Pa­tients of­ten de­mand ex­per­i­men­tal drugs that prove in­ef­fec­tive — re­port

A new pa­per by a team of FDA of­fi­cials finds that on­ly about 30% of drugs re­quest­ed for ex­pand­ed ac­cess go on to be ap­proved by the agency.

“Ex­pand­ed ac­cess pro­vides just that: ac­cess. There is no guar­an­tee that the prod­uct sought will be ef­fec­tive and/or safe, much less that it will be ef­fec­tive and/or safe for the par­tic­u­lar pa­tient,” the au­thors write.

Back­ground

In re­cent years, the de­bate over pa­tient ac­cess to un­ap­proved drugs has risen to the na­tion­al stage. So called “right-to-try” laws, al­so known as right-to-ask laws, seek to by­pass FDA to pro­vide ac­cess to un­ap­proved drugs and have been en­act­ed in 37 states. In Au­gust, the US Sen­ate passed a bill that would ex­pand right-to-try na­tion­wide, though the House has yet to con­sid­er the bill.

The de­bate fo­cus­es on a pa­tient’s right to ac­cess un­ap­proved drugs to treat se­ri­ous or life-threat­en­ing dis­eases out­side of a clin­i­cal tri­al. Pro­po­nents of right-to-try have ar­gued that FDA is a bar­ri­er to pa­tient ac­cess, while FDA has coun­tered that it ap­proves near­ly all re­quests for ac­cess it re­ceives.

Un­der FDA’s ex­pand­ed ac­cess pro­gram, physi­cians can re­quest ac­cess to a drug for in­di­vid­ual pa­tients or a group of pa­tients un­der an ex­pand­ed ac­cess in­ves­ti­ga­tion­al new drug ap­pli­ca­tion (IND) or via a new pro­to­col un­der an ex­ist­ing IND.

While FDA main­tains that clin­i­cal tri­als are the best op­tion for pa­tients to get ac­cess to un­ap­proved drugs, the agency ac­knowl­edges that it’s not al­ways pos­si­ble for a pa­tient to en­roll in a clin­i­cal tri­al.

FDA has al­so said that in most cas­es phar­ma­ceu­ti­cal com­pa­nies de­ny re­quests for ex­pand­ed ac­cess, of­ten cit­ing sup­ply or safe­ty con­cerns. Right-to-try pro­po­nents have coun­tered that drug­mak­ers turn down such re­quests out of fear that ad­verse events that oc­cur be­cause of ex­pand­ed ac­cess use could de­rail their de­vel­op­ment pro­grams or open the com­pa­ny up to oth­er li­a­bil­i­ty is­sues.

Ex­pand­ed Ac­cess and Ap­proval

Ac­cord­ing to the au­thors, FDA re­ceived 6,054 unique ex­pand­ed ac­cess re­quests be­tween FY2010 and FY2014. Af­ter ex­clud­ing ex­pand­ed ac­cess re­quests for mul­ti­ple pa­tients and clean­ing the re­sults for du­pli­cate and “non­sub­mit­ted” INDs, the au­thors were left with 5,394 unique re­quests, 5,298 of which were al­lowed to pro­ceed.

Of those, the au­thors were able to iden­ti­fy 408 unique drugs and fixed-dose com­bi­na­tions.

By 30 Sep­tem­ber 2015, 122 (30%) of those drugs had been ap­proved by the agency for at least one in­di­ca­tion, though not nec­es­sar­i­ly for the in­di­ca­tions sought in ex­pand­ed ac­cess re­quests.

Six of the top ten most-re­quest­ed drugs went on to be ap­proved, though the pa­per does not men­tion the names of those drugs be­cause of con­fi­den­tial­i­ty rea­sons.

Look­ing at it from an­oth­er di­rec­tion, 3,365 of the 5,298 re­quests were for drugs that lat­er went on to be ap­proved, with a hand­ful of drugs ac­count­ing for a large pro­por­tion of those re­quests.

The au­thors al­so found lit­tle ev­i­dence to sup­port the ar­gu­ment that ad­verse events that oc­cur as a re­sult of ex­pand­ed ac­cess treat­ment can jeop­ar­dize a drug de­vel­op­ment pro­gram.

“Over the last decade, span­ning al­most 11,000 ex­pand­ed ac­cess re­quests, there were on­ly 2 in­stances in which a clin­i­cal hold was placed on com­mer­cial drug de­vel­op­ment due to ad­verse events oc­cur­ring un­der ex­pand­ed ac­cess. In both in­stances the de­vel­op­ment of the drugs con­tin­ued af­ter these is­sues were ad­dressed and the holds were lift­ed,” the au­thors write.

And the au­thors cast doubt on the ar­gu­ment that li­a­bil­i­ty con­cerns keep drug­mak­ers from pro­vid­ing ex­pand­ed ac­cess to their prod­ucts. A search of three le­gal data­bas­es, Google Schol­ar and HeinOn­line turned up no re­sults for prod­uct li­a­bil­i­ty suits against drug­mak­ers for per­son­al in­juries as a re­sult of ex­pand­ed ac­cess treat­ment.


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.

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.

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.”

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Tim Mayleben (file photo)

Es­pe­ri­on's goldilocks cho­les­terol fight­er wins FDA ap­proval — will its 'tra­di­tion­al' pric­ing ap­proach spur adop­tion?

It’s more effective than decades-old statins but not as good as the injectable PCSK9 — the goldilocks treatment for cholesterol-lowering, bempedoic acid, has secured FDA approval.

Its maker, Esperion Therapeutics, is betting that their pricing strategy — a planned list price of between $10 to $11 a day — will help it skirt the pushback the PCSK9 cholesterol fighters, Repatha and Praluent, got from payers for their high sticker prices.

The sky-high expectations for the pair of PCSK9 drugs that were first approved in 2015 quickly simmered — and despite a 60% price cut, coupled with data showing the therapies also significantly cut cardiovascular risk, sales have not really perked up.

Esperion is convinced that by virtue of being a cheaper oral therapy, bempedoic acid will hit that sweet spot in terms of adoption.

“We’re kind of like the old comfortable shoe,” Esperion’s chief commercial officer Mark Glickman remarked in an interview with Endpoints News ahead of the decision date. “It’s an oral product, once-daily and nontitratable — these are things that just resonate so true with patients and physicians and I think we’ve kind of forgotten about that.”

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James Collins, Broad Institute via Youtube

UP­DAT­ED: A space odyssey for new an­tibi­otics: MIT's ma­chine learn­ing ap­proach

Drug development is complex, expensive and comes with lousy odds of success — but in most cases, if you make it across the finish line brandishing a product with an edge (and play your cards right) it can be a lucrative endeavor.

As it stands, the antibiotic market is cursed — it harbors the stink of multiple bankruptcies, a dearth of innovation, and is consequently barely whetting the voracious appetites of big pharma or venture capitalists. Enter artificial intelligence — the biopharma industry’s cure-all for the pesky process of making a therapeutic, including data mining, drug discovery, optimal drug delivery, and addressable patient population.

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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.

Today, the US Patent and Trademark Office ruled that Gilead was likely to lose the last two of those challenges as well. The USPTO ruled against Gilead on the first two patents earlier this month.

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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.

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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)

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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.

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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.