PHASE-0 (MICRO-DOSING): A NEW APPROACH
08 Apr 2018
Developing and launching a new pharmaceutical drug to the market is an immensely expensive operation. Pharmaceutical scientists and physicians are constantly engaged in research to find the best ways to diagnose and treat disease; with focus on the ‘Risk vs. Benefit ratio'(always trying to see that the amount of benefit clearly outweighs the associated risk). It is a unique challenge as out of every 9,000-10,000 compounds researched, maybe one reaches the market
Though science and technology advances in drug discovery and development have taken a leap, registration of new molecules was on the decline. To overcome this, in 2004, the US Food and Drug Administration (FDA) introduced its ‘Critical Path’ document which showcased examples of how newer methodologies if incorporated early in the drug development process may help in bringing new therapeutic agents to the market. This was also supported by other regulatory agencies like EMEA. Later, in 2006, FDA issued a new Exploratory Investigational New Drug guidance that allowed studies to be conducted at dose levels which do not produce signi?cant clinical toxicity, termed as ‘Phase 0’ (micro-dosing) trials. These studies can be initiated without the detailed preclinical toxicology studies required for Phase 1 studies. Phase 0 trials are aimed to basically understand the pharmacokinetics and pharmacodynamics before ensuing Phase 1 trials.
In a Phase 0 trial, the new viable tool in drug development, the first in man PK studies, a micro-dose of the drug is used. A micro-dose is defined as less than 1/100th of the dose of a test substance calculated (based on animal data) to yield a pharmacologic effect of the test substance with a maximum dose of ≤100 micrograms (source: Guidance for Industry, Investigators, and Reviewers; Exploratory IND Studies; Jan-2006); Initial dose ≤1/50th of the no-observed-adverse-effect level (NOAEL).
Table: Advantages and Disadvantages of Phase 0 trial
Adverse events risk is lower as micro-dosing uses minute quantities of the drug
Results may not be indicative of larger doses
First in man study - can indicate appropriate drugs for future development
Minute quantities of drug requires sophisticated tools for assessment
Provide basis for pharmacological dose
Patients may be skeptical for enrolling due to the short period, and as they may have to undergo washout for participating in further studies
May help to arrive at the cost of the drug and help planning for further development
Phase 0 trials must also be considered keeping the patient’s safety in focus as the toxicology data is limited. Patient has to be informed clearly about the lack of therapeutic intent and the investigational nature. The study must be designed from inputs of all stakeholders such as, clinicians, biostatisticians, translational scientists etc.
Phase 0 trials can help in reducing time and costs, at the same time helping to plan better subsequent phase trials
1) US Department of Health and Human Services, Food and Drug Administration (FDA). Innovation of Stagnation, Challenge and Opportunity on the Critical Path to New Medicinal Products. Critical Path Report. Rockville, Md: FDA; March 2004.
2) US Department of Health and Human Services, Food and Drug Administration (FDA), Center for Evaluation and Research. Guidance for Industry: Investigators and Reviewers. Exploratory IND Studies. January 2006.
3) Jun. Zhang, Yong-ming Cai, Zong-peng Zhang, Duan-yun Si, Changxiao Liu. Phase 0 clinical trials: An efficient way to development of new drugs. Asian Journal of Pharmacodynamics and Pharmacokinetics 2010; 10(4):261-270.