Methodological issues in clinical trial design for TMS

2012 ◽  
Author(s):  
Mark A. Demitrack ◽  
Sarah H. Lisanby
Keyword(s):  
Major Depression ◽  
Trial Design ◽  
Magnetic Stimulation ◽  
Clinical Trial Design ◽  
Treatment Resistance ◽  
Methodological Issues ◽  
Multicenter Trials ◽  
Number Of Patients ◽  
New Treatment ◽  
Methodological Considerations

This article explores the emergence of transcranial magnetic stimulation (TMS) as a new therapeutic approach and the implications of this technology for the study and treatment of neuropsychiatric disorders, with a focus on major depression. Relapse, chronicity, and varying degrees of treatment resistance characterize major depression. A substantial number of patients are not effectively treated with pharmacology or medications alone. It is proposed that TMS, along with other device-based therapies emerging in psychiatry, may define a potential new treatment platform, with existing therapeutics for major depression. Through the example of a study, this article describes the methodological considerations in the development of TMS for the treatment of major depression. Device-based approaches to therapeutic neuromodulation hold the promise of significant clinical advantages compared to existing treatments for major depression, but evidence in well designed and properly blinded multicenter trials is still lacking, hence, research in this area is ongoing.

scholarly journals Phase 0 and window of opportunity clinical trial design in neuro-oncology: a RANO review

2020 ◽  
Vol 22 (11) ◽  
pp. 1568-1579 ◽  
Author(s):  
Michael A Vogelbaum ◽  
Daria Krivosheya ◽  
Hamid Borghei-Razavi ◽  
Nader Sanai ◽  
Michael Weller ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Trial Design ◽  
Human Study ◽  
Clinical Trial Design ◽  
Drug Level ◽  
New Drugs ◽  
Window Of Opportunity ◽  
Surgical Specimen ◽  
Number Of Patients ◽  
Phase 0

Abstract Glioblastoma is a devastating disease with poor prognosis. Few effective chemotherapeutics are currently available, and much effort has been expended to identify new drugs capable of slowing tumor progression. The phase 0 trial design was developed to facilitate early identification of promising agents for cancer that should undergo accelerated approval. This design features an early in-human study that enrolls a small number of patients who receive subtherapeutic doses of medication with the goals of describing pharmacokinetics through drug blood level measurements and determining intratumoral concentrations of the investigational compound as well as pharmacodynamics by studying the biochemical and physiological effects of drugs. In neuro-oncology, however, the presence of the blood–brain barrier and difficulty in obtaining brain tumor tissue warrant a separate set of considerations. In this paper, we critically reviewed the protocols used in all brain tumor related in-human phase 0 and phase 0–like (“window of opportunity”) studies between 1993 and 2018, as well as ongoing clinical trials, and identified major challenges in trial design as applied to central nervous system tumors that include surgical specimen collection and storage, brain tumor drug level analysis, and confirmation of drug action. We therefore propose that phase 0 trials in neuro-oncology should include (i) only patients in whom a resection of the tumor is planned, (ii) use of clinical doses of an investigational agent, (iii) tissue sampling from enhancing and non-enhancing portions of the tumor, and (iv) assessment of drug-specific target effects. Standardization of clinical protocols for phase 0/window of opportunity studies can help accelerate the development of effective treatments for glioblastoma.

Randomized Clinical Trial Design for Assessing Noninferiority When Superiority Is Expected

2007 ◽  
Vol 25 (31) ◽  
pp. 5019-5023 ◽  
Author(s):  
Boris Freidlin ◽  
Edward L. Korn ◽  
Stephen L. George ◽  
Robert Gray
Keyword(s):  
Clinical Trial ◽  
Randomized Clinical Trial ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Tolerability Profile ◽  
Modest Improvement ◽  
Noninferiority Trials ◽  
New Treatment ◽  
Formal Test ◽  
Hybrid Trial

The randomized clinical trial (RCT) is the gold standard for definitive evaluation of new therapies. RCTs designed to show that the therapeutic efficacy of a new therapy is not unacceptably inferior to that of standard therapy are called noninferiority trials. Traditionally, noninferiority trials have required very large sample sizes. Sometimes, a new treatment regimen with a favorable toxicity and/or tolerability profile is also expected to have some modest improvement in efficacy. In such specialized settings we describe a hybrid trial-design approach that requires a dramatically smaller sample size than that of a standard noninferiority design. This hybrid design can naturally incorporate a formal test of superiority as well as noninferiority.

Clinical Trials in Childhood Cancer

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.

The influence of treatment-resistance on the serotonin 2A receptor in unipolar melancholic depression

2011 ◽  
Vol 26 (S2) ◽  
pp. 602-602
Author(s):  
C. Baeken ◽  
R. De Raedt ◽  
N. Vanderbruggen ◽  
D. Zeeuws ◽  
L. Santermans ◽  
...  
Keyword(s):  
Major Depression ◽  
Treatment Guidelines ◽  
Treatment Resistance ◽  
Current Treatment ◽  
Anterior Cingulate ◽  
Treatment Resistant ◽  
Melancholic Depression ◽  
Number Of Patients ◽  
And Gender ◽  
Spect Scan

IntroductionMajor depression is one of the most common mental diseases, and quite a number of patients are resistant to several psychopharmacological interventions, even when applying current treatment guidelines. To date, it remains unclear as to how the serotonergic system is implicated in treatment-resistance found in melancholically depressed patients.Objectives & aimsIn this study, we examined the involvement of post-synaptic 5-HT2A receptors in the pathophysiology of treatment resistance in major depression with 123I-5-I-R91150 SPECT, focusing on the frontal cortex and hippocampus.Method15 unipolar antidepressant naïve (ADN) patients and 15 treatment-resistant depressed (TRD) patients, all of the melancholic subtype, matched for age and gender were studied. All subjects were antidepressant free when they underwent a static 123I-5-I-R91150 SPECT scan.ResultsCompared to ADN patients, TRD patients displayed significantly less 5-HT2A receptor binding index (BI) in the dorsal regions of the prefrontal cortex and in the anterior cingulate cortex. No hippocampal 5-HT2A receptor BI differences were observed.ConclusionsOur results suggest that when confronted with treatment resistance in melancholic depression the 5-HT2A receptors in the DPFC-ACC axis are significantly more down-regulated when compared to depressed ADN patients. This might to some extent explain the observed continued cognitive problems and might reflect the long-term serotonin depletion with reduced neurogenesis in treatment resistant patients.

scholarly journals Neoadjuvant checkpoint blockade for cancer immunotherapy

Science ◽  
2020 ◽  
Vol 367 (6477) ◽  
pp. eaax0182 ◽  
Author(s):  
Suzanne L. Topalian ◽  
Janis M. Taube ◽  
Drew M. Pardoll
Keyword(s):  
De Novo ◽  
Clinical Trial Design ◽  
Treatment Resistance ◽  
Common Denominator ◽  
Ongoing Research ◽  
Checkpoint Pathway ◽  
Neoadjuvant Immunotherapy ◽  
Activity Spectrum ◽  
New Treatment ◽  
Cancer Immunotherapies

Cancer immunotherapies that target the programmed cell death 1 (PD-1):programmed death-ligand 1 (PD-L1) immune checkpoint pathway have ushered in the modern oncology era. Drugs that block PD-1 or PD-L1 facilitate endogenous antitumor immunity and, because of their broad activity spectrum, have been regarded as a common denominator for cancer therapy. Nevertheless, many advanced tumors demonstrate de novo or acquired treatment resistance, and ongoing research efforts are focused on improving patient outcomes. Using anti–PD-1 or anti–PD-L1 treatment against earlier stages of cancer is hypothesized to be one such solution. This Review focuses on the development of neoadjuvant (presurgical) immunotherapy in the era of PD-1 pathway blockade, highlighting particular considerations for biological mechanisms, clinical trial design, and pathologic response assessments. Findings from neoadjuvant immunotherapy studies may reveal pathways, mechanisms, and molecules that can be cotargeted in new treatment combinations to increase anti–PD-1 and anti–PD-L1 efficacy.

Methodological issues with adaptation of clinical trial design

2006 ◽  
Vol 5 (2) ◽  
pp. 99-107 ◽  
Author(s):  
H. M. James Hung ◽  
Sue-Jane Wang ◽  
Robert T. O'Neill
Keyword(s):  
Clinical Trial ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Methodological Issues

Integrating radiomics into clinical trial design

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Jessica J. Waninger ◽  
Michael D. Green ◽  
Catherine Cheze Le Rest ◽  
Benjamin Rosen ◽  
Issam El Naqa
Keyword(s):  
Clinical Trial ◽  
Trial Design ◽  
Clinical Trial Design

Avenues to Precision Oncology

2020 ◽  
pp. 36-45
Author(s):  
Alexander Meisel
Keyword(s):  
Precision Medicine ◽  
Trial Design ◽  
Ad Hoc ◽  
Molecular Targets ◽  
Clinical Trial Design ◽  
Predictive Biomarkers ◽  
Precision Oncology ◽  
Companion Diagnostics ◽  
Bona Fide ◽  
The One

Until recently, the clinical management of cancer heavily relied on anatomical and histopathological criteria, with ad hoc guidelines directing the therapeutic choices in specific indications. In the last years, the development and therapeutic implementation of novel anticancer therapies significantly improved the clinical outcome of cancer patients. Nonetheless, such cutting-edge approaches revealed the limitation of the one-size-fits-all paradigm. The newly discovered molecular targets can be exploited either as bona fide targets for subsequent drug development, or as tools to precision medicine, in the form of prognostic and/or predictive biomarkers. This article provides an overview of some of the most recent advances in precision medicine in oncology, with a focus on novel tissue-agnostic anticancer therapies. The definition and implementation of biomarkers and companion diagnostics in clinical trials and clinical practice are also discussed, as well as the changing landscape in clinical trial design.

scholarly journals Creating Price Indexes for Measuring Productivity in Mental Health Care

2001 ◽  
Vol 4 (1) ◽  
Author(s):  
Susan H. Busch ◽  
Ernst R. Berndt ◽  
Richard G. Frank
Keyword(s):  
Mental Health ◽  
Health Care ◽  
Major Depression ◽  
Price Index ◽  
Time Varying ◽  
Measurement Issues ◽  
The Past ◽  
Price Indexes ◽  
Treatment Technologies ◽  
New Treatment

Economists have long suggested that to be reliable, a preferred medical care price index should employ time-varying weights to measure outcomes-adjusted changes in the price of treating an episode of illness. In this article, we report on several years of research developing alternative indexes for the treatment of the acute phase of major depression, for the period 1991–1996. The introduction of new treatment technologies in the past two decades suggests well-known measurement issues may be prominent in constructing such a price index.We report on the results of four successively re

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