Evidence-Based Medicine for Rare Diseases: Implications for Data Interpretation and Clinical Trial Design

Clinical trials are the bedrock of evidence-based medicine. Introduced in the mid 20th century, they heralded a move away from opinion and anecdote to a more scientific evaluation of new treatments. Indeed, it could be argued that it is the clinical trial and the application of scientific method to determine which treatments work that distinguishes ‘medicine’ from ‘alternative medicine’. The aim of this short section is to outline the way in which clinical trials are likely to evolve over the next few years....

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A novel, hybrid, single- and multi-site clinical trial design for CLN3 disease, an ultra-rare lysosomal storage disorder

Clinical Trials ◽

10.1177/1740774519855715 ◽

2019 ◽

Vol 16 (5) ◽

pp. 555-560 ◽

Cited By ~ 1

Author(s):

Heather R Adams ◽

Sara Defendorf ◽

Amy Vierhile ◽

Jonathan W Mink ◽

Frederick J Marshall ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Rare Diseases ◽

Trial Design ◽

Neurodegenerative Disorder ◽

Clinical Trial Design ◽

Trial Participation ◽

Local Participation ◽

Cln3 Disease ◽

Study Participants

Background Travel burden often substantially limits the ability of individuals to participate in clinical trials. Wide geographic dispersion of individuals with rare diseases poses an additional key challenge in the conduct of clinical trials for rare diseases. Novel technologies and methods can improve access to research by connecting participants in their homes and local communities to a distant research site. For clinical trials, however, understanding of factors important for transition from traditional multi-center trial models to local participation models is limited. We sought to test a novel, hybrid, single- and multi-site clinical trial design in the context of a trial for Juvenile Neuronal Ceroid Lipofuscinosis (CLN3 disease), a very rare pediatric neurodegenerative disorder. Methods We created a “hub and spoke” model for implementing a 22-week crossover clinical trial of mycophenolate compared with placebo, with two 8-week study arms. A single central site, the “hub,” conducted screening, consent, drug dispensing, and tolerability and efficacy assessments. Each participant identified a clinician to serve as a collaborating “spoke” site to perform local safety monitoring. Study participants traveled to the hub at the beginning and end of each study arm, and to their individual spoke site in the intervening weeks. Results A total of 18 spoke sites were established for 19 enrolled study participants. One potential participant was unable to identify a collaborating local site and was thus unable to participate. Study start-up required a median 6.7 months (interquartile range = 4.6–9.2 months). Only 33.3% (n = 6 of 18) of spoke site investigators had prior clinical trial experience, thus close collaboration with respect to study startup, training, and oversight was an important requirement. All but one participant completed all study visits; no study visits were missed due to travel requirements. Conclusions This study represents a step toward local trial participation for patients with rare diseases. Even in the context of close oversight, local participation models may be best suited for studies of compounds with well-understood side-effect profiles, for those with straightforward modes of administration, or for studies requiring extended follow-up periods.

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Effektivitas Suplementasi Vitamin D Dalam Mempercepat Konversi Sputum Pada Pasien Tuberkulosis

Media Kesehatan Politeknik Kesehatan Makassar ◽

10.32382/medkes.v16i1.1970 ◽

2021 ◽

Vol 16 (1) ◽

pp. 58

Author(s):

Muhammad Sobri Maulana ◽

Nurfadhilah Al Adabiyah

Keyword(s):

Systematic Review ◽

Clinical Trial ◽

Vitamin D ◽

Mycobacterium Tuberculosis ◽

Clinical Outcome ◽

Evidence Based Medicine ◽

Evidence Based ◽

Mdr Tb ◽

Sputum Conversion ◽

Based Medicine

Latar Belakang: Tuberculosis merupakan penyakit infeksi oleh Mycobacterium tuberculosis. Tuberculosis merupakan salah satu diantara sepuluh penyebab utama kematian di dunia. Penelitian terdahulu membuktikan bahwa suplementasi vitamin D dapat meningkatkan aktivitas anti-mikrobial, mempercepat konversi sputum dan kultur, mengurangi inflamasi, meningkatkan clinical outcome, serta meningkatkan mediator untuk aktivitas anti-mikrobial. Meskipun demikian, masih terdapat perbedaan pendapat akan manfaat suplementasi vitamin D pada pasien tuberculosis paru.Tujuan: Mengevaluasi bukti yang ada sampai saat ini terkait manfaat suplementasi vitamin D terutama dalam mempercepat konversi sputum. Metode: Pencarian literatur dilakukan pada tiga databases terkemuka yakni PubMed, SCOPUS, dan Cochrane dengan kata kunci berupa “Tuberculosis”, “Vitamin D”, “Suplementation”, dan “Sputum Conversion” dengan seluruh kata yang berhubungan. Dari seleksi artikel berdasarkan kriteria inklusi dan eksklusif didapatkan 1 systematic review oleh Jollifee D et al (2019) dan 1 clinical trial oleh Afzal A et al (2018), yang kemudian ditelaah berdasarkan aspek validity, importance, dan applicability menggunakan form telaah dari Oxford Center for Evidence Based Medicine. Hasil: Kedua artikel memenuhi kriteria validity, importance, dan applicability masing-masing. Dari segi efikasi, penelitian Jollifee D et al membuktikan bahwa pemberian suplementasi vitamin D tidak mempercepat konversi kultur sputum pada populasi umum (aHR 1.06, 95% CI 0.91-1.23; P=0.44; P for heterogeneity=0.84), namun mempercepat konversi kultur sputum pada populasi MDR-TB(aHR 13.44, 95% CI 2.96-60.90). Kedua studi membuktikan bahwa pemberian suplementasi vitamin D mampu mempercepat konversi apusan sputum namun konversi apusan sputum memiliki validitas yang lebih rendah sebagai marker prognosis untuk outcome suatu tatalaksana dibandingkan konversi kultur sputum. Kesimpulan: Pemberian suplementasi vitamin D tidak mempercepat konversi kultur sputum namun mempercepat konversi apusan sputum. Diperlukan penelitian lebih lanjut terkait manfaat suplementasi vitamin D pada percepatan konversi kultur sputum populasi MDR-TB.

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Limits of Evidence Based Medicine for rare diseases: The case of Budd-Chiari syndrome

Digestive and Liver Disease ◽

10.1016/j.dld.2016.02.025 ◽

2016 ◽

Vol 48 (6) ◽

pp. 689 ◽

Cited By ~ 3

Author(s):

Andrea Mancuso

Keyword(s):

Rare Diseases ◽

Evidence Based Medicine ◽

Evidence Based ◽

Budd Chiari Syndrome ◽

Chiari Syndrome ◽

Based Medicine

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Evidence-Based Medicine and Rare Diseases

Advances in Experimental Medicine and Biology - Rare Diseases Epidemiology: Update and Overview ◽

10.1007/978-3-319-67144-4_12 ◽

2017 ◽

pp. 207-220 ◽

Cited By ~ 1

Author(s):

Simon Day

Keyword(s):

Rare Diseases ◽

Evidence Based Medicine ◽

Evidence Based ◽

Based Medicine

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Clinical Trials in Childhood Cancer

Oxford Textbook of Cancer in Children ◽

10.1093/med/9780198797210.003.0005 ◽

2020 ◽

pp. 38-45

Author(s):

Maria Grazia Valsecchi ◽

Stefania Galimberti ◽

Pamela Kearns

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Rare Diseases ◽

Treatment Strategy ◽

Trial Design ◽

Methodological Approach ◽

Clinical Trial Design ◽

New Treatment ◽

Diagnosis Therapy ◽

Collaborative Efforts

Many important improvements have been achieved in the last decades in the diagnosis, therapy, and prognosis of paediatric cancers. These were possible through clinical trials that were mainly the result of collaborative efforts of national and international groups. For a clinical trial to have the best chance of success, it must ask a clear question that is seen as important both to the clinicians who will implement the trial and to the patients who will participate. Moreover, the design of such trials needs a sound methodological approach in order to provide reliable evidence. This chapter has the following aims: (a) to review the most common conventional approaches that allow to reliably define the benefit of a new drug or a new treatment strategy, and (b) to provide information on novel strategies for clinical trial design that can be useful in the context of rare diseases such as paediatric cancers.

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