Off-Label Medication: From a Simple Concept to Complex Practical Aspects

Off-label use of drugs is widely known as unapproved use of approved drugs, and it can be perceived as a relatively simple concept. Even though it has been in existence for many years, prescribing and dispensing of drugs in an off-label regimen is still a current issue, triggered especially by unmet clinical needs. Several therapeutic areas require off-label approaches; therefore, this practice is challenging for prescribing physicians. Meanwhile, the regulatory agencies are making efforts in order to ensure a safe practice. The present paper defines the off-label concept, and it describes its regulation, together with several complex aspects associated with clinical practices regarding rare diseases, oncology, pediatrics, psychiatry therapeutic areas, and the safety issues that arise. A systematic research of the literature was performed, using terms, such as “off-label”, ”prevalence”, ”rare diseases”, ”oncology”, ”psychiatry”, ”pediatrics”, and ”drug repurposing”. There are several reasons for which off-label practice remains indispensable in the present; therefore, efforts are made worldwide, by the regulatory agencies and governmental bodies, to raise awareness and to ensure safe practice, while also encouraging further research.

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From Off-Label to Repurposed Drug in Non-Oncological Rare Diseases: Definition and State of the Art in Selected EU Countries

Medicine Access Point of Care ◽

10.5301/maapoc.0000016 ◽

2017 ◽

Vol 1 ◽

pp. maapoc.0000016 ◽

Cited By ~ 3

Author(s):

Paola Minghetti ◽

Elena P. Lanati ◽

Josie Godfrey ◽

Oriol Solà-Morales ◽

Olivier Wong ◽

...

Keyword(s):

Rare Diseases ◽

Drug Repurposing ◽

Orphan Drugs ◽

New Drugs ◽

Success Rates ◽

Great Opportunity ◽

Off Label ◽

Research Activities ◽

Oncological Diseases ◽

Repurposed Drugs

Introduction Almost 8,000 rare diseases exist worldwide, affecting approximately 350 million people. Nevertheless, only 5% receive a specific authorized or licensed treatment. The need for effective and rapidly available therapies is still unmet for many patients. Objective The objective is to define repurposing versus off-label drugs, and to evaluate pathways of repurposed drugs for rare non-oncological diseases in Italy, France, England, and Spain (the EU4 countries). Methods This original paper is based on 3 research activities: (i) a nonsystematic literature research; (ii) a questionnaire-based survey to regulatory experts; and (iii) research on approval timelines and therapy prices of repurposed non-oncology orphan drugs. Official approval dates in England are not available if the National Institute for Health and Care Excellence does not appraise the products. Results Only France provides a specific adaptive pathway from off-label to repurposed drugs. Pricing and reimbursement assessment for the drug samples varied across the EU4 countries: time-to-market for repurposed drugs versus new drugs is longer in all analyzed countries; that is, 979 days versus 462 days in Italy, 502 days versus 350 days in France, and 624 versus 378 days in Spain. Repurposed drugs have higher success rates from development to approval than novel drugs (30% vs. 11%). Small- and medium-sized enterprises owned 9 of 12 repurposed non-oncology orphan drugs, of which only 4 were reimbursed in all EU4 countries. Prices were more homogeneous across EU4 although the reimbursement rates were different. Conclusions Drug repurposing represents a great opportunity to treat rare non-oncological diseases. However, a more homogenous assessment across EU4 could ensure reimbursement and prices high enough to reward organizations investing in this field.

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Human and Machine Intelligence Together Drive Drug Repurposing in Rare Diseases

Frontiers in Genetics ◽

10.3389/fgene.2021.707836 ◽

2021 ◽

Vol 12 ◽

Author(s):

Anup P. Challa ◽

Nicole M. Zaleski ◽

Rebecca N. Jerome ◽

Robert R. Lavieri ◽

Jana K. Shirey-Rice ◽

...

Keyword(s):

Rare Disease ◽

Rare Diseases ◽

Medical Center ◽

Drug Repurposing ◽

Machine Intelligence ◽

Machine Learning Techniques ◽

Human Knowledge ◽

Innovative Strategy ◽

Domain Experts ◽

Approved Drugs

Repurposing is an increasingly attractive method within the field of drug development for its efficiency at identifying new therapeutic opportunities among approved drugs at greatly reduced cost and time of more traditional methods. Repurposing has generated significant interest in the realm of rare disease treatment as an innovative strategy for finding ways to manage these complex conditions. The selection of which agents should be tested in which conditions is currently informed by both human and machine discovery, yet the appropriate balance between these approaches, including the role of artificial intelligence (AI), remains a significant topic of discussion in drug discovery for rare diseases and other conditions. Our drug repurposing team at Vanderbilt University Medical Center synergizes machine learning techniques like phenome-wide association study—a powerful regression method for generating hypotheses about new indications for an approved drug—with the knowledge and creativity of scientific, legal, and clinical domain experts. While our computational approaches generate drug repurposing hits with a high probability of success in a clinical trial, human knowledge remains essential for the hypothesis creation, interpretation, “go-no go” decisions with which machines continue to struggle. Here, we reflect on our experience synergizing AI and human knowledge toward realizable patient outcomes, providing case studies from our portfolio that inform how we balance human knowledge and machine intelligence for drug repurposing in rare disease.

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Repositioning Drugs for Rare Immune Diseases: Hopes and Challenges for a Precision Medicine

Current Medicinal Chemistry ◽

10.2174/0929867324666170830101215 ◽

2018 ◽

Vol 25 (24) ◽

pp. 2764-2782 ◽

Cited By ~ 3

Author(s):

Erica Valencic ◽

Alenka Smid ◽

Ziga Jakopin ◽

Alberto Tommasini ◽

Irena Mlinaric-Rascan

Keyword(s):

Precision Medicine ◽

Rare Diseases ◽

Business Models ◽

Drug Repositioning ◽

Drug Action ◽

Primary Immunodeficiency Diseases ◽

Computational Sciences ◽

Approved Drugs ◽

Molecular Mode ◽

Viable Business

Human primary immunodeficiency diseases (PIDs) are a large group of rare diseases and are characterized by a great genetic and phenotypic heterogeneity. A large subset of PIDs is genetically defined, which has a crucial impact for the understanding of the molecular basis of disease and the development of precision medicine. <p> Discovery and development of new therapies for rare diseases has long been de-privileged due to the length and cost of the processes involved. Interest has increased due to stimulatory regulatory and supportive reimbursement environments enabling viable business models. <p> Advancements in biomedical and computational sciences enable the development of rational, designed approaches for identification of novel indications of already approved drugs allowing faster delivery of new medicines. Drug repositioning is based either on clinical analogies of diseases or on understanding of the molecular mode of drug action and mechanisms of the disease. All of these are the basis for the development of precision medicine.

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Structural Basis of Antisickling Effects of Selected FDA Approved Drugs: A Drug Repurposing Study

Current Computer - Aided Drug Design ◽

10.2174/1573409914666180129163711 ◽

2018 ◽

Vol 14 (2) ◽

pp. 106-116 ◽

Cited By ~ 1

Author(s):

Olujide O. Olubiyi ◽

Maryam O. Olagunju ◽

James O. Oni ◽

Abidemi O. Olubiyi

Keyword(s):

Drug Repurposing ◽

Structural Basis ◽

Approved Drugs ◽

Fda Approved Drugs

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Screening of an FDA-Approved Library for Novel Drugs against Y. pestis

Antibiotics ◽

10.3390/antibiotics10010040 ◽

2021 ◽

Vol 10 (1) ◽

pp. 40

Author(s):

David Gur ◽

Theodor Chitlaru ◽

Emanuelle Mamroud ◽

Ayelet Zauberman

Keyword(s):

Drug Repurposing ◽

Mortality Rates ◽

Systematic Screening ◽

Antibiotic Resistant ◽

Gram Negative ◽

Therapy Initiation ◽

Novel Drugs ◽

Resistant Strains ◽

Approved Drugs ◽

Fda Approved Drugs

Yersinia pestis is a Gram-negative pathogen that causes plague, a devastating disease that kills millions worldwide. Although plague is efficiently treatable by recommended antibiotics, the time of antibiotic therapy initiation is critical, as high mortality rates have been observed if treatment is delayed for longer than 24 h after symptom onset. To overcome the emergence of antibiotic resistant strains, we attempted a systematic screening of Food and Drug Administration (FDA)-approved drugs to identify alternative compounds which may possess antibacterial activity against Y. pestis. Here, we describe a drug-repurposing approach, which led to the identification of two antibiotic-like activities of the anticancer drugs bleomycin sulfate and streptozocin that have the potential for designing novel antiplague therapy approaches. The inhibitory characteristics of these two drugs were further addressed as well as their efficiency in affecting the growth of Y. pestis strains resistant to doxycycline and ciprofloxacin, antibiotics recommended for plague treatment.

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Repurposing of Antimicrobial Agents for Cancer Therapy: What Do We Know?

Cancers ◽

10.3390/cancers13133193 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3193

Author(s):

Christina Pfab ◽

Luisa Schnobrich ◽

Samir Eldnasoury ◽

André Gessner ◽

Nahed El-Najjar

Keyword(s):

Clinical Trials ◽

Antimicrobial Agents ◽

Large Body ◽

Drug Repurposing ◽

Extensive Discussion ◽

Attrition Rates ◽

Beneficial Effects ◽

Stage Of Development ◽

Development Costs ◽

Approved Drugs

The substantial costs of clinical trials, the lengthy timelines of new drug discovery and development, along the high attrition rates underscore the need for alternative strategies for finding quickly suitable therapeutics agents. Given that most approved drugs possess more than one target tightly linked to other diseases, it encourages promptly testing these drugs in patients. Over the past decades, this has led to considerable attention for drug repurposing, which relies on identifying new uses for approved or investigational drugs outside the scope of the original medical indication. The known safety of approved drugs minimizes the possibility of failure for adverse toxicology, making them attractive de-risked compounds for new applications with potentially lower overall development costs and shorter development timelines. This latter case is an exciting opportunity, specifically in oncology, due to increased resistance towards the current therapies. Indeed, a large body of evidence shows that a wealth of non-cancer drugs has beneficial effects against cancer. Interestingly, 335 drugs are currently being evaluated in different clinical trials for their potential activities against various cancers (Redo database). This review aims to provide an extensive discussion about the anti-cancer activities exerted by antimicrobial agents and presents information about their mechanism(s) of action and stage of development/evaluation.

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In Silico Modeling of FDA-Approved Drugs for Discovery of Therapies Against Neglected Diseases: A Drug Repurposing Approach

In Silico Drug Design ◽

10.1016/b978-0-12-816125-8.00021-3 ◽

2019 ◽

pp. 625-648 ◽

Cited By ~ 2

Author(s):

Carolina L. Belllera ◽

María L. Sbaraglini ◽

Lucas N. Alberca ◽

Juan I. Alice ◽

Alan Talevi

Keyword(s):

In Silico ◽

Drug Repurposing ◽

Neglected Diseases ◽

In Silico Modeling ◽

Approved Drugs ◽

Fda Approved Drugs

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Drug Repurposing for Rare Diseases

Trends in Pharmacological Sciences ◽

10.1016/j.tips.2021.01.003 ◽

2021 ◽

Author(s):

Helen I. Roessler ◽

Nine V.A.M. Knoers ◽

Mieke M. van Haelst ◽

Gijs van Haaften

Keyword(s):

Rare Diseases ◽

Drug Repurposing

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Suggested Research Agenda for the Railroad Industry

Journal of Transportation Management ◽

10.22237/jotm/1157069160 ◽

2006 ◽

Vol 17 (2) ◽

pp. 38-45

Author(s):

Barton Jennings

Keyword(s):

Research Agenda ◽

Academic Research ◽

The United States ◽

Regulatory Agencies ◽

Degree Programs ◽

Safety Issues ◽

Railroad Industry ◽

Transportation Infrastructures ◽

Research Initiatives ◽

Service Standards

The railroad industry is experiencing a worldwide resurgence. International trade is booming as populations continue to grow and transportation infrastructures are nearing capacity. In the United States, the industry is being pressured to provide more services, while at the same time traffic levels are skyrocketing on a network that is much smaller than it was just fifty years ago. Additionally, security and safety issues are challenging the industry, as well as the regulatory agencies associated with railroading. To help with these problems, the industry is calling for more academic involvement through new degree programs and research initiatives. This paper reviews five major areas where academic research could assist the railroad industry in these challenges: capacity expansion, service standards, safety, security, and data management and analysis.

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Potential 2019-nCoV 3C-like Protease Inhibitors Designed Using Generative Deep Learning Approaches

10.26434/chemrxiv.11829102.v1 ◽

2020 ◽

Cited By ~ 7

Author(s):

Alex Zhavoronkov ◽

Vladimir Aladinskiy ◽

Alexander Zhebrak ◽

Bogdan Zagribelnyy ◽

Victor Terentiev ◽

...

Keyword(s):

Homology Modelling ◽

Drug Repurposing ◽

Hiv Protease ◽

Learning Approaches ◽

Protein Targets ◽

Chemical Libraries ◽

Internal Resources ◽

Novel Coronavirus ◽

Approved Drugs ◽

Novel Drug

<div> <div> <div> <p>The emergence of the 2019 novel coronavirus (2019-nCoV), for which there is no vaccine or any known effective treatment created a sense of urgency for novel drug discovery approaches. One of the most important 2019-nCoV protein targets is the 3C-like protease for which the crystal structure is known. Most of the immediate efforts are focused on drug repurposing of known clinically-approved drugs and virtual screening for the molecules available from chemical libraries that may not work well. For example, the IC50 of lopinavir, an HIV protease inhibitor, against the 3C-like protease is approximately 50 micromolar. In an attempt to address this challenge, on January 28th, 2020 Insilico Medicine decided to utilize a part of its generative chemistry pipeline to design novel drug-like inhibitors of 2019-nCoV and started generation on January 30th. It utilized three of its previously validated generative chemistry approaches: crystal-derived pocked- based generator, homology modelling-based generation, and ligand-based generation. Novel druglike compounds generated using these approaches are being published at www.insilico.com/ncov-sprint/ and will be continuously updated. Several molecules will be synthesized and tested using the internal resources; however, the team is seeking collaborations to synthesize, test, and, if needed, optimize the published molecules. </p> </div> </div> </div>

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