1. PERSONALISED MEDICINES AND THE REGULATORS Dr Mike James CambReg Consulting mikejames@cambreg.co.uk

2. 12 October 20122 Talk Outline  The ideal situation  Legal requirements  Special considerations for new science oMHRA Expert Advisory Group oCHMP Guideline oScientific Advice  Personalised medicines on the market  Companion diagnostic methods

3. 12 October 20123 The Ideal View

4. 12 October 20124 Clinical Studies  The usual rules apply to personalised medicine studies:  clinical trial: any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy (2001/20/EC)

5. 12 October 20125 Key Requirements  GCP standard studies  EC approval  MHRA (or similar) acceptance of study: oQuality data Drug substance and drug product manufacture (GMP) Specifications oSafety data (if species restricted?) Pharmacology Toxicology oRisk and Benefit statement

6. 12 October 20126 Additional Considerations  Mechanism of action – do you really understand it? oImmunomodulators and TG1412 oMHRA Expert Advisory Group oCHMP Paper (Guideline on Strategies to Identify and Mitigate Risks for First-in Human Clinical trials with Investigational Medicinal Products)

7. 12 October 20127 EAG Remit  FTIM studies with new compounds acting (directly or indirectly) via the immune system with a novel target or a novel mechanism of action or having a secondary potential effect on the immune system via a mechanism of action which currently is not well characterised  FTIM studies with novel compounds acting via a possible or likely species specific mechanism  Any FTIM studies which are otherwise seen as requiring expert advice  Clinical trials involving classes of compound where MHRA may wish to seek external expert advice or CHM may wish to have oversight  Expert advice on whether a product’s mechanism of action is novel and comes within the scope of the EAG  Expert advice on pre-meeting scientific advice documentation for within scope compounds  Clinical trials where there is a difficult risk benefit balance  Clinical trials where a new class safety issue has been identified

8. 12 October 20128 First in Man Considerations - 1 Risk Factors  Mode of action oPleiotropic effect targets oCytokine cascade o(Knock out) animal models oRelevance of animal models  Human target oCell and disease specificity oExpression and biological function oIntra-subjects differences (healthy and patients)

9. 12 October 20129 First in Man Considerations - 2  Quality oStrength and potency Biological activity and link to non-clinical dose What is a safe dose for humans? Bioassay to control activity oQualification of materials Even early studies require knowledge of what is present (pharmacologically active impurities) oDose Accuracy of small doses for steep dose-response

10. 12 October 201210 First in Man Considerations - 3 Non-clinical  Animal models and applicability to man oSpecies restricted effects – animal studies less useful? oIn vitro human cell studies can be useful oPD to address mode of action oPK and toxicokinetics?  Calculation of human starting dose (NOAEL and/or MABEL)

11. 12 October 201211 First in Man Considerations - 4 Clinical  Caution is the watchword oStudy population (volunteers or patients) oDose and dose escalation scheme First dose of active in a single subject Observation period before second subject oFacilities and staff suitable for emergency rescue oJustification for more than one site

12. 12 October 201212 Examples of Real Personalised Medicines  Herceptin (Roche) oAntibody against HER2 protein on metastatic breast cancer oNot all breast cancers over express HER2 oDiagnosis of suitable patients – companion diagnostic methods  Provenge (Dendreon) – US only at present oAutologous cellular immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. oDiagnosis of PC by conventional means (no special test kit)

13. 12 October 201213 Herceptin (‘Main Stream’)  MoAb produced in CHO cells  Approved in Europe on 28 August 2000  Serum and animal protein free system  Lyophilised powder for reconstitution  Development followed classical route for a new entity with large clinical studies  Approximately £ 20 000 per patient per year

14. 12 October 201214 Provenge (Advanced Therapy)  Activated autologous cell infusion  Complex and costly product ($93,000 per course)  Regulatory concerns: oAPC harvesting and transport oIncubation with fusion protein oManufacture of fusion protein oTransport of activated product oSpecifications linked to activity (increased survival) oStability of activated APC oAnimal models and pharmacology

15. 12 October 201215 Provenge Treatment  Patient's own WBCs, primarily antigen presenting cells (APCs), are extracted by leucapheresis.  WBCs incubated with a fusion protein (PA2024) consisting of PAP (prostatic acid phosphatase present on 95% of prostate cancer cells) and GM-CSF that helps the APCs to mature.  Activated blood product is re-infused into the patient to cause an immune response against cancer cells carrying the PAP antigen.  Complete treatment is three courses with two weeks between successive courses

16. 12 October 201216 Companion Diagnostic Kits  May be used for oselection of patients suitable for the medication ooptimal and individualised dosing oexclusion of populations expected to suffer from severe adverse side effects  At least 9 kits available in USA for HER2+ but none from Roche at present  Parallel development during clinical studies for joint marketing?

17. 12 October 201217 Regulation of Diagnostics  In vitro diagnostic devices (IVDs) controlled by Directive 98/79/EC (In Vitro Diagnostic Directive)  To be marketed a CE mark of conformity must be attached (by the manufacturer at present)

18. 12 October 201218 IVD Classification

19. 12 October 201219 Essential Requirements Based on a risk approach of the IVD giving erroneous results in:  Analytical and diagnostic sensitivity  Analytical and diagnostic specificity  Accuracy  Repeatability  Reproducibility

20. Questions?