Regulatory aspects in modified-release drug delivery

Modified-release products are produced with the goal of delivering medicines that are efficacious, are acceptably safe and have a predictable time course of delivery. In this context, modified release refers to all types of formulations with modified release, including fast (rapid), delay, sustained release, targeted, and controlled-release formulations for the various routes of administration possible. Achieving regulatory approval is an integral part in the development and commercialization of any modified-release product. This overview chapter will emphasize conventional products, recognizing that although approaches differ somewhat between the major regulatory jurisdictions regulatory authorities will require documentation demonstrating that, in common with more standard preparations, such pharmaceutical products meet Good Manufacturing Practices (GMP); quality control specifications; and pharmaceutical product interchangeability (1). In general, such approval requires evidence that the following are well defined: n As an active drug substance in its properties, manufacture, characterization, control, choice of storage container, and stability n The drug product in terms of its formulation, manufacturing process, manufacture, excipient control, its control, choice of storage container and stability n The pharmacokinetics and biopharmaceutics and, possibly, pharmacodynamics of the drug product and/or n Demonstration of safety and efficacy by clinical trial The precise nature and form of the evidence does differ greatly between the countries providing regulatory approval. In general, two somewhat different but increasingly convergent strategies are used. The United States has very detailed process driven procedures that are applied in product approval as described in a later chapter by Marroum (2). In contrast, the European Union (EU) provides guidelines for what is seen as the norm for various delivery systems (3). Here, it is possible to depart from the guidance with justification. The Japanese (4) and Canadian (5) systems appear to have a number of aspects in common with the US system. In contrast, the Australian system is somewhat more flexible, largely following, and formally adopting, the European Medicines Agency (EMEA) guidelines (6) but utilizing other sources of guidance or adopting a case by case approach where appropriate. The World Health Organization (WHO) provides effectively an overall harmonizing system. Interestingly, EMEA, WHO, and FDA each have one formulation category referred to as Delayed Release (1). The second is referred to as Prolonged Release by EMEA and as Extended (controlled, prolonged, sustained) Release by WHO and FDA

Impact of pharmacometrics on drug approval and labeling decisions: A survey of 42 new drug applications

The value of quantitative thinking in drug development and regulatory review is increasingly being appreciated. Modeling and simulation of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression is often referred to as the pharmacometrics analyses. The objective of the current report is to assess the role of pharmacometrics at the US Food and Drug Administration (FDA) in making drug approval and labeling decisions. The New Drug Applications (NDAs) submitted between 2000 and 2004 to the Cardio-renal, Oncology, and Neuropharmacology drug products divisions were surveyed. For those NDA reviews that included a pharmacometrics consultation, the clinical pharmacology scientists ranked the impact on the regulatory decision(s). Of about a total of 244 NDAs, 42 included a pharmacometrics component. Review of NDAs involved independent, quantitative evaluation by FDA pharmacometricians, even when such analysis was not conducted by the sponsor. Pharmacometric analyses were pivotal in regulatory decision making in more than half of the 42 NDAs. Of the 14 reviews that were pivotal to approval related decisions, 5 identified the need for additional trials, whereas 6 reduced the burden of conducting additional trials. Collaboration among the FDA clinical pharmacology, medical, and statistical reviewers and effective communication with the sponsors was critical for the impact to occur. The survey and the case studies emphasize the need for early interaction between the FDA and sponsors to plan the development more efficiently by appreciating the regulatory expectations better