Next-gen­er­a­tion se­quenc­ing: FDA of­fers guid­ance to stream­line path to mar­ket

The FDA on Thurs­day fi­nal­ized two guid­ance doc­u­ments re­lat­ed to next-gen­er­a­tion se­quenc­ing (NGS) and draft­ed new guid­ance on in­ves­ti­ga­tion­al in vit­ro di­ag­nos­tics (IVDs) in on­col­o­gy tri­als – all of which of­fer rec­om­men­da­tions to pro­vide test de­vel­op­ers with a more ef­fi­cient path to mar­ket.

The fi­nal­ized guid­ance doc­u­ments pro­vide NGS test de­vel­op­ers with rec­om­men­da­tions for de­sign­ing, de­vel­op­ing and val­i­dat­ing tests, as well as us­ing ge­net­ic vari­ant data­bas­es to sup­port clin­i­cal va­lid­i­ty.

Jef­frey Shuren

“The rapid adop­tion of NGS tech­nolo­gies in re­search and clin­i­cal set­tings is help­ing to iden­ti­fy count­less new ge­net­ic vari­ants. How­ev­er, in­for­ma­tion about ge­net­ic vari­ants is gen­er­al­ly stored in a man­ner that is not pub­licly ac­ces­si­ble,” ex­plained Jef­frey Shuren, di­rec­tor of FDA’s Cen­ter for De­vices and Ra­di­o­log­i­cal Health. “To­day’s re­lease of the FDA’s fi­nal guid­ance on ge­net­ic vari­ant data­bas­es will help change this par­a­digm by en­cour­ag­ing da­ta shar­ing and the ac­cu­mu­la­tion in pub­lic data­bas­es of ev­i­dence sup­port­ing the clin­i­cal va­lid­i­ty of ge­nom­ic tests to help pro­vide an even more ef­fi­cient path to mar­ket.”

The 7-page draft guid­ance, mean­while, de­scribes how spon­sors of cer­tain on­col­o­gy tri­als can use an op­tion­al stream­lined sub­mis­sion process to de­ter­mine whether use of an in­ves­ti­ga­tion­al IVD — in­clud­ing those that in­cor­po­rate NGS tech­nol­o­gy — in a tri­al of in­ves­ti­ga­tion­al can­cer drug or bi­o­log­i­cal prod­ucts is con­sid­ered sig­nif­i­cant risk, non­signif­i­cant risk or ex­empt from re­view.

Scott Got­tlieb

“This is a step to­ward our goal of hav­ing a com­mon fil­ing for a drug and di­ag­nos­tic sys­tem where the drug is co-de­vel­oped with a di­ag­nos­tic test,” FDA Com­mis­sion­er Scott Got­tlieb said in re­marks on Thurs­day.

Back­ground

NGS can en­able doc­tors to look across mil­lions of DNA changes that may de­ter­mine whether a per­son has or is at risk of de­vel­op­ing a ge­net­ic dis­ease, or to in­form treat­ment de­ci­sions, FDA ex­plained.

“The rapid adop­tion of NGS-based tests in both re­search and clin­i­cal prac­tice is lead­ing to iden­ti­fi­ca­tion of an in­creas­ing num­ber of ge­net­ic vari­ants (e.g., path­o­gen­ic, be­nign, and of un­known sig­nif­i­cance), in­clud­ing rare vari­ants that may be unique to a sin­gle in­di­vid­ual or fam­i­ly,” FDA said.

To date, FDA has au­tho­rized three NGS on­co-pan­els:

  • Foun­da­tionOne CDx, which was ap­proved in No­vem­ber 2017, and can de­tect ge­net­ic mu­ta­tions in 324 genes;
  • MSK-IM­PACT, al­so ap­proved in No­vem­ber 2017, which can de­tect ge­net­ic mu­ta­tions in 468 genes; and
  • On­comine Dx Tar­get Test, ap­proved in June 2017, which can de­tect ge­net­ic mu­ta­tions in 23 genes.

“Oth­er tests us­ing NGS tech­nol­o­gy au­tho­rized by FDA to date in­clude: Prax­is Ex­tend­ed RAS Pan­el (de­tects two genes) and Foun­da­tion­Fo­cus BR­CA (al­so de­tects two genes),” an FDA spokesper­son told Fo­cus.

“These pan­els can ac­cel­er­ate can­cer drug de­vel­op­ment and im­prove clin­i­cal out­comes by re­duc­ing pa­tient screen­ing time and costs. These tech­nolo­gies can help re­duce the risks as­so­ci­at­ed with the need for mul­ti­ple tis­sue biop­sies. And these plat­forms can be rapid­ly up­dat­ed to de­tect new onco­genes or gene vari­ants as these mark­ers are iden­ti­fied by re­searchers,” Got­tlieb ex­plained.

In 2017, FDA al­so took sev­er­al ac­tions to stream­line the de­vel­op­ment and re­view of a va­ri­ety of ge­net­ic-based tests – au­tho­riz­ing a third-par­ty op­tion for au­tho­riz­ing tu­mor pro­fil­ing tests, and out­lin­ing stan­dard­ized de­vel­op­ment cri­te­ria for con­sumer car­ri­er screen­ing tests to al­low for their mar­ket­ing with­out pri­or agency re­view. FDA al­so es­tab­lished such cri­te­ria for ge­net­ic health risk tests and pro­posed to al­low their mar­ket­ing af­ter a one-time agency re­view.

Fi­nal Guid­ance

One 41-page guid­ance fi­nal­ized Thurs­day, known as “Con­sid­er­a­tions for De­sign, De­vel­op­ment, and An­a­lyt­i­cal Val­i­da­tion of Next Gen­er­a­tion Se­quenc­ing (NGS)–Based In Vit­ro Di­ag­nos­tics (IVDs) In­tend­ed to Aid in the Di­ag­no­sis of Sus­pect­ed Germline Dis­eases,” pro­vides rec­om­men­da­tions for de­sign­ing, de­vel­op­ing and val­i­dat­ing NGS-based tests.

The guid­ance of­fers per­spec­tive on what the agency looks for in pre­mar­ket sub­mis­sions to de­ter­mine a test’s an­a­lyt­i­cal va­lid­i­ty, in­clud­ing how well the test de­tects the pres­ence or ab­sence of a ge­nom­ic change.

The oth­er 16-page guid­ance is­sued Thurs­day, ti­tled “Use of Pub­lic Hu­man Ge­net­ic Vari­ant Data­bas­es to Sup­port Clin­i­cal Va­lid­i­ty for Ge­net­ic and Ge­nom­ic-Based In Vit­ro Di­ag­nos­tics,” de­scribes how test de­vel­op­ers may re­ly on clin­i­cal ev­i­dence from FDA-rec­og­nized pub­lic data­bas­es to sup­port clin­i­cal claims.

The guid­ance de­scribes how prod­uct de­vel­op­ers can use these data­bas­es to sup­port the clin­i­cal val­i­da­tion of NGS tests that they are de­vel­op­ing. These pub­lic data­bas­es may in­clude re­sources like Clin­Gen, which is main­tained by the Na­tion­al In­sti­tutes of Health (NIH). Us­ing FDA-rec­og­nized data­bas­es will pro­vide test de­vel­op­ers with an ef­fi­cient path for mar­ket­ing clear­ance or ap­proval of a new test.

On 26 April, FDA will hold a we­bi­nar on the two fi­nal guid­ance doc­u­ments.


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

Lessons for biotech and phar­ma from a doc­tor who chased his own cure

After being struck by a rare disease as a healthy third year medical student, David Fajgenbaum began an arduous journey chasing his own cure. Amidst the hustle of this year’s JP Morgan conference, the digital trials platform Medable partnered with Endpoints Studio to share Dr. Fajgenbaum’s story with the drug development industry.

What follows is an edited transcript of the conversation between Medable CEO Dr. Michelle Longmire and Dr. Fajgenbaum, and it is full of lessons for biotech executives charged with bringing the next generation of medicines to patients.

Gilead los­es two more patent chal­lenges on HIV pill, set­ting up court­room fight in Delaware

Gilead sustained two more losses in their efforts to rid themselves of an activist-backed patent lawsuit from the US government over a best-selling HIV pill.

Urged on by activists seeking to divert a portion of Gilead’s revenue to clinics and prevention programs, the Department of Health and Human Services made a claim to some of the patents for the best-selling HIV prevention drug, Truvada, also known as PrEP. Gilead responded by arguing in court that HHS’s patents were invalid.

Bank­rupt an­tibi­otics mak­er Ar­a­digm turns to old part­ner/in­vestor for fi­nal $3M fire sale

Grifols once paid Aradigm $26 million for a stake in its inhaled antibiotics. But with Aradigm now in bankruptcy, the Spanish drugmaker is dishing out a final $3.2 million to buy it all.

The fire sale — which comes one year after Aradigm filed for Chapter 11 following a regulatory trifecta for disaster — will see Grifols obtain assets and IP to Apulmiq (formerly Pulmaquin and Linhaliq in Europe), Lipoquin and free ciprofloxacin. In addition to waiving its claims in the bankruptcy case, Grifols also agreed to milestone payments up to $3 million more upon any regulatory approvals.

DB­V's peanut pre­ven­tion patch ap­proach­es key stage of ap­proval process

Almost a year and a half after DBV Technologies pulled its peanut allergy immunotherapy patch from FDA review, the biotech will get their day in court. The FDA has scheduled an advisory committee hearing for May 15.

In the two-horse race to develop the first immunotherapy for peanut allergy, DBV had the early lead, filing an NDA for their patch in 2018. But on December 20 of that year, the company withdrew their application after, they said, meeting with regulators and determining they had not submitted “sufficient detail regarding data on manufacturing procedures and quality controls.” Aimmune filed their BLA 3 days later and won approval as the first immunotherapy for peanuts this month.

Jim Scholefield via PR Newswire

Mer­ck los­es its chief dig­i­tal of­fi­cer, spot­light­ing tal­ent hunt for the hottest ti­tle in Big Phar­ma

Over the last few years we’ve seen the chief digital officer title become one of the hottest commodities in Big Pharma as global organizations hunt the best talent to sharpen the cutting edge of their tech platforms.

But Merck just discovered how hard it may be to keep them focused on pharma.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 72,800+ biopharma pros reading Endpoints daily — and it's free.

An­to­nio Gual­ber­to starts post-Ku­ra ca­reer at Ei­sai sub­sidiary H3; eF­FEC­TOR co-founder Siegfried Re­ich jumps to Turn­ing Point

→ Days after Kura Oncology announced the departure of co-founder Antonio Gualberto, we finally know where he wound up. Eisai subsidiary H3 Biomedicine has recruited him as CMO to finding the right patients to its four clinical-stage small molecule assets hitting genomic drivers of cancer.

“Challenges of these and many other precision medicine approaches are on one hand technical, a need for robust and precise diagnostics, and in the other hand derived by the challenge to alter standard clinical practice in settings where patient screening, e.g. by tumor DNA sequencing, is not standard practice,” he wrote to Endpoints News on his way back to Boston from Eisai’s Tokyo offices. “Only compelling clinical activity can drive clinicians and pathologists to modify standard clinical practice.”

Kathy High (file photo)

Gene ther­a­py pi­o­neer Kathy High has left Spark af­ter com­plet­ing $4.3B union with Roche

Kathy High dedicated the past seven years of her life shepherding experimental gene therapies she’s developed at Children’s Hospital of Philadelphia toward the market as president and head of R&D at Spark Therapeutics. Now that the biotech startup is fully absorbed into Roche — with an FDA approval, a $4.3 billion buyout and a promising hemophilia program to boast — she’s ready to move on.

Roche confirmed her departure with Endpoints News and noted “she will take some well-deserved time off and then will begin a new chapter in a sabbatical at a university.”

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 72,800+ biopharma pros reading Endpoints daily — and it's free.

Tal Zaks (Moderna via YouTube)

For two decades, a new vac­cine tech­nol­o­gy has been slow­ly ap­proach­ing prime time. Now, can it stop a pan­dem­ic?

Two months before the outbreak, Moderna CMO Tal Zaks traveled from Cambridge, MA to Washington DC to meet with Anthony Fauci and the leaders of the National Institutes of Health.

For two years, Moderna had worked closely with NIH researchers to build a new kind of vaccine for MERS, one of the deadliest new viruses to emerge in the 21st century. The program was one test for a new technology designed to be faster, cheaper and more precise than the ways vaccines had been made for over a century. They had gathered evidence the technology could work in principle, and Fauci, the longtime head of the National Institute of Allergy and Infectious Diseases and a longtime advocate for better epidemic preparedness, wanted to see if it, along with a couple of other approaches, could work in a worst-case scenario: A pandemic.

“[We were] trying to find a test case for how to demonstrate if our technology could rapidly prepare,” Zaks told Endpoints News.

Zaks and Fauci, of course, wouldn’t have to wait to develop a new test. By year’s end, an outbreak in China would short circuit the need for one and throw them into 24/7 work on a real-world emergency. They also weren’t the only ones with new technology who saw a chance to help in a crisis.

An ocean away, Lidia Oostvogels was still on vacation and relaxing at her mother’s house in Belgium when her Facebook started changing. It was days after Christmas and on most people’s feeds, the news that China had reported a novel virus to the World Health Organization blurred into the stream of holiday sweaters and fir trees. But on Oostvogels’s feed, full of vaccine researchers and virus experts, speculation boiled: There was a virus in China, something contained to the country, but “exotic,” “weird,” and maybe having to do with animals. Maybe a coronavirus.

Lidia Oostvogels

“I was immediately thinking like, ‘Hey, this is something that if needed, we can play a role,'” Oostvogels told Endpoints.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 72,800+ biopharma pros reading Endpoints daily — and it's free.

Christos Kyratsous (via LinkedIn)

He built a MERS treat­ment in 6 months and then the best Ebo­la drug. Now Chris­tos Kyrat­sous turns his sights on Covid-19

TARRYTOWN, NY — In 2015, as the Ebola epidemic raged through swaths of West Africa, Kristen Pascal’s roommates sat her down on their couch and staged an intervention.

“Are you sure this is what you want to be doing with your life?” she recalls them asking her.

Special report

Pascal, a research associate for Regeneron, had been coming home at 2 am and leaving at 6 am. At one point, she didn’t see her roommate for a week. For months, that was life in Christos Kyratsous’ lab as the pair led a company-wide race to develop the first drug that could effectively treat Ebola before the outbreak ended. For Pascal, that was worth it.

“I’m ok, I don’t have Ebola,” Pascal told them. “I see that death toll rising and I can’t not do something about it.”

Last August, Regeneron learned they had succeeded: In a large trial across West Africa, their drug, REGN-EB3, was vastly more effective than the standard treatments. It was surprise news for the company, coming just 10 months into a trial they thought would take several years and a major victory in the global fight against a deadly virus that killed over 2,000 in 2019 and can carry a mortality rate of up to 90%.

For Kyratsous and Pascal, though, it brought only fleeting reprieve. Just four months after the NIH informed them REGN-EB3 worked, Kyratsous was back in his office reading the New York Times for updates on a new outbreak on another continent, and wondering alongside Pascal and senior management whether it was time to pull the trigger again.

In late January, as the death toll swelled and the first confirmed cases outside China broke double digits, they made a decision. Soon they were back on the phone with the multiple government agencies and their coronavirus partners at the University of Maryland’s Level 3 bio lab. The question was simple: Can Kyratsous and his team use a process honed over two previous outbreaks, and create a treatment before the newest epidemic ends? Or worse, if, as world health experts fear, it doesn’t vanish but becomes a recurrent virus like the flu?

“Christos likes things immediately,” Matt Frieman, Regeneron’s coronavirus collaborator at the University of Maryland, told Endpoints. “That’s what makes us good collaborators: We push each other to develop things faster and faster.”

Kristen Pascal (Regeneron)

Click on the image to see the full-sized version

The first time Regeneron tried to respond to a global outbreak, it was something of a systems test, Kyratsous explains from his office at Regeneron’s Tarrytown headquarters. Kyratsous, newly promoted, has crammed it with photos of his family, sketches of viral vectors and a shark he drew for his 3-year-old son. He speaks rapidly – an idiosyncrasy his press person says has only been aggravated this afternoon by the contents of his “Regeneron Infectious Diseases”-minted espresso glass – and he gesticulates with similar fluidity, tumbling through antibodies, MERS, the novel coronavirus, Ebola-infected monkeys.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 72,800+ biopharma pros reading Endpoints daily — and it's free.