Summary drug discovery and development
Chapter 1
The main threads in the evolution of ideas and technologies are:
- Clinical medicine, which relied largely on herbal remedies right up to the 20 th century.
- Pharmacy, set up to serve the demand for herbal preparations
- Organic chemistry
- Pharmacology, setting out to explain the effect of plant-derived pharmaceutical preparations
in physiological terms
Factors that could explain the apparent drop in research productivity:
- The increasing regulatory hurdles, which causes development to take longer and to be more
expensive.
- Me-too drugs
The hope is that this downward trend will be reversed as the benefit of new technologies to the drug
discovery process works through the system.
Chapter 2 The nature of disease and the purpose of therapy
Top missions of pharmaceutical companies: improve the public’s health, relieve the human burden of
disease and to improve the quality of life.
Concepts of disease
Therapeutic intervention, including the medical use of drugs, aims to prevent, cure or alleviate disease
states.
What is health?
WHO defines health as: a state of complete physical, mental and social wellbeing and not merely the
absence of sickness or infirmity. However, health cannot be regarded as a definable state – a fixed
point on a map, representing a destination that all are seeking to reach. Rather, it seems to be a
continuum, through which we can move in either direction, becoming more or less well adapted for
survival in out particular environment. Better definition would be: health is a dynamic state of
wellbeing characterized by physical, mental and social potential which satisfies the demands of life
commensurate with age, culture and personal responsibility.
What is disease?
1
,Deviation from normality does not define disease
Phenomenology and aetiology are important factors – the naturalistic view
The definitions quoted above are examples of the naturalistic, or observation-based, view of disease,
defined by phenomenology and backed up in many cases by an understanding of aetiology. By itself
this is insufficient, because there is no general set of observable characteristics that distinguish
disease, and sometimes there aren’t any observable features (mental disease).
Harm and disvalue – the normative view
This value-based view holds that disease is simply any condition the individual or society finds
disagreeable or harmful (disvalues).
In conclusion, disease proves extremely difficult to define, the closest is a combination of three
factors: phenomenology, aetiology and disvalue.
The aims of therapeutics
Components of disvalue
The disvalue experienced by a sick individual has two distinct components: present symptoms and
disabilities (morbidity) and future prognosis. Very commonly, both components of disvalue are
present, and both need to be addresses with therapeutic measures.
The element of disvalue is the most important determinant of what is considered appropriate to treat.
Function and dysfunction: the biological perspective
Deviation of the norm, in terms of structure and function at the cellular level, arise through deviations
in the pattern of protein expression by individual cells, and they may arise either through faults in the
instruction set itself (genetic mutations) of through environmental factors that alter the way in which
the instruction set is translated (that affect gene expression).
Levels of biological organization
There are two important conclusions to be drawn from the bidirectionality of influence between
events at different levels of the bioaxis. One is that it is difficult to pinpoint the cause of a given
disease. Second is that altered gene expression plays a crucial role in pathogenesis and the production
of any long-term phenotypic change.
2
,Therapeutic targets
The principal aim of therapeutic intervention is to alleviate the condition of the individual patient.
Genetic, biochemical and physiological deviations which are not associated with any disvalue for the
patient are not treated as diseases because they neither cause symptoms nor carry an unfavourable
prognosis. The disciplines of pharmacoeconomics and pharmacoepidemiology reflect the (a) wish to
quantify disease-related disvalue and therapeutic benefit in economic terms, and (b) to assess the
impact of disease and therapy for the population as a whole, and not just for the individual patient.
The relationship between drug targets and therapeutic targets
Many complex biological steps intervene between the primary drug target and the therapeutic target.
Therapeutic interventions
The desired effect of any therapeutic interventions is to improve symptoms or prognosis or both.
From a pathological point of view, therapeutic intervention may be directed at disease prevention,
alleviation of the effects of existing disease, or permanent cure.
Measuring therapeutic outcome
Effect, efficacy, effectiveness and benefit
- Pharmacological effects of drugs (effect on cells, organs and systems) are, in principle,
simple to measure in animals. These measures enable us to describe quantitively the
pharmacological properties of drugs, but say nothing about their usefulness.
- Efficacy describes the ability of a drug to produce a desired therapeutic effect in patients
under carefully controlled conditions (randomized controlled clinical trial). Efficacy tests
what the drug can do under optimal conditions, which is what the prescriber usually wants to
know.
- Effectiveness describes how well the drug works in real life, where the patients are
heterogeneous, and not randomized. The desired outcome is generally less defined than in
efficacy trials. The focus is on overall usefulness of the drug in the population going about its
normal business.
- Benefit comprises effectiveness expressed in monetary terms. It allows cost and benefit to be
compared directly.
Effect and efficacy are generally measured at the level of cells, tissues, systems and individuals,
effectiveness and benefit are measures of drug action as it affects populations and society at large.
3
, Pharmacoepidemiology and pharmacoeconomics
Pharmacoepidemiology is the study of the use and effects of drugs in human populations. It is a
special area of clinical pharmacology which deals with population, rather than individual, aspects of
drug action, and provides the means of quantifying variability in the response to drugs. Variability is
important mainly at the level of clinical trials, because this is essential in drawing correct inferences
from clinical trials. Pharmacoeconomics, a branch of health economics, is a subject that grew up
around the need for healthcare providers to balance the ever-growing costs of healthcare against
limited resources. The aim is to measure the benefits and costs of drug treatments.
Pharmacoeconomics covers four levels of analysis:
1. Cost identification consist of determining the full cost in monetary units of a particular
therapeutic intervention, including hospitalization as well as drug costs. It pays no attention to
outcome.
2. Cost-effectiveness analysis aims to quantify outcome as well as cost.
3. Cost-utility analysis is designed to include allowance for quality of life, as well as survival, in
the calculation, and it yet more controversial, for it becomes necessary somehow to quantify
quality.
4. Cost-benefit analysis translates healthcare improvements into monetary units that can be
directly balanced against costs, to assess whether any given procedure is, on balance,
‘profitable’.
Chapter 3 Therapeutic modalities
Therapeutics covers all types of intervention aimed at alleviating the effects of disease. Therapeutic
interventions within the field of conventional medicine:
- Advice and counselling
- Psychological treatments
- Dietary and nutritional treatments
- Physical treatments (incl surgergy)
- Pharmacological treatments
- Biological and biopharmaceutical treatments
Conventional therapeutic drugs
Advantages and disadvantages of small-molecule drugs:
Advantages:
- Synthetic chemicals have the potential to bind specifically to any chosen biological target
- Doctors and patients are familiar with conventional drugs as medicines
- Oral administration of often possible
- Small-molecule drugs make up more than 3/4th of new products registered
- Therapeutic peptides are generally straightforward to design
Disadvantages
- The flow of new small-molecule drugs seems to be diminishing
- Side effects and toxicity remain a serious and unpredictable problem
- Humans and other animals have highly developed mechanisms for eliminating foreign
molecules
- Oral absorption is poor for many compounds
Biopharmaceuticals
These are therapeutic protein or nucleic acid preparations made by techniques involving recombinant
DNA technology. The scope of protein biopharmaceuticals includes copies of endogenous mediators,
blood clotting factors, enzyme preparations and monoclonal antibodies, as well as vaccines. Overall, it
offers great promise for the future, and rapid progress is being made in the technologies producing
them.
4
Chapter 1
The main threads in the evolution of ideas and technologies are:
- Clinical medicine, which relied largely on herbal remedies right up to the 20 th century.
- Pharmacy, set up to serve the demand for herbal preparations
- Organic chemistry
- Pharmacology, setting out to explain the effect of plant-derived pharmaceutical preparations
in physiological terms
Factors that could explain the apparent drop in research productivity:
- The increasing regulatory hurdles, which causes development to take longer and to be more
expensive.
- Me-too drugs
The hope is that this downward trend will be reversed as the benefit of new technologies to the drug
discovery process works through the system.
Chapter 2 The nature of disease and the purpose of therapy
Top missions of pharmaceutical companies: improve the public’s health, relieve the human burden of
disease and to improve the quality of life.
Concepts of disease
Therapeutic intervention, including the medical use of drugs, aims to prevent, cure or alleviate disease
states.
What is health?
WHO defines health as: a state of complete physical, mental and social wellbeing and not merely the
absence of sickness or infirmity. However, health cannot be regarded as a definable state – a fixed
point on a map, representing a destination that all are seeking to reach. Rather, it seems to be a
continuum, through which we can move in either direction, becoming more or less well adapted for
survival in out particular environment. Better definition would be: health is a dynamic state of
wellbeing characterized by physical, mental and social potential which satisfies the demands of life
commensurate with age, culture and personal responsibility.
What is disease?
1
,Deviation from normality does not define disease
Phenomenology and aetiology are important factors – the naturalistic view
The definitions quoted above are examples of the naturalistic, or observation-based, view of disease,
defined by phenomenology and backed up in many cases by an understanding of aetiology. By itself
this is insufficient, because there is no general set of observable characteristics that distinguish
disease, and sometimes there aren’t any observable features (mental disease).
Harm and disvalue – the normative view
This value-based view holds that disease is simply any condition the individual or society finds
disagreeable or harmful (disvalues).
In conclusion, disease proves extremely difficult to define, the closest is a combination of three
factors: phenomenology, aetiology and disvalue.
The aims of therapeutics
Components of disvalue
The disvalue experienced by a sick individual has two distinct components: present symptoms and
disabilities (morbidity) and future prognosis. Very commonly, both components of disvalue are
present, and both need to be addresses with therapeutic measures.
The element of disvalue is the most important determinant of what is considered appropriate to treat.
Function and dysfunction: the biological perspective
Deviation of the norm, in terms of structure and function at the cellular level, arise through deviations
in the pattern of protein expression by individual cells, and they may arise either through faults in the
instruction set itself (genetic mutations) of through environmental factors that alter the way in which
the instruction set is translated (that affect gene expression).
Levels of biological organization
There are two important conclusions to be drawn from the bidirectionality of influence between
events at different levels of the bioaxis. One is that it is difficult to pinpoint the cause of a given
disease. Second is that altered gene expression plays a crucial role in pathogenesis and the production
of any long-term phenotypic change.
2
,Therapeutic targets
The principal aim of therapeutic intervention is to alleviate the condition of the individual patient.
Genetic, biochemical and physiological deviations which are not associated with any disvalue for the
patient are not treated as diseases because they neither cause symptoms nor carry an unfavourable
prognosis. The disciplines of pharmacoeconomics and pharmacoepidemiology reflect the (a) wish to
quantify disease-related disvalue and therapeutic benefit in economic terms, and (b) to assess the
impact of disease and therapy for the population as a whole, and not just for the individual patient.
The relationship between drug targets and therapeutic targets
Many complex biological steps intervene between the primary drug target and the therapeutic target.
Therapeutic interventions
The desired effect of any therapeutic interventions is to improve symptoms or prognosis or both.
From a pathological point of view, therapeutic intervention may be directed at disease prevention,
alleviation of the effects of existing disease, or permanent cure.
Measuring therapeutic outcome
Effect, efficacy, effectiveness and benefit
- Pharmacological effects of drugs (effect on cells, organs and systems) are, in principle,
simple to measure in animals. These measures enable us to describe quantitively the
pharmacological properties of drugs, but say nothing about their usefulness.
- Efficacy describes the ability of a drug to produce a desired therapeutic effect in patients
under carefully controlled conditions (randomized controlled clinical trial). Efficacy tests
what the drug can do under optimal conditions, which is what the prescriber usually wants to
know.
- Effectiveness describes how well the drug works in real life, where the patients are
heterogeneous, and not randomized. The desired outcome is generally less defined than in
efficacy trials. The focus is on overall usefulness of the drug in the population going about its
normal business.
- Benefit comprises effectiveness expressed in monetary terms. It allows cost and benefit to be
compared directly.
Effect and efficacy are generally measured at the level of cells, tissues, systems and individuals,
effectiveness and benefit are measures of drug action as it affects populations and society at large.
3
, Pharmacoepidemiology and pharmacoeconomics
Pharmacoepidemiology is the study of the use and effects of drugs in human populations. It is a
special area of clinical pharmacology which deals with population, rather than individual, aspects of
drug action, and provides the means of quantifying variability in the response to drugs. Variability is
important mainly at the level of clinical trials, because this is essential in drawing correct inferences
from clinical trials. Pharmacoeconomics, a branch of health economics, is a subject that grew up
around the need for healthcare providers to balance the ever-growing costs of healthcare against
limited resources. The aim is to measure the benefits and costs of drug treatments.
Pharmacoeconomics covers four levels of analysis:
1. Cost identification consist of determining the full cost in monetary units of a particular
therapeutic intervention, including hospitalization as well as drug costs. It pays no attention to
outcome.
2. Cost-effectiveness analysis aims to quantify outcome as well as cost.
3. Cost-utility analysis is designed to include allowance for quality of life, as well as survival, in
the calculation, and it yet more controversial, for it becomes necessary somehow to quantify
quality.
4. Cost-benefit analysis translates healthcare improvements into monetary units that can be
directly balanced against costs, to assess whether any given procedure is, on balance,
‘profitable’.
Chapter 3 Therapeutic modalities
Therapeutics covers all types of intervention aimed at alleviating the effects of disease. Therapeutic
interventions within the field of conventional medicine:
- Advice and counselling
- Psychological treatments
- Dietary and nutritional treatments
- Physical treatments (incl surgergy)
- Pharmacological treatments
- Biological and biopharmaceutical treatments
Conventional therapeutic drugs
Advantages and disadvantages of small-molecule drugs:
Advantages:
- Synthetic chemicals have the potential to bind specifically to any chosen biological target
- Doctors and patients are familiar with conventional drugs as medicines
- Oral administration of often possible
- Small-molecule drugs make up more than 3/4th of new products registered
- Therapeutic peptides are generally straightforward to design
Disadvantages
- The flow of new small-molecule drugs seems to be diminishing
- Side effects and toxicity remain a serious and unpredictable problem
- Humans and other animals have highly developed mechanisms for eliminating foreign
molecules
- Oral absorption is poor for many compounds
Biopharmaceuticals
These are therapeutic protein or nucleic acid preparations made by techniques involving recombinant
DNA technology. The scope of protein biopharmaceuticals includes copies of endogenous mediators,
blood clotting factors, enzyme preparations and monoclonal antibodies, as well as vaccines. Overall, it
offers great promise for the future, and rapid progress is being made in the technologies producing
them.
4
