Q32:Please list, in general terms, the principles of safety pharmacology studies in humans?

Answer:

Since pharmacological effects vary depending on the specific properties of each test substance, the studies should be selected and designed accordingly. The following factors should be considered:

1. Effects related to the therapeutic class of the test substance, since the mechanism of action may suggest specific adverse effects (e.g., proarrhythmia is a common feature of antiarrhythmic agents)

2. Adverse effects associated with members of the chemical or therapeutic class, but independent of the primary pharmacodynamic effects (e.g., antipsychotics and QT prolongation)

3. Ligand binding or enzyme assay data suggesting a potential for adverse effects

4. Results from previous safety pharmacology studies, from secondary pharmacodynamic studies, from toxicology studies, or from human use that warrant further investigation to establish and characterize the relevance of these findings to potential adverse effects in humans

During early development, sufficient information (e.g., comparative metabolism) may not always be available to rationally select or design the studies in accordance with the points stated above; in such circumstances, a more general approach in safety pharmacology investigations can be applied.

A hierarchy of organ systems can be developed according to their importance with respect to life-supporting functions. Vital organs or systems, the functions of which are acutely critical for life (e.g., the cardiovascular, respiratory, and central nervous systems), are considered to be the most important ones to assess in safety pharmacology studies. Other organ systems (e.g., the renal or gastrointestinal system), the functions of which can be transiently disrupted by adverse pharmacodynamic effects without causing irreversible harm, are of less immediate investigative concern. Safety pharmacology evaluation of effects on these other systems may be of particular importance when considering factors such as the likely clinical trial or patient population (e.g., gastrointestinal tract in Crohn’s disease, renal function in primary renal hypertension, immune system in immunocompromised patients).

         General Considerations on Test Systems

Consideration should be given to the selection of relevant animal models or other test systems so that scientifically valid information can be derived. Selection factors can include the pharmacodynamic responsiveness of the model, pharmacokinetic profile, species, strain, gender and age of the experimental animals, the susceptibility, sensitivity, and reproducibility of the test system and available background data on the substance

         Use of In Vivo and In Vitro Studies

In vitro systems can be used in supportive studies (e.g., to obtain a profile of the activity of the substance or to investigate the mechanism of effects observed in vivo).

In conducting in vivo studies, it is preferable to use unanesthetized animals. Data from unrestrained animals that are chronically instrumented for telemetry, data gathered using other suitable instrumentation methods for conscious animals, or data from animals conditioned to the laboratory environment are preferable to data from restrained or unconditioned animals. In the use of unanesthetized animals, the avoidance of discomfort or pain is a foremost consideration.

Experimental Design

a. Sample Size and Use of Controls

The size of the groups should be sufficient to allow meaningful scientific interpretation of the data generated. Thus, the number of animals or isolated preparations should be adequate to demonstrate or rule out the presence of a biologically significant effect of the test substanceThe exclusion of controls from studies should be justified.

b. Route of Administration

In general, the expected clinical route of administration should be used when feasible. Regardless of the route of administration, exposure to the parent substance and its major metabolites should be similar to or greater than that achieved in humans when such information is available. Assessment of effects by more than one route may be appropriate if the test substance is intended for clinical use by more than one route of administration (e.g., oral and parenteral) or where there are observed or anticipated significant qualitative and quantitative differences in systemic or local exposure.

D. Dose Levels or Concentrations of Test Substance

1. In Vivo Studies

In vivo safety pharmacology studies should be designed to define the dose-response relationship of the adverse effect observed. The time course (e.g., onset and duration of response) of the adverse effect should be investigated, when feasible. Generally, the doses eliciting the adverse effect should be compared to the doses eliciting the primary pharmacodynamic effect in the test species or the proposed therapeutic effect in humans, if feasible. It is recognized that there are species differences in pharmacodynamic sensitivity. Therefore, doses should include and exceed the primary pharmacodynamic or therapeutic range. In the absence of an adverse effect on the safety pharmacology parameters evaluated in the study, the highest tested dose should be a dose that produces moderate adverse effects in this or in other studies of similar route and duration. These adverse effects can include dose-limiting pharmacodynamic effects or other toxicity. In practice, some effects in the toxic range (e.g., tremors or fasciculation during ECG recording) may confound the interpretation of the results and may also limit dose levels. Testing of a single group at the limiting dose as described above may be sufficient in the absence of an adverse effect on safety pharmacology endpoints in the test species.

2. In Vitro Studies

In vitro studies should be designed to establish a concentration-effect relationship. The range of concentrations used should be selected to increase the likelihood of detecting an effect on the test system. The upper limit of this range may be influenced by physico-chemical properties of the test substance and other assay specific factors. In the absence of an effect, the range of concentrations selected should be justified.

F. Studies on Metabolites, Isomers, and Finished Products

In vitro or in vivo testing of the individual isomers should also be considered when the product contains an isomeric mixture.

Safety pharmacology studies with the finished product formulations should be conducted only for formulations that substantially alter the pharmacokinetics and/or pharmacodynamics of the active substance in comparison to formulations previously tested (i.e., through active excipients such as penetration enhancers, liposomes, and other changes such as polymorphism).

G. Safety Pharmacology Core Battery

The purpose of the safety pharmacology core battery is to investigate the effects of the test substance on vital functions. In this regard, the cardiovascular, respiratory, and central nervous systems are usually considered the vital organ systems that should be studied in the core battery.

H. Follow-up Studies For Safety Pharmacology Core Battery

Follow-up studies are meant to provide a greater depth of understanding than, or additional knowledge to, that provided by the core battery on vital functions. The following subsections provide lists of studies to further evaluate these organ systems for potential adverse pharmacodynamic effects. These lists are not meant to be comprehensive or prescriptive, and the studies should be selected on a case-by-case basis after considering factors such as existing nonclinical or human data. In some cases, it may be more appropriate to address these effects during the conduct of other nonclinical and/or clinical studies.

I. Conditions Under Which Studies Are Not Necessary

Safety pharmacology studies may not be needed for locally applied agents (e.g., dermal or ocular) where the pharmacology of the test substance is well characterized, and where systemic exposure or distribution to other organs or tissues is demonstrated to be low.

Safety pharmacology studies prior to the first administration in humans may not be needed for cytotoxic agents for treatment of end-stage cancer patients. However, for cytotoxic agents with novel mechanisms of action, there may be value in conducting safety pharmacology studies.

For biotechnology-derived products that achieve highly specific receptor targeting, it is often sufficient to evaluate safety pharmacology endpoints as a part of toxicology and/or pharmacodynamic studies; therefore, safety pharmacology studies can be reduced or eliminated for these products

J.Laboratory Practice (GLP)

It is important to ensure the quality and reliability of nonclinical safety studies. This is normally accomplished through the conduct of the studies in compliance with GLP. Due to the unique design of, and practical considerations for, some safety pharmacology studies, it may not be feasible to conduct these in compliance with GLP. It has to be emphasized that data quality and integrity in safety pharmacology studies should be ensured even in the absence of formal adherence to the principles of GLP. When studies are not conducted in compliance with GLP, study reconstruction should be ensured through adequate documentation of study conduct and archiving of data. Any study or study component not conducted in compliance with GLP should be adequately justified, and the potential impact on evaluation of the safety pharmacology endpoints should be explained.