1. All Wales Therapeutics and Toxicology Centre Cardiff, Wales, UK
Medicines Regulation and Pharmacovigilance: monitoring for safety Phil Routledge and Alison Thomas
All Wales Therapeutics and Toxicology Centre
Cardiff, Wales, UK

2. Why do we need medicines regulation?
To ensure that medicines are efficacious, pure and acceptably safe
Year
Serious Incident
Response
1848
Chloroform-associated deaths
Lancet Commission & prototype pharmacovigilance system in British Empire
1937
Sulfanilamide/ diethylene glycol poisoning
US FDA act amended (1938) to outlaw misbranding/ false advertising claims
1961
Phocomelia associated with thalidomide
Kefauver-Harris amendment (1962), UK Yellow card system (1964), UK Medicines Act (1968)
1974
Sclerosing peritonitis associated with practolol
Skegg and Doll’s recommendations on collecting adverse events in clinical trials
1980
hepatotoxicicity associated with benoxaprofen
UK Grahame-Smith working party on promoting pharmacovigilance
1982
Lactic acidosis associated with phenformin
2nd UK Grahame-Smith working party on post-marketing surveillance
Advances in drug regulation often occur after major incidents involving serious toxicity of medicines. Thus the present Yellow Card Scheme was introduced in 1964, only after the serious congenital abnormality phocomelia (literally “seal limbs”) was discovered in association with the use of thalidomide in pregnancy in However, while effective and efficient regulatory systems are necessary to protect the consumer, they will always depend upon the support and cooperation of all health-care professionals and also of patients. It is therefore essential that all health-care professionals, patients and carers are aware of their role in improving medicines safety.
Routledge PA. 150 years of pharmacovigilance. Lancet 1998; 351:

3. Why is continued surveillance required after product licensing and launch?
A medicine receives a product licence (marketing authorisation) for a specified indication if it is considered to be efficacious, pure and acceptably safe after extensive clinical trials (phase 1 to 3)
Some side-effects (adverse drug reactions or ADRs) are rare or delayed and may not have been identified during the pre-licensing/ pre-marketing phase, where often less than 3,000 people will have been treated with the medicine
Surveillance of medicines after licensing/ marketing is therefore vital for the whole of the life of the medicine as a therapeutic agent
Most medicines have been tested on about people before marketing. Therefore, effective post-marketing surveillance, especially spontaneous reporting of suspected toxicity by all prescribers, is the most sensitive way to detect the relatively rare but often serious non-dose-related (type B) ADRs.

4. What is an adverse Drug Reaction (ADR)?
A response to a drug (medicine) which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function
WHO Technical Report No 498 (1972)
 A serious adverse drug reaction means an adverse reaction which is fatal, life-threatening, disabling, incapacitating, or which results in or prolongs hospitalization
EU directive 75/319/EEC
An adverse drug reaction (ADR) is a response to a drug (medicine) which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function (WHO Technical Report No 498 (1972))
A serious adverse drug reaction means an adverse reaction which is fatal, life-threatening, disabling, incapacitating, or which results in or prolongs hospitalization (EU directive 75/319/EEC)

5. What is an ADR? (European perspective)
In Europe, definition amended in 2010 to ensure that it covers noxious and unintended effects resulting not only from the authorised use of a medicinal product at normal doses but also from use outside the terms of the marketing authorisation (including overdose, misuse, abuse and medication errors)
In Europe, the definition of an ADR was amended in 2010 to ensure that it covered noxious and unintended effects resulting not only from the authorised use of a medicinal product at normal doses but also from use outside the terms of the marketing authorisation (including overdose, misuse, abuse and medication errors).

6. What is Pharmacovigilance?
The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem
The aims of pharmacovigilance are to enhance patient care and patient safety in relation to the use of medicines; and to support public health programmes by providing reliable, balanced information for the effective assessment of the risk-benefit profile of medicines
Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem.
The aims of pharmacovigilance are to enhance patient care and patient safety in relation to the use of medicines; and to support public health programmes by providing reliable, balanced information for the effective assessment of the risk-benefit profile of medicines

7. What is the yellow card scheme?
Started in 1964 after the thalidomide disaster (1961)
Relatively inexpensive to run (paper-based & electronic reporting)
Open to all healthcare professionals and patients/carers
However under-reporting exists (<10% of serious suspected ADRs reported)
The yellow card is relatively inexpensive to run(paper-based & electronic reporting) but since all healthcare professionals and patients/carers can report, it is potentially the system most likely to detect very rare ADRs. However gross under-reporting exists and it is estimated that less than 10% of serious suspected ADRs are reported via the scheme.

8. Why report suspected ADRs via the Yellow Card Scheme?
ADR reporting helps to improve medicines safety and protect patients by ensuring that prescribers are aware of, and monitoring patients for suspected adverse effects while receiving medicines

9. Serious or result in harm New drugs and vaccines (▼)
What to report?
You should report suspected adverse drug reactions to the Yellow Card Scheme at: via the app or through some clinical systems (SystmOne, VISION, MiDatabank). Yellow Cards can be used for reporting suspected adverse drug reactions to medicines, vaccines, herbal or complementary remedies, whether self-medicated or prescribed. This includes suspected ADRs associated with misuse, overdose, medication errors or from use of unlicensed and off-label medicines. Report all suspected ADRs that are:
Serious or result in harm
Serious reactions: fatal, life-threatening, a congenital abnormality, disabling or incapacitating, resulting in hospitalisation, or medically significant
resulting in any harm to the patient
New drugs and vaccines (▼)
new drugs and vaccines display a black triangle (▼) to encourage reporting of all suspected ADRs. It does not mean the drug is unsafe.
A list of these products under additional monitoring is on the MHRA website: mhra.gov.uk/blacktriangle
It is important that health professionals use Yellow Cardsto report suspected adverse drug reactions to medicines, vaccines, herbal or complementary remedies, whether self-medicated or prescribed. This includes suspected ADRs associated with misuse, overdose, medication errors or from use of unlicensed and off-label medicines.
It is important to report all suspected ADRs that are serious or result in harm, and all suspected ADRs (irrespective of severity) to new medicines and vaccines. The can be identified by the black triangle (▼) next to the medicine in the BNF or BNF for children. The black triangle is there to encourage reporting of all suspected ADRs. It does not mean the medicine is unsafe. A list of these products under additional monitoring is on the MHRA website: mhra.gov.uk/blacktriangle
If unsure whether to complete a Yellow Card for a suspected ADR, it is better to report it – only a suspicion is needed

10. UK Yellow Card Centres (YCCs)
Established in the UK by MHRA to support it in promoting the spontaneous reporting of suspected ADRs
Clinical Pharmacologists and Pharmacists work together to deliver educational opportunities and other resources
Centres also introduce and evaluate educational and other initiatives to increase appropriate yellow card reporting
YCC Scotland
YCC Northern & Yorkshire
YCC North West
YCC West Midlands
Regional Monitoring Centres have been Established in the UK by MHRA to support it in promoting the spontaneous reporting of suspected ADRs. In the Centres, Clinical Pharmacologists and Pharmacists work together to deliver educational opportunities and other resources. Staff in the Centres also introduce and evaluate educational and other initiatives to increase appropriate yellow card reporting.
YCC Wales

11. Yellow Card Mobile App Secure – no ADRs stored on device
View numbers of YCs
Simple to submit updates to reports
Can view submitted reports
The new Yellow Card smartphone app only app that allows patients, carers and healthcare professionals to report suspected ADRs directly to the Yellow Card Scheme to help MHRA. Users can select specific medicines or vaccines to track and receive news and alerts about them.

12. iDAPs: interactive drug analysis profile mhra.gov.uk/yellowcard
The MHRA also makes interactive Drug Analysis Profiles (iDAPs) available on the Yellow Card websiteall licensed medicines for which MHRA have received reports of suspected adverse reactions. Each iDAP contains complete data for all spontaneous suspected adverse drug reactions, or side effects, which have been reported on that drug substance  to the MHRA, via the Yellow Card Scheme from healthcare professionals and members of the public. They also include reports from pharmaceutical companies. iDAPs enable anyone interact with the data to understand more about the types of reactions that have been reported, and at a high level about who experienced the side effects. There is a time lag of around one month from receipt of a report to it appearing in the iDAP.
When reviewing the data within an iDAP it is important to do so in the context of the essential guidance at the bottom of the report to ensure that the data is not misinterpreted.
Text adapted from

13. New ADR e-learning module
Developed by MHRA. CPD-accredited by European Union of Medical Specialists. Access to module:
Drug Safety Update May 2017:
Complements existing e-learning for pharmacists & nurses

14. What other important approaches to pharmacovigilance are there?
Case reports in scientific literature
Cohort studies (prospective)
Case Control studies (retrospective)
Disease (Drug therapy) Registers (e.g. for biologics)
Record linkage schemes (e.g. MHRA’s Clinical Practice Research Datalink [CPRD]which links anonymised primary care data with large data registries and other relevant data)
There are several ways to identify new ADRs to medicines. Case reports in Case reports in the Scientific Literature are valuable. In cohort studies, a group of people exposed to the medicine are followed up prospectively over a period of time to assess the rate of occurrence of ADRs compared with a group not taking the medicine.
Case Control Studies are used to retyrospectively compare a group of patients with a particular suspected ADR with a group without that ADR to see if a particular medicine is associated with a greater frequency of exposure in those who experienced the suspected ADR. Unlike cohort studies, they do not allow the incidence of the ADR to be measured.
Disease (Drug therapy) Registers (e.g. for biologics) are collections of data related to patients with a specific medical condition (e.g. rheumatoid arthritis). They can be valuable in the pharmacovigilance of medicines used in patients with that that particular condition.
By linking data from several sources (e.g. health registries and administrative claims data) record linkage schemes can help to identify associations between medicines and suspected ADRs. One extremely valuable scheme for pharmacovigilance purposes is the MHRA’s Clinical Practice Research Datalink [CPRD] which links anonymised primary care data with large data registries and other relevant data.

15. Conclusions
In the past, major advances in the regulation of medicines have often followed extremely serious episodes of drug toxicity (e.g. after the thalidomide tragedy)
Some adverse drug reactions (ADRs) are rare or delayed and may not have been identified during the pre-licensing/ pre-marketing phase
Continuing surveillance of medicines is therefore vital for the whole of the life of a medicine as a therapeutic agent
There are several approaches to pharmacovigilance, but the yellow card scheme can be used by all health professionals as well as by patients/ carers to identify possible new ADRs, even those which may occur infrequently
If you are unsure whether to complete a Yellow Card for a suspected ADR, it is better to report it – only a suspicion is needed
In the past, major advances in the regulation of medicines have often followed extremely serious episodes of drug toxicity (e.g. after the thalidomide tragedy)
Some adverse drug reactions (ADRs) are rare or delayed and may not have been identified during the pre-licensing/ pre-marketing phase
Continuing surveillance of medicines is therefore vital for the whole of the life of a medicine as a therapeutic agent
There are several approaches to pharmacovigilance, but the yellow card scheme can be used by all health professionals as well as by patients/ carers to identify possible new ADRs, even those which may occur infrequently
If unsure whether to complete a Yellow Card for a suspected ADR, it is better to report it – only a suspicion is needed

16. I am a clinical pharmacologist
Clinical Pharmacology and Therapeutics (CPT) is one of 30 physician specialties in the medical career pathway.
Consultants trained in this specialty lead on all aspects of medicines management.
It is the only medical specialty in the NHS focusing on the safe, effective, and cost-effective use of medicines.
Clinical pharmacologists play a crucial role in refining the use of currently available medicines, and in developing the pioneering medicines of tomorrow.
Clinical pharmacologists have diverse career paths working, for example, in the NHS, regulatory bodies, clinical trials units, universities or the pharmaceutical industry.