Drug development in the UK

Question 1

Target discovery (2-3 years)

Answer 1

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.

Question 2

Lead identification (0.5-1 year)

Answer 2

Assay development
High throughout screening for 'hit' - global protein profiling. Protein-protein interaction profiling.
Medicinal chemistry
Combinatorial
Structure-based

Question 3

Lead optimization (1-3 years)

Answer 3

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

Question 4

Efficacy definition

Answer 4

To characterise and integrate non-clinical and human pharmacodynamics to provide an assessment of overall therapeutic efficacy.

Question 5

Quality definition

Answer 5

To ensure that drug substance is synthesised in a consistent and controlled way to optimise drug product quality characteristic.

Question 6

GLP/Regulatory toxicology outputs

Answer 6

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.

Question 7

Drug marketing authorisation: drug license

Answer 7

Required the submission of a complex dossier of information which includes 4 parts.

Question 8

Drug marketing authorisation: drug license - Part 1

Answer 8

Identification of product.

Administrative data and incl; summary of product characteristics (SPC) and expert reports.

Question 9

Drug marketing authorisation: drug license - Part 2

Answer 9

Product manufacture.
Composition and method of production.
Control of starting materials, control tests on intermediate/final products.
Bioavailability/bioequivalence.

Question 10

Drug marketing authorisation: drug license - Part 3

Answer 10

Pre-clinical data
Single dose toxicity
Repeated dose toxicity
Reproductive studies
Mutagenicity studies
Carcinogenicity studies
Pharmacodynamics
Pharmacokinetics
Local tolerance

Question 11

Drug marketing authorisation: drug license - Part 4

Answer 11

Clinical results

Clincal pharmacology and clinical trial results

Question 12

Drug development - Preclincal (1-2 years)

Answer 12

GLP toxicology
Process chemistry
Scale-up and API production
Formulation
ADME/Pk

Question 13

Drug development - Phase I (1-2 years)

Answer 13

Safety
Tolerable
Pk
API production
GMP formulation.

Question 14

Drug development - Phase II (1-2 years)

Answer 14

Clinical proof of principle
Dose range finding
Early side effect profile
API product

Question 15

Drug development - Phase III (2-4 years)

Answer 15

Large safety studies
Large efficacy studies
Large scale manufacturing

Question 16

Clinical trial categories

Answer 16

1. Treatment
2. Preventation
3. Diagnostic
4. Screening
5. Quality of life

Question 17

A therapeutic trial is…

Answer 17

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.

Question 18

The placebo effect

Answer 18

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.

Question 19

Factors which can influence the outcome of the trial

Answer 19

Demographics (population characteristics; age, sex, weight, disease, duration etc)
Randomisation (sequential/block/dynamic placement in arms of trial.
Ethics (clear purpose and intent)

Question 20

Clinical trial design type

Answer 20

Randomisation control studies (blinded or unblinded).
Non-randomised concurrent studies (unblinded).
Historical control studies (unblinded).
Cross over trial design.
Factorial design.
Hybrid design.

Question 21

Study power

Answer 21

The ability to detect (statistically) a true difference in outcome between the control arm and the intervention arm.

Question 22

Null hypothesis =

Answer 22

No difference between treatment.

Question 23

Type 1 errors =

Answer 23

Finding a difference when there is not one (probability α)

Question 24

Type 2 errors =

Answer 24

Finding no difference when there is (probability β)

Question 25

Clinical trial endpoint measures

Answer 25

1. Clinical measures (Liver/kidney function, blood/urine chemistry, eye testing)
2. Pk measures (Cmax, Tmax, t1/2, AUC, Bioavailability clearance, elimination, disposition)
3. PD measures (Target affinity, dose-response, biomarkers, clinical measures)
4. Safety measures (Extent of exposure, common adverse events, common lab tests)

Question 26

Phase 1 trials - Aims

Answer 26

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.

Question 27

Phase 1 trials - Types

Answer 27

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)

Question 28

Phase 1 trials - Errors

Answer 28

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.

Question 29

Phase 2 trials - Aims

Answer 29

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

Question 30

Phase 2 trials - Therapeutic exploration

Answer 30

Involves participants with target disease (100s of patients).
Can include refractory patients.
Uses target route of administration.

Question 31

Phase 2 trials - Measures

Answer 31

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.

Question 32

Phase 2 trials - Outcomes

Answer 32

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.

Question 33

Phase 3 trials - Aims

Answer 33

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.

Question 34

Phase 3 trials - Outcomes

Answer 34

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).

Question 35

Phase 4 trials - Post-licensing studies

Answer 35

To investigate new indictions for drug.
In specific patient sub-groups.
To investigate safety concerns.

Question 36

Phase 4 trials - Outcomes

Answer 36

Technology appraisals - Use of new and existing medicines/treatment.
Clinical guidelines - Specific diseases/conditions.