Many people in the UK and elsewhere are currently remembering where they were and what they were doing on the day that Diana Princess of Wales died: August 31st marks 20 years since that fateful day.
For Clinical Pharmacologists, we may well remember where we were when we heard the news that six volunteers were fighting for their lives in a hospital in West London following administration of a test drug in a first-in-man study. I was on a train passing through the leafy Sussex countryside when I heard the news on the evening of March 14th, 2006. The trial was with TGN1412: a humanized monoclonal antibody that binds to and is a strong agonist for the CD28 receptor. The agent was under development by TeGenero. Mercifully, all the volunteers survived but not without life-changing injuries.
The event certainly changed the conduct of early phase clinical trials. Regulators were swift to issue new guidance (EMA, 2007). It was helpful for our industry to be scrutinized by the outside world: practices that we had no longer questioned as they were “industry standard” were suddenly exposed to public scrutiny. Among the many valuable recommendations for study conduct and design, one lesson stood out to me: Don’t dose a cohort of subjects simultaneously. Had just one volunteer in the TeGenero trial been dosed with active drug and observed before the rest of the cohort were dosed, the impact of the adverse event would have been dramatically reduced.
At the time, the “standard approach” was a 6+2 (6 active subjects and 2 placebo) dosed simultaneously. The EMA 2007 guideline (issued in response to the disaster) called for sequential dosing in which… it will usually be appropriate to design the administration of the first dose so that a single subject receives a single dose of the active IMP [Investigational Medicinal Product]. The same concept is captured in the 2017 revised guidance (EMA 2017) in which the term “sentinel” dosing is now commonly used and understood.
Strangely enough, our community used to use the sentinel approach in the 1980s. In my first few years in the industry, I travelled to a Phase 1 unit in Dundee, Scotland to assist in 14C ADME studies. The unit at that time adopted a “lead volunteer” approach for single rising dose studies. The study design was published in 1989 (McEwen 1989 and see below)—I suspect we could use the same design now and be fully aligned with the EMA’s most recent guideline. In fact, it’s a more elegant design than some of the new standard sentinel designs. Perhaps a question for the historians (and us all): why did we forget and why did it take a disaster to re-learn what we once knew?
Table 1: Design of a typical ascending dose pilot Phase 1 study involving 26 subjects in five separate double-blind study sessions*
*reproduced from Xenobiotic Metabolism and Disposition: The design of Studies on Novel Compounds: CRC Press 1989 Chapter 7 Studies in man with potential therapeutic agents. J McEwen.
Note: On each occasion, one subject in the group receives placebo and only one subject receives the “leading” dose.
More regrettably, a healthy volunteer died in another early phase clinical trial conducted almost a decade later. In 2007, there was some acknowledgement that the study drug was “new” in the sense that it was a monoclonal antibody with stimulatory activity. Not so this time. The Portuguese company Bial had developed a conventional small molecule, and serious adverse events weren’t expected to occur in the trial: the pharmacology was known and small molecules in the same class (FAAH inhibitors) had already been studied in humans. Extensive toxicology studies had been conducted—in greater duration and extent than stipulated by regulatory guidelines: three months’ toxicology in mouse, dog, and monkey and six months in rat. The early part of the study went well: a single rising dose phase (with a sentinel dosing approach) in eight cohorts, a food effect cohort had been conducted, and no less than four multiple dose cohorts (treatment once a day for 10 days) had been successfully completed.
But on the 5th day of the final multiple dose cohort, things started to go wrong. On Sunday evening of January 10th, 2016, one subject was admitted to the hospital with a suspected stroke that was not considered to be drug related. On Monday morning of January 11th, the news on the hospitalized subject was positive, and the remaining volunteers were dosed for the 6th day of administration. During that day, the condition of the hospitalized subject deteriorated, and he fell into a coma. The study was stopped. In the following few days, four other subjects developed neurological symptoms and at 13:25 on Sunday, January 17th, Guillaume Molinet, an artist and father of four children, died aged 49.
Undoubtedly, many valuable lessons have already been learned from this tragedy; the revised EMA guideline is as good an expression of these lessons as any.
Whilst the cause of the toxicity observed in the Bial trial remains uncertain, off target effects unique to the test drug were likely involved. Van Esbroeck et al (2017) concluded from in vitro studies that “promiscuous lipase inhibitors (such as BIA 10-2474) have the potential to cause metabolic dysregulation in the nervous system.” Extensive studies of potential off target effects thus must be conducted with more rigor than that done by Bial. This is especially true for agents that bind irreversibly (as FAAH inhibitors do) and for agents that bind to targets that are members of large families such as serine hydrolases.
For me, there was one prominent study design learning: don’t dose higher than necessary. In the 1980s, one of my colleagues described a “first-in-man single rising dose” study (with his tongue only partially in his cheek) as a “poisoning study.” He meant that the trial’s objective was to escalate the dose until toxicity was observed, thus allowing the “maximum tolerated dose” (MTD) to be discovered. Sadly, this thinking has remained ingrained in the minds of “first-in-man” practitioners despite critical commentary. After the TeGenero accident in 2006, Cohen wrote an “Editor’s view” entitled, “Should we tolerate tolerability as an objective in early drug development” (Cohen 2007). He argued that early drug development is about pharmacodynamics and pharmacokinetics and should be powered for these primary objectives rather than tolerability. The recent guidance issued by EMA also advocates this reasoning (at least for healthy volunteer trials): “A trial design using a MTD approach is considered to be inappropriate for healthy volunteers.” In hindsight, which is indeed a wonderful thing, it seems that had the designers of the trial with BIA 10-2474 been more conscious of exposure response relationships and less concerned with MTD, they may well have decided that the top multiple dose cohort was unnecessary. Whilst first-in-human trials do need to explore high exposures to gain confidence to proceed to studies in larger, more diverse populations, a conscious decision on the upper acceptable exposure needs to be made by blending a priori knowledge with accruing data from the study itself.
The lesson from this most recent tragedy is that understanding exposure response relationships is much more informative for drug developers than attempting to define MTD, and it happens to be safer too.
Annelot CM van Esbroeck et al. (June 2017). Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474. Science, 356(6342), 1084-1087.
Cohen A. (2007). Should we tolerate tolerability as an objective in early drug development? Br J Clin Pharmacol 64(3), 249-252.
EMA. (July 2006). Strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products. European Medicine’s Agency.
EMA. (July 2017). Strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products. Revision 1. European Medicine’s Agency.
McEwen J. (1989). Studies in man with potential therapeutic agents. In Xenobiotic Metabolism and Disposition: The Design of Studies on Novel Compounds. CRC Press.
For another perspective on lessons learned from the Bial tragedy, please watch this webinar by my colleague, Dr. Neil Benson: