Group 6 - First-in-human trials

First-in-human (FIH) trials, also called phase I trials, should give initial information about the toxicity and dose of new therapies, drugs and agents. Some say it's the most dangerous part in drug developement. So don't the two quotes contradict each other? Let's have a look at it.

based on preclinical data

In FIH trials, a new therapy method is tested on humans for the first time. Therefore no information from earlier human test is available. Instead, decision makers have to rely on laboratory and animal tests to decide whether to start a FIH trial. These informations however show several imperfections. First of all some studies have shown that the preclinical data sometimes isn't correct due to missing data or missing measures for random treatment allocation. Furthermore neutral or unsuccessful studies might not be published or FIH trials start before the peer review of the preclinical data has been completed. This lack of information leads to a higher risks for participants if a FIH trial is allowed to be conducted. Another problem lies in the transformation from preclinical data to clinical trials. Though researchers try to use human-like animals for the preclinical studies, these aren't human and the human body behaves differently than animal ones. So the information about drugs gained from animals cannot be directly transferred to humans. A negative example of this occured in England in 2006. A FIH trial for the new TGN1412 antibody has been conducted on healthy volunteers with preclinical inforamtion from testing this antibody on monkeys. Though only giving 1/500 of the dose from the monkeys to the humans, six participiants experienced multi-organ failure. Several other cases happened over the years showing that even deciding on whether to start a FIH trial can be extremely risky.

unfavorable risk-benefit ratio

For all clinical trials a positive risk-benefit ratio is designated. However achieving this is hard in FIH trials, due to great uncertainties about risks and benefits from the trials. Risks in general increase due to the fact that no human information about the drug is available and as already mentioned, it's hard to predict events in the human trial from animal studies. Another factor is the diversity of the risk. Different stakeholders involved in the trial might have different views on the takable risks (i.e investors and participants). So due the absence of a strict framework for assessing risks, a systematic risk analysis for FIH trials is hard to conduct. Benefits from a FIH trial can be divided into two categories: individual and soical. The social benefit is therapy-dependant and can reach from curing a disease to showing no real benfit for treatments. In contrast the individual benefit from a medical side is really small. We will have a closer look at the participants in FIH trials and their individual risks and possible benefits now.

healthy volunteers

For FIH trials healthy volunteers are favored because they provide the cleanest data. Furthermore they are said to handle unexpected and adverse reactions to the newly tested drug better than already sick people. But this also means that the volunteers don't get any medical benefit from the trials because they are healthy. To compensate for being part of the trial, volunteers can get other sorts of benefits. These include direct money or indirect payment by enabling them to plug into different health tests they couln't afford otherwise. This however leads to a great amount of low-income people volunteering in the trials to get some money. Thereby they often neglect thinking about possible risks, because on short-term the money is more important to them. This can also introduce distorted trials, because volunteers might conceal health information that would disqualify them from participating, just to earn the money. So on one hand the study can loose in worth and the volunteers increase their own risk in getting harmed because the combination of the concealed health aspects with the new therapy might introduce serious medical side effects. Repeated volunteers (to earn more money) are also unfavorable concerning the data quality because it reduces generalizability and the volunteers might react different to the newly tested drug due to long-term aspects from before tested drugs. In general one could say that the healthy volunteerss have most to loose, but often they neglect this fact because earning money and/or gaining health care benefits is more important to them regarding their social situation.

ill patients

On the other hand some FIH trials also use seriously ill partients where all known therapeutic options have been exhausted. Trials with these patients mostly test new therapies with serious risks, which often occurs in oncology and the testing of new chemotherapy drugs. Proponents might say that these patients have nothing to loose, so one can test new therapies with them. However one could argue as well that ill participants have the same right not to be harmed than others. So by testing new therapies ill patients undergo the same risks as other participants. But their risk of getting harmed might be increased because their body is already weakened so that adverse reactions might harm them more and earlier than healthy patients. Ill patients might also gain hope by participating in the trials or experience altruism. Hopes regaring an improvement are however mostly illustionistic, because FIH trials are used to give informations of toxicity and maximum doses of new agents rather than testing their effect on diseases (in long term). The applied dose is mostly too small to show any health benefits.

A great problem coming along with todays FIH trials is the way of transporting information and getting quick consent. Doctors and researchers have to explain the FIH trial in detail to possible participants and get their written consent, as well as informing the participants that they can resign from the trial at any time. However studies have shown that healthy volunteers as well as ill patients don't understand the exact reasons for the trial. They tend to look at the benefits and deliberately overlook the risks. While as already mentioned, healthy volunteers see benefits in earning money, ill patients see their benefit in gaining hope for a cure and altruism. So in general participants give consent to a trial that they don't totally understand and where they overestimate benefits as well as underestimating risks.

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So all in all taking ill patients for FIH trials can be seen as the better choice, since they don't risk their healthy life and already experience the disease that the new tested drug should work against. So the choice of participants still is controverse. The same controversary holds for the current general FIH trials. However, on some time starting with trials on humans is necessary, so discussing possible improvements in FIH trials is necessary and wanted.