PHARMACEUTICAL MEDICINE
1. INTRODUCTION
DEFINITION
Medical discipline = speciality for medical doctors
→ includes discovery, development, evaluation registration, monitoring and medical
aspects of marketing of medicines for the benefit of patients and the health of the
community.
Pharmaceutical medicine is responsible for ensuring and maintaining standards in the
discipline and
→ curriculum for higher medical training to equip specialists with the comprehensive
skills and competence increasingly demanded by the industry for the public good
AUTHORIZATION & ADMINISTRATION OF DRUGS
EMA = European medicines agency
→ authorization for new medicines
In the last decade, the total number of drug approvals has generally increased, with some
peak years
→ most approvals are new molecular entities (NMEs)
PHARMACEUTICAL CLASSES
1st wave: small molecules
→ Chemically synthesized and can easily enter cells to interact with specific
biological targets
→ Ex. statins (= cholesterol lowering)
→ Screen large numbers of compounds
→ Small molecule drugs are typically discovered through large-scale
screening of chemical libraries
→ Off-target effects/toxicity
→ A major challenge with small molecules is their potential to bind to
unintended targets, leading to side effects or toxicity
2nd wave: biologicals (= monoclonal antibodies)
→ Drugs derived from organisms
→ Designed by target specific action to the target
→ Fewer off-target effects
→ NO trial & error
→ Biggest advantage: frequency is much lower, you don’t need to take the drug that
often, so therapy compliance is much better
→ Ex. PCK9-inhibitors
3rd wave: genetic medicines
→ ATMP = Advanced Therapy Medicinal Product
, → Treats or modulates underlying cause
→ Included siRNA, gene therapy, …
→ No off target effects
→ Often for rare diseases or genetic causes
→ mRNA based vaccines induce the endogenous production of non-self proteins by
administering “synthetic” mRNA…
Endogenous expression of a “viral” antigen to which an immune response is
induced
→ So not only used for the inhibition of proteins, but also for the induction
→ Ex. siRNA
THE DRUG LIFECYCLE
Drug discovery:
Target selection
Target validation
Search for & selection of an NME
THREE LIFE PERIODS
1) Early development
→ Testing of the compound
→ Costs money investment needed to get a drug on the market
2) Middle phase
→ Sales of the compound
→ Income = return of investment
→ Hopefully bigger than spent money in early development
3) Late phase
→ No more market exclusivity
→ After 20 years (patent expires)
→ Declined sales due to copies of the drug coming to the market
DRUG DEVELOPMENT
Exploratory phase = early development = non-clinical research, phase I & phase II
trials
→ Looking for the potential of the drug
→ Proving that the drug does what it is supposed to do & checking if it is safe
Confirmatory phase = late development = phase III & phase IV trials
→ Confirming what was found in early development
Pre-clinical or non-clinical development:
Non-clinical ADME
Toxicology & safety testing
Clinical development:
Phase I = exploring the safety of the drug in healthy people
Phase II = exploring the efficacy in a small group of patients
Phase III = confirming safety & efficacy in a large group of patients
,First-in-human (FIH) test = trial for the first time in humans
→ Approval form authority needed
→ Clinical Trial Application (CTA) in Europe
→ Request admitted in Clinical Trial Information System (CTIS)
→ All clinical trials need to be submitted through 1 central directive
→ Clinical trial Regulation (CTR)
Post-approval phase = approval for marketing
→ Common Technical Document (CTD) = summary of all the risk found in the clinical
trials
→ Through a Marketing Authorization (MA) in Europe
→ Through a New Drug Application (NDA) in US
→ Reimbursement & commercialization need to be established
→ Through pharmacovigilance, post-marketing surveillance & society
Guidelines:
Quality standards & guidelines during early phase
o Good Laboratory Practice (GLP)
o Good Clinical Practice (GCP)
o Good Manufacturing Practice (GMP)
o Good Documentation Practice (GDP)
Ethical standards during clinical trials
o Nuremberg code
o Declaration of Helsinki
Regulations during post-approval phase
o CTR
o Medical device regulation (MDR)
o In vitro diagnostic regulation (IVDR)
o Belgian law on experiments
2. DRUG DESIGN & DISCOVERY
PROF. DANIËLLE COPMANS
INTRODUCTION
MANAGEMENT
Strategically: Is it desirable to do?
→ Are there unmet medical needs in the present or future?
→ Ex. Alzheimer’s disease still has no real treatment, so there’s an unmet
need for a treatment for AD
→ Ex. Dafalgan, analgetics, highly competitive market. No place for a new
analgetica.
→ Market analysis: opportunities, risk assessment
Scientifically/technically: Can it be done?
→ Is there a model that models the disease that is present in humans?
→ Are those models or targets validated?
, → Are you sure that when you hit the target, that this will lead to a decrease of the
disease?
→ Are there any known compounds or will we have to screen for them ourselves?
→ First-in-class = first compound that has a mode of action in this group/class/target
→ Fast follower = the drug immediately after the first-in-class, mostly a different
type of drug with the same mode of action
→ Me-too = another drug in the same class with the same mode of action that will
compete with the other drugs already on the market
→ Ex. Pfizer and their drug research for Alzheimer’s and Parkinson’s. They ended
their neuroscience discovery, because the animal model shows a clear effect of
treatment, but humans didn’t show a decrease of the disease! The models were
there, but they were not good models. So, the models did not mimic the human
disease well!
→ A model in an animal for a human disease can be called a non-clinical
proxy, the better it mimics the clinical situation the better
→ Ex. 2 paintings showing similarities between both but still major
differences, painting on left is human disease and right is non-
clinical proxy
Operational: Can we do it?
→ Do we have the expertise and a qualified staff to do it?
→ Do we have the facilities?
→ What are the costs?
OBJECTIVE DRUG DISCOVERY & DESIGN
Identify pharmacologically active molecules, for which there are clear indications.
→ will reach the pharmacological target in the body in sufficient amounts
such that they can exert their desired effect
→ without toxicity!
The best model for patients are patients with the same disease
→ Even better would be the patient themselves
→ Not possible, so we try to get as close as possible
Models in this stage try to find molecules with activity and clear indications
→ Until preclinical development there are many ways to reach this end goal
TARGET BASED OR PHENOTYPIC DISCOVERY
DISCOVERY & DESIGN RESEARCH ANTITUMORAL COMPOUNDS
IN VITRO ANTIPROLIFERATION ASSAY
To test how compounds work against cancer or tumours
1) Tumour cells in a 96-well plate
→ They adhere to the bottom to the plastic layer, where they will proliferate
→ Mitochondrial reductase enzymes purple colour
→ The brighter the colour is, the more alive cells (aka a lot of
proliferation has taken place)
1. INTRODUCTION
DEFINITION
Medical discipline = speciality for medical doctors
→ includes discovery, development, evaluation registration, monitoring and medical
aspects of marketing of medicines for the benefit of patients and the health of the
community.
Pharmaceutical medicine is responsible for ensuring and maintaining standards in the
discipline and
→ curriculum for higher medical training to equip specialists with the comprehensive
skills and competence increasingly demanded by the industry for the public good
AUTHORIZATION & ADMINISTRATION OF DRUGS
EMA = European medicines agency
→ authorization for new medicines
In the last decade, the total number of drug approvals has generally increased, with some
peak years
→ most approvals are new molecular entities (NMEs)
PHARMACEUTICAL CLASSES
1st wave: small molecules
→ Chemically synthesized and can easily enter cells to interact with specific
biological targets
→ Ex. statins (= cholesterol lowering)
→ Screen large numbers of compounds
→ Small molecule drugs are typically discovered through large-scale
screening of chemical libraries
→ Off-target effects/toxicity
→ A major challenge with small molecules is their potential to bind to
unintended targets, leading to side effects or toxicity
2nd wave: biologicals (= monoclonal antibodies)
→ Drugs derived from organisms
→ Designed by target specific action to the target
→ Fewer off-target effects
→ NO trial & error
→ Biggest advantage: frequency is much lower, you don’t need to take the drug that
often, so therapy compliance is much better
→ Ex. PCK9-inhibitors
3rd wave: genetic medicines
→ ATMP = Advanced Therapy Medicinal Product
, → Treats or modulates underlying cause
→ Included siRNA, gene therapy, …
→ No off target effects
→ Often for rare diseases or genetic causes
→ mRNA based vaccines induce the endogenous production of non-self proteins by
administering “synthetic” mRNA…
Endogenous expression of a “viral” antigen to which an immune response is
induced
→ So not only used for the inhibition of proteins, but also for the induction
→ Ex. siRNA
THE DRUG LIFECYCLE
Drug discovery:
Target selection
Target validation
Search for & selection of an NME
THREE LIFE PERIODS
1) Early development
→ Testing of the compound
→ Costs money investment needed to get a drug on the market
2) Middle phase
→ Sales of the compound
→ Income = return of investment
→ Hopefully bigger than spent money in early development
3) Late phase
→ No more market exclusivity
→ After 20 years (patent expires)
→ Declined sales due to copies of the drug coming to the market
DRUG DEVELOPMENT
Exploratory phase = early development = non-clinical research, phase I & phase II
trials
→ Looking for the potential of the drug
→ Proving that the drug does what it is supposed to do & checking if it is safe
Confirmatory phase = late development = phase III & phase IV trials
→ Confirming what was found in early development
Pre-clinical or non-clinical development:
Non-clinical ADME
Toxicology & safety testing
Clinical development:
Phase I = exploring the safety of the drug in healthy people
Phase II = exploring the efficacy in a small group of patients
Phase III = confirming safety & efficacy in a large group of patients
,First-in-human (FIH) test = trial for the first time in humans
→ Approval form authority needed
→ Clinical Trial Application (CTA) in Europe
→ Request admitted in Clinical Trial Information System (CTIS)
→ All clinical trials need to be submitted through 1 central directive
→ Clinical trial Regulation (CTR)
Post-approval phase = approval for marketing
→ Common Technical Document (CTD) = summary of all the risk found in the clinical
trials
→ Through a Marketing Authorization (MA) in Europe
→ Through a New Drug Application (NDA) in US
→ Reimbursement & commercialization need to be established
→ Through pharmacovigilance, post-marketing surveillance & society
Guidelines:
Quality standards & guidelines during early phase
o Good Laboratory Practice (GLP)
o Good Clinical Practice (GCP)
o Good Manufacturing Practice (GMP)
o Good Documentation Practice (GDP)
Ethical standards during clinical trials
o Nuremberg code
o Declaration of Helsinki
Regulations during post-approval phase
o CTR
o Medical device regulation (MDR)
o In vitro diagnostic regulation (IVDR)
o Belgian law on experiments
2. DRUG DESIGN & DISCOVERY
PROF. DANIËLLE COPMANS
INTRODUCTION
MANAGEMENT
Strategically: Is it desirable to do?
→ Are there unmet medical needs in the present or future?
→ Ex. Alzheimer’s disease still has no real treatment, so there’s an unmet
need for a treatment for AD
→ Ex. Dafalgan, analgetics, highly competitive market. No place for a new
analgetica.
→ Market analysis: opportunities, risk assessment
Scientifically/technically: Can it be done?
→ Is there a model that models the disease that is present in humans?
→ Are those models or targets validated?
, → Are you sure that when you hit the target, that this will lead to a decrease of the
disease?
→ Are there any known compounds or will we have to screen for them ourselves?
→ First-in-class = first compound that has a mode of action in this group/class/target
→ Fast follower = the drug immediately after the first-in-class, mostly a different
type of drug with the same mode of action
→ Me-too = another drug in the same class with the same mode of action that will
compete with the other drugs already on the market
→ Ex. Pfizer and their drug research for Alzheimer’s and Parkinson’s. They ended
their neuroscience discovery, because the animal model shows a clear effect of
treatment, but humans didn’t show a decrease of the disease! The models were
there, but they were not good models. So, the models did not mimic the human
disease well!
→ A model in an animal for a human disease can be called a non-clinical
proxy, the better it mimics the clinical situation the better
→ Ex. 2 paintings showing similarities between both but still major
differences, painting on left is human disease and right is non-
clinical proxy
Operational: Can we do it?
→ Do we have the expertise and a qualified staff to do it?
→ Do we have the facilities?
→ What are the costs?
OBJECTIVE DRUG DISCOVERY & DESIGN
Identify pharmacologically active molecules, for which there are clear indications.
→ will reach the pharmacological target in the body in sufficient amounts
such that they can exert their desired effect
→ without toxicity!
The best model for patients are patients with the same disease
→ Even better would be the patient themselves
→ Not possible, so we try to get as close as possible
Models in this stage try to find molecules with activity and clear indications
→ Until preclinical development there are many ways to reach this end goal
TARGET BASED OR PHENOTYPIC DISCOVERY
DISCOVERY & DESIGN RESEARCH ANTITUMORAL COMPOUNDS
IN VITRO ANTIPROLIFERATION ASSAY
To test how compounds work against cancer or tumours
1) Tumour cells in a 96-well plate
→ They adhere to the bottom to the plastic layer, where they will proliferate
→ Mitochondrial reductase enzymes purple colour
→ The brighter the colour is, the more alive cells (aka a lot of
proliferation has taken place)
