Stem cell clin­ics fac­ing rough weather

Stem cell ther­a­pies may of­fer the po­ten­tial to treat dis­eases or con­di­tions for which few treat­ments ex­ist. Some­times called the body’s “mas­ter cells,” stem cells are the cells that de­velop into blood, brain, bones, and all of the body’s or­gans. They have

BioSpectrum (Asia) - - Bio Content - Narayan Kulka­rni narayan.kulka­rni@mmac­tiv.com

The U.S. Food and Drug Ad­min­is­tra­tion (US FDA), in two com­plaints filed on May 9, in fed­eral court, is seek­ing per­ma­nent in­junc­tions to stop two stem cell clin­ics from mar­ket­ing stem cell prod­ucts with­out its ap­proval and for sig­nif­i­cant de­vi­a­tions from cur­rent good man­u­fac­tur­ing prac­tice re­quire­ments.

“Cell-based re­gen­er­a­tive medicine holds sig­nif­i­cant med­i­cal op­por­tu­nity, but we’ve also seen some bad ac­tors lever­age the sci­en­tific prom­ise of this field to ped­dle un­ap­proved treat­ments that put pa­tients’ health at risk. In some in­stances, pa­tients have suf­fered se­ri­ous and per­ma­nent harm af­ter re­ceiv­ing these un­ap­proved prod­ucts. In the two cases filed on May 9, the clin­ics and their lead­er­ship have con­tin­ued to dis­re­gard the law and more im­por­tantly, pa­tient safety. We can­not al­low un­proven prod­ucts that ex­ploit the hope of pa­tients and their loved ones,” said FDA Com­mis­sioner Scott Got­tlieb, M.D. “We sup­port sound, sci­en­tific re­search and reg­u­la­tion of cell-based re­gen­er­a­tive medicine, and the FDA has ad­vanced a com­pre­hen­sive pol­icy

frame­work to pro­mote the ap­proval of re­gen­er­a­tive medicine prod­ucts. But at the same time, the FDA will con­tinue to take en­force­ment ac­tions against clin­ics that abuse the trust of pa­tients and en­dan­ger their health with in­ad­e­quate man­u­fac­tur­ing con­di­tions or by pur­port­ing to have treat­ments that are be­ing man­u­fac­tured and used in ways that make them drugs un­der the ex­ist­ing law but have not been proven safe or ef­fec­tive for any use.”

A per­ma­nent in­junc­tion is be­ing sought against US Stem Cell Clinic LLC of Sun­rise, Florida, its Chief Sci­en­tific Of­fi­cer Kristin Comella and its co-owner and managing of­fi­cer Theodore Gradel for mar­ket­ing to pa­tients stem cell prod­ucts with­out FDA ap­proval and while vi­o­lat­ing cur­rent good man­u­fac­tur­ing prac­tice re­quire­ments, in­clud­ing some that could im­pact the steril­ity of their prod­ucts, putting pa­tients at risk. The FDA is tak­ing this action be­cause US Stem Cell Clinic did not ad­dress the vi­o­la­tions out­lined in a warn­ing let­ter to the clinic and failed to come into com­pli­ance with the law. The FDA is seek­ing an or­der of per­ma­nent in­junc­tion re­quir­ing US Stem Cell and the in­di­vid­ual de­fen­dants to cease mar­ket­ing their stem cell prod­ucts un­til, among other things, they ob­tain nec­es­sary FDA ap­provals and cor­rect their vi­o­la­tions of cur­rent good man­u­fac­tur­ing prac­tice re­quire­ments.

The FDA is also seek­ing a per­ma­nent in­junc­tion to stop Cal­i­for­nia Stem Cell Treat­ment Cen­ter Inc., with lo­ca­tions in Ran­cho Mi­rage and Bev­erly Hills, Cal­i­for­nia; Cell Sur­gi­cal Network Cor­po­ra­tion of Ran­cho Mi­rage, Cal­i­for­nia; and El­liot B. Lan­der, M.D. and Mark Ber­man, M.D., from mar­ket­ing to pa­tients stem cell prod­ucts with­out FDA ap­proval. Ber­man and Lan­der con­trol the op­er­a­tions of ap­prox­i­mately 100 for-profit af­fil­i­ate clin­ics, in­clud­ing the Cal­i­for­nia Stem Cell Treat­ment Cen­ter. The FDA is seek­ing an or­der of per­ma­nent in­junc­tion re­quir­ing Cal­i­for­nia Stem Cell Treat­ment Cen­ter Inc. and Cell Sur­gi­cal Network Cor­po­ra­tion and the in­di­vid­ual de­fen­dants to cease mar­ket­ing their stem cell prod­ucts un­til, among other things, they ob­tain nec­es­sary FDA ap­provals and cor­rect their vi­o­la­tions of cur­rent good man­u­fac­tur­ing prac­tice re­quire­ments.

US Stem Cell Clinic

The FDA is­sued a warn­ing let­ter to US Stem Cell Clinic in Au­gust 2017 for mar­ket­ing stem cell prod­ucts with­out FDA ap­proval and for sig­nif­i­cant de­vi­a­tions from cur­rent good man­u­fac­tur­ing prac­tice re­quire­ments, in­clud­ing some that could im­pact the steril­ity of their prod­ucts. The warn­ing let­ter also cited an FDA inspection of the clinic which found that it was pro­cess­ing adi­pose tis­sue (body fat) into stro­mal vas­cu­lar frac­tion (a cel­lu­lar prod­uct de­rived from body fat) and ad­min­is­ter­ing the prod­uct both in­tra­venously or di­rectly into the spinal cord of pa­tients to treat a va­ri­ety of se­ri­ous dis­eases or con­di­tions, in­clud­ing Parkin­son’s disease, amy­otrophic lat­eral scle­ro­sis (ALS), chronic ob­struc­tive pul­monary disease (COPD), heart disease and pul­monary fi­bro­sis. The FDA has not ap­proved any bi­o­log­i­cal prod­ucts man­u­fac­tured by US Stem Cell Clinic for any use.

Dur­ing the inspection of US Stem Cell Clinic in April and May 2017, FDA in­ves­ti­ga­tors also doc­u­mented ev­i­dence of sig­nif­i­cant de­vi­a­tions from cur­rent good man­u­fac­tur­ing prac­tices in the man­u­fac­ture of at least 256 lots of stem cell prod­ucts by the clinic. For ex­am­ple, the clinic was cited for its fail­ure to es­tab­lish and fol­low ap­pro­pri­ate writ­ten pro­ce­dures de­signed to pre­vent mi­cro­bi­o­log­i­cal con­tam­i­na­tion of prod­ucts pur­port­ing to be ster­ile, which puts pa­tients at risk for in­fec­tions.

The com­plaint for per­ma­nent in­junc­tion against US Stem Cell Clinic was filed by the U.S. Depart­ment of Jus­tice on be­half of the FDA in the US. District Court for the South­ern District of Florida.

Cal­i­for­nia Stem Cell Treat­ment Cen­ter and Cell Sur­gi­cal Network Cor­po­ra­tion

In Au­gust 2017, the FDA took action to pre­vent the use of a po­ten­tially dan­ger­ous and un­proven treat­ment be­long­ing to StemIm­mune Inc. in San Diego, Cal­i­for­nia and ad­min­is­tered to pa­tients at the Cal­i­for­nia Stem Cell Treat­ment Cen­ters in Ran­cho Mi­rage and Bev­erly Hills. On be­half of the FDA, the U.S. Mar­shals Ser­vice seized five vials of Vac­cinia Virus Vac­cine (Live) – a vac­cine that is re­served only for peo­ple at high risk for small­pox, such as some mem­bers of the U.S. mil­i­tary. The seizure came af­ter FDA in­spec­tions at StemIm­mune and the Cal­i­for­nia Stem Cell Treat­ment Cen­ters con­firmed that the vac­cine was used to cre­ate an un­ap­proved stem cell prod­uct (a com­bi­na­tion of ex­cess amounts of vac­cine and stro­mal vas­cu­lar frac­tion – a cel­lu­lar prod­uct de­rived from body fat). The prod­uct was then ad­min­is­tered to cancer pa­tients with po­ten­tially com­pro­mised im­mune sys­tems and for whom the vac­cine posed a po­ten­tial for harm, in­clud­ing the pos­si­bil­ity of in­flam­ma­tion and swelling of the heart and sur­round­ing tis­sues. The un­proven and po­ten­tially dan­ger­ous treat­ment was be­ing in­jected in­tra­venously and di­rectly into pa­tients’ tu­mors.

Cal­i­for­nia Stem Cell Treat­ment Cen­ter prod­ucts are also be­ing used for the ex­per­i­men­tal treat­ment of pa­tients who suf­fer from a va­ri­ety of se­ri­ous dis­eases or con­di­tions, in­clud­ing cancer, arthri­tis, stroke, amy­otrophic lat­eral scle­ro­sis (ALS), mul­ti­ple scle­ro­sis (MS), mac­u­lar de­gen­er­a­tion, Parkin­son’s disease, chronic ob­struc­tive pul­monary disease (COPD) and di­a­betes. The FDA has not ap­proved any bi­o­log­i­cal prod­ucts man­u­fac­tured by Cal­i­for­nia Stem Cell Treat­ment Cen­ter for any use.

Dur­ing in­spec­tions of Cal­i­for­nia Stem Cell Treat­ment Cen­ter’s Bev­erly Hills and Ran­cho Mi­rage fa­cil­i­ties in July 2017, FDA in­ves­ti­ga­tors doc­u­mented, among other vi­o­la­tions, ev­i­dence of sig­nif­i­cant de­vi­a­tions from cur­rent good man­u­fac­tur­ing prac­tice re­quire­ments. For ex­am­ple, the clin­ics were cited for fail­ing to es­tab­lish and fol­low ap­pro­pri­ate writ­ten pro­ce­dures de­signed to pre­vent mi­cro­bi­o­log­i­cal con­tam­i­na­tion of prod­ucts pur­port­ing to be ster­ile, which puts pa­tients at risk for in­fec­tions.

The com­plaint for per­ma­nent in­junc­tion was filed

by the U.S. Depart­ment of Jus­tice on be­half of the FDA in the U.S. District Court for the Cen­tral District of Cal­i­for­nia.

These cases sup­port the FDA’s com­pre­hen­sive pol­icy frame­work for the de­vel­op­ment and over­sight of re­gen­er­a­tive medicine prod­ucts, in­clud­ing novel cel­lu­lar ther­a­pies. The FDA is­sued four guid­ance doc­u­ments in Novem­ber 2017, two fi­nal and two draft that build upon the FDA’s ex­ist­ing risk-based reg­u­la­tory ap­proach. Un­der this frame­work the FDA de­tailed its ef­fi­cient, sci­ence-based process for help­ing to en­sure the safety and ef­fec­tive­ness of these ther­a­pies, while sup­port­ing de­vel­op­ment in this area. One of the two draft guid­ance doc­u­ments laid out a novel and ef­fi­cient clin­i­cal de­vel­op­ment model by which promis­ing cell-based prod­ucts could pur­sue re­view and ap­proval by the FDA. The suite of guid­ance doc­u­ments also de­scribes a risk-based frame­work for how the FDA in­tends to fo­cus its en­force­ment ac­tions against those prod­ucts that raise re­ported safety concerns or po­ten­tial sig­nif­i­cant safety concerns.

ISSCR ap­plauds Fed­eral in­junc­tions

Pleased with fed­eral in­junc­tions against the stem cell clin­ics, the In­ter­na­tional So­ci­ety for Stem Cell Re­search (ISSCR), with more than 4,000 mem­bers from over 60 coun­tries, states that fed­eral prose­cu­tors in the U.S. have taken action to halt the mar­ket­ing and delivery of un­proven stem cell treat­ments at clin­ics they al­lege are op­er­at­ing out­side of FDA reg­u­la­tion.

ISSCR in a re­lease notes that ac­cord­ing to court fil­ings an­nounced by the Depart­ment of Jus­tice and the FDA, these clin­ics have been of­fer­ing stem cell in­ter­ven­tions whose safety and ef­fec­tive­ness have not been es­tab­lished in clin­i­cal tri­als, nor have they gone through the FDA ap­proval process. If true, these clin­ics put pa­tients at un­known risk, and elude reg­u­la­tory author­ity. A num­ber of Amer­i­cans have al­ready been blinded or par­a­lyzed from un­proven stem cell treat­ments, some of which were mar­keted in a way that caused pa­tients to be­lieve they were par­tic­i­pat­ing in le­git­i­mate clin­i­cal tri­als.

“Hold­ing clin­ics re­spon­si­ble for vi­o­lat­ing reg­u­la­tions will put oth­ers on no­tice that they can no longer op­er­ate out­side the Com­pre­hen­sive Re­gen­er­a­tive Medicine Pol­icy Frame­work set forth by the FDA last year,” says ISSCR pres­i­dent Hans Clevers. “We’re pleased that the FDA is en­forc­ing these guide­lines, and hope this le­gal action will send a firm mes­sage to the many rogue clin­ics ped­al­ing un­proven stem cell in­ter­ven­tions that they are not above the law,” he said.

The ISSCR has long been con­cerned with the pro­lif­er­a­tion of clin­ics of­fer­ing stem cell in­ter­ven­tions

that have lit­tle ba­sis in sci­ence or medicine and that prey upon the hopes of des­per­ate pa­tients. The or­ga­ni­za­tion of­fers its as­sis­tance and sci­en­tific ex­per­tise to gov­ern­ments and reg­u­la­tory au­thor­i­ties world­wide as they try to cur­tail this prob­lem.

ISCT pro­poses wider action

Re­act­ing to the US FDA action on seek­ing court or­ders pre­vent­ing two US stem cell clin­ics ad­min­is­ter­ing un­proven cel­lu­lar ther­apy treat­ments to pa­tients, Vancouver based In­ter­na­tional So­ci­ety Cell and Gene Ther­apy (ISCT), the global pro­fes­sional so­ci­ety of clin­i­cians, re­searchers, reg­u­la­tory spe­cial­ists, tech­nol­o­gists and in­dus­try part­ners in the cell and gene ther­apy sec­tor, says “The most re­cent FDA ac­tions high­light to the en­tire cell ther­apy com­mu­nity that the Un­proven Cel­lu­lar Ther­a­pies (UCT), busi­ness stretches across the globe, not just in spe­cific re­gions where reg­u­la­tions are less tight.”

Dr. Mas­simo Do­minici, chair of the ISCT Pres­i­den­tial Task Force (PTF) on the Use of Un­proven Cel­lu­lar Ther­a­pies and pro­fes­sor of on­col­ogy at the Univer­sity of Mo­dena and Reg­gio Emilia, Italy says, “It is vi­tal that reg­u­la­tors, as re­cently demon­strated by the FDA, con­tinue to iden­tify and shut down clin­ics con­duct­ing un­proven and po­ten­tially harm­ful cel­lu­lar in­ter­ven­tions. How­ever, all rep­re­sen­ta­tives of the ISCT Pres­i­den­tial Task Force agree that the job can­not be left to reg­u­la­tors only. There is no magic bul­let for UCT with com­plex chal­lenges. Pa­tients af­fected by dis­eases with a high-un­met med­i­cal need have few op­tions. It is up to the cell ther­apy com­mu­nity to col­lec­tively drive more ther­a­pies through ap­proval, re­duce costs through in­no­va­tive de­vel­op­ment and man­u­fac­tur­ing strate­gies and ed­u­cate the pub­lic and pa­tients about the dan­gers of un­proven cel­lu­lar ther­apy. As a re­sult, ISCT will con­tinue to co­or­di­nate global in­ter­dis­ci­pli­nary ef­forts to im­ple­ment these longer-term so­lu­tions.”

ISCT noted that it has for a num­ber of years been bring­ing groups to­gether span­ning the in­ter­na­tional cell and gene ther­apy com­mu­nity, in­clud­ing col­lab­o­ra­tions with more than 30 sci­en­tific so­ci­eties and in­sti­tu­tions, to lead and co­or­di­nate di­rect action to com­bat and raise aware­ness about un­eth­i­cal and un­proven cel­lu­lar ther­a­pies. It first dis­cussed un­proven cell ther­a­pies with the FDA in 2012. Di­rect action has ranged from es­tab­lish­ing a mul­ti­lat­eral task force, im­ple­ment­ing a long term pro­gram of reg­u­la­tory har­mo­niza­tion, to pub­lish­ing a ref­er­ence guide, trans­lated in six lan­guages, au­thored by 23 lead­ing fig­ures in the field, for the pa­tient com­mu­nity.

“Cell and gene ther­a­pies are ad­dress­ing a va­ri­ety of cur­rently un­met med­i­cal needs. Sev­eral prod­ucts have been ap­proved af­ter demon­stra­tion of safety and clin­i­cal ef­fi­cacy. Many more are cur­rently pro­gress­ing through clin­i­cal de­vel­op­ment. How­ever, clin­ics of­fer­ing po­ten­tially dan­ger­ous un­proven cell ther­a­pies present a sig­nif­i­cant risk of erod­ing pub­lic con­fi­dence in our new, emerg­ing field,” says John Rasko, Pres­i­dent, ISCT and Head, Cell & Molec­u­lar Ther­a­pies, RPA Hospi­tal, Syd­ney, Aus­tralia. “The FDA action, and wider col­lab­o­ra­tions at the ISCT An­nual Meet­ing in May, have re­in­forced the need for ISCT and its mem­bers num­ber­ing over 1,500 across 50 coun­tries to con­tinue on its mis­sion of pro­mot­ing the de­vel­op­ment of, and ac­cess to, prop­erly man­u­fac­tured and doc­u­mented cell and gene ther­a­pies to pa­tients. As these ap­proved ther­a­pies are de­liv­ered, this will ul­ti­mately re­duce the de­mand for un­proven treat­ments.”

Ac­cord­ing to a re­port au­thored by Paul Knoepfler, In­sti­tute of Pe­di­atric Re­gen­er­a­tive Medicine, Shriners Hospi­tal for Chil­dren North­ern Cal­i­for­nia, Sacramento, and Leigh Turner and Cen­ter for Bioethics, School of Pub­lic Health, & Col­lege of Phar­macy, Univer­sity of Min­nesota and pub­lished on Jan 12, 2018 hun­dreds of busi­nesses in the US cur­rently ad­ver­tise a wide range of non-US FDA-ap­proved stem cell in­ter­ven­tions. Be­tween 2009 and 2014, the num­ber of new US stem cell busi­nesses with web­sites grew rapidly, at least dou­bling on av­er­age ev­ery year. From 2014 to 2016, ap­prox­i­mately 90-100 new stem cell busi­ness web­sites ap­peared per year. More than 700 stem cell mar­keters were op­er­at­ing in the US.

In con­trast, from 2012 to the present, reg­u­la­tory ac­tiv­ity in the form of FDA warn­ing let­ters has been lim­ited. These data point to a prob­lem­atic dis­con­nect be­tween a rapidly ex­pand­ing US di­rect-to-con­sumer stem cell in­dus­try and lim­ited FDA over­sight of this mar­ket­place. More con­sis­tent, timely and ef­fec­tive FDA ac­tions are ur­gently needed.

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