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 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+

Date Reported Drug/Company Deaths Phase/Cause
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