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Implementation of the Generic Drug User Fee Amendments (GDUFA I) as part of the Food and Drug Administration Safety and Innovation Act of 2012 (Generic Drug User Fee Amendments. https://www.fda.gov/industry/fda-user-fee-programs/generic-drug-user-fee-amendments) successfully allowed the U.S. Food and Drug Administration (FDA) to modernize review of Abbreviated New Drug Applications (ANDAs) with goal dates. The goal of this study was to assess the success of GDUFA I in decreasing ANDA time to approval and the number of review cycles across the five fiscal years of GDUFA I. Results of this study underscore FDA's continuous progress within its generic drug program and highlight the ongoing collaborative communication process between FDA and ANDA applicants that must continue for the timely approval of high-quality, safe, and effective generic drugs for the American public.

The U.S. Food and Drug Administration Center for Devices and Radiological Health (FDA/CDRH) has recently published several in vivo test guidance documents that mention refinements, reductions, or replacement animal testing strategies to facilitate the leveraging of data from large animal safety tests for conventional rodent testing. In response to the recently enacted Food and Drug Administration Safety and Innovation Act Section 907, which facilitates expedited access to novel therapies commonly described as Breakthrough Therapy Designation, FDA/CDRH has discussed efficient regulatory strategies for first-in-human investigation, including early feasibility study guidance. Large gains in humane care and translational research could also be attained by examples in FDA’s Guidance for the Use of International Organization for Standardization 10993-1, which states that large animal safety studies may be considered as replacement rodent tests if the scientific principles, methods, and end points (SPME) are considered and applied. This article discusses SPME for the replacement of conventional rodent testing by the inclusion and integration of clinical, diagnostic, and pathologic data obtained from well-designed large animal studies. The recommendations include consideration for study designs that utilize methods for an overall more comprehensive interrogation of animal systems.

Since the vast majority of prescription drugs consumed by Americans are off patent ('generic'), their regulation and supply is of wide interest. We describe events leading up to the US Congress's 2012 passage of the Generic Drug User Fee Amendments (GDUFA I) as part of the Food and Drug Administration Safety and Innovation Act (FDASIA). Under GDUFA I, generic manufacturers agreed to pay approximately $300 million in fees each year of the five-year program. In exchange, the US Food and Drug Administration (FDA) committed to performance goals.We describe GDUFA I's FDA commitments, provisions, goals, and annual fee structure and compare it to that entailed in the authorization and implementation of GDUFA II on October 1, 2017. We explain how user fees required under GDUFA I erected barriers to entry and created scale and scope economies for incumbent manufacturers.Congress changed user fees under GDUFA II in part to lessen these incentives. In order to initiate and sustain user fees underGDUFAlegislation,FDArequires the submission of self-reported data on generic manufacturers including domestic and foreign facilities. These data are public and our examination of them provides an unprecedented window into the recent organization of generic drug manufacturers supplying the US market. Our results suggest that generic drug manufacturing is increasingly concentrated and foreign.We discuss the implications of this observed market structure for GDUFA II's implementation among other outcomes., National Institute on Aging (Grant R01AG043560)

In early 2012, the Breakthrough Therapy Act was introduced into the US House of Representatives and the Senate. The bills received bipartisan support and were included as an amendment to the Food and Drug Administration Safety and Innovation Act in the Prescription Drug User Fee Act V. On July 9, 2012, the breakthrough therapy designation was signed into law. As of June 13, 2014, a total of 48 products have been designated as breakthrough therapies by the Center for Drug Evaluation and Research, and 4 of those have received FDA new molecular entity approval.

Relatively few neonatal drug development studies have been conducted, but an increase is expected with the enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA). Understanding the safety of drugs studied in neonates is complicated by the unique nature of the population and the level of illness. The objective of this study was to examine neonatal safety data submitted to the FDA in studies pursuant to the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) between 1998 and 2015.FDA databases were searched for BPCA and/or PREA studies that enrolled neonates. Studies that enrolled a minimum of 3 neonates were analyzed for the presence and content of neonatal safety data.The analysis identified 40 drugs that were studied in 3 or more neonates. Of the 40 drugs, 36 drugs received a pediatric labeling change as a result of studies between 1998 and 2015, that included information from studies including neonates. Fourteen drugs were approved for use in neonates. Clinical trials for 20 of the drugs reported serious adverse events (SAEs) in neonates. The SAEs primarily involved cardiovascular events such as bradycardia and/or hypotension or laboratory abnormalities such as anemia, neutropenia, and electrolyte disturbances. Deaths were reported during studies of 9 drugs.Our analysis revealed that SAEs were reported in studies involving 20 of the 40 drugs evaluated in neonates, with deaths identified in 9 of those studies. Patients enrolled in studies were often critically ill, which complicated determination of whether an adverse event was drug-related. We conclude that the traditional means for collecting safety information in drug development trials needs to be adjusted for neonates and will require the collaboration of regulators, industry, and the clinical and research communities to establish appropriate definitions and reporting strategies for the neonatal population.

In the past, dosage regimens authorized for adults were extrapolated to children relying mainly on empirical dosage adjustments. However, children are not small adults, but a distinct and heterogeneous group in terms of physiology, disease occurrence, pharmacokinetics, pharmacodynamics and also psychological, cognitive, and behavioral aspects. Even though it would be helpful to know the physiological changes and the special drug treatment needs in children, this task could not be performed due to ethical reasons. Important issues to consider for the development of paediatric drug products refer to the administration of the accurate dose, the use of the appropriate excipients, and acceptability. The latter is crucial and taste-screening methods (like electronic tongues) have been developed. A new era in paediatric medicines started with the entry into force of paediatric regulations. In the early ‘80s, the FDA started the set-up of a regulatory framework by authorizing issues like the Paediatric Rule, the Best Pharmaceuticals for Children Act, the Paediatric Research Equity Act, and the Food and Drug Administration Safety and Innovation Act. Similar efforts have been made in the EU, mainly through the entry into force of the Paediatric Regulation and the establishment of the Paediatric Committee, the Paediatric Investigation Plan, the Paediatric Use Marketing Authorization, and the European Paediatric Research Network. Other efforts to bridge the gap, between knowledge in adults and the children’s special requirements, include the extrapolation concept of safety/efficacy aspects, the application of modeling/simulation approaches in paediatric drug development, and the development of a paediatric Biopharmaceutics Classification Scheme.

The United States Food and Drug Administration (FDA) has long recognized the key role it plays in ensuring patients have timely access to safe and effective drugs. Over the past 25 years, FDA has developed multiple programs, including Fast Track, Accelerated Approval, and Priority Review, to expedite the development and review of new drugs for the patients who need them. With the passage of the Food and Drug Administration Safety and Innovation Act (FDASIA) in 2012, FDA has an additional tool to foster efficient drug development, Breakthrough Therapy designation. Building on past successes, like Fast Track, Breakthrough focuses on early collaboration and communication between drug developers and FDA. These programs reflect the growing recognition that robust scientific drug development must also be efficient and as timely as possible. FDA continues to look for opportunities to streamline drug development, especially in areas with unmet need, while focusing on those products that show real promise to posit...

Objective To raise pharmacist awareness about the needs and concerns of our patients with visual impairment and to review useful strategies to foster medication adherence. Summary As patient-centered pharmacists, we need to understand the challenges faced by our patients with low vision and tailor pharmaceutical care to best fit their needs. Evidence-based best practices in labeling and written communication have been developed by the American Foundation for the Blind in partnership with the American Society of Consultant Pharmacists. These recommendations include the use of specific font styles, minimum font size, and other standards known to enhance usability for those with limited vision. Recent advances in assistive technologies such as audio output and object recognition software can be used to ease the medication-taking process and effectively communicate important drug and safety information in a manner that can be understood by those with low vision. In July 2012, the Prescription Accessible Drug Labeling Promotion Act of 2012 (HR 4087) was signed into law. This new legislation is an addition to the Food and Drug Administration Safety and Innovation Act, which required the development and ultimate implementation by pharmacies of national best practices intended to improve the accessibility of prescription drug labeling for the visually impaired. Conclusion As a patient-centered profession, we need to advocate for our patients with special needs by partnering with government and patient groups to support and enact legislation intended to enhance people's ability to adhere to drug therapy.

Pediatric drug development in the United States has grown under the current regulations made permanent by the Food and Drug Administration Safety and Innovation Act of 2012. Over 1200 pediatric studies have now been submitted to the US FDA, but there is still a high rate of failure to obtain pediatric labeling for the indication pursued. Pediatric oncology represents special problems in that the disease is most often dissimilar to any cancer found in the adult population. Therefore, the development of drug dosing in pediatric oncology patients represents a special challenge. Potential approaches to pediatric dosing in oncology patients include extrapolation of efficacy from adult studies in those few cases where the disease is similar, inclusion of adolescent patients in adult trials when possible, and bridging the adult dose to the pediatric dose. An analysis of the recommended phase 2 dose for 40 molecularly targeted agents in pediatric patients provides some insight into current practices. Increased knowledge of tumor biology and efforts to identify and validate molecular targets and genetic abnormalities that drive childhood cancers can lead to increased opportunities for precision medicine in the treatment of pediatric cancers.

Early evidence suggests that provisions of the Food and Drug Administration Safety and Innovation Act of 2012 are associated with reductions in the total number of new national drug shortages. However, drugs frequently used in acute unscheduled care such as the care delivered in emergency departments may be increasingly affected by shortages. Our estimates, based on reported national drug shortages from 2001 to 2014 collected by the University of Utah’s Drug Information Service, show that although the number of new annual shortages has decreased since the act’s passage, half of all drug shortages in the study period involved acute care drugs. Shortages affecting acute care drugs became increasingly frequent and prolonged compared with non–acute care drugs (median duration of 242 versus 173 days, respectively). These results suggest that the drug supply for many acutely and critically ill patients in the United States remains vulnerable despite federal efforts.

President Obama on July 9 signed into law the Food and Drug Administration Safety and Innovation Act, bipartisan legislation that many groups believe will preserve patients’ access to critical drugs. A prominent feature of the law’s provisions pertaining to drug shortages is the requirement for

The US Food and Drug Administration Safety and Innovation Act (FDASIA) was signed on 9 July 2012. This law created a new "breakthrough therapy" (BT) designation program for investigational drugs and biologics intended to treat a serious disease and having "preliminary clinical evidence [that] indicates that the drug may demonstrate substantial clinical improvement over existing therapies on one or more clinically significant endpoints."(1) Many questions have been posed about the impact of this new program on drug development.

The advances in pharmaceutical sciences and technology have been so significant that Peter Drucker’s quote that “the future has already happened” applies readily for medicines developed for adults. For pediatric patients, the future is about to happen. The continuation of focused partnerships and knowledge sharing and leveraging are critical to ensure that pediatric patients have timely access to high quality drug products that were developed with pediatric patients in mind. An overview of regulatory efforts, regulations and legislation to address the challenges for pediatric drug development are discussed. The implementation of regulatory incentives, the Pediatric Rule, Best Pharmaceuticals for Children Act, and Pediatric Research Equity Act, is having an impact and has led to incorporation of information for dosing of approximately 500 drug products since 1998 starting with implementation of the Pediatric Rule. There are significant accomplishments and a lot more work ahead for the pediatric community. The labeling information is usually for older pediatric patients and the need for information for safe and effective dosing of patients of 6 years old or younger remains. Some of the study outcomes are inconclusive with respect to safety and efficacy, and support the hypotheses that better understanding of drug delivery to pediatric patients is needed for determining and delivering the right dose to the pediatric patients. The 2012 Food and Drug Administration Safety and Innovation Act and implementation of Quality by Design paradigm focusing on drug product design and manufacturing process are expected to have a synergistic effect for continuing to advance development of pediatric dosage forms and formulations for the benefit of the pediatric patients.

PURPOSE OF REVIEW To provide current information on off-label medication use in pediatric gastroenterology, including a discussion on US legislative efforts to address the issue. RECENT FINDINGS Medications used to treat pediatric gastrointestinal illnesses are frequently prescribed off-label. Acid suppressors, antiemetics, laxatives, and antitumor necrosis factor therapies are types of medications frequently used off-label in the pediatric gastroenterology arena. Pediatric studies conducted under US Federal laws are generating much-needed data on the safety and effectiveness of medications used to treat pediatric patients. Moreover, a new US law, the Food and Drug Administration Safety and Innovation Act, may further the development of pediatric medications in part by requiring pediatric-specific study plans earlier in the overall drug development process. As of today, there still are gaps in our knowledge about these medications, including for the treatment of pediatric gastroenterology diseases. SUMMARY Medications are widely used off-label in pediatrics, including medications intended to treat gastrointestinal diseases, such as antitumor necrosis factor and laxatives. Although legislation is helping to generate and make available important information about pediatric medications, most still do not contain pediatric data. Therefore, providers need to understand the potential risks and benefits of prescribing off-label products to pediatric patients.

In July 2012, Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA). The Advancing Breakthrough Therapies for Patients Act was incorporated into a Title of FDASIA to expedite clinical development of new, potential “breakthrough” drugs or treatments that show dramatic responses in early-phase studies. Using this regulatory pathway, once a promising new drug candidate is designated as a “Breakthrough Therapy”, the U.S. Food and Drug Administration (FDA) and sponsor would collaborate to determine the best path forward to abbreviate the traditional three-phase approach to drug development. The breakthrough legislation requires that an FDA guidance be drafted that details specific requirements of the bill to aid FDA in implementing requirements of the Act. In this article, we have proposed criteria to define a product as a Breakthrough Therapy, and discussed critical components of the development process that would require flexibility in order to enable expedited development of a Breakthrough Therapy. Clin Cancer Res; 19(16); 4297–304. ©2013 AACR.

In 2001, a sentinel publication from the Institute of Medicine, “Exploring the Biological Contributions to Human Health: Does Sex Matter?” concluded that ‘until the question of sex is routinely asked and the results—positive or negative—are routinely reported, many opportunities to obtain a better understanding of the pathogenesis of disease and to advance human health will surely be missed’ [1]. Given the acknowledged lack of enrolment of women in clinical trials, particularly cardiovascular trials, the National Institutes of Health (NIH) implemented guidelines in 1993, for the inclusion of women in all phases of clinical trials, and the requirement to design phase III clinical trials that specifically assess sex-based differences [2]. Nevertheless, an assessment of female enrolment in all NIH-funded clinical studies between 1993 and 1998 found one-fifth of the non-sex specific studies still failed to enroll female subjects. Furthermore, among the studies that did include women, 60 %–70 % did not analyze or report results based on sex [3]. Of note, European and other international trials, which lack legislation regarding inclusion of women in clinical studies, enroll a larger proportion of female subjects than do US-specific trials, although they still do not achieve levels representative of the diseased population [4]. The lack of information by sex and gender has very real implications for care. For example, between 2000 and 2007, the Food and Drug Administration (FDA) approved 78 highrisk cardiovascular devices, based on a patient population comprised mainly of men (67 %); 28 % of the studies did not even provide the sex-distribution of their populations; sexspecific analyses were reported in only 41 % (51/123) of studies [5]. The general lack of sex-specific analysis for new device approval is best illustrated by the implantable cardioverter-defibrillator experience where approval was granted despite very low enrolment of women in the key trials. The implications of this lack of data are now apparent; a metaanalysis has demonstrated a lack of efficacy of implantable cardioverter-defibrillators in primary prevention trials in women with heart failure [6]. A review of the key meta-analyses describing the efficacy of the key evidence-based medications for secondary prevention post-acute myocardial infarction reveals a general lack of data on women (women comprised between 18.8 % and 30 % of the populations analyzed) [7–9], and in the case of beta blockers, no evaluation of sex-specific outcomes were provided whatsoever [10]. These examples highlight the uneven approach to accommodating sex and gender issues in cardiovascular care and prevention, and they underscore the importance of conducting research that incorporates the study of sex differences in study design and reporting. Yet, important progress has been made recently. Legislation in the United States now requires sex-specific reporting. Recently enacted legislation, the Food and Drug Administration Safety and Innovation Act in 2012, requires the FDA to report annually and publicly on the extent to which applications for FDA approval of new drugs and medical devices are reported by sex, age, race, and ethnicity [11]. In Canada, the Canadian Institutes of Health Research (CIHR) established a Gender and Health Institute in 2000, which introduced guidelines requiring all applicants for CIHR funding to indicate whether they will consider sex/gender differences in their proposed research. And, there are indications that the Heart and Stroke Foundation of Canada will shortly follow suit. Nevertheless, these are only guidelines, and compliance with K. H. Humphries (*) Department of Medicine, University of British Columbia and Centre for Health Evaluation & Outcome Sciences, Vancouver, BC, Canada e-mail: Khumphries@providencehealth.bc.ca

e17502 Background: Breakthrough Therapy (BT) designation is a new regulatory program introduced in Section 902 of the Food and Drug Administration Safety and Innovation Act of 2012. Its goal is to ...

For rare serious and life-threatening disorders, there is a tremendous challenge of transforming scientific discoveries into new drug treatments. This challenge has been recognized by all stakeholders who endorse the need for flexibility in the regulatory review process for novel therapeutics to treat rare diseases. In the United States, the best expression of this flexibility was the creation of the Accelerated Approval (AA) pathway. The AA pathway is critically important for the development of treatments for diseases with high unmet medical need and has been used extensively for drugs used to treat cancer and infectious diseases like HIV. In 2012, the AA provisions were amended to enhance the application of the AA pathway to expedite the development of drugs for rare disorders under the Food and Drug Administration Safety and Innovation Act (FDASIA). FDASIA, among many provisions, requires the development of a more relevant FDA guidance on the types of evidence that may be acceptable in support of using a novel surrogate endpoint. The application of AA to rare diseases requires more predictability to drive greater access to appropriate use of AA for more rare disease treatments that might not be developed otherwise. This white paper proposes a scientific framework for assessing biomarker endpoints to enhance the development of novel therapeutics for rare and devastating diseases currently without adequate treatment and is based on the opinions of experts in drug development and rare disease patient groups. Specific recommendations include: 1) Establishing regulatory rationale for increased AA access in rare disease programs; 2) Implementing a Biomarker Qualification Request Process to provide the opportunity for an early determination of biomarker acceptance; and 3) A proposed scientific framework for qualifying biomarkers as primary endpoints. The paper’s final section highlights case studies of successful examples that have incorporated biomarker endpoints into FDA approvals for rare disease therapies. The focus of this paper is on the situation in the Unites States, but the recommendations are reasonably applicable to any jurisdiction. Electronic supplementary material The online version of this article (doi:10.1186/s13023-014-0195-4) contains supplementary material, which is available to authorized users.