Drug Development (Block 1) Flashcards
Drug research
Testing 10,000 compounds
Preclinicals
<250 compounds
Clinical trials
Usually one lead compound
Drug discovery
First five years
Changes in drug discovery
Moving on from basic research to high throughput screening and on further to machine learning
High Throughput Screening (HTS)
Allows for testing thousands of compounds against single protein; introduced in 1990s
Machine learning
Brings together all the basic research to put everything into a network to see things from a different angle
Discovery timeline order
1) target identification and validation
2) Hit identification and lead identification
3) lead optimisation
4) nonclinical development
Target identification followed by
Identifying compounds that will hit that target via bioassay developments
Hit identification and lead identification
HTS and in silico screening
Between which stages does compound selection take place?
Lead optimisation and nonclinical development
Why does this process need to be completed?
To meet specific requirements to present information to regulatory authorities
Regulatory authorities in Europe and USA
Europe -> EMA
USA -> FDA
Clinical Trial Authorisation (CTA)
Drug companies contact EMA to apply for CTA
1) Justify the compound exhibits pharma activity to meet unmet need
2) Support product being reasonably safe from humans
3) Justify exposing humans to reasonable risks when used in limited, early-stage clinical studies
4) Manufacturing route
Animal pharmacology and toxicology studies
data to demonstrate drug efficacy and safety for initial testing in humans
Manufacturing information
Data to support that the adequate, consistent and stable batches of drug will be used
Clinical protocols and investigator information
Detailed protocols, information of clinical investigator(s), information on process for obtaining ethics approval
G x P criteria
Standards at which studies must be performed
Why are G x P criteria needed?
To ensure everyone adheres to the same standards that address risk control measures, standard quality and equality, and public safety.
Which sections are regulated by G x P?
Preclinical -> GLP (Good Lab Practice)
Clinical -? GCP (good clinical practice)
Manufacturing -> GMP (Good manufacturing practice)
Goals of preclinical studies to support CTA
Understand exposure related to efficacy
Identify organ toxicities and reversibility
Understanding of therapeutic index (efficacy vs toxicity)
Identify safe starting dose
Guide dosing regimens and escalation schemes
IND/IMPD will continue to be updated during clinical development with new significant information (eg. toxicology, clinical data etc)
ADME
Absorption
Distribution
Metabolism
Excretion
Types of DMPK studies -Absorption
Pharmacokinetic/toxicokinetic
Bioanalytical method development and validation
Permeability studies
Transporter assays
Types of DMPK studies -Distribution
Protein binding
Quantitative whole body autoradiography (QWBA)
Types of DMPK studies -Metabolism
In vitro cross-species metabolism
Metabolite identification
CYP450 metabolism
Transporter assays
Types of DMPK studies - Excretion
Mass balance
Transporter assays
Pivotal toxicology studies
Shows whether anything is happening in other (non-target) organs
Multiple doses in 2 animal species - rodent and non-rodent
Doses must exceed intended human exposure
Prior to FTiH generally conduct a 28 day study
Recovery group included to see if toxicology is reversible
Study is under GLP conditions, ideally with drug manufactured to GMP
No Observed Adverse Affect Level (NOAEL)
Study designed to explore ascending does groups and establish a dose response curve
Toxicokinetics (TK)
Critical to understand exposures associated NOAEL and MTD
Will be used in the calculation of starting dose for human clinical trials
Do not want to exceed exposures associated effect levels in humans
Interspecies differences in protein binding are taken into account
What is meant by the term GLP?
Good Laboratory Practice is a set of guidelines to ensure quality and integrity of non-clinical lab studies
Phase 1
1st time new investigational medicinal product is tested in humans
Usually healthy volunteers
Sometimes patients with advanced disease (eg. cancer)
Small numbers of subjects (20-80)
Aim is to evaluate safety, tolerability and pharmacokinetics
Clinical Pharmacology studies to explore ADME
These are called Phase I studies, but can span clinical development
What is clinical pharmacology?
Providing scientific basis for rational safe and effective prescribing
PK-PD
The relationship between dose & therapeutic effect
The relationship between dose & toxicity
Exploring the causes of interindividual variability
Cmax
Peak clinical conc in plasma
Single Ascending Dose study (SAD)
First Time in Human Study (FTiH) is generally a single ascending dose study (SAD)
Cohort 6-8 active drug; 2-4 placebo
Double- blind
Emerging data is continually reviewed by a safety monitoring committee
Doses can be either escalated or de-escalated
Multiple Ascending Dose (MAD) study
Cohort design, placebo controlled
Aim is to dose long enough to achieve steady state
i.e. concentrations remain constant – reached equilibrium
Generally achieved in 4-5 half-lives
Main endpoint is safety, tolerability and pharmacokinetics
Will determine what dose(s) can be studied in Phase 2
Absorption and bioavailability
Not all of a drug that gets administered will enter the systemic circulation; during disintegration, dissolution, and transport some of the active compound may be lost.
Bioavailability is a function of
Fabs – fraction absorbed
FG – fraction escaping gut metabolism
FH – fraction escaping hepatic metabolism
Bioavailability (definition)
The fraction of drug that reached then circulation
Absolute bioavailability
assessment of systemic drug availability of extravascular dose compared with IV dose
Relative bioavailability
compares bioavailability of one formulation with another
Comparative bioavailability study
Two or more formulations of the same drug are compared, are usually designed as crossover studies. Each patient acts as his or her own control. This allows for the direct comparison of treatments.
Food effect studies
Initial studies are done in the fasted state and then food effect studies follow.
Study design:
Statistically sized cross-over design
PK of drug assessed following drug administration under fasted and fed conditions
Distribution - tissue penetration studies
studying whether the drug actually reaches target site in sufficient concentration; clinical studies to understand relationship between plasma concentrations and concentrations at site of action may be required
Metabolism
Most early healthy volunteer studies exclude co-medications
CYP450 enzymes are the main metabolising enzyme system
If drug is a substrate, inhibitor or inducer of a common pathway (eg. CYP3A4), the impact on exposure when dosed with other agents may need to be considered
What could be the impact on exposure of Drug A (CYP3A4 substrate) when dosed with Drug B (strong CYP3A4 inhibitor)?
CYP450 liability is assessed non-clinically as part of DMPK package
However understanding this doesn’t predict the impact on clinical exposure
Clinical DDI study is conducted:
New Drug is dosed alone or in combination with a known inhibitor
Cross-over design
Endpoint is PK
Compare AUC and Cmax following drug administered alone or in combinatation
Dosing recommendations will be based on whether impact is clinically relevant
What type of study is done to investigate drug excretion?
Mass balance study
Aim of mass balance study
understand full clearance mechanisms of drug and metabolites
Mass balance study (details)
Single dose of radio-labelled (C14) drug: plasma, urine and faeces collected
Radiolabelled drug and concentrations of parent and metabolite(s) measured
Assesses the major routes of clearance:
may influence whether a renal and hepatic impairment study is required
Proportion of parent drug converted to metabolite(s)
Metabolite identification (eg. detection of unique human metabolites, active metabolites)
Renal and hepatic impairment studies
liver and kidney are major routes of elimination -> impairment = significant change in exposure
Assessment of influence renal and hepatic impairment on exposure can lead to dosage adjustment warnings on the label
Until these studies are done, patient population will need to be restricted
Requirement for studies will depend on major route(s) of elimination
‘special’ populations
Elderly
Risk of altered exposure
Obese
Ethnic groups – if the main programme is conducted in the West, specific PK study may be required to justify dose in certain ethnic groups (eg. Chinese, Japanese)
Why is obesity specifically included?
PK variability due to alterations in Vd and Clearance. Vd could be overestimated for hydrophilic drugs due to poor penetration into adipose tissue. Obese patients have increased organ mass which may lead to increased renal blood flow thus increasing renal clearance. Those with gastric bypass have loss of surface area for drug absorption.
Why are the elderly specifically included?
physiologic alterations include reduced gastric acid secretions affecting absorption, reduced renal and hepatic blood flow which slows the rate of clearance, and reduced serum protein concentrations which increases free drug concentrations.
Pharmacokinetic variability
Most clinical pharmacology studies are conducted in healthy volunteers, however, it is important to understand PK in target patient population bc weight/body surface area, renal or hepatic function, illness severity, clinical indication, age, concomitant medications, and ethnicity can have an impact
PK sampling - phase one (healthy volunteer)
Intensive PK samples can be taken in Phase 1
Easy to calculate Cmax, AUC, clearance, volume of distribution etc.
PK parameters calculated for each individual
PK sampling - phase 2 and 3
Generally only sparse PK samples collected
Impossible to calculate PK parameters if individual data used in isolation; used in combination with phase 1 information
Population pharmacokinetics
all data is analysed together
allows exploration of mean exposure and variability sources
use simulations to predict appropriate dosing regimen for majority of individuals
Phase 2
Main aim is proof of concept– some form of clinical efficacy
Endpoint may be different to that explored in Phase 3
Generally in patients with condition under study (or related condition)
Further safety and PK evaluation
Can be comparator studies or single arm
May explore dose range
May be open label or blinded
End of phase 2 meeting
Review of data and agreement for design of Phase III study
Sponsor looks for regulatory agreement for:
Endpoints and timing of endpoints of trial (eg. mortality, clinical cure)
Size
Patient population
Comparator and blinding
Dose
Duration
Paediatric plan
Regulatory agreement
Clinical trial application; includes protocol, investigators brochure, IMPD, scientific advice, informed consent and patient information leaflet, investigational product labelling and GMP-related documents, and ethics
Phase 3
Pivotal studies designed and executed to provide statistically significant evidence of efficacy and safety
Generally randomised controlled trial (RCT) against standard of care or placebo
Parallel study design
Sometimes adaptive design can be used
Often two identical independent studies required
Nearly always double blind
Types of phase 3 trials
Superiority
Non-inferiority
Equivalence
Superiority trial
To determine a clinically relevant difference between two treatments. i.e. want to show new treatment is statistically significantly better than existing therapy or placebo
Non-inferiority trial
To determine whether new treatment is not inferior to another established treatment
Equivalence trial
To determine whether a new treatment is neither worse nor better than another established treatment
More often used for approval of generics, or formulation changes
Regulatory review
Submission documents reviewed by team of technical experts
EU – centralised procedure
Regulatory defence
Additional analysis may be required
Regulatory inspections
Process could take up to 2 years (longer in some countries)
Biggest reason for drug failure
Efficacy
Second biggest reason for drug failure
safety
Label and patient information leaflet
Core information is included in the summary of product characteristics (SPC) or label
Patient information leaflet are also produced written in clear, easy-to-understand language for general public and patients
Post-approval
Post-marketing commitments
Pharmacovigilance
Paediatic investigation plan
Post-marketing commitments
studies required by regulatory authorities but not included in original package
May remove some restrictions on the label
Pharmacovigilance
science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem
Up to approval, evidence of safety and efficacy is limited to data from clinical trials, where patients are selected carefully and followed up under controlled conditions
Safety of medicines is monitored throughout their use in healthcare practice
Paediatric investigation plan
drugs are first approved for adults and aren’t always tested for children so there is a government push to bring in a focus on it; in the EU it’s mandatory unless there’s a specific waiver for conditions that don’t exist in paediatric patients
Development in paediatric patients
children aren’t just small adults; process are different and must be accounted for
