View attachment 50865 New York University’s medical school has quietly shut down eight studies at its prominent psychiatric research center and parted ways with a top researcher after discovering a series of violations in a study of an experimental, mind-altering drug. A subsequent federal investigation found lax oversight of study participants, most of whom had serious mental issues. The Food and Drug Administration investigators also found that records had been falsified and researchers had failed to keep accurate case histories.
In one of the shuttered studies, people with a diagnosis of post-traumatic stress caused by childhood abuse took a relatively untested drug intended to mimic the effects of marijuana, to see if it relieved symptoms.
“I think their intent was good, and they were considerate to me,” said one of those subjects, Diane Ruffcorn, 40, of Seattle, who said she was sexually abused as a child. “But what concerned me, I was given this drug, and all these tests, and then it was goodbye, I was on my own. There was no follow-up.”
It’s a critical time for two important but still controversial areas of psychiatry: the search for a blood test or other biological sign of post-traumatic stress disorder, which has so far come up empty, and the use of recreational drugs like ecstasy and marijuana to treat it. At least one trial of marijuana, and one using ecstasy, are in the works for traumatized veterans, and some psychiatrists and many patients see this work as having enormous promise to reshape and improve treatment for trauma. But obtaining approval to use the drugs in experiments is still politically sensitive. Doctors who have done studies with these drugs say that their uncertain effects on traumatic memory make close supervision during treatment essential.
The New York Times pieced together details of the research and the investigation through documents, letters and emails, as well as interviews with a participant and several researchers familiar with the project. The violations “jeopardize subject safety and welfare, and raise concerns about the validity and integrity of the data collected at your site,” the F.D.A. said in a letter, obtained by The Times, to Dr. Alexander Neumeister, the studies’ lead investigator.
Dr. Charles Marmar, the chairman of the psychiatry department at N.Y.U., said that people working with Dr. Neumeister had reported concerns about the lab’s compliance with research standards. Once some of those issues were confirmed, Dr. Marmar said, the university placed Dr. Neumeister on leave, “and suspended all activity, suspended access to all accounts. I took control of those studies.” Dr. Neumeister later submitted his resignation.
Georges Lederman, a lawyer for Dr. Neumeister, said there may have been protocol violations, “but N.Y.U. has taken the position that those violations were more egregious than we believe they actually were.” The issues could have been easily remedied, he said, and noted that they did not cause the sponsor of the research, the pharmaceutical giant Pfizer, to shut it down. Both the university and Mr. Lederman said there was no evidence that any study participant had been harmed.
Pfizer said that N.Y.U. was responsible for conducting the trial, and that the company had previously tested the same drug, know as an F.A.A.H. inhibitor, for osteoarthritic pain, without significant side effects. “The safety profile we observed does not preclude future development of our compound,” a Pfizer spokesman said by email.
Careful oversight is a centerpiece of ethical research practice, particularly when studies involve people taking an experimental drug. Earlier this year, six patients in a French trial of another experimental drug with similar, marijuana-like effects were hospitalized with severe neurological problems; one has reportedly died.
Study participants with mental disorders are especially susceptible to adverse reactions, experts said. “These are people who are more vulnerable to being exploited in the research process, and more vulnerable to things going wrong during the research, so you want extra vigilance,” said Elisa Hurley, the executive director of Public Responsibility in Medicine and Research, a national nonprofit devoted to promoting high research standards. “If someone in my family were in a situation like this, I would want to be sure that the institution was crossing its t’s and dotting its i’s.”
The study was an attempt to extend a small trial that Dr. Neumeister had done previously, suggesting that cannabis might relieve anxiety in some people with post-traumatic stress disorder. “We know very well that people with PTSD who use marijuana often experience more relief from their symptoms than they do from antidepressants and other psychiatric medications,” Dr. Neumeister said in a 2014 N.Y.U. news release after the first trial.
The research team decided to use a drug intended to produce some of marijuana’s effects, made by Pfizer, which financed the trial. Some participants took the drug over a seven-day period; others took a placebo pill. The N.Y.U. team performed scans on each person to see whether brain activation patterns correlated with symptom relief.
The study called for recruiting 50 people with a PTSD diagnosis, according to study documents. Only 14 enrolled at the N.Y.U. site, according to federal documents, and many had participated in previous studies by Dr. Neumeister. One had completed a study of another drug 16 days earlier, when the protocol called for a 30-day window, according to the F.D.A.
The federal inspection, from July 16 to Aug. 5 last year, found that the research team had failed to assess at least three subjects 24 hours after they had taken the experimental drug, contrary to study protocol, according to the F.D.A. letter. In several instances, the agency found, Dr. Neumeister had falsified documents by signing a fellow investigator’s name on reports. “However, in fact, you or another study employee actually conducted these study procedures,” not the colleague, the F.D.A. concluded.
Ms. Ruffcorn, who writes a popular Facebook blog on trauma called A Little Bent, said the most unsettling part of the experience was not the loose monitoring, but the preparations for the trial. To participate, the N.Y.U. team told her, she first had to stop taking all her medications. But the study had several false starts, requiring her to stop taking medication, then restart, then stop again — and restart.
“It was horrible,” she said. “I had flashbacks, returning nightmares, every symptom coming on full force, not to mention the withdrawal. After going off and back on four or five times, I told them, ‘I can’t do this anymore.’”
That’s when she was flown to New York to enter the trial.
Ms. Ruffcorn said she had several odd symptoms after the trial, including a hyper, wired sensation that occurred without the usual memories of abuse. For months, she tried to find out whether those reactions were tied to the experimental drug, but because the study was shut down and the data belonged to Pfizer, the N.Y.U. doctors could not tell her whether she’d taken the drug or a placebo.
Earlier this month, after much persistence, she found out that she’d taken the placebo. “It was a big relief,” she said.
Dr. Neumeister and N.Y.U. continue to disagree over the seriousness of the research violations, both sides said. But the university has tossed out all of the data as unreliable, and tracked down the study participants to check on their health, Dr. Marmar said.
“I honestly believed I had the best qualified and among the most ethical researchers on the faculty” running these studies, Dr. Marmar said.
By Benedict Carey - The NY Times/June 27, 2016
FAAH Inhibitor Phase 2 Trials Halted due to Patient Death, "Severe Adverse Reactions"
The research and development arm of Janssen Pharmaceuticals, a Johnson & Johnson JNJ +0.88% company, announced on Sunday (January 17) their voluntary suspension of dosing in two Phase 2 clinical trials of their FAAH inhibitor.
Janssen spokesperson Greg Panico confirmed yesterday that the experimental drug is JNJ-42165279.
Following a Phase 1 trial where few, mild side effects were reported, Janssen had launched Phase 2 trials of the compound in patients with social anxiety disorder or major depressive disorder with anxious distress. FAAH inhibitors have been under development for these and other neurological conditions. The inhibitors slow the degradation of anandamide and related endocannabinoids, chemicals the body makes that act on cannabinoid receptors.
Janssen’s decision is a precautionary response to January 15 reports of severe adverse reactions in a Phase 1 clinical trial of another company’s experimental drug in the same general class.
On Friday, January 15, the University of Rennes Hospital announced the admission of five patients with severe neurological injuries who had been participating in a first-in-human clinical trial of BIA 10-2474, an FAAH inhibitor developed by Portugal-based Bial-Portela. The study had been conducted on behalf of Bial beginning in July by the clinical research organization Biotrial at their private, 150-bed facility in Rennes. The most severely injured patient died on Sunday.
Human safety record of other FAAH inhibitors
However, Janssen’s drug, as well as Pfizer’s FAAH inhibitor, PF-04457845, have shown considerable safety in both Phase 1 and Phase 2 trials. The human safety of these experimental drugs has led to speculation that the Bial tragedy may not have been due to the pharmacological class itself but, rather, unforeseen off-target effects.
Nevertheless, Janssen has informed health authorities, research sites and study investigators of the Phase 2 trial suspension for JNJ-42165279, instructing that study participants be informed as soon as possible.
Recognizing that volunteers in Phase 2 clinical trials are suffering from disorders the experimental drug is intended to treat, Janssen also advised investigators to have study participants seek guidance from their treating physicians about existing FDA-approved medications to manage their respective conditions. Janssen “will reevaluate our decision to suspend dosing in these clinical trials when we have additional information,” according to their press release.
As I reported yesterday, Janssen just published a November 2015 paper in ACS Medicinal Chemistry Letters showing the high selectivity of JNJ-42165279 for human FAAH relative to other neurochemical receptors, enzymes, transporters or ion-channels, even at concentrations 1,000 times higher than than needed to inhibit FAAH.
Pfizer’s FAAH inhibitor was tested even more extensively, including the larger superfamily of enzymes to which FAAH belongs. Similar data are not available from Bial regarding the compound implicated in the severe adverse reactions in France.
The Pfizer PFE +1.42% drug did not perform better than placebo in a Phase 2 trial in patients with pain from osteoarthritis in the knee (Yes, drug companies do indeed publish negative outcomes of clinical trials). Pfizer also discontinued a Phase 2 study in patients with Tourette syndrome. Both Sanofi-Aventis and Vernalis have FAAH inhibitors in development.
The human safety assessment of Janssen’s JNJ-42165279 is not yet published in a peer-reviewed journal but has been reported at the 2014 annual meeting of the American College of Neuropsychopharmacology.
The pharmacology and tolerability of the drug was examined in a double-blind, randomized, placebo-controlled, single and multiple dosing studies in healthy males at 25 or 75 milligrams daily for 10 days, and healthy females and subjects 65 to 85 years old at 100 mg daily. The only clinical abnormalities reported were what the investigators described as a “slight, transient increase in liver enzymes” appearing in the blood for three subjects (of six) taking 75 mg and two subjects (of 12) at the 100 mg level. These levels normalized shortly after completion of the study.
Regarding safety signals in Phase 2 work, the Janssen spokesperson said, “Our two Phase 2 studies were testing 25 mg once daily, and to date, there have been no observable effects on liver transaminases or serious adverse events in these studies, for which dosing is now suspended as a precaution.”
Bial update–some good news
Some good news emerged from Rennes yesterday, January 19, where the Bial study was launched in July by the clinical research organization Biotrial at their private, 150-bed facility in Rennes. Yesterday, January 19, two of the patients were well enough to be discharged to neurological care at their local hospitals.
Another volunteer in the same group who had been under observation but never developed symptoms was also released.
The university hospital at Rennes continues to follow up with the 84 volunteers who received other doses of BIA 10-2474 without apparent side effects during the study. Neurologists there have confirmed that 18 subjects have received neurological examinations and MRIs, with none showing the cerebral hemorrhage or necrosis observed in the hospitalized patients. The hospital states that another 22 participants have been scheduled for examinations.
By David Kroll - Forbes/Jan 20, 2016
Big Pharma studies involving synthetic cannabis drugs, including but not limited to JNJ-42165279 - which is currently being tested on PTSD patients in the US and Europe - are in the news once again. DF News will be keeping an eye on this and other studies run by large pharmaceutical corporations such as Johnson & Johnson and Pfizer.
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