Phase 0 Trials Definition

Several applicants in the same application for a new drug. Multi-drug exploratory clinical trials (e.g., cassette microdosing) may be submitted as part of a single market authorization application for a new investigational drug.100,108 In some developmental scenarios with toxicological concerns, it may be important to obtain additional preclinical toxicological data before moving to Phase I. Although Phase 0 exposures do not directly investigate toxicity in humans, PET microdosing studies can demonstrate the potential for inference toxicity by observing abnormally high concentrations in potentially sensitive tissues/organs in humans. This could be useful in development scenarios with poor animal models of human disease or drug effects. Depending on the specifics of development, it may therefore also be advantageous to conduct a Phase 0 study in scenarios where additional toxicological data are obtained. The purpose of phase 0 trials is not to test therapeutic effects, but to verify that the drug behaves as expected in humans and to collect preliminary data on what the drug does to the body and what the body does with the drug. The development of a new cancer drug is an expensive, long-term and risky undertaking with a failure rate of over 90%. More than half of new oncology drugs fail later in clinical development, increasing the cost and time required to deliver effective treatments to patients.1,2 To accelerate the discovery and development of new molecular agents, the FDA published an exploratory guidance on investigational new drugs (INDs) in 2006 to support clinical evaluation prior to dose escalation. Safety and tolerability studies associated with a traditional IND.3 The objectives and endpoints of Phase 0 (or pre-Phase I) studies conducted as part of an exploratory IND may include the evaluation of modulation of a suspected drug target in humans; optimization of the target analysis methodology using human samples; provision of pharmacokinetic (PK) data; evaluation of PK/pharmacodynamic relationships (); and the selection of the most promising lead compound among several chemical agents or formulations.4 Unlike other phases of clinical trials, there is almost no chance that participants in Phase 0 trials will benefit. The advantage in the future will be for other people. And because drug doses are low, there is also a lower risk for study participants. It is common for some Phase III studies to continue while regulatory submissions are pending with the appropriate regulatory authority. This allows patients to continue receiving potentially life-saving drugs until the drug can be obtained through purchase.

Other reasons for conducting trials at this stage include the sponsor`s attempts at “label extension” (to show that the drug goes beyond the initial use for other types of patients or diseases for which the drug has been approved for marketing), to obtain additional safety data, or to support marketing claims for the drug. Studies at this stage are classified by some companies as “phase IIIB studies”. [15] The design of individual studies may be modified during a study – usually in Phase II or III – to account for interim results for treatment, to adjust statistical analysis, or to quickly complete an unsuccessful design, a process known as an “adaptive design”. [18] [19] [20] Examples include the World Health Organization`s Solidarity 2020 study, the European Discovery study, and the UK`s RECOVERY Study with hospitalized individuals with severe COVID-19 infection, each of which applies adaptive plans to rapidly change study parameters as results emerge from experimental therapeutic strategies. [21] [22] [23] Typically, patients are assigned to a drug candidate based on their genetics and receive it three or four days before surgery, says Shwetal Mehta, PhD, COO of the Ivy Brain Tumor Center, a nonprofit organization that conducts Phase 0 trials in the GBM. Most drug candidates for Phase 0 trials in neuro-oncology have previous safety data in other indications, she adds. In addition to extending applications to vulnerable populations, Phase 0 research can also be extended to other safety-related scenarios, such as drug therapy in extreme environments. When people move into new environments such as space, hyperthermic and hypothermic environments (e.g., polar environments), and hyperbaric and hypobaric environments (underwater and high-altitude), exposure to changing physiological and pharmacologically changing conditions requires dedicated clinical research to inform drug therapy.200,201,202,203 Such environments are unlikely to have access to the emergency medical services that typical research centers rely on, hence the inherent safety appeal of phase 033.138.139 approaches. Answering these questions while administering a treatment unknown to as few people as possible often requires multiple clinical trials at different “stages”. Each phase is designed to answer specific questions while ensuring the safety of participants. The results of these phases show whether the new drug or treatment is reasonably safe and effective.

Phase 0 studies provide an opportunity to evaluate pharmacokinetics and confirm the effect of a drug on its intended molecular target in human samples much earlier in clinical development. Experience with exploratory IND studies is limited but positive.8 If a drug`s impact on a target can be assessed earlier in a drug`s development cycle and requires fewer patients than a traditional IND, it follows that clinical trials are smaller and development times can be shortened. Because Phase 0 studies focus on proof of concept rather than identifying a dose for Phase II trials based on toxicity, the number of participants needed is less than in a Phase I trial, typically only 10 to 15. Phase 0 study designs should therefore take into account the statistical limitations of clinical trials with small samples, the analytical performance of the PD test to be used, intrapatient variability, and interpatient molecular and histological heterogeneity in measuring PK/endpoint effects. The issue of intrapatient variability is of particular importance when the primary endpoint is derived from invasive tumour biopsies which, by their nature, do not allow for frequent tissue removal. In this case, post-treatment effects should be measured by pre-treatment variability in outcomes, which can be studied between patients rather than in a single patient, making it much more difficult to obtain statistical significance because the variability of inter-patient outcomes is by definition greater (often much larger) than intrapatient intrapatient variability. TDGD was primarily considered a confounding variable in extrapolating drug exposure from a microdose to therapeutic doses. However, for drugs with TMDD potential, a microdosing study can provide valuable information to verify the effects of target binding in humans.