A Discussion of Biotechnology The Future of the Pharmaceutical Industry? A Discussion of Biotechnology ..................................................................................1 The Future of the Pharmaceutical Industry?..................................................................

..1 Background and Sco e...................................................................................................! Pharmacogenetics and Pharmacogenomics....................................................................! "ecom#inant Proteins.....................................................................................................$ %accines.........................................................................................................................& Thera eutic Anti#odies................................................................................................1! Stem 'ells....................................................................................................................1( The Future of Biotechnology in the )*.......................................................................1+

Background and Sco e In the last millennium ,and stretching into this one-. a great /enture 0as undertaken #y colla#orati/e la#oratories in eighteen countries1 The 2uman 3enome Pro4ect. The aim of this ro4ect 0as to identify and se5uence all the some !6666 !7666 genes that make u human D8A. 8ot more than forty years since 9atson and 'rick announced they had cracked the code of life. it is remarka#le that such de/elo ment has occurred in this field. The 2uman 3enome Pro4ect has im lications in many fields. such as D8A forensics. agriculture and anthro ology: this essay. ho0e/er. 0ill concern itself e; licitly 0ith the harmaceutical industry. 8aturally. there are many ethical. legal and social issues 0ith any genetic mani ulation. This essay 0ill not address any of these issues. since it is not the ur ose of this iece of 0riting. Instead. it 0ill focus on the strategies used in the harmaceutical industry to use gene technology in the attem t roduce safer and more efficacious medicines. Pharmacogenetics and Pharmacogenomics Pharmacogenetics is the study of ho0 an indi/idual<s genetic make=u affects the res onse of the #ody to drugs. 2istorically. ad/ances in this field 0ere largely due to mistake ,sometimes /ery gra/e mistakes-. For e;am le. it 0as found that treatment of tu#erculosis 0ith the drug isonia>id lead to mi;ed drug res onse #eha/iour in atients. For some. the recommended dose 0as not ade5uate enough to treat the condition. For others. the recommended dose resulted in a manifestation of to;ic effects. It 0as found that the en>yme ?i/er 8=acetyltransferase 0as res onsi#le for the drug<s meta#olism and further study re/ealed that the en>yme e;isted in t0o olymor hs. Polymor hism is a henomenon 0here an en>yme is e; ressed in more than one form. each form differing #y erha s a fe0 amino acids. This is not to #e confused 0ith truncated or ill=e; ressed roteins@en>ymes resulting from D8A damage. Polymor hisms are 0ell esta#lished differences in en>yme structure and function i.e. a significant ro ortion of the o ulous e;hi#it the olymor hism. not 4ust a fe0 indi/idual cases. In the case of isonia>id. the t0o olymor hs of li/er 8= acetyltransferase lead to the different res onses to the drug. Ane olymor h meta#olised the drug too 5uickly for any thera eutic affect to #e noted= indi/iduals e;hi#iting this en>yme are du##ed Bfast acetylators.C The other olymor h did not meta#olise the drug fast enough. thus leading to a #uild u that conse5uently lead to the re/iously mentioned to;ic effects= indi/iduals e;hi#iting this en>yme are du##ed Bslo0 acetylators.C Incidences like the isonia>id case and many others lead to a greater understanding of the role genetics lays in drug res onse. The 2uman 3enome Pro4ect ser/ed to dee en this le/el of a0areness and no0 the study of harmacogenetics is 0ell esta#lished. The ne;t 5uestion 0as. of course. 0hat can #e done a#out it? Pharmacogenomics is the ractical element of using genetics in drug design and holds the romise tailor=made drugs may one day #e a#le to #e rescri#ed to #est suit an indi/idual #ased on the atient<s genetic make=u . This notion is already #eginning to #ecome a reality. as #iotechnology and harmaceutical com anies de/elo drugs that interact 0ith D8A. For e;am le. already on the market are Bsmall interfering

"8AC ,si"8A- molecules. that target areas on D8A to halt transcri tion of certain genes 0here it may #e desira#le to do so. In summary. e;citing ne0 com ounds are gri ing the harmaceutical industry<s attention that can mani ulate and use D8A to the atient<s ad/antage. This essay 0ill no0 go on to look at some of these com ounds and strategies that are used to synthesise them. "ecom#inant Proteins "ecom#inant roteins are so named as they are synthesised from recom#inant D8A. The #asic strategy is to recom#ine D8A from one s ecies 0ith a host cell<s D8A. The host cell can then roduce that rotein 0here it could not #efore. Ad/antages of using recom#inant roteins are1 Proteins can #e roduced #y organisms that are easy to culture 2igh yielding Dasy to reco/er 'ost effecti/e Safer than using nati/e roteins

First. the correct gene that is res onsi#le for e; ression of the desired rotein must #e identified and isolated. The gene is cut /ia restriction en>ymes that lea/e Bsticky ends.C "estriction en>ymes recognise se5uences of D8A that #racket genes and catalyse the hydrolysis of the nucleotides either side of the gene. 2o0e/er. they cut the D8A in such a 0ay that single sense or anti=sense strands are left un aired. These are the Bsticky endsC and the gene can #e incor orated into a /ector<s D8A. Ane the gene has #een cut it is re licated #y some form of D8A am lification rocess. such as the P'" , olymerase chain reaction-. Aften. a lasmid is used as a /ector. Plasmids are circular segments of D8A often found in rokaryotic cells. The /ector lasmid is often synthesised to also incor orate an anti#iotic resistance gene for reasons that 0ill #e discussed later. The lasmid is cut 0ith the same restriction en>yme to yield com limentary sticky ends. The gene and lasmid are then mi;ed in the ho e that some lasmids 0ill incor orate the gene. The /ector is then inserted into host cells. ty ically #acteria ,although not al0ays-. The #acteria are then cultured on gro0th media im regnated 0ith the anti#iotic that the lasmid contains the resistance gene for. In this 0ay. only host cells that ha/e taken u the lasmids ,and therefore the gene- 0ill gro0. Af course. not all lasmids in this rocess 0ill result in ha/ing the gene. Some 0ill merely re=seal themsel/es at the stage 0here the gene is introduced. Sometimes. the lasmids are synthesised to ha/e t0o genes for anti#iotic resistance. each for a different anti#iotic ,e.g. enicillin and tetracycline-. The lasmid is engineered so that the gene is incor orated in the middle of the second resistance gene. thus interru ting it. Ance the host cells ha/e #een cultured on the first gro0th media 0ith anti#iotic to 0hich all lasmids contain the resistance gene. a small sam le of the cells are transferred to a second gro0th media im regnated 0ith the second anti#iotic. This is often done /ia /el/et lating: here. the to layers of cells adhere to a late and are sim ly transferred. #ut the colonies are in the same osition. The t0o media can then #e com ared. 'ells that gro0 on the second media contain lasmids 0ith the intact gene for resistance to the second anti#iotic= these only contain recom#ined lasmids

and not the desired gene. 'ells that cannot gro0 on the second media ha/e taken u lasmids that ha/e the anti#iotic resistance gene interru ted and so do contain the desired gene. Fermentation. 2ar/esting and Purification Ance the ure culture of cells that contain the recom#inant D8A /ector is o#tained. the material is fro>en in glycerol and stored in a master cell #ank at tem eratures lo0er than =176 o'. 9orking cell #anks of smaller sam les are then generated from the master cell #ank #efore the cultures are remo/ed to ferment industrial /olumes of the acti/e harmaceutical ingredient ,API-. 2ere are details of the fermentation rocess1 The am oule is remo/ed from the 0orking cell #ank. added to nutrient #roth and allo0ed to gro0. This is termed the rimary culture hase Seed culture is transferred to a small scale ,16 166 ?- fermentor and allo0ed to gro0. This is termed the seed fermentation hase The contents of the rimary. small scale fermentor are transferred to a large scale ,1666 166666 ?- fermentor and the culture is gro0n to a s ecific density. This is termed the roduction scale fermentor. Ance the a ro riate cell density is achie/ed. roduction of the desired rotein is initiated #y acti/ating the e; ression romoter ,heat and@or chemicals-. All stages must o Be erformed under sterile conditions o Be monitored throughout o Adhere closely to /alidated rocedures

At the end of fermentation. the cells are har/ested ,e.g. centrifugation-. If the desired rotein is e;tracellular. the cells are discarded from the centrifuged solution and the su ernatant medium is rocessed for reco/ery. If the rotein is intracellular. the medium is discarded and the cells are 0ashed and then lysed to release their contents. The cellular de#ris is then filtered and the filtrate is rocessed for reco/ery. The rotein of interest is generally resented as a lo0 concentration 0ith a 0ide range of contaminants. ranging from small molecules such as anti#iotics and sol/ents to large #iological macromolecules such as other host cell roteins and car#ohydrates. The desired rotein. therefore. must #e urified and concentrated. Eany techni5ues can #e em loyed to urify the rotein such as ultracentrifugation and electro horesis. This essay 0ill detail the most 0idely used techni5ue1 the a lication of chromatogra hy to urify the rotein. 'hromatogra hical methods in use are1 Ion e;change chromatogra hy Si>e e;clusion chromatogra hy 2ydro ho#ic interaction Affinity chromatogra hy

Ion Exchange Chromatography (IEX) IDF se arates the desired rotein #y e; loiting differences in charge. Strongly charged molecules 0ill #ind more strongly than 0eakly charged molecules. thus achie/ing se aration.

Size Exclusion Chromatography (SEC) SD' se arates the rotein of interest from other im urities #y e; loiting difference in si>e. Smaller molecules are hindered #y the orous #eads and take longer to ass through the column than larger molecules.

Affinity Chromatography (AC) A' is a highly s ecific techni5ue that utilises rotein s ecific ligands to effect se aration. Eany rocessed no0 use A' as a single ste urification rocess and is highly cost effecti/e.

Formulation Ance the API is urified. it needs to #e formulated rior to resentation and use. Formulation is a critical stage in the manufacture of #io harmaceuticals as it ensures the efficacy. 5uality. sta#ility and safety of the roduct rior to reaching the atient. The formulation needs to consider the route of administration. for e;am le1 To ical1 the su#stance is re5uired directly to 0here the action is re5uired e.g. sul#utamol for asthma inhalers Dnteral1 the desired effect is systemic ,non=local-: the su#stance is gi/en /ia the digesti/e tract ,e.g. oral anti#iotics-. Parental1 the desired effect is systemic: the su#stance is gi/en #y routes other than the digesti/e tract ,e.g. intra/enous anti#iotics-.

D;am les of "ecom#inant Protein Products The first commercial a lication 0as the roduction of human insulin from E. coli #y Dli ?illy. Ather e;am les are1 Protein 2uman insulin 2uman somatotro in Interferon G!a@ G!# Tissue lasminogen inacti/ator Interleukin ! Factor %III Drythro oietin Year 1&+! 1&+7 1&&! 1&+H 1&&$ 1&&! 1&+& Host E. coli E. coli E. coli E. coli Ieast Animal cells E. coli Animal cells Eammalian cells Eammalian cells Application Dia#etes 3ro0th hormone 'ancer Eyocardial infarction@ ulmonary em#olism 'arcinoma@ melanoma 2aemo hilia Anaemia ,in AIDS-

Case Stu y ! Somatotropin (Human "ro#th Hormone) Somatotro in deficiency can arise from se/eral human illnesses such as1 Turner<s syndrome1 artial or com lete a#sence of an F chromosome in females S2AF deficiency1 chromosomal gene deletion 2ormone deficiency1 malformation of hy othalamus. ituitary gland or trauma2y o ituitarism1 non=functioning ituitary gland

Patients 0ith these conditions are una#le to roduce sufficient 5uantities of nati/e gro0th hormone and therefore re5uire re lacement thera y. The en>yme used to #e isolated from the ituitary glands of cada/ers and 0as /ery e; ensi/e. In 1&+7. unusual cases of 'reut>feldt=Jaco# disease ,a degenerati/e neurological disorder- 0ere re orted in indi/iduals 0ho had recei/ed cada/er=sourced somatotro in treatment ten to fifteen years re/ious. Based on the assum tion that infectious rions 0ere resent in the cada/er=deri/ed 232. it 0as remo/ed from the market. Then. in 1&+7. an E. coli deri/ed recom#inant en>yme. 2umatro eK ,somatotro in for in4ection- 0as marketed #y Dli ?illy L com any. Somatotro in has recently #ecome the first B#iosimilarC to #e a ro/ed for use. Protein Sta#ility Proteins ha/e oor hysical and chemical sta#ility. e/en 0hen refrigerated or fro>en. T0o methods are used to im ro/e sta#ility1 ?yo hilisation ,free>e dryingPD3lyation ,the attachment of a fle;i#le strand or strands of olyethylene glycol ,PD3- to a rotein.-

$yophilisation Ad/antages1 Einimal damage and thus minimal loss of acti/ity ?o0 finial moisture content of roduct. therefore longer shelf life Dase of reconstruction

Disad/antages1 Slo0 2igh o erating e; enses

2o0e/er. the ad/antages out0eigh the disad/antages. Princi les1

PE"lyation The si>e. 0eight. sha e and the linkage used to connect the PD3 strand to the molecule determine the im act PD3lyation has on1 Delayed a#sor tion Decreased roteolysis Increased circulation lifetime Slo0ed renal clearance "educed immunogenicity

Im ortant notes on PD3s1 8on=to;ic Am ho hilic PD3lyation roceeds /ia co/alent #onds #et0een a s ecific acti/e grou on the rotein and a chemically reacti/e grou on the PD3 PD3lyation can #e either linear or #ranched

'urrently a/aila#le PD3lyated drugs include1 PD3interferon anti/iral agent PD3figrastim chemothera eutic PD3adenosine isomerase en>yme re lacement

%accines Immunity Ac%uire Immunity D; osure of the immune system to antigens leads to roduction of anti#odies ,IgB#y B lym hocytes M ac5uired immunity. %accination uses modified antigens ,to reduce clinical risk- to stimulate anti#ody roduction. Immunisation may #e either thera eutic or ro hylactic. D;am les1 EE". cholera and tetanus /accines. Passi&e Immunity Introduction of anti#odies into the system confers assi/e immunity 0hich is transient. Antisera are anti#ody containing serum re arations from animals that react 0ith a circulating antigen. This immunisation is often only tem orary and can #e thera eutic or ro hylactic. D;am les1 snake /enom antisera. s ider anti/enins. EE" 'ontro/ersy In 1&&+. a a er u#lished #y the ?ancet ,9akefield et al- s arked fears of an autism connection 0ith the EE" /accine. This resulted in arents making the otentially dangerous decision to refuse to ha/e their child /accinated. As a result.

incidences of measles ha/e #een on the rise since 1&&+. "ecent re orts ha/e refuted 9akefield<s claims and the 3E' ha/e recently charged 9akefield 0ith Serious Professional Eisconduct. Ty es of %accines T0o con/entional ty es of /accines are a/aila#le1 9hole cell /accines o ?i/e@attenuated /accines o *illed /accines Su#unit /accines

"esearch continues into recom#inant /accines and D8A /accines. 'hole Cell (accines Feature Dose 8o. Doses Ad4u/ant needed? Duration of immunity Anti#ody res onse 'ell mediated immunity "e/ersion to /irulence D;am les1 ?i/e@attenuated /accines1 EE" Polio /irus Iello0 fe/er B'3 Live/attenuated vaccines ?o0 Single 8o Eany years IgB 3ood Possi#le Killed vaccines 2igh Eulti le Ies ?ess IgA. IgB Poor Im ossi#le

*illed /accines1 Pertussis ,0hoo ing cough'holera

Case Study Flu Vaccine Influen>a kills hundreds of thousands of eo le er year 0orld0ide. Flu /accines are a/aila#le #oth as an in4ection of killed /irus and as a nasal s ray of li/e attenuated influen>a /irus ,?AI%-. Flu /accines are made seasonally using three strains chosen #y the 92A 3lo#al Influen>a Sur/eillance 8et0ork. A %irus=?ike Particle %accine ,%?P- is a three dimensional mimic of the /irus. #ut does not carry any of the genes that allo0 for /iral re roduction or infection. This

stimulates the immune system against a ossi#le later emergence of the authentic /irus. Initial results sho0 that this form of /accine may #e /ery effecti/e. %?P /accines can #e mass= roduced 5uite effecti/ely. Su)unit (accines These are ty ically com rised of surface antigens or #acterial olysaccharide ca sule fragments that are immunogenic. Eany /accines are con4ugated into roteins to increase the o/erall immune res onse in those 0ith 0eaker rimary immune systems ,e.g. children under t0o years old-. Case Study- Pneumococcal Vaccines Streptococcus pneumoniae is the largest re/enta#le killer in children under fi/e. The organism causes many ty es of infection such as neumonia. sinusitis. otitis media. meningitis. #acteraemia. endocarditis and #rain a#scesses. S. pneumoniae is also the most common cause of #acterial meningitis in adults and children. !$=%alent Pneumococcal Polysaccharide %accine ,PP%-1 o Eanufactured using ca sular olysaccharides from !$ /irulent strains o 2ighly effecti/e in those older than ! years H=%alent Pneumococcal 'on4ugate %accine ,P'%-1 o Eanufactured using ca sular olysaccharides from H /irulent strains con4ugated 0ith di htheria '"E1&H rotein. o Eore effecti/e for immune res onse in toddlers under ! years old.

*ther (accines Recombinant Vaccines These are created #y utilising #acteria or yeast to roduce large 5uantities of a single /iral or #acterial rotein. This rotein is then urified and in4ected into the atient and the atient<s immune system makes anti#odies to the disease agent<s rotein: thus rotecting the atient from natural disease e.g. 3ardasilN for 2uman Pa illoma/irus ,2P%-. ?i/e recom#inant Vaccinia /iruses ha/e #een constructed conferring immunity to diseases in e; erimental animals. A single recom#inant Vaccinia /accine e; ressing genes for influen>a /irus haemagglutanin. he atitis B ma4or surface antigen and her es sim le; /irus glyco rotein confers immunity to all three diseases in monkeys. DNA Vaccines D8A /accination is an e; erimental techni5ue used to efficiently stimulate immune res onses to rotein antigens. The direct in4ection of mani ulated gene material into the host results in a small amount of its cells roducing the induced gene<s roducts ,i.e. the antigen-. The foreign gene e; ression 0ithin the host has im ortant immunological conse5uences. resulting in the s ecific immune acti/ation of the host against the gene deli/ered antigen.

Thera eutic Anti#odies Thera eutic anti#odies are la#oratory=engineered anti#odies that recognise and #ind to a rotein antigen on the surface of a cell. Dach thera eutic anti#ody recognises a different antigen and. in general. can #e used alone. in com#ination 0ith chemothera y or as a carrier of su#stances such as to;ins or radiation. After #inding to the targeted site. the thera eutic anti#ody can #lock the gro0th of a tumour and@or recruit the #ody<s immune system to attack the target an can also sensitise a cancer cell to chemothera y. 8otes on Anti#odies Anti#odies are roteins that #ond /ery tightly to their target antigens. Dach anti#ody is made u of t0o identical light chains and t0o identical hea/y chains. Anti#odies may #e1 Polyclonal= A mi;ture of anti#ody molecules secreted against a s ecific antigen. each recognising a different e ito e. Eonoclonal= A ure #reed anti#ody that is s ecific to a single e ito e.

Polyclonal Anti)o ies

+onoclonal Anti)o ies A mouse is immunised #y an in4ection of antigen F to stimulate the roduction of anti#odies targeted against F. The anti#ody forming lym hocyte cells are then isolated from the mouse<s s leen. Eonoclonal anti#odies are roduced #y fusing these single anti#ody=forming cells to tumour cells gro0n in culture. The resulting cell is called a hy#ridoma. Dach hy#ridoma roduces relati/ely large 5uantities of identical anti#ody molecules. By allo0ing the hy#ridoma to multi ly in culture. it is ossi#le to roduce a o ulation of cells. each of 0hich roduces identical anti#ody molecules.

These anti#odies are called monoclonal anti#odies #ecause they are roduced #y the identical offs ring of a single. cloned anti#ody roducing cell. Ance a monoclonal anti#ody is made. it can #e used as a s ecific ro#e to track do0n and urify the s ecific rotein that induced its formation.

Problems wit !urine !onoclonal Antibodies Although murine anti#odies are /ery similar to that of human<s. there are differences. The human immune system hence recognises murine anti#odies as foreign. ra idly remo/ing them from circulation and causing systemic inflammatory effects. A solution to this ro#lem 0ould #e to generate human anti#odies directly from humans. "ypes o# !onoclonal Antibodies Eouse hy#ridoma technology generates mouse monoclonal anti#odies ,mA#s-. 3enetic engineering has allo0ed the generation of chimeric. humanised and human mA#s.

In contrast to chimeric mA#s. only the com lementarily=determining regions ,'D"s- are of mouse origin in humanised mA#s. The /aria#le domains of anti#odies contain three such hy er/aria#le 'D"s. 0hich form the anti#ody=#inding site. Therefore. antigen s ecificity can #e conferred #y grafting a ro riate murine 'D"s onto human /aria#le ,%- regions using genetic engineering. Examples of ,herapeutic Anti)o ies $olair% FolairK is a monoclonal anti#ody made #y 8o/artis and used mainly in allergy= related asthma thera y 0ith the ur ose of reducing allergic hy ersensiti/ity. The mA# selecti/ely #inds to human immunoglo#ulin D ,IgD-. IgD is commonly in/ol/ed 0ith allergies 0hen resent in high amounts in the #ody. Eode of action1

&erceptin% 2erce tin is a humanised mA#. It #inds to 2D"!. a rece tor for e idermal gro0th factor ,D3F- that is found on some tumour cells ,some #reast cancers. lym homas-. To date. 2erce tin seems to #e the only mA# effecti/e on solid tumours. Eode of action1

ReoPro% This is manufactured using the antigen #inding fragments and inhi#its the clum ing of latelets #y #inding to the rece tors on their surface that are normally linked together #y fi#rinogen. It is therefore hel ful in re/enting reclogging of the coronary arteries in atients 0ho ha/e undergone angio lasty. Dia'nostic mAbs Anti#odies are used in se/eral diagnostic tests to detect small amounts of drugs. to;ins or roteins1 EA#s to human chorionic gonadotro in ,2'3- are used in regnancy testing kits. Diagnosis of certain cancers in tissue #io sies. 9estern Blotting and D?ISA techni5ues. Directed against 'arcinoma= associated antigen 2uman carcino= em#ryonic antigen 2uman cardiac myosin Disease/ condition Small lung cell carcinoma 'olorectinal cancer Eyocardial infarction imaging

Antibody 8ofetumo#a#

Type Eurine Fa# fragment Arcitumo#a# Eurine Fa# fragment Imicroma# enetate Eurine Fa# fragment Stem 'ells Stem cells are e;traordinary #ecause1

They can di/ide and make identical co ies of themsel/es o/er and o/er again ,self rene0al"emain uns ecialised 0ith no s ecific function or #ecomeO S ecialised ,differentiated- 0ith the otential to roduce o/er !66 different ty es of cells in the #ody.

There are t0o ty es of stem cells1 Dm#ryonic1 from inner mass if #lastocysts ,a- left o/er from I% fertilisation in the la#oratory or ,#- from a#orted foetuses. Adult stem cells1 Stem cells ha/e #een found all o/er the #ody including the #lood. #one marro0. li/er. kidney. cornea. dental ul . um#ilical cord. #rain. skin. muscles. sali/ary glands etc.

Dm#ryonic %s. adult stem cells1 Embryonic Pluri otent1 can #ecome almost any cell Sta#le1 can undergo many cell di/isions Dasy to o#tain #ut #lastocyst is destroyed Possi#ility of re4ection Adult Eulti otent1 can #ecome many cells #ut not all ?ess sta#le1 ca acity for self rene0al is limited Difficult to isolate in adult tissue 2ost re4ection minimised

Stem 'ell Treatments 2uman diseases such as Parkinson<s disease and leukaemia ,as #one marro0 trans lants- are currently #eing treated 0ith stem cells. Stem cell thera y also has the otential to regenerate tissues@ organs and cure more diseases such as dia#etes and multi le sclerosis. The Future of Biotechnology in the )* Bioscience !617. a osition a er u#lished 0ith the )*. coincided 0ith the 76 th anni/ersary of the u#lication of the structure of D8A: 0ith a flood of media ieces on genes. genetics and #iotechnology are fuelling a mood of great o timism a#out the sector<s future. Added to this 0ere continuing e; ectations on 0hat the 23P announced in !666 could deli/er for human health. 2o0e/er. financial conditions ha/e 0orsened in recent years and in/estors are #ecoming increasingly reluctant to in/est in emerging #ioscience com anies and the u#lic markets are all #ut closing do0n. 8either the go/ernment nor the #ioscience industry has #een a#le to re/ent this financial free>e. Eean0hile. the harmaceutical industry faces its o0n issues 0ith a atent BcliffC e5ui/alent to P1Q6 #illion in sales as se/eral #lock#usters come off atent in the ne;t fe0 years. This is cou led 0ith an increasing recognition that it must look to third arties to hel re lenish its i eline. Bioscience !617 0as u#lished shortly #efore the introduction of the BD) 'linical Trails Directi/eC issued after the T38 1Q1! Anti#ody 'T Study. "ather than harmonising clinical trials acti/ity across Duro e. the Directi/e has had the o osite effect 0ith different mem#er states im lementing its re5uirements more. or less. stringently. It must #e re/ie0ed to ensure consistency and to re/ent Britain ricing itself out of drug de/elo ment. The )*<s artici ation in glo#al clinical trials dro ed from (R in !66! to !R in !66(.

Ea4or de/elo ments in the )S highlight one of the most im ortant issues facing harmaceuticals and #iotechnology data1 drug ricing. " L D is increasingly e; ensi/e: studies ut the cost of utting a ne0 drug for ma4or chronic diseases onto the market at u 0ards of P+66 million ,including the cost of failures-.