IMPORTANCE Some new drug applications fail because of inadequate drug performance and others are not approved because the information submitted to the US Food and Drug Administration (FDA) is unsatisfactory to make that determination. Resubmission of failed applications is costly, delaying marketing approval and the availability of new drugs to patients.OBJECTIVE To identify the reasons that FDA marketing approval for new drugs was delayed or denied. DESIGN, SETTING, AND PARTICIPANTSA retrospective review of FDA documents and extraction of data were performed. We examined all drug applications first submitted to the FDA between 2000 and 2012 for new molecular entities (NMEs), which are active ingredients never before marketed in the United States in any form. Using FDA correspondence and reviews, we investigated the reasons NMEs failed to obtain FDA approval. MAIN OUTCOMES AND MEASURESReasons for delayed FDA approval or nonapproval of NME applications. RESULTSOf the 302 identified NME applications, 151 (50%) were approved when first submitted and 222 (73.5%) were ultimately approved. Seventy-one applications required 1 or more resubmissions before approval, with a median delay to approval of 435 days following the first unsuccessful submission. Of the unsuccessful first-time applications, 24 (15.9%) included uncertainties related to dose selection, 20 (13.2%) choice of study end points that failed to adequately reflect a clinically meaningful effect, 20 (13.2%) inconsistent results when different end points were tested, 17 (11.3%) inconsistent results when different trials or study sites were compared, and 20 (13.2%) poor efficacy when compared with the standard of care. The frequency of safety deficiencies was similar among never-approved drugs compared with those with delayed approval (43 of 80 never approved [53.8%] vs 37 of 71 eventually approved [52.1%]; difference, 1.7% [95% CI, −14.86% to 18.05%]; P = .87). However, efficacy deficiencies were significantly more frequent among the never-approved drugs than among those with delayed approvals (61 of 80 never approved [76.3%] vs 28 of 71 eventually approved [39.4%]; difference, 36.9% [95% CI, 20.25% to 50.86%]; P < .001).CONCLUSIONS AND RELEVANCE Several potentially preventable deficiencies, including failure to select optimal drug doses and suitable study end points, accounted for significant delays in the approval of new drugs. Understanding the reasons for previous failures is helpful to improve the efficiency of clinical development for new drugs.

For more than a decade, industry analysts and policy makers have raised concerns about declining pharmaceutical innovation, citing declining numbers of new molecular entities (NMEs) approved in the United States each year. Yet there is little consensus on whether this is the best measure of "innovation." We examined NME approvals during 1987-2011 and propose the three distinct subcategories of NMEs--first-in-class, advance-in-class, and addition-to-class--to provide more nuanced and informative insights into underlying trends. We found that trends in NME approvals were largely driven by addition-to-class, or "me too," drug approvals, while first-in-class approvals remained fairly steady over the study period. Moreover, the higher proportion of first-in-class drug approvals over the most recent decade is an encouraging sign of the health of the industry as a whole.

We present a longitudinal analysis of investigational new drug applications (INDs) for new, systemic antibacterial drugs under active development between 1980 and 2019, evaluating the characteristics of these investigational drugs and the outcomes of these drug development programs. The number of INDs in active development declined by two-thirds from 39 active INDs at its peak in 1987 to a low 13 in 2001, with decreased development of new cephalosporin, quinolone, and macrolide drugs and reduced participation from large pharmaceutical firms. Antibacterial drug development activity rebounded substantially from 2002 – 2009, primarily led by small pharmaceutical company involvement. As of December 31, 2019, the number of active INDs has declined to an 11-year low, and the number of antibacterial INDs initiated with the FDA from 2010-2019 was lower than any of the previous three decades. Antibacterial drug development programs initiated in the 1980s and 1990s had high success rates, with over 40% of INDs obtaining marketing approval, in a median time of about six years from IND receipt to approval. For drug development programs initiated between 2000 and 2009, we find IND-to-approval rates reduced to 23% with median development times for approved antibacterial drugs increasing to 8.2 years. The majority of INDs in development as of December 31, 2019 come from already established drug classes, most in early stages of development, and few are sponsored by large pharmaceutical companies.

BackgroundThe 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.ResultsThe 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.ConclusionsOur 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 materialThe online version of this article (10.1186/s13023-018-0930-3) contains supplementary material, which is available to authorized users.

Although drugs approved with a boxed warning or priority review are more likely to experience serious post-marketing safety events, other information provided during the FDA drug review that is easy to quantify is generally not associated with post-marketing safety events. It appears that these post-marketing events are not discernible during a pre-marketing review and therefore might not be avoidable using current review data.