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On a near daily basis, medicines make the news. Abstract topics such as international pricing policy or medicines patents, and concrete topics such as medicines shortages are regularly reported on. In this article, we summarise a 40-year-history of medicines policy in the Netherlands. Furthermore, we briefly touch upon future directions in this area.

Importance: US law requires testing of new drugs before approval to ensure that they provide a well-defined benefit that is commensurate with their risks. A major challenge for the US Food and Drug Administration (FDA) is to achieve an appropriate balance between rigorous testing and the need for timely approval of drugs that have benefits that outweigh their risks., Objective: To describe the evolution of laws and standards affecting drug testing, the use of new approval programs and standards, expansions of the role and authority of the FDA, and changes in the number of drugs approved from the 1980s to 2018., Evidence: Sources of evidence included principal federal laws and FDA regulations (1962-2018) and FDA databases of approved new drugs (1984-2018), generic drugs (1970-2018), biologics (1984-2018), and vaccines (1998-2018); special development and approval programs (Orphan drug [1984-2018], Fast-Track [1988-2018], Priority Review and its predecessors [1984-2018], Accelerated Approval [1992-2018], and Breakthrough Therapy [2012-2018]); expanded access (2010-2017) and Risk Evaluation and Mitigation Strategies (2008-2018); and user fees paid to the FDA by industry (1993-2018)., Findings: From 1983 to 2018, legislation and regulatory initiatives have substantially changed drug approval at the FDA. The mean annual number of new drug approvals, including biologics, was 34 from 1990-1999, 25 from 2000-2009, and 41 from 2010-2018. New biologic product approvals increased from a median of 2.5 from 1990-1999, to 5 from 2000-2013, to 12 from 2014-2018. The median annual number of generic drugs approved was 136 from 1970 to the enactment of the Hatch-Waxman Act in 1984; 284 from 1985 to the enactment of the Generic Drug User Fee Act in 2012; and 588 from 2013-2018. Prescription drug user fee funding expanded from new drugs and biologics in 1992 to generic and biosimilar drugs in 2012. The amount of Prescription Drug User Fee Act fees collected from industry increased from an annual mean of $66 million in 1993-1997 to $820 million in 2013-2017, and in 2018, user fees accounted for approximately 80% of the salaries of review personnel responsible for the approval of new drugs. The proportion of drugs approved with an Orphan Drug Act designation increased from 18% (55/304) in 1984-1995, to 22% (82/379) in 1996-2007, to 41% (154/380) in 2008-2018. Use of Accelerated Approval, Fast-Track, and Priority Review for new drugs has increased over time, with 81% (48/59) of new drugs benefiting from at least 1 such expedited program in 2018. The proportion of new approvals supported by at least 2 pivotal trials decreased from 80.6% in 1995-1997 to 52.8% in 2015-2017, based on 124 and 106 approvals, respectively, while the median number of patients studied did not change significantly (774 vs 816). FDA drug review times declined from more than 3 years in 1983 to less than 1 year in 2017, but total time from the authorization of clinical testing to approval has remained at approximately 8 years over that period., Conclusions and Relevance: Over the last 4 decades, the approval and regulation processes for pharmaceutical agents have evolved and increased in complexity as special programs have been added and as the use of surrogate measures has been encouraged. The FDA funding needed to implement and manage these programs has been addressed by expanding industry-paid user fees. The FDA has increasingly accepted less data and more surrogate measures, and has shortened its review times.

Background: Historically, neonatal therapeutic interventions were derived from adult therapeutics, and tragedies resulting from this approach have demonstrated differences in the pathophysiologic and developmental processes between neonates and older patients. Over the past 3 decades, researchers and collaborative research networks have made progress in the systematic evaluation of neonatal therapies, yet most neonatal therapeutic products have been incompletely assessed for safety and efficacy, and remain unlabeled and unapproved., Approach: This work describes the legislative initiatives that have stimulated an increase in pediatric and neonatal studies. It highlights examples of successful neonatal drug studies that have resulted in informative neonatal labeling changes, as well as studies that have produced incomplete information. Strategies that support the design of successful studies, including targeting specific subpopulations, modeling and simulation to inform dose selection, innovative design strategies, biomarkers, and endpoints are discussed. Multi-stakeholder consortia such as the International Neonatal Consortium (INC), are working to improve the tools needed for the development of neonatal therapies. These research tools may be used by trial networks to inform consistent and efficient multicenter studies., Conclusion: More data are needed to support safe and effective use of drugs in neonates, and to obtain these data, a thorough understanding of pathophysiology, drug disposition, biomarkers, and clinically-meaningful endpoints is required. This information will be derived from clinical trials, registries, real-world evidence, and the medical literature. Collaboration of consortia and the development of research networks are essential to achieving these goals., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Evaluation of safety is a critical component of drug review at the US Food and Drug Administration (FDA). Statisticians are playing an increasingly visible role in quantitative safety evaluation and regulatory decision-making. This article reviews the history and the recent events relating to quantitative drug safety evaluation at the FDA. The article then focuses on five active areas of quantitative drug safety evaluation and the role Division of Biometrics VII (DBVII) plays in these areas, namely meta-analysis for safety evaluation, large safety outcome trials, post-marketing requirements (PMRs), the Sentinel Initiative, and the evaluation of risk from extended/long-acting opioids. This article will focus chiefly on developments related to quantitative drug safety evaluation and not on the many additional developments in drug safety in general.

This paper assesses the current regulatory environment, relevant regulations and guidelines, and their impact on continuous manufacturing. It summarizes current regulatory experience and learning from both review and inspection perspectives. It outlines key regulatory aspects, including continuous manufacturing process description and control strategy in regulatory files, process validation, and key Good Manufacturing Practice (GMP) requirements. In addition, the paper identifies regulatory gaps and challenges and proposes a way forward to facilitate implementation., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Creation and clearance of pharmaceutical trademarks continues to be one of the most difficult and challenging areas of trademark law. The Food and Drug Administration (FDA) recently initiated a 2-year Pilot Program under Prescription Drug User Fee Act (PDUFA) IV. The intent of the program is to enable participating pharmaceutical firms to evaluate proposed pharmaceutical marks and submit the data generated from those evaluations to the FDA for review. Submitting a trademark to the FDA warrants questions: What supporting data is needed and accepted when proposing a mark? What issues might arise, and how can they be averted? In a recent Thomson Reuters on-demand webinar (http://science.thomsonreuters.com/news/2010-02/8580404/), a group of renowned experts in the field of trademark development review the FDA pilot program, outline the requirements for submission and discuss what the changes will mean in clearing new pharmaceutical marks. They also present various approaches to trademark development and evaluation in light of the FDA's views., (Copyright (c) 2010 Prous Science, S.A.U. or its licensors. All rights reserved.)

Therapeutic proteins (TPs) may affect the disposition of drugs that are metabolized by cytochrome P450 (CYP) enzymes, as is evident from a review of data in recently published literature and approved Biologic License Applications. Many TPs belonging to the cytokine class appear to differentially affect CYP activities. Cytokine modulators may affect CYP enzyme activities by altering cytokine effects on CYP enzymes. The alteration in CYP enzyme activities seems to result from changes in transcription factor activity for CYP enzyme expression or changes in CYP enzyme stability, which have been observed during altered immunological states such as infection and inflammation. Human growth hormone also appears to differentially affect CYP activities through unknown mechanisms. Because TP-drug interaction research is an evolving area, limited information is available during drug development on TP-drug interactions mediated by CYP inhibition or induction. The authors of this review suggest that effort be made to understand TP-drug interactions for the safe and effective use of TPs in combination with small-molecule drugs.

The relative added value of a drug is currently evaluated in France by the Transparency Commission (TC) of the National Health Authority (HAS), by assigning a level of Improvement in Actual Benefit (IAB). IAB is based on two parameters, efficacy and safety of the product, in a defined target population, either as compared to one or more other drugs with similar indications, or within therapeutic strategy. The items used for evaluation, including the level of clinical effect, the relevance of the comparator, the choice of comparison criteria and the methodology used (indirect comparison, non-inferiority studies, etc.), have been reviewed by the working group in Giens with regard to an analysis of the opinion on TC issued between 2004 and 2007 in several therapeutic areas First of all, this attempt at rationalisation based on the criteria used to assess the relative added value demonstrated the rareness of direct comparative data, and was followed by a discussion on the possible broadening of the evaluation criteria. The group discussed taking into account the Public Health Impact (PHI), which has now been incorporated into the assessment of Actual Benefit (AB). The group believes that PHI seems to be more related to the notion of IAB than to that of AB. Indeed, it is frequently the relative added value of a new drug that produces an impact in public health. Conversely, considering the comparative evaluation criteria of PHI, which are not systematically taken into account in IMSR (such as improvement in the health of the population, meeting a public health need or impact on the healthcare system), PHI could legitimately be included in the assessment of the relative added value of a drug. Other parameters such as compliance or impact on professional practice have been considered. Thus, the notion of relative added value, evaluated at initial registration, could be based on an expected improvement in medical service. The notion of expected medical service leads to the requirement of producing additional data in real life (post-registration studies), which would support the definitive notion of improvement in actual benefit at the time of renewed registration, while taking into account the place occupied by the drug in the therapeutic strategy.

Pharmaceutical patents are anachronistic holdovers from an era in which modern economic understanding and tax tools were unavailable. Superior mechanisms lie somewhere between a first best pricing solution for the entire economy at one extreme and the current arrangements at the other. We discuss the economics of suggested alternatives and suggest that the intertemporal bounty is the best way to meet the multiple objectives of immediate distribution at marginal cost pricing of newly innovated patented drugs and easily administered, efficient inducement to continued innovation. The intertemporal bounty prevents the expansion of monopoly power resulting from co-pay or -insurance provisions common to modern prescription drug plans.

The pharmacokinetic content of the drug registration file is now well standardized. The objectives of the pharmacokinetic documentation is to provide evidence supporting the dosing regimen in patients, to take into account the pathophysiological states of the populations at risk and to anticipate drug-drug interactions. Recommendations on study design and evaluation of parameters of interest are listed in various documents Issued by the Committee for Proprietary Medicinal Products and the International conferences on Harmonization, i.e. the Concept Papers, the Points to Consider and Notes for Guidance. The pharmacokinetic data of the registration file are used to document many sections of the Summary of the Product Characteristics.

Directive 97/55/EC of October 6, 1997 has just amended Directive 84/450/EEC concerning misleading advertising in order for it to encompass comparative advertising. The purpose is to harmonize regulations regarding comparative advertising. Although the basic terms of this Directive are very similar to those imposed in France by the law of January 18, 1992, its transposition should, however, require changes to be made to French law.

The Community law now rules any sector of the economy including the Pharmaceutical Industry, which is controlled with a special attention starting from drugs manufacturing up to marketing. After detailing the Community regulations acknowledged by the Italian legislation since the adoption of the first Pharmaceutical Directive in 1965, the Authors examine the Decree Law of february 1997 by which the EEC Directive 93/39 is acknowledged (as amended Directives EEC 65/65,75/318 and 75/319 relating to medicinal products for human use). A special attention is devoted to the several regulations concerning Pharmacovigilance, whose importance is emphasized.

This article looks at the history and development of drug regulation in Australia, concentrating on the changes that have occurred in the last few years. It touches briefly on the system by which many drugs are subsidized and examines the way in which a de facto "restricted" list became less restricted. It deals with clinical trial approval procedures as these have changed markedly and turns to consider advertising and promotion of drugs. In concluding, it discusses the advantages and some of the shortcomings of the system.