Drug development in the UK Flashcards
Target discovery (2-3 years)
Target identification
Assay development
Bioinformatics
In vivo validation (knockouts etc)
Target-based: disease-relevant molecule used to screen compound libraries for a ‘hit’
Phenotypic: Testing a drug in a cell/tissue/organ to see if it has the desired effect.
Lead identification (0.5-1 year)
Assay development High throughout screening for 'hit' - global protein profiling. Protein-protein interaction profiling. Medicinal chemistry Combinatorial Structure-based
Lead optimization (1-3 years)
Med chemistry
SAR development (structure activity relationship)
Predicting biological activity from molecular structure
Improve potency
In Vivo testing
ADME / Pk
Prelim toxicity
Chemoproteomics - selectivity and/or drug affinity profiling
Efficacy definition
To characterise and integrate non-clinical and human pharmacodynamics to provide an assessment of overall therapeutic efficacy.
Quality definition
To ensure that drug substance is synthesised in a consistent and controlled way to optimise drug product quality characteristic.
GLP/Regulatory toxicology outputs
Positive preclincal data can be submitted for a clinical trial authorisation.
Allows FIM studies to commence based on supplied data.
Assessed by two routes within UK (MHRA and European medicines agency).
Utilise suitability qualified and independent representatives to consider applications objectively.
Drug marketing authorisation: drug license
Required the submission of a complex dossier of information which includes 4 parts.
Drug marketing authorisation: drug license - Part 1
Identification of product.
Administrative data and incl; summary of product characteristics (SPC) and expert reports.
Drug marketing authorisation: drug license - Part 2
Product manufacture.
Composition and method of production.
Control of starting materials, control tests on intermediate/final products.
Bioavailability/bioequivalence.
Drug marketing authorisation: drug license - Part 3
Pre-clinical data Single dose toxicity Repeated dose toxicity Reproductive studies Mutagenicity studies Carcinogenicity studies Pharmacodynamics Pharmacokinetics Local tolerance
Drug marketing authorisation: drug license - Part 4
Clinical results
Clincal pharmacology and clinical trial results
Drug development - Preclincal (1-2 years)
GLP toxicology Process chemistry Scale-up and API production Formulation ADME/Pk
Drug development - Phase I (1-2 years)
Safety Tolerable Pk API production GMP formulation.
Drug development - Phase II (1-2 years)
Clinical proof of principle
Dose range finding
Early side effect profile
API product
Drug development - Phase III (2-4 years)
Large safety studies
Large efficacy studies
Large scale manufacturing
Clinical trial categories
- Treatment
- Preventation
- Diagnostic
- Screening
- Quality of life
A therapeutic trial is…
A carefully and ethically designed experiment with the aim of answering some precisely framed questions.
In its most rigorous form it demands equivalent groups of patients concurrently treated in different ways or in randomised sequential order in cross-over designs.
The placebo effect
A psychological response to a treatment that has no intrinsic drug activity.
All trials subject to possible psychological impact on therapeutic outcomes.
Physiological conditions don’t change with the placebo.
Factors which can influence the outcome of the trial
Demographics (population characteristics; age, sex, weight, disease, duration etc)
Randomisation (sequential/block/dynamic placement in arms of trial.
Ethics (clear purpose and intent)
Clinical trial design type
Randomisation control studies (blinded or unblinded).
Non-randomised concurrent studies (unblinded).
Historical control studies (unblinded).
Cross over trial design.
Factorial design.
Hybrid design.
Study power
The ability to detect (statistically) a true difference in outcome between the control arm and the intervention arm.
Null hypothesis =
No difference between treatment.
Type 1 errors =
Finding a difference when there is not one (probability α)
Type 2 errors =
Finding no difference when there is (probability β)
Clinical trial endpoint measures
- Clinical measures (Liver/kidney function, blood/urine chemistry, eye testing)
- Pk measures (Cmax, Tmax, t1/2, AUC, Bioavailability clearance, elimination, disposition)
- PD measures (Target affinity, dose-response, biomarkers, clinical measures)
- Safety measures (Extent of exposure, common adverse events, common lab tests)
Phase 1 trials - Aims
The PK/PD properties of the drug in humans.
The toxicological properties of the drug in humans.
The appropriate route and frequency of administration of the drug to humans (drug dose and schedule).
Emphasis remains on safety.
Average duration 1 year.
Phase 1 trials - Types
Healthy volunteers. Single ascending dose (SAD). Multiple ascending dose (MAD). PK/PD. Drug-drug interactions (DDI). Bioequivalence/bioavailability. ADME - radiolabeled compound Fed vs fasted (oral) Selected populations (gender, ethnicity) Abuse potential Formulation bridging studies. Drug effect (efficacy/safety)
Phase 1 trials - Errors
Autoimunne/leukemia treatment.
Double blind RCT
1/500th of NOAEL iv dose given
ADR
No deficencies in trial design or implementation, manufacture of drug or animal work.
Revised procedures for trials involving humanised monoclonal antibodies.
Phase 2 trials - Aims
Characterise and integrate non-clinical and human pharmacodynamics to provide an assessment of overall therapeutic efficacy.
First evidence of clinical effectiveness in humans.
Pharmacodynamic dose-ranging.
Emphasis on efficacy and safety
Design influenced by phase 1 results
Phase 2 trials - Therapeutic exploration
Involves participants with target disease (100s of patients).
Can include refractory patients.
Uses target route of administration.
Phase 2 trials - Measures
Confirm primary pharmacology through POP studies.
Validation of clinical endpoints or surrogates.
Drug interactions.
Effectiveness in intended patient population under defined conditions of usage.
Human variability.
Phase 2 trials - Outcomes
Evidence of efficacy or in-efficacy in target conditions.
Decreased safety profile.
Possible dosing regime information/adjustments.
Positive safety and efficacy data will allow drug candidates to progress to phase 3 trials.
Phase 3 trials - Aims
The potential role of the new drug in routine clinical practice.
Emphasis on efficacy.
More complex study design, documentation and personnel requirements.
Strict entry and exclusion criteria.
Will dictate if a drug gains approval for general medical use.
Phase 3 trials - Outcomes
Driven by therapeutic area being examined.
Must have ‘therapeutic validity’
Positive outcomes - Approval for product licence/marketing authorisation.
May include extension of phase 3 studies into marketing phase (phase 4).
Phase 4 trials - Post-licensing studies
To investigate new indictions for drug.
In specific patient sub-groups.
To investigate safety concerns.
Phase 4 trials - Outcomes
Technology appraisals - Use of new and existing medicines/treatment.
Clinical guidelines - Specific diseases/conditions.
