An Overview of Phase I Clinical Studies for New Chemical Entities
by Dennis W. King, President and CEO, STATKING Consulting, Inc.
Dennis King STATKING Consulting
Introduction
Phase I clinical trials, sometimes called first in man (FIM) studies, are the first of three phases of human clinical testing required by the US Food and Drug Administration (US FDA) for approval of new chemical entities (NCEs). A NCE as defined by FDA is a drug that contains no active moiety that has been approved by FDA in any other application submitted under section 505(b) of the Federal Food, Drug and Cosmetic Act. This phase of study of the NCE begins once appropriate progress has been made in non clinical (animal) testing of the NCE.
This article contains an overview of Phase I clinical trials that can help an emerging pharmaceutical company understand the process of conducting Phase I studies. A discussion of the different types of Phase I studies, the regulatory aspects of these studies, the goals of these studies and the team of players needed to execute these studies is given below.
Regulatory Overview
In terms of US FDA regulations, the FDA guidance Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations, is the most general reference for pharmaceutical companies initiating Phase I clinical trials. This guidance describes the general principles for the design and analysis of Phase I bioavailability (BA) and bioequivalence (BE) trials. There are a host of other guidance documents concerning specific aspects of Phase I trials on the FDA web site (www.fda.gov).
Before designing Phase I studies, an emerging pharmaceutical company should always consult personnel from the appropriate therapeutic area branch of FDA. FDA personnel will give guidance on the number and types of Phase I studies necessary for the NCE under study. The company may also invest in the services of a regulatory person, a pharmacokineticist, a pharmacologist and a statistician with experience in their therapeutic area. These professionals will become part of the company’s clinical development team and will work with other team members to plan and execute the clinical development program for the NCE including the Phase I studies.
Types of Phase I Studies
Typically, Phase I studies to understand and confirm the pharmacokinetics/pharmacodynamics (PK/PD) of the NCE fall into two categories: bioavailability and comparative bioavailability studies. In a bioavailability study, single dose studies are conducted on a single cohort of subjects to:
- Understand PK characteristics and estimate PK parameters
- Establish a safety profile
Comparative bioavailability studies compare the bioavailability profiles of two or more levels of a classification factor that may affect bioavailability. When the classification factor is dose level the following characteristics are of interest:
- Evaluation of dose linearity
- Estimation of the Minimum Tolerated Dose (MTD)
- Evaluation of steady state concentration (multiple dose studies only)
Other classification factors for which the comparison of the bioavailability profile is of interest are:
- Food status (fed vs. fasting)
- Drug-Drug Interactions
- Specialized Populations (elderly vs. non-elderly, renal impairment vs. non renal impairment).
Overview of Model Parameters
One of the goals of Phase I PK/PD studies is to assess the PK profile of the NCE. In order to do this, the pharmacokineticist fits non-compartmental models to the data for each subject. Some of the typical PK parameters are shown in a theoretical drug concentration curve in Figure 1.
Figure 1. Theoretical Drug Concentration Curve with PK Parameters
Using the observed drug concentration data, the time to maximum concentration, Tmax, the maximum concentration, Cmax, the area under the concentration curve, AUC0-∞, and the elimination rate, ke are fit for each subject using non-compartmental models. The statistician may then compute summary statistics and confidence intervals for these parameters across all subjects. If concomitant factors are involved in the study, the statistician may compare the PK parameters for the levels of the concomitant factor (for example, fed vs. fasting states).
Service Provider Models
The emerging pharmaceutical company will want to have a clinical operations manager (employee or contractor) who can oversee the conduct of the clinical development program including Phase I trials. This individual will oversee the development of the protocols for the Phase I trials and will contract with the appropriate service providers to execute these trials.
There are two types of service provider models used by emerging pharmaceutical companies to complete Phase I studies: the full service Phase I model and the ala carte model. Some Contract Research Organizations (CROs) provide full Phase I services which consist of the following:
- Study Site Services (IRB approval, drug packaging, medical monitoring, consenting, enrollment and randomization)
- Clinical Laboratory Services
- Drug Concentration Assay Services
- ECG Services
- Pharmacokinetic Modeling
- Biostatistics
- Clinical Data Management
- Clinical Study Monitoring
- Medical Writing
- Safety Reporting
Some CROs may also provide protocol development services. The advantages of the full service model are continuity of services and a single contract with a single provider.
Some emerging pharmaceutical companies make good use of the ala carte model for research services. In this model, a set of service providers is selected to provide the above Phase I services with each provider covering its niche area of expertise. For example, a particular CRO may be strong in biostatistics and clinical data management and would provide only those services on the trial. While the management of this type of model is more challenging for the sponsor company, it can provide a better end product.
Alternative Phase I Study Types
The Phase I studies discussed thus far are those that are typical for most NCE development programs. Specific therapeutic areas may require other specialized types of Phase I studies.
As an example, oncology Phase I studies require a different type of study design. Because of the high mortality rate of certain cancers, Phase I studies in this therapeutic area are typically conducted on patients with the disease. Dose ranging is done with study designs that require the minimum number of patients at each dose level before reaching the MTD. These designs, sometimes called up-and-down designs, are summarized in Chevret (2006) and involve escalating/deescalating dose levels based on the results of dosing a small cohort (typically three or less) of patients at a specific dose level. An example of an Up-and-Down Design is given in Figure 2.
Figure 2. Example Up-and-Down Design
Phase I study designs for other specific therapeutic areas are discussed in Bonate and Howard (2004). A company wishing to conduct Phase I studies for FDA approval should always consult with the FDA review personnel for their therapeutic area.
Conclusions/Recommendations
The conduct of Phase I studies is critical in the development program for a NCE. The emerging pharmaceutical company should develop a reasonable and concise timeline for completing the sequence of Phase I trials required by the FDA. The company should then secure adequate funding to execute these trials under this timeline.
In order to conduct these studies in an efficient manner, the emerging pharmaceutical company should build a strong study team consisting of professionals (clinical trial manager, regulatory, pharmacokineticist, pharmacologist, statistician and other service providers) with experience in the therapeutic area of interest. These professionals will then design and execute the Phase I trials required by FDA for the NCE in a manner that is consistent with Federal regulations and guidelines.
REFERENCES
Bonate, P.L and Howard, D.R. (2004). Pharmacokinetics in Drug Development: Regulatory and Development Paradigms, Volume 2, Arlington, VA: AAPS Press.
Chevret, S. (2006). Statistical Methods for Dose-Finding Experiments, New York, NY: John Wiley & Sons.
Food and Drug Administration. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations. Draft Guidance, March 2003a.
