The discovery and development of a drug is a very long and regulated process. The key stages begin with the research phase, during which candidates are identified, followed by a preclinical phase, during which therapeutic candidates are submitted to a proof of concept.
For this, screening methods in in vitro cell tests or in vivo animal tests are commonly used. In the clinical phase, candidates that have passed the previous phases are tested in humans. If the drug candidate is judged to be safe and effective, it will have to get market approval.
The different stages of drug development
Each drug development follows a unique process, in terms of candidate identification, validation and optimization, pre-clinical and clinical protocols and marketing.
There are, however, some broad outlines in drug development, which are described here.
Pre-clinical - 1-2 years
Measurement of ADME (Absorption, Distribution, Metabolism, and Elimination): potency tests, solubility, LogD, Caco-2 permeability, CYP inhibition, etc.
Measurement of pharmacokinetics and pharmacodynamics PK/PD
Structural optimization and synthesis (chemical or bioproduction)
Selection of candidates
Clinic - 6-7 years old
Phase I: small group of volunteers (less than 100) to test the safety of the drug candidate
Phase II: group of 100-500 patients to test the efficacy of the drug candidate
Phase III: large scale study on 1000-5000 patients to increase the statistical relevance of previous studies
Filing of regulatory dossiers in the regions of the world concerned (FDA in the United States, EMA in Europe, PFSB in Japan) - several validation circuits possible
Placing on the market and follow-up
What defines a cell model?
Cell models, if appropriately designed, can be used to rapidly identify the molecular mechanisms of human diseases and develop new therapies.
The design of a robust, reproducible, relatively easy-to-read test (it should use quantifiable molecular markers) is particularly appropriate when using a molecule library for high-throughput screening.
As soon as the model is designed, the experimenter raises the question of how to quantify the expected effect: either by molecular markers or by phenotypic observation.
A molecular marker that is well identified and characterized in a pathology or cellular process has the great advantage of limiting observations linked to an indirect effect.
The FRET technique typically proves to be relevant when studying conformational changes (e.g. intracellular nuclear receptors), aggregation (especially in neurodegeneration), or measurement of receptor-ligand interactions. FRET is based on the transfer of energy between two fluorophores, possible when the two molecules are physically close. Other methods for measuring molecular markers, such as qPCR or dPCR for modulation of gene expression, ELISA or Western Blot for protein quantification, etc., are also available.
Microscopy and imaging in general are useful in phenotypic studies.
The different types of providers
The development of drugs and biologics involves a large number of actors with different capacities.
Academic structures are involved in the development of drugs, particularly at the level of the in vitro and in vivo models they can propose.
Some very expensive equipment may also be required (e.g. for mass spectrometry or robots for HTS screening) - in this case, academic platforms may be asked by private companies to support them.
Service companies for experimentation
De nombreuses sociétés de services produisent des outils dans le discovery ou le développement de médicament. Cela concerne les tests in vitro par exemple, ou l’optimisation de formulation.
D’autres sociétés sont spécialisées dans les tests réglementaires, comme les expériences de PK/PD et de toxicité.
Il est souvent requis de la part de ces sociétés de travailler en conditions « bonnes pratiques de laboratoire » (BPL, ou GLP en anglais).
Les sociétés de services pour la production
Many service companies produce tools in drug discovery or development. This concerns in vitro tests for example, or formulation optimization.
Other companies specialized in regulatory testing, such as PK/PD and toxicity experiments.
These companies are often required to work under Good Laboratory Practice (GLP) conditions.
The differences between biologics and small molecules
Multiple actors are involved in cell culture: service companies, cell suppliers, and specialized academic platforms.
Size and mode of production
Small molecules are composed of 20 to 100 atoms and are typically produced by chemical synthesis.
Biologics range from a few hundred atoms (e.g. hormones) to 25,000 atoms for antibodies. They are typically produced by a living cell system.
The mode of administration
Small molecules are administered orally. They have a higher cell permeability and can reach intracellular regions through cell membranes. In some cases they can cross the blood-brain barrier (BBB).
Biologics, being larger in size and sometimes more unstable in structure, are administered by injection. Many therapeutic targets are not accessible to biomedical drugs, such as blocking the BBB or the plasma membrane.
The mode of delivery
By blood circulation for small molecules.
By blood and lymphatic route for biomedical drugs.
Small molecules address a wide spectrum of pathologies.
This is also the case for biologics, with drugs in oncology, inflammation, infections, metabolic and cardiovascular diseases.
Low prices for small molecules.
Greater competition for small molecules, largely linked to the generics economy.
Simpler and cheaper development process.
High prices for biologics treatments.
Better success rate for biologics (24.4%) entering clinical phase compared to small molecules (7.1%).
More complex and expensive development process.
Generics refer to molecules that are identical to small molecules whose patents have expired.
In the case of biologics, the names of medicines developed on the basis of medicines already on the market are biosimilars.
The technologies used in drug development
Cell culture & in vitro tests
Imaging on organisms
HTS and HCS screening
Prediction in silico
Cloning, sequencing, recombinant expression
Estimated rates for this type of services
A few hundred to a few thousand euros for a non-regulatory in vitro test.
An in vivo test can be between € 8,000 and € 100,000.
Outsourced HTS screening can cost between € 50,000 and € 100,000, an HCS screening can cost up to double, depending on the number of molecules tested.
Formulation optimization can cost several tens of thousands of Euros for in silico studies, and several hundreds of thousands of Euros for optimization by synthesis and validation.
Regulatory toxicity studies are very expensive and vary considerably depending on the test required.