Evaluation of Safety

E. R. Panick, L. R. Smith, J. A. Russell and W. E. Likos, "Laboratory Evaluation of Safety-Related Additives for Neat Methanol Euel," SAP Paper 902156, (SP 840), Society of Automotive Engineers, Warrendale, Pa., Oct. 1990. 

Peterson, R. J. et al., 1981, Performance-Based Evaluation of Safety Parameter Display Detection, EG G, Sd-B-81-004, November. 

JECFA (1974) Joint FAO/WHO Expert Committee on Food Additives. Evaluation of safety of synthetic beta-carotene. Evaluation 18/68. 

To provide a complete assessment of all these variables, the final evaluation of safety must be made in the in vivo model using the preparation under the proposed conditions for use, following tissue compatibility with many of the techniques already discussed. Confocal microscopy is a relatively new noninvasive technique that allows a detailed examination of the endothelium in the live animal, and thus may prove useful in following changes in this delicate tissue over time. As in ex vivo models, the... 

Fibrates are being combined with statins to expand their potential in the dyslipidemia market. A recent clinical study examined the effects of rosuvastatin (10) and fenofibrate as mono and combination therapy in hyperlipidemic diabetic patients [43]. In late 2006, large scale Phase III clinical trials of rosuvastatin in combination with a next-generation fibrate, ABT 335, were initiated for evaluation of safety and efficacy in patients with mixed dyslipidemia. 

Bayes Theorem and Evaluation of Safety Assessment Studies... 

Many methods have been used for the evaluation of safety in the Post-marketing period, but these can be reduced to five basically different approaches to the problem ... 

The vast subject of clinical trials in new drug development is the subject of Chapter 6 and will be dealt with here only with respect to their use after marketing for the further evaluation of safety. 

In the evaluation of safety in the postmarketing phase, regulatory agencies are greatly more restricted in their enthusiasm for data derived from some of the methods available than from others. Indeed, the EC national agencies separately and the CPMP collectively have developed a legislative framework that is predominantly concerned with spontaneous adverse event monitoring and which is, for all practical purposes, silent on the matter of safety data collected by other methods. 

The primary consideration of a clinical investigation of a device is assessment verification of the manufacturer s claims for the technical performance of the device. Safety considerations are, nevertheless, relevant in that the clinical investigation should determine and assess any undesirable adverse effects, but the main thrust of the clinical evaluation, and in particular of the conformity assessment by a notified body or the manufacturer to permit marketing, is on technical performance rather than a complete evaluation of safety. It is an essential requirement for marketed devices that [A]ny undesirable side-effect must constitute an acceptable risk when weighed against the performances intended. ... 

These comments are directed primarily at efficacy and do not tend to be applied to safety, unless a safety claim (e.g. drug A is less toxic than drug B) is to be made. With the routine evaluation of safety, where p-values are being used as a flag for potential concerns, we tend to be conservative and not worry about inflating the type I error. It is missing a real effect, the type II error, that concerns us more. 

In recent years, natural products such as melatonin and herbs such as valerian have become popular over-the-counter remedies for insomnia. There are no comprehensive evaluations of safety and efficacy of these products. Beyond questions of safety and efficacy, there is no consensus on what their doses should be. Nevertheless, these products continue to be used widely by some patients. 

WEIL, C.S. (1972). Statistics versus safety factors and scientific judgment in the evaluation of safety for man, Toxicol. Appl. Pharmacol. 21, 454-463. 

Bibliography of all publications relevant to the safety of the device Copies of all published and unpublished adverse information Summary of all other unpublished information relevant to an evaluation of safety and effectiveness of the device... 

Bibliography of all published reports that concern the safety or effectiveness of the device Identification, discussion, and analysis of other data, information, and reports relevant to the evaluation of safety and effectiveness. 

System analysis for the assessment of the HYSOLAR program and of a utilisation program for the evaluation of safety, reliability and environmental aspects of the selected hydrogen application technologies, as well as of an educational and training program. 

However evaluation of safety in animal models of disease may be difficult to conduct with strict adhere to current good laboratory practices (cGLPs) due to novel routes of administration, limited animal numbers, uniqueness of the animal model of disease, and/or novel surgical procedures. In such cases the principles of the regulation can still be followed, and where deviations occur, they should be evaluated for their impact on the expected clinical application and discussed. An in-depth discussion should be provided to support a regulatory submission. 

Klaassen, C.D., and J. Doull. 1980. Evaluation of safety Toxicological evaluation. Pp. 26 in Cassarett and Doull s Toxicology, The Basic Science of Poisons, J. Doull, C.D. Klaassen, and M.O. Amdur, eds. New York. Macmillan. 

When the patients who received a drug candidate have the disease manifestations completely eradicated and experience no other effects while patients treated with a placebo have a continuation of the disease process, the evaluation is not difficult. However, that is rarely, if ever, the case, and evaluation requires detailed statistical analysis of the collected data. An ICH guide-line covers statistical issues related to the scope of clinical trials, design techniques to minimize bias, types of clinical trial designs, conduct considerations, data analysis for efficacy, evaluation of safety and tolerance, and reporting. 

Terry RW. Nifedipine therapy in angina pectoris evaluation of safety and side effects. Am Heart J 1982 104(3) 681-9. 

Hitmen DP, Lesoway R, Kostuk WJ. Acute, single, intravenous doses of cibenzoline an evaluation of safety, tolerance, and hemodynamic effects. Qin Pharmacol Ther 1987 41(5) 537 5. 

Tang RS, Spaete RR, Thompson MW, MacPhail M, Guzzetta JM, Ryan PC, Reisinger K, Chandler P, Hilty M, Walker RE, Gomez MM, Losonsky GA. Development of a PIV-vectored RSV vaccine Preclinical evaluation of safety, toxicity and enhanced disease and initial clinical testing in healthy adults. Vaccine. 2008 26 373-6382. 

In May 1980, Notification 698 from the MHLW specified the type of data required for the evaluation of safety in animals and Guidelines for Toxicity Studies were subsequently established in 1984. It is necessary to generate data on acute, sub-acute and chronic toxicity, effect on reproduction, dependence, antigenicity, mutagenicity, carcinogenicity and local irritation. 

Gait, J.E. Smith, S. Brown, S.L. Evaluation of safety data from controlled clinical trials The clinical principles explained. Drug Inf. J. 2000, 34, TTi-l l. 

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