Dalbavancin safety in the phase 2/3 clinical development program

Drug development for Alzheimer's disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3 clinical trials that failed to show efficacy of investigational drugs. Despite differences in clinical and behavioral characteristics, these disorders have shared pathologies and common challenges in designing early-phase trials that are predictive of late-stage success. Here, we discuss exploratory clinical trials in neurodegenerative dementias. These are generally phase 1b or phase 2a trials that are designed to assess pharmacologic effects and rely on biomarker outcomes, with shorter treatment durations and fewer patients than traditional phase 2 studies. Exploratory trials can establish go/no-go decision points, support proof-of-concept and dose selection, and terminate drugs that fail to show target engagement with suitable exposure and acceptable safety profiles. Early failure saves valuable resources including opportunity costs. This is especially important for programs in academia and small biotechnology companies but may be applied to high-risk projects in large pharmaceutical companies to achieve proof-of-concept more rapidly at lower costs than traditional approaches. Exploratory studies in a staged clinical development program may provide promising data to warrant the substantial resources needed to advance compounds through late-stage development. To optimize the design and application of exploratory trials, the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration convened an advisory panel to provide recommendations on outcome measures and statistical considerations for these types of studies and study designs that can improve efficiency in clinical development.

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Pregnancy outcomes and postpartum relapse rates in women with RRMS treated with alemtuzumab in the phase 2 and 3 clinical development program over 16 years

Multiple Sclerosis and Related Disorders ◽

10.1016/j.msard.2020.102146 ◽

2020 ◽

Vol 43 ◽

pp. 102146 ◽

Cited By ~ 1

Author(s):

Jiwon Oh ◽

Anat Achiron ◽

Elisabeth G. Celius ◽

Christina Chambers ◽

Joy Derwenskus ◽

...

Keyword(s):

Pregnancy Outcomes ◽

Development Program ◽

Clinical Development ◽

Phase 2 ◽

Clinical Development Program ◽

Relapse Rates

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Immunogenicity of Mepolizumab in Patients with Severe Eosinophilic Asthma: Experience from the Clinical Development Program

10.1055/s-0039-1678313 ◽

2019 ◽

Author(s):

H Ortega ◽

E Meyer ◽

G Brusselle ◽

K Asano ◽

RG Price ◽

...

Keyword(s):

Development Program ◽

Clinical Development ◽

Eosinophilic Asthma ◽

Severe Eosinophilic Asthma ◽

Clinical Development Program

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The PARTHENON Clinical Development Program: the Role of Ticagrelor in Patients with Atherothrombotic Disease

Cardiovascular Drugs and Therapy ◽

10.1007/s10557-017-6749-7 ◽

2017 ◽

Vol 31 (4) ◽

pp. 433-444 ◽

Cited By ~ 2

Author(s):

Paul P. Dobesh ◽

Manesh Patel

Keyword(s):

Development Program ◽

Clinical Development ◽

Clinical Development Program ◽

Atherothrombotic Disease

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Edaravone in Amyotrophic Lateral Sclerosis’Lessons from the Clinical Development Program and the Importance of a Strategic Clinical Trial Design

US Neurology ◽

10.17925/usn.2018.14.1.47 ◽

2018 ◽

Vol 14 (1) ◽

pp. 47 ◽

Cited By ~ 5

Author(s):

Said R Beydoun ◽

Jeffrey Rosenfeld

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Amyotrophic Lateral Sclerosis ◽

Trial Design ◽

Development Program ◽

Clinical Trial Design ◽

Clinical Development ◽

Disease Heterogeneity ◽

Clinical Development Program ◽

Lateral Sclerosis

Edaravone significantly slows progression of amyotrophic lateral sclerosis (ALS), and is the first therapy to receive approval by the Food and Drug Administration (FDA) for the disease in 22 years. Approval of edaravone has marked a new chapter in pharmaceutical development since the key trial included a novel strategic clinical design involving cohort enrichment. In addition, approval was based on clinical trials that had a relatively small patient number and were performed outside of the US. Edaravone was developed through a series of clinical trials in Japan where it was determined that a well-defined subgroup of patients was required to reveal a treatment effect within the study period. Amyotrophic lateral sclerosis is associated with wide-ranging disease heterogeneity (both within the spectrum of ALS phenotypes as well as in the rate of progression). The patient cohort enrichment strategy aimed to address this heterogeneity and should now be considered as a viable, and perhaps preferred, trial design for future studies. Future research incorporating relevant biomarkers may help to better elucidate edaravone’s mechanism of action, pharmacodynamics, and subsequently ALS phenotypes that may preferentially benefit from treatment. In this review, we discuss the edaravone clinical development program, outline the strategic clinical trial design, and highlight important lessons for future trials.

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Clinical Development of Antidepressive Drugs - the Viewpoint of the Industry

European Psychiatry ◽

10.1016/s0924-9338(09)70311-6 ◽

2009 ◽

Vol 24 (S1) ◽

pp. 1-1

Author(s):

C. de Bodinat ◽

B. Delalleau

Keyword(s):

Depressive Disorders ◽

Rating Scale ◽

Development Program ◽

Placebo Response ◽

Clinical Development ◽

Short Term ◽

Double Blind ◽

Clinical Development Program ◽

Term Efficacy ◽

Number Of Patients

The clinical development program strategy of a new treatment of depression to be registered in Europe must be built in agreement with recommendations of the CHMP guidance.Demonstration that an antidepressant is effective in treatment of major depressive disorders requires consideration of specific recommendations notably regarding the use of placebo and reference drugs, efficacy assessment, designs features and safety aspects.In the field of depression, comparisons between test medicinal product and reference drugs are difficult to interpretate since the level of placebo response is high and variable. An adequate evaluation of antidepressant efficacy is firstly based on randomised double blind comparison versus placebo. For short term efficacy, studies with 6 week-treatment period are required and three arm trials including placebo and active control are recommended. Regarding the long term efficacy, relapse prevention study is the design recommended for demonstrating that the short term effect can be maintained over time.Assessment of efficacy criteria includes both clinical relevance and statisitical significance, particularly:Improvement expressed as difference between baseline and post-treatment score in symptomatology and as proportion of responders.Remission, defined as a condition where no or only few signs remained, with a justified cut-off on a validated rating-scale.In randomised withdrawal trials, efficacy is expressed as number of patients relapsing and/or time to relapse.The acceptable scales for use as primary endpoint include the HAM-D17 scale, the MADRS scale. Cautions regarding designs features, safety assessment and the global methodological issues faced in conducting such program will be detailed in the presentation.

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