Phase I Clinical Trials: Is The Treatment Safe?

The first step in testing an experimental drug (or other treatment) in humans. Clinical trials of medicines and biologicals typically proceed through ‘phases’ of development whereas clinical trials of medical devices are more appropriately represented by ‘stages Phase 1 trials evaluate the drug’s safety and toxicity at different dose levels and determine drug pharmacokinetics. Because little is known about the possible risks and benefits of the drug being tested, Phase 1 trials usually include only a small number of participants (approximately 20 to 80). Testing of other biomedical interventions, such as diagnostic tests or medical devices, also begins with Phase 1 trials. The primary aims of Phase 1 Clinical Trials are to determine the safety, tolerability and pharmacokinetics (PK) of a compound. Trials have historically been conducted in the logical sequence of single ascending dose, multiple ascending dose, examination of preliminary effect of food on exposure, and potential drug-drug interaction, with assessments to determine the effect of gender, age, bioavailability and bioequivalence performed as necessary.

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These studies are conducted to elucidate the PK and PD of multiple doses of the compound, again usually in a CRU. The dose levels and dosing intervals (ie, time between consecutive doses) are selected as those that are predicted to be safe from single dose data. Samples are collected and analyzed to allow the determination of PK profiles and a better understanding of how the drug is processed by the body; with multiple dosing, a key part of the PK analysis is to identify if accumulation of the drug occurs. As for single ascending dose studies, dose escalation proceeds according to the protocol assuming strict safety and PK criteria are met. Additional studies may be performed, including definitive electrocardiogram (ECG) investigations to thoroughly evaluate the QT/QTc prolongation potential of a compound, which can increase the risk of potentially fatal proarrhythmias. This blog will describe the different designs commonly used in Phase 1 clinical trials.

Phase 1 trials are distinct then for several reasons:

• Few number of participants

• Short duration of trial

• Participants are usually healthy volunteers

• Results are used to determine whether to progress the drug further

Phase 1 trials are also unique because they are unlikely to improve the health of the subjects who enroll in the trial. 

These are studies in which a small group of subjects receive a single dose of the compound in a clinical setting, usually a Clinical Research Unit (CRU). Close safety monitoring and usually PK assessments are performed for a predetermined time. If the compound is deemed to be well tolerated, and the PK data are broadly as expected, dose escalation occurs, either within the same group or a further group of healthy subjects, according to the approved protocol. Dose escalation usually continues until the maximum dose has been attained per the protocol unless predefined maximum exposure is reached or intolerable side effects become apparent. Additionally, dose escalation may be discontinued (or may proceed more cautiously than planned) if there is evidence of a supra-proportional relationship between dose and exposure, such that exposures at higher dose levels become difficult to predict. Studies usually include sequential groups in a parallel design for maximum exposure or are of a crossover design to provide more information on dose linearity. These studies are conducted to elucidate the PK and PD of multiple doses of the compound, again usually in a CRU. The dose levels and dosing intervals (ie, time between consecutive doses) are selected as those that are predicted to be safe from single dose data.

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Samples are collected and analyzed to allow the determination of PK profiles and a better understanding of how the drug is processed by the body; with multiple dosing, a key part of the PK analysis is to identify if accumulation of the drug occurs. As for single ascending dose studies, dose escalation proceeds according to the protocol assuming strict safety and PK criteria are met. To minimize the effect of bias, subjects are usually randomly assigned to treatment using computer generated randomization codes produced by Statisticians. Studies are usually placebo controlled to determine whether effects observed are due to the study drug or environmental conditions, and are often conducted in a single (subject) blinded manner to allow informed decision on dose escalation, with safety and PK data being available for investigator review. Optimal dose-finding approaches should consider both efficacy and toxicity and perhaps endpoints should be redefined to incorporate late occurring toxicities, and to address pseudo-progression and delayed responses. Large Phase I trials with expansion cohorts are feasible to implement, but should be developed with sound statistical designs, and rigorous monitoring of safety outcomes.

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