A go-go FDA is open­ing up the fast lane to re­gen­er­a­tive med ap­provals

The FDA on Thurs­day launched a new pol­i­cy frame­work for re­gen­er­a­tive med­i­cine, build­ing off a pre­vi­ous frame­work from 2005, as part of ef­forts to bring new cell, stem cell and tis­sue prod­ucts to pa­tients as ef­fi­cient­ly as pos­si­ble while man­ag­ing the pro­lif­er­a­tion of un­scrupu­lous ac­tors hawk­ing un­proven ther­a­pies.

FDA’s an­nounce­ment in­clud­ed the re­lease of two new draft guid­ance doc­u­ments – one on ways to ex­pe­dite ap­provals for re­gen­er­a­tive med­i­cines for se­ri­ous con­di­tions and one on med­ical de­vices used with re­gen­er­a­tive ther­a­pies – and two fi­nal guid­ance doc­u­ments of­fer­ing clar­i­ty on when cell and tis­sue-based prod­ucts would be ex­cept­ed from the reg­u­la­tions and clar­i­fy­ing how the agency in­ter­prets the reg­u­la­to­ry de­f­i­n­i­tions of “min­i­mal ma­nip­u­la­tion” and “ho­mol­o­gous use.”

“We’re adopt­ing a risk-based and sci­ence-based ap­proach that builds up­on ex­ist­ing reg­u­la­tions to sup­port in­no­v­a­tive prod­uct de­vel­op­ment while clar­i­fy­ing the FDA’s au­thor­i­ties and en­force­ment pri­or­i­ties,” FDA Com­mis­sion­er Scott Got­tlieb said in a state­ment. “This will pro­tect pa­tients from prod­ucts that pose po­ten­tial sig­nif­i­cant risks, while ac­cel­er­at­ing ac­cess to safe and ef­fec­tive new ther­a­pies.”

But the new guid­ance doc­u­ments were not re­leased along­side any new warn­ing let­ters or en­force­ment ac­tions against a grow­ing mar­ket of un­ap­proved di­rect-to-con­sumer (DTC) stem cell prod­ucts.

Leigh Turn­er, as­so­ciate pro­fes­sor at the Uni­ver­si­ty of Min­neso­ta Cen­ter for Bioethics and co-au­thor of an ar­ti­cle in Cell about DTC stem cell clin­ics, told Fo­cus that FDA still has yet to crack down on these un­scrupu­lous com­pa­nies prof­it­ing off un­proven treat­ments, not­ing the mar­ket is “quite large, quite ac­tive and there’s been a long time with­out mean­ing­ful over­sight.”

Turn­er took is­sue with a pro­vi­sion in the “min­i­mal ma­nip­u­la­tion” and “ho­mol­o­gous use” fi­nal guid­ance that says FDA will use dis­cre­tion in en­force­ment over the next 36 months. “To me, it’s a mat­ter of what is the en­force­ment ac­tiv­i­ty go­ing to be over that time frame. If it’s a 3-year pe­ri­od where FDA won’t do much, that strikes me as a green light for the in­dus­try” sell­ing un­ap­proved prod­ucts.

“If I ran one of these [DTC stem cell] clin­ics in Flori­da or Cal­i­for­nia, I would see to­day’s ac­tion by FDA to mean busi­ness as usu­al,” he added.

An FDA spokesper­son clar­i­fied to Fo­cus via email, “The FDA does not in­tend to ex­er­cise such en­force­ment dis­cre­tion for those HCT/Ps [hu­man cells, tis­sues, and cel­lu­lar and tis­sue-based prod­ucts] that pose a po­ten­tial sig­nif­i­cant safe­ty con­cern. Go­ing for­ward, the FDA will ap­ply a risk-based ap­proach to en­force­ment tak­ing in­to ac­count how prod­ucts are be­ing ad­min­is­tered as well as the dis­eases and con­di­tions for which they are be­ing used.

“Specif­i­cal­ly, un­der lim­it­ed con­di­tions, when a prod­uct re­quires an in­ves­ti­ga­tion­al new drug ap­pli­ca­tion (IND) or pre­mar­ket ap­proval (bi­o­log­ics li­cense ap­pli­ca­tions or BLAs), the agency in­tends to fo­cus its en­force­ment ac­tions on prod­ucts that pose high­er risks.  For ex­am­ple, ac­tions re­lat­ed to prod­ucts ad­min­is­tered by high­er-risk routes of ad­min­is­tra­tion (e.g., those ad­min­is­tered by in­tra­venous in­jec­tion or in­fu­sion, aerosol in­hala­tion, in­traoc­u­lar in­jec­tion, or in­jec­tion or in­fu­sion in­to the cen­tral ner­vous sys­tem) will be pri­or­i­tized over those as­so­ci­at­ed with a low­er risk (e.g., those ad­min­is­tered by in­tra­der­mal, sub­cu­ta­neous, or in­tra-ar­tic­u­lar in­jec­tion).”

Back­ground

The 21st Cen­tu­ry Cures Act (Cures Act) cre­at­ed what’s known as the Re­gen­er­a­tive Med­i­cine Ad­vanced Ther­a­py (RMAT) des­ig­na­tion (pre­vi­ous­ly known as the RAT des­ig­na­tion), which can be used to speed the re­view of cell ther­a­pies, ther­a­peu­tic tis­sue en­gi­neer­ing prod­ucts, hu­man cell and tis­sue prod­ucts or any com­bi­na­tion prod­uct us­ing such ther­a­pies or prod­ucts.

Pe­ter Marks, di­rec­tor of FDA’s Cen­ter for Bi­o­log­ics Eval­u­a­tion and Re­search (CBER), said on Tues­day that as of last Fri­day, the agency has re­ceived 34 RMAT des­ig­na­tion re­quests, act­ed on 31 re­quests and grant­ed 11 RMAT des­ig­na­tions. Hu­ma­cyte and Veri­cel are two ex­am­ples of com­pa­nies that have al­ready re­ceived the RMAT des­ig­na­tion.

Ad­van­tages of the RMAT des­ig­na­tion in­clude all the ben­e­fits of the fast track and break­through des­ig­na­tions, in­clud­ing ear­ly in­ter­ac­tions be­tween the agency and spon­sors.

But as op­posed to the break­through des­ig­na­tion, the RMAT des­ig­na­tion does not re­quire ev­i­dence to in­di­cate that the drug may of­fer a sub­stan­tial im­prove­ment over avail­able ther­a­pies, ac­cord­ing to one of the draft guid­ances re­leased Thurs­day.

And like break­through des­ig­na­tions, RMAT des­ig­na­tions do not mean the prod­uct will be ap­proved and do not change the statu­to­ry stan­dards for demon­stra­tion of safe­ty and ef­fec­tive­ness need­ed for ap­proval.

In ad­di­tion to cre­at­ing the RMAT, Sec­tion 3034 of the Cures Act al­so man­dates that FDA is­sue guid­ance clar­i­fy­ing how FDA will eval­u­ate de­vices used in the re­cov­ery, iso­la­tion or de­liv­ery of RMATs, which al­so was re­leased on Thurs­day.

Guid­ance and Ex­am­ples

In spelling out how FDA de­ter­mines what should be con­sid­ered for an RMAT des­ig­na­tion, one of the draft guid­ances notes that CBER in­tends to con­sid­er “the rig­or of da­ta col­lec­tion; the na­ture and mean­ing­ful­ness of the out­comes; the num­ber of pa­tients or sub­jects, and the num­ber of sites, con­tribut­ing to the da­ta; and the sever­i­ty, rar­i­ty, or preva­lence of the con­di­tion.”

The draft of­fers two hy­po­thet­i­cal ex­am­ples of pre­lim­i­nary clin­i­cal ev­i­dence that CBER would con­sid­er suf­fi­cient, what an RMAT re­quest should con­tain and con­sid­er­a­tions in clin­i­cal tri­al de­sign.

The oth­er draft guid­ance spec­i­fies that de­vices in­tend­ed for use with a spe­cif­ic RMAT may be con­sid­ered a com­bi­na­tion prod­uct. It al­so ad­dress­es how FDA in­tends to sim­pli­fy and stream­line its ap­pli­ca­tion of reg­u­la­to­ry re­quire­ments for com­bo de­vices and cell or tis­sue prod­ucts; what, if any, in­tend­ed us­es or spe­cif­ic at­trib­ut­es would re­sult in a de­vice used with a re­gen­er­a­tive ther­a­py that would make it a Class III de­vice; fac­tors to con­sid­er in de­ter­min­ing whether a de­vice may be la­beled for use with a spe­cif­ic RMAT or class of RMATs; when a de­vice may be lim­it­ed to a spe­cif­ic in­tend­ed use; and ap­pli­ca­tion of the least bur­den­some ap­proach to demon­strate how a de­vice may be used with more than one cell type.

Both draft guid­ance doc­u­ments will have 90-day com­ment pe­ri­ods.

The two fi­nal guid­ance doc­u­ments to­geth­er su­per­sede a 2014 draft guid­ance re­lat­ed to adi­pose tis­sue and the one on defin­ing ho­mol­o­gous use and min­i­mal ma­nip­u­la­tion fi­nal­izes a draft from De­cem­ber 2014 on min­i­mal ma­nip­u­la­tion of hu­man cells, tis­sues, and cel­lu­lar and tis­sue-based prod­ucts (HCT/Ps) and an­oth­er draft from Oc­to­ber 2015 on the ho­mol­o­gous use of HCT/Ps.

In one fi­nal­ized guid­ance, FDA says, “Ho­mol­o­gous use means the re­pair, re­con­struc­tion, re­place­ment, or sup­ple­men­ta­tion of a re­cip­i­ent’s cells or tis­sues with an HCT/P that per­forms the same ba­sic func­tion or func­tions in the re­cip­i­ent as in the donor. This cri­te­ri­on re­flects the Agency’s con­clu­sion that there would be in­creased safe­ty and ef­fec­tive­ness con­cerns for HCT/Ps that are in­tend­ed for a non-ho­mol­o­gous use, be­cause there is less ba­sis on which to pre­dict the prod­uct’s be­hav­ior, where­as HCT/Ps for ho­mol­o­gous use can rea­son­ably be ex­pect­ed to func­tion ap­pro­pri­ate­ly.”

FDA al­so de­fines “min­i­mal ma­nip­u­la­tion” as: “1) For struc­tur­al tis­sue, pro­cess­ing that does not al­ter the orig­i­nal rel­e­vant char­ac­ter­is­tics of the tis­sue re­lat­ing to the tis­sue’s util­i­ty for re­con­struc­tion, re­pair, or re­place­ment; 2) For cells or non­struc­tur­al tis­sues, pro­cess­ing that does not al­ter the rel­e­vant bi­o­log­i­cal char­ac­ter­is­tics of cells or tis­sues.”

The oth­er guid­ance fi­nal­izes a draft from 2014 and of­fers sev­en ques­tions and an­swers de­scrib­ing which es­tab­lish­ments are not re­quired to com­ply with cer­tain re­quire­ments if they re­move HCT/Ps from an in­di­vid­ual and im­plant them in­to the same in­di­vid­ual dur­ing the same sur­gi­cal pro­ce­dure.

In terms of the ways FDA has adapt­ed its reg­u­la­to­ry mod­el to meet the “rev­o­lu­tion­ary na­ture of the prod­ucts,” Got­tlieb point­ed to the ex­am­ple of “how we’re con­sid­er­ing in­no­v­a­tive tri­al de­signs where­by in­di­vid­ual aca­d­e­m­ic in­ves­ti­ga­tors would fol­low the same man­u­fac­tur­ing pro­to­cols and share com­bined clin­i­cal tri­al da­ta in sup­port of ap­proval from the FDA. This is an in­no­v­a­tive way of mak­ing sure that small in­ves­ti­ga­tors who are work­ing with cells that are be­ing man­u­fac­tured in ways that ren­der them sub­ject to our cur­rent laws and reg­u­la­tions — be­cause the cells are, for ex­am­ple, more than ‘min­i­mal­ly ma­nip­u­lat­ed.’”


First pub­lished here. Reg­u­la­to­ry Fo­cus is the flag­ship on­line pub­li­ca­tion of the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety (RAPS), the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care and re­lat­ed prod­ucts, in­clud­ing med­ical de­vices, phar­ma­ceu­ti­cals, bi­o­log­ics and nu­tri­tion­al prod­ucts. Email news@raps.org for more in­for­ma­tion.

Author

Zachary Brennan

managing editor, RAPS

Eli Lil­ly’s first PhI­II show­down for their $1.6B can­cer drug just flopped — what now?

When Eli Lilly plunked down $1.6 billion in cash to acquire Armo Biosciences a little more than a year ago, the stars seemed aligned in its favor. The jewel in the crown they were buying was pegilodecakin, which had cleared the proof-of-concept stage and was already in a Phase III trial for pancreatic cancer.

And that study just failed.

Lilly reported this morning that their cancer drug flopped on overall survival when added to FOLFOX (folinic acid, 5-FU, oxaliplatin), compared to FOLFOX alone among patients suffering from advanced pancreatic cancer.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 62,300+ biopharma pros reading Endpoints daily — and it's free.

Mi­rati preps its first look at their KRAS G12C con­tender, and they have to clear a high bar for suc­cess

If you’re a big KRAS G12C fan, mark your calendars for October 28 at 4:20 pm EDT.

That’s when Mirati $MRTX will unveil its first peek at the early clinical data available on MRTX849 in presentations at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston.

Mirati has been experiencing the full effect of a rival’s initial success at targeting the G12C pocket found on KRAS, offering the biotech some support on the concept they’re after — and biotech fans a race to the top. Amgen made a big splash with its first positive snapshot on lung cancer, but deflated sky-high expectations as it proved harder to find similar benefits in other types of cancers.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 62,300+ biopharma pros reading Endpoints daily — and it's free.

The FDA will hus­tle up an ex­pe­dit­ed re­view for As­traZeneca’s next shot at a block­buster can­cer drug fran­chise

AstraZeneca paid a hefty price to partner with Daiichi Sankyo on their experimental antibody drug conjugate for HER2 positive breast cancer. And they’ve been rewarded with a fast ride through the FDA, with a straight shot at creating another blockbuster oncology franchise.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 62,300+ biopharma pros reading Endpoints daily — and it's free.

Sean Parker, AP

Sean Park­er helps cre­ate a CRISPRed cell ther­a­py 2.0 play — and he’s got a high-pro­file set of lead­ers on the team

You can rack up one more high-profile debut effort in the wave of activity forming around cell therapy 2.0. It’s another appealing Bay Area group that’s attracted some of the top hands in the business to a multi-year effort to create a breakthrough. And they have $85 million in hand to make that first big step to the clinic.

Today it’s Ken Drazan and the team at South San Francisco-based ArsenalBio that are coming from behind the curtain for a public bow, backed by billionaire Sean Parker and a collection of investors that includes Beth Seidenberg’s new venture investment operation based in LA.
Drazan — a J&J Innovation vet with a long record of entrepreneurial endeavors — exited the stage in 2018 when his last mission ended as he stepped aside as president of Grail. It wasn’t long, though, before he was helping out with a business plan for ArsenalBio that revolved around the work of a large group of interconnected scientists supported by the Parker Institute for Cancer Immunology.
The biotech started by putting together an “arsenal” of technologies aimed at making cell therapies for cancer much, much better than the rather crude first-generation drugs that hit the market from Novartis and Kite.
Their drugs have become the baseline against which all others are being measured.
“The technology set we’re developing is independent of the chassis,” Drazan tells me. “It doesn’t have to be autologous (extracted from the patient) or allogeneic (off the shelf). It doesn’t have to be a T cell, it could be a B cell.” But they are starting out on the autologous side, where they have the most knowledge and insight into manufacturing techniques.
It also doesn’t have to be close to the clinic.
Drazan expects the biotech will be working its way through preclinical operations for “a few years,” with enough money from the $85 million launch round to get into humans.
By today’s superheated fundraising standards, that’s not a huge amount of cash. Lyell, another cell therapy 2.0 startup we featured last week, raised $600 million in a year, including a big chunk of cash from GlaxoSmithKline. Drazan is interested in dealmaking as well, but he also knows he has the cash necessary to support the company for a good run — a key part of what it takes to bring together a stellar team of top players.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 62,300+ biopharma pros reading Endpoints daily — and it's free.

Hal Barron, GSK's president of R&D and CSO, speaks to Endpoints News founder and editor John Carroll in London at Endpoints' #UKBIO19 summit on October 8, 2019

[Video] Cel­e­brat­ing tri­al fail­ures, chang­ing the cul­ture and al­ly­ing with Cal­i­for­nia dream­ers: R&D chief Hal Bar­ron talks about a new era at GSK

Last week I had a chance to sit down with Hal Barron at Endpoints’ #UKBIO19 summit to discuss his views on R&D at GSK, a topic that has been central to his life since he took the top research post close to 2 years ago. During the conversation, Barron talked about changing the culture at GSK, a move that involves several new approaches — one of which involves celebrating their setbacks as they shift resources to the most promising programs in the pipeline. Barron also discussed his new alliances in the Bay Area — including his collaboration pact with Lyell, which we covered here — frankly assesses the pluses and minuses of the UK drug development scene, and talks about his plans for making GSK a much more effective drug developer.

This is one discussion you won’t want to miss. Insider and Enterprise subscribers can log-in to watch the video.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

UCB tries to win some re­spect in the crowd­ed pso­ri­a­sis mar­ket with a dual IL-17 ap­proach — and it won't be easy

For a pharma company with about $5 billion in revenue, a couple of respectably sized blockbuster drugs on the market and some high-profile partners like Amgen, Belgium’s UCB has kept an unusually low profile on the pipeline side of things over the years.
Until now.
Just days after striking a $2.1 billion deal to buy Ra Pharmaceuticals and its C5 rival to Soliris, UCB is posting positive top-line Phase III results for a dual IL-17 inhibitor that it’s steering into one of the most competitive commercial spaces in the industry. And despite plenty of obvious challenges as they struggle to roll out Evenity with Amgen and patent expirations loom on its franchise drugs, including Cimzia, the company just may be ready to tackle some of the biggest players on the planet.
In their first of 3 Phase III studies for bimekizumab, researchers touted top-line wins on statistically significant results on clearing plaque psoriasis, including a victory over J&J’s IL-23 contender Stelara on key endpoints. The drug targets both IL-17A and IL-17F, a modification on the IL-17A strategy laid out for Taltz (Eli Lilly) and Cosentyx (Novartis). And the new group also includes J&J’s Tremfya and AbbVie’s Skyrizi.
We don’t know the PASI90 and IGA scores — but UCB knows that with the kind of heavyweight competition it faces with Novartis and others, marginal gains for patients won’t stack up. So we’ll be watching for the hard numbers. And there’s another head-to-head with Cosentyx that will play a big role in pushing up analysts’ projections on peak sales, which currently fall well short of blockbuster status.
UCB hasn’t exactly been in the spotlight for the last few years, but it’s in a position now that the company has to win some respect in R&D, with blockbuster projects that can keep investors’ attention at a time the industry is experiencing booming R&D development efforts around the planet.
It hasn’t been easy. There was a setback on a lupus drug partnered with Biogen. But there have been some advances, with a deal to buy Proximagen’s NDA-ready nasal spray therapy USL261, designed as a rescue therapy for acute repetitive seizures, for $150 million in cash and another $220 million in sales and regulatory milestones. There was even a report that the company was kicking the deflated tires at Acorda, though nothing came of that.
Late last year UCB also committed to spend up to £200 million on a new R&D hub in the UK.
That may not translate into a lot of excitement right now, but they’re trying. And there’s a subtle promise that more deals may be in the works.

Med­ical an­i­ma­tion: Mak­ing it eas­i­er for the site and the pa­tient to un­der­stand

Medical animation has in recent years become an increasingly important tool for conveying niche information to a varied audience, particularly to those audiences without expertise in the specialist area. Science programmes today, for example, have moved from the piece-to-camera of the university professor explaining how a complex disease mechanism works, to actually showing the viewer first-hand what it might look like to shrink ourselves down to the size of an ant’s foot, and travel inside the human body to witness these processes in action. Effectively communicating a complex disease pathophysiology, or the novel mechanism of action of a new drug, can be complex. This is especially difficult when the audience domain knowledge is limited or non-existent. Medical animation can help with this communication challenge in several ways.
Improved accessibility to visualisation
Visualisation is a core component of our ability to understand a concept. Ask 10 people to visualise an apple, and each will come up with a slightly different image, some apples smaller than others, some more round, some with bites taken. Acceptable, you say, we can move on to the next part of the story. Now ask 10 people to visualise how HIV’s capsid protein gets arranged into the hexamers and pentamers that form the viral capsid that holds HIV’s genetic material. This request may pose a challenge even to someone with some virology knowledge, and it is that inability to effectively visualise what is going on that holds us back from fully understanding the rest of the story. So how does medical animation help us to overcome this visualisation challenge?

Swamy Vijayan. Plexium

San Diego up­start de­buts dis­cov­ery en­gine that puts a twist to pro­tein degra­da­tion

For years, the idea of protein degradation — utilizing the cell’s natural garbage disposal system to mark problematic proteins for destruction — remained an elegant but technically difficult concept. But now established as a promising clinical strategy, with major biopharma players such as Bayer, Gilead and Vertex trying to grab a foothold via partnership deals, a San Diego startup is looking to exploit it and push its limits.

CSL ac­cus­es ri­val Pharm­ing of par­tic­i­pat­ing in a scheme to rip off IP on HAE while re­cruit­ing se­nior R&D staffer

Pharming has landed in the middle of a legal donnybrook after recruiting a senior executive from a rival R&D team at CSL. The Australian pharma giant slapped Pharming with a lawsuit alleging that the Dutch biotech’s new employee, Joseph Chiao, looted a large cache of proprietary documents as he hit the exit. And they want it all back.
Federal Judge Juan Sanchez in the Eastern District Pennsylvania court issued an injunction on Tuesday prohibiting Chiao from doing any work on HAE or primary immune deficiency in his new job and demanding that he return any material from CSL that he may have in his possession. And he wants Pharming to tell its employees not to ask for any information on the forbidden topics.
For its part, Pharming fired off an indignant response this morning denying any involvement in extracting any kind of IP from CSL, adding that it’s cooperating in the internal probe that CSL has underway.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 62,300+ biopharma pros reading Endpoints daily — and it's free.