Orphan drug development faces numerous challenges, including low disease prevalence, patient population heterogeneity, and strong presence of paediatric patient populations. Consequently, clinical ...trials for orphan drugs are often smaller than those of non-orphan drugs, and they require the development of efficient trial designs relevant to small populations to gain the most information from the available data. The International Rare Diseases Research Consortium (IRDiRC) is aimed at promoting international collaboration and advance rare diseases research worldwide, and has as one of its goals to contribute to 1000 new therapies for rare diseases. IRDiRC set up a Small Population Clinical Trials (SPCT) Task Force in order to address the shortcomings of our understanding in carrying out clinical trials in rare diseases.
The IRDiRC SPCT Task Force met in March 2016 to discuss challenges faced in the design of small studies for rare diseases and present their recommendations, structured around six topics: different study methods/designs and their relation to different characteristics of medical conditions, adequate safety data, multi-arm trial designs, decision analytic approaches and rational approaches to adjusting levels of evidence, extrapolation, and patients' engagement in study design.
Recommendations have been issued based on discussions of the Small Population Clinical Trials Task Force that aim to contribute towards successful therapy development and clinical use. While randomised clinical trials are still considered the gold standard, it is recommended to systematically take into consideration alternative trial design options when studying treatments for a rare disease. Combining different sources of safety data is important to give a fuller picture of a therapy's safety profile. Multi-arm trials should be considered an opportunity for rare diseases therapy development, and funders are encouraged to support such trial design via international networks. Patient engagement is critical in trial design and therapy development, a process which sponsors are encouraged to incorporate when conducting trials and clinical studies. Input from multiple regulatory agencies is recommended early and throughout clinical development. Regulators are often supportive of new clinical trial designs, provided they are well thought through and justified, and they also welcome discussions and questions on this topic. Parallel advice for multiregional development programs should also be considered.
Postural stimulation tests (PST) from 146 patients with primary aldosteronism were reviewed: 83 had an aldosterone-producing adenoma (APA), 48 idiopathic hyperaldosteronism (IHA), nine primary ...adrenal hyperplasia (PAH), and six aldosterone-producing renin-responsive adenoma (AP-RA). Plasma aldosterone and cortisol levels were measured after overnight recumbency and in response to upright posture for 2 to 4 h. The test was considered invalid in 32% of the patients because cortisol levels increased during the maneuver. As both cortisol and aldosterone are responsive to ACTH in subjects with primary aldosteronism, as well as in normal subjects, we examined their percent variation instead of the absolute values. In order to validate those tests in which cortisol increased, we subtracted the percent cortisol change from the percent aldosterone response. An aldosterone increase of less than 30% (considered a positive response for the presence of an adenoma) identified 76 of the 89 patients with an adenoma (APA and AP-RA) (sensitivity of 85%). Among the 13 false-negative tests, six were proven cases of AP-RA. In each and every case an adenoma was detected by CT/MRI scanning (or bilateral adrenal vein catheterization). Hypertension was ameliorated or cured by surgery. A postural response of less than 30% was also present in 11 of the 57 patients who did not have a discrete adenoma confirmed by imaging techniques (specificity of 81%). Among these false-positive results there were the nine cases of PAH where the hypertension could be ameliorated or cured by partial removal of hyperplastic adrenal tissue.
New treatments for diabetes Irony, Ilan; Parks, Mary H; Meyer, Robert J
The New England journal of medicine,
2007-May-24, Letnik:
356, Številka:
21
Journal Article
New treatments for diabetes Bloomgarden, Zachary T; Inzucchi, Silvio E
The New England journal of medicine,
2007-May-24, Letnik:
356, Številka:
21
Journal Article
The Food and Drug Administration has seen a significant increase in investigational new drug (IND) applications for the use of allogeneic islets of Langerhans to treat type 1 diabetes mellitus. The ...current regulatory framework for clinical use of allogeneic islets of Langerhans is described. In addition, expectations and considerations for information to be included in the manufacturing, preclinical, and clinical sections of an IND for allogeneic islets of Langerhans to treat type 1 diabetes mellitus are discussed.
Licorice-induced hypermineralocorticoidism Farese, R.V. Jr. (San Francisco General Hospital Medical Center, San Francisco); Biglieri, E.G; Shackleton, C.H.L ...
The New England journal of medicine,
10/1991, Letnik:
325, Številka:
17
Journal Article
Recenzirano
Odprti dostop
This brief report presents a case study of the duration of the suppressive effects of licorice on 11 beta-hydroxysteroid dehydrogenase activity and the renin-aldosterone system before and after ...licorice withdrawal in a patient with chronic licorice intoxication
One of the critical path initiatives of the Food and Drug Administration (FDA) is to accelerate the development and availability of a safe and effective artificial pancreas for the treatment of ...diabetes mellitus. The FDA has established a multidisciplinary group of scientists and clinicians, in partnership with the National Institutes of Health (NIH), to address the clinical, scientific and regulatory challenges related to this unique medical product.
Janet Woodcock – Food and Drug Administration, Rockville, MD, USA
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