We need a T shirt that says “MPN Lives Matter.”
Forget the T shirt, we need a mob to stop traffic and scream and shout at the entrance to the FDA, at the doors of Big Pharma: “MPN Lives Matter.”
Because, once again, we’re getting screwed. Another Phase III trial for a myelofibrosis drug has exploded and we’re out in the cold. Without a paddle.
Two years ago it was Sanofi, crawling out from a secret weekend meeting to pull the plug on fedratinib after botching a trial, killing and injuring MPN patients. “MPN Lives Don’t Count for Jack.” Hundreds of MF patients left to fend for themselves, no drugs, no compensation, no apologies, no explanation. We headed on home.. Nothing to show for our clinical trial experience except maybe some debt, some tired bones, and some bitter regrets.
Two weeks ago we saw pacritinib vanish from the the treatment landscape even as our docs were warming up their prescription pads. Finally a drug for low platelet MF patients. And then … POW! Just like that.
The FDA descended from on high, swept the table clean of pills and decreed “No more pacritinib for you.” Once again hundreds of MF patients who were benefiting from a clinical trial drug, many sick and weak, were now out in the cold with nothing to cover their naked need for relief but some hints and rumors.
And once again the cone of silence descended over the scene. Nobody’s talking. Negotiations in progress. Confidentiality required. Privacy guaranteed. Blah Blah. It would be a joke if it weren’t so damned insulting to all our friends who believed enough in our money grubbing clinical trial system to swallow the pills, make their appointments, get jabbed and prodded only to be told to turn in their electronic diaries, any inventory of pills, sign this release and get lost.
Last time it took MPNforum four months of intense undercover investigative work to put together the sad Sanofi story. This time we don’t have to go much further than the printed record to figure out a likely scenario.
Let’s start with the conclusion: There’s plenty of blame to go around but the truly nasty guys in the black hats this time are the Feds.
Even if it were really necessary to call a time out on a trial that had been completed and amply reported on, did the FDA have to mount a Secret Operation, taking doctors and patients by surprise? Why call in a SWAT team in full camo to come kicking in the doors and windows when a kinder, gentler approach would have been just as effective? This is a drug that was helping most everybody on the trial. Forcing MF patients to go cold turkey on pacritinib was flat out cruel. Their physicians had to violate their Hippocatic Oath. Primum non nocere. There was plenty of nocere in the wake of this action.
Everyone knows a sudden cessation of JAK inhibitors is going to send your spleen and symptoms through the roof. Ask Tefferi. Ask Verstovsek. Ask your grandmother or kid sister.
This FDA full clinical hold — even if it were necessary for the safety of patients — could have been phased in gradually over several weeks easing the impact on patients.
But was it really necessary? Let’s take a look at what we know for sure.
There were two arms to the trial: The pacritinib group that got the pill and the Best Available Therapy group that got something else.
Last summer Dr. Ruben Mesa reported on pacritinib at the big ASCO meeting.
Conclusions: This study demonstrated PAC was well tolerated and induced significant and sustained SVR and symptom control even in patients with severe thrombocytopenia. PAC therapy resulted in RBC transfusion independence in a significant proportion of pts.Clinical trial information: NCT01773187
It was a report signed by a Who’s Who of the worlds most experienced, renowned hematologists and researchers Very positive, no drug related serious inexplicable events.
Two months ago Dr. Alessandro Vannucchi at ASH did the honors Same deal. Very promising. Conclusions: Comparisons vs BAT were favorable for all patient subpopulations examined for both endpoints. These results support the use of pacritinib across all intermediate- or high risk MF pt subgroups analyzed.
Yes there were deaths on this trial.
It would be inevitable. The protocol for the trial almost demanded it. To qualify for the PERSIST trials of pacritinib you had to be really sick had failed other drugs and most of all had critically low platelets that would disqualify you from such amenities as a stem cell transplant or Jakafi. There was a low longevity bar. To qualify for participation in this trial you were required to have at least a six month life expectancy.
“The FDA’s February 8, 2016, letter, “says a CTI press release, ” notes the interim overall survival results from PERSIST-2 show a detrimental effect on survival consistent with the results from PERSIST-1. The deaths in PERSIST-2 in pacritinib-treated patients include intracranial hemorrhage, cardiac failure and cardiac arrest.”
We have heard that the difference in death rates between the two arms of the trial are small, but significant although no one has attributed the cause of death to the action of pacritinib. The deaths that concern the FDA referred to the pacritinib-treated patients presumably faring worse than patients treated with BAT drugs. Isn’t that what we would expect?
Even though there were two arms to the trial, there was an escape hatch. If you get worse, if your big spleen got bigger enough, if your low platelets got low enough, you might get the opportunity to cross over to the pacritinib arm. Otherwise you had to stay with your BAT friends for 24 weeks, then get measured to see how much worse your disease was, and you could cross over to the sunny side of the street.
It’s a recipe for confusion and disaster.
The Independent Data Monitoring Committee (IDMC) for the PERSIST trial recommended the BAT patients not be able to cross over before 24 weeks. The reason: Survival curves and muddying the statisticl waters. How can you tell if pacritinib is better than BAT unless you set up rigid barriers?
CTI BioPharma and its partner Baxalta consulted with experts and then notified the FDA they rejected that recommendation and intended to follow the original protocol and permit cross over. We have a good example right in this issue about the impact the crossover rule had on patients. The effect of this decision may well have influenced the ultimate FDA action…but we won’t know that for sure until the FDA breaks its Code of Silence.
Consider someone in the BAT arm who wants to cross over but was told he is not sick enough and has to wait, like Howard in our abandoned patient story. After 24 weeks, he crosses over and starts taking pacritinib. He is six months older and likely six months sicker than he was when the trial started but now he’s part of the pacritinib arm. If he dies, he dies on the pacritinib arm.
The procession of patients too sick to stay on BAT and moving on to pacritinib and those graduating after 24 weeks, older and likely weaker than when they started, changes the dynamic. The pacritinib arm is not only no longer randomly selected it is heavily weighted toward the most ill.
Understandably a look at the survival data could set off warning bells. “Hey look there are more people dying on the pacritinib arm than the BAT arm. What’s going on? Let’s make everyone throw away their pills immediately and close up the trial.”
This is not to say those kinds of things can’t be easily unravelled and accounted for statistically BUT it does point out the likelihood that more people died on the pacritinib than the BAT arm. Not seeing the data but relying on the Vannucchi and Mesa reports of safety and CTI”s own account of its failure to follow the IDMC’s recommendation and reading that deaths on trial were an issue for the FDA, it’s a reasonable working hypothesis. Until someone starts publishing the data.
Meantime, if we were counting on pacritinib for symptomatic relief despite our low platelet levels, we’re still screwed…without many easily apparent options.
How about an X-Large “MPN Lives Matter” T-shirt ?
Got a comment on this story? Weigh in. And while you’re at it, let the FDA know what you think:
Contact FDA: Toll Free (855) 543-3784, email@example.com
© 2016, MPNforum. All rights reserved under Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License