Human Preclinical Studies and Phase 0 Clinical Trials

The drug development process includes various steps from discovery (discovery of a new compound or biological product) to preclinical research (measuring the safety, toxicity, and efficacy in animal models), and then to clinical trials (testing the safety and efficacy in humans - either healthy volunteers or patients). The clinical trials are phased from phase 1 & 2 (early phase trials) to phase 3 (pivotal, confirmatory, late-phase trials), and to phase 4 (post-marketing clinical trials). A diagram indicates various stages of drug development. With innovative clinical trial designs, the clinical trial phases are blurred, for example, seamless phase 1/2 trial and seamless 2/3 trial. In rare disease areas, the drug development process may not have all phases of clinical trials. The adequate and well-controlled study may be phase 3, phase 2, or phase 1 (for example, expansion cohort studies).

Preclinical development, also called preclinical study or nonclinical study, is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug safety data are collected, typically in laboratory animals. Traditionally, the phase 1 study may be the first-in-human trials with the purpose of studying the drug's:

• pharmacokinetics (ADME: absorption, distribution, metabolism, and excretion) and pharmacodynamics (enzyme, protein,...) 
• toxicity, safety and side effects associated with increasing doses
• maximum tolerable dose
• early evidence of effectiveness

There are now two new steps that may be utilized in drug development: Preclinical human studies and phase 0 clinical trials. A revised drug development diagram is as follows: 

Human pre-clinical studies are those pre-clinical studies utilizing the human subjects (either utilizing the specimens collected from human subjects or performing testing in human decedents). Human pre-clinical studies are 'pre-clinical' because they are not conducted under IND (investigational new drug) and they are conducted for collecting the data to support the IND-enabling studies. 

In a paper by Abdallah et al, "A novel prostate cancer immunotherapy using prostate-specific antigen peptides and Candida skin test reagent as an adjuvant", they described a human pre-clinical study where peptides based on the prostate-specific antigen amino acid sequences were evaluated in terms of their recognition by peripheral immune cells from prostate cancer patients using interferon-γ enzyme-linked immunospot assay. A sample size of 10 patients with prostate cancer was selected for the study. The authors concluded: 

"We described a human preclinical study of a novel prostate cancer immunotherapy consisting of PSA peptides and Candida skin test reagent as an adjuvant. As solubility and formulation have been developed, it would be feasible to further evaluate the utility of this new therapy particularly when a proportion of prostate cancer patients seem to have immune cells with the ability to recognize these PSA peptides already. Therefore, whether this immunotherapy may enhance immune responses to PSA leading to tumor regression should be examined."

Dr. Locke's team in UAB recently conducted pioneer xenotransplantation of a gene-modified pig kidney. The study was described in the paper by Porrett et al "First clinical-grade porcine kidney xenotransplant using a human decedent model". The pig kidney was transplanted to a human decedent (brain dead patient). The purposes of this human preclinical study were stated as the following:

"Xenotransplantation is arguably the most pragmatic solution to the organ shortage crisis, but safety and efficacy concerns have limited advancement into humans. In preparation for a phase I clinical trial of porcine renal xenotransplantation at the University of Alabama at Birmingham, we asked what gaps in knowledge must be filled before such a clinical trial could be ethically offered to research subjects. We thus aimed to develop a human preclinical model which would permit the in vivo evaluation of critical safety and feasibility tenets of the pig-to-NHP model without risk to a living human. Our study was designed to test five central questions: (1) Is the current suite of porcine genetic modifications sufficient to avoid hyperacute rejection in humans? (2) Would prospective flow-based crossmatching correlate with graft survival free of hyperacute rejection? (3) Would life-threatening intraoperative complications occur during a renal porcine xenotransplant? (4) Would porcine cells and/or pathogens be detected in the blood of a human recipient? (5) Could porcine renal xenotransplantation be safely performed under the conditions necessary for a clinical trial? To this end, we designed and performed this experiment under clinical-grade conditions which included the transplantation of 10-GE porcine kidneys designed specifically for human transplantation into the conventional anatomic position using processes and facilities in compliance with multiple regulatory agencies."

In human preclinical studies, while human subjects are involved, there is no IND needed. Consents by the patients (in the first example) or by the relatives (in the second example) are needed. 

Phase 0 Clinical Trial: the concept of phase 0 clinical trial came from the FDA's guidance for industry "Exploratory IND Studies". The term 'phase 0 clinical trial' was not used in the guidance, but was used for exploratory IND studies. Phase 0 clinical trial may now be called 'early phase 1' clinical trial, for example, in NIH.gov website and in clinicaltrials.gov:

According to the FDA guidance "Exploratory IND Studies", the exploratory IND studies (therefore phase 0 clinical trials or early phase 1 clinical trials) are defined as the following:

"Exploratory IND studies usually involve very limited human exposure and have no therapeutic or diagnostic intent. Such studies can serve a number of useful goals. For example, an exploratory IND study can help sponsors

• Determine whether a mechanism of action defined in experimental systems can also be observed in humans (e.g., a binding property or inhibition of an enzyme)
• Provide important information on pharmacokinetics (PK)
• Select the most promising lead product from a group of candidates5 designed to interact with a particular therapeutic target in humans, based on PK or pharmacodynamic (PD) properties
• Explore a product’s biodistribution characteristics using various imaging technologies

 Whatever the goal of the study, exploratory IND studies can help identify, early in the process, promising candidates for continued development and eliminate those lacking promise. As a result, exploratory IND studies may help reduce the number of human subjects and resources, including the amount of candidate product, needed to identify promising drugs. The studies discussed in this guidance involve dosing a limited number of subjects with a limited range of doses for a limited period of time.

Existing regulations provide more flexibility with regard to the preclinical testing requirements for exploratory IND studies than for traditional IND studies. However, sponsors submitting the kinds of studies described in this guidance have not always taken full advantage of that flexibility. Sponsors often provide more supporting information in their INDs than is required by the regulations. Because exploratory IND studies involve administering either subpharmacologic doses of a product, or doses expected to produce a pharmacologic, but not a toxic, effect, the potential risk to human subjects is less than for a traditional phase 1 study that, for example, seeks to establish a maximally tolerated dose. Because exploratory IND studies present fewer potential risks than do traditional phase 1 studies that look for dose-limiting toxicities, such limited exploratory IND investigations in humans can be initiated with less, or different, preclinical support than is required for traditional IND studies.  "

In cancer.org website,"Types and Phases of Clinical Trials", Phase 0 clinical trials were specifically mentioned: 

Phase 0 clinical trials: Exploring if and how a new drug may work

Even though phase 0 studies are done in humans, this type of study isn’t like the other phases of clinical trials. The purpose of this phase is to help speed up and streamline the drug approval process. Phase 0 studies may help researchers find out if the drugs do what they’re expected to do. This may help save time and money that would have been spent on later phase trials.

Phase 0 studies use only a few small doses of a new drug in a few people. They might test whether the drug reaches the tumor, how the drug acts in the human body, and how cancer cells in the human body respond to the drug. People in these studies might need extra tests such as biopsies, scans, and blood samples as part of the process.

Unlike other phases of clinical trials, there’s almost no chance the people in phase 0 trials will benefit. The benefit will be for other people in the future. And because drug doses are low, there’s also less risk to those in the trial.

Phase 0 studies aren’t widely used, and there are some drugs for which they wouldn’t be helpful. Phase 0 studies are very small, often with fewer than 15 people, and the drug is given only for a short time. They’re not a required part of testing a new drug.

Phase 0 clinical trials are mainly conducted in the oncology area and there are quite some phase 0 (or early phase 1) studies are listed in clinicaltrials.gov. An example of a phase 0 study was published in JCO (Kummar et al 2009 "Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies").