PERSONALISED MEDICINES AND THE REGULATORS

Dr Mike JamesCambReg Consulting

mikejames@cambreg.co.uk

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Talk Outline

The ideal situationLegal requirementsSpecial considerations for new science

o MHRA Expert Advisory Group o CHMP Guidelineo Scientific Advice

Personalised medicines on the marketCompanion diagnostic methods

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The Ideal View

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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)

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Key Requirements

GCP standard studies EC approval MHRA (or similar) acceptance of study:

o Quality data• Drug substance and drug product manufacture (GMP)• Specifications

o Safety data (if species restricted?)• Pharmacology• Toxicology

o Risk and Benefit statement

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Additional Considerations

Mechanism of action – do you really understand it?o Immunomodulators and TG1412 o MHRA Expert Advisory Groupo CHMP Paper (Guideline on Strategies to Identify and Mitigate Risks for First-in

Human Clinical trials with Investigational Medicinal Products)

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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

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First in Man Considerations - 1Risk FactorsMode of action

o Pleiotropic effect targetso Cytokine cascadeo (Knock out) animal modelso Relevance of animal models

Human targeto Cell and disease specificityo Expression and biological functiono Intra-subjects differences (healthy and patients)

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First in Man Considerations - 2

Qualityo Strength and potency

• Biological activity and link to non-clinical dose• What is a safe dose for humans?• Bioassay to control activity

o Qualification of materials• Even early studies require knowledge of what is

present (pharmacologically active impurities)o Dose

• Accuracy of small doses for steep dose-response

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First in Man Considerations - 3

Non-clinicalAnimal models and applicability to man

o Species restricted effects – animal studies less useful?

o In vitro human cell studies can be usefulo PD to address mode of actiono PK and toxicokinetics?

Calculation of human starting dose (NOAEL and/or MABEL)

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First in Man Considerations - 4

Clinical Caution is the watchword

o Study population (volunteers or patients)o Dose and dose escalation scheme

• First dose of active in a single subject• Observation period before second subject

o Facilities and staff suitable for emergency rescueo Justification for more than one site

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Examples of Real Personalised Medicines

Herceptin (Roche)o Antibody against HER2 protein on metastatic breast cancero Not all breast cancers over express HER2o Diagnosis of suitable patients – companion diagnostic

methods Provenge (Dendreon) – US only at present

o Autologous cellular immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

o Diagnosis of PC by conventional means (no special test kit)

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Herceptin (‘Main Stream’)

MoAb produced in CHO cellsApproved in Europe on 28 August 2000Serum and animal protein free systemLyophilised powder for reconstitution Development followed classical route for a

new entity with large clinical studiesApproximately £ 20 000 per patient per year

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Provenge (Advanced Therapy)

Activated autologous cell infusion Complex and costly product ($93,000 per course) Regulatory concerns:

o APC harvesting and transporto Incubation with fusion proteino Manufacture of fusion proteino Transport of activated producto Specifications linked to activity (increased survival)o Stability of activated APCo Animal models and pharmacology

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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

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Companion Diagnostic Kits

May be used foro selection of patients suitable for the medicationo optimal and individualised dosing o exclusion of populations expected to suffer from

severe adverse side effects At least 9 kits available in USA for HER2+ but

none from Roche at presentParallel development during clinical studies for

joint marketing?

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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)

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IVD Classification

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Essential Requirements

Based on a risk approach of the IVD giving erroneous results in:

Analytical and diagnostic sensitivityAnalytical and diagnostic specificityAccuracyRepeatabilityReproducibility

Questions?