CLINICAL PHARMACOLOGY 2003 (PART 5)

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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. ...

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3 Discovery and development of drugs SYNOPSIS the agent will do to man. Medicinal therapeutics rests on the two great supporting pillars of • Preclinical drug development. Discovery of pharmacology: new drugs in the laboratory is an exercise in prediction • Selectivity: the desired effect alone is obtained; • Techniques of discovery. Sophisticated 'We must learn to aim, learn to aim with molecular modelling allows precise design of chemical substances' (Paul Ehrlich).2 potential new therapeutic substances and • Dose:'.. .The dose alone decides that something new technologies have increased the rate of is no poison' (Paracelsus).3 development of potential medicines. For decades the rational discovery of new • Studies in animals and in humans medicines has depended on modifications of the • Prediction. Failures of prediction occur and a molecular structures of increasing numbers of known drug may be abandoned at any stage, natural chemical mediators. Often the exact molecu- including after marketing. New drug lar basis of drug action is unknown, and this book development is a colossally expensive and contains frequent examples of old drugs whose commercially driven activity. • Orphan drugs and diseases. 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 Preclinical drug Paul Ehrlich (1845-1915), German scientist who pioneered the scientific approach to drug discovery. The 606th organic development 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(in animals) became a successful medicine (Salvarsan 1910); it and a minor variant were used against syphillis until superseded by penicillin in 1945. Pharmacology and medicinal chemistry have transformed 3 Paracelsus (1493-1541) was a controversial figure who has medicine from an intellectual exercise in diagnosis into a been portrayed as both ignorant and superstitious. He had powerful force for the relief of human disease (CT Dollery no medical degree; he burned the classical medical works 1994)' (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 The development of new medicines (drugs) is an as a result of a drunken debauch or because he was thrown exercise in prediction from laboratory studies in down a steep incline by 'hitmen' employed by jealous local vitro and in vivo (animals), which forecast what physicans. But he was right about the dose. 41
3 DISCOVERY AND DEVELOPMENT OF DRUGS mechanism of action remains mysterious. The evol- (chemistry, biochemistry, pharmacology), and ution of molecular medicine (including recombinant an overall lack of understanding of how DNA technology) in the past 20 years has led to a physiological and pathophysiological processes new pathway of drug discovery: pharmacogenomics.4 contribute to the interaction of drug and This broad term encompasses all genes in the disease. genome that may determine drug response, desired • New drugs could be targeted at selected groups and undesired. Completion of the Human Genome of patients based on their genetic make-up. Project in 2001 has yielded a minimum of 30 000 This concept of 'the right medicine for the right potential drug targets, although the function of patient' is the basis of pharmacogenetics (see p. 122), many of these genes remains unknown. In the future, the genetically determined variability in drug drugs may be designed according to individual response. Pharmacogenetics has gained momen- genotypes, thereby to enhance safey as well as tum from recent advances in molecular genetics efficacy. and genome sequencing, due to: The chances of discovering a truly novel medicine, i.e. one that does something valuable that • Rapid screening for specific gene had previously not been possible (or that does polymorphisms (see p. 122). safely what could only previously have been • Knowledge of the genetic sequences of target achieved with substantial risk), are increased when genes such as those coding for enzymes, ion the development programme is founded on precise channels, and other receptor types involved in knowledge, at molecular level, of the biological drug response. processes it is desired to change. The commercial rewards of a successful product are potentially The expectations of pharmacogenetics and its enormous and provide a massive incentive to progeny, pharmacoproteomics (understanding of and developers to invest and risk huge sums of money. drug effects on protein variants), are high. They include: Studies of signal transduction, the fundamental process by which cells talk to one another as • Identification of subgroups of patients with a intracellular proteins transmit signals from the disease or syndrome based on their genotype. surface of the cell to the nucleus inside, have • Targeting specific drugs for patients with specific opened an entirely new approach to the gene variants. development of therapeutic agents that can target Consequences of these expectations include: discrete steps in the body's elaborate pathways of smaller clinical trial programmes, better under- chemical reactions. The opportunities are endless.5 standing of the pharmacokinetics and dynamics The molecular approach to drug discovery should according to genetic variation, simplified monitor- enable a 'molecular dissection' of any disease pro- ing of adverse events after marketing. A great cess. There are two immediate consequences: challenge will be to determine the function of each polymorphic gene (or gene product) and whether it • More potential drugs and therapeutic targets has pharmacological or toxicological importance. will be produced than can be experimentally Some of the expectations for both pharmaco- validated in animals and man. A further risk is genomics and pharmacogenetics have been exagg- that this 'production line' approach could lead to erated: at the least, the timescale over which the a loss of integration of the established specialities expectations may be realised is longer than first thought. 4 An example of the opportunity created by Nevertheless, exploitation of the new tech- pharmacogenomics comes in the announcement by a major nologies will create more potential medicines, and pharmaceutical company of plans to search the entire human more doctors will become involved in clinical genome for genetic evidence of intolerance to one of its drugs. If achieved, adverse reactions to the drug would be testing; it is expedient that they should have some virtually eliminated. acquaintance with the events and processes that 5 Culliton B J 1994 Nature Medicine 1:1 precede their involvement. 42
P R E C L I N I C A L DRUG D E V E L O P M E N T 3 Sources of compounds Therapeutic targets Chemical libraries Traditional medical uses of natural products Historical compound collections Natural product libraries Combinatorial libraries Empirical understanding of physiology and pathology Rational synthesis Molecular cloning of receptors and signalling molecules Antisense oligonucleotides 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: TECHNIQUES OF DISCOVERY • Idea or hypothesis (see Figure 3.1) • Design and synthesis of substances The newer technologies, the impact of which have yet • Studies on tissues and whole animal (preclinical to be fully felt include: studies) • Studies in man (clinical studies) (see Chapter 4) 6 • Grant of an official licence to make therapeutic The cost of development of a new chemical entity (NCE) claims and to sell (see Chapter 5) (a novel molecule not previously tested in humans) from synthesis to market (general clinical use) is estimated at • Postlicensing (marketing) studies of safety and US$ 500 million; the process may take as much as 15 years comparisons with other medicines. (including up to 10 years of clinical studies), which is relevant to duration of patent life and so to ultimate It will be obvious from the account that follows profitability; if the developer does not see profit at the end of that drug development is an extremely arduous, the process, the investment will not be made. The drug may highly technical and enormously expensive oper- fail at any stage, including the ultimate, i.e. at the official ation. Successful developments (1% of compounds regulatory body after all the development costs have been that proceed to full test eventually become licensed incurred. It may also fail (due to adverse effects) within the first year after marketing, which constitutes a catastrophe (in medicines) must carry the cost of the failures reputation and finance) for the developer as well as for some (99%).6 It is also obvious that such programmes are of the patients. likely to be carried to completion only when the Pirated copies of full regulatory dossiers have substantial organisations and the individuals within them black market value to competitor companies who have used are motivated overall by the challenge to succeed them to leap-frog the original developer to obtain a licence for their unresearched copied molecule. Dossiers may be and to serve society, as well as to make money. enormous, even one million pages or the electronic equivalent, the latter being very convenient as it allows instant searching. 43
3 DISCOVERY AND DEVELOPMENT OF DRUGS Molecular modelling aided by three-dimensional express human genes, for example, in microbial, computer graphics (including virtual reality) allows Escherichia coll or yeast, cells so that they manu- the design of structures based on new and known facture proteins that medicinal chemists have not molecules to enhance their desired, and to eliminate been able to synthesise; they also produce hor- their undesired, properties to create highly selective mones and autacoids in commercial amounts (such targeted compounds. In principle all molecular as insulin and growth hormone, erythropoietins, structures capable of binding to a single high- cell growth factors and plasminogen activators, affinity site can be modelled. interferons, vaccines and immune antibodies). Transgenic animals (that breed true for the gene) are Combinatorial chemistry involves the random also being developed as models for human disease mixing and matching of large numbers of chemical as well as for production of medicines. building blocks (amino acids, nucleotides, simple The polymerase chain reaction (PCR) is an alterna- chemicals) to produce 'libraries' of all possible tive to bacterial cloning. This is a method of gene combinations. This technology can generate billions amplification that does not require living cells; it of new compounds that are initially evaluated takes place in vitro and can produce (in a cost- using automated robotic high-throughput screening effective way) commercial quantities of pure poten- devices that can handle thousands of compounds a tial medicines. day.7 These screens utilise radio-labelled ligand displacement on single human receptor subtypes or Genetic medicines. Synthetic oligonucleotides are enzymes on nucleated (eukaryotic) cells. If the being developed to target sites on DNA sequences screen records a positive response the compound is or genes (double strand DNA: triplex approach) or further investigated using traditional laboratory messenger RNA (the antisense approach) so that methods, and the molecule is manipulated to the production of disease-related proteins is blocked. enhance selectivity and/or potency (above). These oligonucleotides offer prospects of treatment for cancers and viruses without harming healthy Proteins as medicines: biotechnology. The targets tissues.8 of most drugs are proteins (cell receptors, enzymes) Gene therapy of human genetic disorders is 'a and it is only lack of technology that has hitherto strategy in which nucleic acid, usually in the form prevented the exploitation of proteins (and pep- of DNA, is administered to modify the genetic tides) as medicines. This technology is now avail- repertoire for therapeutic purposes', e.g. cystic able. But there are great practical problems in fibrosis. The era of "the gene as drug" is clearly getting the proteins to the target site in the body upon us' (R G Crystal). Significant problems (they are digested when swallowed and cross cell remain; in particular the methods of delivery. Three membranes with difficulty). methods are available: an injection of 'naked' DNA; Biotechnology involves the use of recombinant using a virus as carrier with DNA incorporated DNA technology/genetic engineering to clone and into its genome; or DNA encapsulated within a 7 liposome. 'It is too early to say what success these programmes may have but automation of assays, possibly coupled to similar Immunopharmacology. Understanding of the mol- automation of syntheses, promises to speed up the search for new leads which is the rate-limiting step in the introduction ecular basis of immune responses has allowed the of really novel therapeutic agents. Their value in medicine definition of mechanisms by which cellular func- will depend upon the significance of the control mechanism tion is altered by a legion of local hormones or concerned in the pathogenesis of a disease process. Critics autacoids in, for example, infections, cancer, auto- fear that the result may well be large numbers of drugs in immune diseases, organ transplant rejection. These search of a disease to treat' (CT Dollery, ibidem). The demand for competent clinical trialists, already great, will processes present targets for therapeutic inter- increase to meet the demand; the financial rewards to vention. Hence the rise of immunopharmacology. competent (and honest) clinical trialists are great, in the 8 competitive world of drug introduction (see also McNamee Cohen J S, Hogan M E 1994 The new genetic medicines. D 1995 Lancet 345:1167). Scientific American (Dec): 50-55. 44
PR E C L I N IC A L S T U D I E S IN ANIMALS 3 Positron emission tomography (PET) allows non- forget the fundamental importance of chemical and invasive pharmacokinetic and pharmacodynamic pharmaceutical aspects. An impure, unstable drug measurements in previously inaccessible sites, e.g. or formulation is useless. Pure drugs that remain the brain in intact humans and animals. pure drugs after 5 years of storage in hot, damp climates are vital to therapeutics. The record of Older approaches to discovery of new medicines manufacturers in providing this is impressive. that continue in use include: • Animal models of human disease or an aspect of it of varying relevance to man. Preclinical studies in • Natural products, the basis for many of today's medicines for pain, inflammation, cancer, animals10 cardiovascular problems. Modern technology for screening has revived interest and intensified the In general, the following tests are undertaken: search by multinational pharmaceutical companies which scour the world for leads from Pharmacodynamics: to explore actions relevant to microorganisms (in soil or sewage or even from the proposed therapeutic use, and other effects at a insects entombed in amber 40 million years ago), range of doses from fungi, plants and animals. Developing countries in the tropics (with their luxuriant Pharmacokinetics: to discover how the drug is natural resources) are prominent targets in this distributed in and disposed of by, the body. search and have justly complained of Toxicology: to see whether and how the drug exploitation ('gene robbery'). Many now require causes injury (in vitro tests and intact animals) in: formal profit-sharing agreements to allow such — single-dose studies (acute toxicity) searches — repeated-dose studies (subacute, intermediate, • Traditional medicine, which is being studied for and chronic or long-term toxicology) possible leads to usefully active compounds General toxicology studies are performed in two • Modifications of the structures of known drugs; these species, usually a rodent and dog. Regulatory are obviously likely to produce more agents requirements differ around the world but signifi- having similar basic properties, but may deliver cant alignment has been made. Single and repeat worthwhile improvements. It is in this area that dose study requirements are given in Tables 3.1 and the much-complained-of, me-too and me-again 3.2. The dosing regimens are selected to produce a drugs are developed (sometimes purely for range of plasma concentrations, the highest of commercial reasons). which will be several times greater than that • Random screening of synthesised and natural achieved in man. products. • New uses for drugs already in general use as a result Special toxicology involves areas in which a of intelligent observation and serendipity,9 or particularly horrible drug accident might occur on advancing knowledge of molecular mechanisms, a substantial scale; all involve interaction with e.g. aspirin for antithrombosis effect. genetic material or its expression in cell division. Mutagenicity (genotoxicity) tests are designed DRUG QUALITY to identify compounds that may induce genetic damage. A standard battery of tests is conducted It is easy for an investigator or prescriber, interested and include: in pharmacology, toxicology and therapeutics, to • A test for gene mutation in bacteria, e.g. Ames 9 Serendipity is the faculty of making fortunate discoveries test by general sagacity or by accident: the word derives from a 10 fairy tale about three princes of Serendip (Sri Lanka) who Mouse, rat, hamster, guinea pig, rabbit, cat, dog, monkey had this happy faculty. (not all used for any one drug). 45
3 DISCOVERY AND DEVELOPMENT OF DRUGS TABLE 3. 1 Single and repeated dose toxicity requirements man unless there is serious reason to be suspicious to support studies in healthy normal volunteers (Phase 1) and of the drug, e.g. if the mutagenicity test is unsatis- in patients (Phase 2) in the European Union (EU), and Phases I, factory; the molecular structure, including likely 2 & 3 the USA and JapanI metabolites in man, gives rise to suspicion; or the Duration of clinical trial Minimum duration of histopathology in repeated-dose animal studies repeated dose toxicity studies raises suspicions. Rodents Non-rodents Full scale (most of the animal's life) carcino- Single dose 2 weeks2 2 weeks genicity tests will generally be required only if the Up to 2 weeks 2 weeks 2 weeks drug is to be given to man for above one year, or Up to 1 month 1 month 1 month it resembles a known human carcinogen, or it is Up to 3 months 3 months 3 months Up to 6 months 6 months 6 months mutagenic (in circumstances relevant to human >6 months 6 months chronic3 use) or it has major organ-specific hormonal agonist action. 'In Japan, if there are no Phase 2 clinical trials of equivalent duration to the planned Phase 3 trials, conduct of longer duration It may be asked why any novel compound toxicity studies is recommended as given in Table 3.2. should be given to man before full-scale formal 2 ln the USA, specially designed single dose studies with extended carcinogenicity studies are completed. The answers examinations can support single dose clinical studies. 3 Regulatory authorities may request a 12-month study or accept a are that animal tests are uncertain predictors,11 that 6-month study, determined on a case-by-case basis. such a requirement would make socially desirable See p. 56 for a description of a clinical trial. drug development expensive to a seriously detri- mental degree, or might even cause potentially valuable novel ventures to cease. For example, tests TABLE 3.2 Repeated dose toxicity requirements to would have to be done on numerous compounds support Phase 3 studies in the EU, and marketing in all that are eventually abandoned for other reasons. regions ' This may seem right or wrong, but it is how things Duration of clinical trial Minimum duration of are at present. repeated dose toxicity studies Rodents Non-rodents Toxicology testing of biotechnology-derived phar- Up to 2 weeks 1 month 1 month maceuticals. The standard regimen of toxicology Up to 1 month 3 months 3 months studies is not appropriate for biotechnology- Up to 3 months 6 months 3 months derived pharmaceuticals. The choice of species >3 months 6 months Chronic2 used will depend on the expression of the relevant 'When a chronic non-rodent study is recommended if clinical use receptor. If no suitable species exists, homologous > I month. 2 proteins or transgenic animals expressing the human Regulatory authorities may request a 12-month study or accept a receptor may be studied. Additional immunological 6-month study, determined on a case-by-case basis. studies are also required, and the genotoxicity and carcinogenicity studies are modified. • An in-vitro test with cytogenetic evaluation of Reproduction studies have to be extensive because chromosomal damage with mammalian cells or of the diversity of physiological processes that may an in-vitro mouse lymphoma thymidine kinase be affected, and because the consequences of error (tK) assay in this field are potentially horrific. Tests include • An in-vivo test for chromosomal damage using rodent haematopoietic cells. Usually the first two tests are performed before 11 A sardonic comment on the relevance for man or human exposure, but all must be complete prior carcinogenicity tests in animals was made by investigators who induced cancer in animals using American 'dimes' to Phase II studies. Additional tests may be (10 cent coin) and the plastic of credit cards. They advised required. the US Government to consider banning money as unsafe for Definitive carcinogenicity (oncogenicity) tests humans (Moore GE et al 1977 Journal of the American are often not required prior to the early studies in Medical Association 238: 397) 46
PREDICTION 3 effects on fertility, reproductive performance, fetal many known respects animals are similar to man, organogenesis, and peri- and postnatal develop- but in many respects they are not. Increasingly, ment. Studies are in mammals, usually the rat. the low-prediction tests are being defined and Embryo-fetal development studies are conducted in eliminated. It will be a long time before in-vitro a non-rodent, usually the rabbit. Later development tests become sufficiently robust to eliminate the studies include growth, behaviour and intellectual need for tests in whole animals, but we welcome function of progeny, and their fertility (second the progress that is being made towards this end. generation effects). The incentive to eliminate whole animal tests is not only ethical, it is economic, for whole animals are Local tolerability studies. In most acute and very expensive to breed and house and keep in repeat dose studies, the test drug is administered by health. The European Union instructs researchers to the oral route. Additional studies are required when choose non-(whole) animal methods if they are the clinical route of administration is parenteral. 'scientifically satisfactory [and] reasonably and There are two objectives. First, to determine if the practically available'. 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 Prediction major laboratory exercise requiring great and diverse scientific skills and significant financial It is frequently pointed out that regulatory guidelines resource. 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 ETHICS 12 directors fear to risk holding up their expensive No one will read the above scheme with satis- coordinated programmes with disagreements that faction and some people will read it with disgust. result in their having to go back to the laboratory, with Experienced toxicologists point out that: consequent delay and financial loss. Knowledge of the mode of action of a potential The majority of toxicity tests (which particularly new drug obviously greatly enhances prediction are subject to ethical criticism) are firmly based on from animal studies of what will happen in man. studies in whole animals, because only in them is it Whenever practicable such knowledge should be possible to approach the complexity of organisation obtained; sometimes this is quite easy, but some- of body systems in humans, to explore any times it is impossible. Many drugs have been intro- consequences of variable absorption, metabolism duced safely without such knowledge, the later and excretion, and to reveal not only direct toxic acquisition of which has not always made an im- effects but also those of a secondary or indirect portant difference to their use, e.g. antimicrobials. nature due to induced abnormalities in integrative Pharmacological studies are integrated with those mechanisms, or distant effects of a toxic metabolite of the toxicologist to build up a picture of the produced in one organ that acts on another.13 undesired as well as the desired drug effects. The use of animals would be totally unjustified if In pharmacological testing the investigators know results useful to man could not be obtained. In what they are looking for and choose the experi- ments to gain their objectives. In toxicological testing the investigators have less 12 An admirable discussion of the issues will be found in clear ideas of what they are looking for; they are Paton W 1984 Man and mouse. Oxford, London and in screening for risk, unexpected as well as predicted, Zbinden G 1990 Alternatives to animal experimentation. and certain major routines must be done. Toxicity Trends in Pharmacological Sciences 11:104 13 Brimblecome R W, Dayan A D 1993 In: Burley D M, Clarke testing is therefore liable to become mindless J M, Lasagna L (eds) Pharmaceutical Medicine. Arnold, routine to meet regulatory requirements to a greater London extent than are the pharmacological studies. The 47
3 DISCOVERY AND DEVELOPMENT OF DRUGS predictive value of special toxicology (above) is particularly controversial. Orphan drugs and All drugs are poisons if enough is given and the task of the toxicologist is to find out whether, where diseases and how a compound acts as a poison to animals, and to give an opinion on the significance of the A free market economy is liable to leave untreated, data in relation to risks likely to be run by human rare diseases, e.g. some cancers (in all countries) beings. This will remain a nearly impossible task and some common diseases, e.g. parasitic infections until molecular explanations of all effects can be (in poor countries). provided. Toxicologists are in an unenviable position. Where a drug is not developed into a usable When a useful drug is safely introduced they are medicine because the developer will not recover the considered to have done no more than their duty. costs then it is known as an orphan drug, and When an accident occurs they are invited to explain the disease is an orphan disease; the sufferer is a how this failure of prediction came about. When health orphan.14 Drugs for rare diseases inevitably they predict that a chemical is unsafe in a major must often be licensed on less than ideal amounts of way for man, this prediction is never tested. clinical evidence. The remedy for these situations lies in govern- ment itself undertaking drug development (which CONCLUSION ON PRECLINICAL is likely to be inefficient) or in government-offered TESTING incentives, e.g. tax relief, subsidies, exclusive mar- As drugs are developed and promoted for long- keting rights, to pharmaceutical companies and, term use in more and relatively trivial conditions, in the case of poor countries, international aid pro- e.g. minor anxiety, and affluent societies become grammes; such programmes are being imp- less and less willing to tolerate small physical or lemented.15 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. GUIDETO FURTHER READING Occasional failures of prediction are inevitable, Banks R E et al 2000 Proteomics: new perspectives, new with consequent public outcry. biomedical opportunities. Lancet 356:1749-1756 Limited resources of scientific manpower and Beeley N, Berger A 2000 A revolution in drug discovery: money will not be used to the best advantage if the combinatorial chemistry still needs logic to drive public shock over thalidomide (p. 81) and science forward. British Medical Journal 321:581-582 subsequent events is allowed to express itself in Black J W 1986 Pharmacology: analysis and governmental regulations requiring a plethora of exploration. British Medical Journal 293: 252 expensive tests (and toxicity testing is very Crystal R G 1995 The gene as a drug. Nature Medicine expensive), many of them of dubious meaning for 1:15 anything other than the animal concerned. Such a Di Masi J A1995 Success rates for new drugs entering policy would prevent industrial laboratories from clinical testing in the United States. Clinical devoting resources to investigation of molecular Pharmacology and Therapeutics 58:1 mechanisms of drug action, in the knowledge of which alone lies health with safety. 14 The cost of treating a patient having the rare genetic When the preclinical testing has been completed Gaucher's liposome storage disease with genetically to the satisfaction of the developer and of the engineered enzyme is US$ 145 000 to 400 000 per annum national or international regulatory agency, it is according to severity. Who can and will pay? More such situations will occur. time to administer the drug to man and so to launch 15 Official recognition of orphan drug status is accorded in the the experimental programme that will decide USA (pop 240 million) where the relevant disease affects whether the drug is only a drug or whether it is also fewer than 200,000 people; in Japan (pop 121 million) for a medicine. This is the subject of the next chapter. fewer than 50,000 people. 48
ORPHAN DRUGS AND DISEASES 3 Dollery C T 1999 Drug discovery and development in Meyer B R1992 Biotechnology and therapeutics: the molecular era. British Journal of Clinical Experimental treatments and limited resources. Pharmacology 47: 5-6 Clinical Pharmacology and Therapeutics 51: 359 Fears R, Robert D, Poste G 2000 Rational or rationed Roses A D 2000 Pharmacogenetics and future drug medicine? The promise of genetics for improved development and delivery. The Lancet 355: clinical practice. British Medical Journal 320: 933 1358-1361 Gale E A M 2001 Lessons from the glitazones: a story Smith A E 1999 Gene therapy — where are we? Lancet of drug development. Lancet 357:1870-1875 354 (suppl 1): stl-4 Graeme-Smith D G 1999 How will knowledge of the Sykes R 1998 Being a modern pharmaceutical human genome affect drug therapy? British company. British Medical Journal 317:1172 Journal of Clinical Pharmacology 47: 7-10 Wolf R C, Smith G, Smith R L 2000 Pharmacogenetics. Lachmann P 1992 The use of animals in research. British Medical Journal 320: 987-990 British Medical Journal 305:1 Lasagna L1982 Will all new drugs become orphans? Clinical Pharmacology and Therapeutics 31: 285 49