1. In Vitro and animal studies are rarely sufficient to anticipate safety problems that may result in the development of pharmaceuticals.
Preclinical studies, including both in vitro and animal studies provide valuable information and are the foundation for designing for “First in Man” phase 1 studies, but the results are rarely directly transferrable for humans. Subject safety is paramount in carefully controlled phase 1 clinical trials, which typically use healthy volunteers. Subjects are dosed and observed in clinical trial units where medical personnel are available immediately to avert any untoward events unanticipated from the previous work done in animals.
2. The purposes of phase 1 clinical trials are initial estimation of safety and tolerability, assessment of pharmacokinetics (PK) and pharmacodynamics(PD), and potential indications of a product’s clinically relevant activity.
The goals for safety in phase 1 include determining the tolerability of the dose range expected to be needed for later studies and determining the nature of the adverse events related to the product by attempting to find a maximum tolerated dose. Pharmacokinetics provides data on how the body affects the drug in terms of absorption, distribution, metabolism and excretion (ADME). Pharmacokinetics also examines food effects and special physiologically-compromised populations. Pharmacodynamics provides data on what the drug does to the body. For example, pharmacodynamics provides data to evaluate the therapeutic window (minimum effective dose versus minimum toxic dose) and the duration of action. Phase 1 clinical trials often include some measures of clinically relevant activity to give sponsors an indication of the potential efficacy of a compound.
3. An Investigational New Drug application (IND) is required for phase 1 clinical trials conducted on investigational drugs and biologics in the US.
This requirement comes from 21CFR312.20. The sponsor company must present FDA with data that show the new product is safe in animals and is stable and manufactured reproducibly within pre-defined specifications. They must also demonstrate that the clinical trial will be 1) conducted by qualified personnel; 2) will be conducted under a protocol providing safety for subjects, and 3) will generate scientifically useful results. The IND must include:
- Chemistry, Manufacturing and Controls (CMC) information- assures proper identification, quality, purity, strength, and stability of the investigational drug
- Pharmacology information-effects and mechanism of action in animals that potentially will prove therapeutic in humans
- Toxicology information-integrated summary of the sponsor’s data on completed toxicology studies
- Investigator Brochure (IB)-a synopsis of the IND that informs the investigators on what is known from preclinical studies about the pharmacodynamics, pharmacokinetics, and safety of the investigational product, the manufacturing process, and the clinical rationale for development
- Protocol-outlines the investigation that will be performed including the number of subjects, subject characteristics, study design, safety monitoring, and toxicity based rules for stopping or adjusting the dose
4. FDA does not provide an explicit approval of an IND.
An IND goes into effect 30 days after it is received by FDA, unless FDA notifies the sponsor that the investigation described in the IND is subject to a clinical hold under 21CFR312.42. A clinical hold is an order issued by FDA to delay a proposed clinical investigation or to suspend an on-going investigation. So, while the FDA does not approve trials, they can stop them.
5. First in Man is only one of several kinds of phase 1 clinical trials.
Other common phase 1 studies include food effect studies, age/gender/race effect studies, dose finding studies, liver or renal impairment studies and drug-drug interaction studies. Food effect studies are recommended for all orally administered new drugs and evaluate the effect of food on the bioavailability of the product. Food can change bioavailability by delaying gastric emptying, changing gastrointestinal pH, increasing blood flow, or physically or chemically interacting with a drug product’s dosage form. Age/gender/race effect studies are designed to assess differences among subgroups that can occur because of age-related metabolic changes, hormonal differences, and genetic polymorphisms. Dose finding studies generate safety and PK information to choose a dose range for clinical efficacy trials. Hepatic impairment studies explore the impact of liver disease on pharmacokinetics and are required if the liver contributes more than 20% to drug metabolism and excretion or if there is a narrow therapeutic window. Renal impairment studies explore the impact of renal disease on pharmacokinetics and are required if alteration to PK is expected in patients with renal disease or dose adjustment is likely needed for patients with renal disease (for example, when elimination occurs primarily through the kidneys). Drug-drug interaction (DDI) studies evaluate potential PK interactions between the investigational product and marketed compounds likely to be coadministered. These studies are important because they may impact dosing or warnings on the label.