Ethical Principles Do Not Support Mandatory Preanesthesia Pregnancy Screening Tests: A Narrative Review.

Respect for patient autonomy is a pillar of medical ethics, manifested predominantly through informed consent. Mandatory (routine) nonconsented preoperative urine pregnancy testing does not adequately respect patient autonomy, is potentially coercive, and has the potential to cause harm medically, psychologically, socially, and financially. Inaccuracies in pregnancy testing can result in false-positive and false-negative results, especially in early pregnancy. There is substantial scientific evidence that anesthesia is not harmful to the fetus, raising the question of whether pregnancy testing provides substantial benefit to the patient. Not performing a preanesthesia pregnancy test has not been associated with significant medicolegal consequences. We review the ethical implications of mandatory preanesthesia pregnancy testing in light of these facts.

Off-Label Use vs Off-Label Marketing of Drugs: Part 1: Off-Label Use-Patient Harms and Prescriber Responsibilities.

Once medical drugs and devices are approved for marketing by the FDA they can legally be used for purposes and in ways other than the ones for which they have been tested and approved. However, it is illegal for manufacturers to advertise or promote such unapproved uses of the drugs and devices. Part 1 of this review focuses on off-label use of FDA-approved therapies. Part 2 addresses illegal off-label marketing of drugs and devices. While off-label use can be beneficial to patients, unless carefully undertaken off label use may undermine the important safety mission of the FDA, can expose patients to elevated risks without proven benefits (or possibly no benefit), and can reduce motivation of companies to study the safety and risks of off-label use of therapies. These problems are further amplified when off-label use occurs among very vulnerable patient populations such as the elderly, patients with mental health disorders, pregnant women and pediatric patients. This review considers ethical issues in off-label use, as well as important steps for physicians considering an off-label prescription of a drug or device.

Data Safety and Monitoring Boards Should Be Required for Both Early- and Late-Phase Clinical Trials.

Phase I and II clinical trials increasingly combine therapeutic and toxicity endpoints. Recently, therapeutic agents have even achieved U.S. Food and Drug Agency approval based on early phase trials alone. These developments point to new challenges in assuring the safety of human research subjects and patients. Given their size and use of real-world patients, phase III studies warrant independent monitoring by a Drug Safety Monitoring Board (DSMB). Requirements should also be extended to include many phase I and II clinical trials. Measures should be taken to establish and standardize minimum qualifications for service on a DSMB.

Update to Drugs, Devices, and the FDA: How Recent Legislative Changes Have Impacted Approval of New Therapies.

Two major legislative actions since 2015, the 21st Century Cures Act of 2016 and the U.S. Food and Drug Administration (FDA) Reauthorization Act of 2017, contain significant provisions that potentially streamline drug development times, and by extension, may reduce costs. Evidence suggests, however, that development times have already been significantly affected by previous legislation and FDA programs, through accelerated approval pathways and adoption of more flexible definitions of clinical evidence of efficacy. The COVID-19 pandemic is pushing researchers and commercial entities to further test the limits of drug and vaccine development times and approvals, at an as yet unknown level of risk to patients. COVID-19 drug and vaccine trials are even now making use of accelerated drug approval programs, blended trials, and adaptive trial design to accelerate approval of therapeutics in the pandemic.

"Warp Speed" Operations in the COVID-19 Pandemic: Moving Too Quickly?

The COVID-19 (coronavirus disease-2019) pandemic has presented unprecedented challenges to regulatory organizations, the biotech and pharmaceutical industry, and the publishing industry. This Translational Perspectives paper attempts to highlight some of the challenges and perils of moving extraordinarily fast in an effort to save human lives in the midst of a global pandemic. As with the development of all new therapeutic approaches, it will take time to assess the risks and benefits of developing new therapies at "warp speed".

The anesthesiologist and global climate change: an ethical obligation to act.

PURPOSE OF REVIEW: Pollution and global warming/climate change contribute to one-quarter of all deaths worldwide. Global healthcare as a whole is the world's fifth largest emitter of greenhouse gases, and anesthetic gases, intravenous agents and supplies contribute significantly to the overall problem. It is the ethical obligation of all anesthesiologists to minimize the harmful impact of anesthesia practice on environmental sustainability. RECENT FINDINGS: Focused programs encouraging judicious selection of the use of anesthetic gas agents has been shown to reduce CO2 equivalent emissions by 64%, with significant cost savings. Good gas flow management reduces nonscavenged anesthetic gas significantly, and has been shown to decrease the consumption of volatile anesthetic agent by about one-fifth. New devices may allow for recapture, reclamation and recycling of waste anesthetic gases. For propofol, a nonbiodegradable, environmentally toxic agent, simply changing the size of vials on formulary has been shown to reduce wasted agent by 90%. SUMMARY: The 5 R's of waste minimization in the operating room (OR) (Reduce, Reuse, Recycle, Rethink and Research) have proven benefit in reducing the environmental impact of the practice of anesthesiology, as well as in reducing costs.

Limitations of Animal Studies for Predicting Toxicity in Clinical Trials: Part 2: Potential Alternatives to the Use of Animals in Preclinical Trials.

Dramatically rising costs in drug development are in large part because of the high failure rates in clinical phase trials. The poor correlation of animal studies to human toxicity and efficacy have led many developers to question the value of requiring animal studies in determining which drugs should enter in-human trials. Part 1 of this 2-part series examined some of the data regarding the lack of concordance between animal toxicity studies and human trials, as well as some of the potential reasons behind it. This second part of the series focuses on some alternatives to animal trials (hereafter referred to as animal research) as well as current regulatory discussions and developments regarding such alternatives.

Ethical Issues in Organ Transplantation at End of Life: Defining Death.

End-of-life vital organ transplantation involves singular ethical issues, because survival of the donor is impossible, and organ retrieval is ideally as close to the death of the donor as possible to minimize organ ischemic time. Historical efforts to define death have been met with confusion and discord. Fifty years on, the Harvard criteria for brain death continue to be problematic and now face significant legislative efforts to limit their authority.

Phase II Trials in Drug Development and Adaptive Trial Design.

Phase II clinical studies represent a critical point in determining drug costs, and phase II is a poor predictor of drug success: >30% of drugs entering phase II studies fail to progress, and >58% of drugs go on to fail in phase III. Adaptive clinical trial design has been proposed as a way to reduce the costs of phase II testing by providing earlier determination of futility and prediction of phase III success, reducing overall phase II and III trial sizes, and shortening overall drug development time. This review examines issues in phase II testing and adaptive trial design.

Limitations of Animal Studies for Predicting Toxicity in Clinical Trials: Is it Time to Rethink Our Current Approach?

Animal testing is used in pharmaceutical and industrial research to predict human toxicity, and yet analysis suggests that animal models are poor predictors of drug safety in humans. The cost of animal research is high-in dollars, delays in drug approval, and in the loss of potentially beneficial drugs for human use. Human subjects have been harmed in the clinical testing of drugs that were deemed safe by animal studies. Increasingly, investigators are questioning the scientific merit of animal research. This review discusses issues in using animals to predict human toxicity in pharmaceutical development. Part 1 focuses on scientific concerns over the validity of animal research. Part 2 will discuss alternatives to animal research and their validation and use in production of human pharmaceuticals.

Expanded Patient Access to Investigational New Devices: Review of Emergency and Nonemergency Expanded Use, Custom, and 3D-Printed Devices.

U.S. Food and Drug Administration (FDA) approval of Class III medical devices can take from 3 to 7 years. Although this is shorter than times for drug approvals, patients with serious or life-threatening diseases and disorders may not have time to wait for device approval to access needed treatments. The FDA has a number of pathways, similar to drug approval processes, for expanded use of unapproved medical devices in patients for whom no reasonable alternative therapy is available. Additionally, the FDA regulates the manufacture and use of "custom" medical devices-those made for use by 1 specific patient. With the advent of 3-dimensional printing and bioprinting, new rules are evolving to address concerns that lines may be blurred between "custom" treatments and unregulated human experimentation.

Self-reported functional status predicts post-operative outcomes in non-cardiac surgery patients with pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PHTN) is associated with increased post-procedure morbidity and mortality. Pre-procedure echocardiography (ECHO) is a widely used tool for evaluation of these patients, but its accuracy in predicting post-procedure outcomes is unproven. Self-reported exercise tolerance has not been evaluated for operative risk stratification of PHTN patients. OBJECTIVE: We analyzed whether self-reported exercise tolerance predicts outcomes (hospital length-of-stay [LOS], mortality and morbidity) in PHTN patients (WHO Class I-V) undergoing anesthesia and surgery. METHODS AND FINDINGS: We reviewed 550 non-cardiac, non-obstetric procedures performed on 370 PHTN patients at a single institution between 2007 and 2013. All patients had cardiac ECHO documented within 1 year prior to the procedure. Pre-procedure comorbidities and ECHO data were collected. Functional status (< or ≥ 4 metabolic equivalents of task [METs]) was assigned based on responses to standard patient interview questions during the pre-anesthesia clinic visit. Multiple logistic regression was used to develop a risk score model (Pulmonary Hypertension Outcome Risk Score; PHORS) and determine its value in predicting post-procedure outcomes. In an adjusted model, functional status <4 METs was independently associated with a LOS >7 days (p < .003), as were higher ASA class (p < .002), open surgical approach (p < .002), procedure duration > 2 hours (p < .001), and the absence of systemic hypertension (p = .012). PHORS Score ≥2 was associated with an increased 30-day major complication rate (28.7% vs. 19.2%; p < 0.001) and ICU admission rate (8.6% s 2.8%; p = .007), but no statistical difference in hospital readmissions rate (17.6% vs. 14.0%; p = .29), or mortality (3.5% vs. 1.4%; p = .75). Similar ECHO findings did not further improve outcome prediction. CONCLUSIONS: Poor functional status is associated with severe PHTN and predicts increased LOS and post-procedure complications in patients with moderate to severe pulmonary hypertension with different etiologies. A risk assessment model predicts increased LOS with fair accuracy. A thorough evaluation of underlying etiologies of PHTN should be undertaken in every patient.

Expanding Patient Access to Investigational Drugs: Single Patient Investigational New Drug and the "Right to Try".

With drug approval times taking an average of 8 years from entry into clinical trials to full U.S. Food and Drug Administration (FDA) approval, patients with life-threatening and severely debilitating disease and no reasonable therapeutic options are advocating for expanded access (EA) to investigational drugs prior to approval. Special investigational new drug (IND) application categories allow patients who meet specific criteria to receive treatment with non-approved drugs. The FDA approves over 99% of all single-patient INDs, providing emergency approval within hours, and non-emergency approval within an average of 4 days. "Right-to-try" laws passed in 38 states would allow patients to bypass FDA processes altogether, but contain controversial provisions that some claim risk more harm than benefit to desperate and vulnerable patients. This review focuses on FDA EA to non-approved drugs through a special category of IND-the single-patient IND-and "right-to-try" (R2T) access outside of the FDA.

Expanding Patient Access to Investigational New Drugs: Overview of Intermediate and Widespread Treatment Investigational New Drugs, and Emergency Authorization in Public Health Emergencies.

Individual patients with life-threatening or severely debilitating diseases can petition the U.S. Food and Drug Administration (FDA) through their physicians to have expanded access (EA) to drugs that are in clinical trials but have not reached full FDA approval (the "single-patient" investigational new drug [IND] application). Additionally, recent state and federal laws-so-called "right to try legislation"-allow patients to approach drug companies directly for access prior to FDA approval. While these pathways provide potential access for individual patients to investigational drugs, different EA pathways permit entire groups of certain patients to access investigational drugs prior to FDA approval. This review focuses on special categories of EA INDs intended for multiple patients-the intermediate-group IND and the widespread-treatment IND-as well as emergency authorization for use of investigational drugs and biological products (e.g., vaccines) in public health emergencies.

Overcoming the Declining Trends in Innovation and Investment in Cardiovascular Therapeutics: Beyond EROOM's Law.

Eroom's law (Moore's law spelled backwards), describes adverse trends towards declining innovation and rising costs of drug development over the last several decades. Therapeutics for cardiovascular diseases (CVD) appear to have been particularly sensitive to these trends. Thirty-three percent fewer CVD therapeutics were approved between 2000 and 2009 compared to the previous decade, and the number of CVD drugs starting all clinical trial stages declined in both absolute and relative numbers between 1990 and 2012. In the last 5 years, drugs to treat CVD disease comprised just 6% of all new drug launches. This review discusses the decline in CVD therapeutics, the reasons behind it, and ways in which this trend is being or might be addressed.

Technology Transfer: From the Research Bench to Commercialization: Part 1: Intellectual Property Rights-Basics of Patents and Copyrights.

Progress in medicine hinges on the successful translation of basic science discoveries into new medical devices, diagnostics, and therapeutics. "Technology transfer" is the process by which new innovations flow from the basic research bench to commercial entities and then to public use. In academic institutions, intellectual property rights do not usually fall automatically to the individual inventor per se, but most often are the property of the institution. Technology transfer offices are tasked with seeing to it that such intellectual property rights are properly managed and commercialized. This 2-part series explores the technology transfer process from invention to commercialization. Part 1 reviews basic aspects of intellectual property rights, primarily patents and copyrights. Part 2 will discuss the ways in which inventions become commercialized through startup companies and licensing arrangements with industry players.

Technology Transfer: From the Research Bench to Commercialization: Part 2: The Commercialization Process.

Technology transfer (TT) encompasses a variety of activities that move academic discoveries into the public sector. Part 1 of this 2-part series explored steps in acquisition of intellectual property (IP) rights (e.g., patents and copyrights). Part 2 focuses on processes of commercialization, including the technology transfer office, project development toward commercialization, and licensing either through the establishment of startup companies (venture capital-backed or otherwise) or directly to industry. In private industry, TT often occurs through the sale of IP, products, or services, but in universities, the majority of TT occurs through the licensing of IP.

Decisions regarding forgoing life-sustaining treatments.

PURPOSE OF REVIEW: Decisions to forego life-sustaining treatments are complex, and disagreements between physicians and patients occur. This review discusses recent findings regarding what factors influence physicians and patients or their surrogates in these decisions and considers whether futility arguments regarding life-sustaining treatments should be abandoned. RECENT FINDINGS: Cardiopulmonary resuscitation is one paradigm in the literature for studying end-of-life decision-making. Outcomes for cardiopulmonary resuscitation are poor, and physicians tend to over-rely on tacit versus evidence-based knowledge for resuscitation decisions. Physician decisions are often inherently biased regarding elderly and intellectually impaired patients. Patient decisions regarding life-sustaining treatments are poorly understood by physicians, and also include inherent bias against the elderly and intellectually impaired. Although patients and their decision-makers frequently incorporate religious or spiritual beliefs in their decisions, physicians rarely discuss these factors with them. Defining 'futility' is problematic, and futility arguments have limited utility in clinical end-of-life treatment discussions. SUMMARY: Further research is needed about factors that affect both physicians and patients with regard to forgoing life-sustaining interventions. Physicians need more information regarding religious/spiritual preferences of patients and decision-makers. 'Futility' arguments in end-of-life decision-making are flawed and should probably be abandoned.