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Drug Discovery Steps and Milestones, Proof of concept = demonstration that…
Drug Discovery Steps and Milestones
Target-based drug
discovery
and
development
:
key steps
Therapeutic concept
Target selection
Target validation
Lead discovery
Lead optimization
Pre-clinical development
Clinical development
Regulatory approval (NDA approval)
1 more item...
This process highly depends on regulation authorities
GxP
have to be respected (X=clinical, manufacturing, laboratory)
In addition, to progress to human testing (
FTIH
), the candidate has to demonstrate:
IND
(
Investigational New Drug
)
application
= application for candidate drugs to progress to human testing
High safety
It can be manufactured and industrialized easily
Drug formulation is finalized
Candidate
= final drug going into testing/development. It has all the right characteristics of a drug: efficacy, safety, developability
Hit
= SMOL/biologic able to modulate the target
Hit-to-candidate
In order to progress through discovery, high throughput screenings are conducted to assess the compound's:
Activity
Selectivity
PK profile
Development of a "
screening cascade
" showing how to progress across phases and which thresholds/requirements should be met
Key properties
that the candidate should possess to progress further into development
Good efficacy
(
demonstrated
also in vivo)
Selective and potent towards the desired molecular target
Good PK profile
Scalable chemistry and manufacturing
No major safety concerns
Patentable
Lead
= a selected prototype molecule, whose activity is similar to the final drug to propose
Target
= gene product that can potentially be modulated to provide beneficial effect for a disease
Target-to-hit
Input to identify hits can come from:
Rational drug design
High throughput screenings
Screening of large random libraries of compounds to identify those modulating a biological target
Types:
In vitro
(biochemical/cellular assays)
In vivo
(assays on animal models)
Target identification in areas where there is an
unmet medical need
Evidence for target identification
Association with the disease
Expression in disease-relevant regions
Modulation of target in disease conditions
Target modulation can rescue phanotype
Druggability
Clinical evaluation and development
Phase 2
(
a
+
b
)
Goals
: evaluation of
safety
+
tolerability
+
efficacy
, evaluation of dose administered in Phase 3
Proof of concept
= the drug has to demonstrate its effectiveness in treating the disease
Considerable number of patients
Phase 3
Goals: evaluation of safety + tolerability +
efficacy
, evaluation of
superiority over standard of care
Allows
regulatory filing
NDA
(
New Drug Application
) = application submitted to FDA for the approval of a new drug for sale and marketing
Large number of patients
in
multiple institutes
Phase 1
Goals
: evaluation of
safety
+
tolerability
, evaluation of dose administered in Phase 2, investigation of the mechanism of action
Few healthy volunteers
(exception: rare/severe disorders)
Approximately
15 years
for 1 drug to complete the whole process
Multiple players involved
Foundations
Pharma companies
Governments
Hospitals and clinics
Only institutions where clinical development can be conducted
Academia
Vaccine
development process: the
accelerated SARS-CoV-2 vaccine development
Governmental fundings
Review on a rolling basis
Previous knowledge on similar viruses
Many patients available
Large scale vaccine production before approval
Clinical phases overlapping
Proof of concept
= demonstration that the drug is effective in treating the disease