After Sanofi’s MF drug trial blew up, who could tell us why?
Special Patient Safety Report
– Zhenya Senyak
It never should have happened. ..
In the Spring of 2013, a 71 year old woman with myelofibrosis became acutely ill while on a clinical trial for a new drug. In addition to nausea and diarrhea she was disoriented and confused. She was referred the Mayo Clinic (Rochester) neurology department for examination. The report came back: Wernicke’s encephalopathy, brain lesions.
JAKARTA was a big, international clinical trial of Sanofi’s myelofibrosis drug, fedratinib (SAR302503). Over 100 sites worldwide. At every site, an investigator, a physician, was required to identify unanticipated events that jeopardized patient health. The onset of confusion, vision issues, cerebral bleeding, staggering was just such an unanticipated event.
The physician/investigator on-site is required to report such events to the local Institutional Review Board (the IRB).
The IRB was obligated to review and report to trial overseers, the Data Monitoring Committee and the trial’s Sponsor, Sanofi so all the site investigators could be notified. In the US, they were required to report such events promptly to the FDA and to the Office of Human Research Protection. Nothing happened. The research protocol wasn’t changed. No new consent forms signed. No one seemed to have learned of the event.
In the Sanofi SAR302503 trials, there are unconfirmed reports of one death and seven unanticipated severe events, some resulting in irreversible injury. The clinical trial nevertheless continued full speed until November 14. It was abruptly terminated November 18 to the dismay of patients and investigators.
What happened? Apparently the local IRBs and possibly even the FDA and Sanofi thought everything was OK until November when someone started putting the clues together. That was more than two years since the start of JAKARTA and more than five years since the molecule was first tested in humans.
How did things go so wrong?
Clinical Trial…on trial.
JAKARTA — the multi-national myelofibroisis drug trial sponsored by French giant pharma Sanofi — is a wake-up call. We can’t just turn over, go back to sleep and dream of a secure medical test environment.
Even though every alarm bell, emergency siren, and wailing ambulance sounded as JAKARTA blew up, some of us refused to get aroused. “Ah, too bad…but Clinical Trials are risky after all.” And: “Our safety is looked after by doctors, committees, the FDA.”
Now, wide awake, more than two months later, we know the truth. Clinical Trials of new drugs may ultimately—and rarely – produce useful medicine but they are routinely tests of potentially toxic substances on human subjects. Us. At the very least, we need to rewrite our perception of Clinical Trials. Our belief in a safety network of rules, regulations and overseeing angels was shredded by the reality of JAKARTA.
Phase III trials are drug testing’s gold standard. In Phase III, a roughly calibrated dosage of a drug known to have some degree of efficacy is tested on human subjects against a control population. Unlike the small Phase I or II dosage and toxicity trials — a lot like stepping barefoot and naked into an ocean filled with stingrays, sharks and jelly fish — Phase III has lifeguards in place, or so we thought.
JAKARTA was a Phase III trial that makes the Gold Standard look like badly tarnished brass. A deep and deadly ignorance permeated JAKARTA. Just two weeks before Sanofi pulled the plug, the company made a milestone payment conditional on achieving acceptable safety and efficacy results. Sanofi was only days away from filing its FDA approval application when it reversed course and unceremoniously backed out. Trial closed. Drug development terminated. Every MF patient on the study out in the cold.
Clearly, nearly everyone — patients, doctors and overseers — was taken by surprise by a seemingly successful study of a good drug by a truly big drug company spectacularly blowing up right at the finish line.
How safe are clinical trials really?
The sudden and abrupt termination of JAKARTA shook the MPN world. Sanofi had already trumpeted its successes. What no patient – and very few investigators – knew was death and severe disability had surfaced in the course of testing SAR302503 (fedratinib) in its MF trial months earlier.
The breakdown of interlocking clinical trial patient safety mechanisms was absolute. This report reflects on the whole process of clinical trial, not just about Sanofi’s ill-fated run for the gold with Fedratinib. Its JAKARTA worldwide Phase III trial of SAR302503 exposed the vulnerabilities of the clinical trial system itself. The system is totally dependent on the trial investigator/physician sounding the alarm and everyone else down the line following the rules. It doesn’t always happen.
Its JAKARTA worldwide Phase III trial of SAR302503 exposed the vulnerabilities of the clinical trial system itself.
MPN Clinical Trial and patient risk.
Today, when traditional and alternative therapies fail us or our MPNs enter a proliferative stage or when acute MF progresses into blast phase, we have basically three choices: Stem cell transplant, experimental drug trial, or enjoy our last days as creatively, comfortably and peacefully as possible. Long before that time, while on approved therapeutic interventions, we can exercise any of those options. That’s why examination of the clinical trial process is so essential to us. Some day we may need it. We think of Clinical Trial as our ace in the hole. For some, it turns out to be the Ace of Spades.
For now, Clinical Trial is the best option available for testing and tweaking potentially useful drugs. It’s one reason Clinical Trials have become a multi-billion dollar growth industry. Soon enough, our genomic databases, biotechnology and data processing power will bring about a new era where drug testing is done in the body of a computer. Until then it is done in our bodies, often with awful results. We need to be alert to the risk and strongly defend our right to know what’s happening in our Clinical Trial.
We need a patient advocate on our trial to minimize our risk.
“The ability of DMCs [Data Monitoring Committees] to provide the anticipated additional assurance of patient safety and trial integrity therefore depends on appropriate selection of DMC members….One or more individuals (often non-scientists) who may help bring to the DMC the perspectives of the population under study may be a useful addition … the member could be someone with the disease or condition under study or a close relative of such an individual, for example.”
We are an at-risk population. Our immune systems are often compromised, our blood lines out of balance. Our platelets are too high or too low. We have elevated risks of bleeding incidents or thrombosis or hemorrhage. All this in addition to likely anemia, fatigue, etc. We have a myeloproliferative neoplasm. An investigative MPN drug clinical trial may address one or more of our symptoms. And we take the risk to derive the benefit. We risk weakening our immune systems. We risk organ and tissue damage. We risk wasting precious time. We risk qualifying for stem cell transplant.
But failure of oversight is not a risk we normally consider. When we calculate if the risk of entering Clinical Trial is worth the gain, we now need to factor in the possibility that there may be no guards on the watchtower.
The Sanofi trial of SAR302503 demonstrated the Fedratinib drug was effective for some patients but not safe at higher dosage levels according to unconfirmed reports for others. JAKARTA resulted in patient injury, permanent and devastating patient disability, and patient death. The trial also demonstrated how broken the Clinical Trial process is in reality even though it appears bullet proof and multi-layered on paper.
Overlapping security, safety and management systems all failed to prevent or even help recognize a pattern of deadly emerging symptoms of a neurological disorder in the Sanofi SAR302503 trials. What was lacking was intimate patient contact, adequate processing of patient complaints, comprehensive diagnostic procedures. What was missing was one person advocating for patients at every trial site.
Signs of Wernicke’s encephalopapthy (see below), a serious neurological disorder that can result in disability and death, arose in Phase II SAR302503 trials. The disease, caused by depletion of thiamine (vitamin B1) resources is characterized by confused mental state, unsteady gait, and vision issues. It can be difficult to diagnose but is easily treated in early stages and irreversible in later stages.
MRI confirmation of Wernicke’s encephalopathy and its association with the drug provided in an MF trial was made at the Mayo Clinic (Rochester) this Spring. The results were published in August. Nevertheless, the trial continued for three full months with patients and physicians ignorant of any increased risk.
With Sanofi not talking and the FDA claiming it can’t, instead of a clear, airing of events patients, caregivers and the medical community are forced to speculate.
It’s not that hard to connect the dots.
Fact: The 71 year old myelofibrosis patient referred to the Mayo Clinic (Rochester) neurology department was in a clinical trial suffering effects of the trial’s experimental drug. Fact: The only MF drug known to cause Wernicke’s encephalopathy is fedratinib, the drug on the JAKARTA trial. Fact: This unanticipated event confirmed in the Mayo Clinic (Rochester) neurology department required a report by the trial investigator and review by clinical supervisory committees and ultimately the FDA.
That did not happen.
The FDA did confirm to MPNforum: “Sponsors investigating a drug under an IND (Investigative New Drug) are required to notify the FDA and all participating investigators, in a written IND safety report, of any adverse experience associated with the use of the drug that is both serious and unexpected…The sponsor must notify the FDA and all participating investigators in an IND safety report of potential serious risks, from clinical trials or any other source, as soon as possible… Unexpected fatal or life-threatening suspected adverse reactions represent especially important safety information and must be reported to FDA as soon as possible but no later than 7 calendar days following the sponsor’s initial receipt of the information.”
FDA regulations like that could give us warm and fuzzy feeling of security…until we realize it doesn’t always happen like that.
We interviewed several clinical site investigators and never found one who knew there was a serious threat in the JAKARTA trial. Physicians continued to dose patients with the potentially deadly drug right until the plug was pulled on the trial in mid-November.
Most significantly, patients taking the drug knew nothing! Informed consent was not an option.
To this day, more than two full months past trial termination, no official public accounting has been provided, no official data on death or injury made available to patients or their physicians. At least some of the patients are believed to have suffered irreversible neurological and cognitive damage. No one has taken responsibility for failure to diagnose, failure to report, or failure to terminate the trial earlier. The FDA has declined the MPNforum Freedom of Information Act request for documents and an appeal is now pending.
Nothing in fact has been learned that will help prevent future calamitous events in Clinical Trial except perhaps this: We are now aware of how imperfect the safety safeguards are. We need a patient representative in place at each trial site. The FDA has recommended such a representative in its Guidance for years. Now is the time to make it mandatory and write it into every Investigative New Drug research protocol. The Zebra Coalition is preparing a petition asking the FDA Commissioner make such a patient advocate part of the clinical trial process.
The Rise and Fall of JAKARTA in 10 Steps:
What follows is a chronological presentation of documentation, background and exhibits tracing the evolution of events. In general, links are provided where possible to permit direct examination of documents.
(1) The official record from clinicaltrials.gov
|1||Active, not recruiting||Phase III Study of SAR302503 in Intermediate-2 and High Risk Patients With Myelofibrosis
This is our first stop in reviewing a clinical trial, the clinicaltrials.gov document that lays out the research design, the goals of the trial testing the Investigational Medicinal Product (IMP), the endpoints, the requirements to join, the sites open for the trial. What it doesn’t say anything at all about is risk. That comes later when you’re handed the informed consent form to sign. ( If you’re considering a clinical trial, download the document, talk to your doctor about it, read the Consent Form over carefully before handing it over to a friend or lawyer for review. We spend more time buying a car than evaluating a clinical trial.)
(2) Sanofi claims good results, preparing to file for FDA approval
Here’s the announcement that brightened the eyes of MF patients and hematologists alike. The JAKARTA results announced before the big European Hematology Association conference in Stockholm were uniformly upbeat. Note the broad hint in the third paragraph that SAR302503 is ready for prime time.
(3) Publication of M.R .Wicklund and David Knopman’s paper, “Brain MRI findings in Wernicke encephalopathy,” August, 2013.
This is the publication in the medical literature establishing the presence of Wernicke in the SAR302593 trial. Published in August, it is believed to reflect work done in Apri, 2013.
(4) BACKGROUND: Wernicke’s encephalopathy…What every ER physician should know. “…, Wernicke’s encephalopathy continues to be an unrecognized and often misunderstood disease. The cause of Wernicke’s encephalopathy is thiamine deficiency as a result of any nutritionally deficient state…. Unfortunately, the syndrome is most often recognized only on autopsy, especially among nonalcoholics. Despite advances in magnetic resonance imaging, Wernicke’s encephalopathy remains primarily a clinical diagnosis. …, physician knowledge of this disease is vital because the failure to diagnose results in severe neurologic morbidity and possible mortality, but the treatment is safe and effective. The classic clinical triad of Wernicke’s encephalopathy consists of mental status changes, ophthalmoplegia, and gait ataxia. However, the complete triad may be present in as few as 10% of cases. Conversely, other signs of disease such as hypothermia, vestibular dysfunction, and other ocular abnormalities can be present….Thus, reliance on the presence of the clinical triad as the sole criterion for disease is often inadequate and may lead to underdiagnosis. The most constant component of disease when determined from retrospective autopsy studies is mental status changes. The degree and nature of cognitive impairment range from apathy or mild confusion to complete coma.” From: Ann Emerg Med.2007;50:715-721, Myths and Misconceptions of Wernicke’s Encephalopathy: What Every Emergency Physician Should Know , M. Donnino, J.Vega, J. Miller. http://www.synergymedical.org/acog/em/cola8/17681641.pdf See, too: Neuroimaging Findings in Acute Wernicke’s Encephalopathy: Review of the Literature, Giulio Zuccoli and Nicolò Pipitone2
(5) First patient reports sign of trouble — November 14, 2013 — e-mail to MPNforum, (anonymized)
(Note: November 7, a week before this first patient e-mailed MPNforum with this notice, according to unconfirmed reports Sanofi informed some study site Investigators of a potential safety issue and recommended reducing the SAR302503 dose and adding a thiamine supplement. MPNforum has not obtained a copy of that letter to site investigators and cannot verify it but we have heard reports from two independent sources and consider it likely.)
(6) MPNforum Story, November 15
This story, verified with Sanofi, appeared in TSR.
(7) Sanofi Quits JAKARTA. Press release, November 18.
Click on release to enlarge. Media contacts and advice to patients follow, below
“Patients currently in fedratinib trials should consult with their treating physician to determine the best alternative course of therapy for their myelofibrosis.”
(8) Three questions from MPNForum to Sanofi. November 18 and the official Sanofi response, November 20, 2013
SANOFI: In response to your specific questions regarding our recent actions regarding investigational JAK-2 agent fedratinib, I am pleased to provide the following information:
MPNforum: (1) … the difference between SAR302503 and ruxolitinib clearly, in the judgment of the FDA and Sanofi, bore some responsibility for the onset of Wernicke’s. Knowing the difference between the two molecules, the pathways targeted, etc. could save future lives. If not already known and understood, what work is being done to investigate that difference?
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: (2) It appears the interruption of the trial was mandated by the FDA but the closing out of further clinical development of SAR302503 was a Sanofi decision. I want to know why…beyond the risk/benefit rationale quoted in the release, Sanofi made that decision. Why is all this time and capital investment being left on the table, Sanofi’s reputation damaged, instead of tweaking the drug or perhaps developing a screening mechanism to avoid future SAE’s?
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: (3) Finally, I’d like to know the actual number of SAEs and their outcomes and the centers in which they occurred.
SANOFI: Because our investigation and analysis of safety signals is ongoing, we are not releasing specific numbers.
(9) Behind the Collapse of Sanofi’s Fedratinib (MPNforum Special Report) December 15.“
This is a special brief report prepared at the time of ASH-New Orleans. It contains a short video of Dr. Claire Harrison and the creation of the Zebra Coalition. It is included here mostly for the comments reflecting patient and caretaker response to the Sanofi actions.
S.T.: December 22, 2013 at 5:13 pm … My sister … 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 ear and ” no one else has that side effect”. 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.
J.T.: 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…. 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.