Safety assessment objectives

As with any scientific study or experiment (but especially for those in safety assessment), the essential first step is to define and understand the reason(s) for the conduct of the study, its objectives. There are three major (scientific) reasons for conducting subchronic and chronic studies, but a basic characteristic of all but a few... 

In addition to rodent studies, regulatory guidelines for pharmaceuticals require that repeated dose safety studies of up to nine months (in the United States, six months elsewhere) in duration be conducted in a nonrodent species. The most commonly used nonrodent species is the dog, followed by the monkey and pig. Another nonrodent model used to a limited extent in systemic safety evaluation is the ferret. The major objectives of this chapter are (1) to discuss differences in rodent and nonrodent experimental design, (2) to examine the feasibility of using the dog, monkey, pig, and ferret in safety assessment testing, and (3) to identify the advantages and limitations associated with each species. 

Some would say that this is the current state of the art. Much of the necessary library could be assembled from test systems that have been extensively evaluated and have already undergone extensive validation (Gad, 2000, 2001). Three critical steps must be taken for the eventual fulfillment of these objectives (1) acceptance of a scientific approach to the problem of safety assessment (2) development of an operative validation and acceptance process for new test procedures (3) clear enunciation of an acceptance criterion for new test designs by regulatory authorities. 

A scientific approach to safety assessment, such as the one presented in this chapter, does have proponents and adherents. Such an approach requires those involved in both the management and conduct of the safety assessment process to continually question (and test) both the efficacy and the validity of their evaluation systems and processes. More to the point, it requires recognition of the fact that we have always done it this way is not a reason for continuing to do so. This approach asks first what is the objective behind the testing, and then it asks how well our testing is meeting this objective. 

The following list suggests practical exercises that could be used to both support the assessment objectives given above and enrich the study of chemistry in addition, it should suggest plenty of opportunities for the enhancement and assessment of practical skills. The list is neither exhaustive nor prescriptive the actual selection of practical work, whether from this list or from elsewhere, has to be governed by local factors such as the facilities available, safety considerations and the ability of the class. 

The objective of the book is not to turn the reader into a specialist in thermal safety. It is to guide those who perform risk analysis of chemical processes, develop new processes, or are responsible for chemical production, to understand the thermal aspects of processes and to perform a scientifically founded-but practically oriented-assessment of chemical process safety. This assessment may serve as a basis for the optimization or the development of thermally safe processes. The methods presented are based on the author s long years of experience in the practice of safety assessment in industry and teaching students and professionals... 

The groundwater transport of radionuclides through waterbearing interbed layers in the Columbia River basalt formation will be controlled by reactions of the radionuclides with groundwater and interbed solids. These interactions must be understood to predict possible migration of radionuclides from a proposed radioactive waste repository in basalt. Precipitation and sorption on interbed solids are the principle reactions that retard radionuclide movement in the interbeds. The objective of the work described herein was to determine the sorption and desorption behavior of radionuclides important to safety assessment of a high-level radioactive waste repository in Columbia River basalt. The effects of groundwater composition, redox potential, radionuclide concentration, and temperature on these reactions were determined. 

Additional safety studies may be required to support the movement into new indications, and the complex designer biopharmaceuticals will continue to require creative approaches to safety assessment. In either case, the requirement for, and design and execution of, those studies should be driven by sound scientific rationale. Ultimately, the objective of preclinical safety evaluation is well articulated in ICH S6 ... 

Transitioning into an initial exploratory clinical evaluation rests upon safety and functional understanding built during preclinical evaluation. The preclinical program establishes assessment objectives related to specific product characteristics and the supporting production processes. Translational medicine study results define the extent to which preclinical information demonstrates... 

Randomization and blinding important where effects cannot be measured objectively. Safety assessment relative to the disease to be treated, in comparison with other therapeutic approaches, considering the characteristics of sub-groups of patients, and considering the animal toxicology and pharmacology data. 

If these questions do not have satisfying answers, the organization may wish to modify its objectives. These examples describe different vantage points to use in assessing objectives for the process safety system and should play a role in defining the metrics system objectives. 

Toxicologists must rely on results obtained from an alternative method if it is to serve as a replacement for an in vivo toxicity test. Two measures of alternative method performance must be known in order to define reliability from a test user s point of view. First, a toxicologist must know it is possible to consistently reproduce the data obtained from the alternative method over long periods of time. A test that does not provide the same results on the same test substance repeatedly would not be useful in the safety assessment process. Second, it must be possible to consistently predict in vivo toxicity endpoints at a known level of accuracy and precision. These measures of reliability are objective endpoints that can be measured experimentally. The part of the validation process that provides the data needed to confirm the reliability of an alternative method as proposed by its developers is the validation study. 

In order to sustain, and more objectively, to improve upon the ability of human, natural and mixed systems to withstand and adapt to endogenous or exogenous changes, ideally indefinitely, much greater chemical safety assessment is essential. 

Establishing completeness of analysis is a key objective of the safety assessment. Where there are activities to complete or information still to be ascertained these constraints on the analysis should be explicitly declared in the report along with expected resolution, timescales and potential impact on clinical risk. In some cases it can be useful to set out what the pessimistic world might look like should those outstanding activities fail to complete. 

Developing an objective approach to risk management is as much about the language we use as it is the processes we put in place. Those who have the authority to undertake a safety assessment have a responsibility to wield that power carefully and shrewdly and this can quickly be undermined when one resorts to emotive and reactive language. This is as true for the language of the safety case as it is in the corridor conversations with colleagues. Those who operate in CRM have a duty to propagate objectivity by example and to communicate in a way that drives a safety culture which is not rash but considered. 

The audit plan should be made by the leader of safety audit project based on this safety audit objectives, preliminary information and preliminary assessment of internal control and risk level. The audit program shall include the following contents (1) the basis for preparing the audit program (2) the name of the audited entity and... 

LMRs with oxide-fueled core Models modified and newly developed mto the code so far mclude models for reactivity feedback effects and pool thermal-hydraulics In order to venfy the logic of the models developed, and to assess the effectiveness of the inherent safety features based upon the negative reactivity feedbacks m achieving the safety design objectives of passive safety, a preliminary analysis of UTOP and ULOF/LOHS performance has been attempted... 

The Committee noted that blood in stool is a very crude and often late sign of gastrointestinal damage (or cancer in adults). This analysis is based on records of customer complaints and therefore is not suitable for the safety assessment of carrageenan. More useful information to collect would be the objective assessment of occult blood in subgroups receiving formula with and without carrageenan. 

Core battery CNS procedures are by design simple tests, using very traditional techniques, which can be carried out rapidly in a routine and objective fashion. They are the first techniques to be employed in safety assessment and are frequently applied at the very beginning of the discovery process as a screen to eliminate substances with a potential for CNS risk. Because of their use early in the safety evaluation process, such studies are conducted most usually in the rat or the mouse, diough (as we shall see) analogous methods have been developed and validated and are in use with dogs, primates, and pigs. 

FIH studies are typically conducted in healthy subjects beginning with a single ascending dose study with the primary objective being safety assessment. Secondary objectives include PK and PD assessments if possible. Statistical analyses are typically descriptive. Dose escalation continues until potential... 

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