International MPN News, Science & Opinion

When clinical trials turn deadly.

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. IClinical trials 2000 to 2013t’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.

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“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.”

FDA Guidance -Clinical Trial Data Monitoring Committees, US Food and Drug Administration (2006

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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.

divider horizon lineJAKARTA – The Sanofi trial 

SUMMARY

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. 

CONCLUSION

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.

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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.  

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(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

Condition: Hematopoietic Neoplasm
Interventions: Drug: SAR302503; Drug: Placebo

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.)

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(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.

Sanofi Press Release, May 2013

Sanofi press release cropped
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(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.

US National Library of MedicineNational Institutes of Health

Brain MRI findings in Wernicke encephalopathy.Wicklund MR, Knopman DS.

Abstract
A 71-year-old woman with myelofibrosis on chemotherapy experienced an acute illness with nausea, vomiting, and diarrhea. Two weeks later, she developed an acute confusional state characterized by disorientation and fluctuating alertness with normal speech and language. Her neurologic examination demonstrated an upper motor neuron pattern of right hemiparesis. She reported double vision though ophthalmoparesis was not appreciated. Her gait was normal.MRI Wernicke While hospitalized, she developed generalized tonic-clonic seizures. Brain MRI revealed a small area of restricted diffusion of the left precentral gyrus (figure). She was diagnosed with a stroke with secondary seizures; however, as the confusional state resolved, she developed profound retrograde and anterograde amnesia. Review of the brain MRI showed high T2 signal in the medial thalamus and contrast enhancement of the mamillary bodies; a diagnosis of Wernicke-Korsakoff syndrome was entertained and she was started on thiamine replacement. The encephalopathy and hemiparesis resolved though she remains severely amnestic.
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(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

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(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.)

11/14/13

“I just got a phone call from my Dr. that has me a bit freaked. The SAR302503 trial has been halted by the FDA. I am not to take the drug anymore until further notice. They want me in B——- for some special tests tomorrow morning. They don’t want me to start another med yet as if the trial is resumed after these test results, I wouldn’t qualify. If it takes more that a week or so I guess I’ll go back on Jakafi. Feeling a little anxious & bummed.”
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(6) MPNforum Story, November 15

This story, verified with Sanofi, appeared in TSR.

Sanofi clinical hold forum nov 15

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(7) Sanofi Quits JAKARTA.  Press release, November 18.

Click on release to enlarge. Media contacts and advice to patients follow,  below

Sanofi Quits Cropped
Press Release:  Sanofi has notified investigators of all ongoing fedratinib trials, as well as health authorities, of its decision to halt the trials.   Patients currently in fedratinib trials should consult with their treating physician to determine the best alternative course of therapy for their myelofibrosis.  Contacts: Sanofi Media Relations Sanofi Tel: +33 (0) 1 53 77 94 74 Tel: +33 (0) 1 53 77 45 45 Global Oncology Communications Megan Thomas Tel: +1 (617) 768-8078 Mobile: + 1 (617) 447-0258 E-mail: megan.thomas@sanofi.com
“Patients currently in fedratinib trials should consult with their treating physician to determine the best alternative course of therapy for their myelofibrosis.”
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(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.  divider scross gif

(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.

Dan I was on the Sanofi SAR302503 trial for 1 1/2 years. For at least 6 months I reported having pressure type headaches, like my head was being squeezed in 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 know.

Laura   …  we have a right to know far more than we do now.

Jamie… the conduct of clinical trials is not perfect. There are safeguards in place. …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….

Dave   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.

divider horizon lineDoes the FDA have our backs?

The  JAKARTA trial was sponsored under the health authority of the Food and Drug Administration in the US.   The FDA has powerful rules in place to protect patients. (See Appendix for citations.)  It also has strict regulations and guidance measures for Sponsors, Institutional Review Boards, Investigators and Safety Monitoring Committees. But the FDA is only as good as its resources permit and only as effective as the data it gets from Clinical Trial Sponsors.  Its resources are limited, its ability to directly monitor on-going clinical trials negligible and when something blows up  — like the Sanofi Fedratinib trial —  regulations and law under which the FDA operates heavily favor the drug companies over patients by severely restricting access to Clinical Trial records.

We filed a FOIA request with the FDA for documents a week after Sanofi pulled its trial.  We were denied and provided a long list of regulations and Federal law that prohibited the FDA from divulging information from an Investigative New Drug application or trial. When Sanofi announced it had terminated its trial and stopped Fedratinib drug development, we filed a new FOIA request.  After 20 days, we should get the FDA denial and then go through the appeals process.

Finally, there’s The Magic Pill.

We don’t volunteer for Clinical Trials to test dosage and toxicity levels or swallow sugar pills.  We line up in hopes of getting that magic pill that will relieve our symptoms, roll back our disease and return us to the hearty days of health and happiness.   Truth is, there may be relief, even long term relief available through experimental and approved medicines, but there has yet to be a magic pill.  We need to make the cold-eyed risk/benefit calculation: How much pain and discomfort and loss of time are we willing to accept in a clinical trial knowing there is likely no cure at the pharmacy.  The brilliant genetically designed imatinib (Gleevec)  precisely aimed at the disease causing mutation was able to reduce Chronic Lymphoid Leukemia from an acute to a manageable chronic disease.  Even  though, for many, it  eventually stopped working,  short of stem cell transplant it is the biggest blood cancer breakthrough to date.

For us that means yes, we might consider signing on for a Phase III trial if we can get a patient advocate on board and a clear shot at clinical improvement…And even then, we’ll keep in mind the Sanofi Fedratinib debacle and listen for the sound of distant alarms.

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APPENDIX

Some relevant publications from the Department of Health and Human Services (HHS),  Food and Drug Administration (FDA), Office of Human Research Protection (OHRP) , the European Medicines  Agency (EMA) and others.

FDA doc on Clinical Trial Data Monitoring Committees

http://www.fda.gov/RegulatoryInformation/Guidances/ucm127069.htm

OHRP – Reviewing and Reporting Unanticipated Problems and Adverse Events  (VIDEO)

http://www.youtube.com/watch?v=hsUS0k3Ie_g&p=5965CB14C2506914

Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events

http://www.hhs.gov/ohrp/policy/advevntguid.html

 (Here’s the official definition of events that merit immediate reporting)

Unanticipated problem involving risks to subjects or others:  Any incident, experience, or outcome that meets all of the following criteria:

  1. unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied;
  2. related or possibly related to a subject’s participation in the research; and
  3. suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) related to the research than was previously known or recognized.

HHS  Pamphlet,  Protection of Human Subjects, Title 45 Code of Fedl Regs,part 46

http://www.hhs.gov/ohrp/humansubjects/regbook2013.pdf.pdf

 HHS, OHRP, Compliance Oversight

http://www.hhs.gov/ohrp/about/staff/index.html#oversight

“Don’t Mess with the DSMB”  NEJM  http://www.nejm.org/doi/full/10.1056/NEJMe1007445

Mayo Clinic – Informed Consent and Research Subject/IRB and Investigator responsibilities

http://www.mayo.edu/research/documents/28-informed-consent-the-research-subjectpdf/DOC-10027563

IRBs – Responsibilities, Organization, etc.   CFR Title 45 Part 46

http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html

Code of Federal Regulations  (CFR) Title 21  CFR 50.25  Informed Consent

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.25

European Medicines Agency.. Clinical trials in human medicine

http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000489.jsp&mid=WC0b01ac058060676f

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The Zebra Coalition

The Zebra Coalition is an effort to correct the clinical trial balance zebra herdin which patients are so marginalized we have no voice in our treatment and no right to view results of the trial in which we participate. It is an effort to lower some of the risk facing patients by bringing a patient advocate into every clinical trial. The Patient Rights on Clinical Trial petition is the Coalition’s attempt to direct the attention of the FDA, Congress, and the medical establishment to the grave dangers faced by unprotected patients despite the network of law and regulations in effect. The petition is scheduled to launch shortly.


© MPNforum.com, 2014. Unauthorized use and/or duplication of this material without express and written permission is prohibited. Excerpts and links may be used, provided that full and clear credit is given to MPNforum.com with appropriate and specific direction to the original content.

Comments on: "When clinical trials turn deadly." (6)

  1. Adjusting dosage in the way you describe is a logistical problem and it is still very risky since a large portion of the patients aren’t going to show up to get their thiamine monitored. If something happens to those patients Sanofi would still be the one blamed. Also, adjusting dosages implies a very small window between an effective dose and a toxic dose and no one wants to deal with that.

    These rare and ambiguous side effects are a big problem in drug development. If I had to guess, I would say that it could be that Sanofi thought they might be able to avoid the side effect but that it added too much risk to their Jak program. Basically, there a few things to consider:
    (1) The data from both ruxo and the Pfizer compound suggest that the effect seen in myelofibrosis (decrease in spleen size, etc) may not be related to the inhibition of Jak2. In fact, these drugs work about the same regardless of whether there is a Jak2 mutation. This possibility lowers the value of the Sanofi compound since its big selling point was that it was the most Jak2 selective compound out there. There was another Jak2 selective compound (the Exelixis compound) but it also had safety issues and is no longer being pursued.
    (2) there are relatively few patients with myelofibrosis, so it is hard to make the financial case for targeting it.
    (3) there is already a compound on the market (ruxo) that is likely better than the Sanofi compound

    Overall, Sanofi may have just looked at all of this and decided it just wasn’t worth it to continue.

    John

  2. In your first question to Sanofi you say that “the difference between SAR302503 and ruxolitinib clearly, in the judgment of the FDA and Sanofi, bore some responsibility for the onset of Wernicke’s.” Where did you find that information? Has either Sanofi or the FDA said that? Certainly Sanofi would never imply that they were filing an NDA if they thought there was a safety issue.

    The occurence of an SAE is not necessarily due to the drug. It is common for SAEs to occur in the placebo group as well as the treatment group. As far as I have been able to find, we haven’t seen enough data to decide whether the safety issue was drug related or not, but I’m very happy to see that you are pushing Sanofi and the FDA on that.

    Keep up the good work!

    • Good questions, John, thanks for raising them. The way this world works Sanofi won’t and the FDA can’t directly confirm the fedratinib trial was terminated because of a suspected link between the drug and Wernicke’s encephalopathy. As a result, we are forced to seek other sources of information and, as we said, speculate. Sanofi did concede it terminated the trial based on “reports of cases consistent with Wernicke’s…” after the FDA ordered a clinical hold on the trial. (See Step7 in “The Rise and Fall of Jakarta in 10 Steps” following my article.

      My first question to Sanofi (Step 8) was direct. The Sanofi response was evasive. Behind the question was the fact that fedratinib and ruxolitinib are both JAK inhibitors. The only event causing both the clinical hold and the termination of the trial was the evidence of Wernicke’s in those participating in the fedratinib trial. Therefore, since thousands of ruxolitinib patients over the past five or six years have been free of Wernicke’s, something in the makeup of the fedratinib molecule is different enough from ruxolitinib to have played a role in contributing to Wernicke’s in some patients.

      As to the association of fedratinib with Wernicke’s, we have the corroboration of the Wicklund and. Knopman report (Step 3), the reports from a Sanofi spokesperson prior to the termination and the first patient to alert us of the Sanofi letter urging immediate testing of thiamine levels, In addition we had reports from highly credible anonymous sources – confirmed by others – that there were likely seven cases of Wernicke’s in that trial and one death. All incidents occurred at the higher dosage level. We can’t confirm that yet.

      I agree Sanofi would not have been ready to file its NDA for FDA approval if it was aware of the deadly effects fedratinib was likely having on some in the trial. That might be the most frightening aspect of this whole tragic story. The Sponsor of a very large scale trial is ignorant of events that most say also occurred in the Phase II trial and was confirmed in Phase III Jakarta by the published Wicklund and Knopman report months before the trial was terminated.

      Maybe Sanofi just didn’t connect the dots. Maybe some dots were missing. In any case, the site investigators were unaware of the danger. Worst of all, patients were ignorant of possible unanticipated severe adverse effects as they continued to take the drug!

      It is this widespread ignorance of Wernicke’s in this trial that has sparked the creation of the Zebra Coalition and the impetus to get a Patient Advocate on every clinical trial.

      Finally, you’re right about SAEs occurring in clinical trials that are not drug-related, whether within the interventional or placebo cohort. It’s irrelevant. The FDA requires prompt reporting of EVERY severe adverse event, a reporting process that goes from investigator to IRB to Sponsor to Data and Safety Committee to the FDA. In case of death, the requirement is 7 days.

      It’s possible for events to slip through the cracks, for SAEs to not be recognized as drug-related. The most critical link in the chain is the report from the site investigator to the IRB or Sponsor. Without that input there is no way to assemble a trial wide pattern. But even if that single MRI-confirmed case of Wernicke’s in the Spring of 2013 went unreported, in the final analysis it’s the sponsor, Sanofi, that receives all reports and has the earliest and clearest overview. At the least, I think we can say it was a hazy view until the near the very end.

      • Thanks for your reponse! I completely agree with your main point, that Sanofi should be completely transparent about the reasons for terminating their clinical trial.

        You brought up the question of why Fedratinib had safety issues that haven’t been seen in patients taking ruxo. Unfortunately there is essentially no way of answering that question. There are two main possibilities:

        (1) The issue is due to a different set of Jaks being inhibited by the two drugs. That is possible since it appears that Fedratinib inhibits Jak2 substantially better than Jak1, while ruxo inhibits the two proteins to about the same extent.

        (2) More likely, the safety issue is due to inhibiting some completely unrelated protein (not a member of the Jak family). Identifying such a protein is essentially impossible.

        Even if we had a good hypothesis regarding why Fedratinib had safety issues, the only way of proving that would be to test the hypothesis in patients, which would be extremely unethical.

        John

      • The other possibility, of course, is to adjust the dosage and carefully monitor thiamine levels of patients. Fedratinib was working for some patients who would willingly go back on the drug. A surprising element in all this is the Wernicke’s issue didn’t surface in the U.S. throughout the dosage/toxicity Phase I/II trials. I talked to the P.I. who saw no case at much higher doses than the reported 500mg level at which, reportedly, all SAEs occurred. We’re still shooting in the dark here since neither Sanofi nor the FDA is releasing more data. We have a FOIA appeal pending and continue conversation with inside sources. As to the Ruxo/Fedrat comparatives, I’ll send you an e-mail withdiagrams of the comparative structural formulas.

        Zhen

  3. […] According to the MPNforum report: “More than two full months past trial termination, no official public accounting has been provided, no data on death or injury was 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 full story can be accessed at: http://www.mpnforum.com/jakarta […]

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