Six healthy men suffered from severe side effects leading to brain damage and in one case even to death.

BIA 10-2474 is the code for an inhibitor of the enzyme FAAH (Fatty acid amide hydrolase) with the possible purpose of curing neurological and psychological diseases. Inhibiting this enzyme lowers the pain sensitivity. The study started in July 2015, aiming for 128 healthy probands in the age of 18 to 55. 84 test persons received the drug in different doses without problems. But for test person number 85 to 90 is was different: after only three days first neurological side effects occurred, partly severe side effects that might lead to irreversible disabilities. [5][6]

Serious negative adverse events appeared after 5, respectively 6 daily doses of 50 mg. No warning signs occurred among the other probands receiving daily administrated doses under 50 mg or doses up to 100 mg in a single dose. [7]

The pharmaceutical quality of the product met the requirements for a clinical trial[7], the research institutes Biotrial and Bial are renown and were inspected in terms of clinical praxis and compliance with regulations. FAAH-inhibitors are subject of research for more than two decades now, and such a drastic reaction was not expected. [5][6] This shows how unpredictable the individual respond to pharmaceuticals is.

Arguments Contra Healthy Test Persons

In the following, we will discuss why patients should be used for FIH studies rather than healthy young test persons.

Questionable benefit for the test person

An important criterion for all drugs should be a good risk-to-benefit ratio. For healthy test persons there is clearly risk, but no medical benefit. Usually the probands get payed for participating. But financial compensation only gives rise to ethical abuse and leads us to the next argument. [9]

Financial compensation: Mainly poor will take the risk

There's a great ethical debate on financial compensation in clinical research. The ethical concerns include undue inducements, disproportionate burden on the poor and commodification. Especially there are ethical concerns regarding vulnerable populations (that means groups with limited autonomy of the individual in making a decision, like children, mentally challenged population, etc.), when someone else is making the decision for them and receiving the compensation, without carrying the risk. [10]

If the pharmaceuticals would be tested on patients, there would be no need of paying a fee as compensation - the patients' benefit is obvious - and there would be no participation in the studies for the "wrong" reasons.

Unpredictability

Preclinical research can fail to predict in three ways: it might not predict human risks, it might predict nonexistent risks or it might predict clinical benefits that don't apply for humans. If the third one is the case, healthy humans are exposed with a useless risk, until the drug reaches the next phase and in tests with patients it turns out that the drug does not have the desired medical benefit. This is avoidable by doing the first tests with patients. [3]

As mentioned earlier, also the individual response to pharmaceuticals is not completely predictable. Moreover the dosage has strong effect ("The dose makes the poison.") and so there is always the risk of exceeding the safe threshold.

I don't want to say that "it's not that bad" if diseased patients suffer from undesired side effects (this would arise ethical debates about the worth of a human being and if e.g. healthy humans are more valuable and this would go too far), but fatally ill patients might more likely "be okay" with e.g. a light paralysis, if the medication saves their live. In this sense, healthy individuals who die or have serious health problems as a result of research participation experience a greater loss than those facing the same kinds of harm from an untreatable condition [3]. Which leads to the next argument:

Critically ill patients

The worse the disease, the fewer treatment options usually exist. Additionally, most pharmaceuticals can only be applied for a certain time, because the body adapts to the continued presence of the drug and the microorganisms or cancer cells develop resistance. [11]

For fatally ill patients this means the treatment options get rarer and rarer while the disease progresses. Not allowing critically ill patients to participate in a possibly promising trial, means not enabling the chance of possible curing the patient.

Fast-track development in the US and the EU (that means accelerated approval/making new drugs available as rapidly as possible, especially for life-threatening diseases) is a first step in the right direction. [12]

Reaction might not be comparable

The target of the investigational intervention might only exist in people with a particular health problem, so studies with healthy test persons might not show similar effects. Metabolism and immune system of a patient and a healthy individual might differ considerably. Some FIH studies might even be riskier for healthy people than for patients, for example, trials involving monoclonal antibodies, because such substances can provoke an exaggerated immune response. However, for patients with compromised immune systems this is a lower risk. [3]