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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
12 October 2012
2
The Ideal View
12 October 2012
3
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)
12 October 2012
4
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
12 October 2012
5
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)
12 October 2012
6
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
12 October 2012
7
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)
12 October 2012
8
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
12 October 2012
9
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)
12 October 2012
10
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
12 October 2012
11
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)
12 October 2012
12
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
12 October 2012
13
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
12 October 2012
14
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
12 October 2012
15
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?
12 October 2012
16
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)
12 October 2012
17
IVD Classification
12 October 2012
18
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
12 October 2012
19
Questions?