FUTILITY ANALYSES IN ALZHEIMER’S DISEASE (AD) CLINICAL TRIALS: A RISKY BUSINESS

2020 ◽  
pp. 1-2
Author(s):  
P.S. Aisen ◽  
R. Raman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Financial Risk ◽  
Phase 1 ◽  
Symptomatic Improvement ◽  
Sufficient Evidence ◽  
Phase 2 ◽  
Financial Loss ◽  
Phase 3

In the standard, orderly progression of drug development trials, a moderately-sized Phase 2 trial demonstrates safety and efficacy of one or more doses of the investigational product, followed by large confirmatory Phase 3 trials of one or two doses leading to regulatory approval. The large and lengthy Phase 3 trials often include interim futility analyses using statistical methods to assess lack of benefit, so that programs “fail early” by identifying ineffective treatments early if evidence points toward lack of efficacy, in part to limit financial loss and redirect resources. For disease-modifying drug development programs in Alzheimer’s disease (AD), finding an optimal strategy is particularly challenging. A slowing of decline rather than symptomatic improvement indicates disease-modification, and primary outcomes for such trials are noisy and sometimes subjective. As a result, very large, lengthy trials are required to see efficacy signals, so Phase 2 trials may look like Phase 3 programs or Phase 3 trials may directly follow Phase 1 trials. In other words, enormous trials may be launched without sufficient evidence of preliminary efficacy of the doses studied, dramatically increasing the financial risk to sponsors. In such instances, futility analyses embedded in trials would seem to be particularly important.

Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

2010 ◽  
Vol 9 (4) ◽  
pp. 214-219
Author(s):  
Robyn J. Barst
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Drug Development ◽  
Phase 1 ◽  
Preclinical Studies ◽  
Phase 2 ◽  
Phase 3 ◽  
Preclinical Testing ◽  
New Drug ◽  
Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

scholarly journals New approaches to symptomatic treatments for Alzheimer’s disease

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Jeffrey Cummings
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuropsychiatric Symptoms ◽  
Symptomatic Treatment ◽  
Phase 2 ◽  
Phase 3 ◽  
Trial Conduct ◽  
Outcomes Measures ◽  
New Treatments ◽  
And Behavior

Abstract Background Successful development of agents that improve cognition and behavior in Alzheimer’s disease (AD) is critical to improving the lives of patients manifesting the symptoms of this progressive disorder. Discussion There have been no recent approvals of cognitive enhancing agents for AD. There are currently 6 cognitive enhancers in Phase 2 trials and 4 in phase 3. They represent a variety of novel mechanisms. There has been progress in developing new treatments for neuropsychiatric symptoms in AD with advances in treatment of insomnia, psychosis, apathy, and agitation in AD. There are currently 4 AD-related psychotropic agents in Phase 2 trials and 7 in Phase 3 trials. Many novel mechanisms are being explored for the treatment of cognitive and behavioral targets. Progress in trial designs, outcomes measures, and population definitions are improving trial conduct for symptomatic treatment of AD. Conclusions Advances in developing new agents for cognitive and behavioral symptoms of AD combined with enhanced trial methods promise to address the unmet needs of patients with AD for improved cognition and amelioration of neuropsychiatric symptoms.

scholarly journals Parkinson’s Disease Drug Development Since 1999: A Story of Repurposing and Relative Success

2021 ◽  
pp. 1-9
Author(s):  
Deirdre M. Boucherie ◽  
Gonçalo S. Duarte ◽  
Tiago Machado ◽  
Patrícia R. Faustino ◽  
Cristina Sampaio ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Development ◽  
Success Rate ◽  
Phase 1 ◽  
Phase 2 ◽  
Development Programs ◽  
Inclusion Criteria ◽  
Phase 3 ◽  
Heterogeneous Nature

Background: A global overview of drug development programs in Parkinson’s disease over the last few decades is lacking, while such programs are challenging given the multifaceted and heterogeneous nature of the disease. Objective: To indirectly assess drug development programs in Parkinson’s disease, exploring some factors associated with compound attrition at different trial phases. Methods: We assessed all Parkinson’s disease trials in the WHO trials portal, from inception (1999) to September 2019. Independent authors selected trials and extracted data. The success rate was the number of compounds that progressed to the next drug development phase divided by the number of compounds in that phase. Results: Overall, 357 trials (studying 152 compounds) fulfilled our inclusion criteria, with 62 (17.3%) phase 1 trials, 135 (37.8%) phase 2 trials, 85 (23.8%) phase 3 trials, and 53 (14.8%) phase 4 trials. The success rate was 42.4% from phase 2 to 3. Original compounds received regulatory approval by the FDA in 21.4% of cases, compared with 6.7% of repurposed compounds, representing an overall success rate of 14.9%. We found 172 trials (48.2%) conducted for repurposing previously licensed compounds. These figures were approximately the same regarding approval by the EMA. Most compounds were approved to treat parkinsonism and motor fluctuations. Conclusion: We found a moderate-to-high success rate in all phases of drug development. This was largely based on the success of original compounds, despite almost half of the identified trials attempting compound repurposing.

scholarly journals Alzheimer’s disease: An overview of the current treatments

Bionatura ◽  
2019 ◽  
Vol 02 (Bionatura Conference Serie) ◽  
Author(s):  
Carolina Serrano-Larrea ◽  
David Clavijo-Calderón
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Therapy ◽  
Clinical Trials ◽  
Nerve Growth Factor ◽  
Phase 1 ◽  
Phase 2 ◽  
Adeno Associated Virus ◽  
The World ◽  
Phase 2 Clinical Trials

Alzheimer’s disease (AD) affects millions of people around the world and although there are treatments that help control symptoms and slow down the progress of the disease, there is still no cure. Current treatments include three acetylcholine inhibitors, a glutamate inhibitor and a combination of the two. Due to the failure of hundreds of clinical trials with monotherapies, multitarget treatments are currently being investigated that consider both brain and peripheral factors. Gene therapy is one of the most promising therapies to treat and prevent the development of AD. Nowadays, there is no available medical treatment based on gene therapy to treat AD; however, there are treatments in phase 1 and phase 2 clinical trials with promising results. In this review, we will focus on the most important gene therapy treatments, CERE-110 (adeno-associated virus AAV2-Nerve Growth Factor), Intracerebral AAV gene delivery of APOE2 and gene therapy using PPARγ-coactivator-1α(PGC-1α)

PENERAPAN MODEL QUANTUM LEARNING UNTUK MENINGKATKAN HASIL BELAJAR AUTOCAD SISWA KELAS X TEKNIK PEMESINAN SMK NEGERI 1 STABAT

2013 ◽  
Vol 5 (1) ◽  
Author(s):  
Abdul Hasan Saragih
Keyword(s):  
Positive Response ◽  
Phase 1 ◽  
First Grade ◽  
Learning Model ◽  
Second Phase ◽  
Phase 2 ◽  
Phase 3 ◽  
The Third ◽  
Third Phase ◽  
Quantum Learning

This classroom research was conducted on the autocad instructions to the first grade of mechinary class of SMK Negeri 1 Stabat aiming at : (1) improving the student’ archievementon autocad instructional to the student of mechinary architecture class of SMK Negeri 1 Stabat, (2) applying Quantum Learning Model to the students of mechinary class of SMK Negeri 1 Stabat, arising the positive response to autocad subject by applying Quantum Learning Model of the students of mechinary class of SMK Negeri 1 Stabat. The result shows that (1) by applying quantum learning model, the students’ achievement improves significantly. The improvement ofthe achievement of the 34 students is very satisfactory; on the first phase, 27 students passed (70.59%), 10 students failed (29.41%). On the second phase 27 students (79.41%) passed and 7 students (20.59%) failed. On the third phase 30 students (88.24%) passed and 4 students (11.76%) failed. The application of quantum learning model in SMK Negeri 1 Stabat proved satisfying. This was visible from the activeness of the students from phase 1 to 3. The activeness average of the students was 74.31% on phase 1,81.35% on phase 2, and 83.63% on phase 3. (3) The application of the quantum learning model on teaching autocad was very positively welcome by the students of mechinary class of SMK Negeri 1 Stabat. On phase 1 the improvement was 81.53% . It improved to 86.15% on phase 3. Therefore, The improvement ofstudent’ response can be categorized good.

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