Dr. Claire Harrison at ASH 2013 on Sanofi’s Fedratinib and clinical trial safety
I keep writing this story and ripping it up.
– Zhenya Senyak
Sometimes it starts with zebras grazing placidly under the African sun while nearby a pride of lions tears into one of their own, newly brought down. This time they escaped claw and fang. This time they’re OK. They go back to living.
What choice do they have after all?
The Sanofi story starts that way because we hear about death of one of our own on a clinical trial and feel impotent. What can we do about it?
It doesn’t take long to realize the source of frustration and anger.
By the time we head toward a clinical trial we’ve run out of options. We rely on the good intentions, the professionalism and honesty of physicians and medical institutions, the oversight of the FDA. Some guys are good, some aren’t.
Because we’re weak and in pain, because we need this chance for relief, for a cure, we let ourselves forget clinical trials are part of a multi-billion dollar industry. In that often predatory system, we can become just the fodder fed in at one end to produce blockbuster drugs at the other. Or not.
They can write off their losses. We can’t.
We have to change the way things are done.
One of us died, at least four of us were seriously injured in the Sanofi Phase III trial of Fedratinib (SAR302503), the old TargeGen Jak2 inhibitor. The trial was suddenly put on hold and three days later, Sanofi packs up its bags and folds all further development.
What of the 400 or so patients on trial? Patient counseling? We’re told to get in touch with our hematologists. Make sure they check our thiamine levels.
For an explanation we’re fed corporate gobbledygook: “Following a risk benefit analysis…Sanofi determined the risk to patient safety outweighed the benefit fedratinib would bring to patients.”
How many ways is that statement bullshit? What, for example, is the risk to patient safety in getting booted out of a trial with no notice, no options, no counseling? And if the risk, based on the minimal information we’ve been permitted to learn, is based on a thiamine deficiency, vitamin B1, isn’t that something easily treated? Watch the Claire Harrison video and hear it for yourself.
The only thing about that Corporate PR statement I believe is that Sanofi did actually undertake a risk benefit analysis the weekend of November 16 and it weighed its own risk against its own benefits. With its weak oncology reputation further tattered by these reports, what chance does it have to come up against Jakafi?
Maybe worse than the cold calculations of a distant corporation, is the failure of our own government, the FDA, not only to monitor effectively but to release information to us, the patients, the guinea pigs lining up for a crippling bolus of drugs. After Sanofi refused to answer simple questions – how many of us injured? where did it take place, why didn’t you address the problem by screening patients and providing supplements instead of folding — we turned to the FDA.
Our request for information was denied . We filed a Freedom of Information Act request and the FDA’s FOIA group denied that as well on the grounds – get this – that it violates trade secrecy! Our appeal gets bumped up another bureaucratic notch to the OGIS and the Department of Justice.
We have to change the way things are done. Patients need open, honest communications with principal investigators. We need a seat at the table when clinical trial results are being evaluated.
Researchers don’t discuss procedures, risks, injuries, results with us any more than they would with laboratory guinea pigs and knock-out mice. Their job is to follow the trial protocols, report any severe adverse events not to us but to the study sponsor.
180 million reasons for Sanofi to quit.
But why did Sanofi come this far with the highly successful JAKARTA trials and fold right at the Phase III finish line, with all the FDA paperwork for an NDA done, just weeks from filing and almost certain approval?
So far we don’t know. But our investigation and leads from inside sources might provide a clue. 180 million clues.
Sanofi bought TargeGen three years ago for $560 million…to be doled out as the drug reached various milestones. Reportedly, $30 million was recently paid to the original investors for achieving Phase III end points. What remained were two payments of $90 million each, due upon receipt of FDA and EHA approval. That’s $180 million that won’t have to be paid now that that the trial is closed and further development cancelled.
For giant Sanofi, with sales of 35 billion euros or so a year, it might not be a compelling reason on its own but put in the balance with bad publicity and uncertainty about the root issues attached to the drug, it just adds 180 million other arguments on the side of closing down the clinical trial.
And so far as those patients benefitting from the drug?
Ah, that’s too bad.
What can we do?
Our first step is to form a taskforce, draft a petition and get it signed by thousands of blood cancer patients, a petition asking that clinical trial investigators be included under the new Sunshine Act that’s part of the Affordable Care Act. It’s a beginning. We need to pressure the FDA to be more responsive to patients. This is an election year, if we organize we can change things.
If you can participate send an e-mail to ourMPNforum@gmail.com. No message necessary. In the SUBJECT AREA type Zebra.
We’ll know what you mean.
Chronology of abandonment
Thursday, November 14: A patient told MPNforum she received notice from Sanofi to discontinue fedratinib.
Friday, November 15: A Sanofi spokesman calls MPNforum to alert patients patients that a “temporary clinical hold” had been placed on the drug due to four cases of Wernicke’s encephalopathy, one fatal. Sanofi would issue a press release on Monday and would make medical experts available via teleconference.
Monday, November 18: Sanofi pulls the plug on all fedratinib clinical trials.
November 21 Sanofi responded to three questions:
MPNforum: As SAR302503 (fedratinib) bears many similarities with ruxolitinib (Jakafi) what work is being done to investigate the difference that might have produced these events.
SANOFI: Sanofi has completed a detailed review of each patient with Wernicke’s like symptoms. The underlying cause is unknown. The cause is thought to be multi-factorial. Sanofi is collaborating with the steering committee and investigators to present and publish the results of the trials. Sanofi has contacted other companies who are engaged in the development of JAK2 therapies to share information on the cases in the interest of protecting patient safety and supporting new therapies
MPNforum: Why pull the drug instead of addressing the toxicity issue (See Dr. Claire Harrison video, above, on managing thiamine (vitamin B1) deficiency?
SANOFI: Sanofi has determined that the potential risk to patients being treated with Fedratinib outweighs the potential benefits. While the company recognizes that many patients have derived individual benefit as participants in the clinical trials, the safety of patients is paramount, and the potential risk has led to this difficult decision. Patients should consult with their physicians to seek alternative treatment as appropriate.
MPNforum: How many severe adverse events happened and at what centers did they occur.
SANOFI: Because our investigation and analysis of safety signals is ongoing, we are not releasing specific numbers.
How we were blindsided:
MPNforum Headline: Fedratinib (SAR-302503): Clinical hold on Sanofi trial, Patients to stop taking drug Story in TSR here
The FDA Denial of request for information: Click to enlarge, note reason given.
Take me back to the Contents
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Comments on: "Behind the collapse of Sanofi’s Fedratinib… a TSR Special Report" (13)
What I am very thankful for is this forum that allows knowledge and the experiences of others, suffering from these rare diseases and families a place to be shared.
One always feels very vulnerable and ill prepared from the very beginning. “Who do I listen to?” is the biggest question. Doctors giving bits of information and not the whole picture is not what one needs. My sister as my brother has said above was misguided in this very uncertain road that she was now navigating.
She was almost bullied into taking this trial drug SARS and told that this was her only hope.
When she was showing that it was taking a toll on her, the doctor showed no understanding or desire to work with her to find a way that would work for her. She felt like she was failing at this trial “boot camp”. She was already feeling physically weakened and of course this takes a bite out of you emotionally as well. So in my mind it isn’t just the drug companies that are at fault but the doctors who are responsible for conducting and supposedly monitoring their patient through the procedure. Everything should be documented and any flags raised should be reported to the drug companies. When my sister voiced her worries all she got was a deaf hear and ” no one else has that side affect”. She was the only one in his trial group. I feel terrible now looking back as I didn’t do more to challenge this particular
hemotologist. My sister got to the point that she was terrified to see him.
That is a horrible state of affairs. She has since changed her doctor and the new one, he gets her.
No one asks for a disease and it is not something anyone merits so doctors stop punishing those who need your help.Compassion and a listening ear go a long way.
Thanks for sharing your story, Susan, painful as it is. The protocols in place for clinical trial are problematic in several respects. In the most scrupulous and rigorous facilities, with excellent, caring investigators, patient responses are carefully monitored and adverse effects are reported within 24 hours to the study sponsor (the drug company). Unfortunately, the communications links from investigator to sponsor to FDA to institutional review board don”t include the patient on the clinical trial … until a new consent form is mandated by an unanticipated serious adverse event.
The Sanofi trial of federatinib (SAR302503) apparently fell short in realizing the goal of rapid, accurate reporting in clinical trials. In addition to your sister having her fears and systemic responses tp toxic dose levels ignored, it is likely an early SAE went unreported. The abrupt termination of the Phase III trial when FDA approval seemed imminent and inevitable took investigators as well as patients by surprise.
We’re in a particularly vulnerable state when entering a clinical trial, often weakened by our MPN having failed traditional established therapies and desperate for a successful therapeutic path. We’re not in a good position to advocate for ourselves and if we get a lousy attending physician – overworked, uncaring, or incompetent – it can affect the outcome of our trial, Clinical trial is a time we most need the support of our physicians as well as our families and advocates. So glad you and your brother are there for your sister and your family is part of the Zebra Coalition working to bring patient rights into the clinical trial process.
My sister has been dealing with MF for over a year now and at one point was part of this drug trial. I am so glad that she decided to get out because the side effects were nasty and now we learn that others had even worse reactions to the test drug. In a well managed trial each participant would undergo a preliminary profile of their current drug regimen, state of health etc. to establish a baseline for comparison. This was not done with my sister. Then the study would introduce small amounts of the test drug into the patient and monitor the results. This was not done with my sister. Instead they gave her the maximum dosage from the very beginning and only reduced it after she experienced horrendous side effects. When it all became too much for her she stopped the trial and sought out other alternatives. This trial in my sister’s case was very sloppily managed and a waste of time for all concerned. If this is how a multi-billion dollar company runs their drug trials then it’s no wonder it takes so long to produce positive results. For now, a bone marrow transplant is the only viable solution because Jakafi effectiveness seems to be waning rapidly.
That’s a an excellent and sad commentary, James. Thank you for sharing it. The way things are now, patients never hear of Severe Adverse Events on their trials, events that might well affect their own safety and survival. Please consider joining the Zebra Coalition to petition for a change in the clinical trial culture. Just send an e-mail with Zebra in the subject line to ourMPNforum@gmail.com and we’ll get a draft of the petition out to you for input and review the middle of January. Our objective is to get 1000 signatures of patients, doctors, caregivers, and administrators of medical institutions on a petition to extend patient rights on clinical trial. And get it into the hands of the FDA and medical establishment.
I was on the Sanofi SAR302503 trial for 11/2 years. For at least 6 months I reported having
pressure type headaches, like my head was being squeezed iin a vise. The drug trial was stopped due to brain lesions. If Sanofi was so concerned about patient well being I would think that we would be subjected to diagnostic imaging to find out how many others are also affected. I guess the truth is that nobody having any responsibility really wants to now.
Wow! I don’t want the “crickets” mentioned in the comment above either but we have a right to know far more than we do now. How many of these drugs are getting so much attention because they’re “for us” anyway? Aren’t some intended for other diseases as the endgame? We have a right to know.
I love the way that Dr Harrison says Weirneke’s encephalopathy.
The crossing of the blood brain barrier is certainly pertinent. One wonders if Jakafi and the other compounds in the drug development pipeline do the same?
I would add this; the conduct of clinical trials is not perfect. There are safeguards in place. I mentioned before that The Informed Consent document that patients sign needs to detail the risks and the possibility of ‘unforeseen risks’ as well.
The Institutional Review Board (IRB) at an institution has the power to not approve the conduct of the trial if they think that the risk is too great. They also have the power to stop a trial if there are too many adverse events and/or serious adverse events.
Patients can also withdrawal from a trial at any point in time.
I was a member of an IRB at a large University and feel that we were very conservative and always put patient safety first. I have SOME faith in the system, but again, it is not perfect.
Good points, all, Jamie. But the Sanofi story includes (1) keeping patients in the dark while knowing of Severe Adverse Events (SAE’s) and continuing to be uncommunicative after termination of the trial and (2) abruptly, within four days of notification, pulling the plug, sending patients off on their own with no more advice than “talk to your doctor.” For some, who have failed Jakafi and were doing well on SAR302503 this move was and still is devastating. (Just curious about IRBs: Since the investigation doctors on clinical trial report SAEs to the sponsor (Sanofi) and the sponsor reports to the FDA, what role does an IRB play after it give its initial approval to the research protocol?)
Who looks out for the best interest of the patients in the clinical trials? I suppose it’s the FDA, but there should be a third party that represents only the patients. I was kicked out of a drug trial recently when I had one blood test that showed elevated liver enzymes. That test was likely caused by another drug I was on, but the trial did not allow for any retesting or reconsideration. I was out the door and had no recourse. We need an organization that will fight for us.
Claire Harrison, intelligent doctor, explains the situation very well. Explains that they do not know if a neurological problem beyond the condition caused by B1 deficiency was present.
Too subtle to know completely at that stage.
Too many words bombarding my brain on this one! THANK YOU! Zhen for ALL YOU DO on our behalf! Again, too many words of gratitude – I mention you and MPNforum EVERY chance I get, so people will hopefully check out all the work – and excellent information you provide as we fight this seemingly endless battle.
STOP. Take a breath. This is clearly a drug that wasn’t panning out, or Sanofi would be be pursuing it for the very reason that they stand to make huge profits.
We are LUCKY to have these big drug companies, whatever some may think of them, researching drugs for our rare diseases. As an MF patient diagnosed over 32 years ago, I have seen 25 years when no drug companies were willing to even bother with MPNs. Too rare a disease, compared with breast cancer, diabetes, etc. Now there is a flurry of activity. I am thrilled to see it, finally.
Not all of these drugs will come to fruition. That’s life. But I have no interest in vilifying and fighting those who tried and gave up. Let’s encourage development of drugs for MPNs, not fight companies who tried and failed. It might take a a lot of failures to get our CURE.
Let’s not scare off those who are interested in finding a cure for our disease. It is a waste of everyone’s time and energy. We need big pharma and the FDA to get our cure.
There is finally investment and interest in our disease. Rejoice! Hope!
It used to be crickets! Let’s not go back there..
Wow! Quite the investigation.Thank you for all this digging, I agree we need mores answers, a better process, and real support for people who were in the trial.