Tackling a global healt h crisis: init ial st eps

The Review on Ant im icr obial Resist ance Chair ed by Jim O’Neill February 2015

Cont ent s 1. Execut ive sum m ary

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2. Int roduct ion

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3. We under- invest in t he ƭ nancial and hum an capit al needed t o t ackle AM R

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4 . Five st eps t hat can be t aken now t o t ackle AM R

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A. Set up a global AM R innovat ion f und t o boost t he num ber of early research ideas

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B. M ake sure we are get t ing t he m ost of out of exist ing drugs

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C. Im prove t he use of diagnost ics wherever t hey can m ake a diƬ erence

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D. At t ract and ret ain a high calibre skills base

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E. M odernise t he surveillance of drug resist ance globally

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5. The next st eps

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6 . Acknowledgem ent s

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1. Execut ive summ ary In Decem ber we published our ƭ rst report 1 showing t hat inf ect ions caused by drug- resist ant pat hogens are one of t he biggest healt h problem s t he world f aces t oday. Bact eria and ot her pat hogens have always evolved t o resist t he new drugs t hat m odern m edicine uses t o com bat t hem . But in recent years t he rise in drug resist ance has been a part icular worry, especially t he em ergence of ant ibiot icresist ant superbugs. Unless act ion is t aken t o address t his huge global issue, our conservat ive est im at e is t hat it will cost t he world an addit ional 10 m illion lives a year by 20 50 , m ore t han t he num ber of people current ly dying f rom cancer annually. It will also have a cum ulat ive cost of 10 0 t rillion USD, m ore t han one and a half t im es annual world GDP t oday, or roughly t he equivalent t o losing t he UK econom y f rom global out put every year. We now t urn our at t ent ion t o how t his problem can be t ackled. This paper is t he ƭ rst in a series t hat works t owards global and sust ainable solut ions. There are m any angles t o t he problem t hat we will need m ore t im e t o consider. In part icular, t he f ocus of our next paper, due t o be published in t he spring, will be how t o st im ulat e t he m arket f or com panies t o invest in and develop new ant im icrobials and diagnost ics, which is not f ully addressed here. There we will assess pot ent ial ‘push’ and ‘pull’ incent ives t o encourage t he developm ent of new ant im icrobial drugs, and set out our proposals f or act ion by policy m akers. In lat er papers we will also f ocus on im port ant issues such as t he use of ant ibiot ics in agricult ure and pot ent ial alt ernat ives t o ant im icrobials. In t he m eant im e, t here are several areas where we t hink t hat act ion can be t aken wit hout delay and t hese areas f orm t he basis of t his paper. These ideas will not be news t o people versed in t he issues raised by ant im icrobial resist ance (AM R). The reason f or st ressing t hem here is t o highlight and cat alyse act ion on each area, wit hout wait ing f or an overall package t o be agreed. These ƭ ve speciƭ c st eps f or act ion are: 1.

In cr ease ear l y sci en ce f u n d i n g t o t ack l e AM R: est ablished f unders m ust address t his but in addit ion an ‘AM R innovat ion f und’ would act as an early research grant m aker f or blue sky science, and as a non- proƭ t incubat or f or ideas t hat are m ore m at ure. Too m any good ideas are not being pursued f or lack of f unding.

2. M ak e ex i st i n g d r u g s go f u r t h er : a syst em at ic program m e of re- exam ining exist ing ant ibiot ics could t est whet her changing t he dosing or com bining t hem wit h ot her agent s or ot her ant im icrobials could slow down t he spread of drug resist ance and t reat ‘resist ant inf ect ions’ m ore eƬ ect ively. 3.

Su p p or t t h e d evel op m en t an d u se o f r el evan t d i agn o st i c t ech n o l o gi es: if we had t he right diagnost ics, m ore pat ient s would receive t he right ant ibiot ic t o t reat t heir inf ect ion, but f ewer ant ibiot ics would be prescribed unnecessarily.

1. An t i m i cr obi al Resi st ance: Tack l i n g a cr i si s f or t h e heal t h and w eal t h of n at i ons. ht t p:/ / am r - r evi ew .or g/ p ub l i cat i on s

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4 . In vest i n t h e p eo p l e w h o w i l l sol ve t h e p r o b l em : m any com panies have ret reat ed f rom ant ibiot ic discovery in recent decades. It is crucial t o t rain t he next generat ion of doct ors, scient ist s, m icrobiologist s, pharm acologist s, m edicinal chem ist s and biochem ist s, as well as econom ist s, social scient ist s and vet s, am ong ot hers. They will need t o ƭ nd novel approaches and t herapies f or m icrobial diseases, whilst m aint aining a connect ed and global out look. 5.

M od er n i se t h e w ay su r vei l l an ce of d r u g r esi st an ce i s d o n e an d u sed gl ob al l y: a m ore joined up and digit al global approach is needed, using t he lat est advances in m olecular t est ing and inf orm at ics, t o im prove access t o real t im e global- scale surveillance inf orm at ion.

We know t hat f urt her act ion will be required t o m ake ant im icrobial developm ent com m ercially at t ract ive and sust ainable over t he long t erm . This is likely t o involve changes t o t he current m arket f or ant im icrobials. In cont rast , none of t he act ions above require a change t o t he current drugs m arket and yet t hey can all buy t im e and lay t he groundwork f or f ut ure discoveries. The Review will cover t hese and addit ional issues in m ore det ail in lat er publicat ions, including t he m arket f ailures surrounding t he developm ent of new ant im icrobial drugs. In t his process we will need t o ensure t hat appropriat e m easures t aken t o count er AM R do not inadvert ent ly disrupt econom ic progress in developing count ries. Indeed, alt hough t he Review was com m issioned by t he UK Prim e M inist er, it has a global out look and M argaret Chan, Direct or General of t he World Healt h Organizat ion (WHO) has shown support f or it s work: “ The UK is dem onst rat ing st rong leadership in raising awareness about t he global t hreat posed by ant im icrobial resist ance. Form ing t his Review is a crucial st ep t owards ensuring t hat t he world has eƬ ect ive m edicines t o com bat inf ect ious diseases. WHO will work closely wit h t he Review and ot her key part ners on t his im port ant init iat ive.” We will recom m end a ƭ nal package of act ions t o t he UK Prim e M inist er and Governm ent s across t he world by t he sum m er of 20 16 . Over t he course of t he Review, we have com m it t ed t o explore t he f ollowing t hem es: 1.

The im pact of ant im icrobial resist ance on t he world’s econom y if t he problem is not t ackled.

2. How we can change our use of ant im icrobial drugs t o reduce t he rise of resist ance, including t he gam e- changing pot ent ial of advances in genet ics, genom ics and com put er science. 3.

How we can boost t he developm ent of new ant im icrobial drugs.

4 . The pot ent ial f or alt ernat ive t herapies t o disrupt t he rise in resist ance and how t hese new ideas can be boost ed. 5.

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The need f or coherent int ernat ional act ion t hat spans regulat ion and use of drugs (including ant ibiot ics) across hum ans, anim als and t he environm ent .

Th e Revi ew on An t i m i cr ob i al Resi st an ce, Ch ai r ed b y Ji m O’Nei l l

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New t herapies

Vaccines

Sur veillance

Diagnost ics

Drugs 4

2. Int roduct ion The best scient iƭ c breakt hroughs of t en rely t o som e ext ent on serendipit y as well as hard work. But we seem t o be st acking t he odds against ourselves in t he ƭ ght against inf ect ious diseases and t he challenge of drug resist ance. The f act t hat com m ercial incent ives t o develop new ant im icrobials are low com pared t o ot her ƭ elds is a well- est ablished problem . Whereas ant im icrobials once represent ed an at t ract ive and highly proƭ t able sect or of t he global pharm aceut ical indust ry, a num ber of f act ors m ean t hat t hey now t end t o generat e lower or even negat ive ret urns on invest m ent com pared t o higher- priced or longer course t reat m ent s f or cancer or chronic diseases. This problem is not conƭ ned t o t he corporat e world. It is also an issue in academ ia and in t he governm ent al and charit able organisat ions t hat f und m edical research. This is not surprising: as t he global burden of inf ect ious diseases reduced st eadily during t he 20 t h cent ury, so did societ y’s f ocus on eƬ ort s t o com bat t hem . Unf ort unat ely, t im e has shown t hat t his was m isjudged. The HIV/ AIDS epidem ic t hat st art ed in t he 19 80 s present ed t he world wit h one of it s great est ever healt h challenges, one t hat rem ains f or m any count ries. The ‘cont rol’ of HIV relies on drugs and behaviour change, but largely t he f orm er, and t his is at risk in f ut ure decades. The global ƭ ght against m alaria has been very successf ul, but t he em ergence of drug- resist ant m alaria st rains is now raising alarm bells across Sout h East Asia. And perhaps m ost worryingly f or m odern m edicine, wit h t he num bers of ant ibiot icresist ant bact eria rising across t he globe, m ore and m ore doct ors around t he world are using last line of def ence drugs, wit h no new ant ibiot ics t o replace t he ones t hat are becom ing ineƬ ect ive, f or exam ple in t he t reat m ent of gonorrhoea. Bet t er awareness and st rong leadership have already sparked change t hanks t o init iat ives by t he WHO, t he European Com m ission and m any individual count ries, but f urt her decisive act ion is needed urgent ly t o t urn t hese good int ent ions int o result s. In t his paper, ƭ rst we highlight t he undercurrent s t hat m ake it diƯ cult f or t he very good individuals working in t his ƭ eld t o progress great science. In a nut shell, we t hink t here is a problem of chronic under- invest m ent in bot h t he ƭ nancial and hum an capit al needed t o t ackle AM R. Then we t urn t o ƭ ve act ions t hat we t hink can and should be considered im m ediat ely, wit hout wait ing f or an exhaust ive and deƭ nit ive solut ion, or an int ernat ional agreem ent , urgent and necessary t hough t hese long- t erm m easures are.

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3. We under- invest in t he ƭ nancial and human capit al needed t o t ackle AMR Adequat e long t erm invest m ent in research and developm ent (R&D) is a prerequisit e f or t he sust ained m edical innovat ions t hat have t ransf orm ed how illnesses are diagnosed, m anaged and cured. Globally, t he sum s involved in m aint aining t his cycle of innovat ion are huge: m ore t han 26 0 billion USD is spent each year 2 by privat e com panies, governm ent s and charit able or philant hropic organisat ions on healt hcare R&D. This spending has hist orically been dom inat ed by t he US, Europe and Japan. But t oday t he involvem ent of em erging econom ies is growing rapidly, wit h healt h research spending in China increasing by 17% annually in recent years.3 AM R represent s a t ruly global problem , so t his em erging shif t t owards a m ore globalised landscape of research f unding present s an opport unit y t o reƮect t he diverse needs and priorit ies of pat ient s worldwide m ore adequat ely. Whet her t his spending is guided by public policy, alt ruist ic int ent , or com m ercial beneƭ t t he dist ribut ion of f unding f or research act ivit ies at all st ages of t he developm ent process is f undam ent al in det erm ining t he progress hum anit y m akes against diƬ erent cat egories of disease. In a survey conduct ed by t his Review of researchers, f unding organisat ions and privat e com panies wit h an int erest in AM R, 80 % of respondent s cit ed poor f unding or econom ic incent ive problem s as t he m ost diƯ cult obst acle t o creat ing new ant ibiot ics.

Public and charit able funders invest relat ively lit t le in AMR The lat e- m iddle part of t he 20 t h cent ury saw a shif t in t he collect ive f ocus of t he m edical com m unit y away f rom t he t hreat of inf ect ious diseases. This was driven in no sm all part by t he belief – now shown t o have been m ist aken – t hat ant ibiot ics, vaccines and enhanced public healt h had won t he bat t le against inf ect ions which had been a signiƭ cant cause of m ort alit y and m orbidit y unt il t he m iddle of t he cent ury. There was t hen a corresponding shif t t owards t ackling chronic and noncom m unicable diseases, t he burden of which has grown in recent decades, in large part due t o increased lif e expect ancy, but aided by t he abilit y of ant ibiot ics t o ƭ ght inf ect ions. M ore t han 80 % of disabilit y- adjust ed lif e years (DALYs) lost in t he developed world are now at t ribut able t o non- com m unicable diseases. 4 But t his shif t has lef t AM R, as well as m any ot her areas of inf ect ious disease research, chronically underf unded. Globally, our collect ive research priorit ies should reƮect not sim ply t he current burden of disease, but also a m ore f ar- sight ed recognit ion of t he f ut ure healt h challenges t he world m ay f ace. In t his respect , t he Ebola crisis in West Af rica present s us wit h a lesson of t he cost s of underest im at ing t he t hreat t hat an inf ect ious disease m ay pose and t he im pact t hat not being able t o t reat it m ay have.

2. Moses H, Mat heson D H M, Cai r n s- Sm i t h S, Geor ge B P, Pal isch C, Dor sey E D. The an at om y of m ed ical r esear ch: US and in t er n at i onal com par i son s. Journal of t he American Medical Associat ion 2015; 313(2 ): 174 – 18 9 . 3. Ibi d. 4 . Gl obal Bur den of Di sease st ud y 20 10

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There are som e encouraging signs am ong non- proƭ t and governm ent f unders of m oney st art ing t o Ʈow again t o support research relat ed t o AM R. M ajor charit able f oundat ions such as t he Wellcom e Trust in t he UK and t he Bill & M elinda Gat es Foundat ion in t he US have begun t o increase t heir f ocus on drug resist ance wit hin t he areas t hey priorit ise. In t he UK, t he Research Councils, t oget her wit h ot her governm ent f unders, are working on a holist ic approach t o AM R research wit h a relat ively sm all init ial 25 m illion GBP invest m ent . In addit ion, key init iat ives such as t he European Innovat ive M edicines Init iat ive (IM I) New Drugs For Bad Bugs project , and t he Biom edical Advanced Research and Developm ent Agency (BARDA) Broad Spect rum Ant ibiot ics Program m e in t he US have bet ween t hem invest ed nearly 6 50 m illion USD over t he past ƭ ve years direct ly int o new ant im icrobial discovery eƬ ort s in part nership wit h indust ry. M ost recent ly, t he Whit e House has request ed a sharp increase in f unding f rom Congress, up t o a t ot al of 1.2 billion USD, t o bolst er US f ederal f unding in 20 16 t o t ackle AM R, including 6 50 m illion USD t o ext end t he exist ing NIH and BARDA program m es of work. There are also prom ising m oves t owards im proved coordinat ion of AM R research f unding, such as t hrough t he European Joint Program m ing Init iat ive on AM R (JPIAM R). However, signiƭ cant ly m ore can be done t o ensure t hat research eƬ ort s t ranscend not just nat ional borders but also boundaries bet ween organisat ions and scient iƭ c specialt ies. Given t he scale and urgency of t he problem , governm ent s need t o re- balance nat ional R&D budget s f urt her and f ast er t o support high qualit y research on AM R. To illust rat e t he point t hat governm ent s invest relat ively lit t le in AM R, we have reviewed publicly available inf orm at ion f or t he US Nat ional Inst it ut e of Healt h (NIH), which is t he world’s largest single f under of healt h and biom edical R&D, wit h an annual budget of around 30 billion USD. Out of t hat t ot al budget , NIH allocat ed around 34 1 m illion USD5 annually on average, over t he past ƭ ve years, t arget ed at AM R. This m oney represent s only 1.2% of t he NIH’s grant f unding and is dwarf ed by t he 5.2 billion USD spent annually on cancer research in t he sam e period, absorbing 18.6 % of it s t ot al. Reviewing t he dat a f or Europe was m ore diƯ cult because t here is current ly no single source of dat a on spending on AM R- relat ed research by public bodies in m em ber st at es across Europe. But t he pict ure we gat hered by consult ing expert s and f unders was t hat t he absolut e num bers allocat ed t o AM R were sm aller t han in t he Unit ed St at es, but t hat t he proport ion of spend allocat ed t o AM R was broadly sim ilar. In Europe, spending by m em ber st at es is supplem ent ed by f unding f rom t he European Com m ission. Over t he course of t he 20 0 7– 13 budget cycle a t ot al of 56 0 m illion USD6 has been direct ed t owards AM R- relat ed research, which represent s 1.8 % of all grant awards across relevant f unding t hem es. These num bers st ack up poorly t o t he am ount s spent on diseases such as cancer and diabet es. A m ore com prehensive pict ure of f unding in Europe is current ly being prepared by t he EU- wide JPIAM R.

5. Fi gur es ar e gi ven in 2 0 10 USD. 6 . h t t p:/ / eur opa.eu/ r api d/ pr ess- r el ease_ MEMO- 13- 9 9 6 _ en.ht m

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Privat e and comm ercial invest ment is also insuƯ cient The value of overall healt h R&D spending by governm ent s globally is only half t hat of f unding f rom privat e organisat ions.7 M uch of t he lat t er is f rom pharm aceut ical com panies, whose research eƬ ort s are also dom inat ed by non- com m unicable diseases; 22 of t he 25 indicat ions wit h t he great est num ber of product s under developm ent are non- com m unicable and chronic condit ions, wit h t he rem aining t hree indicat ions being HIV/ AIDS, hepat it is C, and inƮuenza.8 Act ive clinical t rials, as recorded by t he World Healt h Organizat ion Int ernat ional Clinical Trials Regist ry Plat f orm , are sim ilarly skewed t owards non- com m unicable diseases, which out num ber t hose f or com m unicable diseases by a rat io of nearly t hree t o one. There are 6 7,0 0 0 clinical t rials current ly regist ered in noncom m unicable diseases, of which around t wo t hirds are in cancer. There are only 23,0 0 0 clinical t rials current ly regist ered in inf ect ious diseases, of which nearly half are in HIV/ AIDS, TB and m alaria. These t rials will undoubt edly cont ribut e t o addressing som e of t he alarm ing challenges t hat we highlight ed in our ƭ rst paper of em erging resist ance t o t reat m ent s f or t hese condit ions. However, t he num ber of t rials looking at bact erial inf ect ions ot her t han TB is m inuscule in com parison: a m ere 182,9 or less t han 1% of non- com m unicable clinical t rials. Unlike public f unding, t he signiƭ cant change needed t o increase f ocus on AM Rrelat ed research am ongst privat e f unders can only be achieved in t he presence of a com pelling com m ercial rat ionale. Pat t erns of R&D spending by privat e com panies will ult im at ely respond m ost eƬ ect ively t o long- t erm m arket f orces. But at t he m om ent , t he discovery and developm ent of new ant ibiot ics appears com m ercially unat t ract ive in com parison t o invest m ent int o t reat m ent s f or cancer and chronic diseases, where prices are higher and t reat m ent t im es longer. For privat e f unding of ant ibiot ic research and developm ent t o increase, m arket s need t o adjust t o ensure t hat t he long t erm ƭ nancial value at t ached t o t hem is suƯ cient t o incent ivise a signiƭ cant and sust ained increase in research spending. Som e of t hese changes will be down t o governm ent s, healt h providers and healt h regulat ors t o bring about . We will f ocus t he recom m endat ions of our next paper on t hese quest ions, looking in part icular at what so- called ‘pull incent ives’ are needed. But t he pharm aceut ical sect or will also need t o adjust it s research priorit ies independent ly of t he act ion of governm ent s, recognising t hat AM R lef t unaddressed is a risk t o t he viabilit y of m any ot her t reat m ent s, including cancer, diabet es and rout ine surgery.

7. Røt t i ngen J- A, Regm i S, Eide M, Young A J, Vi er gever R F, År dal C, et al . Map pi ng of avai l abl e h eal t h r esear ch an d devel opm en t dat a: w h at ’s t her e, w hat ’s m i ssi ng, an d w h at r ol e i s t her e f or a gl obal obser vat or y? The Lancet 2 0 13; 38 2 : 12 86 – 130 7 8. Cit el in e Phar m a R&D Ann ual Revi ew , 20 14 9 . Dat a ex t r act ed f r om WHO Int er nat i on al Cl i ni cal Tr i al s Regi st r y Pl at f or m w ebsi t e, ht t p :/ / apps.w ho.in t / t r i al sear ch/ , accessed Jan uar y 19 t h 2 0 15

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We also under- invest in t he human capit al needed t o t ackle AMR AM R is a challenge wit h m any f acet s and a global reach. Tackling it will require pulling t oget her t he eƬ ort s of t he best basic and applied researchers including clinicians, inf ect ious diseases specialist s, m icrobiologist s, ‘om ics expert s and drug and m edical t echnology developers, all in close collaborat ion wit h pharm acologist s, public healt h prof essionals, big dat a expert s, social scient ist s and vet s, am ong ot hers. We also need t o m ake AM R a problem t hat bot h appeals t o and is rewarding f or specialist s f rom ot her disciplines, including com put er science, m at hem at ics, and engineering and physical science. We have observed t he skills and capabilit y pict ure f or drug discovery and developm ent across t he relevant disciplines and career pat hs t hrough our conversat ions wit h academ ics, governm ent oƯ cials and com panies. A st ory em erged t hat is not dissim ilar t o t he f unding short age we describe above: we seem t o be under- invest ing in t he hum an capit al needed t o t ackle AM R especially when considering it relat ive t o ot her ƭ elds. We regularly m eet m any brilliant individuals working t o m ake a diƬ erence t o t his global healt h problem but t hey are of t en working against t he grain of t heir prof essional ƭ eld and receiving less recognit ion f or t heir work t han t hey m ight do in ot her specialit ies. The publicly available dat a we reviewed is consist ent wit h t hese general observat ions. Som e f urt her det ails are set out below. What is not surprising is t hat clinicians, researchers and t he inst it ut ions em ploying t hem nat urally f ollow t he m oney, as illust rat ed by t he successes of areas of research t hat are bet t er f unded in com parison, such as cancer or HIV/ AIDS. We are st acking t he odds against winning t he ƭ ght on AM R if we do not act now t o m ake sure t he next generat ion of high calibre cross- disciplinary prof essionals are being t rained, support ed and encouraged.

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4. Five st eps t hat can be t aken now t o t ackle AMR To people f am iliar wit h t he challenge of AM R, none of t he ideas below will com e as a surprise. They are f or t he m ost part well- rehearsed wit hin t he m edical com m unit y. The reason f or highlight ing t hem here, however, is t o cat alyse act ion and call on decision m akers t o deploy adequat e resources now. Som e have t he pot ent ial t o m ake a real diƬ erence wit hin a sm all num ber of years. We know t hat f urt her act ion will be needed t o m ake t he m arket f or new ant ibiot ics com m ercially at t ract ive and sust ainable over t he long t erm , but none of t he act ions below requires a change in t he current shape of t he drugs m arket t o be im plem ent ed. Equally no change t o t hat m arket would m ake t hese act ions redundant .

A. Set up a global AMR innovat ion fund t o boost t he num ber of early research ideas Concert ed act ion will be needed t o drive invest m ent in R&D f ocused on a new generat ion of drugs, using exist ing drugs bet t er, im proving diagnost ics and ƭ nding alt ernat ives t o ant ibiot ics. There is a short age of invest m ent in all st ages of drug developm ent in t his ƭ eld, and t his is som et hing t hat can only be rect iƭ ed on a sust ainable basis by ensuring t hat new ant im icrobials are a com m ercially viable part of t he global pharm aceut icals m arket : t his will be t he f ocus of our next paper. However, t here is also a pat t ern of under- invest m ent in basic, early and m id- st age scient iƭ c research. It is t his t ype of work – usually undert aken in academ ic set t ings or in part nership bet ween academ ia or public healt h organisat ions and sm all and m edium com panies – t hat is t he essent ial precursor f or t he t ype of breakt hroughs we need in t he ƭ eld of drug resist ance. It is t his work t hat is som et im es picked up by larger com panies who have t he capabilit y and experience t o t ake drugs all t he way t o m arket . In t he cont ext of t he t ot al sum s involved in m edical R&D and drug discovery, t his kind of research need not be expensive but it is rarely at t ract ive t o privat e invest ors as a com m ercial proposit ion. So f unding f or t his basic, of t en blue sky, and t ranslat ional science depends largely on resources f rom governm ent and charit able organisat ions. Already t here is progress in t he way policy is being shaped. The draf t global act ion plan published by t he WHO; t he coordinat ed st rat egy across t he diƬ erent part s of t he US Governm ent ; t he joint program m ing init iat ive bet ween European research f unders across Europe: t hese are all clear signs t hat policy m akers are t aking AM R seriously and aim ing t o m ount a coordinat ed response. The im m ediat e next st ep on t he journey is f or f unders t o allocat e grant s where t hey are m ost needed, wit h signs in t he UK and elsewhere t hat f unding bodies have already em barked on t his. We t hink an ‘AM R Innovat ion Fund’ dedicat ed t o f unding research on all aspect s of AM R can help t ransf orm t hese eƬ ort s f rom int ent ions int o result s f ast er.

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It will be im port ant t hat t he f und has wide eligibilit y f or academ ic, public healt h and indust ry scient ist s and is global in it s reach t o support good ideas wherever t hey arise. We have shown in our ƭ rst paper on t he econom ic cost of AM R t hat em erging econom ies st and t o lose t he m ost f rom rising drug resist ance. Ideas and solut ions generat ed close t o where t hese problem s are m ost acut e m ay be m ore f ert ile and t ailored t o t he needs of t hose clinicians and healt h workers on t he f ront line. The det ails f or how t his f und would be set up and how it would allocat e f unds are very im port ant and we will work t hrough t hese ahead of our next paper. To do t his we will cont inue our dialogue wit h governm ent s, f unders, regulat ors, researchers and com panies, wit h t he det erm inat ion t o build on what is working whilst keeping an open m ind t o why ot her t hings have not worked so f ar. During t his process we are keen t o f ost er part nerships bet ween developed and developing count ries in research and science, and enhanced m onit oring of AM R t hrough im proved surveillance.

B. Make sure we are get t ing t he m ost of out of exist ing drugs When econom ist s look at t he challenge of AM R, t hey usually cat egorise issues bet ween dem and and supply. The availabilit y of drugs is a supply side quest ion, wit h t he supply being m ade up of all t he drugs t hat have been discovered already plus all t he new drugs or new t herapies t hat could be discovered in t he f ut ure. The com parison wit h f ossil f uels of t en springs t o m ind: we seek t o use our exist ing ƭ nit e resources (oil and gas ƭ elds) m ore eƯ cient ly, and at t he sam e t im e we look f or new sources of power (solar, wind et c.). When we asked what has been done t o get m ore out of exist ing drugs, we were surprised by t he answer when it cam e t o ant ibiot ics: not m uch has been done and cert ainly not hing syst em at ic or com prehensive. Not all t he scient ist s we spoke t o agreed on how we could m ake m ore eƯ cient use of t he exist ing arsenal of drugs. But on t he whole t hey did agree t hat t hree avenues are wort h t rying and have not been exhaust ively explored so f ar: 1.

Is t he dosing and lengt h of t reat m ent f or m ost exist ing ant ibiot ics consist ent wit h t he goal of m inim ising resist ance?

2. Have we t est ed available ant ibiot ics suƯ cient ly in com binat ion wit h ot her ant ibiot ics or diƬ erent agent s t o see if com binat ions could t reat ‘resist ant inf ect ions’ m ore eƬ ect ively and/ or prevent increased resist ance? 3.

Do we know which old libraries and pat ent lit erat ure have been syst em at ically m ined, and how recent ly, and whet her t here are ‘f orgot t en’ com pounds t hat could be put t o use?

It is not clear whet her large pharm aceut ical com panies wit h t he abilit y t o do t his kind of applied research have done it . Nor is it clear whet her universit ies, or public and charit able program m es have been f unded t o do it . We have com e upon f our

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possible explanat ions. First , t he pat h t o com m ercial ret urn is unclear because m ost of t hese old drugs are oƬ pat ent and it could be diƯ cult t o pat ent a new com binat ion or dose of said drugs. Second, t his area could be seen as less excit ing f or m any f unding bodies and scient ist s t han f unding or undert aking work at t he cut t ing edge of m icrobiology research int o novel com pounds. Third, it could be t hat t he regulat ory pat hway f or approval is t oo unclear or burdensom e. Fourt h, it can be surprisingly diƯ cult t o f orm ulat e com binat ion product s so t hat bot h drugs work eƬ ect ively t oget her. We will consider t his in det ail in preparing our next paper. The reasons f or t he slow progress in t his area will inf orm t he recom m endat ions we m ake f or speeding it up. If it t urns out t hat t here are insuƯ cient com m ercial incent ives at play, it could be just iƭ ed f or governm ent s t o play a m ore direct role in procuring a program m e of research, or change incent ives t o encourage ot hers t o do so. In t he m eant im e, eƬ ort s in t his area should be boost ed and inf orm at ion shared on what has and has not been t ried already.

C. Improve t he use of diagnost ics wherever t hey can m ake a diƬ erence Anot her way t o t ackle AM R is t o reduce t he dem and f or drugs – t he less ant ibiot ics are used t he slower resist ance t ends t o build up. By im proving t he accuracy of prescribing, bet t er diagnost ics can help reduce our use of ant ibiot ics when t hey are not needed. Every t im e an ant ibiot ic is used it gives advant age t o bact eria t hat are resist ant t o it , and encourages ot hers t o becom e resist ant . Theref ore unnecessary prescribing or overt reat m ent increase t he rat e of resist ance. For exam ple, about 80 % of gonorrhoea cases in t he UK are caused by bact eria suscept ible t o penicillin and about 70 % are suscept ible t o ciproƮoxacin. However, healt h guidelines prescribe t he use of m ore powerf ul ant ibiot ics (cef t riaxone and azit hrom ycin) as t he st andard t reat m ent , because we cannot give a rapid, accurat e diagnosis of inf ect ions t hat could be t reat ed wit h penicillin or ciproƮoxacin. If we could diagnose bact erial inf ect ions and resist ance m ore quickly and accurat ely, even if only f or cert ain t ypes of inf ect ion, we could ‘save’ our m ost powerf ul ant ibiot ics by using t hem only f or cases resist ant t o ot her opt ions. This would m ake our drugs last longer. There has been recent recognit ion of t his issue in t he UK, US and Europe wit h t he proposal of prizes t o provide a ‘pull incent ive’ t o com panies looking t o develop new diagnost ic devices. The 10 m illion GBP Longit ude Prize 20 14 is a welcom e incent ive, as was t he Sept em ber announcem ent by t he US Governm ent of it s int ent t o launch a sim ilar init iat ive, wit h prizes pot ent ially in t he region of 25 m illion USD, and t he 1 m illion EUR European Horizon prize. However, it is generally agreed t hat t hey will not provide a t ot al solut ion t o t his problem , and f urt her act ion is needed t o supplem ent t hat which has been t aken already. Earlier in t his paper we set out a proposal f or an “ AM R innovat ion f und” t o provide a ‘push’ incent ive t o generat e early discoveries in academ ia and t he labs of sm all com panies. We do not t hink t his should be lim it ed t o drug discovery, and t heref ore

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ideas f or new diagnost ic t ools should beneƭ t f rom t his f und, increasing f unding opport unit ies f or innovat ive ideas. Beyond grant s and prizes however, t he m ost eƬ ect ive way t o nurt ure innovat ion in t his ƭ eld will be t o m ake sure t hat healt h providers are ready t o t ake up appropriat e diagnost ic t echnologies. Healt h policy m akers need t o begin considering now how t o est ablish clear incent ives t o prom ot e t he upt ake and usage of point - of - care diagnost ics once t hey are available. This is part icularly im port ant in set t ings where t he cost s of deploying new diagnost ics will f all on individual providers, but t he beneƭ t s accrue t o healt h syst em s and societ y m ore broadly. They also need t o consider how t o encourage t he behaviour change t hat will be needed t o ensure t hat t hese devices are used appropriat ely when t hey com e t o m arket , and t hat t he result s are act ed upon. These issues should be ant icipat ed now; if t hey are not , and t he rout e t o m arket appears unworkable t hen developm ent of t hese vit al t ools will be st iƮed. We will be analysing t he econom ic and healt hcare ƭ nancial m anagem ent issues as t hey relat e t o diagnost ics f urt her in our next paper, including whet her t here is a need f or f urt her incent ives t o bring diagnost ic t ools t o m arket and how t his could best be done.

D. At t ract and ret ain a high calibre skills base Over t he past m ont hs we heard recurring com m ent s about t he qualit y of t he skills base involved in t ackling AM R, including t hat AM R is f ailing t o at t ract t he new generat ion of researchers it needs in academ ia and public and com m ercial labs. There are also concerns about hospit als’ recruit m ent of inf ect ious disease doct ors, wit h current skills and expert ise dwindling due t o ret irem ent s. This is com pounded by t he f act t hat large pharm aceut ical com panies and t heir research t eam s are wit hdrawing f rom t he ƭ eld, wit h a loss of inst it ut ional m em ory and experience hard earned t hrough previous drug discovery program m es. Finally, AM R as a ƭ eld is not at t ract ing suƯ cient part nerships wit h prof essionals f rom ot her disciplines such as chem ist ry which are needed t o solve t he problem . We t ried t o t est t hese concerns against publicly available inf orm at ion where possible. We f ound t hat dat a about : a) t he em ploym ent and t raining of inf ect ious disease clinicians in t he Unit ed St at es, and b) t he academ ic im pact of publicat ions relevant t o t he AM R ƭ eld seem t o corroborat e som e of t he concerns about t he AM R skills base. First , looking at published dat a in t he Unit ed St at es, we f ound t hat HIV and Inf ect ious Disease doct ors were t he lowest paid am ong 25 m edical prof essions exam ined in an annual com pensat ion report f or 20 13.10

10 . Th i s i s based on r esear ch under t ak en b y Med scape as p ar t of t hei r 2 0 13 ann ual com p en sat i on r epor t : ht t p :/ / w w w .m edscape.com / f eat ur es/ sl i desh ow / com pen sat ion / 20 13/ publ ic

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We t hen f ound applicat ion dat a f or 18 of t he sam e 25 prof essions: inf ect ious disease had t he second lowest applicat ion rat es. At 8 4 applicant s f or every 10 0 program m e places it is one of only t wo specialit ies t hat receive f ewer applicat ions t han t here are places. Given t he relat ively lower pay com bined wit h of t en longer hours and no prospect of com plem ent ing incom e t hrough privat e pract ice, it is not hard t o see why inf ect ious disease has diƯ cult y recruit ing new doct ors. This is also t rue in developing count ries, and is part icularly worrying because wit h rising resist ance levels t he need f or inf ect ious disease doct ors is becom ing great er. We also f ound som e evidence conƭ rm ing a sim ilar pat t ern f or academ ic researchers. There is a view am ong AM R expert s t hat t he ƭ eld has suƬ ered poorer academ ic st at us hist orically in com parison wit h som e ot her areas of m edicine. Concerns include t hat : 1.

AM R has been less f avoured by f unding bodies (t hough t his is changing in som e count ries);

2. Indust ry- sponsored research is less f avoured (e.g. by universit ies) t han research f unded by research councils et c.; and 3.

The highest ranked specialist AM R journals are judged by som e universit ies not t o have suƯ cient im pact f or academ ic excellence assessm ent s.

M icrobiology journals f orm a relat ively sm all ƭ eld. For inst ance, t here are ƭ ve t im es m ore cancer publicat ions t han t here are m icrobiology. 11 We t hen looked f or ways t o judge t he im pact of m icrobiology as a ƭ eld, regardless of it s size. Am ongst t he several diƬ erent m et rics used t o assess t he im pact of a journal, t he m ost com m on one is t o look at t he num ber of cit at ions t hat t he average art icle receives in it s ƭ rst t wo years af t er publicat ion. While t his is a t est designed t o t est t he im pact of speciƭ c journals we used it t o com pare diƬ erent ƭ elds in t his case, t o see how im pact diƬ ered across disciplines. We f ound t hat m icrobiology journals do less well by t his score t han any ot her ƭ eld we exam ined, and inf ect ious disease is t he second lowest . The average m icrobiology paper receives 2.7 cit at ions in it s ƭ rst t wo years and an inf ect ious disease paper receives just under 3, whereas cancer publicat ions get 3.5 cit at ions in t his period, and im m unology ones get alm ost 4 . This is not due t o m icrobiology’s lower num ber of publicat ions, as we only f ound a very sm all (0 .0 5) non- st at ist ically signiƭ cant correlat ion bet ween t his m easure of im pact and num ber of publicat ions. Anot her widely used m et ric t o judge an academ ic or journals’ prest ige is t he “ h- index” . Using t his m et ric again shows t hat m icrobiology is under- represent ed wit h no m icrobiology journals ranked in t he t op 30 m edical journals in t he world, while oncology, im m unit y, pharm acology, neurology and endocrinology all have at least t wo t op 30 journals. While t hese diƬ erences m ight not seem signiƭ cant , t he num ber of cit at ions a researcher get s has a huge bearing on t heir academ ic career.

11. Fi gur es based on w w w .scim agojr .com / jour nal r ank .php dat a

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