Phase I trials are safety trials (Phase I/II may also investigate effectiveness). Frequently the sponsor
opens cohorts with increasing dosages. For example, if the expected enrollment is, say 400, they may start with a cohort of 30 patients with one dose. The adverse events (AEs) are carefully monitored. If these are acceptable, that cohort is closed and the next cohort is
opened with a higher dose, and so forth for a few different, increasing dosages, up to the max planned dose. The AEs recorded are
everything for every day your are on the trial, from a runny nose to admission to a hospital for a stroke. Obviously the majority of these AEs aren't drug-related, but some are. If you are in a medication trial, your AEs are tracked throughout the trial and sometimes in a follow-up period as well.
AEs are graded by the docs, PAs, and research nurses on a 1-5 scale according to an official guide that lists what qualifies for each grade for every possible condition. A grade 1 AE usually requires no medication and just monitoring; grade 2 requires medication. Grade 3 and 4 are Serious Adverse Events (SAEs) and usually require hospitalization (4 is life-threatening). Grade 5 is death. Each of your AEs is tracked for start and stop date, grade and changes of grade, all medications and treatments given for it and how/whether the AE resolved or is ongoing.
There may be a fine line between the dose of a drug that is safe (and effective) and a highly toxic or lethal dose. Good examples are the cytotoxic drugs used for chemotherapy. We know all too well the AEs that patients frequently need to undergo because a dose that wouldn't cause problems won't be strong enough to affect the cancer.
Phase I trials have the most risk, since they are testing whether the drug is safe to take. The more serious your medical condition, the more risk you are usually willing to take, especially if there is some promise of extending your life for even a couple of months and other options have failed.
Fairly often, the sponsor knows what AEs the drug is likely to cause, e.g., from animal studies. So in the case of the subject who died of liver complications, this might have been an organ of special attention in the study, if, for example, the drug is metabolized by the liver and not the kidneys. For each and every AE you have during a study, your study team must answer the difficult question "Is this AE related to the study medication" with a choice of answers, e.g. No, Not likely, Possibly, Probably, Definitely.
The study team learns over the course of the study how to answer this. For example, if you alone had some minor itching during the week after your transfusion of the drug, it probably wasn't drug related. If, on the other hand, a number of subjects develop sever itching all over their bodies beginning about
20 min after the start of the infusion, to the extent the infusion has to be interrupted or halted and IV or oral medications given, this is clearly drug-related.
Note that "side effect" is a more popular term of convenience. As a physiology prof. pointed out to our class in univ., a drug has only effects and no "side" effects. We just categorize them into what's desired and what's not
Djin