What did some clinical trials go wrong

Drug Studies: Rare and Mysterious Death

After the death of a test person and severe damage to health in other participants in a phase 1 study, the cause remains unclear. The closeness of the authorities and the companies involved makes clarification more difficult.

A serious incident in a Phase 1 study conducted by Biotrial resulted in one death. Photo: picture alliance

A phase 1 drug study is an early step on the long road to ensure patient safety with new drugs. A serious incident has now occurred in the French Rennes. Severe damage to the central nervous system occurred in five out of six study participants who received an increased dose of a test substance in parallel. A test person died as a result.

In this country people pay particular attention to such news. After the USA, Germany is the second most important country for clinical studies: in the last eleven years, more than 10,000 clinical trials have been approved by the German regulatory authority, the Federal Institute for Drugs and Medical Devices (BfArM). These included more than 2,700 tests that, like the fatally failed test in France, were carried out with healthy test subjects. The BfArM counted more than 100,000 healthy volunteers in the studies. Not a single serious incident of this type and of this magnitude was observed.

For comparison: since the safety requirements were increased in 2007, more than 12,000 phase 1 clinical trials have been carried out in the EU without serious complications.

The active ingredient examined is an inhibitor of the body's own enzyme fatty acid amide hydrolase (FAAH). FAAH is involved in the breakdown of the body's own endocannabinoids. An inhibition of this enzyme is attributed, among other things, to analgesic effects. No studies with this drug are currently being carried out in Germany. So far, however, a total of seven clinical trials with FAAH inhibitors have been approved, all of which have already been completed. In none of these studies in Germany had serious incidents occurred in patients or healthy volunteers.

Research from newspapers and whistleblowers

Many facts about what has tragically gone wrong in France are still unknown. This is due to the fact that so far neither the French authorities, nor the Portuguese pharmaceutical company Bial or the company Biotrial responsible for carrying out the clinical study have shown themselves to be particularly communicative.

Even the cryptic name of the active ingredient used, "BIA 10–2474", had to come to light through research in newspapers and whistleblowers before it was officially announced. "Code names for drug candidates serve to disguise their structure," explains Christopher Southan of the University of Edinburgh in the journal Nature. "In my opinion that should change."

In the meantime, however, a study protocol describing the molecular structure has been leaked to the daily Le Figaro. Only after its publication was this protocol approved by the French authorities. Now other researchers can also help with the processing and find out why the active ingredient had such devastating effects on the test subjects.

The incident in France is very reminiscent of a failed clinical phase 1 study in the UK in 2006, which led to tightening of safety regulations in the EU the following year.

The active ingredient TGN1412, which is supposed to be effective against autoimmune diseases, led to acute, shock-like side effects within a few hours after its administration in the clinical trial in all six test subjects. The necks and heads of the test subjects were massively swollen. Eyewitnesses reported that those affected doubled over in pain and "sometimes tore their clothes off".

Everyone was immediately transferred to the intensive care unit. Two participants were still in mortal danger days later with multiple organ failure and had to stay in hospital for up to 14 weeks. In the end, however, they all survived - although they still suffer from the consequences to this day. Probably the biggest mistake that was made at the time was to administer the dose to all six subjects at the same time. More subjects were affected and you had to fight “on several fronts” at the same time.

"From this case, at least I had concluded that it was a big mistake to test multiple participants with identical doses on one day of the Phase 1 study," said Catherine Hill, expert in planning and conducting clinical drug tests formerly a member of the French medical and health product approval authority (ANSM) in Nature.

But evidence is growing that this mistake was made again in France. A total of 90 volunteers between the ages of 18 and 55 received the active ingredient, the dose of which was slowly increased with the individual administrations. No harmful side effects were found.

The six participants who became ill later were given a higher dose as the first several times on consecutive days. And according to the current state of knowledge, at the same time. The first subject fell ill on January 10th, was admitted to a clinic and died on January 17th. The other five were admitted to a clinic on January 11th.

One of the test subjects could be discharged quickly, all others whose condition is described as serious but stable have been discharged or transferred to clinics close to their home. No abnormalities were found in 28 test subjects who took the active ingredient in single doses, all others should be examined promptly.

Nevertheless, the question arises whether such a strong side effect could not have been generally ruled out with the help of computer simulations and preclinical studies on cell cultures and animals. “The phase 1 studies are made as safe as possible through the preclinical tests on cell cultures and animals. In terms of subject safety, this is a highly regulated process. Without studies with test persons, however, you will ultimately never be able to say with absolute certainty what will happen in people, ”said Maik Pommer, press spokesman for the BfArM to Deutsches Ärzteblatt.

“This is exactly why these tests with healthy volunteers are essential.” In addition to the preclinical examinations, the fact that test subjects are initially only given a very low dose, which is only gradually increased, ensures that there are hardly any serious incidents. The dose is well below that examined in the pre-clinical stage and also below the therapeutic dose.

Clinical trials in Europe have had to be officially approved since 2004. In France, for example, the permit is issued by the ANSM and in Germany by the BfArM. To ensure the safety of the participants in clinical trials, the BfArM scientists monitor every clinical trial. In doing so, they evaluate the documents for the pharmaceutical production of the drugs examined, the appropriateness and the results of the pharmacological and toxicological preliminary tests, as well as the test plan, which describes exactly how the study is to be carried out.

Clinical testing is accompanied by BfArM

The BfArM objects to around half of all initial applications and calls for improvements or subsequent deliveries. In most cases, these agency requirements are implemented so that around 95 percent of the clinical trials applied for can be approved. Another prerequisite for conducting drug studies on humans in Germany is the approval of an ethics committee. An approved clinical trial will continue to be monitored by the BfArM during its course to ensure that previously unknown risks do not impair the safety of the study participants.

The usually very high level of safety and strict monitoring of clinical studies make the financial incentive appear even greater. The young and perfectly healthy patients put themselves and their bodies into the hands of research mainly because of the easy money. The test persons in France received 1,900 euros for their participation in the study with the FAAH inhibitor - per week. A good wage as long as everything goes well.

Dustin Grunert