Adapt to Translate

The article presents the advantages and limitations of adaptive clinical trials for assessing the effectiveness of medical interventions and specifies the conditions that contributed to their development and implementation in clinical practice. I advance two arguments by discussing different cases of adaptive trials. The normative argument is that responsible adaptation should be taken seriously as a new way of doing clinical research insofar as a valid justification, sufficient understanding, and adequate operational conditions are provided. The second argument is historical. The development of adaptive trials can be related to lessons learned from research in cases of urgency and to the decades-long efforts to end the productivity crisis of pharmaceutical research, which led to the emergence of translational, personalized, and, recently, precision medicine movements.

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Obstacles in conducting clinical trials in the Saudi Arabia

International Journal of Clinical Trials ◽

10.18203/2349-3259.ijct20174864 ◽

2017 ◽

Vol 4 (4) ◽

pp. 166

Author(s):

Salem D. Al Suwaidan ◽

Aseel S. Alsuwaidan

Keyword(s):

Clinical Trials ◽

Saudi Arabia ◽

Clinical Practice ◽

Clinical Research ◽

Strategic Plan ◽

Good Clinical Practice ◽

European Countries ◽

Regulatory Authorities ◽

Research Institution

Background: Conducting clinical research in accordance with the standards of regulatory authorities and within the guidelines of the good clinical practice (GCP) is a matter of concern. It has been noticed that some increment in the conduction of clinical trials outside USA and European countries in the last two decades. The main objective of this study is to identify the magnitude of some obstacles that affect the conduction of clinical trials in accordance with the GCP.Methods: Developing questionnaire in accordance with the criteria of the GCP would make assessment on how to buildup infrastructure including policy and procedures of the research institution. Recommendation of the study is to perform this questionnaire every other year to assess the progress and development of the research institution.Conclusions: To identify good clinical researchers, what sort of obstacle(s) regarding conducting clinical trials, and from these obstacles how to resolve it and build up infrastructure for the research institution and also to establish the strategic plan for the research institution.

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Baseline Characteristics Of Patients With Chronic Myeloid Leukemia In a Prospective Observational Study (SIMPLICITY)

Blood ◽

10.1182/blood.v122.21.4026.4026 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4026-4026 ◽

Cited By ~ 1

Author(s):

Jorge E. Cortes ◽

Rüdiger Hehlmann ◽

Carlo Gambacorti-Passerini ◽

Stuart Goldberg ◽

H. Jean Khoury ◽

...

Keyword(s):

Clinical Trials ◽

Clinical Practice ◽

Chronic Myeloid Leukemia ◽

Clinical Research ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

First Line ◽

Historical Cohort ◽

Prospective Cohorts

Abstract Background Oral BCR-ABL tyrosine kinase inhibitors (TKIs), including imatinib (IM), dasatinib (DAS) and nilotinib (NIL), have improved survival in chronic-phase chronic myeloid leukemia (CP-CML). Few data are available that compare TKIs in daily clinical practice across multiple regions. Methods SIMPLICITY is an ongoing observational cohort study of adult patients with newly diagnosed CP-CML receiving first-line treatment with IM, DAS or NIL in the USA and Europe (Eu) outside of clinical trials (NCT01244750). The primary objective is to assess effectiveness of these TKIs in clinical practice. The study includes three ‘prospective’ cohorts of patients treated with IM, DAS or NIL since 2010 (the study opened after first-line approval of all three TKIs) and a ‘historical’ cohort treated with IM since 2008. Preliminary baseline demographics are presented for prospective cohorts. Results 860 prospective patients (Eu: 32%, USA: 68%) were enrolled through June 20, 2013, receiving IM (n=399), DAS (n=229) or NIL (n=232). Median age at initiation of first-line TKI was 56 years, with significant differences in pairwise comparisons between DAS and IM and NIL and IM (Table). Demographics were consistent across cohorts. Only 30% of patients had Hasford or Sokal scores recorded. ECOG performance status (PS) was available in 54% of patients. The number of baseline comorbidities per patient (mean: 3.2 + 2.7) was balanced across cohorts; 51% of patients presented with ≥3 comorbidities. Patients in the IM cohort had a higher prevalence of gastrointestinal comorbidities (P=.006 and .007 for DAS vs IM and NIL vs IM, respectively), and the NIL cohort had a higher prevalence of musculoskeletal comorbidities than the DAS cohort (P=.015). The proportions of patients with cardiovascular comorbidities were 38%, 36% and 42% in the DAS, NIL and IM cohorts, respectively, consisting primarily of hypertension (31%) and hyperlipidemia (17%) (P>.05 across cohorts). Coronary artery disease was present in 9%, cardiac arrhythmias in 6%, myocardial infarction in 3% and peripheral arterial disease in 2% of patients. The proportion of patients with diabetes was 10%. Clinicians reported effectiveness as the most common reason for TKI selection; familiarity and cost were also cited as reasons for IM selection (P<.001 vs DAS and NIL). Comorbidities were not drivers of TKI selection in this analysis. Conclusions This is the first report from the prospective cohorts of SIMPLICITY. Demographics were consistent across cohorts. Overall, the SIMPLICITY population is older with potentially more comorbidities than patients enrolled in first-line clinical trials with restrictive inclusion criteria (NEJM 2003 348 994; NEJM 2010 362 2260; NEJM 2010 362 2251). Initial TKI selection does not appear to be driven by baseline comorbidity, rather by perceived effectiveness, cost and familiarity. Hasford/Sokal scores were not recorded in the majority of patients prior to starting first-line TKI therapy. Outcomes data are being collected across cohorts that will inform about a multi-region population treated outside clinical trials. Disclosures: Cortes: Ariad: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria, Research Funding. Hehlmann:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding. Gambacorti-Passerini:Bristol-Myers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Goldberg:Bristol-Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Oncology: Honoraria, Research Funding, Speakers Bureau; Ariad: Honoraria, Research Funding, Speakers Bureau. Khoury:Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria; Teva: Honoraria. Mauro:Novartis Oncology: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Speakers Bureau. Michallet:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Paquette:Ariad: Consultancy; Incyte: Consultancy, Honoraria; Novartis: Consultancy. Foreman:ICON Clinical Research: Employment, My employer ICON Clinical Research receives research funding from pharmaceutical companies including manufacturers of CML drugs Other. Mohamed:Bristol-Myers Squibb: Employment. Zyczynski:Bristol-Myers Squibb: Employment. Hirji:Bristol-Myers Squibb: Employment. Davis:Bristol-Myers Squibb: Employment.

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Biomarkers in Mild Stages of Alzheimer’s disease: Utility in clinical practice and their relation with nutritional and lifestyle factors

Functional Foods in Health and Disease ◽

10.31989/ffhd.v6i10.299 ◽

2016 ◽

Vol 6 (10) ◽

pp. 627

Author(s):

Carol Dillon ◽

Patricio Pérez Leguizamon ◽

Silvina Heisecke ◽

Diego M. Castro ◽

Jorge Lopez Camelo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Clinical Practice ◽

Clinical Research ◽

Lifestyle Factors ◽

Clinical Settings ◽

Treatment Methods ◽

Primary Endpoints ◽

Alzheimer’S Disease Dementia

Background: The use of biomarkers in basic and clinical research as well as in clinical practice has become so common that their presence as primary endpoints in clinical trials is now accepted. A biomarker refers to a broad subcategory of medical signs. The aims of this article are to consider the of use biomarkers in Mild stages of Alzheimer’s disease (AD) in research and clinical settings, in addition to defining their utility in clinical practice relating this with nutritional and lifestyle factors as possible treatment. Methods: We searched MEDLINE, PubMed, and AgeLine databases using different keywords.Conclusions: A summary of the utility of biomarkers in AD and nutritional and lifestyle factors used as treatment in mild stages are described.Key words: Biomarkers, Alzheimer’s disease, Dementia, Utility, Clinical practice, Nutritional

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The use of remdesivir outside of clinical trials during the COVID-19 pandemic

Journal of Pharmaceutical Policy and Practice ◽

10.1186/s40545-020-00258-8 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Vesa Halimi ◽

Armond Daci ◽

Nevenka Ridova ◽

Irina Panovska-Stavridis ◽

Milena Stevanovic ◽

...

Keyword(s):

Clinical Trials ◽

Clinical Practice ◽

Antiviral Activity ◽

Clinical Research ◽

Compassionate Use ◽

Expanded Access ◽

Early Access ◽

Scientific Background ◽

Access Scheme

Abstract With a scientific background from filoviruses, paramyxoviruses, SARS-CoV, and MERS-CoV, remdesivir entered into the COVID-19 battle to become one of the favorable therapeutic candidates with potential antiviral activity in the treatment of this disease. Globally, remdesivir was accessed and investigated through clinical research (clinical trials) and clinical practice (compassionate use, expanded access, early access scheme, and emergency use). Currently, remdesivir approval status differs between states. This paper aims to review and analyze regulatory approaches for accessing and investigating remdesivir, by communicating regulatory variability between countries in terms of terminology, modalities, and protocols.

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Why was early therapeutic research on psychedelic drugs abandoned?

Psychological Medicine ◽

10.1017/s0033291721004207 ◽

2021 ◽

pp. 1-6

Author(s):

Wayne Hall

Keyword(s):

Clinical Trials ◽

North America ◽

Clinical Research ◽

Terminal Illness ◽

Pharmaceutical Research ◽

War On Drugs ◽

Controlled Clinical Trials ◽

Psychedelic Drugs ◽

The 1950S ◽

1960S And 1970S

Abstract Background Advocates of the therapeutic use of psychedelic drugs have argued that a promising approach to treatment was prematurely abandoned in the 1960s primarily because of Richard Nixon's ‘War on Drugs’. This paper (1) briefly describes research in the 1950s and 1960s in North America on the use of LSD to treat alcohol dependence, anxiety in terminal illness, and anxiety and depression; and (2) discusses the factors that led to its abandonment. Method An analysis of historical scholarship on psychedelic research in the 1950s, 1960s and 1970s in North America. Results Research on psychedelic drugs in psychiatry was abandoned for a number of reasons that acted in concert. A major factor was that clinical research on psychedelic drugs was caught up in the tighter regulation of pharmaceutical research after the Thalidomide disaster in 1963. Psychedelic drugs also presented special challenges for randomised, placebo-controlled clinical trials in the 1970s that were not as positive as the claims made by their advocates in the 1950s and 1960s. Clinical research became more difficult after 1965 when Sandoz ceased providing psychedelic drugs for research and their nonmedical use was prohibited in 1970. Conclusions The demise of psychedelic drug research was not solely due to the ‘War on Drugs’. It was hastened by tighter regulation of pharmaceutical research, the failure of controlled clinical trials to live up to the claims of psychedelic advocates, and the pharmaceutical industry's lack of interest in funding clinical trials.

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Placebo Orthodoxy in Clinical Research II: Ethical, Legal, and Regulatory Myths

The Journal of Law Medicine & Ethics ◽

10.1111/j.1748-720x.1996.tb01860.x ◽

1996 ◽

Vol 24 (3) ◽

pp. 252-259 ◽

Cited By ~ 76

Author(s):

Benjamin Freedman ◽

Kathleen Cranley Glass ◽

Charles Weijer

Keyword(s):

Clinical Trials ◽

Clinical Research ◽

The United States ◽

Human Experimentation ◽

Medical Interventions ◽

Placebo Controls ◽

United States Food ◽

Considerable Controversy ◽

States Food ◽

Continued Use

Placebo-controlled trials are held by many, including regulators at agencies like the United States Food and Drug Administration (FDA), to be the gold standard in the assessment of new medical interventions. Yet the use of placebo controls in clinical trials has been the focus of considerable controversy. In this two-part article, we challenge a number of common beliefs concerning the value of placebo controls. Part I critiques statistical and other scientific justifications for the use of placebo controls in clinical research. The continued use of placebo controls in clinical trials on diseases for which accepted treatment exists raises equally important ethical, legal, and regulatory issues for which various justifications have been given. Defense of this practice relies on normative as well as empirical myths.In their attack on the prevailing use of placebo controls, Kenneth Rothman and Karin Michels emphasize that this practice stands in violation of the World Medical Association's guidelines on the ethics of human experimentation, most commonly known as the Helsinki Declaration.

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Good Clinical Practice (GCP) – an alternative, unarticulated narrative

Indian Journal of Medical Ethics ◽

10.20529/ijme.2021.064 ◽

2021 ◽

pp. 01-04

Author(s):

Samir Malhotra

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Clinical Practice ◽

Clinical Research ◽

Gold Standard ◽

Scientific Community ◽

Good Clinical Practice ◽

Official Document ◽

Market Expansion ◽

New Drug Development

GCP has become the gold-standard for clinical research; initiated as a guideline pertaining to new drug development, it became a law in many countries, extending its scope to include all research. GCP is an excellent document that outlines the responsibilities of stakeholders involved in clinical research. Widely acclaimed, and deservedly so, it is considered as the “go-to” document whenever questions arise during the conduct of a clinical trial. This article presents another narrative, one that has not been articulated so far. Irrespective of whether we consider GCP as a law or a guideline, it is viewed as an “official” document, without the overt realisation that this was actually an initiative of the pharmaceutical industry, the “masters of mankind”. While the stress on documentation and monitoring in GCP was justified, its over-interpretation led to increased costs of clinical trials, with the result that smaller companies find it difficult to conduct the already expensive trials. GCP as an idea is now so entrenched within the scientific community that the real aims which led to its birth and that can be mined from the ICH website, like the need for market expansion, have remained largely unnoticed and undocumented, and are being expressed here.

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Impact of COVID-19 pandemic on design and conduct of clinical trials: developing best practices based on lessons learned for risk and change management

International Journal of Clinical Trials ◽

10.18203/2349-3259.ijct20210148 ◽

2021 ◽

Vol 8 (1) ◽

pp. 79

Author(s):

Marina A. Malikova

Keyword(s):

Clinical Trials ◽

Best Practices ◽

Clinical Research ◽

Risk Mitigation ◽

Geographic Location ◽

Study Drug ◽

Lessons Learned ◽

Drug Mechanism ◽

Push Forward ◽

Study Teams

The coronavirus disease 2019 (COVID- 19) pandemic is disrupting clinical research in most of the world. We have seen an immediate impact on clinical trials due to challenges coming from the COVID-19 travel bans, hospitals/clinics’ visitation restrictions, social distancing precautions and shifting operations to work remotely on a short notice. These factors have translated into the issues challenging clinical trials such as operations, milestones, budgets, data integrity, etc. Given the complex risk/benefit considerations associated with each specific clinical trial, there is no single solution to manage the risks in clinical trials conduct due to COVID-19. Each trial is unique with respect to patient population, study drug mechanism of action, concomitant medications, and geographic location needs. It is important to continue to engage the networks and communities to push forward with creative risk mitigation and develop solutions during this challenging time. Risk assessment should be a continuous and living process as the situation evolves over the coming weeks to months. Routine and ongoing cross checks with study teams are already proving to maintain alignment on key timelines, critical risk points and other study specific challenges as we are moving towards de-centralized settings in the conduct of clinical trials. We have analyzed lessons learned and attempted to develop best practices to mitigate risks and adjust clinical research operations during this unprecedented time.

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Journey across epidemiology’s third variables: an anesthesiologist’s guide for successfully navigating confounding, mediation, and effect modification

Regional Anesthesia and Pain Medicine ◽

10.1136/rapm-2020-101984 ◽

2021 ◽

pp. rapm-2020-101984 ◽

Cited By ~ 1

Author(s):

Joshua Levy ◽

Rebecca Lebeaux ◽

Brock Christensen ◽

Tor Tosteson ◽

Yvon Bryan

Keyword(s):

Clinical Trials ◽

Clinical Study ◽

Clinical Research ◽

Patient Outcomes ◽

Clinical Studies ◽

Effect Modification ◽

Medical Interventions ◽

Patient Health ◽

Independent Variable ◽

The Relationship

Observational clinical research studies aim to assess which exposures (treatments or other factors; independent variable) affect patient outcomes (dependent variable). These exposures include medical interventions in situations where clinical trials are not possible or prior to their conduct and completion. However, the assessment of the relationship between exposures and outcomes is not straightforward, as other variables may need to be considered prior to reaching valid conclusions. Here, we present three hypothetical scenarios in regional anesthesia to review the epidemiological concepts of confounding, mediation, and effect modification. Understanding these concepts is critical for assessing the design, analysis, and interpretation of clinical studies. These terms may be confusing to anesthesiologists and researchers alike, where such confusion could affect the conclusions of a clinical study, mislead the target audience, and ultimately impact patient health.

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Lewy Body Dementia Association’s Industry Advisory Council: proceedings of the second annual meeting

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00868-7 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Jennifer G. Goldman ◽

Bradley F. Boeve ◽

Melissa J. Armstrong ◽

Doug R. Galasko ◽

James E. Galvin ◽

...

Keyword(s):

Clinical Trials ◽

Clinical Research ◽

Annual Meeting ◽

Lewy Body ◽

Lewy Body Dementia ◽

Lessons Learned ◽

Advisory Council ◽

Collaborative Group

AbstractIn 2019, the Lewy Body Dementia Association formed an Industry Advisory Council to bring together a collaborative group of stakeholders with the goal of accelerating clinical research into Lewy body dementia treatments. At the second annual meeting of the Industry Advisory Council, held virtually on June 18, 2020, the key members presented ongoing and planned efforts toward the council’s goals. The meeting also featured a discussion about the effects of the COVID-19 pandemic on Lewy body dementia clinical research, lessons learned from that experience, and how those lessons can be applied to the design and conduct of future clinical trials. This report provides a brief summary of the meeting proceedings with a focus on efforts to improve and adapt future Lewy body dementia clinical research.

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