Abstract:The United States Food and Drug Administration (FDA) has created approval pathways and designations to accelerate access to medications indicated for serious or life-threatening conditions with limited treatment options. Implemented in 2012, the most recent of these is the breakthrough therapy designation (BTD). The purpose of this article was to review the evidence surrounding approval of medications with nononcology indications approved with the BTD designation from 2012 to 2016. Fifteen medications were ide… Show more
“…The increased proportion of first-in-class drugs supports the benefit of expedited review mechanisms towards the development of new therapies that provide important and novel clinical benefit to patients [26]. These findings are consistent with previous reviews of expedited approval and review pathways showing the increased historical uptick in usage of expedited mechanisms and particularly following the enactment of breakthrough therapy designation [15,18].…”
Section: Discussionsupporting
confidence: 82%
“…As the use of accelerated programs increases, it is crucial to understand the nature and overlap in these trends to determine if the programs, as designed, are meeting their goals. Previous analyses have reviewed trends and implications of expedited drug development and approval programs [8][9][10][11], including the impact on reducing clinical development times [12], patient access [13], pricing [14], therapeutic outcomes [15,16], and short and longer-term clinical safety and efficacy [17][18][19].…”
Background: Increased understanding of the molecular causes of disease has begun to fulfill the promise of precision medicine with the development of targeted drugs, particularly for serious diseases with unmet needs. The drug approval regulatory process is a critical component to the continued growth of precision medicine drugs and devices. To facilitate the development and approval process of drugs for serious unmet needs, four expedited approval programs have been developed in the US: priority review, accelerated approval, fast track, and breakthrough therapy programs. Methods: To determine if expedited approval programs are fulfilling the intended goals, we reviewed drug approvals by the US Food and Drug Administration (FDA) between 2011 and 2017 for new molecular entities (NMEs). Results: From 2011 through 2017, the FDA approved 250 NMEs, ranging from 27 approvals in 2013 to 46 in 2017. The NME approvals spanned 22 different disease classes; almost one-third of all NMEs were for oncology treatments. Conclusions: As these pathways are utilized more, additional legislative changes may be needed to re-align incentives to promote continued development of innovative drugs for serious unmet needs in a safe, efficacious, and affordable manner.
“…The increased proportion of first-in-class drugs supports the benefit of expedited review mechanisms towards the development of new therapies that provide important and novel clinical benefit to patients [26]. These findings are consistent with previous reviews of expedited approval and review pathways showing the increased historical uptick in usage of expedited mechanisms and particularly following the enactment of breakthrough therapy designation [15,18].…”
Section: Discussionsupporting
confidence: 82%
“…As the use of accelerated programs increases, it is crucial to understand the nature and overlap in these trends to determine if the programs, as designed, are meeting their goals. Previous analyses have reviewed trends and implications of expedited drug development and approval programs [8][9][10][11], including the impact on reducing clinical development times [12], patient access [13], pricing [14], therapeutic outcomes [15,16], and short and longer-term clinical safety and efficacy [17][18][19].…”
Background: Increased understanding of the molecular causes of disease has begun to fulfill the promise of precision medicine with the development of targeted drugs, particularly for serious diseases with unmet needs. The drug approval regulatory process is a critical component to the continued growth of precision medicine drugs and devices. To facilitate the development and approval process of drugs for serious unmet needs, four expedited approval programs have been developed in the US: priority review, accelerated approval, fast track, and breakthrough therapy programs. Methods: To determine if expedited approval programs are fulfilling the intended goals, we reviewed drug approvals by the US Food and Drug Administration (FDA) between 2011 and 2017 for new molecular entities (NMEs). Results: From 2011 through 2017, the FDA approved 250 NMEs, ranging from 27 approvals in 2013 to 46 in 2017. The NME approvals spanned 22 different disease classes; almost one-third of all NMEs were for oncology treatments. Conclusions: As these pathways are utilized more, additional legislative changes may be needed to re-align incentives to promote continued development of innovative drugs for serious unmet needs in a safe, efficacious, and affordable manner.
“…This is in accordance with the staggered way in which quetiapine doses are prescribed. For instance, an schizophrenia adult patient should start with an initial dose of 25 mg twice daily on day 1 with increments of 25-50 mg divided two or three times on days 2 and 3, finally achieving a dose ranging from 150 to 400 mg by day 4 [42].…”
Quetiapine is an atypical antipsychotic widely used for the treatment of schizophrenia and the depressive episodes of bipolar disorder. The aim of this work was to investigate the effect of variants in relevant pharmacogenes in the pharmacokinetics of quetiapine and to exploratorily evaluate adverse drug reaction (ADR) incidence based on genetic polymorphism. Specifically, 49 healthy volunteers enrolled in two bioequivalence clinical trials were included in this study. In addition, 80 variants in 19 relevant pharmacogenes were genotyped, including cytochrome P450 (CYP) genes, catechol-O-methyl transferase (COMT), other enzymes (e.g., UGT1A1 or UGT1A4), and transporters (e.g., SLCO1B1, ABCB1, or ABCG2). The COMT rs13306278 T allele was significantly related to quetiapine-increased exposure. We demonstrated the existence of quetiapine derivatives with a catechol-like structure (7,8-dihydroxi-quetiapine and 7,8-dihydroxi-N-desalkyl-quetiapine), which would be COMT metabolites and would explain quetiapine accumulation through CYP2D6 and CYP3A4 negative feedback. Moreover, CYP3A5 and CYP2B6 phenotypes were related to quetiapine exposure variability, which confirms (for CYP3A5) and suggests (for CYP2B6) that these enzymes play an important role in quetiapine’s metabolism. Finally, the ABCG2 rs2231142 T allele was related to quetiapine accumulation. Further studies are required to confirm the clinical relevance of our findings.
National Regulatory Authorities (NRAs) globally are facing the challenge of evaluating pharmaceutical products in a speedy manner, whilst simultaneously ensuring adequate efficacy, safety and quality of approved products. Additionally, common expectations include that the evaluation process is competent, flexible, commensurate with risk, efficient and rapid. In 2014, the Australian regulatory system was out of step with global regulatory developments which led to a comprehensive regulatory review and reform process. As part of the reforms, two Facilitated Regulatory Pathways (FRP) were developed for prescription medicines: Priority Review (PR) and Provisional Approval (PA). Furthermore, regulatory reliance and recognition arrangements have been expanded with the Therapeutic Goods Administration (TGA) making increased use of evaluation reports by trusted NRAs. The new pathways have been utilised by the pharmaceutical industry in Australia since 2017, with the number of medicines going through these pathways gradually increasing. Additional facilitated pathways have been developed following the review, providing alternatives to the standard pathway for registration of prescription medicines in Australia. The reform is timely, helping to position Australia well in the current global regulatory climate.
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