From The Editor | March 29, 2016

France Tragedy Reminds Us Phase 1 Researchers Must Live With Tragic Results

Source: Clinical Leader
Ed Miseta

By Ed Miseta, Chief Editor, Clinical Leader
Follow Me On Twitter @EdClinical

France Reminds Us Phase 1 Researchers Must Live With Tragic Results

The recent clinical research tragedy in France that resulted in the death of one patient and the hospitalization of four others shocked many who work in the clinical research space. The adverse effects experienced by the previously healthy patients, reportedly involving deep brain bleeds, were both rare and disturbing.    

Roger Mills spent most of his professional life in the clinical trial space. Prior to his recent retirement from Janssen R&D as a Senior Director and Clinical Lead, he spent over 30 years in academic medicine and the pharma and healthcare industries. Prior to joining J&J, he served as medical director of the heart transplant program at the University of Florida and later was a staff cardiologist at the Cleveland Clinic.

During his time in the pharma industry, Mills had the opportunity to serve as a study-responsible physician in a Phase 1 trial. “The active part of the compound was a human hormone, and we had experience with it using intravenous administration,” he says. “We conducted a very careful Phase 1 trial with first-in-human precautions because we were administering it in a novel formulation linked to another molecule.”

During that trial, Mills and a colleague personally visited the clinical pharmacology unit, located in a center in Belgium, to be present for the first-in-human dosing. He notes the setting for the trial was hardly dramatic. It consisted of a healthy young man lying on a gurney with an IV, an automatic BP cuff, and ECG telemetry electrodes in place.

The experience, however, left him feeling these types of tests were anything but routine. An experienced study nurse was brought in to administer the subcutaneous injection. No one knew for sure what the reaction from the patient would be, which had everyone feeling on edge. As Mills and the others looked on, the patient was injected. Everyone watched and waited…and nothing happened.

In this particular trial, it was known that one of the six subjects in the first series would be receiving a placebo. Was this the one? No one knew for sure. So, on the following morning, they went through the process again. “Another subject, in the same setting, with another injection,” says Mills. “Again, nothing happened. Since the arithmetic demanded that at least one of those first two subjects received the assigned active drug, we knew one of the two subjects had been the first human being to ever be injected with the first dose of the compound. This was something that none of us involved in the study took lightly. Anytime you are the first to inject a new compound into a human being, there will be risks involved. It is a responsibility that folks in the clinical space will always take very seriously.”

So what do you think about when you are the “responsible” physician, standing at the bedside of a patient, watching a new medicine get injected into a human for the first time? Mills likes to reference a comment by F. Scott Fitzgerald, which he believes captures the experience perfectly. Fitzgerald wrote, “The test of a first-rate intelligence is the ability to hold two opposed ideas in mind at the same time and still retain the ability to function.”

“When administering this type of trial, I think there are generally two thoughts that will go through a researcher’s mind,” says Mills. “One idea is, ‘my goodness, we are making such a fuss over something that we know is safe.’ The other, not surprisingly, is “I hope and pray that nothing goes wrong with this human subject’s life, but if it does, I hope my emergency plan works and the patient will be all right.’”

Mills was recently reminded of this trial experience while reading about the Phase 1 tragedy in France. Thankfully, his patients completed the trial with no adverse reactions. Sadly, that was not the case for the subjects in the Bial trial in Rennes. “This is the enormous responsibility that is shouldered by everyone who does research involving human subjects,” he says, with his voice giving away the sadness he clearly feels for the unfortunate victims and their families. “Despite our very best efforts, sometimes something can unexpectedly go off the tracks. In medical research, nothing is ever a certainty.”

When a tragedy like this arises, it is normal for most of us to instinctively feel sympathy for the subjects. And rightly so. These were perfectly healthy individuals who placed themselves in danger to test a new compound that might someday bring relief to patients suffering from pain. The death of even one patient, and the ongoing health issues of the survivors, is something friends and family members will have to struggle and cope with for years.

While it appears the trial may have involved actions that went against EMA recommendations released in 2007, the individuals who oversaw the trial are certainly feeling the anguish of the tragedy as well. Having worked on a Phase 1 trial himself, Mills notes he also feels sympathy for those researchers, who had high hopes for a safe and effective new drug, and were somehow terribly, terribly wrong in their analysis. “We cannot brush bad outcomes under the rug,” he states. “We have to talk about them, and we have to make sure the media and the lay public understands pharmaceutical research is not a strictly commercial activity. It is very difficult. It is very human. Occasionally, it can also become very dangerous. Unfortunately, it is also a necessary part of the drug discovery process, and a necessary part of industry efforts to make life better for all patients.”