Preclinical drug research
Contents
Pharmaceutical industry .................................................................................................................... 1
Therapeutic modalities .................................................................................................................... 11
Drug discovery: choosing the (right)target ....................................................................................... 23
Role of medicinal chemistry in drug discovery ................................................................................. 31
Drug discovery process: drug screening technologies ...................................................................... 36
Pharmacokinetics ............................................................................................................................ 52
Pharmacology: role in drug discovery .............................................................................................. 70
Patent issues in drug discovery ........................................................................................................ 75
Management of drug discovery ....................................................................................................... 76
Drug development: introduction ..................................................................................................... 78
Assessing drug safety....................................................................................................................... 82
Pharmaceutical development ........................................................................................................ 125
Paediatric drug development ........................................................................................................ 138
Pharmaceutical industry
Process of developing a molecule to a drug is very long – can take up to 15 years
- Very risky: high probability of failure
- Drug development = expensive
Drug can have 3 names:
1. Chemical name: used by scientists eg acetylsalicylic acid
2. Generic name: universal name eg aspirin
o When a drug is developed, it is patented
o When the patent expires, other companies can resell the drug for a much cheaper
price = it becomes a generic drug
3. Trade name: registered trademark name eg Sedergine®
→ if another company resells it, they give it a new tradename, even though it remains the
same generic drug
In drug discovery you go from a molecule to a drug.
- Chemicals: small molecules with a certain, simple molecular structure → eg aspirin,
fluoxetine, omeprazole
- Natural products: more complex molecules → eg artemether (for malaria), paclitaxel,
vinblastine
- Biologicals: large (complex) molecules → very variable and quite large group of compounds
eg monoclonal AB (MAB) → eg insulin, EPO, interferon, vaccines, gene therapy,…
1
,1 – 2 billion USD to develop drug:
- 21,5% - preclinical trial
- 56,9% - clinical trials
- 8,3% - approval
- 9,8% - pharmacovigilance
Phases of drug development:
1. Discovery: can be up to 10 years
2. Patent application
3. Preclinical studies: in vitro or in vivo experiment to obtain preliminary
efficacy, toxicity and pharmacokinetic information
4. Clinical:
o Phase I: low doses are given to healthy volunteers designed to test the safety, side
effects, best dose, pharmacokinetics, pharmacodynamics and formulation method
for the drug
▪ 20 – 100 healthy volunteers
▪ Mainly done on male students, because the company doesn’t want to risk
damaging a foetus if a woman was to be pregnant and they don’t want to
interfere with the fertility of women (because in men sperm is made
continuously while female eggs are not)
▪ Often run by contrast research organizations who conduct these studies on
behalf of pharmaceutical companies (outsourced)
o Phase II: trials on patients (vs placebo group) to asses how well the drug works as
well as to continue phase I safety assessments in a larger group
▪ 50 – 300 patients
▪ If possible, companies try to enrol only men (is obviously not always
possible) here as well, but if you want/need women you need to provide
preclinic evidence that it is not teratogenic and that it doesn’t have an effect
on female fertility (so you need to do more preclinical tests)
▪ First indication of the therapeutic potential of the drug
o Phase III: randomized controlled multi-centre trials on large, diverse patient groups
(300–3,000 or more depending upon the disease/medical condition studied) and are
aimed at being the definitive assessment of how effective the drug is, in comparison
with current 'gold standard' treatment
→ most expensive part because there are a lot of doctors, medical personnel,…
involved → if this phase fails, it means that the company loses a lot of money (so its
best to fail in the preclinical trial because then you lose less money)
- Pharmacovigilance: company must follow up on the drug after its on the market to see if it
doesn’t cause any other detrimental effects (because even if you have a population of
100000 during phase III, there can still be undetected effects)
2
,Time for each phase can vary. This
depends on the indication… For each
phase of the clinical development you
need different preclinical packages.
So the sequence: preclinical → clinical
→ market is not correct
Correct is: preclinical – phase I –
preclinical – phase II - …
This course focuses mainly on the
preclinical part before phase I
Patents start before the preclinical
trials and expires after 20 years, so if all
goes well the patent can only be
profitable for about 5 years.
- in the past: when there was a new indication for the drug, the duration of the patent could
be expanded by 5 years, but not it is not possible anymore: all indications must be addressed
from the start
- the timing to take a patent is critical and very difficult
o too early: there is not much time after registration of the drug to earn profits before
the patent expires
o too late: because of espionage, your idea can be stolen
Therapeutic areas
The therapeutic areas that companies spend most R&D costs on are:
1. Neurological: Alzheimer, schizophrenia, depression, epilepsy, Parkinson – high failure rate
(so quite low revenue)
2. Metabolic: cancer, osteoporosis, diabetes, obesity
3. Cardiovascular: atherosclerosis, coronary disease, heart failure (has decreases in the last few
years because there are a lot of options available already)
4. Infectious diseases: viral, bacterial, fungal, (parasitic)
3
, Annual population growth rate
The 60+ and 80+ population has increased loads in all the different
regions. So, we have to deal with diseases linked with age (can be very
lucrative). Problem is that the older population often has to take more
than one drug, so interactions can happen, but again it can be very
lucrative for big pharma → focus on other regions and/or age-related
diseases
The older population spends more on healthcare.
Table: sales in certain area – cardio and CNS are the highest
Blockbuster drugs
- Humira: MAB for juvenile arthritis
- Herceptin: MAB for breast cancer
- Red squares: biologicals – are very important now
- 70% of the industry profits come from 20% of the drugs
marketed
→ driving force behind recent mergers (big pharma are
buying up smaller companies to improve their portfolio).
- Pharmaceutical industry is a core sector for Europe (600 000
employees), but competitiveness is declining.
Challenges for pharmaceutical sales
- Generic drugs: a pharmaceutical drug that contains the same
chemical substance as a drug that was originally protected by chemical patents.
There is a shrinking of market exclusivity and subsequently a drop in earnings.
This means that there is a smaller budget for R&D for new drugs. Generic drugs
are allowed for sale after the patents on the original drugs expire. Because the
active chemical substance is the same, the medical profile of generics is believed
to be equivalent in performance. It has the same active pharmaceutical
ingredient, but it may differ in some characteristics such as manufacturing
process, formulation, taste, packaging. Generics are good for the patient, because they
are cheaper.
- Price containment: a process of judiciously reducing costs in a business or limiting them
to a constant level. When pharmaceutical company want to release their drug to the
market, they need to negotiate with all the countries (the ministers of health) about the
amount they can charge for this drug → there are strict rules about incentives from
pharmaceutical companies for GPs (companies can’t choose what they charge)
- Poor product differentiation: the better the differentiation, the better the sales (eg better
taste, longer half-life, more potency…)
- Increased competition from ‘me-too’ drugs: different pharmaceutical companies focus on
the same indications and the same molecules → many similar drugs on the market
- Parallel importation: In the Single Market parallel traders can buy pharmaceuticals in any
EU/EEA country and then under strictly regulated conditions move medicines to the
destination market, repackage them to comply with national legislation and linguistic needs,
and sell them at a lower price than the standard local price, in competition with that same
identical product sold by the manufacturer or its local licensee. This is possible because
prices of individual drugs vary between Member States.
- Counterfeiting of drugs: fraud; eg people sell fake drugs online – unofficial drugs
4
Contents
Pharmaceutical industry .................................................................................................................... 1
Therapeutic modalities .................................................................................................................... 11
Drug discovery: choosing the (right)target ....................................................................................... 23
Role of medicinal chemistry in drug discovery ................................................................................. 31
Drug discovery process: drug screening technologies ...................................................................... 36
Pharmacokinetics ............................................................................................................................ 52
Pharmacology: role in drug discovery .............................................................................................. 70
Patent issues in drug discovery ........................................................................................................ 75
Management of drug discovery ....................................................................................................... 76
Drug development: introduction ..................................................................................................... 78
Assessing drug safety....................................................................................................................... 82
Pharmaceutical development ........................................................................................................ 125
Paediatric drug development ........................................................................................................ 138
Pharmaceutical industry
Process of developing a molecule to a drug is very long – can take up to 15 years
- Very risky: high probability of failure
- Drug development = expensive
Drug can have 3 names:
1. Chemical name: used by scientists eg acetylsalicylic acid
2. Generic name: universal name eg aspirin
o When a drug is developed, it is patented
o When the patent expires, other companies can resell the drug for a much cheaper
price = it becomes a generic drug
3. Trade name: registered trademark name eg Sedergine®
→ if another company resells it, they give it a new tradename, even though it remains the
same generic drug
In drug discovery you go from a molecule to a drug.
- Chemicals: small molecules with a certain, simple molecular structure → eg aspirin,
fluoxetine, omeprazole
- Natural products: more complex molecules → eg artemether (for malaria), paclitaxel,
vinblastine
- Biologicals: large (complex) molecules → very variable and quite large group of compounds
eg monoclonal AB (MAB) → eg insulin, EPO, interferon, vaccines, gene therapy,…
1
,1 – 2 billion USD to develop drug:
- 21,5% - preclinical trial
- 56,9% - clinical trials
- 8,3% - approval
- 9,8% - pharmacovigilance
Phases of drug development:
1. Discovery: can be up to 10 years
2. Patent application
3. Preclinical studies: in vitro or in vivo experiment to obtain preliminary
efficacy, toxicity and pharmacokinetic information
4. Clinical:
o Phase I: low doses are given to healthy volunteers designed to test the safety, side
effects, best dose, pharmacokinetics, pharmacodynamics and formulation method
for the drug
▪ 20 – 100 healthy volunteers
▪ Mainly done on male students, because the company doesn’t want to risk
damaging a foetus if a woman was to be pregnant and they don’t want to
interfere with the fertility of women (because in men sperm is made
continuously while female eggs are not)
▪ Often run by contrast research organizations who conduct these studies on
behalf of pharmaceutical companies (outsourced)
o Phase II: trials on patients (vs placebo group) to asses how well the drug works as
well as to continue phase I safety assessments in a larger group
▪ 50 – 300 patients
▪ If possible, companies try to enrol only men (is obviously not always
possible) here as well, but if you want/need women you need to provide
preclinic evidence that it is not teratogenic and that it doesn’t have an effect
on female fertility (so you need to do more preclinical tests)
▪ First indication of the therapeutic potential of the drug
o Phase III: randomized controlled multi-centre trials on large, diverse patient groups
(300–3,000 or more depending upon the disease/medical condition studied) and are
aimed at being the definitive assessment of how effective the drug is, in comparison
with current 'gold standard' treatment
→ most expensive part because there are a lot of doctors, medical personnel,…
involved → if this phase fails, it means that the company loses a lot of money (so its
best to fail in the preclinical trial because then you lose less money)
- Pharmacovigilance: company must follow up on the drug after its on the market to see if it
doesn’t cause any other detrimental effects (because even if you have a population of
100000 during phase III, there can still be undetected effects)
2
,Time for each phase can vary. This
depends on the indication… For each
phase of the clinical development you
need different preclinical packages.
So the sequence: preclinical → clinical
→ market is not correct
Correct is: preclinical – phase I –
preclinical – phase II - …
This course focuses mainly on the
preclinical part before phase I
Patents start before the preclinical
trials and expires after 20 years, so if all
goes well the patent can only be
profitable for about 5 years.
- in the past: when there was a new indication for the drug, the duration of the patent could
be expanded by 5 years, but not it is not possible anymore: all indications must be addressed
from the start
- the timing to take a patent is critical and very difficult
o too early: there is not much time after registration of the drug to earn profits before
the patent expires
o too late: because of espionage, your idea can be stolen
Therapeutic areas
The therapeutic areas that companies spend most R&D costs on are:
1. Neurological: Alzheimer, schizophrenia, depression, epilepsy, Parkinson – high failure rate
(so quite low revenue)
2. Metabolic: cancer, osteoporosis, diabetes, obesity
3. Cardiovascular: atherosclerosis, coronary disease, heart failure (has decreases in the last few
years because there are a lot of options available already)
4. Infectious diseases: viral, bacterial, fungal, (parasitic)
3
, Annual population growth rate
The 60+ and 80+ population has increased loads in all the different
regions. So, we have to deal with diseases linked with age (can be very
lucrative). Problem is that the older population often has to take more
than one drug, so interactions can happen, but again it can be very
lucrative for big pharma → focus on other regions and/or age-related
diseases
The older population spends more on healthcare.
Table: sales in certain area – cardio and CNS are the highest
Blockbuster drugs
- Humira: MAB for juvenile arthritis
- Herceptin: MAB for breast cancer
- Red squares: biologicals – are very important now
- 70% of the industry profits come from 20% of the drugs
marketed
→ driving force behind recent mergers (big pharma are
buying up smaller companies to improve their portfolio).
- Pharmaceutical industry is a core sector for Europe (600 000
employees), but competitiveness is declining.
Challenges for pharmaceutical sales
- Generic drugs: a pharmaceutical drug that contains the same
chemical substance as a drug that was originally protected by chemical patents.
There is a shrinking of market exclusivity and subsequently a drop in earnings.
This means that there is a smaller budget for R&D for new drugs. Generic drugs
are allowed for sale after the patents on the original drugs expire. Because the
active chemical substance is the same, the medical profile of generics is believed
to be equivalent in performance. It has the same active pharmaceutical
ingredient, but it may differ in some characteristics such as manufacturing
process, formulation, taste, packaging. Generics are good for the patient, because they
are cheaper.
- Price containment: a process of judiciously reducing costs in a business or limiting them
to a constant level. When pharmaceutical company want to release their drug to the
market, they need to negotiate with all the countries (the ministers of health) about the
amount they can charge for this drug → there are strict rules about incentives from
pharmaceutical companies for GPs (companies can’t choose what they charge)
- Poor product differentiation: the better the differentiation, the better the sales (eg better
taste, longer half-life, more potency…)
- Increased competition from ‘me-too’ drugs: different pharmaceutical companies focus on
the same indications and the same molecules → many similar drugs on the market
- Parallel importation: In the Single Market parallel traders can buy pharmaceuticals in any
EU/EEA country and then under strictly regulated conditions move medicines to the
destination market, repackage them to comply with national legislation and linguistic needs,
and sell them at a lower price than the standard local price, in competition with that same
identical product sold by the manufacturer or its local licensee. This is possible because
prices of individual drugs vary between Member States.
- Counterfeiting of drugs: fraud; eg people sell fake drugs online – unofficial drugs
4
