FDA lays down the law on gene ther­a­py, of­fer­ing guid­ances on both dis­eases and pro­ce­dures

As first an­nounced in Jan­u­ary, the FDA’s Cen­ter for Bi­o­log­ics Eval­u­a­tion and Re­search (CBER) on Wednes­day of­fered a swath of new draft guid­ance doc­u­ments on hu­man gene ther­a­pies — of­fer­ing a look at what it ex­pects from an in­dus­try that’s be­gin­ning to take off.

The six guid­ance doc­u­ments fo­cus on de­vel­op­ing he­mo­phil­ia, rare dis­ease and reti­nal dis­or­der gene ther­a­pies, and in­clude one on chem­istry, man­u­fac­tur­ing and con­trol (CMC) in­for­ma­tion, one on long term fol­low-up ob­ser­va­tion­al stud­ies col­lect­ing da­ta on ad­verse events and one on the test­ing of retro­vi­ral vec­tor-based ther­a­pies.

Last De­cem­ber, the FDA ap­proved a new gene ther­a­py, priced at $850,000, from Spark Ther­a­peu­tics for the treat­ment of chil­dren and adult pa­tients with an in­her­it­ed form of vi­sion loss that may re­sult in blind­ness. And back in 2016, FDA be­gan to see the num­ber of gene and cell ther­a­py ap­pli­ca­tions spike.

Last No­vem­ber, the FDA al­so an­nounced its pol­i­cy frame­work for re­gen­er­a­tive med­i­cine, in­clud­ing a draft guid­ance that de­scribes the ex­pe­dit­ed pro­grams, such as the break­through ther­a­py des­ig­na­tion, and the re­gen­er­a­tive med­i­cine ad­vanced ther­a­py (RMAT)  des­ig­na­tion, that may be avail­able to spon­sors of these ther­a­pies. Com­pa­nies have al­ready weighed in on such guid­ance.

(Links to guid­ance doc­u­ments are in head­ers be­low).

He­mo­phil­ia

The 15-page draft guid­ance pro­vides rec­om­men­da­tions on the clin­i­cal tri­al de­sign and re­lat­ed de­vel­op­ment of co­ag­u­la­tion fac­tor VI­II (he­mo­phil­ia A) and IX (he­mo­phil­ia B) ac­tiv­i­ty as­says, in­clud­ing how to ad­dress dis­crep­an­cies in fac­tor VI­II and fac­tor IX ac­tiv­i­ty as­says.

The draft guid­ance al­so in­cludes rec­om­men­da­tions re­gard­ing pre­clin­i­cal and clin­i­cal con­sid­er­a­tions to sup­port de­vel­op­ment of he­mo­phil­ia gene ther­a­pies (GTs), as well as in­for­ma­tion on ex­pe­dit­ed pro­grams and com­mu­ni­ca­tion with the FDA.

Rare Dis­ease

This 14-page draft guid­ance pro­vides rec­om­men­da­tions on de­vel­op­ing a GT prod­uct in­tend­ed to treat a rare dis­ease in adult and/or pe­di­atric pa­tients. The guid­ance re­lates to the man­u­fac­tur­ing, pre­clin­i­cal, and clin­i­cal tri­al de­sign is­sues for all phas­es of the clin­i­cal de­vel­op­ment pro­gram.

“Such in­for­ma­tion is in­tend­ed to as­sist spon­sors in de­sign­ing clin­i­cal de­vel­op­ment pro­grams for such prod­ucts, where there may be lim­it­ed study pop­u­la­tion size and po­ten­tial fea­si­bil­i­ty and safe­ty is­sues as well as is­sues re­lat­ing to the in­ter­pretabil­i­ty of bioac­tiv­i­ty/ef­fi­ca­cy out­comes that may be unique to rare dis­eases or to the na­ture of the GT prod­uct it­self,” the FDA said.

Reti­nal Dis­or­ders

This 13-page draft guid­ance pro­vides rec­om­men­da­tions to stake­hold­ers de­vel­op­ing GTs for reti­nal dis­or­ders af­fect­ing adult and pe­di­atric pa­tients. The fo­cus per­tains to is­sues spe­cif­ic to GT prod­ucts for reti­nal dis­or­ders and pro­vides rec­om­men­da­tions re­lat­ed to prod­uct de­vel­op­ment, pre­clin­i­cal test­ing and clin­i­cal tri­al de­sign.

CMC

This 54-page draft guid­ance pro­vides spon­sors of a GT in­ves­ti­ga­tion­al new drug ap­pli­ca­tion (IND) with rec­om­men­da­tions re­gard­ing CMC in­for­ma­tion re­quired to as­sure prod­uct safe­ty, iden­ti­ty, qual­i­ty, pu­ri­ty and strength (in­clud­ing po­ten­cy) of the in­ves­ti­ga­tion­al prod­uct.

The draft ap­plies to GTs and to com­bi­na­tion prod­ucts that con­tain a hu­man gene ther­a­py in com­bi­na­tion with a drug or de­vice.

“The field of gene ther­a­py has pro­gressed rapid­ly since FDA is­sued the April 2008 guid­ance. There­fore, FDA is up­dat­ing the guid­ance to pro­vide cur­rent FDA rec­om­men­da­tions re­gard­ing the CMC con­tent of a gene ther­a­py IND,” the FDA said.

When fi­nal­ized, the draft is in­tend­ed to su­per­sede the doc­u­ment en­ti­tled “Guid­ance for FDA Re­view­ers and Spon­sors: Con­tent and Re­view of Chem­istry, Man­u­fac­tur­ing, and Con­trol (CMC) In­for­ma­tion for Hu­man Gene Ther­a­py In­ves­ti­ga­tion­al New Drug Ap­pli­ca­tions (INDs),” from April 2008.

Long Term Fol­low-Up

This 36-page draft guid­ance pro­vides spon­sors with rec­om­men­da­tions re­gard­ing the de­sign of pro­to­cols for long term fol­low-up ob­ser­va­tion­al stud­ies for the col­lec­tion of da­ta on de­layed ad­verse events fol­low­ing the ad­min­is­tra­tion of a GT.

When fi­nal­ized, the draft is in­tend­ed to su­per­sede the doc­u­ment en­ti­tled “Guid­ance for In­dus­try: Gene Ther­a­py Clin­i­cal Tri­als–Ob­serv­ing Par­tic­i­pants for De­layed Ad­verse Events” from No­vem­ber 2006. This draft, when fi­nal­ized, is al­so in­tend­ed to sup­ple­ment the guid­ance dis­cussed be­low.

Test­ing of Retro­vi­ral Vec­tor-Based Hu­man Gene Ther­a­pies

This 16-page draft pro­vides spon­sors of retro­vi­ral vec­tor-based hu­man GTs with rec­om­men­da­tions re­gard­ing the test­ing for repli­ca­tion com­pe­tent retro­virus (RCR) dur­ing the man­u­fac­ture of retro­vi­ral vec­tor-based prod­ucts, and dur­ing fol­low-up mon­i­tor­ing of pa­tients who have re­ceived retro­vi­ral vec­tor-based prod­ucts.

“Rec­om­men­da­tions in­clude the iden­ti­fi­ca­tion and amount of ma­te­r­i­al to be test­ed, and gen­er­al test­ing meth­ods,” the FDA said. “In ad­di­tion, rec­om­men­da­tions are pro­vid­ed on mon­i­tor­ing pa­tients for ev­i­dence of retro­vi­ral in­fec­tion af­ter ad­min­is­tra­tion of retro­vi­ral vec­tor-based gene ther­a­py prod­ucts.”

When fi­nal­ized, the draft is in­tend­ed to su­per­sede the doc­u­ment en­ti­tled “Guid­ance for In­dus­try: Sup­ple­men­tal Guid­ance on Test­ing for Repli­ca­tion Com­pe­tent Retro­virus in Retro­vi­ral Vec­tor Based Gene Ther­a­py Prod­ucts and Dur­ing Fol­low-up of Pa­tients in Clin­i­cal Tri­als Us­ing Retro­vi­ral Vec­tors,” from No­vem­ber 2006.

The draft guid­ance, when fi­nal­ized, is al­so in­tend­ed to sup­ple­ment the long term fol­low-up and CMC guid­ance doc­u­ments dis­cussed above.


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

Brian Kaspar. AveXis via Twitter

AveX­is sci­en­tif­ic founder fires back at No­var­tis CEO Vas Narasimhan, 'cat­e­gor­i­cal­ly de­nies any wrong­do­ing'

Brian Kaspar’s head was among the first to roll at Novartis after company execs became aware of the fact that manipulated data had been included in its application for Zolgensma, now the world’s most expensive therapy.

But in his first public response, the scientific founder at AveXis — acquired by Novartis for $8.7 billion — is firing back. And he says that not only was he not involved in any wrongdoing, he’s ready to defend his name as needed.

I reached out to Brian Kaspar after Novartis put out word that he and his brother Allen had been axed in mid-May, two months after the company became aware of the allegations related to manipulated data. His response came back through his attorneys.

Endpoints News

Basic subscription required

Unlock this story instantly and join 57,700+ biopharma pros reading Endpoints daily — and it's free.

We­bi­nar: Re­al World End­points — the brave new world com­ing in build­ing fran­chise ther­a­pies

Several biopharma companies have been working on expanding drug labels through the use of real world endpoints, combing through the data to find evidence of a drug’s efficacy for particular indications. But we’ve just begun. Real World Evidence is becoming an important part of every clinical development plan, in the soup-through-nuts approach used in building franchises.

I’ve recruited a panel of 3 top experts in the field — the first in a series of premium webinars — to look at the practical realities governing what can be done today, and where this is headed over the next few years, at the prodding of the FDA.


ZHEN SU — Merck Serono’s Senior Vice President and Global Head of Oncology


ELLIOTT LEVY — Amgen’s Senior Vice President of Global Development


CHRIS BOSHOFF — Pfizer Oncology’s Chief Development Officer

A premium subscription to Endpoints News is required to attend this webinar. Please upgrade to either an Insider or Enterprise plan for access. Already have Endpoints Premium? Please sign-in below. You can contact our Subscriptions team at help@endpointsnews.com with any issues.

Endpoints Premium

Premium subscription required

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

UP­DAT­ED: Pay­back? An­a­lysts say Sarep­ta was blind­sided by an FDA re­jec­tion dri­ven by reg­u­la­to­ry re­venge

In one of the least anticipated moves of the year, the FDA has rejected Sarepta’s application for an accelerated approval of its Duchenne MD drug golodirsen after fretting over safety issues.

In a statement that arrived after the bell on Monday, Sarepta explained the CRL, saying:

Endpoints News

Basic subscription required

Unlock this story instantly and join 57,700+ biopharma pros reading Endpoints daily — and it's free.

FDA de­ci­sion on Ver­tex's CF triple will come just ahead of planned CEO shake­up

Vertex has clinched a priority review for the all-important cystic fibrosis triple that will blaze the trail for treating a large group of patients unhelped by its current drugs.

FDA regulators have set a PDUFA date of March 19, 2020, just a year after the Boston biotech posted positive Phase III results showing that people with two F508del mutations experienced statistically significant improvements in lung function after a 4-week regimen of VX-445, tezacaftor and ivacaftor. After reviewing 24-week data among patients with one F508del mutation and one minimal function mutation — and thoroughly comparing the VX-445 triple with another combo featuring VX-659 on scores like safety, drug-drug interactions, and photosensitivity — Vertex ultimately went with VX-445.

An MIT spin­out kills one of its ‘liv­ing ther­a­peu­tics’ af­ter flunk­ing an ear­ly-stage study — shares rout­ed

Just a few weeks after bagging $80 million in a deal to collaborate with Gingko Bioworks on its special blend of engineered bacteria used for “living therapeutics,” little Synlogic in Boston $SYBX is tossing one of its two clinical programs after watching an early-stage study go down in defeat.

Their Phase Ib/IIa study for SYNB1020 to counter the accumulation of ammonia in the body, a condition called hyperammonemia or urea cycle disorder, floundered at the interim readout, forcing the biotech to kill it and reserve its cash for pipeline therapies with greater potential.

Elan­co to buy Bay­er's an­i­mal health busi­ness for $7.6B, as deal­mak­ing gath­ers steam in the sec­tor

Last week, Elanco explicitly dodged answering questions about its rumored interest in Bayer’s animal health business in its post-earnings call. On Tuesday, the Eli Lilly spinoff disclosed it was purchasing the German drug maker’s veterinary unit in a cash-and-stock deal worth $7.6 billion. 

Elanco $ELAN has been busy on the deal-making front. In April, it laid out plans to swallow its partner, Kansas-based pet therapeutics company Aratana $PETX. A July report by Reuters suggested a potential Bayer deal was being explored, and Bloomberg last week said the deal was imminent, citing sources. 

As­traZeneca's di­a­betes drug Farx­i­ga helps pa­tients with heart dis­ease and with­out di­a­betes in land­mark tri­al

Months ago, data on J&J’s $JNJ Invokana indicated the diabetes drug conferred cardiovascular (CV) benefit in patients who do and do not have preexisting CV disease. On Tuesday, AstraZeneca’s $AZN rival treatment, Farxiga, was shown to cut the risk of CV death or the worsening of heart failure in patients with heart disease, in a landmark trial.

The treatments, in addition to Jardiance from Eli Lilly $LLY, belong to a class of diabetes drugs called sodium-glucose co-transporter 2 (SGLT2) inhibitors, which work by curbing the absorption of glucose via the kidneys so that surplus glucose is excreted through urination.

Levi Garraway. Broad Institute via Youtube

Roche raids Eli Lil­ly for its next chief med­ical of­fi­cer as San­dra Horn­ing plans to step down

We found out Monday morning where Levi Garraway was headed after he left Eli Lilly as head of oncology R&D a few days ago. Roche named Garraway as their new chief medical officer, replacing Sandra Horning, who they say is retiring from the company.

Endpoints News

Basic subscription required

Unlock this story instantly and join 57,700+ biopharma pros reading Endpoints daily — and it's free.

Af­ter a posse of Wall Street an­a­lysts pre­dict a like­ly new win for Sarep­ta, we're down to the wire on a crit­i­cal FDA de­ci­sion

As Bloomberg notes, most of the Wall Street analysts that cover Sarepta $SRPT are an upbeat bunch, ready to cheer on the team when it comes to their Duchenne MD drugs, or offer explanations when an odd setback occurs — as happened recently with a safety signal that was ‘erroneously’ reported last week.

Ritu Baral Cowen
Endpoints News

Basic subscription required

Unlock this story instantly and join 57,700+ biopharma pros reading Endpoints daily — and it's free.