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Background The Office of Orphan Products Development (OOPD) of the United States (U.S.) Food and Drug Administration (FDA) has awarded over 700 grants to conduct clinical trials of medicals products for rare diseases since 1983, leading to over 70 marketing approvals. However, despite recent progress in rare disease product development, thousands of rare diseases still have no approved treatments. An assessment of this clinical trial grants program was undertaken to provide an in-depth analysis of the characteristics and outcomes of the program. Results of this analysis will be used to inform future goals of the program, as well as internal data collection to continue to maximize the program’s impact in supporting rare disease product development. Results Between fiscal years 2007—2011, OOPD funded 85 clinical trial grants. These grants spanned 18 therapeutic areas, included all pre-approval phases (Phases 1–3), and approximately 75% of the grants studied small molecule drugs. Nine (11%) product approvals, of seven drugs and two devices, were at least partially supported by grants funded within this 5-year timeframe. Four of the seven drugs approved were new molecular entities (NMEs). The average time from funding to approval was seven years. We also found a suggested association between collaboration with multiple types of stakeholders and the success of grants, where we defined success as either positive or negative study findings or a future marketing approval. Conclusions The clinical trials funded by OOPD provided valuable information for future product development, and there were a notable number of approvals that occurred using the support of the grants program. There was a suggested association between collaboration and successful outcomes. Efficient and innovative trial designs and collaboration among stakeholders appear vital to continue to effectively bring products to rare disease patients. Ongoing program assessments will ensure that the funding continues to be used to optimally meet the treatment needs of the rare disease community.

The Orphan Drug Act (ODA) of 1983 was enacted to provide financial incentives to drug sponsors to develop therapies for rare diseases. Although this act increased the number of orphan products approved, there are still a limited number of products available for the pediatric population because orphan drug products are exempt from the Pediatric Research Equity Act. The objectives of this study were (i) to evaluate the pediatric orphan drug studies submitted to the US Food and Drug Administration (FDA) in the period of 2007-2018 and (ii) to examine whether orphan drug products were fully labeled with a pediatric indication in infants and neonates. Out of the 468 indications evaluated, 171 (37%) were FDA-labeled for use in the pediatric population. Labeling for the 12 to

Objective Under the circumstances that several oncology drugs have been approved under expedited programs in the US, this study aimed to analyze the relationship between the expedited programs and characteristics of approvals in the recent decade, and the attitude of the Food and Drug Administration (FDA) toward the development and review of oncology drugs. Results Of the 162 approvals that were analyzed, the proportion of orphan drug (OD) designation was higher in accelerated approval (AA) than regular approval (RA). In contrast, no difference was observed in the proportions of priority review (PR) in AA versus RA or in ODs versus non-ODs. In the development time, no difference was observed in any of the expedited programs. Regarding review time, a significant difference was observed in PR versus standard review (SR). In the characteristics of the pivotal study, such as randomization, number of patients, and endpoints, differences were observed in AA versus RA and in ODs versus non-ODs. Conversely, no significant difference was noted in PR versus SR. Conclusion The overall results of this research validated the attitude of the FDA toward applying each expedited program to facilitate an earlier delivery of innovative oncology drug products to patients with cancer.

Background The Orphan Drug Act was enacted in 1983 to encourage the development of drugs for rare diseases. Previous research has attempted to examine the impact of the Act by assessing either the number of orphan designations that have been granted or the number of new orphan drugs approved for marketing. This study provides a more in-depth understanding of the effect of the Orphan Drug Act by investigating all types of drug approvals with an orphan designation, along with multiple characteristics of the drugs, over the entire 35 years of the Act. These orphan approvals include: new molecular entities (new drugs approved first for a rare disease), secondary indications (an expansion from the first approved indication), and new formulations. Results The results show that the number of approvals for orphan indications has been increasing over time, and the upward trend is especially large in the most recent years. Much of this increase has been driven by the increase in secondary indications being approved for previously approved drugs, although there have also been increases in the number of approved new drugs. We also find that while oncology indications have been increasing significantly, there has also been an increase in other therapeutic areas. Additionally, we find that the proportion of biologic drugs being approved has increased over time. Lastly, while other parts of this drug landscape have dramatically altered over time, the proportion of orphan approvals receiving priority review has not changed. Conclusions Our data suggest that the Orphan Drug Act appears to have stimulated significant drug development for rare diseases. Additionally, approvals of orphan indications have been increasing over time. This increasing effect has not targeted a single area of the rare disease space, rather, gains in approvals have been seen across: therapeutic areas, approval types (both new drugs and secondary indications), and for both biologics and small molecule drugs. Electronic supplementary material The online version of this article (10.1186/s13023-018-0930-3) contains supplementary material, which is available to authorized users.

Regulators from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) do not always agree on interpretation of data for a drug's safety and efficacy.The authors compared all new molecular entities approved or rejected in a 5-year period from 2007 to 2011, identified where FDA and EMA reviews resulted in different regulatory decisions, and explored potential mechanisms for the discrepancies. Thirteen entities were associated with different regulatory decisions, and 2 drugs were withdrawn from their respective markets in 2010: one from the US (Mylotarg; gemtuzumab ozogamicin) and the other in Europe (Thelin; sitaxentan sodium).There are relatively few cases where FDA and EMA substantively differ with regard to product approvals and market withdrawals. It is likely that the scientific and cultural differences between FDA and EMA will continue to diminish over time, because these two agencies increasingly work together as pharmaceutical product development increasingly becomes a global endeavor.

The twin forces of payors seeking fair pricing and the rising costs of developing new medicines has driven a closer relationship between pharmaceutical companies and diagnostics companies, because stratified medicines, guided by companion diagnostics, offer better commercial, as well as clinical, outcomes. Stratified medicines have created clinical success and provided rapid product approvals, particularly in oncology, and indeed have changed the dynamic between drug and diagnostic developers. The commercial payback for such partnerships offered by stratified medicines has been less well articulated, but this has shifted as the benefits in risk management, pricing and value creation for all stakeholders become clearer. In this larger healthcare setting, stratified medicine provides both physicians and patients with greater insight on the disease and provides rationale for providers to understand cost-effectiveness of treatment. This article considers how the economic value of stratified medicine relationships can be recognized and translated into better outcomes for all healthcare stakeholders.

New drug and biologic product marketing applications submitted to FDA's Center for Drug Evaluation and Research (CDER) between 2006 and 2010 were analyzed to identify rare disease application characteristics associated with higher approval rates. The results show that approval rates were similar for rare and common disease applications. Larger company size, prior regulatory experience and priority review designation were associated with higher approval rates. The study findings show that rare disease product development is feasible, and increased interactions between product developers and FDA in early investigational phases can facilitate product development.

In 2006, the US Food and Drug Administration (FDA) published draft guidance to provide recommendations for development, validation, implementation, and interpretation of patient-reported outcome (PRO) measures that can support treatment benefit claims in product labeling. Here, we summarize and discuss FDA approvals of anticancer products in the context of the draft guidance. We identified anticancer product approvals having efficacy claim(s) based at least in part on a PRO. In addition, we collated limitations of PRO instruments commonly submitted for regulatory review over the period from October 1, 2004 to September 30, 2006. From 1995 onward, nine indications were approved for seven anticancer products based at least in part on a PRO. In eight of nine approvals, PRO data supplemented other evidence of clinical benefit. In seven approvals, the PRO measured a single symptom or functional domain that was directly attributable to the treatment benefit observed in the disease. The FDA's draft PRO guidance describes principles that have been used in anticancer product approvals for more than a decade. PRO end points typically support treatment benefit claims that refer to a patient's symptoms or ability to function. Single-item PROs may be acceptable. PRO data should be both internally consistent and aligned with other evidence of clinical benefit. The FDA encourages sponsors to consult with the FDA early in the process of PRO development.

Hypoglycemia complicating diabetes therapy is well recognized to be an ever-present threat to patients, their families, providers, payers, and regulators. Despite this being widely acknowledged, the regulatory stance on hypoglycemia as an endpoint in clinical trials to support new product registration has not evolved in any meaningful way since the publication of a position paper by an American Diabetes Association (ADA) Workgroup in 2005. As the impact of hypoglycemia on persons affected by diabetes is of major importance when assessing new treatments, the historical position of regulatory agencies on hypoglycemia is reviewed with respect to product approvals. The purpose of this article is to present proposals for facilitating development of therapies that reduce hypoglycemia risk through (1) development of composite measures of benefit for regulatory endpoints and (2) facilitation of the fulfillment of an unmet clinical need for reducing hypoglycemia. In view of greater comprehension of the effects of hypoglycemia, coupled with improved methodology to assess its frequency, the authors recommend: (1) a numerical cut point of

Background Millions of patients are treated with opioid analgesics (OpAs) to relieve pain. Unfortunately, these medications are subject to abuse and/or unintended misuse. Abuse deterrent formulations (ADFs) represent an intervention strategy to decrease abuse/misuse without affecting patient access. The Food and Drug Administration (FDA) has issued Draft Guidance “Abuse deterrent opioids, Evaluation and Labeling” and is currently actively pursuing scientific input on this issue. Methods The development of ADF technologies was reviewed using peer reviewed journals describing OpA post marketing studies, web sites containing FDA announcements on product approvals and manufacturer product use profiles. Results Reviewed is the FDA recent approval of a product label describing the abuse deterrent characteristics of OxyContin ® (physical barrier formulation), and the FDA determination that studies were insufficient for an Opana ® (physical barrier) ADF label. Additional reviewed marketed OpAs with ADF technologies include: Suboxone ® and Embeda ® (opioid agonist/antagonist combinations), Oxecta ® (aversion technology), and Nucynta ® (physical barrier). Reviewed ADF technologies currently in development include: new physical barrier and aversion technologies, an innovative extended release formulation as well as novel polymer–opioid conjugates. As ADF technologies are part of a comprehensive intervention strategy to promote safe OpA use, additional components including governmental, community, and educational initiatives are reviewed. Conclusions The outcomes of the recent ADF labeling applications for OxyContin ® (Tier 3 approval) and Opana ® (non-approval) suggest that the threshold for ADF labeling will be appropriately high. The presented findings indicate that ADF technologies can be a critical component of a comprehensive strategy to promote the safe and effective use of OpAs.

The premise of this paper is a concern over the dismal record of approvals for biotechnology products despite the enormous resources poured into their development. The authors have described a number of issues which may help to explain the dearth of biotechnology product approvals. Included among those issues are suggestions for improving the development process by ensuring the presence of several key resources which may be overlooked by emerging biotechnology companies. Particularly, the authors advocate creative approaches to development rather than relying too strongly on approaches used in the past. As well, the authors suggest that applicants should intelligently use the resources of the Food and Drug Administration (FDA) for guidance and input into the development process. Finally, the authors suggest that when both applicants and FDA work smarter and faster, there will be many more approvals of biotechnology products.

 A total of 96 antidiabetic products were retrieved: 53 approved by the EMA (Table 1) and 43 by the FDA (Table 2). Generics were excluded.  Only two products with a PRO labeling claim were found in Europe (i.e., insulin glulisine and exenatide), and none in the USA. PROs identified in both claims were self-monitored blood glucose (SMBG) profiles and were used as secondary endpoints. See Tables 3 and 4.  Although insulin glulisine and exenatide were also approved by the FDA (on the same studies used in Europe) their US label did not mention any results based on SMBG profiles. Reasons for not including them in the label were not given in the corresponding medical reviews.  However, the analysis of other products’ reviews, such as insulin aspart or liraglutide (see Table 5), showed a reluctance from reviewers to include results based on SMBG profiles in the labels. Reviewers questioned the validity of the glucose profiles based on self-collected readings because of compliance issues and of a lower degree of accuracy of values obtained from glucometers vs. lab measures in a clinic.  Although measured in some cases, other PROs, such as quality of life or treatment satisfaction, were never considered for inclusion in labeling with any reasons given. This was consistent for both agencies. RESULTS Table 1. EMA Products Table 2. FDA Products

Drugs remain a key element in the effective containment of health care costs. In 1993, 29 new drugs were approved for marketing by the US Food and Drug Administration (FDA). These entities, according to a 1993 Office of Technology Assessment study, each took on average 12 years and $359 million each to discover and develop. The FDA reported that the average review time for these entities was 26.5 months, some 3 months less than reported in 1992. Under the prescription Drug User Fee Act of 1992, which will generate an additional $327 million over the period 1993–1997, the FDA will hire an additional 600 review staff.

FDA in 2008 approved the marketing of an assortment of 34 unique new molecular entities, vaccines, imaging agents, and blood products—5 more than the previous year’s total. A brief synopsis of several product approvals is provided below. A full listing of products approved in 2008 and their

6131 Background: No systematic examination of temporal trends in oncology approvals in the United States (US) has been conducted. Methods: Internal databases at the US Food and Drug Administration (FDA) were queried to determine the number of first-time approvals for New Molecular Entities (NMEs) (both traditional drugs and therapeutic biologics) for oncology indications between the years 1986 and 2005, inclusive; 1986 was the first year for which database records were available for both drugs and biologics. Correlation analysis was used to analyze the data for time-dependent changes in approvals and approval rates. Results: During the period examined, 70 NMEs received first-time approval for an oncology indication ( Table ); 52 (74%) were drugs and 18 were biologics. The median annual number of approvals was 3 (range, 1 to 7); the maximum number of approvals during the period examined occurred in 2004. Statistical analysis showed a weak positive correlation between the number of oncology approvals and time, and between the proportion of applications approved as a percentage of all oncology product applications and time. Conclusions: Available data suggest that the number and rate of oncology product approvals has remained stable in the US over the last two decades. [Table: see text] No significant financial relationships to disclose.