Safety pharmacology studies

Safety pharmacology studies may also be conducted in conjunction with the toxicity studies. These focus on identifying secondary pharmaceutical side effects that may occur, when the drug is administered in the therapeutic range. Emphasis is placed on identifying effects on vital systems, particularly the central nervous, cardiovascular and respiratory systems. 

Case Study 1 Safety Pharmacology Studies for an IND for Beta Thalassemia Susan Perrine, M.D., Professor of Pediatrics, Medicine, Pharmacology, and Experimental Therapeutics, Boston University School of Medicine... 

Functional changes, that is, safety pharmacology studies. 

Electrocardiograms and Cardiovascular Measurements. The availability of excellent GLP-validated telemetry systems has led to recent increases in the number of cardiovasular safety pharmacology studies conducted in primates. In addition, telemetry is now sometimes included as a design element in standard safety studies. Because of the ability to collect large amounts of high quality data over an extended time, total numbers of animals can often be reduced by appropriate application of... 

In the EU, the CPMP issued a draft Note for Guidance on Safety Pharmacology Studies in Medicinal Product Development in 1998, but it has not yet been finalized or put in force, and as of the middle of 2001, USFDA has remained mute on guidelines. 

As a starting place, unlike older pharmacology studies, safety pharmacology studies are normally conducted as GLP studies. At the same time, unlike other safety assessment studies, these do not need to vastly exceed intended therapeutic doses so as to identify signs of toxicity. In this sense, they are closer to hazard tests. 

The initiative to add mandated safety pharmacology studies to the drug development process is overdue in arriving. However, its actual implementation and the use of the resulting data in risk/benefit decision will take some time to be worked out. During the year 2001, many small companies were put in a difficult position when the... 

Anderson, H., Spliid, H., Larsen, S. and Dali, V (2000). Statistical analysis of time to event data from preclinical safety pharmacology studies. Tox. Methods 10 111-125. 

CPMP (1998). Note for Guidance on Safety Pharmacology Studies in Medicinal Product Development. 

Fujimori, K. (1999). The role of general pharmacological studies and pharmacokinetics in the evolution of drugs (1) The role of general/safety pharmacology studies in the development of pharmaceuticals International harmonization guidelines. Folia Pharmacologica Japo-... 

Safety pharmacology studies investigate the undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above. 

Anonymous, ICH S7A Safety pharmacology studies for human pharmaceuticals, CPMP/ICH/539/00, 2000. 

ADRs in humans fall into five types. Of these, acute safety pharmacology studies can reasonably be expected to predict Type A ADRs (see Table 13.2).2 This means that —75% of clinical ADRs are potentially predictable on the basis of non-clinical safety pharmacology studies. 

Note Conventional safety pharmacology studies can reasonably be expected to predict "Type A" ADRs. Functional toxicological measurements may predict "Type C" ADRs. Conventional toxicology studies address "Type D" ADRs. Prediction of "Type B" responses requires a more extensive non-clinical and clinical evaluation, often only addressing risk factors for the idiosyncratic response. "Type E" ADRs are rarely investigated non-clinically using functional measurements unless there is cause for concern. 

Provides guidance on the timing of safety pharmacology Anon.24 studies in relation to clinical development. Establishes that safety pharmacology studies should be conducted prior to first administration to humans... 

Defines the objective of safety pharmacology studies to Anon23 reveal functional effects on major physiological systems (e.g., cardiovascular, respiratory, renal, and central nervous systems)... 

Provides the general framework for in vitro and in vivo Anon.25 safety pharmacology studies, including studies addressing the risk for a drug to slow cardiac repolarization... 

Safety pharmacology studies have been subdivided into "core battery," "follow-up," and "supplemental" studies.25 The "core battery" studies are aimed to investigate the effects of NCEs on the cardiovascular, respiratory, and central nervous systems that are considered as vital organ systems based on the fact that acute failure of these systems would pose an immediate hazard to human life. In some instances, based on scientific rational, the "core battery" may or may not be supplemented.25 Additionally, ADRs may be either (1) suspected based on the pharmacological class, or the chemical class, or (2) identified... 

Doses selected for safety pharmacology studies are typically based on the criteria established in the ICH S7A guidance.25 Doses should exceed those projected for clinical efficacy and at the upper limit be bound by (1) adverse pharmacodynamic effects in the safety pharmacology study (2) moderately adverse effects in other non-clinical studies that follow a similar route and duration of dosing or (3) limit of solubility/toxicity. In the absence of adverse effects, the maximum administrable dose can be used. If nonreusable animals enter the study, then the maximum tolerated dose may be appropriate. Most importantly, the doses/concentrations should establish the dose/concentration-response relationship of the adverse effect. 

Conditions under Which Safety Pharmacology Studies Are Not Necessary... 

Timing of Safety Pharmacology Studies in Relation to Clinical Development... 

The safety pharmacology "core battery" studies should be available prior to first administration in humans. Furthermore, "follow-up" and "supplemental" studies should also be available prior to first administration in humans if there are specific cause for concerns. During clinical development, additional studies may be warranted to clarify observed or suspected adverse effects in animals or humans. Finally, prior to product approval, effects on organ systems that are defined as part of "follow-up" and "supplemental" studies should be assessed, unless not warranted. Available information from toxicology or clinical studies can support this assessment and replace the need for stand-alone safety pharmacology studies. 

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