PHASE 0

Introduction

Currently, Preclinical trials using animal models, cell culture methods and bioinformatics methods takes up to 18 months and the typical development for investigation of new drugs takes between ten to fifteen years and associated with high cost and low rate of approval, which explains us that magnitude of resources being wasted on investigating Non-promising molecules. This clearly indicates that some grievances exist in the traditional drug development model.

Identifying the compelling need for re-evaluation of and an innovative paradigm shift in the traditional drug development model, FDA, as part of its critical path initiative, established task Force on Methodology for the Development of Innovative Cancer Therapies (MDICT) comprised of experts from National Cancer Institute (NCI), academia, industry, and FDA and held multiple discussions with pharmaceutical industry.  In January 2006, as an outcome, FDA issued guidance on Exploratory IND studies.

Micro dosing (or micro-dosing)

It is a technique for studying the behavior of drugs in humans through the administration of doses so low they are unlikely to produce whole body effects, but high enough to allow the cellular response to be studied. This helps to know the pharmacokinetics of the drug with almost no risk of side effects.  This is called a Phase 0 study and is usually conducted before clinical Phase I to predict whether a drug is viable for the next phase of testing. Human micro dosing aims to reduce the resources spent on non-viable drugs and the amount of testing done on animals. 

Phase 0 clinical trials

Exploratory IND studies, often called as Phase 0  clinical trials, are conducted prior to traditional phase I dose escalation, safety and tolerability studies with very limited human exposure(<30 patients) and have no therapeutic or diagnostic potential. These studies assess feasibility for further clinical development of a drug or biological product regulated by Center for Drug Evaluation and Research (CDER). Bridging the gap between traditional preclinical studies and clinical development, Phase 0 trials provide an opportunity to assess pharmacokinetics (PK) and pharmacodynamics (PD) of new molecules early in humans with reduced preclinical testing.

Designing Phase 0 trials:

By design, Phase 0 trials portend lower risks to human subject than traditional phase I trials. As such, fewer preclinical supporting data are required prior to conducting a Phase 0 trial. The initial agent dose depends in part on the stated trial objectives, but should not be greater than 1/50th of the no-observed-adverse-effect level (NOAEL) estimated from animal toxicology testing. Validated pharmacodynamics assays, ideally with low variability in the molecular target, are suitable for application to Phase 0 trials if the investigational agent can reasonably be expected to demonstrate target modulation at a non-toxic dose. Standard operating procedures should be defined in advance and revised as necessary based on results of the Phase 0 trial.

The biggest difference between Phase 0 and the later phases of clinical trials is that there’s no chance the volunteer will be helped by taking part in a Phase 0 trial.
Because drug doses are low, there’s also less risk to the patient in Phase 0 studies compared to phase I studies. Phase 0 studies help researchers find out whether the drugs do what they are expected to do. If there are problems with the way the drug is absorbed or acts in the body, this should become clear very quickly in a Phase 0 clinical trial. This process may help avoid the delay and expense of finding out years later in phase II or even phase III clinical trials that the drug does not act as it was expected to basing on lab studies.

Ethics of Phase 0 trials

Proponents argue that Phase 0 clinical trials have the potential to expedite the development of new oncology drugs while exposing fewer research subjects to the risks of experimental treatments. At the same time, Phase 0 oncology trials raise important ethical concerns that have received little attention.  In particular, there is a question of whether it is ethical to enroll individuals in research that offers them no potential for clinical benefit. Further concern focuses on the inclusion of terminally ill and consequently vulnerable cancer patients in these trials. There is a need to evaluate the concerns of Phase 0 clinical trial.

Merits/Advantages of Phase 0 trials

• Due to their design, Phase 0 trials can be conducted in less time with fewer patients than Phase I trials.
• By conducting a Phase 0 trial on a particular drug, the process for Phase I and II trials on that drug is accelerated.
• Phase 0 trials could facilitate rational drug selection, identify therapeutic failures early, and compress timelines for anticancer drug development.
• Phase 0 trials provide initial rationale and guiding principles for further drug development based on studies in humans.
• Phase 0 trials help to evaluate the effects of the drug at the molecular level and   identifies the lead agent from the group of compounds in order to optimize the starting dose of subsequent phases of the trial

Demerits of Phase 0 trials

• Sometimes the results obtained from Phase 0 trials are not relevant to the results of later phases.
• Since micro dose evaluation is conducted in Phase 0 trials researches have to depend on BA (Bioavailability)/BE (Bioequivalence) labs as parameters are limited and expensive.

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Written by
Harisha Kothapalli
harisha.kothapalli@clinzen.com