ASIA NEEDS A LE­GAL FRAME­WORK TO COM­BAT RARE DIS­EASES

BioSpectrum (Asia) - - Bio Content - Aishwarya Venkatesh aishwarya.venkatesh@mmac­tiv.com

An es­ti­mated 350 mil­lion peo­ple world­wide suf­fer from rare dis­eases and one in ev­ery 20 peo­ple are bat­tling rare dis­ease. Though most of these dis­eases are treat­able, lack of a pol­icy to sup­port and fos­ter the de­vel­op­ment of or­phan drugs, is dis­cour­ag­ing pharma com­pa­nies from ven­tur­ing into or­phan op­er­a­tions. It is now time to look at the struc­tural frame­work and de­vise a strat­egy to ad­dress this long­stand­ing un-met med­i­cal need. To raise aware­ness for rare dis­eases and im­prove ac­cess to treat­ment and med­i­cal rep­re­sen­ta­tion for in­di­vid­u­als with rare dis­eases and their fam­i­lies, Rare Dis­ease Day has been ob­served on the last day of Fe­bru­ary each year since 2008. This year it will be ob­served on Fe­bru­ary 28. To gen­er­ate more aware­ness about rare dis­eases and to em­pha­size the need for le­gal poli­cies, BioSpec­trum Asia analy­ses trends, op­por­tu­ni­ties and chal­lenges in Asia’s or­phan drug mar­ket.

An es­ti­mated 350 mil­lion peo­ple world­wide suf­fer from rare dis­eases and one in ev­ery 20 peo­ple are bat­tling rare dis­ease. Though most of these dis­eases are treat­able, lack of a pol­icy to sup­port and fos­ter the de­vel­op­ment of or­phan drugs, is dis­cour­ag­ing pharma com­pa­nies from ven­tur­ing into or­phan op­er­a­tions. It is now time to look at the struc­tural frame­work and de­vise a strat­egy to ad­dress this long­stand­ing un-met med­i­cal need. To raise aware­ness for rare dis­eases and im­prove ac­cess to treat­ment and med­i­cal rep­re­sen­ta­tion for in­di­vid­u­als with rare dis­eases and their fam­i­lies, Rare Dis­ease Day has been ob­served on the last day of Fe­bru­ary each year since 2008. This year it will be ob­served on Fe­bru­ary 28. To gen­er­ate more aware­ness about rare dis­eases and to em­pha­size the need for le­gal poli­cies, BioSpec­trum Asia analy­ses trends, op­por­tu­ni­ties and chal­lenges in Asia’s or­phan drug mar­ket.

Or­phan dis­eases, once rare, are now af­fect­ing larger pop­u­la­tions, with one in ev­ery 5000 peo­ple suf­fer­ing from a rare ge­netic dis­or­der. The World Health Or­ga­ni­za­tion de­fines it as a dis­ease with 6.5 to 10 cases in ev­ery 10,000 peo­ple. About 6000 to 8000 rare dis­eases, mostly ge­netic in na­ture have been iden­ti­fied across the world and only around 500 of them have known ther­a­pies. Half of the pop­u­la­tion of or­phan dis­ease pa­tients are chil­dren as most of the ge­netic or­phan dis­eases oc­cur at birth or child­hood. Gen­er­ally, or­phan dis­eases are con­sid­ered to be se­vere, pro­gres­sive, de­gen­er­a­tive, lifethreat­en­ing or chron­i­cally de­bil­i­tat­ing dis­eases. De­spite know­ing the causes of or­phan dis­eases, most of these dis­eases are still non-cur­able as they lack sat­is­fac­tory treat­ments.

A rare dis­ease af­fects a small number of peo­ple in com­par­i­son to the gen­eral pop­u­la­tion and the clas­si­fi­ca­tion of a rare dis­ease varies across con­ti­nents, re­gions and coun­tries. For in­stance, the FDA clas­si­fies a dis­ease as rare if it af­fects less than 200,000 out of about 315 mil­lion Amer­i­cans. In Ja­pan, the Min­istry of Health, La­bor and Wel­fare states that a dis­ease must af­fect less than 50,000 of the coun­try’s 127 mil­lion cit­i­zens in or­der to be con­sid­ered rare. And, while a dis­ease may be clas­si­fied as rare in one coun­try, the dis­ease may be more preva­lent in an­other coun­try. Fur­ther­more, the sta­tus of a dis­ease may change over time, be­com­ing more preva­lent as doc­tor aware­ness and di­ag­no­sis abil­i­ties im­prove. Also, for the past three decades big pharma has not showed much in­ter­est in or­phan drug space as they would not lead to sub­stan­tial sales un­der nor­mal mar­ket con­di­tions be­cause of the high costs and risks of drug de­vel­op­ment, in­suf­fi­cient knowl­edge of patho­phys­i­o­log­i­cal mech­a­nisms of rare dis­eases that the drugs di­ag­nose or treat, and dif­fi­cul­ties in con­duct­ing clin­i­cal tri­als with small pa­tient pop­u­la­tions and a small po­ten­tial mar­ket. How­ever, nearly two-thirds of the world’s pop­u­la­tion re­side in Asia and hence even the rarest dis­ease will have many pa­tients seek­ing treat­ment.

Dr Ti­mothy Low, Head of Med­i­cal Af­fairs Asia Pa­cific, Shire, said that de­spite med­i­cal ad­vance­ments, many pa­tients suf­fer­ing from a rare dis­ease still lack ac­cess to ap­pro­pri­ate med­i­cal in­ter­ven­tions. “Ef­fec­tive ther­a­pies are still not avail­able to more than 95 per cent of the pa­tients suf­fer­ing from rare dis­eases op­tion – that means only a priv­i­leged one in 20 peo­ple liv­ing with rare dis­eases to­day can po­ten­tially take

med­i­ca­tion to sus­tain their lives – if they can ac­cess or af­ford it to be­gin with,” he added.

The need for or­phan treat­ments in Asia is huge and with lit­tle in place so far, Asia rep­re­sents a lu­cra­tive mar­ket for or­phan op­er­a­tions. Also, with in­creas­ing un-met need, govern­ment and reg­u­la­tory au­thor­i­ties are also en­cour­ag­ing or­phan drug re­search. Ac­cord­ing to Na­tional Or­ga­ni­za­tion for Rare Dis­eases (NORD) es­ti­mates, close to half (41%) of the new med­i­ca­tions ap­proved by the FDA in 2016 were or­phan drugs. In 2017 nearly 60 or­phan drugs were ap­proved by the USFDA. Since the in­tro­duc­tion of Or­phan Drug Act (ODA) in 1983 in a few coun­tries across the globe, there has been a steady up­ward trend in or­phan drug ap­provals. In each of the past two years, over 300 drugs were des­ig­nated as be­ing or­phan drugs by the FDA.

Dr Meenakshi Bhat, con­sul­tant in clin­i­cal ge­net­ics at the Cen­ter for Hu­man Ge­net­ics in In­dia ac­cen­tu­ated, “In­dia never had enough aware­ness and or­ga­nized ap­proach to­wards rare dis­eases. We have the tal­ent and the money, how­ever, it is not co­or­di­nated into ac­tual

“In Asia bar­ring Aus­tralia and Ja­pan, only South Korea, and Tai­wan have es­tab­lished sys­tem­atic eco­nomic and reg­u­la­tory in­cen­tives to en­cour­age the de­vel­op­ment of drugs for rare dis­eases. China is also ac­tively pro­mot­ing the regulation of rare dis­eases and or­phan drugs. How­ever, a rare dis­ease frame­work doesn’t re­ally ex­ist in South­east Asia”

- Dr Ti­mothy Low, Head of Med­i­cal Af­fairs Asia Pa­cific, Shire

de­liv­er­ables. We have the largest biotech com­pa­nies in In­dia. Many are in­ter­ested in investing in rare dis­or­ders R&D. But the mo­ment they think in terms of mar­ket­ing and business, which is where the hes­i­tancy is.”

Tak­ing the lower limit of global preva­lence es­ti­mate, pop­u­lous na­tions like In­dia and China should have more than 70 mil­lion rare dis­ease cases each. Cur­rently, drug de­vel­op­ers in these coun­tries are re­ceiv­ing no for­mal in­cen­tives from the govern­ment. Hence or­phan drugs need to be im­ported which makes them highly un­af­ford­able. As the Asian phar­ma­ceu­ti­cal mar­kets are still in nascent stage, the op­por­tu­ni­ties for or­phan drugs in Asia are also im­mense and get­ting in­creas­ingly pop­u­lar.

“Asia Pa­cific is cur­rently way un­der-rep­re­sented in the area of rare dis­eases,” high­lighted, Dr Low. “If you sim­ply look at the mar­ket po­ten­tial >2 bil­lion pop­u­la­tion, > $16 tril­lion GDP, and > $230 bil­lion mar­ket, and es­ti­mated of 100 mil­lion peo­ple af­fected by rare dis­eases, we see a sig­nif­i­cant op­por­tu­nity to build a lead­ing rare dis­ease and spe­cialty business in the re­gion.”

Few Asian coun­tries have im­ple­mented the ODA and have a well-de­fined sys­tem for or­phan drugs. They pro­vide health in­sur­ance cov­er­age, ex­pe­dited regis­tra­tion, and ex­clu­sive mar­ket­ing pe­ri­ods and pro­vide many such in­cen­tives to woo pharma com­pa­nies. How­ever, other Asian coun­tries are only now be­gin­ning to look at rare dis­eases, and what they can do to help their cit­i­zens af­flicted with them. Re­cently, China’s FDA, long crit­i­cized for its slow drug-review process, is of­fer­ing to grant con­di­tional ap­provals for or­phan meds al­ready ap­proved abroad, even with­out in-China trial data.

Dr Low ex­plained, “In Asia bar­ring Aus­tralia and Ja­pan, only South Korea, and Tai­wan have es­tab­lished sys­tem­atic eco­nomic and reg­u­la­tory in­cen­tives to en­cour­age the de­vel­op­ment of drugs for rare dis­eases. China is also ac­tively pro­mot­ing the regulation of rare dis­eases and or­phan drugs. How­ever, a rare dis­ease frame­work doesn’t re­ally ex­ist in South­east Asia. The cur­rent reg­u­la­tions only set forth gen­eral cri­te­ria to ac­cel­er­ate the regis­tra­tion and ap­proval of or­phan drugs, but de­tailed rules have not been im­ple­mented and fur­ther in­cen­tives have not been pro­posed. Thus, the press­ing is­sue for such Asian coun­tries with­out or­phan drug leg­is­la­tion is to es­tab­lish do­mes­tic leg­isla­tive reg­u­la­tions and in­cen­tives to en­cour­age the de­vel­op­ment of or­phan drugs. Take Sin­ga­pore for ex­am­ple, the Or­phan Drug Act which came into force in 1991 gave a def­i­ni­tion of or­phan drugs and of the le­gal frame­work for im­ports. But it lacks a for­mal reg­u­la­tory frame­work for or­phan drugs; there­fore work­ing with clin­i­cians to in­crease the un­der­stand­ing of dis­ease; as well as with pay­ers, pol­i­cy­mak­ers, pa­tients to com­mit to find­ing pric­ing so­lu­tions for medicines that are sus­tain­able is ab­so­lutely crit­i­cal.”

Need for a le­gal pol­icy

The US FDA es­ti­mates that around 200 drugs en­ter de­vel­op­ment ev­ery year and a third of them re­ceive ap­proval. How­ever, these drugs also present sig­nif­i­cant chal­lenges in­clud­ing dif­fi­culty in ex­e­cu­tion of clin­i­cal tri­als, reg­u­la­tory hur­dles, and a chang­ing re­im­burse­ment en­vi­ron­ment. With proper strate­gic plan­ning, spon­sors seek­ing or­phan drug des­ig­na­tion and ap­proval can more skill­fully nav­i­gate these clin­i­cal, reg­u­la­tory and fi­nan­cial chal­lenges.

Lack of a pol­icy or a le­gal frame­work in many Asian coun­tries is de­ter­ring the de­vel­op­ment of these drugs and thus many rare dis­eases pa­tients die of the dis­ease. In­creas­ing number of peo­ple fall­ing prey to these dis­eases have re­it­er­ated the need for a sound le­gal pol­icy and frame­work to sup­port drug de­vel­op­ment for dis­eases.

Chul-Woong, Re­gional Team Lead, Rare Dis­ease, Emerg­ing Mar­kets, Asia, Pfizer, ob­served, “Re­cently

“Pro­vid­ing qual­ity and ef­fec­tive treat­ment for rare dis­ease is a com­plex chal­lenge due to mul­ti­ple fac­tors. Due to the lim­ited number of in­di­vid­u­als af­fected by a rare dis­ease, there is of­ten lack of ex­pe­ri­ence in manag­ing them. Many pa­tients are mis­di­ag­nosed and of­ten re­ceive in­ad­e­quate treat­ment. Se­cur­ing fund­ing for medicines for rare dis­ease medicines is an­other bar­rier. It is also de­pen­dent on many coun­tryspe­cific fac­tors, in­clud­ing pa­tient and so­ci­etal ben­e­fits, dis­ease bur­den, health pri­or­i­ties, ex­ist­ing stan­dards of care, sup­ply chains, abil­ity to pay, and stage in the phar­ma­ceu­ti­cal life cy­cle.”

- Chul-Woong, Re­gional Team Lead, Rare Dis­ease, Emerg­ing Mar­kets, ASIA, Pfizer

in some Asian coun­tries, we have wit­nessed var­i­ous gov­ern­ments seek­ing pol­icy changes with the goal im­prove their ex­ist­ing health­care sys­tems in re­la­tion to the treat­ment of rare dis­eases. This is en­cour­ag­ing, how­ever im­proved pa­tient ac­cess still re­mains a chal­lenge across Asia. Medicines are among the most pow­er­ful tools for pa­tients to cure, treat, and pre­vent ill­ness and dis­abil­ity. All pa­tients should have ac­cess to the medicines their doc­tors pre­scribe.”

For long, Or­phan Drug Act (ODA) has been con­sid­ered as a key game changer that can al­ter the dy­nam­ics of or­phan drugs and rare dis­eases in any coun­try. The ODA, for­mu­lated by the US, in 1983 can be rightly termed as the cat­a­lyst that fos­tered the de­vel­op­ment of these drugs. Fol­low­ing the ex­am­ple of the US FDA’s Or­phan Drug Act es­tab­lished in 1983, some Asian coun­tries have de­vel­oped or­phan drug leg­is­la­tion, such as Sin­ga­pore’s Or­phan Drug Ex­emp­tion to the Medicines Act and Ja­pan’s Or­phan Drug Amend­ment to the Phar­ma­ceu­ti­cal Af­fairs Law. Un­der this Act, or­phan drugs en­joy many reg­u­la­tory and com­mer­cial in­cen­tives such as tax cred­its, grants, waived FDA fees, re­duced time­lines for clin­i­cal de­vel­op­ment and higher prob­a­bil­ity of reg­u­la­tory ap­proval, cou­pled with com­mer­cial driv­ers such as premium pric­ing, faster up­take, lower mar­ket­ing costs and longer mar­ket ex­clu­siv­ity. Only five Asian coun­tries have so far im­ple­mented this Act- Tai­wan, Korea, Aus­tralia, Ja­pan, and Sin­ga­pore. Pro­grams en­cour­ag­ing or­phan drug de­vel­op­ment are avail­able in many coun­tries in Asia that ad­dress such un­met med­i­cal needs, but these pro­grams are known by dif­fer­ent ter­mi­nolo­gies in dif­fer­ent coun­tries in Asia and they are not ad­dressed un­der a pol­icy or a le­gal frame­work. Also, coun­tries with a huge pop­u­la­tion like China and In­dia do not have a pol­icy that can at­tract global play­ers to show cor­po­rate in­ter­est in this area. If the gov­ern­ments in these coun­tries do not for­mu­late a pol­icy to ad­dress these rare dis­or­ders, or­phan dis­eases will un­for­tu­nately re­main or­phan.

Chal­lenges in Or­phan Drug Space

There are many chal­lenges faced in the or­phan drug space. There is lit­tle known about the nat­u­ral his­tory of rare dis­eases and hence di­ag­no­sis and de­vel­op­ment of a drug is a huge chal­lenge. There are over 7000 rare dis­eases which oc­cur over a broad spec­trum of ill­nesses that have lit­tle or noth­ing in com­mon with each other. The dis­ease af­fects a very small pop­u­la­tion of the so­ci­ety and mostly young chil­dren and hence struc­tur­ing clin­i­cal tri­als is very dif­fi­cult. Many a times the dis­ease is lo­cal­ized to one coun­try and is not preva­lent in other coun­tries. Hence, with­out ad­e­quate fi­nan­cial as­sis­tance by the govern­ment, pharma com­pa­nies will reap very lit­tle or no prof­its through their or­phan business.

Dr Low said, “Ma­jor chal­lenges for R&D in the rare dis­ease field stem from the im­pact of the unique

char­ac­ter­is­tics of the small pa­tient pop­u­la­tions; high risk of fail­ure in­her­ent in de­vel­op­ing break­through medicines in ar­eas of high un­met need; ex­cep­tion­ally com­plex sci­ence and clin­i­cal/man­u­fac­tur­ing process; and the com­mit­ment to in­vest in the nec­es­sary ser­vices re­quired to sup­port pa­tient out­comes, which in­clude train­ing and ed­u­ca­tion, treat­ment ad­min­is­tra­tion and tar­geted di­ag­nos­tic ap­proaches. Also, only 1-2 per cent of ev­ery 10,000 sub­stances syn­thetized in a lab­o­ra­tory will go through all stages of R&D to be launched on the mar­ket. In case of Eu­rope, of the 1,360 po­ten­tial treat­ments eval­u­ated as or­phan medicines to date, only 143 have gained a mar­ket­ing au­tho­riza­tion by Euro­pean Medicines Agency (EMA). This means that al­most 9 out of ev­ery 10 treat­ments that make it all the way to or­phan sta­tus have not yet made it to or even failed to get to pa­tients.”

Chul-Woong, added, “Pa­tient Ac­cess re­mains the big­gest chal­lenge faced by the phar­ma­ceu­ti­cal in­dus­try. We believe all pa­tients should have ac­cess to the medicines their doc­tors pre­scribe and are com­mit­ted to part­ner­ing with Gov­ern­ments and other stake­hold­ers to find novel so­lu­tions for over­com­ing ac­cess chal­lenges in un­der­served com­mu­ni­ties. We need to work on holis­ti­cally ad­dress­ing the com­pli­cated bar­ri­ers to ac­cess.”

Lu­cra­tive mar­ket, loom­ing patent cliff at­tract­ing Big Pharma

De­spite the in­her­ently small mar­ket, these drugs have gained mo­men­tum over the years. Many re­ports in­di­cate that or­phan drugs are the next block­busters and many phar­ma­ceu­ti­cal com­pa­nies want them in their prod­uct port­fo­lio. An­a­lysts es­ti­mate that the or­phan drugs mar­ket is ex­pected to grow at a CAGR of 11.4% dur­ing the fore­cast pe­riod 2017–2023 to touch an ag­gre­gate of $246.55 bil­lion by 2023. Ac­cord­ing to a study pub­lished by Reuters, the or­phan on­col­ogy drug Ri­tuxan (generic: Ri­tux­imab) is the world’s sec­ond most prof­itable drug.

As re­ported by To­tal Bio­pharma, it is es­ti­mated that bi­o­log­i­cal patents worth $67 bil­lion is due to ex­pire by 2020. With many block­buster drugs los­ing pro­tec­tion, big pharma com­pa­nies have now grav­i­tated to­wards

spe­cialty drugs, or­phan drugs, and the bi­o­log­ics mar­ket. If proper leg­is­la­tion and frame­work is en­acted, or­phan busi­nesses may swell in this patent pool and thus can even­tu­ally treat many po­ten­tial rare dis­or­ders. The last decade had been the most pro­duc­tive pe­riod in or­phan drug de­vel­op­ment, both in des­ig­na­tions and ap­provals with many big bio­pharma com­pa­nies hav­ing at least one or­phan drug in their pipe­line. The ex­tended pe­riod of ex­clu­siv­ity for these drugs means that they are in­su­lated from generic com­pe­ti­tion for a po­ten­tially longer pe­riod than their non-or­phan coun­ter­parts as or­phan drug ex­clu­siv­ity does not have any as­so­ci­a­tion with patents. Cel­gene, BMS, No­var­tis, Roche, J&J, Shire, Ab­bvie, Merck &Co, Alex­ion, Pfizer are some of the top com­pa­nies in or­phan drug space.

How­ever de­spite ad­vance­ments, lack of a sound le­gal frame­work en­cour­ag­ing in-house or­phan drug R&D in all Asian coun­tries is a ma­jor de­ter­rent to the de­vel­op­ment of drugs and many Asian coun­tries still im­port these drugs. These im­ported drugs are in­ac­ces­si­ble to many pa­tients as they are very costly and ma­jor­ity of Asia’s pop­u­la­tion is below poverty line and can­not af­ford them. Or­phan drug de­vel­op­ment pro­vides am­ple op­por­tu­ni­ties for re­search and de­vel­op­ment and re­duc­ing the dis­ease bur­den of the so­ci­ety and im­prov­ing health­care of the coun­try at large. How­ever, with­out a proper sys­tem and guid­ance from the reg­u­la­tory bod­ies or phar­ma­co­log­i­cal as­so­ci­a­tions, it is chal­leng­ing for a phar­ma­ceu­ti­cal com­pany to in­vest in the de­vel­op­ment of or­phan mol­e­cules from scratch. It is im­por­tant to in­te­grate or­phan drugs into the health­care sys­tem of Asia as with treat­ment, these pa­tients lead a nor­mal life but with­out treat­ment, one in three chil­dren will not live past their fifth birth­day.

Source Eval­u­atePharma. Fe­bru­ary 2017

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