Challenges in Evaluating Safety and Efficacy in Drug Development for Rare Diseases: A Review for Pharmacists

2020 ◽  
pp. 089719002093097
Author(s):  
Kanya K. Shah ◽  
Stephen Kogut ◽  
Angela Slitt
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Rare Disease ◽  
Rare Diseases ◽  
The United States ◽  
Priority Review ◽  
Pharmaceutical Companies ◽  
Federal Programs ◽  
Financial Barriers ◽  
Safety And Efficacy

A rare disease, or orphan disease, in the United States is a condition with a national prevalence of fewer than 200,000 diagnoses. As therapies for rare diseases are developed and brought to market, pharmacists should understand the challenges of drug development for rare diseases and aid in educating patients about the approval process for rare disease therapies. Developing drugs for treating rare diseases presents unique challenges in proving the drug’s safety and efficacy with adequate study design, power, and validity. Results of the clinical trials for rare diseases may be weakened by small patient populations, limited disease information, and difficulty defining end points and biomarkers. In addition to investigational barriers, pharmaceutical companies face financial barriers in justifying the investment of bringing a rare disease therapy to market. Federal programs, such as the Orphan Drug Act of 1983, expedited review, the Rare Pediatric Disease Priority Review Vouchers (RPD PRV) program, and the 21st Century Cures Act, give pharmaceutical companies motivation to develop therapies for rare diseases. The objective of this article is to provide pharmacists with an understanding of the challenges in designing clinical trials for drugs for rare diseases and discuss federal programs that address efforts to develop safe and efficacious drugs for rare diseases.

Current Advances in Clinical Trials for Rare Disease Populations: Spotlight on the Patient

2021 ◽  
Vol 16 ◽  
Author(s):  
Erica Winter ◽  
Scott Schliebner
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Development ◽  
Rare Disease ◽  
Rare Diseases ◽  
Statistical Analyses ◽  
Clinical Trial Designs ◽  
Novel Approaches

: Characterized by small, highly heterogeneous patient populations, rare disease trials magnify the challenges often encountered in traditional clinical trials. In recent years, there have been increased efforts by stakeholders to improve drug development in rare diseases through novel approaches to clinical trial designs and statistical analyses. We highlight and discuss some of the current and emerging approaches aimed at overcoming challenges in rare disease clinical trials, with a focus on the ultimate stakeholder, the patient.

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.

scholarly journals Trends of Clinical Trials for Drug Development in Rare Diseases

2018 ◽  
Vol 13 (3) ◽  
pp. 199-208
Author(s):  
Ryuichi Sakate ◽  
Akiko Fukagawa ◽  
Yuri Takagaki ◽  
Hanayuki Okura ◽  
Akifumi Matsuyama
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Rare Diseases

scholarly journals Tackling rare diseases: Clinical trials on chips

2020 ◽  
Vol 245 (13) ◽  
pp. 1155-1162 ◽  
Author(s):  
Sandra H Blumenrath ◽  
Bo Y Lee ◽  
Lucie Low ◽  
Ranjini Prithviraj ◽  
Danilo Tagle
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Data Collection ◽  
Rare Disease ◽  
Study Design ◽  
Rare Diseases ◽  
Working Group ◽  
Design Data ◽  
Chip Technology ◽  
Microphysiological Systems

Technological advances with organs-on-chips and induced pluripotent stem cells promise to overcome hurdles associated with developing medical products, especially for rare diseases. Organs-on-chips—bioengineered “microphysiological systems” that mimic human tissue and organ functionality—may overcome clinical trial challenges with real-world patients by offering ways to conduct “clinical trials-on-chips” (CToCs) to inform the design and implementation of rare disease clinical studies in ways not possible with other culture systems. If applied properly, CToCs can substantially impact clinical trial design with regard to anticipated key outcomes, assessment of clinical benefit and risk, safety and tolerability profiles, population stratification, value and efficiency, and scalability. To discuss how tissue chips are best used to move the development of rare disease therapies forward, a working group of experts from industry, academia, and FDA as well as patient representatives addressed questions related to disease setting, test agents for microphysiological systems, study design and feasibility, data collection and use, the benefits and risks associated with this approach, and how to engage stakeholders. While rare diseases with no current therapies were considered the ultimate target, participants cautioned against stepping onto too many unknown territories when using rare disease as initial test beds. Among the disease categories considered ideal for initial CToC tests were well-defined diseases with known clinical outcomes; diseases where tissues on chips can serve as an alternative to risky first-in-human studies, such as in pediatric oncology; and diseases that lend itself to immuno-engineering or genome editing. Participants also considered important challenges, such as hosting the chip technology in-house, the high variability of cell batches and the resulting regulatory concerns, as well as the financial risk associated with the new technology. To make progress in this area and increase confidence with the use of tissue chips, the re-purposing of approved drugs ought to be the very first step. Impact statement Designing and conducting clinical trials are extremely difficult in rare diseases. Adapting tissue chips for rare disease therapy development is pivotal in assuring that treatments are available, especially for severe diseases that are difficult to treat. Thus far, the NCATS-led National Institutes of Health (NIH) Tissue Chip program has focused on deploying the technology towards in vitro tools for safety and efficacy assessments of therapeutics. However, exploring the feasibility and best possible approach to expanding this focus towards the development phase of therapeutics is critical to moving the field of CToCs forward and increasing confidence with the use of tissue chips. The working group of stakeholders and experts convened by NCATS and the Drug Information Association (DIA) addresses important questions related to disease setting, test agents, study design, data collection, benefit/risk, and stakeholder engagement—exploring both current and future best use cases and important prerequisites for progress in this area.

Acamprosate for the Treatment of Alcohol Dependence: A Review of Double-Blind, Placebo-Controlled Trials

CNS Spectrums ◽  
2000 ◽  
Vol 5 (2) ◽  
pp. 58-69 ◽  
Author(s):  
Barbara J. Mason ◽  
Raymond L. Ownby
Keyword(s):  
Clinical Trials ◽  
Alcohol Dependence ◽  
Latin American ◽  
The United States ◽  
Concomitant Treatment ◽  
Controlled Clinical Trials ◽  
Double Blind ◽  
Safety And Efficacy ◽  
Double Blind Placebo ◽  
Alcohol Dependent

AbstractAcamprosate (calcium acetyl-homotaurine) is a synthetic compound that crosses the blood-brain barrier and has a chemical structure similar to that of the naturally occurring amino acid neuromediators, homotaurine and γ-aminobu-tyric acid (GABA). Acamprosate appears to act primarily by restoring normal N-methyl-D-aspartate (NMDA) receptor tone in the glutamate system, and has been shown to have a specific dose-dependent effect on decreasing voluntary alcohol intake in animals with no effects on food and water consumption. The safety and efficacy of acamprosate in alcohol-dependent outpatients is currently under evaluation in the United States. Acamprosate has been available by prescription since 1989 in France and more recently in most European and Latin American coutries as well as Australia, South Africa, and Hong Kong. More than 4 million people have been treated with acamprosate since it became commercially available.The purpose of this article is to review all available double-blind, placebo-controlled clinical trials evaluating the safety and efficacy of acamprosate treatment of alcohol dependence. This work encompasses 16 controlled clinical trials conducted across 11 European countries and involves more than 4,500 outpatients with alcohol dependence. Fourteen of 16 studies found alcohol-dependent patients treated with acamprosate had a significantly greater rate of treatment completion, time to first drink, abstinence rate, and/or cumulative abstinence duration than patients treated with placebo. Additionally, a multinational open-label study of acamprosate in 1,281 patients with alcohol dependence found acamprosate to be equally effective across four major psychosocial concomitant treatment programs in maintaining abstinence and reducing consumption during any periods of relapse. An absence of known strong predictors of response to acamprosate, in conjunction with a modest but consistent effect on prolonging abstinence, and an excellent safety profile, lend support to the use of acamprosate across a broad range of patients with alcohol dependence.

scholarly journals Orphan drugs

2013 ◽  
Vol 66 (9-10) ◽  
pp. 373-378
Author(s):  
Svetlana Golocorbin-Kon ◽  
Aleksandra Vojinovic ◽  
Mladena Lalic-Popovic ◽  
Nebojsa Pavlovic ◽  
Momir Mikov
Keyword(s):  
Rare Diseases ◽  
United States Of America ◽  
Turning Point ◽  
Life Quality ◽  
Orphan Drugs ◽  
The United States ◽  
Pharmaceutical Companies ◽  
Time Loss ◽  
Number Of Patients ◽  
The Right

Introduction. Drugs used for treatment of rare diseases are known worldwide under the term of orphan drugs because pharmaceutical companies have not been interested in ?adopting? them, that is in investing in research, developing and producing these drugs. This kind of policy has been justified by the fact that these drugs are targeted for small markets, that only a small number of patients is available for clinical trials, and that large investments are required for the development of drugs meant to treat diseases whose pathogenesis has not yet been clarified in majority of cases. The aim of this paper is to present previous and present status of orphan drugs in Serbia and other countries. The beginning of orphan drugs development. This problem was first recognized by Congress of the United States of America in January 1983, and when the ?Orphan Drug Act? was passed, it was a turning point in the development of orphan drugs. This law provides pharmaceutical companies with a series of reliefs, both financial ones that allow them to regain funds invested into the research and development and regulatory ones. Seven years of marketing exclusivity, as a type of patent monopoly, is the most important relief that enables companies to make large profits. Conclusion. There are no sufficient funds and institutions to give financial support to the patients. It is therefore necessary to make health professionals much more aware of rare diseases in order to avoid time loss in making the right diagnosis and thus to gain more time to treat rare diseases. The importance of discovery, development and production of orphan drugs lies in the number of patients whose life quality can be improved significantly by administration of these drugs as well as in the number of potential survivals resulting from the treatment with these drugs.

scholarly journals Exon-Skipping in Duchenne Muscular Dystrophy

2021 ◽  
pp. 1-16
Author(s):  
Shin’ichi Takeda ◽  
Paula R. Clemens ◽  
Eric P. Hoffman
Keyword(s):  
Clinical Trials ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Drug Development ◽  
Rare Disease ◽  
19Th Century ◽  
Exon Skipping ◽  
Clinical Development ◽  
Therapeutic Development ◽  
The 19Th Century

Duchenne muscular dystrophy (DMD) is a devastating, rare disease. While clinically described in the 19th century, the genetic foundation of DMD was not discovered until more than 100 years later. This genetic understanding opened the door to the development of genetic treatments for DMD. Over the course of the last 30 years, the research that supports this development has moved into the realm of clinical trials and regulatory drug approvals. Exon skipping to therapeutically restore the frame of an out-of-frame dystrophin mutation has taken center stage in drug development for DMD. The research reviewed here focuses on the clinical development of exon skipping for the treatment of DMD. In addition to the generation of clinical treatments that are being used for patient care, this research sets the stage for future therapeutic development with a focus on increasing efficacy while providing safety and addressing the multi-systemic aspects of DMD.

scholarly journals Medical Affairs in Pharmaceutical Companies and Related Pharmaceutical Regulations in Japan

2021 ◽  
Vol 8 ◽  
Author(s):  
Hideki Maeda
Keyword(s):  
Clinical Trials ◽  
Scientific Evidence ◽  
The United States ◽  
Current Status ◽  
Pharmaceutical Companies ◽  
Medical Needs ◽  
Long Time ◽  
Post Marketing ◽  
History Of ◽  
Scientific Value

Medical affairs has received a lot of attention in recent years in Japan, but it is also often misunderstood or poorly understood in the healthcare industry in Japan. In the United States, the function of medical affairs has been established for a long time, whereas its history in Japan is relatively short. Many scandals in clinical trials occurred with inappropriate relationship between medical doctors and the sales departments of pharmaceutical companies from 2012. These incidents undermined confidence in clinical trials in Japan and triggered the enforced separation of sales departments from the conduct of post-marketing clinical trials and evidence generation. There have been growing compliance issues identified in marketing and sales practices, and off-label promotion is also becoming an issue in Japan. These issues resulted in the establishment of independent medical affairs departments from sales departments in pharmaceutical companies operating in Japan. Due to the short history of medical affairs in Japan, the roles and responsibilities vary between companies in Japan. Medical affairs departments aim to fulfill unmet medical needs through the generation of scientific evidence and to deliver scientific value to key stakeholders and patients. People working in medical affairs need to engage in scientific exchange activities with key opinion leaders independent of sales departments. Through these activities, medical affairs ensures that patients receive optimal medical care. Medical affairs in Japan is still developing, and its roles, responsibilities, and functions are improving. This article covers the history of medical affairs in Japan and the current status and future perspectives of medical affairs in Japan.

scholarly journals Using four decades of FDA orphan drug designations to describe trends in rare disease drug development: substantial growth seen in development of drugs for rare oncologic, neurologic, and pediatric-onset diseases

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Kathleen L. Miller ◽  
Lewis J. Fermaglich ◽  
Janet Maynard
Keyword(s):  
Drug Development ◽  
Rare Disease ◽  
Orphan Drug ◽  
Recent Decade ◽  
The United States ◽  
Orphan Drug Designation ◽  
Therapeutic Area ◽  
The Past ◽  
The Impact ◽  
Pediatric Onset

Abstract Background Orphan drug designations are a useful proxy to investigate trends in rare disease drug development. Drug developers must receive a designation before they are eligible for the economic incentives of the Orphan Drug Act in the United States. We created a database of all orphan drugs designated between 1983 and 2019 that included numerous drug characteristics, including therapeutic area. In addition, we constructed a “broad disease” categorization of designations as an alternative to therapeutic area, based on disease etiology and age of onset rather than organ system. By looking at the pattern of orphan drug designations over the past four decades, this analysis studied the impact of the evolving rare disease drug development landscape and considers the future of rare disease therapies over the coming decades. Results Between 1983 and 2019, a total of 5099 drugs and biologics received orphan drug designation. Designations more than doubled between the 1980s and 1990s, almost doubled between the 1990s and 2000s, and almost tripled in number between the 2000s and 2010s. The top three therapeutic areas represented in the orphan drug designations were: oncology (1910, 37%), neurology (674, 13%), and infectious diseases (436, 9%). The broad disease categorization found that the proportion of designations for pediatric-onset diseases has increased in the most recent decade to 27%. Conclusions Analysis of the last four decades of orphan drug designation indicates seismic shifts have occurred in the rare disease drug development space. The number of designations granted more than quadrupled between the 1990s and 2010s. While these substantial increases led to growth in the absolute number of designations within all therapeutic areas (bar one) and broad disease categories, the relative proportions have seen considerable change over time. In the most recent decade, there have been notable increases in the proportion of drugs in oncology, pediatric-onset diseases, and neurologic disorders. The dramatic rise in overall orphan designations over the past four decades suggests we may continue to see an upward trajectory in designations leading to an increased number of approvals for drugs and biologics designed specifically for diagnosing, preventing, and treating rare diseases in the coming decades.

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