Discovery and development of drugs SYNOPSIS • Preclinical drug development.. Preclinical drug development Pharmacology and medicinal chemistry have transformed medicine from an intellect
Trang 1Discovery and development of
drugs
SYNOPSIS
• Preclinical drug development Discovery of
new drugs in the laboratory is an exercise in
prediction
• Techniques of discovery Sophisticated
molecular modelling allows precise design of
potential new therapeutic substances and
new technologies have increased the rate of
development of potential medicines.
• Studies in animals and in humans
• Prediction Failures of prediction occur and a
drug may be abandoned at any stage,
including after marketing New drug
development is a colossally expensive and
commercially driven activity.
• Orphan drugs and diseases.
Preclinical drug
development
Pharmacology and medicinal chemistry have transformed
medicine from an intellectual exercise in diagnosis into a
powerful force for the relief of human disease (CT Dollery
1994)'
The development of new medicines (drugs) is an
exercise in prediction from laboratory studies in
vitro and in vivo (animals), which forecast what
the agent will do to man Medicinal therapeutics rests on the two great supporting pillars of pharmacology:
• Selectivity: the desired effect alone is obtained; 'We must learn to aim, learn to aim with chemical substances' (Paul Ehrlich).2
• Dose:' The dose alone decides that something
is no poison' (Paracelsus).3 For decades the rational discovery of new medicines has depended on modifications of the molecular structures of increasing numbers of known natural chemical mediators Often the exact molecu-lar basis of drug action is unknown, and this book contains frequent examples of old drugs whose
1 In this chapter we are grateful for permission from Professor Sir Colin Dollery to quote directly and indirectly from his Harveian Oration, 'Medicine and the
pharmacological revolution' (1994) Journal of the Royal College of Physicians of London 28: 59-69.
2 Paul Ehrlich (1845-1915), German scientist who pioneered the scientific approach to drug discovery The 606 th organic arsenical that he tested against spirochaetes (in animals) became a successful medicine (Salvarsan 1910); it and a minor variant were used against syphillis until superseded
by penicillin in 1945.
3 Paracelsus (1493-1541) was a controversial figure who has been portrayed as both ignorant and superstitious He had
no medical degree; he burned the classical medical works (Galen, Avicenna) before his lectures in Basel (Switzerland) and had to leave the city following a dispute about fees with
a prominent churchman He died in Salzburg (Austria) either
as a result of a drunken debauch or because he was thrown down a steep incline by 'hitmen' employed by jealous local
physicans But he was right about the dose.
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mechanism of action remains mysterious The
evol-ution of molecular medicine (including recombinant
DNA technology) in the past 20 years has led to a
new pathway of drug discovery: pharmacogenomics 4
This broad term encompasses all genes in the
genome that may determine drug response, desired
and undesired Completion of the Human Genome
Project in 2001 has yielded a minimum of 30 000
potential drug targets, although the function of
many of these genes remains unknown In the future,
drugs may be designed according to individual
genotypes, thereby to enhance safey as well as
efficacy
The chances of discovering a truly novel
medicine, i.e one that does something valuable that
had previously not been possible (or that does
safely what could only previously have been
achieved with substantial risk), are increased when
the development programme is founded on precise
knowledge, at molecular level, of the biological
processes it is desired to change The commercial
rewards of a successful product are potentially
enormous and provide a massive incentive to
developers to invest and risk huge sums of money
Studies of signal transduction, the fundamental
process by which cells talk to one another as
intracellular proteins transmit signals from the
surface of the cell to the nucleus inside, have
opened an entirely new approach to the
development of therapeutic agents that can target
discrete steps in the body's elaborate pathways of
chemical reactions The opportunities are endless.5
The molecular approach to drug discovery should
enable a 'molecular dissection' of any disease
pro-cess There are two immediate consequences:
• More potential drugs and therapeutic targets
will be produced than can be experimentally
validated in animals and man A further risk is
that this 'production line' approach could lead to
a loss of integration of the established specialities
4 An example of the opportunity created by
pharmacogenomics comes in the announcement by a major
pharmaceutical company of plans to search the entire human
genome for genetic evidence of intolerance to one of its
drugs If achieved, adverse reactions to the drug would be
virtually eliminated.
5 Culliton B J 1994 Nature Medicine 1:1
(chemistry, biochemistry, pharmacology), and
an overall lack of understanding of how physiological and pathophysiological processes contribute to the interaction of drug and disease
• New drugs could be targeted at selected groups
of patients based on their genetic make-up This concept of 'the right medicine for the right
patient' is the basis of pharmacogenetics (see p 122),
the genetically determined variability in drug response Pharmacogenetics has gained momen-tum from recent advances in molecular genetics and genome sequencing, due to:
• Rapid screening for specific gene polymorphisms (see p 122)
• Knowledge of the genetic sequences of target genes such as those coding for enzymes, ion channels, and other receptor types involved in drug response
The expectations of pharmacogenetics and its
progeny, pharmacoproteomics (understanding of and
drug effects on protein variants), are high They include:
• Identification of subgroups of patients with a disease or syndrome based on their genotype
• Targeting specific drugs for patients with specific gene variants
Consequences of these expectations include: smaller clinical trial programmes, better under-standing of the pharmacokinetics and dynamics according to genetic variation, simplified monitor-ing of adverse events after marketmonitor-ing A great challenge will be to determine the function of each polymorphic gene (or gene product) and whether it has pharmacological or toxicological importance Some of the expectations for both pharmaco-genomics and pharmacogenetics have been exagg-erated: at the least, the timescale over which the expectations may be realised is longer than first thought
Nevertheless, exploitation of the new tech-nologies will create more potential medicines, and more doctors will become involved in clinical testing; it is expedient that they should have some acquaintance with the events and processes that precede their involvement
Trang 3Sources of compounds
Chemical libraries
Historical compound collections
Natural product libraries
Combinatorial libraries
Rational synthesis
Antisense oligonucleotides
Therapeutic targets
Traditional medical uses of natural products
Empirical understanding of physiology and pathology
Molecular cloning of receptors and signalling molecules
Genomics
Drug discovery screening assays
Lead optimisation and candidate selection
Drug development
Fig 3.1 Drug discovery sources in context Different types of chemical compounds (top left) are tested against bioassays that are relevant
to therapeutic targets, which are derived from several possible sources of information (right).The initial lead compounds discovered by the screening process are optimised by analogue synthesis and tested for appropriate pharmacokinetic properties.The candidate compounds then enter the development process involving regulatory toxicology studies and clinical trials.
New drug development proceeds thus:
• Idea or hypothesis
• Design and synthesis of substances
• Studies on tissues and whole animal (preclinical
studies)
• Studies in man (clinical studies) (see Chapter 4)
• Grant of an official licence to make therapeutic
claims and to sell (see Chapter 5)
• Postlicensing (marketing) studies of safety and
comparisons with other medicines
It will be obvious from the account that follows
that drug development is an extremely arduous,
highly technical and enormously expensive
oper-ation Successful developments (1% of compounds
that proceed to full test eventually become licensed
medicines) must carry the cost of the failures
(99%).6 It is also obvious that such programmes are
likely to be carried to completion only when the
organisations and the individuals within them
are motivated overall by the challenge to succeed
and to serve society, as well as to make money
TECHNIQUES OF DISCOVERY
(see Figure 3.1)
The newer technologies, the impact of which have yet
to be fully felt include:
6 The cost of development of a new chemical entity (NCE) (a novel molecule not previously tested in humans) from synthesis to market (general clinical use) is estimated at US$ 500 million; the process may take as much as 15 years (including up to 10 years of clinical studies), which is relevant to duration of patent life and so to ultimate profitability; if the developer does not see profit at the end of the process, the investment will not be made The drug may fail at any stage, including the ultimate, i.e at the official regulatory body after all the development costs have been incurred It may also fail (due to adverse effects) within the first year after marketing, which constitutes a catastrophe (in reputation and finance) for the developer as well as for some
of the patients.
Pirated copies of full regulatory dossiers have substantial black market value to competitor companies who have used them to leap-frog the original developer to obtain a licence for their unresearched copied molecule Dossiers may be enormous, even one million pages or the electronic equivalent, the latter being very convenient as it allows instant searching.
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Molecular modelling aided by three-dimensional
computer graphics (including virtual reality) allows
the design of structures based on new and known
molecules to enhance their desired, and to eliminate
their undesired, properties to create highly selective
targeted compounds In principle all molecular
structures capable of binding to a single
high-affinity site can be modelled
Combinatorial chemistry involves the random
mixing and matching of large numbers of chemical
building blocks (amino acids, nucleotides, simple
chemicals) to produce 'libraries' of all possible
combinations This technology can generate billions
of new compounds that are initially evaluated
using automated robotic high-throughput screening
devices that can handle thousands of compounds a
day.7 These screens utilise radio-labelled ligand
displacement on single human receptor subtypes or
enzymes on nucleated (eukaryotic) cells If the
screen records a positive response the compound is
further investigated using traditional laboratory
methods, and the molecule is manipulated to
enhance selectivity and/or potency (above)
Proteins as medicines: biotechnology The targets
of most drugs are proteins (cell receptors, enzymes)
and it is only lack of technology that has hitherto
prevented the exploitation of proteins (and
pep-tides) as medicines This technology is now
avail-able But there are great practical problems in
getting the proteins to the target site in the body
(they are digested when swallowed and cross cell
membranes with difficulty)
Biotechnology involves the use of recombinant
DNA technology/genetic engineering to clone and
7 'It is too early to say what success these programmes may
have but automation of assays, possibly coupled to similar
automation of syntheses, promises to speed up the search for
new leads which is the rate-limiting step in the introduction
of really novel therapeutic agents Their value in medicine
will depend upon the significance of the control mechanism
concerned in the pathogenesis of a disease process Critics
fear that the result may well be large numbers of drugs in
search of a disease to treat' (CT Dollery, ibidem) The
demand for competent clinical trialists, already great, will
increase to meet the demand; the financial rewards to
competent (and honest) clinical trialists are great, in the
competitive world of drug introduction (see also McNamee
D 1995 Lancet 345:1167).
express human genes, for example, in microbial,
Escherichia coll or yeast, cells so that they
manu-facture proteins that medicinal chemists have not been able to synthesise; they also produce hor-mones and autacoids in commercial amounts (such
as insulin and growth hormone, erythropoietins, cell growth factors and plasminogen activators, interferons, vaccines and immune antibodies)
Transgenic animals (that breed true for the gene) are
also being developed as models for human disease
as well as for production of medicines
The polymerase chain reaction (PCR) is an
alterna-tive to bacterial cloning This is a method of gene amplification that does not require living cells; it takes place in vitro and can produce (in a cost-effective way) commercial quantities of pure poten-tial medicines
Genetic medicines Synthetic oligonucleotides are
being developed to target sites on DNA sequences
or genes (double strand DNA: triplex approach) or messenger RNA (the antisense approach) so that the production of disease-related proteins is blocked These oligonucleotides offer prospects of treatment for cancers and viruses without harming healthy tissues.8
Gene therapy of human genetic disorders is 'a
strategy in which nucleic acid, usually in the form
of DNA, is administered to modify the genetic repertoire for therapeutic purposes', e.g cystic fibrosis The era of "the gene as drug" is clearly upon us' (R G Crystal) Significant problems remain; in particular the methods of delivery Three methods are available: an injection of 'naked' DNA; using a virus as carrier with DNA incorporated into its genome; or DNA encapsulated within a liposome
Immunopharmacology Understanding of the
mol-ecular basis of immune responses has allowed the definition of mechanisms by which cellular func-tion is altered by a legion of local hormones or autacoids in, for example, infections, cancer, auto-immune diseases, organ transplant rejection These processes present targets for therapeutic inter-vention Hence the rise of immunopharmacology
8 Cohen J S, Hogan M E 1994 The new genetic medicines Scientific American (Dec): 50-55.
Trang 5Positron emission tomography (PET) allows
non-invasive pharmacokinetic and pharmacodynamic
measurements in previously inaccessible sites, e.g
the brain in intact humans and animals
Older approaches to discovery of new medicines
that continue in use include:
• Animal models of human disease or an aspect of it
of varying relevance to man
• Natural products, the basis for many of today's
medicines for pain, inflammation, cancer,
cardiovascular problems Modern technology for
screening has revived interest and intensified the
search by multinational pharmaceutical
companies which scour the world for leads from
microorganisms (in soil or sewage or even from
insects entombed in amber 40 million years ago),
from fungi, plants and animals Developing
countries in the tropics (with their luxuriant
natural resources) are prominent targets in this
search and have justly complained of
exploitation ('gene robbery') Many now require
formal profit-sharing agreements to allow such
searches
• Traditional medicine, which is being studied for
possible leads to usefully active compounds
• Modifications of the structures of known drugs; these
are obviously likely to produce more agents
having similar basic properties, but may deliver
worthwhile improvements It is in this area that
the much-complained-of, me-too and me-again
drugs are developed (sometimes purely for
commercial reasons)
• Random screening of synthesised and natural
products
• New uses for drugs already in general use as a result
of intelligent observation and serendipity,9 or
advancing knowledge of molecular mechanisms,
e.g aspirin for antithrombosis effect
DRUG QUALITY
It is easy for an investigator or prescriber, interested
in pharmacology, toxicology and therapeutics, to
9 Serendipity is the faculty of making fortunate discoveries
by general sagacity or by accident: the word derives from a
fairy tale about three princes of Serendip (Sri Lanka) who
had this happy faculty.
forget the fundamental importance of chemical and pharmaceutical aspects An impure, unstable drug
or formulation is useless Pure drugs that remain pure drugs after 5 years of storage in hot, damp climates are vital to therapeutics The record of manufacturers in providing this is impressive
Preclinical studies in animals10
In general, the following tests are undertaken:
Pharmacodynamics: to explore actions relevant to
the proposed therapeutic use, and other effects at a range of doses
Pharmacokinetics: to discover how the drug is
distributed in and disposed of by, the body
Toxicology: to see whether and how the drug
causes injury (in vitro tests and intact animals) in:
— single-dose studies (acute toxicity)
— repeated-dose studies (subacute, intermediate, and chronic or long-term toxicology)
General toxicology studies are performed in two species, usually a rodent and dog Regulatory requirements differ around the world but signifi-cant alignment has been made Single and repeat dose study requirements are given in Tables 3.1 and 3.2 The dosing regimens are selected to produce a range of plasma concentrations, the highest of which will be several times greater than that achieved in man
Special toxicology involves areas in which a
particularly horrible drug accident might occur on
a substantial scale; all involve interaction with genetic material or its expression in cell division
Mutagenicity (genotoxicity) tests are designed
to identify compounds that may induce genetic damage A standard battery of tests is conducted and include:
• A test for gene mutation in bacteria, e.g Ames test
10 Mouse, rat, hamster, guinea pig, rabbit, cat, dog, monkey
(not all used for any one drug).
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TABLE 3 1 Single and repeated dose toxicity requirements
to support studies in healthy normal volunteers (Phase 1) and
in patients (Phase 2) in the European Union (EU), and Phases I,
2 & 3 the USA and Japan I
Duration of clinical trial Minimum duration of
repeated dose toxicity studies
Rodents Non-rodents
Single dose
Up to 2 weeks
Up to 1 month
Up to 3 months
Up to 6 months
>6 months
2 weeks 2
2 weeks
1 month
3 months
6 months
6 months
2 weeks
2 weeks
1 month
3 months
6 months chronic 3
'In Japan, if there are no Phase 2 clinical trials of equivalent
duration to the planned Phase 3 trials, conduct of longer duration
toxicity studies is recommended as given in Table 3.2.
2 ln the USA, specially designed single dose studies with extended
examinations can support single dose clinical studies.
3 Regulatory authorities may request a 12-month study or accept a
6-month study, determined on a case-by-case basis.
See p 56 for a description of a clinical trial.
TABLE 3.2 Repeated dose toxicity requirements to
support Phase 3 studies in the EU, and marketing in all
regions '
Duration of clinical trial
Up to 2 weeks
Up to 1 month
Up to 3 months
>3 months
Minimum duration of repeated dose toxicity studies
Rodents Non-rodents
1 month
3 months
6 months
6 months
1 month
3 months
3 months Chronic 2
'When a chronic non-rodent study is recommended if clinical use
> I month.
2 Regulatory authorities may request a 12-month study or accept a
6-month study, determined on a case-by-case basis.
• An in-vitro test with cytogenetic evaluation of
chromosomal damage with mammalian cells or
an in-vitro mouse lymphoma thymidine kinase
(tK) assay
• An in-vivo test for chromosomal damage using
rodent haematopoietic cells
Usually the first two tests are performed before
human exposure, but all must be complete prior
to Phase II studies Additional tests may be
required
Definitive carcinogenicity (oncogenicity) tests
are often not required prior to the early studies in
man unless there is serious reason to be suspicious
of the drug, e.g if the mutagenicity test is unsatis-factory; the molecular structure, including likely metabolites in man, gives rise to suspicion; or the histopathology in repeated-dose animal studies raises suspicions
Full scale (most of the animal's life) carcino-genicity tests will generally be required only if the drug is to be given to man for above one year, or
it resembles a known human carcinogen, or it is mutagenic (in circumstances relevant to human use) or it has major organ-specific hormonal agonist action
It may be asked why any novel compound should be given to man before full-scale formal carcinogenicity studies are completed The answers are that animal tests are uncertain predictors,11 that such a requirement would make socially desirable drug development expensive to a seriously detri-mental degree, or might even cause potentially valuable novel ventures to cease For example, tests would have to be done on numerous compounds that are eventually abandoned for other reasons This may seem right or wrong, but it is how things are at present
Toxicology testing of biotechnology-derived phar-maceuticals The standard regimen of toxicology
studies is not appropriate for biotechnology-derived pharmaceuticals The choice of species used will depend on the expression of the relevant receptor If no suitable species exists, homologous proteins or transgenic animals expressing the human receptor may be studied Additional immunological studies are also required, and the genotoxicity and carcinogenicity studies are modified
Reproduction studies have to be extensive because
of the diversity of physiological processes that may
be affected, and because the consequences of error
in this field are potentially horrific Tests include
11 A sardonic comment on the relevance for man or carcinogenicity tests in animals was made by investigators who induced cancer in animals using American 'dimes' (10 cent coin) and the plastic of credit cards They advised the US Government to consider banning money as unsafe for humans (Moore GE et al 1977 Journal of the American Medical Association 238: 397)
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organogenesis, and peri- and postnatal
develop-ment Studies are in mammals, usually the rat
Embryo-fetal development studies are conducted in
a non-rodent, usually the rabbit Later development
studies include growth, behaviour and intellectual
function of progeny, and their fertility (second
generation effects)
Local tolerability studies In most acute and
repeat dose studies, the test drug is administered by
the oral route Additional studies are required when
the clinical route of administration is parenteral
There are two objectives First, to determine if the
drug is absorbed in sufficient quantities, e.g by
inhalation, and second to test for local tolerability,
e.g by the percutaneous or intravenous routes
It is plain that all the above tests constitute a
major laboratory exercise requiring great and
diverse scientific skills and significant financial
resource
ETHICS 12
No one will read the above scheme with
satis-faction and some people will read it with disgust
Experienced toxicologists point out that:
The majority of toxicity tests (which particularly
are subject to ethical criticism) are firmly based on
studies in whole animals, because only in them is it
possible to approach the complexity of organisation
of body systems in humans, to explore any
consequences of variable absorption, metabolism
and excretion, and to reveal not only direct toxic
effects but also those of a secondary or indirect
nature due to induced abnormalities in integrative
mechanisms, or distant effects of a toxic metabolite
produced in one organ that acts on another.13
The use of animals would be totally unjustified if
results useful to man could not be obtained In
12 An admirable discussion of the issues will be found in
Paton W 1984 Man and mouse Oxford, London and in
Zbinden G 1990 Alternatives to animal experimentation.
Trends in Pharmacological Sciences 11:104
13 Brimblecome R W, Dayan A D 1993 In: Burley D M, Clarke
J M, Lasagna L (eds) Pharmaceutical Medicine Arnold,
London
many known respects animals are similar to man, but in many respects they are not Increasingly, the low-prediction tests are being defined and eliminated It will be a long time before in-vitro tests become sufficiently robust to eliminate the need for tests in whole animals, but we welcome the progress that is being made towards this end The incentive to eliminate whole animal tests is not only ethical, it is economic, for whole animals are very expensive to breed and house and keep in health The European Union instructs researchers to choose non-(whole) animal methods if they are 'scientifically satisfactory [and] reasonably and practically available'
Prediction
It is frequently pointed out that regulatory guidelines are not rigid requirements to be universally applied But whatever the intention, they do tend to be treated
as minimum requirements if only because research directors fear to risk holding up their expensive coordinated programmes with disagreements that result in their having to go back to the laboratory, with consequent delay and financial loss
Knowledge of the mode of action of a potential
new drug obviously greatly enhances prediction from animal studies of what will happen in man Whenever practicable such knowledge should be obtained; sometimes this is quite easy, but some-times it is impossible Many drugs have been intro-duced safely without such knowledge, the later acquisition of which has not always made an im-portant difference to their use, e.g antimicrobials Pharmacological studies are integrated with those
of the toxicologist to build up a picture of the undesired as well as the desired drug effects
In pharmacological testing the investigators know
what they are looking for and choose the experi-ments to gain their objectives
In toxicological testing the investigators have less
clear ideas of what they are looking for; they are screening for risk, unexpected as well as predicted, and certain major routines must be done Toxicity testing is therefore liable to become mindless routine to meet regulatory requirements to a greater extent than are the pharmacological studies The
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predictive value of special toxicology (above) is
particularly controversial
All drugs are poisons if enough is given and the
task of the toxicologist is to find out whether, where
and how a compound acts as a poison to animals,
and to give an opinion on the significance of the
data in relation to risks likely to be run by human
beings This will remain a nearly impossible task
until molecular explanations of all effects can be
provided Toxicologists are in an unenviable position
When a useful drug is safely introduced they are
considered to have done no more than their duty
When an accident occurs they are invited to explain
how this failure of prediction came about When
they predict that a chemical is unsafe in a major
way for man, this prediction is never tested
CONCLUSION ON PRECLINICAL
TESTING
As drugs are developed and promoted for
long-term use in more and relatively trivial conditions,
e.g minor anxiety, and affluent societies become
less and less willing to tolerate small physical or
mental discomforts, the demand for and the supply
of new safer medicines will continue to increase
Only profound knowledge of molecular mechanisms
will reduce risk in the introduction of new drugs
Occasional failures of prediction are inevitable,
with consequent public outcry
Limited resources of scientific manpower and
money will not be used to the best advantage if the
public shock over thalidomide (p 81) and
subsequent events is allowed to express itself in
governmental regulations requiring a plethora of
expensive tests (and toxicity testing is very
expensive), many of them of dubious meaning for
anything other than the animal concerned Such a
policy would prevent industrial laboratories from
devoting resources to investigation of molecular
mechanisms of drug action, in the knowledge of
which alone lies health with safety
When the preclinical testing has been completed
to the satisfaction of the developer and of the
national or international regulatory agency, it is
time to administer the drug to man and so to launch
the experimental programme that will decide
whether the drug is only a drug or whether it is also
a medicine This is the subject of the next chapter
Orphan drugs and diseases
A free market economy is liable to leave untreated, rare diseases, e.g some cancers (in all countries) and some common diseases, e.g parasitic infections (in poor countries)
Where a drug is not developed into a usable medicine because the developer will not recover the costs then it is known as an orphan drug, and the disease is an orphan disease; the sufferer is a health orphan.14 Drugs for rare diseases inevitably must often be licensed on less than ideal amounts of clinical evidence
The remedy for these situations lies in govern-ment itself undertaking drug developgovern-ment (which
is likely to be inefficient) or in government-offered incentives, e.g tax relief, subsidies, exclusive mar-keting rights, to pharmaceutical companies and,
in the case of poor countries, international aid pro-grammes; such programmes are being imp-lemented.15
GUIDETO FURTHER READING
Banks R E et al 2000 Proteomics: new perspectives, new biomedical opportunities Lancet 356:1749-1756 Beeley N, Berger A 2000 A revolution in drug discovery: combinatorial chemistry still needs logic to drive science forward British Medical Journal 321:581-582 Black J W 1986 Pharmacology: analysis and
exploration British Medical Journal 293: 252 Crystal R G 1995 The gene as a drug Nature Medicine 1:15
Di Masi J A1995 Success rates for new drugs entering clinical testing in the United States Clinical Pharmacology and Therapeutics 58:1
14 The cost of treating a patient having the rare genetic Gaucher's liposome storage disease with genetically engineered enzyme is US$ 145 000 to 400 000 per annum according to severity Who can and will pay? More such situations will occur.
15 Official recognition of orphan drug status is accorded in the
USA (pop 240 million) where the relevant disease affects fewer than 200,000 people; in Japan (pop 121 million) for fewer than 50,000 people.
Trang 9Dollery C T 1999 Drug discovery and development in
the molecular era British Journal of Clinical
Pharmacology 47: 5-6
Fears R, Robert D, Poste G 2000 Rational or rationed
medicine? The promise of genetics for improved
clinical practice British Medical Journal 320: 933
Gale E A M 2001 Lessons from the glitazones: a story
of drug development Lancet 357:1870-1875
Graeme-Smith D G 1999 How will knowledge of the
human genome affect drug therapy? British
Journal of Clinical Pharmacology 47: 7-10
Lachmann P 1992 The use of animals in research
British Medical Journal 305:1
Lasagna L1982 Will all new drugs become orphans?
Clinical Pharmacology and Therapeutics 31: 285
Meyer B R1992 Biotechnology and therapeutics: Experimental treatments and limited resources Clinical Pharmacology and Therapeutics 51: 359 Roses A D 2000 Pharmacogenetics and future drug development and delivery The Lancet 355: 1358-1361
Smith A E 1999 Gene therapy — where are we? Lancet
354 (suppl 1): stl-4 Sykes R 1998 Being a modern pharmaceutical company British Medical Journal 317:1172 Wolf R C, Smith G, Smith R L 2000 Pharmacogenetics British Medical Journal 320: 987-990