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Working with Healthcare Stakeholders towards Brain-Based Personalized Medicine

(Edi­tor’s Note: this is Part 3 of the new 3‑part series writ­ten by Dr. Evian Gor­don draw­ing from his par­tic­i­pa­tion at the Per­son­al­ized Med­i­cine World Con­gress on Jan­u­ary, 23, 2012 at Stan­ford Uni­ver­si­ty.)

Work­ing with Health Care Indus­try Stake­hold­ers: Clin­i­cians, Pharma/Biotech, Pay­ers, PBMs, Lawyers, Medicare, FDA

Clin­i­cians seek clear val­i­dat­ed “rules of thumb” that can be eas­i­ly imple­ment­ed and fit into their work­flow and reim­burse­ment regime. Many are explor­ing “Clin­i­cal Deci­sion Sup­port (CDS)” tools on the web and solu­tions linked to “Elec­tron­ic Health Records” (EHR’s). CDC and EHR’s are seed­ing the ground for clin­i­cians to adopt robust Bio­mark­ers that are shown to be unam­bigu­ous­ly clin­i­cal­ly rel­e­vant.

Many of these stake­hold­ers issues are cov­ered in more detail in this book that Stephen Koslow and I edit­ed, from a meet­ing in Wash­ing­ton with 30 Key Opin­ion Lead­ers in Per­son­al­ized Med­i­cine and in Psy­chi­a­try.

Per­son­al­ized Med­i­cine and the Real­i­ty of Get­ting New Com­pounds to Mar­ket

The Phar­ma­ceu­ti­cal Indus­try

The Phar­ma­ceu­ti­cal indus­try is adapt­ing to the com­mer­cial shift to Per­son­al­ized Med­i­cine. Despite their array of ground break­ing drug dis­cov­er­ies, most prof­its have been made on a small num­ber of “block­buster” drugs. So imple­ment­ing a com­mer­cial mod­el that rewards returns from “niche” sub-groups of patients in each dis­or­der (rather than poten­tial­ly from all patients) – requires new expec­ta­tions and new mod­el. The ear­ly winds of change are exem­pli­fied by Phar­ma­ceu­ti­cal com­pa­nies that have recent­ly pur­chased Bio­mark­ers includ­ing:

a. Eli Lil­ly paid US$300m for Avid Radio­phar­ma­ceu­ti­cals Alzheimer’s Demen­tia Test.

b. Take­da licensed Zin­fadel’s Brain Test for iden­ti­fy­ing those at risk for devel­op­ing Alzheimer’s for US$9m and over US$78m for mile­stones achieved.

A vari­ety of major health care indus­tries, includ­ing Med­co, Humana, McKesson Health Solu­tions and Health Advances LLC are offer­ing genet­ic tests for Per­son­al­ized Med­i­cine.

An emerg­ing focus in new drug devel­op­ment is “Com­pan­ion Diag­nos­tics”. Bio­mark­ers can also be thought of as “Com­pan­ion Diag­nos­tics” because they are the com­pan­ion test for mak­ing per­son­al­ized treat­ment deci­sions. Only 1% of mar­ket­ed drugs cur­rent­ly have ‘Com­pan­ion Diag­nos­tics’. How­ev­er, a 2010 Tufts Cen­ter sur­vey found that 30% of Bio­Phar­ma­ceu­ti­cal Com­pa­nies claim that all their com­pounds in devel­op­ment are required to have a Bio­mark­er link­ing the Diag­no­sis and the Ther­a­peu­tic drug.

For exam­ple, Roche CEO of Mol­e­c­u­lar Diag­nos­tics, Paul Brown states that “The com­pa­ny is very com­mit­ted (man­dat­ed) to mol­e­c­u­lar diag­nos­tics. About 160 projects have a ‘Com­pan­ion Diag­nos­tic’ or Bio­mark­er with a project. Align­ing the stake­hold­er imper­a­tives is an ongo­ing chal­lenge: It’s been very much about get­ting the two R&D pro­grams (Diag­nos­tic and Ther­a­peu­tic) in sync very ear­ly on and get­ting the tech­nol­o­gy in synch with the two arms of the FDA – CDER (the Cen­ter for Drug Eval­u­a­tion and Research) for the drug and CDRH (the Cen­ter for Devices and Radi­o­log­ic Health) for the test”. San Fran­cis­co Busi­ness Times. August 17th, 2011.

Phar­ma­cy Ben­e­fit Man­agers (PBMs) respon­si­ble for pro­cess­ing and pay­ing pre­scrip­tion drug claims and who work with Patients, Insur­ers, Employ­ers and Medicare. CVS and Care­mark are cur­rent­ly eval­u­at­ing at least 8 Genom­ic Test – Treat­ment com­bi­na­tions, includ­ing for War­farin, Hepati­tis C, and mul­ti­ple Can­cers.

Large Insur­ance Com­pa­nies (includ­ing Aet­na, Kaiser Per­ma­nente, Unit­ed Health­care) have begun to include pay­ment for select­ed Mol­e­c­u­lar Tests that iden­ti­fy high risk pop­u­la­tions that guide improved Per­son­al­ized out­comes.

All these stake­hold­ers are explor­ing to “Pay for Per­for­mance” (what works) rather than sim­ply for clin­i­cal ser­vice (with its inad­ver­tent pos­si­ble bias to over-ser­vice).

Pay­ing for what works, is like­ly to become a big dri­ver of the adop­tion of Per­son­al­ized Med­i­cine.

Patent and Legal issues

The rules of patentabil­i­ty of Mol­e­c­u­lar Bio­mark­ers are still being resolved in the U.S. Supreme Court.

The essen­tial prin­ci­ple is that “laws of nature” such as Genes, can­not be patent­ed in the same that “dis­cov­er­ing” a new soft­ware process or device can be.

For those researchers min­ing for Bio­mark­ers that include Mol­e­c­u­lar + Neu­roimag­ing + Cog­ni­tion options, the patentabil­i­ty of new com­bi­na­tion Bio­mark­ers is more assured, since it is not lim­it­ed to await­ing the final out­come of the Gene Patent Conun­drum.

The FDA and Reg­u­la­to­ry Guide­lines

The FDA is refin­ing Draft Guide­lines beyond the 2011 In Vit­ro Com­pan­ion Diag­nos­tics Devices Guide­lines (July 2011).

At the PMWC, Eliz­a­beth Mans­field from the FDA, pre­sent­ed an infor­ma­tive insight into the cur­rent chal­lenges. She appealed to all stake­hold­ers to align expec­ta­tions. She out­lined how the FDA is gen­uine­ly try­ing to bridge the gap between its Drugs (CDER) and Diag­nos­tics (CDRH) Divi­sions to help nav­i­gate Per­son­al­ized Med­i­cine claims. “We are learn­ing by doing”.

The FDA is man­dat­ed to be “Safe­ty first” (rather than “Effi­ca­cy first”). How­ev­er, 33,000 peo­ple in the U.S com­mit­ting sui­cide each year, is fair­ly com­pelling evi­dence that “Effi­ca­cy is Safe­ty”.

What I was told in pri­vate meet­ings with Phar­ma exec­u­tives, was that a dri­ver for Phar­ma adopt­ing Bio­mark­ers and ‘Com­pan­ion Diag­nos­tics’ includes the grow­ing pos­si­bil­i­ty that the FDA is going to make it hard­er to reg­is­ter new drugs with­out objec­tive bio­log­i­cal evi­dence of “who is like­ly to respond”. If true, this could be one of the fastest accel­er­ants of Per­son­al­ized Med­i­cine in Psy­chi­a­try (the “FDA iron hand in a vel­vet glove effect”?).

On the oth­er hand, many Big Phar­ma are pulling out of Psy­chi­a­try drug devel­op­ment because they don’t yet have the Bio­mark­er tar­gets and hence a new niche com­mer­cial mod­el. Psy­chi­a­try is run­ning out of new drugs that work on iden­ti­fi­able cohorts.

Con­clu­sion

Skep­ti­cisms, fears and bias­es about Per­son­al­ized Med­i­cine in Psychiatry’s abil­i­ty to sig­nif­i­cant­ly increase clin­i­cal effi­ca­cy, save costs, fund aca­d­e­mics to dis­cov­er fun­da­men­tal mech­a­nisms and new drugs and Phar­ma to make mon­ey — is evi­dent.

The best anti­dote to this skep­ti­cism is unam­bigu­ous Bio­mark­ers that are clin­i­cal­ly rel­e­vant and scal­able at rea­son­able cost.

Those anti­dotes already exist in Can­cer. But they do not yet exist in the Brain.

The PMWC high­light­ed sev­er­al exam­ples where sequenc­ing the entire Genome is now inevitable for far less than $1,000. Exten­sions of stud­ies to include Neu­roimag­ing and Cir­cuits are becom­ing the inevitable way for­ward. From what I can see emerg­ing out of the Brain Resource Inter­na­tion­al Data­base, stan­dard­iza­tion, Bio­mark­er inte­gra­tion and large stud­ies pro­vide the sta­tis­ti­cal pow­er to find mean­ing­ful end points.

Any Brain-based Bio­mark­er (or Gene+Brain+Cognition+Behavior Com­bi­na­tion) that has greater than 80% sen­si­tiv­i­ty and speci­fici­ty of treat­ment out­come, will dri­ve clin­i­cal util­i­ty from the cur­rent “low base” of pre­dic­tive valid­i­ty.

The con­sumer is being increas­ing­ly empow­ered by Per­son­al­ized Med­i­cine as they par­tic­i­pate with their clin­i­cian in the diag­nos­tic and treat­ment deci­sions and data mon­i­tor­ing of their own out­comes.

How­ev­er, con­sumer empow­er­ment via the web is har­ness­ing a wave of dis­con­tent about “side effects and advents events” from fail­ures of the “block­buster” mod­el that inevitably result­ed in the wrong drug pro­vid­ed to the wrong per­son at the wrong time. More­over, adverse reac­tions to drugs rep­re­sent the sixth lead­ing cause of deaths in hos­pi­tal­ized patients in the U.S. This con­tributes to a lack of com­pli­ance in tak­ing drugs as pre­scribed, which is anoth­er sig­nif­i­cant prob­lem. These inad­ver­tent con­se­quences of “Non-Per­son­al­ized Med­i­cine” have result­ed in the rapid esca­la­tion of “Alter­na­tive Med­i­cine” – that rarely employs repli­cat­ed find­ings of well con­trolled dou­ble blind place­bo con­trol or nat­ur­al ran­dom­ized “com­par­a­tive effec­tive­ness” stud­ies (oth­er than in excep­tion­al cas­es such as Cog­ni­tive Behav­ior Ther­a­py [CBT] stud­ies).

Yet many of these “Alter­na­tive” Brain-based inter­ven­tions, includ­ing CBT, Biofeed­back, Neu­ro­feed­back , TMS (Tran­scra­nial Mag­net­ic Stim­u­la­tion), Exer­cise, Nutri­tion and Sleep inter­ven­tions — show sig­nif­i­cant promise to com­ple­ment Per­son­al­ized Health­care med­ica­tion and treat­ment pro­grams, low­er the med­ica­tion dose required or act as first line alter­na­tives in mild or mod­er­ate cas­es. ‘Com­par­a­tive Effec­tive­ness’ data will ulti­mate­ly be the final arbiter of the most clin­i­cal­ly effec­tive ‘Strat­i­fied Per­son­al­ized Med­i­cine Pro­grams’.

The mul­ti­ple stake­hold­ers list­ed above, are like­ly to con­tin­ue to shape Brain-based Per­son­al­ized Med­i­cine.

The “The tri­umph of mar­ket­ing and over sub­stance” of “Block­buster med­ica­tions” in Psy­chi­a­try and the skep­ti­cism about the like­li­hood and pro­hib­i­tive costs of Per­son­al­ized Med­i­cine seem like­ly pre­vail.

These dynam­ics will only be ful­ly halt­ed and reversed by repli­cat­ed Gene-Brain-Cog­ni­tion-Behav­ior Bio­mark­ers that unam­bigu­ous­ly pre­dict treat­ment response in dis­or­der sub-types, end-points or indi­vid­u­als, with greater than 80% sen­si­tiv­i­ty and 80% speci­fici­ty.

Last but by no means least – pay­ment most com­mon­ly has the biggest impact on what sys­tem is imple­ment­ed in the real world. Pay­ment mod­els in health care have begun to shift from “fee-for-ser­vice” (and pos­si­ble over-ser­vice) to “pay-for-per­for­mance out­comes” which is aligned with the essence of Per­son­al­ized Med­i­cine Bio­mark­ers to pre­dict who is most like­ly to respond to what inter­ven­tion.

The New York Times last month (Jan­u­ary 30th) pub­lished an Opin­ion Arti­cle, in which a pre­dic­tion was made that aligns with “pay-for-per­for­mance” out­comes and Per­son­al­ized Med­i­cine. The arti­cle by Ezekiel Eman­u­al and Jef­frey Lieb­man stat­ed: “Here’s a bold pre­dic­tion for the new year. By 2020, the Amer­i­can health insur­ance indus­try will be extinct. Insur­ance com­pa­nies will be replaced by account­able care orga­ni­za­tions — groups of doc­tors, hos­pi­tals and oth­er health care providers who come togeth­er to pro­vide the full range of med­ical care for patients”. Account­able care orga­ni­za­tions (ACOs) will typ­i­cal­ly be paid a fixed amount per patient, along with bonus­es for achiev­ing qual­i­ty tar­gets. The orga­ni­za­tions will make mon­ey by keep­ing their patients healthy and out of the hos­pi­tal and by avoid­ing unnec­es­sary tests, drugs and pro­ce­dures”.

Per­son­al­ized Med­i­cine is not a panacea. But it will inevitably become a new more objec­tive clin­i­cal par­a­digm adopt­ed by many.

You may want to watch my 15-minute pre­sen­ta­tion at the Per­son­al­ized Med­i­cine World Con­fer­ence (PMWC) at Stan­ford Uni­ver­si­ty on Jan­u­ary 23rd.

———————————————————————————————-

Full Series on Per­son­al­ized Med­i­cine and the Brain:

– Dr Evian Gor­don is the Exec­u­tive Chair­man of theBrain Resource Com­pany.  He ini­tially drew upon  his sci­ence and med­ical back­ground to estab­lish the inter­dis­ci­pli­nary Brain Dynam­ics Cen­ter, in 1986.  Through the Brain Dynam­ics Cen­ter and its col­lab­o­ra­tive net­works, Dr Gor­don estab­lished an “inte­gra­tive neu­ro­science” approach, ground­ed in the use of stan­dard­ized meth­ods across mul­ti­ple types of data. Using this approach, Dr Gor­don found­ed the “Brain Resource Com­pany”, that cre­ated the first inter­na­tional data­base on the human brain. The data­base is the asset which under­pins the devel­op­ment of new tools for brain health and its per­son­al­ized appli­ca­tion in the mar­ket, such as assess­ments of brain health, deci­sion sup­port sys­tems, and per­son­al­ized train­ing pro­grams. Brain Resource has also sup­ported the for­ma­tion of a non-prof­it 501c3 Foun­da­tion, called ‘BRAIN­net” (www.BRAINnet.net), through which sci­en­tists have access to many of these datasets for inde­pen­dent research.

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As seen in The New York Times, The Wall Street Journal, BBC News, CNN, Reuters,  SharpBrains is an independent market research firm tracking how brain science can improve our health and our lives.

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