Safety premarketing evaluation

Under the Medical Device Amendments of 1976, the FDA is responsible for premarket evaluation of all laboratory testing devices (in vitro diagnostics) intended to be commercially marketed in the United States. There are two major pathways for introducing a medical device into the marketplace the premarket notification [510(k) clearance] and the premarket approval (PMA). The purpose of the 510(k) is to establish that a device is substantially equivalent (SE) to a legally marketed (predicate) device. The purpose of the PMA evaluation process is to establish the intrinsic safety and effectiveness of a new device. Unless specifically exempt, a sponsor must have an approved PMA or cleared premarket notification [510(k)] by the FDA before a device may be legally marketed for IVD use (Fig. 1). 

Fung, M., Thorton, A., Mazbeck, K., Wu, J.H., Hombuckle, K., and Muniz, E. (2001). Evaluation of the characteristics of safety withdrawal of premarketing prescription drugs from worldwide pharmaceutical markets—1960 to 1999. Drug Information J. 35 293-317. Goldman, S.A. (1998). Limitations and strengths of spontaneous reports data. Clin. Ther. 201 Supplement C, CAO-58. 

This document describes the types of chemical and technological data that the FDA s Office of Premarket Approval in the Center for Food Safety and Applied Nutrition considers necessary for the evaluation of petitions seeking regulation of the safe use of direct food additives or for the affirmation of the use of food ingredients as generally recognized as safe (GRAS). 

There is no process or mechanism currently in place within the FDA to independently evaluate the safety of pharmaceutical excipients. Instead, for drugs subject to FDA premarket approval, excipients are only approved as components of new drugs. 

The E14 guidance on clinical evaluation of the QT/QTc interval prolongation states an adequate premarketing investigation of the safety of a new phar-... 

Laughren, T. (1992). Premarketing safety evaluation of new drugs. In J. Kane J. Lieber-man (Eds.), Adverse effects of psychotropic drugs. New York Guilford. 

Within the FDA s Center for Food Safety and Applied Nutrition, the Office of Food Additive Safety administers premarket approval processes for new direct food additives and food additives that are components of food contact materials. Most food contact materials are regulated via the food contact notification process and authorization of new food contact materials is administered by the Division of Food Contact Notifications (see Chapter 2 for further information). The notifier has the primary responsibility to demonstrate the safety of the proposed use of the food contact material. Review scientists within FDA perform a fair evaluation of the data in a food contact notification, as well as other relevant information, to determine if the knowledge base supports the finding with reasonable certainty that no harm will result from the intended use of the food additive. FDA maintains a number of public online listings that include useful information... 

In the past, phenylpropanolamine was marketed extensively in over-the-counter products for a variety of indications, and dietary supplements were marketed with no premarket safety evaluation, at least by the Food and Drug Administration (FDA), since for dietary supplements that include an ingredient marketed in the USA before 15 October 1994 no FDA review is required. Because many of these products were promoted as foodstuffs, consumers may have assumed that they are safe (SEDA-21, 5). It has been used as an anorectic agent in doses of 3-25 mg/day. 

Premarket Approval (PMA) is the FDA process to evaluate the safety and effectiveness of all Class III devices. Due to the level of risk associated with Class III devices, the FDA has determined that general and special controls alone are insufficient to assure their safety and effectiveness. Therefore these devices require a premarket approval (PMA) application under section 515 of the act, in order to obtain marketing clearance. 

Before presenting oin discussion, we present a brief and select overview of some relevant literature. Peto (1987) discusses some foimdational issues in systematic reviews of randomized trials for rare outcomes, in particular the need for such reviews and considerations of heterogeneity of the treatment effect. Hammad et al. (2011) present a thorough overview of the issues associated with the secondary use of randomized trials to evaluate safety. Bradbum et al. (2007) evaluate statistical meta-analysis methods for rare events. Kaizer et al. (2006) present an interesting example of a hierarchical Bayesian method for meta-analysis of safety. Crowe et al. (2009) provide recommendation for a premarket safety program. 

As summarized by the FDA, an investigational device exemption (IDE) allows a device to be used in a clinical study to collect safety and effectiveness data required to support a PMA application or a Premarket Notification [510(k)j submission to FDA. All clinical evaluations of investigational devices must have an approved IDE before a clinical study can be initiated. An approved IDE permits a device to be shipped lawfully for the purpose of conducting investigations of the device without complying with other requirements of the Eood, Drug, and Cosmetic Act that would apply to devices in commercial distribution (FDA, 2009). 

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