scholarly journals The Use of External Controls in FDA Regulatory Decision Making

2021 ◽  
Author(s):  
Mahta Jahanshahi ◽  
Keith Gregg ◽  
Gillian Davis ◽  
Adora Ndu ◽  
Veronica Miller ◽  
...  
Keyword(s):  
Decision Making ◽  
Natural History ◽  
Product Development ◽  
Rare Diseases ◽  
The United States ◽  
External Control ◽  
Common Source ◽  
Published Data ◽  
History Data ◽  
Benefit Risk Assessment

AbstractThe regulatory standards of the United States Food and Drug Administration (FDA) require substantial evidence of effectiveness from adequate and well-controlled trials that typically use a valid comparison to an internal concurrent control. However, when it is not feasible or ethical to use an internal control, particularly in rare disease populations, relying on external controls may be acceptable. To better understand the use of external controls to support product development and approval, we reviewed FDA regulatory approval decisions between 2000 and 2019 for drug and biologic products to identify pivotal studies that leveraged external controls, with a focus on select therapeutic areas. Forty-five approvals were identified where FDA accepted external control data in their benefit/risk assessment; they did so for many reasons including the rare nature of the disease, ethical concerns regarding use of a placebo or no-treatment arm, the seriousness of the condition, and the high unmet medical need. Retrospective natural history data, including retrospective reviews of patient records, was the most common source of external control (44%). Other types of external control were baseline control (33%); published data (11%); and data from a previous clinical study (11%). To gain further insights, a comprehensive evaluation of selected approvals utilizing different types of external control is provided to highlight the variety of approaches used by sponsors and the challenges encountered in supporting product development and FDA decision making; particularly, the value and use of retrospective natural history in the development of products for rare diseases. Education on the use of external controls based on FDA regulatory precedent will allow for continued use and broader application of innovative approaches to clinical trial design, while avoiding delays in product development for rare diseases. Learnings from this review also highlight the need to update regulatory guidance to acknowledge the utility of external controls, particularly retrospective natural history data.

scholarly journals Benefit–Risk Tradeoffs in Assessment of New Drugs and Devices

Circulation ◽  
2020 ◽  
Vol 142 (20) ◽  
pp. 1974-1988
Author(s):  
Sanjay Kaul ◽  
Norman Stockbridge ◽  
Javed Butler
Keyword(s):  
Risk Assessment ◽  
Decision Making ◽  
Aortic Valve ◽  
Antiplatelet Agents ◽  
The United States ◽  
New Drugs ◽  
Net Benefit ◽  
Nonvalvular Atrial Fibrillation ◽  
Qualitative Approaches ◽  
Benefit Risk Assessment

Balancing benefits and risks is a complex task that poses a major challenge, both to the approval of new medicines and devices by regulatory authorities and in therapeutic decision-making in practice. Several analysis methods and visualization tools have been developed to help evaluate and communicate whether the benefit–risk profile is favorable or unfavorable. In this White Paper, we describe approaches to benefit–risk assessment using qualitative approaches such as the Benefit Risk Action Team framework developed by the Pharmaceutical Research and Manufacturers of America, and the Benefit–Risk Framework developed by the United States Food and Drug Administration; and quantitative approaches such as the numbers needed to treat for benefit and harm, the benefit–risk ratio, and Incremental Net Benefit. We give illustrative examples of benefit–risk evaluations using 4 treatment interventions including sodium glucose cotransporter 2 inhibitors in patients with type 2 diabetes; a direct antithrombin agent, dabigatran, for reducing stroke and systemic embolism in patients with nonvalvular atrial fibrillation; transcatheter aortic valve replacement in patients with symptomatic severe aortic valve stenosis; and antiplatelet agents vorapaxar and prasugrel for reducing cardiovascular events in patients at high cardiovascular risk. Regular applications of structured benefit–risk assessment, whether qualitative, quantitative, or both, enabled by easy-to-understand graphical presentations that capture uncertainties around the benefit–risk metric, may aid shared decision-making and enhance transparency of those decisions.

scholarly journals The LORIS MyeliNeuroGene rare disease database for natural history studies and clinical trial readiness

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Aaron Spahr ◽  
Zaliqa Rosli ◽  
Mélanie Legault ◽  
Luan T. Tran ◽  
Simon Fournier ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Natural History ◽  
Rare Disease ◽  
Rare Diseases ◽  
Parental Stress ◽  
The United States ◽  
Historical Control ◽  
Surrogate Markers ◽  
Disease Research ◽  
Natural History Studies

Abstract Background Rare diseases are estimated to affect 150–350 million people worldwide. With advances in next generation sequencing, the number of known disease-causing genes has increased significantly, opening the door for therapy development. Rare disease research has therefore pivoted from gene discovery to the exploration of potential therapies. With impending clinical trials on the horizon, researchers are in urgent need of natural history studies to help them identify surrogate markers, validate outcome measures, define historical control patients, and design therapeutic trials. Results We customized a browser-accessible multi-modal (e.g. genetics, imaging, behavioral, patient-determined outcomes) database to increase cohort sizes, identify surrogate markers, and foster international collaborations. Ninety data entry forms were developed including family, perinatal, developmental history, clinical examinations, diagnostic investigations, neurological evaluations (i.e. spasticity, dystonia, ataxia, etc.), disability measures, parental stress, and quality of life. A customizable clinical letter generator was created to assist in continuity of patient care. Conclusions Small cohorts and underpowered studies are a major challenge for rare disease research. This online, rare disease database will be accessible from all over the world, making it easier to share and disseminate data. We have outlined the methodology to become Title 21 Code of Federal Regulations Part 11 Compliant, which is a requirement to use electronic records as historical controls in clinical trials in the United States. Food and Drug Administration compliant databases will be life-changing for patients and families when historical control data is used for emerging clinical trials. Future work will leverage these tools to delineate the natural history of several rare diseases and we are confident that this database will be used on a larger scale to improve care for patients affected with rare diseases.

The United States and the Iranian Nuclear Programme

2018 ◽  
Author(s):  
Steven Hurst
Keyword(s):  
United States ◽  
Decision Making ◽  
Domestic Politics ◽  
The United States ◽  
Nixon Administration ◽  
Comprehensive Plan ◽  
The Us ◽  
Nuclear Issue ◽  
The Relationship

The United States, Iran and the Bomb provides the first comprehensive analysis of the US-Iranian nuclear relationship from its origins through to the signing of the Joint Comprehensive Plan of Action (JCPOA) in 2015. Starting with the Nixon administration in the 1970s, it analyses the policies of successive US administrations toward the Iranian nuclear programme. Emphasizing the centrality of domestic politics to decision-making on both sides, it offers both an explanation of the evolution of the relationship and a critique of successive US administrations' efforts to halt the Iranian nuclear programme, with neither coercive measures nor inducements effectively applied. The book further argues that factional politics inside Iran played a crucial role in Iranian nuclear decision-making and that American policy tended to reinforce the position of Iranian hardliners and undermine that of those who were prepared to compromise on the nuclear issue. In the final chapter it demonstrates how President Obama's alterations to American strategy, accompanied by shifts in Iranian domestic politics, finally brought about the signing of the JCPOA in 2015.

Bringing the Real World of Science to Children: A Partnership of the American Museum of Natural History and the City University of New York

2008 ◽  
Vol 12 (1) ◽  
Author(s):  
Anthony G Picciano ◽  
Robert V. Steiner
Keyword(s):  
United States ◽  
New York ◽  
Natural History ◽  
Local Governments ◽  
Compulsory Education ◽  
Development Program ◽  
The United States ◽  
American Museum ◽  
The World ◽  
The City

Every child has a right to an education. In the United States, the issue is not necessarily about access to a school but access to a quality education. With strict compulsory education laws, more than 50 million students enrolled in primary and secondary schools, and billions of dollars spent annually on public and private education, American children surely have access to buildings and classrooms. However, because of a complex and competitive system of shared policymaking among national, state, and local governments, not all schools are created equal nor are equal education opportunities available for the poor, minorities, and underprivileged. One manifestation of this inequity is the lack of qualified teachers in many urban and rural schools to teach certain subjects such as science, mathematics, and technology. The purpose of this article is to describe a partnership model between two major institutions (The American Museum of Natural History and The City University of New York) and the program designed to improve the way teachers are trained and children are taught and introduced to the world of science. These two institutions have partnered on various projects over the years to expand educational opportunity especially in the teaching of science. One of the more successful projects is Seminars on Science (SoS), an online teacher education and professional development program, that connects teachers across the United States and around the world to cutting-edge research and provides them with powerful classroom resources. This article provides the institutional perspectives, the challenges and the strategies that fostered this partnership.

Formulating Industry-Academic Collaborations That Work: Best Practices to Ensure a Strong Relationship After the Agreements are Signed

2020 ◽  
Vol 21 (2) ◽  
pp. 169-177
Author(s):  
Michael B. Dilling ◽  
Anne C. DiSante ◽  
Ross Durland ◽  
Christine E. Flynn ◽  
Leonid Metelitsa ◽  
...  
Keyword(s):  
Decision Making ◽  
Best Practices ◽  
Product Development ◽  
Strong Relationship ◽  
Governance Structure ◽  
Collaborative Relationships ◽  
Skill Sets ◽  
Pragmatic Aspects

Collaborations between academia and industry are growing in scope, duration, and sophistication. The best collaborations recognize the unique strengths and skill sets of both parties and are structured to leverage what each party does best. In many cases, these collaborations develop into long-term relationships, and it is important to develop the systems and structures needed to support these relationships to ensure that they meet the needs of both sides. Successful collaborations require the formulation of a governance structure to facilitate communication, decision-making, assessment of progress, and the inevitable changes of direction that accompany product development. This panel explored the pragmatic aspects of successfully structuring collaborations and managing the relationships after the deal is done. Several dominant themes associated with successful collaborative relationships emerged from the discussion, and these will be explored in this article.

Comparison and analysis of the fda approved orphane drugs registerand the vital and essential drugs list of the Russian Federation

2020 ◽  
pp. 4-16
Author(s):  
D.S. Yurochkin ◽  
◽  
A.A. Leshkevich ◽  
Z.M. Golant ◽  
I.A. NarkevichSaint ◽  
...  
Keyword(s):  
United States ◽  
Russian Federation ◽  
Rare Diseases ◽  
Orphan Drugs ◽  
The United States ◽  
Orphan Diseases ◽  
Essential Drugs ◽  
The Russian Federation ◽  
Comparison And Analysis ◽  
The Government

The article presents the results of a comparison of the Orphan Drugs Register approved for use in the United States and the 2020 Vital and Essential Drugs List approved on October 12, 2019 by Order of the Government of the Russian Federation No. 2406-r. The comparison identified 305 international non-proprietary names relating to the main and/or auxiliary therapy for rare diseases. The analysis of the market of drugs included in the Vital and Essential Drugs List, which can be used to treat rare (orphan) diseases in Russia was conducted.

Ban Ki-moon, 2007–2016

2018 ◽  
Author(s):  
Richard Gowan
Keyword(s):  
United States ◽  
Decision Making ◽  
Security Council ◽  
Large Scale ◽  
Central African Republic ◽  
The United States ◽  
Cautious Approach ◽  
Peacekeeping Operations ◽  
Council Decision ◽  
The Face

During Ban Ki-moon’s tenure, the Security Council was shaken by P5 divisions over Kosovo, Georgia, Libya, Syria, and Ukraine. Yet it also continued to mandate and sustain large-scale peacekeeping operations in Africa, placing major burdens on the UN Secretariat. The chapter will argue that Ban initially took a cautious approach to controversies with the Council, and earned a reputation for excessive passivity in the face of crisis and deference to the United States. The second half of the chapter suggests that Ban shifted to a more activist pressure as his tenure went on, pressing the Council to act in cases including Côte d’Ivoire, Libya, and Syria. The chapter will argue that Ban had only a marginal impact on Council decision-making, even though he made a creditable effort to speak truth to power over cases such as the Central African Republic (CAR), challenging Council members to live up to their responsibilities.

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