Issues In Design Of Clinical Trials Research Articles

Clinical trial design, endpoints and regulatory considerations in heart failure

Following the withdrawal of flosequinan in the early 1990s due to heightened mortality and fatal arrhythmia risks, regulatory agencies have demanded evidence of the efficacy of novel treatments in managing heart failure, with mortality and morbidity endpoints becoming more stringent criteria for approval. In recent times, regulatory agencies have exhibited a greater willingness to permit the evaluation of functional capacity as an efficacy endpoint, albeit limited to specific patient groupings. Consequently, a novel therapeutic intervention for heart failure may be granted approval provided that it enhances survival rates, decreases length of hospital stays, and/or safely improves functional capacity. This article reviews clinical trial design, trial endpoints and regulatory issues in heart failure trials.

A Clinical and Preclinical Assessment of Clinical Trials for Dry Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness for the elderly in high-income countries. Although multivitamin antioxidant nutrients can slow the progression of intermediate "dry" or nonneovascular AMD, no treatment can halt or reverse any stage of dry disease. Multiple biologic pathways have been implicated in AMD pathobiology, including the complement pathway. These pathways have been targeted by various approaches in clinical trials. To date, no treatment has reached their prespecified primary end point in 2 phase III trials, a requirement by the US Food and Drug Administration for a new drug approval. Here, we describe perspectives on the failures and possible successes of various clinical trials that will guide further investigation. These perspectives will also discuss clinical trial design issues to consider in future investigations, and how recent insights into AMD pathobiology might both provide additional explanation for trials not reaching the prespecified primary end points and offer direction for identifying prioritized treatment targets.

Effects of dose change on the success of clinical trials

The search for disease modifying therapies in Alzheimers disease (AD) has recently led to promising results but also revealed design issues in clinical trials themselves. Of particular importance is the potential statistical challenges that can arise when dosages change after an interim analysis, which is not uncommon in contemporary AD trials. Following the recent Aducanumab trials, we sought to study the implications of dose changes on the statistical power of an AD trial. We conducted extensive simulations to calculate statistical power when the relationship between treatment effect size and time is linear or non-linear, and the investigated drug has delayed treatment effect or not. Statistical power depends on many design factors including the dose change time, correlation, population homogeneity, and treatment effect time. We recommend that researchers conduct simulation studies at the interim analysis to justify the modified sample size and/or follow-up time modification meanwhile the type I and II error rates are controlled.

Powering Bias and Clinically Important Treatment Effects in Randomized Trials of Critical Illness.

Recurring issues in clinical trial design may bias results toward the null, yielding findings inconclusive for treatment effects. This study evaluated for powering bias among high-impact critical care trials and the associated risk of masking clinically important treatment effects. Secondary analysis of multicenter randomized trials of critically ill adults in which mortality was the main endpoint. Trials were eligible for inclusion if published between 2008 and 2018 in leading journals. Analyses evaluated for accuracy of estimated control group mortality, adaptive sample size strategy, plausibility of predicted treatment effect, and results relative to the minimal clinically important difference. The main outcome was the mortality risk difference at the study-specific follow-up interval. None. Of 101 included trials, 12 met statistical significance for their main endpoint, five for increased intervention-associated mortality. Most trials (77.3%) overestimated control group mortality in power calculations (observed minus predicted difference, -6.7% ± 9.8%; p < 0.01). Due to this misestimation of control group mortality, in 14 trials, the intervention would have had to prevent at least half of all deaths to achieve the hypothesized treatment effect. Seven trials prespecified adaptive sample size strategies that might have mitigated this issue. The observed risk difference for mortality fell within 5% of predicted in 20 trials, of which 16 did not reach statistical significance. Half of trials (47.0%) were powered for an absolute risk reduction greater than or equal to 10%, but this effect size was observed in only three trials with a statistically significant treatment benefit. Most trials (67.3%) could not exclude clinically important treatment benefit or harm. The design of most high-impact critical care trials biased results toward the null by overestimating control group mortality and powering for unrealistic treatment effects. Clinically important treatment effects often cannot be excluded.

Study design considerations for sleep-disordered breathing devices.

In recent years, sleep-disordered breathing (SDB) has been recognized as a prevalent but under-diagnosed condition in adults and has prompted the need for new and better diagnostic and therapeutic options. To facilitate the development and availability of innovative, safe and effective SDB medical device technologies for patients in the United States, the US Food and Drug Administration collaborated with six SDB-related professional societies and a consumer advocacy organization to convene a public workshop focused on clinical investigations of SDB devices. Sleep medicine experts discussed appropriate definitions of terms used in the diagnosis and treatment of SDB, the use of home sleep testing versus polysomnography, clinical trial design issues in studying SDB devices, and current and future trends in digital health technologies for diagnosis and monitoring SDB. The panel's breadth of clinical expertise and experience across medical specialties provided useful and important insights regarding clinical trial designs for SDB devices.

Acoustic trauma from continuous noise: Minimum exposures, issues in clinical trial design, and comments on magnetic resonance imaging exposures.

Acoustic trauma (AT) is permanent hearing loss after a single noise exposure. A few human cases resulting from continuous, i.e., nonimpulsive noise, have been reported as reviewed by Ward [(1991). "Hearing loss from noise and music," presented at Audio Engineering Society, New York, October 4-8]. This paper updates that review by examining 11 cases in nine reports, from 1950 to 2006, with the intention of determining minimum exposures that may cause AT, including the potential risk of exposure to noise from magnetic resonance imaging machines. Diffuse-field related levels above 120 dBA for 10 s or more, or above 130 dBA for 2-3 s (values well above OSHA's unprotected exposure limits), can lead to AT. These cases appear to represent a susceptible fraction of the population, because much more intense exposures (e.g., 130 dBA for 32 min) have been tolerated by groups of volunteers who suffered only temporary threshold shifts. AT from continuous noise is unlikely to occur in OSHA-compliant hearing conservation programs, and probably rare enough in the general civilian population that clinical trials of drugs aimed at treating it are unlikely to be practical. AT from impulse noise, such as gunfire, which is specifically not the topic of the current work, is more amenable to clinical trials, especially in military settings.

Clinical Trial Design, Endpoints and Regulatory Considerations in Heart Failure

After the withdrawal of flosequinan in the early 1990’s, because of an increased risk of mortality and fatal arrhythmias, the bar for the approval of new drugs in heart failure has been raised and regulatory agencies have requested evidence for the efficacy of new treatments on mortality and morbidity end-points. However, more recently, regulatory agencies have become more open to include the assessment of functional capacity as an efficacy endpoint, at least in selected subgroups of patients. Therefore, a new therapy for the treatment of heart failure can be approved if it improves survival and/or reduces hospitalisations or if it safely improves functional capacity. This article reviews clinical trial design, trial endpoints and regulatory issues in Heart Failure trials.

Protecting the ischaemic penumbra as an adjunct to thrombectomy for acute stroke.

After ischaemic stroke, brain damage can be curtailed by rescuing the 'ischaemic penumbra' - that is, the severely hypoperfused, at-risk but not yet infarcted tissue. Current evidence-based treatments involve restoration of blood flow so as to salvage the penumbra before it evolves into irreversibly damaged tissue, termed the 'core'. Intravenous thrombolysis (IVT) can salvage the penumbra if given within 4.5 h after stroke onset; however, the early recanalization rate is only ~30%. Direct removal of the occluding clot by mechanical thrombectomy considerably improves outcomes over IVT alone, but despite early recanalization in > 80% of cases, ~50% of patients who receive this treatment do not enjoy functional independence, usually because the core is already too large at the time of recanalization. Novel therapies aiming to 'freeze' the penumbra - that is, prevent core growth until recanalization is complete - hold potential as adjuncts to mechanical thrombectomy. This Review focuses on nonpharmacological approaches that aim to restore the physiological balance between oxygen delivery to and oxygen demand of the penumbra. Particular emphasis is placed on normobaric oxygen therapy, hypothermia and sensory stimulation. Preclinical evidence and early pilot clinical trials are critically reviewed, and future directions, including clinical translation and trial design issues, are discussed.

Is intraperitoneal chemotherapy still an acceptable option in primary adjuvant chemotherapy for advanced ovarian cancer?

The role of intraperitoneal (i.p.) chemotherapy in treating newly diagnosed advanced epithelial ovarian cancer (EOC) has been the subject of controversy for almost three decades. Three large intergroup phase III trials (GOG 104, 114, 172) have demonstrated a survival benefit associated with i.p. over intravenous (i.v.) therapy in advanced, low-volume EOC. Despite the positive clinical trial results and a subsequent National Cancer Institute alert in 2006, i.p. treatment has not been widely accepted as the standard of care in the United States and is infrequently used in Europe. The hesitancy of clinicians to use i.p. therapy is likely attributed to higher toxicity, inconvenience, catheter complications, and clinical trial design issues. On the other hand, In a long-term follow-up report from these trials, we showed that the effect of i.p. chemotherapy extends beyond 10 years and that the more cycles of i.p. therapy portends for improved survival over similar cycles of i.v. therapy with younger patients having a higher likelihood of completing 6 cycles of i.p. treatment. More recently, a fourth randomized phase III trial, GOG 252, failed to show a survival advantage associated with i.p. cisplatin and i.p. carboplatin over dose-dense i.v. paclitaxel and carboplatin. Since the use of bevacizumab was incorporated in all arms of the study, this anti-vascular agent may have equalized or negated the clinical advantage of i.p. chemotherapy and dose-dense weekly as suggested in GOG 262. We are awaiting the results of the Asian iPocc trial comparing dose-dense paclitaxel to i.p. chemotherapy without bevacizumab, though the differences in the tumor histology and pharmacokinetics in Asian versus non-Asian patients may influence the interpretation of the results worldwide. In this review, we review the polarizing opinions on the relevance of i.p. therapy in today’s clinical armamentarium. Never before, have oncologists examined the same datasets with divergent conclusions. This topic is confusing to patients and clinicians alike and has led to inconsistent guidelines and reimbursement. However, it might be time to move on. Now more than ever, we have novel combinations to personalize upfront treatments for advanced ovarian cancer. In addition to i.p. therapy we also need to focus on targeted therapy, biomarkers, survivorship, and the sequencing of therapy.

A Structured Review of Antithrombotic Therapy in Peripheral Artery Disease With a Focus on Revascularization: A TASC (InterSociety Consensus for the Management of Peripheral Artery Disease) Initiative.

Peripheral artery disease affects >200 million people worldwide and is associated with significant limb and cardiovascular morbidity and mortality. Limb revascularization is recommended to improve function and quality of life for symptomatic patients with peripheral artery disease with intermittent claudication who have not responded to medical treatment. For patients with critical limb ischemia, the goals of revascularization are to relieve pain, help wound healing, and prevent limb loss. The baseline risk of cardiovascular and limb-related events demonstrated among patients with stable peripheral artery disease is elevated after revascularization and related to atherothrombosis and restenosis. Both of these processes involve platelet activation and the coagulation cascade, forming the basis for the use of antiplatelet and anticoagulant therapies to optimize procedural success and reduce postprocedural cardiovascular risk. Unfortunately, few high-quality, randomized data to support use of these therapies after peripheral artery disease revascularization exist, and much of the rationale for the use of antiplatelet agents after endovascular peripheral revascularization is extrapolated from percutaneous coronary intervention literature. Consequently, guideline recommendations for antithrombotic therapy after lower limb revascularization are inconsistent and not always evidence-based. In this context, the purpose of this structured review is to assess the available randomized data for antithrombotic therapy after peripheral arterial revascularization, with a focus on clinical trial design issues that may affect interpretation of study results, and highlight areas that require further investigation.

Current Therapeutic Cannabis Controversies and Clinical Trial Design Issues.

This overview covers a wide range of cannabis topics, initially examining issues in dispensaries and self-administration, plus regulatory requirements for production of cannabis-based medicines, particularly the Food and Drug Administration “Botanical Guidance.” The remainder pertains to various cannabis controversies that certainly require closer examination if the scientific, consumer, and governmental stakeholders are ever to reach consensus on safety issues, specifically: whether botanical cannabis displays herbal synergy of its components, pharmacokinetics of cannabis and dose titration, whether cannabis medicines produce cyclo-oxygenase inhibition, cannabis-drug interactions, and cytochrome P450 issues, whether cannabis randomized clinical trials are properly blinded, combatting the placebo effect in those trials via new approaches, the drug abuse liability (DAL) of cannabis-based medicines and their regulatory scheduling, their effects on cognitive function and psychiatric sequelae, immunological effects, cannabis and driving safety, youth usage, issues related to cannabis smoking and vaporization, cannabis concentrates and vape-pens, and laboratory analysis for contamination with bacteria and heavy metals. Finally, the issue of pesticide usage on cannabis crops is addressed. New and disturbing data on pesticide residues in legal cannabis products in Washington State are presented with the observation of an 84.6% contamination rate including potentially neurotoxic and carcinogenic agents. With ongoing developments in legalization of cannabis in medical and recreational settings, numerous scientific, safety, and public health issues remain.

Transgender People and HIV Prevention: What We Know and What We Need to Know, a Call to Action.

:Transgender people have been disproportionally affected by HIV, particularly transgender women. Their increased vulnerability to HIV is due to multiple issues, including biological (eg, increased efficiency of HIV transmission through receptive anal sex), epidemiological (eg, increased likelihood of having HIV-infected partners), structural (eg, social stigma limiting employment options), and individual factors (eg, internalized stigma leading to depression and substance use and risk-taking behaviors). There have been limited culturally appropriate HIV prevention interventions for transgender people, with many key prevention studies (eg, the iPrEx PrEP study) enrolling transgender women in a study focusing on men who have sex with men. This has resulted in limited understanding of the optimal ways to decrease transgender people's risk for HIV acquisition. The current supplement of JAIDS is designed to review what is known about HIV prevention for transgender people and to highlight new insights and best practices. The study reviews recent epidemiologic data, the pharmacology of HIV prophylactic agents in individuals who may be using exogenous hormones, and several recent multi-component interventions designed to address the lived experience of transgender people. Additionally, the study reviews the work going on at the NIH to address transgender health in general and HIV prevention in specific, as well as two important papers related to clinical trial design issues and the ethical conduct of research in this frequently disenfranchised population. It is the hope of the HIV Prevention Trials Network (HPTN) that this supplement will promote new knowledge around transgender health and the requisite issues that need to be addressed in order to conduct optimal clinical trials. The ultimate hope is that the information distilled in this supplement will inform investigators, clinicians, and public health officials in order to design further research to develop optimal prevention interventions for transgender people and to implement these interventions in ways that are culturally congruent and health promoting.

Clinical Trial Design Issues in Systemic Sclerosis: an Update

Systemic sclerosis (scleroderma, SSc) is a multisystem disease characterized by vasculopathy, autoimmunity, and fibrosis. SSc has the highest disease-related mortality rate among the rheumatologic illnesses. In the USA, there remains no FDA-approved therapy. As our understanding of SSc pathogenesis improves, targeted therapies interrupting key pathways and mediators will be studied in clinical trials. However, clinical trials in SSc are fraught with challenges. Validated clinical outcome measures do not exist for all disease manifestations. It can be difficult to discern disease activity from damage. SSc is highly heterogeneous, with multiple different phenotypes, and predicting who will have progressive disease is not currently well understood. Biomarkers are in early stages of development and do not represent surrogate outcomes at this time. Given that SSc is uncommon, studies of similar disease aspects or populations can lead to competition for patients. This review will focus on current issues in SSc clinical trial design.

S06.2 Herpes simplex virus vaccine development: pipelines and possibilities

Genital herpes simplex virus (HSV) infection causes recurrent genital ulcers, neonatal herpes, and increases the risk of HIV acquisition. HSV-2, the most common cause of genital herpes, is highly prevalent worldwide, with an estimated 417 million people infected between the ages of 15–49. The urgent need for a prophylactic vaccine against genital HSV has been long recognized. Multiple glycoprotein subunit vaccines candidates have been tested but none have successfully prevented HSV-2 genital ulcer disease in phase III trials. Despite these findings, there is strong interest in pursuing novel vaccine platforms to induce immune responses to protect against HSV acquisition. Therapeutic vaccines to reduce genital symptoms and viral shedding in persons already infected with HSV-2 are also being tested in early phase clinical trials. The global STI vaccine roadmap provided a framework for research priorities to move the HSV vaccine field forward. This presentation will review 1) lessons from prior clinical trials of HSV vaccines, 2) new insights into immunology of HSV infection, 3) current status of HSV vaccine pipeline, with an emphasis on candidates currently in clinical trials and 4) discussion of clinical trial design issues unique to HSV.

Clinical Development and Trial Design of Biosimilar Products: A Japanese Perspective

In recent years, development of biosimilar products has attracted considerable attention. Because of the structural complexity of biologics, it is difficult to demonstrate that a biosimilar product is identical to the reference product. Therefore, for the development of biosimilar products, we need to adopt an approach that is different from generic product development. In this article, we discuss the guidelines for the development of biosimilar products along with the case examples of biosimilar product development in Japan. In addition, we discuss several issues of clinical trial design for demonstrating biosimilarity to a reference product.

NCCN Working Group report: designing clinical trials in the era of multiple biomarkers and targeted therapies.

Defining treatment-susceptible or -resistant populations of patients with cancer through the use of genetically defined biomarkers has revolutionized cancer care in recent years for some disease/patient groups. Research continues to show that histologically defined diseases are diverse in their expression of unique mutations or other genetic alterations, however, which presents opportunities for the development of personalized cancer treatments, but increased difficulty in testing these therapies, because potential patient populations are divided into ever smaller numbers. To address some of the growing challenges in biomarker development and clinical trial design, NCCN assembled a group of experts across specialties and solid tumor disease types to begin to define the problems and to consider alternate ways of designing clinical trials in the era of multiple biomarkers and targeted therapies. Results from that discussion are presented, focusing on issues of clinical trial design from the perspective of statisticians, clinical researchers, regulators, pathologists, and information developers.

Joint WFH-ISTH session: issues in clinical trial design.

Haemophilia therapy is experiencing an unprecedented expansion in the number and novelty of clotting factor concentrates. Every product must be licensed by regulatory authorities, primarily on the basis of its safety and efficacy profiles. The low prevalence of haemophilia, and other inherited bleeding disorders, presents a significant challenge to patient recruitment for preauthorization clinical trials, especially given the low frequency of inhibitory antibodies, the major adverse event related to clotting factor exposure. Other challenges include a lack of harmonization between the major regulatory authorities in certain key areas, the selection of laboratory monitoring methodologies and the difficulty in obtaining high-quality phase IV safety data following authorization. These aspects will be reviewed in this session, which will also highlight the roles played by the World Federation of Hemophilia and International Society on Thrombosis and Haemostasis in the promotion of these discussions.

Studying the Effects of Classic Hallucinogens in the Treatment of Alcoholism: Rationale, Methodology, and Current Research with Psilocybin

Recent developments in the study of classic hallucinogens, combined with a re-appraisal of the older literature, have led to a renewal of interest in possible therapeutic applications for these drugs, notably their application in the treatment of addictions. This article will first provide a brief review of the research literature providing direct and indirect support for the possible therapeutic effects of classic hallucinogens such as psilocybin and lysergic acid diethylamide (LSD) in the treatment of addictions. Having provided a rationale for clinical investigation in this area, we discuss design issues in clinical trials using classic hallucinogens, some of which are unique to this class of drug. We then discuss the current status of this field of research and design considerations in future randomized trials.

The next 10 years in interventional cardiology

Interview by Louise Rishton, Commissioning EditorGregg Stone is Professor of Medicine at Columbia University, Director of Cardiovascular Research and Education at the Center for Interventional Vascular Therapies at Columbia University Medical Center, and Co-Director of Medical Education and Research at the Cardiovascular Research Foundation in New York (NY, USA). He has served as the principle investigator for more than 70 national and international multicenter randomized trials, has authored >1000 book chapters, manuscripts and abstracts published in peer-reviewed journals, and has delivered >2000 invited lectures around the world. His areas of expertise include interventional therapies of acute coronary syndromes and myocardial infarction; drug-eluting stents; adjunct pharmacology; new device angioplasty including distal embolic protection, thrombectomy, vascular brachytherapy and stent grafts; intravascular imaging; saphenous vein graft therapies; chronic total occlusions; vulnerable plaque; contrast nephropathy; mitral valve therapies; clinical trial design and regulatory issues. Along with Martin Leon, Stone is the director of Transcatheter Cardiovascular Therapeutics, the world’s largest symposium devoted to interventional cardiology and vascular medicine. Stone’s medical practice is devoted to interventional cardiology procedures at Columbia University Medical Center.

Designing an adaptive phase II/III trial to evaluate efficacy, safety and immune correlates of new TB vaccines in young adults and adolescents

This article summarises the consensus arrived at a meeting of South African and international stakeholders on specific late phase clinical trial design issues integrating the investigation of immune correlates as an integral part of a phase III protocol for a preventative TB vaccine in an adolescent/adult population. The challenge ahead is to optimize the planning for phase 3 TB vaccine preventative trials, under resource constraints, given that there are no known correlates of protection to shorten and increase the efficiencies of efficacy trials. An adaptive, multi-arm, group sequentially designed trial protocol is proposed incorporating design features that address uncertainties arising from both advances in the field and dynamic study populations and disease states. Such a design allows modifications that protect research subjects, save time, and maximize the impact of scarce financial resources. Further, the protocol underwent joint review by regulators from several African nations at a meeting of the African Vaccine Regulatory Forum (AVAREF), a regional regulatory harmonization initiative, and recommendations are included.