The Accelerating Pace of Medical Development and Challenges in Evaluating Benefit and Risk Alasdair Breckenridge Medicines and Healthcare products Regulatory Agency

Food and Drugs Administration (FDA) European Medicines Agency (EMEA) International Conference on Harmonisation (ICH)

Unacceptable Acceptable Risk Benefits (relative value)

To protect the public health by allowing only medicines which have a satisfactory risk- benefit profile to be marketed and remain so To provide information to prescribers and patients so that these products can be used safely and effectively Not to put unnecessary regulatory hurdles in the way of innovative products Responsibilities of the Medicines’ Regulator

Measures of Drug Efficacy  Peak expiratory flow rate  Standard BP measurement  Joint size and temperature  Rating scales for dementia  Rating scales for depression

Biomarker A biochemical or physiological change that is :-  Quantifiable  Related to an actual or potential health impairment  May be used for measuring the progress of disease or the effects of treatment

Biomarkers  Collagen telopeptide fragments  PET imaging for tumours  Inflammation - Acute protein CRP - Cytokine IL6 - Metalloproteases

Improvement of Risk-benefit Profile Define accurately the population of patients who will respond to a medicine.

Causes of Variation in Drug Response  Genetic  Environmental

Pharmacogenetics and Clinical therapeutics Genes confer disease susceptibility Diseases can be genetically heterogeneous Efficacy, adverse drug reactions and drug interactions are often genotype-dependent

Genetic Polymorphisms Pharmacokinetic Pharmacodynamic Absorption Distribution Metabolism Excretion Receptors Ion Channels Enzymes Immune system

Promise of Pharmacogenetics

Pharmacogenetics  Drug will be approved for patients with defined genotype  Trials will be smaller and shorter  Market for drug may be smaller  Genotype testing before drug administration  Standardization of genotype test  Greater post marketing safety surveillance

Dialogue Between Regulators and Sponsors Briefing Meetings Safe Harbours Regulatory Exemption

New drugs come from molecular, biochemical and physiological research, much of which stems from academic institutions. As it quits the quiet waters of academia, a concept with a market potential is exposed to the entrepreneurs of the biotechnology sector, the credulous greed of the equity market, the well groomed executives of the pharmaceutical industry and the paper maze of the drug regulator before it lands in the broad handshake of the marketing manager- all before it crosses the horizon of the sceptical and budget- driven clinician who might want to use the product. Gale E and Clark A (2000)