Preclinical drug research
Knowledge and insight in the process of drug discovery and preclinical development of pharmaceuticals
/ biologicals & interpret preclinical data in a registration file and recognize relevance to clinical research
INTRODUCTION
- Chemicals = small molecules E.g. aspirin, fluoxetine, omeprazole…
- Natural products = complex molecules E.g. vinblastine, artemether, paclitaxel…
- Biologicals = large (complex) molecules E.g. EPO, insulin, interferon..
Major disease areas: diseases of the circulatory, respiratory & digestive system, oncology, CNS,…
Major spending areas: Alzheimer, schizophrenia (CNS), cancer, diabetes, coronary disease, infections..
PHASES OF DRUG DEVELOPMENT:
1. Pre-human / pre-clinical stage
2. Clinical trials
a. Phase I: expose human volunteers (mostly males) to look at pharmacokinetics + look
at exposure / concentration levels. How is it absorbed, distributed, eliminated…
b. Phase II: enrol a real patients and a placebo group. Sometimes women enrolled.
i. IIa: small group IIb: bigger group
c. Phase III: large cohort of patients from different regions in the world. Costly.
3. Approval
4. Pharmacovigilance (phase IV): follow-up for side effects in large populations.
5. Uncategorized
Clinical trials are the most costly for the companies (57%), 21.5% the pre-clinical stage. This is why in
the best case drug attrition happens in the pre-clinical stage. Approval is 8.3%, phase IV is 9.8%.
The age group of your population should be taken into account because certain organ systems don’t
work optimal anymore. This could mean other concentration levels are present in older people. The
people get older so we’ll have to deal with age-related diseases and co-morbidities. As you get older
the healthcare spending increases. E.g. osteoporosis, arthritis, prostate cancer, type II diabetes.
The total cost for one new marketed drugs is about 0.8 to 1.5 billion USD. BUT this is largely dependent
on therapeutic area. Some diseases are less interesting for pharmaceutical companies because of a
lower income. E.g. tropical diseases, orphan diseases (low number of patients), pediatric diseases..
Companies have a limited time to sell as much as they can of a certain drug. By investing in generics
they avoid competition.
, These phase durations can vary
It takes 10-15 years for a
drugs to make it to the
market but in this period
you already need your
patent because you
want to protect it from
competitors
The pre-clinical development stage happens over and over again before every other phase because for
each phase to start you need a pre-clinical package, depending on the clinical phase. It also differs if
you want to include women, children, old people… It is thus not 100% correct to say the pre-clinical
phase happens first and then the clinical phases. They are interfering with each other.
BLOCKBUSTER DRUGS (SALES > 1 BILLION USD/YEAR)
= Ab for juvenile arthritis
= Ab against long cancer
Most of these are biologicals. Small
biotech companies are bought up by
large pharma companies.
Roche is the biggest player because of 3
blockbusters.
70% of the income of big pharmaceutical companies come from 20% of the drugs marketed. This is the
reason companies are buying up each other. A lot of companies are outsourcing pre-clinical studies to
contract research organizations, which is more profitable. These are bought up by big pharma.
, 30% of the challenges are linked to generic
competition. Why would you pay for a drug with
a patent which will be more expensive, if you
could get a generic, cheaper drug. Dafalgan
would be more expensive than a generic one.
Price containment: when you get a FDA approval,
you need to discuss with each member state how
much you can charge for it.
Poor product differentiation: a drugs can not be approved because it’s essentially the same than one
that is already on the market. ~ Increased competition from “me-too” drugs
Parallel importation: normally you have a provider which is importing the drug, but it’s possible to
get importations from other countries, where the price setting can be different.
Counterfeiting of drugs: fraud. People are buying medication on the internet, for example against a
headache. In some cases these drugs have not been tested and can contain other solvents. ‘Fakes’.
PRODUCT POSITIONING
1. Generics (without a patent) have a lot of sales. It’s easily
accessible so high-sales volume but also high competition. Low
medical differentiation
2. Targeted therapeutics (niche drugs): only for a specific
indication occurring in a small population. This means a very
high medical differentiation (valuable), but because of the
niche, the sales are low. High medical differentiation
3. Mega-blockbusters (large chronic markets): high sales with not too much competition.
FAILURE RATES IN DRUG DEVELOPMENT
It’s important to detect toxicity or non-efficacy as
early as possible. This is why most compounds fail in
pre-clinical development.
In phase I there is still a lot of attrition since this is
where you include human volunteers. Here you will
detect for example no absorption.
Lack of efficacy and PK are the most common causes
for drug attrition. Animal toxicology makes 10%.
Most drugs target the GPCR. A lot of others work on other receptors or transporters. Some HIV
medication is effective but since it’s easily metabolized it gives low exposure levels. Here they combine
the drugs with an enzyme blocker.
Biologicals often have lower toxicity.
, DRUG DISCOVERY PROCESS: THERAPEUTIC MODALITIES
TYPES OF THERAPEUTICS
1. Conventional therapeutics = all types of intervention aimed at alleviating effects of disease
- Improve disease symptoms and/or prognosis - Alleviate effects of existing disease
- Directed towards disease prevention - Achieve permanent cure
2. Non-conventional health products
- Nutraceuticals = range of dietary preparations
o Slimming diets, diets with minerals, vitamins, fiber, antioxidants, …
o Some scientific rationale Not subjected to formal regulatory approval
- Cosmeceuticals = cosmetics supplemented with some active (?) substances
o Reduce skin wrinkles, promote hair growth, …
o Little or no scientific rationale Free sales (but major market !!)
1. CONVENTIONAL THERAPEUTICS
- Small molecule synthetic compounds: most of current drugs (pharmacopoeia)
- Natural products (or semi-synthetically derived): antibiotics, anticancer, opiates, statins…
2. BIOPHARMACEUTICALS
Therapeutic protein or nucleic acid preparations made by techniques involving DNA technology
- Peptide/protein mediators (insulin, GH, EPO, …) - Blood clotting factors
- Cells / tissues (stem cells, graft- & transplant surgery) - Enzymes
- Vaccines (inactivated, attenuated, subunit) - AB’s (antisera, antitoxins, mAb)
BEYOND CURRENT BIOPHARMACEUTICALS
1. GENE THERAPY
= Correcting genetic defects by altering genetic material of cells by recombinant DNA technology
- Introduce new genes to replace missing or dysfunctional ones (virus vector: non-integrated
vs. integrated DNA)
- Aim at single-gene disorders (cystic fibrosis, haemophilia) and cancer
- Restricted to somatic cell treatments (ban on germ-cell gene therapy experiments)
Knowledge and insight in the process of drug discovery and preclinical development of pharmaceuticals
/ biologicals & interpret preclinical data in a registration file and recognize relevance to clinical research
INTRODUCTION
- Chemicals = small molecules E.g. aspirin, fluoxetine, omeprazole…
- Natural products = complex molecules E.g. vinblastine, artemether, paclitaxel…
- Biologicals = large (complex) molecules E.g. EPO, insulin, interferon..
Major disease areas: diseases of the circulatory, respiratory & digestive system, oncology, CNS,…
Major spending areas: Alzheimer, schizophrenia (CNS), cancer, diabetes, coronary disease, infections..
PHASES OF DRUG DEVELOPMENT:
1. Pre-human / pre-clinical stage
2. Clinical trials
a. Phase I: expose human volunteers (mostly males) to look at pharmacokinetics + look
at exposure / concentration levels. How is it absorbed, distributed, eliminated…
b. Phase II: enrol a real patients and a placebo group. Sometimes women enrolled.
i. IIa: small group IIb: bigger group
c. Phase III: large cohort of patients from different regions in the world. Costly.
3. Approval
4. Pharmacovigilance (phase IV): follow-up for side effects in large populations.
5. Uncategorized
Clinical trials are the most costly for the companies (57%), 21.5% the pre-clinical stage. This is why in
the best case drug attrition happens in the pre-clinical stage. Approval is 8.3%, phase IV is 9.8%.
The age group of your population should be taken into account because certain organ systems don’t
work optimal anymore. This could mean other concentration levels are present in older people. The
people get older so we’ll have to deal with age-related diseases and co-morbidities. As you get older
the healthcare spending increases. E.g. osteoporosis, arthritis, prostate cancer, type II diabetes.
The total cost for one new marketed drugs is about 0.8 to 1.5 billion USD. BUT this is largely dependent
on therapeutic area. Some diseases are less interesting for pharmaceutical companies because of a
lower income. E.g. tropical diseases, orphan diseases (low number of patients), pediatric diseases..
Companies have a limited time to sell as much as they can of a certain drug. By investing in generics
they avoid competition.
, These phase durations can vary
It takes 10-15 years for a
drugs to make it to the
market but in this period
you already need your
patent because you
want to protect it from
competitors
The pre-clinical development stage happens over and over again before every other phase because for
each phase to start you need a pre-clinical package, depending on the clinical phase. It also differs if
you want to include women, children, old people… It is thus not 100% correct to say the pre-clinical
phase happens first and then the clinical phases. They are interfering with each other.
BLOCKBUSTER DRUGS (SALES > 1 BILLION USD/YEAR)
= Ab for juvenile arthritis
= Ab against long cancer
Most of these are biologicals. Small
biotech companies are bought up by
large pharma companies.
Roche is the biggest player because of 3
blockbusters.
70% of the income of big pharmaceutical companies come from 20% of the drugs marketed. This is the
reason companies are buying up each other. A lot of companies are outsourcing pre-clinical studies to
contract research organizations, which is more profitable. These are bought up by big pharma.
, 30% of the challenges are linked to generic
competition. Why would you pay for a drug with
a patent which will be more expensive, if you
could get a generic, cheaper drug. Dafalgan
would be more expensive than a generic one.
Price containment: when you get a FDA approval,
you need to discuss with each member state how
much you can charge for it.
Poor product differentiation: a drugs can not be approved because it’s essentially the same than one
that is already on the market. ~ Increased competition from “me-too” drugs
Parallel importation: normally you have a provider which is importing the drug, but it’s possible to
get importations from other countries, where the price setting can be different.
Counterfeiting of drugs: fraud. People are buying medication on the internet, for example against a
headache. In some cases these drugs have not been tested and can contain other solvents. ‘Fakes’.
PRODUCT POSITIONING
1. Generics (without a patent) have a lot of sales. It’s easily
accessible so high-sales volume but also high competition. Low
medical differentiation
2. Targeted therapeutics (niche drugs): only for a specific
indication occurring in a small population. This means a very
high medical differentiation (valuable), but because of the
niche, the sales are low. High medical differentiation
3. Mega-blockbusters (large chronic markets): high sales with not too much competition.
FAILURE RATES IN DRUG DEVELOPMENT
It’s important to detect toxicity or non-efficacy as
early as possible. This is why most compounds fail in
pre-clinical development.
In phase I there is still a lot of attrition since this is
where you include human volunteers. Here you will
detect for example no absorption.
Lack of efficacy and PK are the most common causes
for drug attrition. Animal toxicology makes 10%.
Most drugs target the GPCR. A lot of others work on other receptors or transporters. Some HIV
medication is effective but since it’s easily metabolized it gives low exposure levels. Here they combine
the drugs with an enzyme blocker.
Biologicals often have lower toxicity.
, DRUG DISCOVERY PROCESS: THERAPEUTIC MODALITIES
TYPES OF THERAPEUTICS
1. Conventional therapeutics = all types of intervention aimed at alleviating effects of disease
- Improve disease symptoms and/or prognosis - Alleviate effects of existing disease
- Directed towards disease prevention - Achieve permanent cure
2. Non-conventional health products
- Nutraceuticals = range of dietary preparations
o Slimming diets, diets with minerals, vitamins, fiber, antioxidants, …
o Some scientific rationale Not subjected to formal regulatory approval
- Cosmeceuticals = cosmetics supplemented with some active (?) substances
o Reduce skin wrinkles, promote hair growth, …
o Little or no scientific rationale Free sales (but major market !!)
1. CONVENTIONAL THERAPEUTICS
- Small molecule synthetic compounds: most of current drugs (pharmacopoeia)
- Natural products (or semi-synthetically derived): antibiotics, anticancer, opiates, statins…
2. BIOPHARMACEUTICALS
Therapeutic protein or nucleic acid preparations made by techniques involving DNA technology
- Peptide/protein mediators (insulin, GH, EPO, …) - Blood clotting factors
- Cells / tissues (stem cells, graft- & transplant surgery) - Enzymes
- Vaccines (inactivated, attenuated, subunit) - AB’s (antisera, antitoxins, mAb)
BEYOND CURRENT BIOPHARMACEUTICALS
1. GENE THERAPY
= Correcting genetic defects by altering genetic material of cells by recombinant DNA technology
- Introduce new genes to replace missing or dysfunctional ones (virus vector: non-integrated
vs. integrated DNA)
- Aim at single-gene disorders (cystic fibrosis, haemophilia) and cancer
- Restricted to somatic cell treatments (ban on germ-cell gene therapy experiments)
