New re­search ques­tions FDA’s re­liance on and in­abil­i­ty to en­force post­mar­ket­ing re­quire­ments

As the FDA has in­creas­ing­ly re­lied on post­mar­ket­ing re­quire­ments (PMRs) to sup­port its ap­proval de­ci­sions, a new study pub­lished in the Mil­bank Quar­ter­ly dis­cuss­es how the FDA’s lack of abil­i­ty to en­force PMRs re­veals an agency “on guard against a set of larg­er po­lit­i­cal threats to its man­date.”

The study’s pub­li­ca­tion fol­lows a re­cent re­port from the FDA show­ing that most of the re­quired PMRs and vol­un­tary post­mar­ket­ing com­mit­ments (PM­Cs) are pro­gress­ing on sched­ule.

Matthew Herder Dal­housie

But as Matthew Herder, di­rec­tor of the Health Law In­sti­tute at Dal­housie Uni­ver­si­ty, ex­plains in his pa­per, “FDA has dif­fi­cul­ty en­forc­ing the time­ly com­ple­tion of PMRs, but act­ing up­on PMR da­ta once in hand is more vexed.”

An uniden­ti­fied FDA of­fi­cial told Herder dur­ing his in­ter­views with 23 past and present FDA lead­ers: “[E]ven if you get the study, and you of­ten do, some­times they don’t con­firm the ef­fi­ca­cy of the prod­uct. […] What is FDA sup­posed to do with that? There’s now a huge and vo­cal con­stituen­cy for the prod­uct. Whether or not the study showed it worked, there are peo­ple out there who think it worked, and lots of peo­ple with a fi­nan­cial stake in it. It be­comes a po­lit­i­cal night­mare to try to take a prod­uct off the mar­ket that’s al­ready de­vel­oped that con­stituen­cy by be­ing ap­proved for a pe­ri­od of time. […] [I]n some ways [it’s] a big­ger prob­lem than whether you get the da­ta. It’s whether you can do any­thing with it when you have it.”

Over­all, Herder told Fo­cus that in his con­ver­sa­tions with FDA of­fi­cials, “What I found most sur­pris­ing was how acute­ly aware most FDA of­fi­cials were of the en­force­ment chal­lenges in­volved with PMRs, yet — at the same time — fierce­ly de­fen­sive of con­tin­u­ing to re­ly on them.”

He dis­cuss­es in the pa­per how the FDA lacks the le­gal au­thor­i­ty to with­draw an ap­proval that car­ries a PMR due to a spon­sor’s fail­ure to ful­fill the PMR, and how com­pa­nies “like­ly abide by the terms of a PMR not be­cause they fear FDA en­force­ment, but rather be­cause the ap­proved in­di­ca­tion car­ry­ing the PMR is one of sev­er­al in­di­ca­tions in a se­quence that they plan to sub­mit to the agency.”

Defin­ing what a PMR en­tails at the time of a new treat­ment’s ap­proval can al­so be chal­leng­ing.

“They tend to be short de­scrip­tions of the ques­tion(s) that the FDA would like to have an­swered through one or more post­mar­ket stud­ies, but they of­ten fail to spec­i­fy what type of study de­sign should be em­ployed to an­swer the ques­tion(s) of in­ter­est. Of 110 clin­i­cal tri­als that were en­com­passed in a cross‐sec­tion­al analy­sis of all PMRs is­sued by the FDA dur­ing 2009‐2012, many, if not most, ‘did not re­port enough in­for­ma­tion to es­tab­lish use of ran­dom­iza­tion, com­para­tor type, al­lo­ca­tion, out­come, and num­ber of pa­tients to be en­rolled,’” the study finds.

FDA of­fi­cials al­so may be ret­i­cent to hold up an ap­proval be­cause the de­tails of a PMR are not yet set­tled.

And as the FDA con­tin­ues its push to­ward fur­ther us­ing re­al-world ev­i­dence, one cur­rent FDA of­fi­cial told Herder: “You just let pa­tients take them, and some­how all of these mas­sive in­sur­ance data­bas­es will cough up an an­swer at the end of a year or two about how well the prod­ucts work and how safe they are. We’re not re­al­ly any­where near that de­gree of so­phis­ti­ca­tion in our abil­i­ty to an­a­lyze those big datasets, but there’s a huge amount of pres­sure to push off lots of da­ta col­lec­tion there with­out a lot of method­ol­o­gy to do it.”

Herder added in an email to Fo­cus: “I think the in­abil­i­ty to ef­fec­tive­ly en­force PMRs presents tremen­dous risks for pub­lic health, es­pe­cial­ly for the pro­por­tion of drugs with a PMR that were ap­proved on the ba­sis of lim­it­ed ev­i­dence.”


RAPS: First pub­lished in Reg­u­la­to­ry Fo­cus™ by the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety, the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care prod­ucts. Click here for more in­for­ma­tion.


Zachary Brennan

managing editor, RAPS

Andre Kalil, AP Images

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The first 11 coronavirus patients who arrived in Omaha last week, airlifted across the globe after two weeks quarantined on a cruise ship, showed only minor symptoms or none at all. And then one of them — or one of the couple of Americans who arrived later — got worse. He developed pneumonia, a life-threatening complication for coronavirus patients.

In a biocontainment room at the University of Nebraska Medical Center on Friday, doctors infused him with an experimental Gilead drug once developed for Ebola, called remdesivir. Or they gave him a placebo. For the first time in the US, neither he nor the doctors knew.

The first US novel coronavirus trial was underway and with it, a mad dash for an answer. Sponsored by the NIH, the study marked a critical point in the epidemic. Since the start of the outbreak, the agency had helped lead a global effort to contain the virus. Now, as it spread worldwide and the CDC issued warnings the US could see a major internal outbreak, they were looking at home.

“We don’t have too much time,” Andre Kalil, the trial’s lead investigator, told Endpoints News. “Everything’s moving really fast.”

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Grow­ing ac­cep­tance of ac­cel­er­at­ed path­ways for nov­el treat­ments: but does reg­u­la­to­ry ap­proval lead to com­mer­cial suc­cess?

By Mwango Kashoki, MD, MPH, Vice President-Technical, and Richard Macaulay, Senior Director, of Parexel Regulatory & Access

In recent years, we’ve seen a significant uptake in the use of regulatory options by companies looking to accelerate the journey of life-saving drugs to market. In 2018, 73% of the novel drugs approved by the U.S. Federal Drug Administration (FDA) were designated under one or more expedited development program categories (Fast Track, Breakthrough Therapy, Priority Review, and Accelerated Approval).ᶦ

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The proceeds likely reflected confidence in Jim Wilson, who gathered all the tools he’s built over decades of gene therapy research to assemble the startup and teamed up with Frazier and OrbiMed to hone its focus on rare, monogenic disorders of the central nervous system. Just before the IPO, Deerfield partner Bruce Goldsmith took over from OrbiMed’s Stephen Squinto as CEO.

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Biogen head of R&D Al Sandrock, Sangamo CEO Sandy Macrae

UP­DAT­ED: Bio­gen makes an­oth­er bold Alzheimer’s bet, drop­ping $350M up­front to part­ner with genome-edit­ing fo­cused Sang­amo

While the fate of Biogen’s resurrected Alzheimer’s drug aducanumab remains uncertain, the Cambridge, MA-based drugmaker is joining forces with genome editing company Sangamo Therapeutics to develop therapies for neurological conditions.

Sangamo is set to receive a meaty $350 million upfront in cash and stock and is eligible to receive up to $2.37 billion in milestone payments, in addition to royalties. In return, Biogen gets the rights to two Sangamo preclinical compounds: ST-501 (for use in tauopathies including Alzheimer’s disease) and ST-502 (for synucleinopathies including Parkinson’s disease).

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Take­da swoops in to buy lit­tle biotech part­ner and its celi­ac drug poised to 'change stan­dard of care'

Having spent three years carefully grooming PvP Biologics and its drug for celiac disease, Takeda is happy enough with the proof-of-concept data to buy it all.

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Spark los­es an­oth­er top ex­ec in the wake of $4.3B takeover by Roche — re­port

Days after bidding farewell to co-founder Kathy High, Spark Therapeutics — now operating under Roche — has one more opening on its C-suite.

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Kathy Reape, who joined the Philadelphia-based biotech in 2016 as head of clinical R&D and became chief medical officer in 2018, is reportedly set to leave.

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'The head­lines are the head­lines, but': Bio­Marin talks up po­ten­tial sav­ings as he­mo­phil­ia gene ther­a­py launch looms

BioMarin execs are still staying tight-lipped about their pricing plans for what is poised to be the world’s first hemophilia gene therapy. But as the company enters the final regulatory stretch and approaches a potential launch this summer, they are also dropping more hints to get investors ready.

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