Maximizing Regulatory Review Efficiency: The Evolution of the FDA OCE RTOR Pilot

To promote the efficient review of oncology drug applications, the US Food and Drug Administration (FDA) Oncology Center of Excellence (OCE) launched the Real-Time Oncology Review (RTOR) pilot program in 2018. RTOR allows FDA to review individual sections of eCTD modules of a drug application for oncology drugs in contrast to requiring the applicant to submit complete modules or the complete application before review is initiated. Initially, the program accepted only supplemental applications with simple study designs and easily interpretable endpoints, but the scope has since been expanded to include applications for New Molecular Entities (NME), and other applications with more complex features. Though many applicants experience faster approvals under RTOR, it is difficult to isolate the effect of the RTOR program on review timelines as its contribution is masked by other expedited programs like priority review and breakthrough therapy designation (BTD). This article discusses the expanded scope of RTOR, its interplay with other OCE initiatives to modernize regulatory review, summarizes Genentech’s experiences in planning RTOR submissions from February 2019 to July 2021, and provides considerations for the future of the program.

Time to inclusion in clinical guidance documents for non-oncological orphan drugs and biologics with expedited FDA designations: a retrospective survival analysis

ObjectivesDrug and biological products that treat rare, serious or life-threatening conditions can receive US Food and Drug Administration (FDA) orphan designation and expedited programme designations (accelerated approval, breakthrough therapy, fast track or priority review) meant to incentivise development. Timely recommendations from guidance documents may encourage more rapid and appropriate use and access to these medicines for serious conditions. We sought to determine time between FDA approval and inclusion in guidance documents for non-oncological orphan products overall and by number and type of expedited programme designations.Design and settingRetrospective survival analysis of non-oncological orphan products with ≥1 expedited designation approved since 1992. In June 2020, PubMed, Turning Research into Practice and Guideline Central databases were searched to identify guidance documents influencing US practice that included each product.Main outcomes and measuresThe primary outcome was time to guidance inclusion, defined as any recommendation on use provided within the recommendation framework used by the guidance document.ResultsAmong 135 included non-oncological orphan products, 97.0% (n=131) were designated with priority review, 49.6% (n=67) fast track, 16.3% (n=22) breakthrough therapy and 14.1% (n=19) accelerated approval. Sixty per cent of products (n=81) received ≥2 designations. Overall, 74.1% (n=100) were included in a guidance document. The median time to inclusion was 2.87 years (IQR 2.21–4.18) for the entire cohort. In survival analyses, guidance inclusion was more likely to occur earlier for products with ≥2 designations (HR, 1.84; 95% CI 1.21 to 2.79) and for those with fast-track designation compared with priority review (HR 1.40; 95% CI 1.02 to 2.0). Of 35 products not included in a guidance document, 54.3% (n=19) were approved in 2018 or later.ConclusionsAmong non-oncological orphan products with priority designations, nearly 3 years had passed between FDA approval and inclusion in any guidance document. These findings suggest that despite efforts to expedite availability, appropriate access to these treatments may be delayed because of the lack of timely guidance on their use in clinical practice.

Repercussions of Covid-19 crisis on students’ remote learning in Saudi universities

This study aims to identify the positive and negative repercussions of the novel Coronavirus crisis on students’ remote learning in Saudi universities. A descriptive survey method is carried out using a questionnaire and distributed to a cluster sample of 651 undergraduate students. Results reveal the most prominent positive repercussions, which are that the university cares about the learners' safety and health health and places them at the highest priority, review of recorded lectures and investing time. Results also reveal the most prominent negative repercussions, which are students’ concern about their academic conditions, reduced access to teaching and research facilities and laboratories, and large assignments. Statistically significant differences are also found in favour of males, health disciplines, and King Faisal University and University of Hail. Keywords: Repercussions,covid-19, student,remote learning,Saudi universities

Identifying priority review questions for Cochrane Eyes and Vision: protocol for a priority setting exercise

IntroductionCochrane Eyes and Vision (CEV) is an international network of individuals working to prepare, maintain and promote access to systematic reviews of interventions to treat, prevent or diagnose eye diseases or vision impairment. CEV plans to undertake a priority setting exercise to identify systematically research questions relevant to our scope, and to formally incorporate input from a wide range of stakeholders to set priorities for new and updated reviews.Methods and analysisThe scope of CEV is broad and our reviews include conditions that are common and have a high global disease burden, for example, cataract and dry eye disease, and conditions that are rare but have a high impact on quality of life and high individual cost such as eye cancer. We plan to focus on conditions prioritised by WHO during the development of the Package of Eye Care Interventions. These conditions were selected based on a combination of data on disease magnitude, healthcare use and expert opinion. We will identify priority review questions systematically by summarising relevant data on research in Eyes and Vision from a range of sources, and compiling a list of 10–15 potential review questions (new and/or updates) for each condition group. We will seek the views of external and internal stakeholders on this list by conducting an online survey. Equity will be a specific consideration.Ethics and disseminationThe study has been approved by the ethics committee of the London School of Hygiene & Tropical Medicine. We will disseminate the findings through Cochrane channels and prepare a summary of the work for publication in a peer-reviewed journal.

Expedited development and review pathways for novel oncology drugs.

e13578 Background: Following approval of the Food and Drug Administration (FDA) Safety and Innovation Act in 2012, the FDA launched a 3-year plan to promote innovation, increase stakeholder involvement, secure the drug supply chain, and fund these endeavors by collecting user fees. The FDA created its fourth expedited pathway, Breakthrough Therapy Designation (BTD) to focus on the development and approval of therapies to treat serious and life-threatening conditions that lack adequate therapies. Our 2017 study (ASCO abstract #e18270) identified a trend of increased use of these approaches with oncology drugs, particularly the BTD, which was a nascent pathway at the time. We aimed to reexamine FDA pathway and approval trends in oncology interventions. Methods: We analyzed publicly available data on novel drug approvals by the FDA’s Center for Drug Evaluation and Research (CDER) from 2012-2020 and the 4 expedited pathways (BTD, Accelerated Approval, Fast Track Designation [FTD], and Priority Review). Results: Between 2012 and 2020, CDER approved 380 new chemical entities, including 101 oncology drugs. Due to data limitations, 3 novel oncology biologics (approved by the Center for Biologics Evaluation and Research) and 4 diagnostics were excluded from the analyses. Oncology drugs comprised a mean 27% (range 14-34%) of all approvals from 2012-2020, including 25% from 2012–2016 and 28% from 2017-2020. Of all approved oncology drugs from 2012-2020, 94% (range 82-100%) utilized at least one expedited pathway. Oncology approvals were more likely than non-oncology approvals to have used one or more expedited pathways. Use of these pathways for oncology approvals increased from 2012-2016 to 2017-2020: ≥2 (65% vs 78%) and ≥3 (35% vs 50%) pathways. BTD usage for oncology drugs increased from 35% in 2012-2016 to 57% in 2017-2020, though for 2012-2016, the time interval between awarding the (new) designation and the remainder of development activities must be considered. Presumably because BTD grants additional benefits over FTD, generally the use of FTD for oncology drugs has declined over time. The use of Priority Review and Accelerated Approval has remained the same. Despite the pandemic, for oncology and non-oncology drugs alike, approvals using pathways remained consistent between 2019 and 2020. Conclusions: Efficient FDA review plays an important role in oncology drug development. Since its inception in 2012, BTD has been adopted and expeditiously used, comprising more than half of all novel oncology drug approvals from 2017-2020. Our data show a gradual increase in approvals of drugs granted BTD, which, given the duration of drug development, likely reflects the time between the acceptance of the BTD request and remainder of the pre-submission development activities. As BTD was expressly developed to increase stakeholder interaction and prioritize innovation, the speed-to-adoption and use of this pathway among oncology interventions is promising.

Transplant-associated thrombotic microangiopathy: theoretical considerations and a practical approach to an unrefined diagnosis

Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic stem cell transplant (HSCT) with high morbidity and mortality. The triad of endothelial cell activation, complement dysregulation, and microvascular hemolytic anemia has the potential to cause end organ dysfunction, multiple organ dysfunction syndrome and death, but clinical features mimic other disorders following HSCT, delaying diagnosis. Recent advances have implicated complement as a major contributor and the therapeutic potential of complement inhibition has been explored. Eculizumab has emerged as an effective therapy and narsoplimab (OMS721) has been granted priority review by the FDA. Large studies performed mostly in pediatric patients suggest that earlier recognition and treatment may lead to improved outcomes. Here we present a clinically focused summary of recently published literature and propose a diagnostic and treatment algorithm.

The Potential Benefit of Expedited Development and Approval Programs in Precision Medicine

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.