including unlicensed
remedies
25. The HIV Reporting Scheme
Since the mid-1990s a number of important new
drugs were introduced for the treatment of HIV.
They were released based on the clinical trials
conducted on small groups.
Very limited safety data was available for these
drugs.
26. this Scheme resulted in a significant increase in
the number of UK reports of suspected ADRs
associated with anti-retroviral drugs.
the HIV reporting Scheme, an extension of the
Yellow Card Scheme, was launched in November
1997 by the MHRA and CSM in collaboration with
the Medical Research Council HIV Clinical Trials
Centre
27. SUSPECTED ADRS IN CHILDREN
Safety and efficacy in children cannot be assumed
simply based on data from studies in adults
a pilot Scheme to stimulate reporting of
suspected ADRs in children was set up in the
Trent NHS region in September 1998
A pilot study two years later showed there was an
increase in the no. Of ADR in children due to
meningitis C vaccine
28. the MHRA collaborated with the British Paediatric
Surveillance Unit (BPSU) (now the Royal College of
Paediatrics and Child Health) on their ‘Orange
Card’ reporting Scheme, where consultant
paediatricians report particular disorders under
surveillance in children to the BPSU
CSM established a Paediatric Medicines Working
Group in July 2000 to improve the availability of
medicines for paediatric use.
29. Sept., 2004: proposal for a regulation of
the Council and the European Parliament on
medicinal products for paediatric use.
Paediatric Working Party within the
European Medicines Agency (EMEA).
30. UNLICENSED HERBAL REMEDIES
Traditionally herbal products have been exempt
from licensing requirements by the conditions set
out in Section 12 of the Medicines Act and for
that reason there is a large variety of unlicensed
herbal preparations, including traditional Chinese
and Ayurvedic remedies, which are increasingly
available.
In October 1996, the Yellow Card Scheme was
extended to include reporting for unlicensed
herbal remedies, following a report from Guy’s
Hospital Toxicology Unit on potentially serious
adverse reactions associated with herbal
remedies.
31. Kava-kava (Piper methysticum): produced serious
hepatotoxocity :the CSM prohibited the use of
Kava-kava in unlicensed medicinal products in July
2002 and this was followed by a prohibition order
in January 2003.
In January 2002, the European Commission
adopted formal proposals for a Directive on
Traditional Herbal Medicinal Products. Directive
2004/24/EC amending Directive 2001/83/EC, the
Community code on medicinal products for human
use and this came into force on 30th April 2004
32. This new Directive requires that all medicinal
herbal products will be required to be registered
under the Traditional Herbal Medicines
Registration Scheme (THMRS).
The Directive was implemented in the United
Kingdom on 30 October 2005 : a 7-year
transitional period.
A new UK advisory committee on herbal medicines,
the Herbal Medicines Advisory Committee
(HMAC), has been established to advise the
government on the THMRS, as well as on
unlicensed herbal remedies supplied under Section
12 of the Medicines Act 1968.
33. FACILITATION OF REPORTING – NEW
TECHNOLOGY AND MEDIA
Reporting made easy: conspicuous increase
in the no. of cases reported.
the recent expansion: use of information
technology
pilot Scheme introduced in mid-1998: over
4000 GP electronic reports have been
received
34. Electronic reporting became mandatory for
companies under Directive 2004/27/EC
from 20 November 2005.
the MHRA piloted the use of electronic
reporting for health professionals under
the direction of the CSM’s Electronic
Reporting Working Group, in 2002 resulting
in the launch of the electronic Yellow Card
on the MHRA website.
35. THE ANONYMISED YELLOW CARD
One of the key principles: reports are submitted
and handled in complete confidence.
first used in the HIV reporting initiative
this issue was highlighted by the General Medical
Council’s Guidelines on Confidentiality: led to the
introduction of an ‘anonymised’ Yellow Card in
September 2000
36. the ‘anonymised’ Card asks reporters to include an
identification number or code for the patient; this
should enable the reporter, but not the MHRA to
identify the patient
such an identifier was introduced in order to
address concerns that ‘anonymised’ reporting
might lead to a reduction in the ability to detect
duplicate reports
After six months, over 6000 suspected adverse
reactions had been reported to the MHRA on the
‘anonymised’ reporting form.
37. INDEPENDENT REVIEW OF ACCESS TO
THE YELLOW CARD SCHEME
requests : reports on classes of medicines, copies
of the whole database for genetics research and
requests for the data to develop methodologies
for identifying potential drug safety signals.
These changing demands on the Yellow Card
Scheme raised important ethical, operational and
financial issues in relation to public health.
Conditions: for what purposes, the data should be
made more widely available
38. An independent review of the Yellow Card Scheme
was announced in July 2003 under the lead of Dr
Jeremy Metters.
Dr Metters: small multidisciplinary steering
committee to consider the public health,
scientific, ethical, genetic, data protection, legal
and other issues that would arise from increasing
access to Yellow Card data
Report of an Independent Review of Access to the
Yellow Card Scheme was published: recognised the
importance of the Yellow Card Scheme for public
health and for the benefit of patients
39. access to Yellow Card data could be of benefit to
public health: appropriate controls were set in
place.
The review recommended: establishment of
independent scientific committee by the licensing
authority- evaluate research protocols.
After approval the proposal should be ethically
reviewed by Central Office for Research Ethics
Committees(COREC) system
As per provisions of the Data Protection Act 1998,
consent from a reporter and patient would always
be required before access to their data was
permitted.
40. TheMHRAwelcomed the Review recommendations
and launched a public consultation on six key areas
identified from the recommendations of the
Review, to coincide with the 40th anniversary of
the Yellow Card Scheme on 4 May 2004.
CSM and the government accepted the main
recommendations of the Report of an Independent
Review of Access to the Yellow Card Scheme in
January 2005
a permanent, nonstatutory scientific committee,
an Interim Committee on Yellow Card Data was
convened under the chairmanship of Dr Jeremy
Metters
41. The interim committee acknowledged the
importance of yellow card data and considered the
implications on releasing the data under the
Freedom of Information Act 2005 (FOIA), while
at the same time protecting the confidentiality of
patients and reporters and their personal data
under the Data Protection Act 1998 (DPA).
Based on these guidelines the data have been
categorised into two types:
Category-I: releasable under the FOIA and not
prohibited from release by DPA,
Category-II: data subject to FOIA exemptions
and the restrictions of the DPA.
42. From January 2005 the MHRA has published anonymised,
aggregated Yellow Card data on specific medicines in the
form of Drug Analysis Prints (DAPs) on the Yellow Card
website.
In 2006, a substantive committee, the Independent
Scientific Advisory Committee for MHRA database
research (ISAC) was established
43. FOCUS ON PATIENTS
the government launched its NHS Plan in 2000 to
modernise the National Health Service (NHS) :to
improve patient information, patient choice and
patient and public involvement in the NHS.
The government also encourages wider availability
of medicines and the number of drugs that have
been reclassified from Prescription Only
Medicines (POM) to Pharmacy (P)
number of drugs that have been reclassified from
P to General Sale List (GSL
44. Examples of recent POM to P switches include
chloramphenicol 0.5% eye drops for the
treatmentof acute bacterial conjunctivitis
Zocor Heart Pro (simvastatin 10 mg) to reduce the
risk of a first major coronary event in people who
are likely to be at a moderate risk of coronary
heart disease, while clotrimazole for the
treatment of Candidal vulvovaginitis from P to GSL
45. potential benefit of patient reporting to the
Yellow Card Scheme was realised by the MHRA
prior to the Independent Review of Access to the
Yellow Card Scheme
To investigate : the MHRA undertook a pilot study
of patient reporting in South East London with
NHS Direct in April 2003, involving staff at the
NHS Direct call centre making the reports on
behalf of patient
The Review recommended that A system should be
set up for patients to report ADRs directly to the
MHRA
46. direct reporting of ADRs from patients to the
Scheme, and in September 2004.
the CSM Patient Reporting of Adverse Drug
Reactions Working Group was established to
advise the MHRA and CSM on the development of
different arrangements to pilot direct reporting
by patients or their carers of suspected ADRs and
to communicate about this new initiative
47. Benefits of patient reporting:
i. Identification of ADRs not previously reported
ii. Specific features of ADRs that health
professionals had not considered
Empowering patients with knowledge to
understand the risks and benefits of medicines
will help patients to make informed choices about
the medicines that they are taking
48.
49. Information to include on a
Yellow Card
4 critical pieces of information that must be
included on the report :-
Suspected drug(s)
Suspect reaction(s)
Patient details
Reporter details
50. Suspected Drug(s)
Name of medicine
including brand and batch number if known
Route of administration
Daily dose
Date medicine started
and stopped if applicable
Reason why the medication was given
Multiple drugs can be listed if more than one drug
is suspected of causing the reaction
51. Suspect reaction(s)
Describe the reaction
Include a diagnosis if relevant
Include when the reaction occurred
whether the reaction was considered to be serious
and complete tick box for reasons why
Document if any treatment was given for the
reaction
Eventual outcome tick relevant box
52. Patient Details
Sex of the patient
Age at time of reaction
Weight if known
Do not need to know name or DOB as this could
identify patient and break patient confidentiality
Patients initials and local identification number
(hospital or practice number) which will identify
patient to you in the event of future
correspondence
53. Reporter details
Must be completed in all cases
Name and full address
Need to acknowledge receipt of report
and follow up further information if
necessary.
Profession
54. Additional useful information
Other medication in the last three months
including herbal and over the counter meds.
Use additional sheets if necessary.
If no other meds are being taken or if no more
information is available say so
Include details of any:
rechallenges
relevant medical history
test results
known allergies
suspected drug interactions
55. What happens to a Yellow card once
received?
Acknowledgmen
Provision of
t and/or follow-
information
up for more info
Yellow Cards - Report details
Adverse Drug entered to Commit to
Assessment
Reaction Sentinel database
reports database
Signal Risk-benefit
Signal evaluation and
Evaluation and
detection advice from
Prioritisation
CHM
Regulatory
Impact
action and
Analysis
communication
56. How is the Yellow Card data used to
improve patient safety?
1. Changes to SPC e.g. restriction in use, special
warnings and precautions
2. Publication of
3. Issue of ‘Dear Healthcare professional’ letters
4. Drug Analysis Prints (DAPs)
5. Withdrawal of a medicines if patient safety is
threatened
57. Drug Safety Update
–Published monthly
Register for alerts
http://www.mhra.gov.uk/Publication
58. Drug Analysis Prints (DAPs
Complete list of all suspected ADRs reported via
yellow card scheme for named suspect drug
Inclusion of a particular reaction does not
necessarily mean it has been caused by the drug
Certain reported reactions are conditions which
occur spontaneously
Should not be used for determining incidence
Reporting rates are influenced by seriousness of
ADR, ease of recognition, extent of use
www.mhra.gov.uk/daps
59.
60. Examples of ADRs identified by
Yellow Card Scheme
Vigabatrin and visual field defects
3 reports severe persistent visual field constriction
detected 2-3 years after starting therapy
resulted in a change of recommended dosage, range of
indications and addition of warnings
Cyproterone acetate and hepatotoxicity
dose related
restricted indications
requirement for hepatic function monitoring
Alendronate and severe oesophageal reactions
warnings and revised dosing instructions
Varenicline and depression and suicidal ideation
reports received in the 1st 12 months after launch
addition of warnings and monitoring in patients with
history of psychiatric illness
61. Where to find ADR information
Reference texts
British National Formulary (BNF)
Summary of Product Characteristics (SPC)
Martindale
AHFS Drug information
Meyler’s 'The Side effects of drugs
Davies’ textbook Adverse Drug Reactions
Lee’s textbook Adverse Drug Reactions
Journals
Adverse Drug Reaction Bulletin
Drug Safety Update
Medline/Embase/Pharmline search
Electronic sources
Micromedex
www.mhra.gov.uk
