Pre-clinical evaluation and marketing authorisation Flashcards
What is preclinical evaluation
a part of lead optimisation that identifies safety and toxicology. determines a target dose in humans using animal to human dose prediction. determines a maximum safe dose. identify a therapeutic index - difference between target dose and maximum safe dose.
Dose range would be determined based on the absorption and duration of action of a single dose in different animals. cumulative dosing will also be looked at. this gives an indication of a safe dose in humans based on human equivalent dose (HED) calculation
Selectivity and off-target effects
Secondary pharmacology.
Will look at effects in similar targets, such as kinase inhibitors that likely have affinity for many other kinases. needs development of new screening assays
Will test for adverse drug reactions based on exaggerated pharmacology - target associated. will also look at off-target effects. single dose safety pharmacology will be done using core tests looking at CNS (consciousness, movement, behaviour, body temp), cardiovascular (BP, HR, ECG) and respiratory effects.
In vivo screens also needed to identify the off and on-target effects of metabolites.
in vivo also needed to test for immune reactions
Toxicology testing
uses both in vitro and in vivo. uses 1 rodent and 1 non-rodent species. male and female. takes blood and urine samples for biomarkers. also looks at PK for human dose extrapolation. autopsies conducted on in vivo tests
will look at genotoxicity such as mutagenicity (ames test), or tests for chromosomal abnormalities. ames test uses histidine-dependent salmonella.
toxicology testing is also tissue specific.
Carcinogenicity testing is conducted >6 months use. carcinogenicity will occur if the drug is mutagenic.
Test will also look at the drugs effect on fertility and teratogenicity. also looks at effect on lactation toxicity in offspring.
Acceptability of side effects dependent on the disease treated, e.g., chemo and HIV medicines (increase insulin resistance and [cholesterol]).
Drug-drug interactions also determined based on CYP inhibition screening and effects on transporters. induction can be assessed in cultured hepatocytes.
Criteria to take compound forward to clinical trials
A submission of an Investigational New Drug (IND) application.
Approximately 14 years and 2b USD to develop 1 drug.
PK appropriate in 2 or more species.
dose-dependency of effects.
no relevant DDIs
efficacy in in vivo model
concentration-response profile ensures human dose is less than 100mg.
pre-clinical safety profile likely to give appropriate therapeutic window with repeated doses.
Toxicity and safety profiling in 2 species
What are the 5Rs
Right target - link to disease
right tissue - drug acts in intended tissue
right safety - safety established in humanised systems before clinical trials
right patient - drug designed with the unique genetic, molecular and functional disease profiles of the populations the drug is intended for.
right commercial - drug meets needs of the market for new compound - price or gap in market
Components of marketing authorisation application
Module 1: has administrative, regional, or national information - contains application form, summary of characteristics, labelling, package leaflet, expert signature pages, environmental risk assessment, pharmacovigilance system and a risk management plan.
Module 2: has high level summaries - quality overall summary, non-clinical overview and clinical overview
module 3: chemical pharmaceutical and biological documentation on the quality and manufacturing
module 4: toxicology and pharmacological test data
module 5: clinical trials data
Drug registration procedures in europe
The European medicines agency (EMA) look at module 2 and then explore further difficulties in more detail. The FDA look in detail at modules 3 and 4. modules 2-5 are submitted as a common technical dossier (CTD)
Applications are made for new active substances, hybrid medicinal products, new fixed combinations of active substances, and informed consent for marketing authorisation
EU process: centralised procedure (CP) grants EU-wide approval - will have single trade name across the EU. necessary for HIV, cancer, diabetes, neurodegenerative, immunological, viral, biotech, advanced and orphan medicines. decentralised procedure (DCP) is assessed on a national basis. mutual recognition procedure (MRP) - if approved in one country may be automatically approved in another following application. national procedure (NP) is a single submission which is then assessed
Drug registration procedures in UK
administered by MHRA starting from 2021, with all european marketing authorisation converted to Great Britain marketing authorisation. EU MA still valid in northern ireland however.
can still get a GB MA based on recent EU approval.
a rolling review can be conducted where the common technical dossier is submitted before being completed to identify problems earlier and to allow for faster MA.
