Safety assessments study design

The design and conduct of safety assessment studies and programs also require an understanding of some basic concepts ... 

One of the essential basic skills for the efficient design and conduct of safety assessment studies is to be able to accurately project compound requirements for the conduct of a study. In theory, this simply requires plugging numbers into a formula... 

The topic of preclinical assessment of a clinical candidate has been reviewed in Chapter 29. The topic is mentioned here because the decision as to whether it is safe to take a candidate drug into humans is ultimately a medical judgment that can only be made by individuals responsible for clinical drug development. Preclinical safety assessments are designed to provide the knowledge needed to decide whether it is reasonably safe to study a drug candidate in humans. The term reasonably safe is used in this context because that is what an FDA reviewer must answer when reviewing an IND application. 

The criteria for limited impact is set as acceptance criteria for a number of DEC and for probabilistic safety assessment studies. The following sections define the methodology to assess the acceptability of the releases from a specific design versus the criteria for limited impact. 

In this study detailed fault trees with probability and failure rate calculations were generated for the events (1) Fatality due to Explosion, Fire, Toxic Release or Asphyxiation at the Process Development Unit (PDU) Coal Gasification Process and (2) Loss of Availability of the PDU. The fault trees for the PDU were synthesized by Design Sciences, Inc., and then subjected to multiple reviews by Combustion Engineering. The steps involved in hazard identification and evaluation, fault tree generation, probability assessment, and design alteration are presented in the main body of this report. The fault trees, cut sets, failure rate data and unavailability calculations are included as attachments to this report. Although both safety and reliability trees have been constructed for the PDU, the verification and analysis of these trees were not completed as a result of the curtailment of the demonstration plant project. Certain items not completed for the PDU risk and reliability assessment are listed. 

The RC1 is an automated laboratory batch/semi-batch reactor for calorimetric studies which has proven precision. The calorimetric principle used and the physical design of the system are sound. The application of the RC1 extends from process safety assessments including calorimetric measurements, to chemical research, to process development, and to optimization. The ability of the RC1 to generate accurate and reproducible data under simulated plant scale operating conditions may result in considerably reduced testing time and fewer small scale pilot plant runs. 

The usual way in which transition (or flow ) between the different phases is handled in safety assessment is to use a tiered testing approach. Each tier generates more specific data (and costs more to do so) and draws on the information generated in earlier tiers to refine the design of new studies. Different tiers are keyed to the... 

It should be kept in mind that there are a number of common mistakes (in both the design and conduct of studies and in how information from studies is used) that have led to unfortunate results, ranging from losses in time and money and the discarding of perfectly good potential products to serious threats to people s health. Such outcomes are indeed the great disasters in product safety assessment, especially since many of them are avoidable if attention is paid to a few basic principles. 

Many of the studies done in safety assessment are multiple endpoint screens. Such study types as a 90-day toxicity study or immunotox or neurotox screens are designed to measure multiple endpoints with the desire of increasing both sensitivity and reliability (by correspondence-correlation checks between multiple data sets). 

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. 

Study design 40-60 subjects per treatment arm (high cost) Need for a placebo control arm and a positive control group Need to study more than one dose level of die test compound to assess dose dependency and die safety margin of therapeutic doses... 

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