W

hen three cancer patients died earlier this year while on an experimental therapy, the Food and Drug Administration promptly halted the clinical trial. A few days later, the hold was lifted — a turnaround so fast that it stunned the world of drug development.

On Wednesday, the company behind the trial said two more patients were dead.

“In light of what happened, I think the FDA really dropped the ball,” said Maxim Jacobs, a health care analyst at Edison Investment Research who researches oncology drugs.

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“What did the FDA review during that period from when the hold was announced to when it was lifted? What exactly was the decision-making process? What was the logic behind going so quickly towards lifting the hold?” Jacobs asked.

The FDA declined to comment Wednesday on its decision. But the debate over whether the agency moved too quickly underlines a central tension over its role in both fostering medical innovation and protecting patient safety. It also raises questions over whether the agency is forthcoming enough about how it makes its decisions.

Jacobs and other experts emphasized that there’s no way to know where the FDA might have misstepped in the case of this therapy, developed by Juno Therapeutics. That’s because the curtain is drawn on how the FDA decides whether to halt and restart a trial, giving the public no way to know whether the decisions were made wisely based on the information available.

It’s possible that the FDA has a systematized process to review clinical holds, but it’s impossible to tell because companies consider that information to be trade secrets, said Dr. Aaron Kesselheim, who studies the intersection of law, regulation, and drug development at Brigham and Women’s Hospital.

Other than disclosures for panel hearings that are sometimes held to debate the risks and benefits of a drug up for approval, any glimpse into the FDA’s deliberations before approval is funneled through companies, who can be “overzealous” in withholding some of the information, Kesselheim said.

Juno has been testing a promising but still unproven treatment called CAR-T immunotherapy, one of the many varied approaches to harnessing the immune system to fight cancer.

In July, the company announced that the FDA had placed its study on clinical hold, prohibiting the enrollment of new patients, after three patients died after excess fluids flooded their brains.

But Juno insisted that the problem was not with the genetically engineered blood cells known as CAR-Ts infused into patients’ bodies, but rather with how the CAR-Ts reacted with a chemotherapy drug used to prepare patients for treatment. The company proposed the simple fix of removing that chemotherapy drug — and apparently that explanation for the deaths quickly persuaded the FDA.

The company announced that the FDA had lifted the hold just five days after announcing the halt.

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By comparison, a 2015 analysis that looked at 29 instances in which the FDA halted a drug study between 2008 and 2014 found that these holds were in place for a median of eight months. Another company’s drug trial for hepatitis C, halted by the FDA during the summer at about the same time it halted Juno’s study, still appears to be paused nearly five months later.

Juno said Wednesday that it had voluntarily halted the clinical trial after two more patients died from the same problem and informed the FDA. The agency declined to comment on whether it will impose a hold of its own on Juno’s trial, though an FDA hold typically follows such a move as a matter of procedure.

In a written statement from agency spokeswoman Andrea Fischer, the FDA said that because of the “great promise” of CAR-T and other cellular therapies, the agency does “everything possible to assist sponsors in advancing clinical development programs in an effort to bring promising therapies to patients.” The statement also said that the agency “constantly looks at the risk-benefit profile of experimental therapies and when we have concerns about the risks, we may place the clinical trials on hold.”

Experts said they understood the FDA’s impulse to move quickly on a trial for cancer patients running out of time. “I think the key here is just how sick these patients are and what few options they have,” said Ramsey Baghdadi, cofounder of Washington analysis firm Prevision Policy, who added that he thought the agency had acted appropriately on the case.

Still, the FDA’s ability to appropriately weigh risks and benefits is contingent on the information it has to work with, said Brad Loncar, founder of a cancer immunotherapy fund.

“The onus is on Juno to take to the FDA a well-thought-out, credible hypothesis of why these problems are happening,” Loncar said. “And in this case, especially with the benefit of hindsight, it’s clear they didn’t do that.”

Experts said it would be premature to call for the FDA to immediately shut down Juno’s other trials or other companies’ CAR-T trials. But Jacobs said given these alarming safety problems, the FDA should make sure that companies are collecting a lot of data before they move on to later-stage trials or seek approval.

“We’ve really been rushing into things with these CAR-Ts,” Jacobs said, “and we don’t really have any long-term data with any of these guys.”

In March, the FDA proposed creating new databases that would allow it to monitor the safety of experimental CAR-T treatments across different trials. At the time, the agency said it planned to collect data, store it in a database, and analyze it across the different studies.

But such plans could be stalled as the agency braces for upheaval in the aftermath of the election. Legislation that could reduce requirements for clinical trials may finally make it across the finish line in the next session, and the Trump administration is expected to call for further deregulation.

Rolling back the FDA’s standards would speed the path of new medicines to market, but it could also expose patients to added risks. Pending legislation would allow for FDA approval based on Phase 1 data. Juno’s therapy had already progressed to Phase 2.

“This is a good reminder of why we have a relatively strong FDA, why we have a premarket approval system, and why we want there to be data that can demonstrate that drugs are safe and effective before they’re opened up to wide populations,” said Patricia Zettler, a professor at Georgia State University’s College of Law who specializes in FDA regulations.

Damian Garde and Meghana Keshavan contributed reporting.

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  • I disagree with Brad Loncar. I believe it’s entirely possible that Juno had presented the FDA with a quite valid and believable reason that the fludarabine, and not the CAR-T cells, per se, were responsible. I’ve done clinical research with these cells, and there was a quite credible reason to think the problem had been solved. Apparently, we were incorrect. But to say that the FDA hadn’t been presented with a very credible hypothesis is speculative at best, and most likely incorrect.

  • Rather than declare whether the FDA be blamed, maybe let’s identify whether the informed consent document was updated after the hold was lifted.

    Most patients in Phase 1 trials have very poor prognoses anyway. So long as informed consent documents were updated with the correct risk assessment, why shouldn’t it be the patient’s choice?

  • It seems imperative that the trials continue; the therapy works in some.

    The question of personalizing the therapy by adjusting the amount

    of medication seems appropriate as does the question of the

    drug delivery system. Suggest you do an article interviewing

    Darrell J. Irvine at the Koch Institute.

  • All that said is frought with uncertainty
    We need to understand the fundamental biology of harnessing the anti tumor T cell attack with these CAR-T cells. If the mortality is due to CRS and brain edema we need to develop more effective approaches to mitigate these complications. The promise and effectiveness of this therapy is too high to ditch it too early and blame the FDA.

  • “blah blah blah,” said Maxim Jacobs, a health care analyst at Edison Investment Research who researches oncology drugs.

    The fact that the Statnews “science writer” went first to a stock salesman for an opinion on this important matter – as opposed to, for instance, a doctor or a scientist or a lawyer – tells us everything we need to know about Statnews, about “science writers,” and about who calls the shots around here.

    No wonder the American health care delivery system is chronically bloated, inefficient, and murderously over priced.

  • In a period when, a possible dismantling of FDA and wild deregulation are on the horizon, it looks ironic that the FDA is under fire for lack of adequate standards.
    But, in a future without FDA oversight there will be no clinical trials either. So, a win win situation for almost everyone.

  • TAKE BACK THE D.E.A.!!!

    The D.E.A. and F.D.A. both stand in defiance of Congress and also the Senate as well as the majorty of citizens. Because of the misuse and abuse of responsibility and credibility as well as incompetence and refusal to reform the enforcement power of the D.E.A. should be removed and placed back into the hands of the state. A semi-secret elite police force within what is already a police state is way over the top. America does not need this throwback to the cold war era. These Federal offices have become a haven of renegade Authoritarian despots and tyrants commandeering and miss-directing hundreds of millions even billions into their drug war against American citizens and likewise funding state police regimes both within the U.S. and worldwide.It is these federal agency’s that have created the drug problem solely to commandeer funding and as their power base. Well in excess of sixty percent of F.D.A. employees are lured into going to work for the pharmaceutical industry. The D.E.A. is no more than an arm of the pharmaceutical industry. These renegade authoritarians as well as the pro drug war Authoritarians in the F.B.I. need to be controlled or removed

  • “But the debate over whether the agency moved too quickly underlines a central tension over its role in both fostering medical innovation and protecting patient safety.”

    The FDA is in a no win situation … damned if they do and damned if they don’t.

    My concern is that often doing nothing because something might go wrong in a clinical trial – an experiment no one has to participate in – results in death. I’m glad the FDA is not accountable to the press and the social media 5 second soundbite or tweet that is either out of context or does not provide adequate context for a reasoned assessment and conclusion.

    For example, in stopping this trial, does that mean stopping enrollment? Did the two extra deaths come from people already enrolled or from those newly enrolled after enrollment resumed? That would give some added and important context.

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