things clinicians don’t often consider (cmc, glp...
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Things clinicians don’t often consider (CMC, GLP toxicology, Phase I studies)Dr Lauren Walker, NIHR Royal Liverpool
Things clinicians don’t often consider (CMC, GLP toxicology, Phase I studies)
Dr Lauren WalkerNIHR Clinical Lecturer/ST7 Clinical Pharmacology &
Drug Development• Incredibly costly• Incredibly time consuming• High failure rate• High risk
Challenge in Drug Development
Safety Issues20%
Formulation10%
Define safety and efficacy earlier
Others30%
Efficacy 40%
10% fail because of unwanted PK/unfeasible formulation
20% fail because of toxicology
40% fail because of lack of efficacy
30% Others (economical)
Reasons for Failure during Clinical Development
First in human studies• Transition from animal to human data• High risk part of life
No direct comparison between animal data and human data necessarily
Phase I: when it all goes wrong
Donald Rumsfeld• As we know there are known knowns:
– There are things we know we know• We also know there are known
unknowns:– That is to say we know there are some
things we do not know• But there are also unknown unknowns:
– The ones we don’t know we don’t know
Management of Risk
Risk Assessment
Precaution, facilities, staff
Pre-clinical work• Synthesis – CMC data and GMP• In-vitro testing• Animal testing:– PK– PD (infection models etc.)– Toxicity (single, multiple)– Carcinogenicity– (Pregnancy)
But what species?
Pre-clinical work• 2 species (rodent, non-rodent)• Duration of dosing same or greater than
clinical trial• Sufficient data to calculate first dose
And another….
NCP Pharmacokinetics
• ADME• Human microsomes (CYP450 profiling)• Animal TK studies– Single, multiple doses (if necessary)– PK
• Metabolite profiling (and activity)
Single and Repeat Dose Studies• Usually two species– One small, one large
• Must be conducted to Good Laboratory Practice (GLP) standards– Equivalent of GCP for animal studies – Ensures that studies are conducted robustly
through design, conduct and audit
Species specificity• Always needs justification• Molecule and target dependent– Is the target expressed in the animal?– Does it share homology with the equivalent
human target?– Does the target act on a cascade (e.g. immune
system?)
Toxicology
• Single and repeat dose studies• Cardiovascular effects• Respiratory System• CNS• Genetics• Phototoxicity
Cardiotoxicity• A rapidly moving field• Currently require:– In vitro ionic current studies – K channels, hERG– In vivo QT assay
• Only useful if the molecule can interact with the channel
NCP: Pharmacodynamics
• Very dependent on the type of molecule– Small molecule– Biologic– Advanced therapy
• Proof-of-concept (e.g. infection models etc.)• Risk of cross-reactivity?
Calculation of first dose.....
All things are poison and nothing is without poison, only the dose makes a thing be poison
Paracelsus 1493-1541
Toxicology
Determine No Observable
Adverse Effect Level (NOAEL)
Convert NOAEL to Human
Equivalent Dose (HED)
Apply >/= 10 fold safety
factor
Pharmacology
Estimate Minimum
Anticipated Biological Effect
Level (MABEL)
• Justify on pharmacology
• Adjust for exposure
• Adjust for inter-species
differences in potency
Maximum Recommended Starting Dose
Define safety window based on TK
Add further safety factor, if necessary
Dose or Exposure
Unacceptable Toxicity
Therapeutic Range
Effect
NOAELMABEL PAD
Calculation of first dose……
Things to make you worry…….• Mode of action involves target connected to
multiple signalling pathways• Acts via a cascade system• Novel immune target or not well characterised• Novelty in structure• Expression or function of target varies• Acts via a species specific pathway
Study Designs• Single ascending dose• Multiple ascending dose• Food effect• Drug-drug interaction• AME study• Renal Impairment• Hepatic Impairment
Study Designs - SimpleSingle doses
Multiple doses
Sentinel Dosing
Study Designs - ComplexPart A. Single Ascending Dose and Food Effect
Group A3
Group A1
Group A5
Group A4
Groups A6, A7, A8
Groups A9, A10, A11Optional
Group A2
Group A4 Fed
Part B. Multiple Ascending Dose (14d)
Group B3
Group B1
Groups B4, B5 and B6, Optional
Group B2
Part C. Relative Bioequivalence
Suspension/Solid
Suspension/Solid
Updated IMPD
Methotrexate Days 1, 8 and 15MBS2320 Days 3-15
Part D. Drug-drug interaction
Single Dose
Food Effect
Multiple Dose
Bioequivalence
Patient group & DDI study
..
MHRA Phase I Accreditation• Contingency Planning
– Risk Assessment– Dose escalation– Oversight– Staffing
• Standard Operating Proc– SOPs for everything– Audit– Robust QC– Dedicated QA
• Training– Physicians all ALS trained– Nurses / HCAs ILS trained– PIs trained in Clinical
Pharmacology / Pharm Med• Emergency Scenarios
– Scenario testing & documentation
– Cover by crash team / ART– Access to ITU or HDU
Summary• FIH / Phase I trials are a high risk area for new
drugs• Careful thought and preparation are key• FIH/Phase I trials remain safe