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PERSONALISED MEDICINES AND
THE REGULATORS
Dr Mike James
CambReg Consulting
[email protected]
Talk Outline
The ideal situation
Legal requirements
Special considerations for new science
o MHRA Expert Advisory Group
o CHMP Guideline
o Scientific Advice
Personalised medicines on the market
Companion 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 Group
o 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 - 1
Risk Factors
Mode of action
o Pleiotropic effect targets
o Cytokine cascade
o (Knock out) animal models
o Relevance of animal models
Human target
o Cell and disease specificity
o Expression and biological function
o Intra-subjects differences (healthy and patients)
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First in Man Considerations - 2
Quality
o 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-clinical
Animal models and applicability to man
o Species restricted effects – animal studies less
useful?
o In vitro human cell studies can be useful
o PD to address mode of action
o 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 rescue
o 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 cancer
o Not all breast cancers over express HER2
o 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 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
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Provenge (Advanced Therapy)
 Activated autologous cell infusion
 Complex and costly product ($93,000 per course)
 Regulatory concerns:
o
o
o
o
o
o
o
APC harvesting and transport
Incubation with fusion protein
Manufacture of fusion protein
Transport of activated product
Specifications linked to activity (increased survival)
Stability of activated APC
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 for
o selection of patients suitable for the medication
o 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 present
Parallel 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 sensitivity
Analytical and diagnostic specificity
Accuracy
Repeatability
Reproducibility
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Questions?