Pharmacovigilance and Pharmacogenetics

Core

Introduction

Once a drug has been licensed, the work of evaluating it has only just begun. Most adverse drug reactions are relatively common and recognised during clinical trials, but the rare, serious and delayed reactions are usually missed and only become visible once the drug enters routine clinical use. Pharmacovigilance is the system by which those reactions are identified, assessed and acted upon.

The formal definition is "the identification, assessment and subsequent prevention of adverse drug reactions whilst optimising the benefits" of medicines. In the UK this is the responsibility of the Medicines and Healthcare products Regulatory Agency (MHRA) and, in Europe, of the European Medicines Agency.

The Thalidomide Tragedy

Modern pharmacovigilance was effectively created by a single drug. Thalidomide was marketed from 1957 as a sedative and anti-emetic, including for the treatment of morning sickness in pregnancy, and was sold over the counter in many countries. Between 1957 and 1962, an estimated 10,000 children were born worldwide with severe limb-reduction defects (phocomelia: from the Greek for "seal limb"; arms or legs absent or reduced to flipper-like stumps), along with cardiac, gastrointestinal, ocular and auditory malformations.

The link between thalidomide and these defects was identified by Dr Widukind Lenz and Dr William McBride and reported in 1961. Thalidomide was withdrawn from most markets by the end of 1962. The episode prompted three lasting changes in regulation:

• Mandatory teratogenicity testing in animals before human trials.
• Stratified clinical trial requirements (now Phase I-IV) before licensing.
• The creation of spontaneous reporting systems for adverse events: the UK Yellow Card Scheme was established in 1964 in direct response.

By modern standards, only around 10 cases of a thalidomide-like cluster would now be sufficient to trigger a regulatory signal; an enormous improvement on the thousands needed in 1961.

Why Pharmacovigilance Matters

Adverse drug reactions are the underlying cause of approximately 6.5% of UK hospital admissions, contribute to many more, and prolong inpatient stay. The economic and clinical case for active surveillance is therefore strong.

Limitations of Pre-Marketing Trials

Pre-marketing clinical trials, however well-conducted, cannot detect every adverse effect. Their structural limitations include:

• Small numbers. Most Phase III trials enrol a few thousand patients at most. An ADR with an incidence of 1 in 10,000 will not appear.
• Selected populations. Trials exclude pregnant women, children, the elderly with multiple comorbidities, and patients on multiple other medications; precisely the groups where ADRs are most common.
• Short duration. Trials usually last weeks to months. Chronic and delayed reactions emerge over years.
• Specialist settings. Trials are run in research centres with intensive follow-up, not in the busy clinics where the drug will eventually be used.
• Concomitant medications excluded. Drug-drug interactions are missed if polypharmacy is excluded from the protocol.

For all these reasons, the safety profile of a new medicine is genuinely incomplete at the moment it is licensed. Pharmacovigilance is the means by which that profile is built up over time.

Mechanisms of Adverse Drug Reactions

The classification of ADRs as A, B, C, D, E (Augmented, Bizarre, Chronic, Delayed, End-of-treatment) is covered in detail in Pharmacodynamics. Mechanistically, almost every ADR can be assigned to one of four categories:

• Exaggerated pharmacological response at the intended target. Bleeding from warfarin; hypoglycaemia from insulin; bradycardia from a beta-blocker.
• Desired pharmacological action at an unintended site. Dry mouth from atropine; headache from glyceryl trinitrate; bronchospasm from a non-selective beta-blocker.
• Off-target pharmacological effects. QT-interval prolongation from many drugs (e.g. macrolides, antipsychotics); cough from ACE inhibitors via bradykinin.
• Immune-mediated reactions. Anaphylaxis to penicillin; Stevens-Johnson syndrome from sulphonamides or carbamazepine.

The Yellow Card Scheme

The Yellow Card Scheme is the UK system for spontaneous reporting of suspected adverse drug reactions, run by the MHRA since 1964. Reports can be submitted online, by post, by phone or via the Yellow Card mobile app. Reporter and patient details are kept confidential (not anonymous: identifiers are needed so the MHRA can follow up where required).

Who reports? Originally only doctors. Since 2005, reports are accepted from doctors, dentists, pharmacists, nurses, midwives, coroners, patients and parents. The wider the net, the more reactions captured.

What gets reported?

• All suspected ADRs to drugs marked with the inverted black triangle (▼) in the BNF; new medicines under intensive monitoring. The MHRA keeps the black-triangle status until it is satisfied that the safety profile is well-established (often around 2 years, but no fixed cut-off).
• Serious suspected ADRs to any other drug, regardless of how long it has been licensed. "Serious" means resulting in death, hospital admission, prolonged hospitalisation, congenital abnormality, life-threatening illness, or significant disability.
• Suspected ADRs to vaccines, herbal medicines, e-cigarettes, and medical devices through corresponding schemes.

Strengths of the Yellow Card Scheme:

• Simple, free, and applies to all licensed drugs throughout their life cycle.
• Accessible to all healthcare professionals and to patients.
• Generates the early signals that lead to formal regulatory investigation.

Weaknesses:

• Under-reporting: the single biggest limitation. Studies estimate that fewer than 10% of serious ADRs are actually reported.
• Reports are unquantifiable in isolation: the denominator (how many people were exposed) is not known.
• Reports may be duplicated, biased, or based on weak association.
• The system is vulnerable to publicity: reports surge after media coverage of a suspected reaction, distorting the apparent signal. The 1995 "pill scare" over third-generation combined oral contraceptives is the classic example.

For all these reasons the Yellow Card Scheme is best understood as a signal-generating system rather than a definitive one. Once a signal emerges, the MHRA can commission formal pharmacoepidemiological studies, request data from manufacturers, and ultimately restrict, label or withdraw a drug.

Pharmacogenetics

Pharmacogenetics is the study of how individual genetic variation influences drug response. The closely related term pharmacogenomics covers the same territory at a genome-wide level. The clinical importance is that prescribing decisions made at the population level may be wrong for a particular individual: around 7% of serious ADRs, and a small but significant fraction of fatal drug reactions, can be attributed to person-to-person genetic variability.

Variability of response to common drugs is striking. Roughly 3 in 10 patients do not respond to statins, and 4 in 10 do not respond to a given beta-blocker, with much of that variation under genetic control.

Pharmacokinetic Polymorphisms

The most clinically relevant pharmacogenetic variation affects drug-metabolising enzymes: principally the cytochrome P450 (CYP) family. The CYP system is covered in Pharmacokinetics; pharmacogenetic variants produce four phenotypes:

• Poor metabolisers (PMs): reduced or absent enzyme activity. Higher plasma levels and increased toxicity for parent drugs; reduced effect for pro-drugs.
• Intermediate metabolisers (IMs).
• Extensive (normal) metabolisers (EMs).
• Ultra-rapid metabolisers (UMs): gene duplication, increased enzyme activity. Reduced effect for parent drugs; toxic levels for pro-drugs.

Three CYP-mediated examples are routinely taught at pre-clinical level:

• CYP2D6 and codeine. Codeine is a pro-drug that requires CYP2D6 to be converted to morphine. Ultra-rapid metabolisers can develop morphine toxicity from standard doses; the MHRA contraindicates codeine in breastfeeding mothers and in children under 12 because of fatal cases of opioid toxicity in nursing infants of UM mothers.
• CYP2C9 and warfarin. Variants in CYP2C9 (and in the warfarin target enzyme VKORC1) account for around 30-50% of inter-individual variation in warfarin dose requirement.
• CYP2C19 and clopidogrel. Clopidogrel is a pro-drug. Poor metabolisers convert less of it to its active form and have a higher risk of stent thrombosis. UK guidance increasingly favours alternatives (ticagrelor, prasugrel) where genotype is uncertain.

Beyond CYP enzymes, thiopurine methyltransferase (TPMT) deficiency is a particularly important example. TPMT inactivates azathioprine and 6-mercaptopurine; patients with low TPMT activity (around 1 in 300 of the UK population) accumulate active drug and develop severe myelosuppression. UK guidance recommends checking TPMT activity before starting azathioprine.

Likewise, dihydropyrimidine dehydrogenase (DPD) deficiency causes severe (sometimes fatal) toxicity with 5-fluorouracil and capecitabine, and the MHRA now requires DPD testing before starting these drugs.

Pharmacodynamic Polymorphisms

Polymorphisms in drug targets, rather than metabolising enzymes, can also alter response. VKORC1 variants alter warfarin sensitivity at the receptor level. Variants in the β₂-adrenergic receptor alter the bronchodilator response to salbutamol. Variants in the 5-HT transporter have been associated with response to SSRIs.

HLA-Linked Hypersensitivity

Several severe Type B (immune-mediated) reactions are strongly linked to specific human leucocyte antigen (HLA) alleles. UK practice now genotypes for these before prescribing in at-risk groups:

• HLA-B*5701 and abacavir: up to 8% of HIV patients exposed to abacavir without screening develop a multi-system hypersensitivity reaction; almost all carry HLA-B*5701. Pre-treatment screening reduces the rate of severe reactions to near zero and is now standard.
• HLA-B*1502 and carbamazepine: strongly associated with Stevens-Johnson syndrome and toxic epidermal necrolysis, particularly in patients of Han Chinese, Thai or other South-East Asian ancestry, where the allele is far more prevalent.
• HLA-B*5801 and allopurinol: severe cutaneous reactions, again with strong ethnic variation in allele frequency.

Pharmacogenetics in Oncology

Cancer chemotherapy is the field where pharmacogenetics is most embedded in routine practice. A few standard examples:

• HER2 status in breast cancer determines whether a patient benefits from trastuzumab.
• BRCA1 / BRCA2 mutations identify patients who benefit from PARP inhibitors (olaparib).
• EGFR mutations in non-small-cell lung cancer predict response to EGFR tyrosine kinase inhibitors (gefitinib, erlotinib, osimertinib).
• BCR-ABL translocation in chronic myeloid leukaemia is the target of imatinib.
• KRAS wild-type status is required for benefit from anti-EGFR antibodies (cetuximab, panitumumab) in colorectal cancer.

These tumour-specific markers are not strictly germline pharmacogenetics: they reflect somatic mutations in the cancer, but the underlying principle (matching drug to molecular target) is the same.

Population-Level Differences in Drug Response

Allele frequencies vary between populations, and so do average drug responses. Two examples are worth knowing for pre-clinical exams:

• ACE inhibitors are less effective in Black African and Black African-Caribbean populations, who tend to have lower-renin hypertension. NICE guidance recommends a calcium channel blocker as first-line antihypertensive in this group instead. The mechanism is not strictly genetic but is a population-level pharmacological difference covered in Hypertension and Heart Failure.
• Aldehyde dehydrogenase 2 (ALDH2) deficiency is found in around 30-50% of East Asian populations. Affected individuals accumulate acetaldehyde after alcohol, producing facial flushing, tachycardia and nausea ("Asian flush"). The same enzyme is targeted by disulfiram in alcohol-use disorder.

Population-level differences are descriptive, not prescriptive: individual genotype will always trump average ethnic background, and over-extrapolating from population data to the individual patient is itself a form of bias.

Stratified and Personalised Medicine

The clinical use of pharmacogenetic information is the foundation of stratified medicine: matching the right drug to the right group of patients. The fully individualised version, personalised medicine, sequences and integrates each patient's genome to inform prescribing.

The drivers of this transition are:

• Falling cost of genotyping (whole-genome sequencing now costs a few hundred pounds).
• Growth in evidence linking specific variants to specific drug effects.
• Regulatory acceptance: the MHRA, EMA and FDA increasingly require pharmacogenetic testing in product labelling.
• The NHS Genomic Medicine Service, established in 2018, which makes whole-genome sequencing available within the NHS for selected indications.

The barriers remain real: the evidence for many proposed pharmacogenetic tests is incomplete, turn-around times can be slower than the clinical decision, and the ethical questions about genetic data are unresolved. The pre-clinical student is not expected to know these in detail; only to recognise that the era of "one dose fits all" prescribing is ending.

Summary

• Pharmacovigilance is the science of detecting and managing ADRs once a drug is in clinical use.
• Pre-marketing trials cannot detect rare, delayed, or population-specific reactions because of small numbers, short duration and selection bias.
• The Yellow Card Scheme is the UK signal-generating system, run by the MHRA. It is open to all healthcare professionals and patients.
• Thalidomide is the historical event that established the regulatory framework; black triangle drugs are still subject to intensive ADR reporting for at least two years after licensing.
• Pharmacogenetics explains a substantial fraction of variability in drug response. Examples include CYP2D6 (codeine), CYP2C9 (warfarin), CYP2C19 (clopidogrel), TPMT (azathioprine), DPD (5-fluorouracil), and HLA-linked hypersensitivity (abacavir, carbamazepine).
• The translation of these findings into stratified medicine is the principal direction of modern UK prescribing.

Reviewed by: Dr. Marcus Judge

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