Jon Cole, emergency doc at Minneapolis' Hennepin County Medical Center

FDA warns Min­neso­ta doc for run­ning two ke­t­a­mine tri­als with­out INDs, and with chil­dren and a preg­nant woman

The FDA on Tues­day re­leased a warn­ing let­ter sent to a Min­neso­ta physi­cian who failed to ex­clude vul­ner­a­ble pop­u­la­tions from two clin­i­cal tri­als com­par­ing the anes­thet­ic ke­t­a­mine with haloperi­dol and mi­da­zo­lam as po­ten­tial se­vere ag­i­ta­tion treat­ments.

The let­ter makes clear that not on­ly did Jon Cole, emer­gency doc at Min­neapo­lis’ Hen­nepin Coun­ty Med­ical Cen­ter, nev­er file INDs for the tri­als with the FDA, as re­quired by law, he al­so didn’t write ap­pro­pri­ate pro­to­cols to en­sure that chil­dren and preg­nant women weren’t en­rolled, and didn’t ex­clude those who were un­der the in­flu­ence of in­tox­i­cants, in whom the use of ke­t­a­mine is cau­tioned.

The FDA, which in­spect­ed the tri­al sites in 2019, makes clear that the pro­to­cols for both tri­als “in­volved fac­tors that sig­nif­i­cant­ly in­creased the risks (or de­creased the ac­cept­abil­i­ty of the risks) as­so­ci­at­ed with the use of the drug prod­ucts.”

Jef­frey Ho

Both pro­to­cols al­so re­quired the re­moval of al­ter­na­tive treat­ment op­tions from am­bu­lances by Cole’s co-in­ves­ti­ga­tor, Jef­frey Ho, chief med­ical di­rec­tor for the Hen­nepin EMS, which the FDA said “lim­it­ed the EMT-Ps’ [Emer­gency Med­ical Tech­ni­cian-Para­medics] clin­i­cal judg­ment and lim­it­ed the drug in­ter­ven­tions that were avail­able to the EMT-Ps for ad­min­is­tra­tion to each sub­ject.”

The agency makes clear that back in 2014, the FDA’s Di­vi­sion of Psy­chi­a­try Prod­ucts in­formed Cole that ex­clud­ing sub­jects who “ap­pear to be less than 18 years old” or “ob­vi­ous­ly gravid women” were not re­li­able meth­ods to ex­clude pa­tients from a tri­al, and that his pro­to­col should con­sid­er ex­clud­ing those un­der the in­flu­ence of var­i­ous in­tox­i­cants.

In­stead, one preg­nant woman was en­rolled in the tri­al study­ing ke­t­a­mine vs. haloperi­dol, and two chil­dren un­der the age of 18 were en­rolled in the tri­al study­ing ke­t­a­mine vs. mi­da­zo­lam. And the cause of ag­i­ta­tion was sus­pect­ed drug in­tox­i­ca­tion in 133 study sub­jects en­rolled (38%).

“Ad­min­is­tra­tion of the in­ves­ti­ga­tion­al drugs to these sub­jects placed them at sig­nif­i­cant­ly in­creased risk of the ad­verse events as­so­ci­at­ed with the in­ves­ti­ga­tion­al prod­ucts and de­creased the ac­cept­abil­i­ty of those risks,” the FDA said. “Your fail­ure to ex­clude, and the lack of any pre­cau­tions for, sub­jects un­der the in­flu­ence of var­i­ous in­tox­i­cants sig­nif­i­cant­ly in­creased the risks and/or de­creased the ac­cept­abil­i­ty of the risks as­so­ci­at­ed with the in­ves­ti­ga­tion­al drugs.”

A Form 483 from the FDA in 2019 makes clear that the tri­als were en­rolling pa­tients with­out their con­sent, and se­ri­ous ad­verse events and at least one death were not re­port­ed to the IRB in a time­ly fash­ion.

The FDA’s DPP al­so cau­tioned that ke­t­a­mine should be used by or un­der the di­rec­tion of physi­cians ex­pe­ri­enced in the main­te­nance of an air­way and in the con­trol of res­pi­ra­tion.

How­ev­er, Cole con­duct­ed both stud­ies in the pre-hos­pi­tal set­ting and did not put in place any spe­cif­ic mea­sures to pro­tect study par­tic­i­pants, the FDA said. Ac­cord­ing to the pub­lished re­sults of the ke­t­a­mine vs. haloperi­dol tri­al, the in­tu­ba­tion rate was sig­nif­i­cant­ly high­er in the ke­t­a­mine group, with 39% of sub­jects (25 out of 64) who re­ceived ke­t­a­mine be­ing in­tu­bat­ed vs. 4% of sub­jects (3 out of 82) who re­ceived haloperi­dol.

Back in May 2019, Cole told the FDA that use of these in­ves­ti­ga­tion­al drugs did not sig­nif­i­cant­ly in­crease the risk or de­crease the ac­cept­abil­i­ty of the risk to sub­jects be­cause the drugs were used “es­sen­tial­ly in ac­cord with their ap­proved la­bel­ing.”

But the FDA fired back, in its call for fur­ther an­swers from Cole, “Your state­ment is fac­tu­al­ly in­cor­rect, be­cause none of the three drugs used in Pro­to­cols HSR 14-3841 and HSR 17-4306 is in­di­cat­ed to treat se­vere ag­i­ta­tion or pro­found ag­i­ta­tion.”

Cole did not re­spond to a re­quest for com­ment.

Spe­cial re­port: Meet 20 ex­tra­or­di­nary women who are su­per­charg­ing bio­phar­ma R&D

Even though many biopharma leaders have come together in recent years to address its gender gap, the consensus is clear: We still have a long way to go.

Companies this year were 2.5 times more likely than last year to have a diversity and inclusion program in place, according to a recent BIO survey, but women are still largely absent from executive roles. Getting women to enter the industry isn’t the problem — studies show that they represent just under half of all biotech employees around the world. But climbing through the ranks can be challenging, as women still report facing stereotypes, and, unfortunately, harassment.

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Op­ti­miz­ing Oral Drug De­liv­ery us­ing Zy­dis® Oral­ly Dis­in­te­grat­ing Tablet Tech­nol­o­gy to Ad­dress Pa­tient Chal­lenges


Patients prefer oral dosing, but swallowing tablets can be a challenge for many patients.
The Zydis® orally disintegrating tablet (ODT) platform addresses challenges associated with oral dosing, expanding benefits for patients and options for healthcare providers.
A strong growth trajectory is expected for ODTs given therapeutic innovation and continued technology development.

Many patients prefer conventional tablets for the administration of medications, but some geriatric and pediatric patients and those with altered mental status and physical impairments find swallowing tablets to be difficult. Orally disintegrating tablets (ODTs), which dissolve completely without chewing or sucking, offer a patient-friendly dosage form for the administration of small-molecule drugs, peptides and proteins. With the potential for multiple sites of drug absorption, often faster onset action for the active pharmaceutical ingredient (API), and potentially greater bioavailability, ODTs are an attractive option for drug developers considering first-to-market formulations or product line extensions of existing drugs with compatible API. In this report, we look at how innovation in the industry-leading Zydis ODT platform is expanding oral formulation options and bringing benefits to patients.

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Geoffrey Porges (SVB Leerink)

The 2022 wave com­ing? Top an­a­lyst says Big Phar­ma will have more than $1T avail­able to sat­is­fy its grow­ing ap­petite for biotech M&A

All through this year you could practically feel the frustration of the biotech investor class as M&A activity continued to drag behind expectations — or desires. Buyouts of public companies provide the essential juice for keeping stocks lively, and there’s been a notable lack of juice in 2021.

So is all that about to change, big time?

SVB Leerink’s Geoffrey Porges, a longtime student of biotech M&A, thinks so. In a lengthy analysis he put out last week, Porges totted up the cash flow of the major pharmas and determined that there was a good long list of industry buyers who would have around a half trillion dollars of cash to play with in 2022. Leverage that up with added debt and you could get that deal cache to $1.6 trillion.

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Warren Huff, Reata CEO

FDA slams Reata's kid­ney drug as in­ef­fec­tive ahead of ad­comm meet­ing

The FDA on Monday offered an overwhelmingly negative opinion on Reata Pharmaceuticals’ potential drug to slow the loss of kidney function in those with the rare disease Alport syndrome, according to briefing documents released ahead of an advisory committee meeting Wednesday.

The agency’s review team said it “does not believe the submitted data demonstrate that bardoxolone is effective in slowing the loss of kidney function in patients with AS and reducing the risk of progression to kidney failure.” Originally developed as a cancer drug, bardoxolone was later scuttled by Reata almost a decade ago as a chronic kidney disease drug due to deaths in a Phase III trial.

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No­var­tis pe­ti­tions FDA to block 18 gener­ic com­peti­tors for its megablock­buster heart drug un­til 2024

Novartis is looking to milk one of its most prized possessions a little while longer without any generic competition, mostly because of a newly approved use that the Big Pharma won earlier this year for its megablockbuster heart drug Entresto.

In addition to battling (and winning) litigation last month to block a handful of Indian generics from entering the market early alongside Entresto, the company last week petitioned the FDA to try to stop a total of 18 Entresto generics from launching before 2024 at the earliest.

Mar­ket­ingRx Matchup: How Ab­b­Vie and Bio­haven ads rank in head-to-head mi­graine chal­lenge

Are you ready to rumble? DTC brands that is. MarketingRx is launching a new monthly feature today called MarketingRx Matchup. We’re pitting two pharma brands’ DTC advertising in the same therapeutic category against each other to find out what consumers and patients really think.

Market research company Leger is handling the polling and analysis each month, and I’ll be writing up the results — along with my own take — inside MRx on the first Tuesday of the month.

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Wendy Lund, Organon chief communications officer

Q&A: Organon chief com­mu­ni­ca­tions of­fi­cer Wendy Lund talks about the Mer­ck spin­off, women’s health and why it mat­ters

One of Wendy Lund’s earliest jobs was head of marketing at Planned Parenthood. As the youngest person on its management team, she introduced them to emerging new technologies, and in return, she learned the importance of fighting for what you believe in.

Now as chief communications officer at Organon, the women’s health company recently spun off by Merck, Lund is keeping that point top of mind. That’s in part because women’s health hasn’t been a spotlight therapy area for Big Pharma in years. Several companies have spun off, sold or at least considered selling women’s health assets to focus on “core” products.

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Mar­ket­ingRx roundup: Pfiz­er re-ups pneu­mo­nia ads as Mer­ck threat looms; Re­al Chem­istry founder CEO Jim Weiss steps back

Every autumn, leaves fall from the trees and people start holiday shopping – and for the last few years Pfizer debuts a new “Know Pneumonia” awareness TV ad. This year the commercial, launched a week ago, features different people who talk about why they got vaccinated against pneumococcal pneumonia. Actors portray a young female firefighter with asthma, a mechanic with heart disease and an older woman with her grandchild. A Pfizer spokesperson declined comment on the latest iteration of the long-running campaign.

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Mer­ck pumps the brakes on two more PhI­II tri­als for its lead an­ti-HIV drug

After trial investigators flagged a drop in immune cell counts that an external committee determined was related to treatment last month, Merck has been pausing HIV-related Phase II and III trials ever since.

On Monday, the biopharma company announced it’s pausing enrollment in two of its Phase III trials evaluating its leading anti-HIV drug candidate, which is the once-monthly, oral islatravir.

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