Working with Healthcare Stakeholders towards Brain-Based Personalized Medicine

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(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.

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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.