Madhuri.M : Madhuri.M Spontaneous reporting THE SPONTANEOUS REPORTING SYSTEM : 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 Slide 3: The spontaneous
reporting system process
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 The spontaneous reporting
3.data interpretation Slide 4: The spontaneous
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 The spontaneous reporting
3.data interpretation Slide 5: The spontaneous
3. data interpretation
based on the available data and
the assessments made, a signal
related to the adverse reaction
may be generated The spontaneous
3.data interpretation Slide 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 Spontaneous reporting - UK : 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. Introduction of yellow card scheme : 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
and now patients
MHRA can detect duplicate reports Purpose and achievements of the yellow card scheme : Purpose and achievements of the yellow card scheme Weakness of yellow cards : 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:
Seriousness of the reaction
Whether the reaction is labelled
length of time a drug has been on the market
promotion or publicity about the medicine or the reaction Slide 12: Evidence suggesting under reporting:
reporting may vary between different groups of doctors, with hospital doctors reporting less frequently than general practitioners
lack of time uncertainty as to whether the reaction was caused by a drug
Breaching patient confidentiality Slide 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. Slide 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. Slide 16: Reasons for increase in reporting
introduction of the CSM(committee on safety of medicines) drug safety bulletin Current Problems in Pharmacovigilance
the inclusion of a yellow page in prescription pads used by GPs
increased availability of Yellow Cards to doctors
inclusion in the British National Formulary (BNF) Slide 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. RECENT INITIATIVES TO ENHANCE THESCHEME : RECENT INITIATIVES TO ENHANCE THESCHEME A number of initiatives have been undertaken:
Initiatives aimed at increasing the general reporting base,
those aimed at increasing reporting in particular areas where under-reporting is of particular concern,
those aimed at facilitation of reporting. WIDENING THE YELLOW CARD REPORTING BASE : 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 Slide 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 Slide 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 Nurse Reporting: : 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 Slide 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 SPECIALIST THERAPEUTIC AREAS : 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 The HIV Reporting Scheme : 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. Slide 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 SUSPECTED ADRS IN CHILDREN : 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 Slide 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. Slide 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). UNLICENSED HERBAL REMEDIES : 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. Slide 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 Slide 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. FACILITATION OF REPORTING – NEWTECHNOLOGY AND MEDIA : FACILITATION OF REPORTING – NEWTECHNOLOGY 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 Slide 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. THE ANONYMISED YELLOW CARD : 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 Slide 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. INDEPENDENT REVIEW OF ACCESS TO THE YELLOW CARD SCHEME : 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 Slide 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 Slide 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. Slide 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 Slide 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. Slide 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 FOCUS ON PATIENTS : 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 Slide 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 Slide 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 Slide 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 Slide 47: Benefits of patient reporting:
Identification of ADRs not previously reported
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 Information to include on a Yellow Card : Information to include on a Yellow Card 4 critical pieces of information that must be included on the report :-
Reporter details Suspected Drug(s) : Suspected Drug(s) Name of medicine
including brand and batch number if known
Route of administration
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 Suspect reaction(s) : 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 Patient Details : 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 Reporter details : 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 Additional useful information : 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:
relevant medical history
suspected drug interactions Slide 55: What happens to a Yellow card once received? Provision of information Commit to database Report details entered to Sentinel database Risk-benefit evaluation and
advice from CHM Signal detection Assessment Yellow Cards - Adverse Drug Reaction reports Impact Analysis Signal Evaluation and Prioritisation Regulatory action and communication Acknowledgment and/or follow-up for more info Slide 56: How is the Yellow Card data used to improve patient safety? Changes to SPC e.g. restriction in use, special warnings and precautions
Issue of ‘Dear Healthcare professional’ letters
Drug Analysis Prints (DAPs)
Withdrawal of a medicines if patient safety is threatened Drug Safety Update : Drug Safety Update Published monthly
Register for alerts
http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/index.htm Drug Analysis Prints (DAPs : 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 Examples of ADRs identified by Yellow Card Scheme : 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
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 Where to find ADR information : Where to find ADR information Reference texts
British National Formulary (BNF)
Summary of Product Characteristics (SPC)
AHFS Drug information
Meyler’s 'The Side effects of drugs
Davies’ textbook Adverse Drug Reactions
Lee’s textbook Adverse Drug Reactions
Adverse Drug Reaction Bulletin
Drug Safety Update