After 150-Plus Treatment-Related Deaths in Clinical Trials Since 2014, Lawsuit Is Filed Against FDA to Increase Protection of Human Subjects
Informed Consent regulations must be updated to give trial participants more information on potential life-and-death safety concerns, contends Center for Responsible Science
Los Angeles, Calif., October 24, 2017 —The watchdog group Center for Responsible Science (CRS), along with clinical trial participants and the father of a deceased clinical trial participant, today filed a lawsuit against the Food and Drug Administration (FDA) for denial of CRS’ citizen petition submitted in June 2014. With reports of at least 153 treatmentrelated deaths in clinical trials in the last four years, it’s critical that FDA revise its informed consent regulations to increase protection of these participants. The petition requests that FDA ensure every prospective trial participant receives the information necessary to evaluate the real risks posed by the drug trials in which they may participate so they can make an informed decision on whether or not to take part.
To achieve true informed consent, trial participants need to understand that the drugs they are being given have been tested largely in animal models, which are acknowledged by FDA to sometimes be unreliable predictors of human response, especially for the new biologics coming to market. Indeed, preclinical evaluation of human risk in animal experiments for biologics can be difficult, and sometimes impossible due to species- specific reactions, which can expose human subjects to unexpected, potentially catastrophic effects.
FDA’s 2014 interim response to the petition claimed that it involved “complex issues requiring extensive review and analysis by agency officials.” However, even with the more than 150 clinical trial participant treatment-related deaths since CRS filed the petition, FDA recently provided just a brief response denying it. FDA’s response demonstrates that the agency has undertaken little, if any , review or analysis and has failed to address the serious concerns presented in the petition.
Attorney for plaintiffs, Alan C. Milstein (who previously represented the father of Jesse Gelsinger after the 18-year-old died in a Phase I gene therapy experiment), states: “Despite the lessons which should have been learned in that case, literally hundreds of additional human subject research participants have since died from treatment-related toxicities. The FDA has the obligation to protect human subjects in clinical trials by ensuring they are given all material information about the risks of such research so they can make an informed decision about whether or not to participate. CRS’ petition reflects life-and-death safety concerns and the FDA failed to use reasoned decision-making in denying this petition.”
One of the plaintiffs is the father of a 24-year-old patient, Max Vokhgelt, who died two days after receiving an experimental cancer therapy. While investigators have acknowledged in CAR-T clinical trials that toxicity issues can only be learned from humans, Max was not given that information. FDA’s own guidance language for cellular and gene therapies makes clear that traditional preclinical tests may not always predict human toxicity due to species-specific reactions and other issues.
The plaintiffs’ request in no way inhibits clinical research and the advancement of new medicines. CRS acknowledges that human subjects, whether healthy volunteers or patients, are currently the most powerful contributors in the identification of clinical suitability of new medicines.
“The recent documented failure of traditional preclinical testing to weed out deadly toxicities leaves the human recipient as the real arbiter on the safety of new medicines. Those exposed to new therapies with an unknown safety profile are the true guinea pigs,” says CRS President Dr. Neil Wilcox.
Milstein adds, “We simply are asking FDA to revise informed consent regulations to help ensure that trial participants get all of the information necessary to make an informed decision. That is the least we can do for those who are willing to take the risk to advance medical progress.”
Treatment-related deaths discussed herein reflect what has been reported in the media and some Securities and Exchange Commission (SEC) filings. Because unambiguous and complete reporting of the number of deaths in trial registries and publications does not currently exist, the actual number is likely higher.
The Center for Responsible Science www.crs501.org is a nonpartisan, nonprofit organization advocating for more modern and predictive test methods in drug development.
Dramatic Rise in Treatment-Related Deaths in Clinical Trials
FDA Must Ensure Human Subjects Have the Necessary Information to Make Informed Decisions about Real Risks
Clinical Trial Treatment-Related Deaths
2016-2017 – 143+
2014-2015 – 10+
2012-2013 – 1+
|2017||Juno Therapeutics, Inc. Transcend Lymphoma Trial JCAR017||1||Diffuse alveolar damage|
|2017||Stemline Therapeutics||4||Capillary Leak Syndrome Phase II|
|2017||Kite Pharma ZUMA-1 CAR-T||1||Cerebral Edema brought on by Cytokine Release Syndrome|
|2017||Ionis Pharmaceuticals – inotersen||1||Intracranial hemorrhage Phase III|
|2017||Merck Keytruda Keynote-183||29||Phase III Myocarditis, Stevens-Johnson syndrome, myocardial infarction, pericardial hemorrhage, cardiac failure, respiratory tract infection, neutropenic sepsis, sepsis, multiple organ dysfunction, respiratory failure, and unknown.|
|2017||Merck Keytruda Keynote- 185||19||Phase III intestinal ischemia, cardiorespiratory arrest, suicide, pulmonary embolism, cardiac arrest, pneumonia, sudden death, myocarditis, large intestine perforation, and cardiac failure.|
|2017||Seattle Genetics Vadastuximab talirine||Undisclosed||Undisclosed|
|2017||Bristol-Myer Squibb nivolumab (Opdivo) Approved by FDA 2/17||4||Unknown|
|2017||Takeda – bigatinib ALUNBRIG Approved by FDA 4/17||8||Phase II Pneumonia (2), Sudden death (1) Dyspnea (1), Respiratory Failure (1) Pulmonary embolism(1), Bacterial meningitis (1), Urosepsis (1)|
|2017||Johnson & Johnson Sirukumab FDA voted against approval 8/2/17||34||All phases Cardiovascular events (13), Serious infections (8), Malignancies (6) Other (9)|
|2017||Cellectis UCART123 FDA clinical hold 9/4/17||1||Phase I Cytokine release syndrome and capillary leak syndrome|
|2017||Alnylam Pharmaceuticals Fitusiran for hemophilia A and B||1||Mid-stage Blood clot cerebral venous sinus thrombosis (CVST)|
|2016||BIA 10-2474 BIAL||1||Phase I unprecedented reaction in the brain|
|2016||Juno Therapeutics Inc. JCAR014 for Adult ALL||2||Cerebral Edema and Cytokine Release Syndrome or neurotoxicty|
|2016||Juno Therapeutics Inc. JCAR014 for Lymphoma||1||Cytokine Release Syndrome or neurotoxicity|
|2016||Juno Therapeutics Inc. JCAR014 for CLL||1||Cytokine Release Syndrome, cerebral edema|
|2016||CTI Biopharma Pacritinib||Unknown||Intracranial hemorrhage, cardiac failure, cardiac arrest|
|2016||Gilead Sciences Zydelig||Multiple||Infections|
|2016||Juno Therapeutics, Inc. Rocket Trial JCAR015||3||Phase II Cerebral Edema brought on my Cytokine Release Syndrome|
|2016||Alnylam Pharmaceuticals givosiran||3||“early stage” hemorrhagic pancreatitis and pulmonary embolism|
|2016||Ziopharm Oncology Ad-RTS-hIL-12||3||Phase I Intracranial hemorrhage (1) Other two deaths unknown|
|2016||Alnylam Pharmaceuticals revusiran||17||Phase III Undisclosed cause of death|
|2017||Juno Therapeutics, Inc. Rocket Trial JCAR015||2||Phase II Cerebral Edema brought on by Cytokine Release Syndrome|
|2016||Seattle Genetics||4||Hepatoxicity Phase II|
|2016||Kite Pharma ZUMA-1 CAR-T||3||hemophagocytic lymphohistiocytosis, cardiac arrest in the setting of Cytokine Release Syndrome and pulmonary embolism)|
|2015||Zafgen Inc. – beloranib||2||Pulmonary emboli|
|2015||Juno Therapeutics Inc. JCAR014||1||Encephalopathy Cytokine Release Syndrome|
|2014||Juno Therapeutics, Inc. Rocket Trial JCAR015||3||Phase I Cytokine Release Syndrome|
|2014||Juno Therapeutics, Inc. JCAR014 for Adult ALL||1||Cytokine Release Syndrome|
|2014||Novartis University of Pennsylvania CAR-T Study for Leukemia||3||Cytokine Release Syndrome and Sepsis|
|2012||Bristol-Myers Squibb BMS-986094||1||Phase II Cardiac|