Phase I Trials Today

Single Ascending Dose (SAD)

Single ascending dose (SAD) studies are those in which groups, or cohorts, of up to six patients are given a small dose of the drug and observed for a specific period of time. The initial dose is commonly based on one tenth of the murine equivalent lethal dose in 10% of animals (MELD10) or the human equivalent dose of the no observed adverse effect level (NOAEL, the highest nontoxic dose) achieved in the most sensitive preclinical species multiplied by a safety factor (default is greater than 10-fold). If the cohort does not exhibit any adverse side effects, a new group of patients is then given a higher dose. This continues until intolerable side effects are observed. Once such side effects occur in a patient, the protocol typically explores whether this is sporadic or reproducible, as described later in detail. The highest dose administered to a patient on a Phase I trial is referred to as the maximum administered dose . The dose that is as high as possible but still tolerable for patients is said to be the maximum tolerated dose (MTD).

Often, SAD clinical trials can be categorized as being first-in-human, first-in-class, or a combination of the two. As the name implies, first-in-human clinical trials are those that are conducted for the first time in a human patient. In order to be tested in humans, a drug typically has to first show promise of activity in the laboratory and in animals. Normally, a small group of patients (approximately 20) will be selected for inclusion into a first-in-human Phase I study. First-in-human studies for noncancer indications are almost always done in a single ascending dose manner. The objective of the first-in-human Phase I trial is to find a suitable safe dose (the MTD) for use in later studies that will more thoroughly examine efficacy. Once the MTD has been determined in a Phase I SAD study, later phase studies can be designed and multiple ascending dose studies can be performed.

First-in-class studies examine novel drugs that are uniquely manufactured or based on a new target or indication. Such therapeutics are typically innovative and novel, and no other pharmaceutical products are currently approved for the same therapeutic indication; hence, they have no pharmaceutical substitute.

Multiple Ascending Dose (MAD)

Multiple ascending dose (MAD) studies are conducted to better understand the pharmacokinetics and pharmacodynamics of a drug and determine the dose that is tolerable for repeated administration in therapeutic intent trials (Phase II). In these studies, a group of patients receives a low dose of the drug and the dose is subsequently escalated to a predetermined level. A single schedule that is judged optimal from preclinical studies or multiple schedules may be tested. Specimens (of blood and/or other fluids) are collected at various time points and analyzed to understand how the drug is processed within the body. In cancer, where MAD studies are commonplace, subjects receive repeated doses at a predetermined schedule, and new cohorts of patients receive progressively higher doses on the same schedule (see later discussion).

Method and Model (MeMo)

MeMo trials are studies that are done in anticipation of a Phase I clinical trial. Typically done for “targeted” agents, these trials help in the development of a pharmacodynamic endpoint. They may help identify either a direct tissue or a surrogate tissue marker. This assists in determining if the marker can be measured within the tissue and also helps to refine the assay needed for pharmacodynamic measurement.

Phase I Trials Using Radiolabeled Tracer Doses

The use of radiolabeled experimental agents has become an increasingly important factor in drug development. In preclinical studies, radiolabeled compounds are frequently used in the laboratory to understand the distribution, metabolic fate, and localization of experimental drugs both in vitro and in vivo. Clinical studies performed as part of Phase I trials, or in support of them, may also involve the administration of small doses of radiolabeled compounds, called tracers, to healthy human volunteers or to patients in order to better understand the mechanisms of drug action.

Radiolabeled tracers are synthesized by replacing one or more atoms of an experimental drug agent with a radioisotope. Radioisotopes must have a suitable half-life in order to allow for imaging or detection in biological samples. Examples of commonly used isotopes for detection in tissue or blood samples include carbon ( ¹⁴ C), hydrogen ( ³ H), sulfur ( ³⁵ S), and iodine ( ¹²⁵ I). Isotopes that are commonly used in imaging, specifically in positron emission tomography (PET) scanning, include fluorine ( ¹⁸ F), carbon ( ¹¹ C), and oxygen ( ¹⁵ O).

Radiolabeled compounds have allowed researchers to study many aspects of a drug’s behavior in vivo. Evaluation of the mass balance of a drug can be performed to better understand how much of an applied dose is recovered with respect to time. The metabolism of the drug can be extensively studied to determine if any metabolites might represent a potential toxicological hazard to the patient. Advances in clinical imaging have had great impact on drug discovery and development in recent years. Clinical imaging studies using labeled drug have the potential to facilitate early clinical pharmacokinetic/pharmacodynamic assessments, including target interaction and modulation. This is particularly useful in patients where there are no direct measures of pharmacokinetics/pharmacodynamics throughout the tissues of the body and at the target.

Studies using a method called microdosing offer the prospect of taking a drug directly into human studies by administering extremely low doses of radiolabeled agent. Microdosing studies may also be referred to as Phase 0 studies. Using only tiny amounts of radiolabeled drug, researchers employ microdosing to establish the likely pharmacological dose and thereby determine the first dose for a subsequent Phase I study. However, microdosing is not without controversy among researchers in drug development. Concern has been raised that microdosing may not accurately predict the behavior of clinical doses. It has also been suggested that nonlinearities may be induced when binding, metabolizing, or eliminating systems become saturated, thus resulting in differences between low and high doses.

Drug/Food Metabolic Interaction Studies

The U.S. Food and Drug Administration (FDA) has recommended that the metabolism of an investigational new drug be defined during drug development and that interactions with other drugs be explored as part of an adequate assessment of its safety and effectiveness. Medicines are often used concomitantly with other drugs, and some degree of drug-drug interaction often occurs with concomitant use. Concomitant medications can abruptly alter metabolic routes of absorption and elimination. Although only a small proportion of drug interactions are clinically significant, they sometimes cause serious adverse reactions.

Therefore, early on in the drug development process, appropriate efforts should be made to predict the nature and degree of potential interactions so that patients will not be adversely affected. The important cytochrome P450 (CYP450) family of enzymes is found in the liver and plays a large role in metabolizing drugs. Many metabolic routes of elimination, including most of those occurring via the CYPP450 family of enzymes, can be inhibited, activated, or induced by concomitant drug treatment. The FDA has recommended that detailed studies be performed with the major CYP450 enzymes (CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4). Typically, preclinical testing is performed to investigate the effects of an agent on metabolic factors, such as CYP450, and of inhibition or induction potential. If in vitro experiments reveal the potential for drug-drug interaction, in vivo experiments usually will follow. Therefore, Phase I clinical trials often include testing for the ability of an experimental agent to affect CYP450 and a determination of whether the agent causes a change in concentration of other drugs as a result. With the combination of in vitro studies and in vivo studies in support of Phase I clinical trials, the potential for drug-drug interactions can be studied early in the development process, with further study of observed interactions assessed later in the process, if necessary.

Organ Dysfunction Studies

The desirable and undesirable effects of a drug arising from its concentrations at the sites of action are usually related either to the amount administered (dose) or to the resulting blood concentrations (accumulation), which are affected by its absorption, distribution, metabolism, and/or excretion. Elimination of a drug or its metabolites occurs either by metabolism, usually by the liver, or by excretion, usually by the kidneys and liver.

Although clinical trials for drug approval are often conducted in patients with normal hepatic and renal function, patients in clinical practice, especially those with cancer, may have compromised organ function because of underlying disease. It has been recommended that organ dysfunction studies be designed in the form of a formal dose-escalation Phase I study, with a complete pharmacokinetic and toxicity profile as endpoints. The primary goal of the Phase I study in an organ-impaired population should be to determine if the pharmacokinetics are altered to such an extent that the dosage requires adjustment, based on degree of organ dysfunction, from the dose established in the unimpaired population.

Because of the uniqueness of eligible patients, these studies are typically conducted as multisite studies so that they can be completed in a timely and efficient fashion. In 1999, the National Cancer Institute developed an Organ Dysfunction Working Group (ODWG), comprising approximately 12 to 15 Phase I sites. The ODWG has successfully completed evaluation of oxaliplatin, imatinib, and bortezomib in the renally and hepatically impaired populations. In addition, several additional agents are currently undergoing evaluation.

Thorough QT Phase I Studies

Adverse effects on cardiac health have become one of the most common causes of product withdrawal from the market. As a result, regulatory authorities around the world have recently placed greater emphasis on cardiac safety. The FDA’s regulatory guidance recommends a thorough QT Phase I study to be conducted irrespective of preclinical cardiac findings. When a thorough QT study is not feasible for other reasons, which may be the case in certain therapeutic areas such as oncology, alternative approaches are recommended, such as expanding the number and timings of electrocardiographic (ECG) recordings in other clinical studies in patients.