This is when the IP makes its first contact with humans. This is a highly controlled trial that typically includes between 20 and 100 volunteer participants. The primary focus of this phase is to test the IP for safety, tolerance (usually to dose escalation regimens), and pharmacokinetics (or what the body does to the IP). Healthy volunteers are most commonly used during this phase; however, certain drug designs carry a higher toxicity level in order to be effective to a targeted disease. This higher toxicity would be unethical to administer to a healthy person because it carries a high risk of harm. To this end, the Phase 1 trials for these more toxic compounds will include only participants with the targeted disease. An example of this would be anticancer agents or compounds. According to the FDA, approximately 70% of IND moves on to the next phase. Likewise, it is very rare for Phase 1 trials to occur within a sleep testing facility.

Phase 2 trials are rigid and well controlled and include a small homogeneous patient population, usually no more than 200 participants. These participants have the targeted disease, but no other confounding illnesses. The primary purpose of this phase is to determine whether or not the IP demonstrates efficacy for its intended indication, and within the safe dose range established during the Phase 1 trial. This trial will typically involve use of “double blinding” where neither the investigator nor the participant is aware of which compound is the “active” (IP) or the “comparator” (a similar already-marketed drug for the same indication), or a placebo. In order to be able to measure the effects of these compounds,
participants are randomized in different drug sequences (a means to reduce bias) that involve a period of time per drug and then a “crossover” to the next drug. Hence, the terminology of “Double-Blind Randomized Crossover Trial.” This trial phase is more commonly seen in sleep facilities and may only include 5 to 10 investigating sites.

At or near the conclusion of the Phase 2 trial, the sponsor (investigating agent) will meet with the FDA to review all the data collected to this point, and the determination to advance to a Phase 3 trial is made. Of the number of INDs that have made it to this point, the FDA estimates only 33% will move forward to Phase 3 trials.

This trial phase is an expanded clinical trial intended to gather additional evidence of effectiveness for specific indications and to better understand safety and drug-related adverse effects. This is also referred to as “primary efficacy studies” (10). Phase 3 trials typically have large numbers of participants, ranging from 350 to 1,000 patients. Trials involving large numbers of participants require the developer to seek participants from a wide variety of geographic areas. Factors such as culture, race, and ethnicity can impact participant behavior, whereas reduced or limited diversity can place limits on the generalizability of the findings (11). Therefore, the developer will seek to spread the recruitment efforts across a wide area and, in some cases, take their efforts to other countries in order to satisfy statistical diversification needs.

In the world of clinical trials involving a sleep component, sponsors work with their contract research organization (CRO) to identify multiple facilities capable of handling the protocol requirements as well as the participant volumes. It is very common to see study plans written where the participants are required to have multiple sleep studies in order to complete their trial requirements. To put this into perspective, it is typical practice to have a protocol that, among other requirements, is written to include five or more overnight sleep studies. The plan may or may not include a daytime multiple sleep latency test or maintenance of wakefulness test. If, for example, a hypothetical trial is “powered” (statistically required number of participants needed in order to increase the probability of significant results) by 980 participants and if each of these participants completes the protocol requirements of 5 nocturnal polysomnography (NPSG) studies, a total of 4,900 PSG recordings will be produced for this phase of the study plan. If the sponsor awards the trial to 50 sites, on average each site would generate 98 PSGs for roughly 20 participants. This kind of volume can be burdensome for some sites, whereas others can absorb the volume without issue. Site qualification visits are the sponsors’ means for performing due diligence in determining whether or not sites are adequately equipped to handle their specific trial.

Phase 3 trials can be active for long durations in order to meet the enrollment criteria. For sleep-related trials, duration can be from 18 to 36 months in order to meet the threshold. At the conclusion of the Phase 3 trial, the sponsor makes a formal appeal to the FDA in the form of a new drug application. This request to allow for marketing of the new drug essentially tells the FDA that the sponsor has completed the necessary safety and efficacy requirements in order to gain official approval (12). With formal approval from the FDA, the sponsor can then begin actively promoting and selling their new compound.

Phase 4 trials begin after the marketing application to the FDA has been approved. The primary purpose of Phase 4 trials is to gather long-term safety data as a condition of the FDA approval. These trials are frequently conducted to compare new compounds with other already-marketed products. Because of the length of time it takes to bring a new compound to market, there can be changes in standards of care for the targeted disease or condition. The FDA will often require the sponsor to continue gathering data as a means of postmarketing surveillance.