Improving the in Vivo QTc assay: The value of implementing best practices to support an integrated nonclinical-clinical QTc risk assessment and TQT substitute.

Recent updates and modifications to the clinical ICH E14 and nonclinical ICH S7B guidelines, which both relate to the evaluation of drug-induced delayed repolarization risk, provide an opportunity for nonclinical in vivo electrocardiographic (ECG) data to directly influence clinical strategies, interpretation, regulatory decision-making and product labeling. This opportunity can be leveraged with more robust nonclinical in vivo QTc datasets based upon consensus standardized protocols and experimental best practices that reduce variability and optimize QTc signal detection, i.e., demonstrate assay sensitivity. The immediate opportunity for such nonclinical studies is when adequate clinical exposures (e.g., supratherapeutic) cannot be safely achieved, or other factors limit the robustness of the clinical QTc evaluation, e.g., the ICH E14 Q5.1 and Q6.1 scenarios. This position paper discusses the regulatory historical evolution and processes leading to this opportunity and details the expectations of future nonclinical in vivo QTc studies of new drug candidates. The conduct of in vivo QTc assays that are consistently designed, executed and analyzed will lead to confident interpretation, and increase their value for clinical QTc risk assessment. Lastly, this paper provides the rationale and basis for our companion article which describes technical details on in vivo QTc best practices and recommendations to achieve the goals of the new ICH E14/S7B Q&As, see Rossman et al., 2023 (this journal).

The 'false hope' argument in discussions on expanded access to investigational drugs: a critical assessment.

When seriously ill patients reach the end of the standard treatment trajectory for their condition, they may qualify for the use of unapproved, investigational drugs regulated via expanded access programs. In medical-ethical discourse, it is often argued that expanded access to investigational drugs raises 'false hope' among patients and is therefore undesirable. We set out to investigate what is meant by the false hope argument in this discourse. In this paper, we identify and analyze five versions of the false hope argument which we call: (1) the limited chance at benefit argument, (2) the side effects outweighing benefits argument, (3) the opportunity costs argument, (4) the impossibility of making informed decisions argument, and (5) the difficulty of gaining access argument. We argue that the majority of these five versions do not provide normative ground for disqualifying patients' hopes as false. Only when hope is rooted in a mistaken belief, for example, about the likelihood of benefits or chances on medical risks, or when hope is directed at something that cannot possibly be obtained, should it be considered false. If patients are adequately informed about their odds of obtaining medical benefit, however small, and about the risks associated with an investigational treatment, it is unjustified to consider patients' hopes to be false, and hence, to deny them access to investigational drug based on that argument.

Aggregation and analysis of secondary pharmacology data from investigational new drug submissions at the US Food and Drug Administration.

Secondary pharmacology studies are utilized by the pharmaceutical industry as a cost-efficient tool to identify potential safety liabilities of drugs before entering Phase 1 clinical trials. These studies are recommended by the Food and Drug Administration (FDA) as a part of the Investigational New Drug (IND) application. However, despite the utility of these assays, there is little guidance on which targets should be screened and which format should be used. Here, we evaluated 226 secondary pharmacology profiles obtained from close to 90 unique sponsors. The results indicated that the most tested target in our set was the GABA benzodiazepine receptor (tested 168 times), the most hit target was adenosine 3 (hit 24 times), and the target with the highest hit percentage was the quinone reductase 2 (NQO2) receptor (hit 29% of the time). The overall results were largely consistent with those observed in previous publications. However, this study also identified the need for improvement in the submission process of secondary pharmacology studies by industry, which could enhance their utility for regulatory purpose. FDA-industry collaborative working groups will utilize this data to determine the best methods for regulatory submission of these studies and evaluate the need for a standard target panel.

Participant injury in clinical trials conducted in New Zealand for the benefit of manufacturers: an unfair system?

A patient with a long-standing medical condition was enrolled in a clinical trial, deemed as conducted for the benefit of the manufacturer. The patient entered the trial and, shortly afterward, developed a severe illness that left him with a significant permanent disability. Clinical investigators and clinicians not involved in the trial believed the illness was related to trial participation. Because the trial was for the manufacturer's benefit, the participant was not eligible for compensation from the Accident Compensation Corporation (ACC). Discussions with the trial sponsor took many years to resolve. This case highlights the numerous barriers faced by patients seeking compensation from trial sponsors for adverse events probably resulting from trial participation. Legal changes are required to resolve this situation. Without such changes, potential participants and researchers should consider carefully whether to participate and invite people to participate in trials conducted for the benefit of a manufacturer, as there may be little support available should a trial-related illness occur.

Time for a Fully Integrated Nonclinical-Clinical Risk Assessment to Streamline QT Prolongation Liability Determinations: A Pharma Industry Perspective.

Defining an appropriate and efficient assessment of drug-induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc-prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical evaluations of delayed repolarization still minimally influence ICH E14-based strategies for assessing clinical QTc prolongation and defining proarrhythmic risk. In particular, the value of ICH S7B-based "double-negative" nonclinical findings (low risk for hERG block and in vivo QTc prolongation at relevant clinical exposures) is underappreciated. These nonclinical data have additional value in assessing the risk of clinical QTc prolongation when clinical evaluations are limited by heart rate changes, low drug exposures, or high-dose safety considerations. The time has come to meaningfully merge nonclinical and clinical data to enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring discussed in updated ICH E14 Questions and Answers. Implementing a fully integrated nonclinical/clinical risk assessment for compounds with double-negative nonclinical findings in the context of a low prevalence of clinical QTc prolongation would relieve the burden of unnecessary clinical QTc studies and streamline drug development.

Free to Choose: A Moral Defense of the Right-to-Try Movement.

The claim that individuals legitimately differ with respect to their values seems to be uncontroversial among bioethicists, yet many bioethicists nevertheless oppose right-to-try laws. This seems to be due in part to a failure to recognize that such laws are intended primarily to be political, not legal, instruments. The right-to-try movement seeks to build political support for increasing access to newly developed drugs outside of clinical trials. Opponents of right-to-try laws claim that increasing access outside of clinical trials would undermine evidence-based medicine. They seek to maximize overall gains to patients by protecting them from adverse drug reactions and ensuring that drugs are more effective on average. In contrast, right-to-try activists have a point that regulatory judgments of drug safety and effectiveness impose one set of trade-offs on all individuals, regardless of their different values. That might be acceptable if determinations of safety and effectiveness were black and white, but that does not seem to be the case. This article argues that judgments of safety and effectiveness are in an important respect normative and reflect the perceived value of those ends relative to others. Such judgments, when universally imposed, harm patients who would readily make do with less knowledge of drug safety and effectiveness in exchange for more time and self-determination. The relevant moral principle is that of respect for individual autonomy. Just as that principle should lead one to substitute collective decisions for individual ones to regulate a natural monopoly, the same principle should lead one to substitute individual decisions for collective ones to avoid a government monopoly on access to newly developed drugs. It is argued that reforms should increase the number of treatment options available to patients outside of clinical trials. The final section of the article discusses ways in which current regulations might be reformed so as to provide more treatment options outside of clinical trials, without undermining evidence-based medicine.

The Practice of Pharmaceutics and the Obligation to Expand Access to Investigational Drugs.

Do pharmaceutical companies have a moral obligation to expand access to investigational drugs to patients outside the clinical trial? One reason for thinking they do not is that expanded access programs might negatively affect the clinical trial process. This potential impact creates dilemmas for practitioners who nevertheless acknowledge some moral reason for expanding access. Bioethicists have explained these reasons in terms of beneficence, compassion, or a principle of rescue, but their arguments have been limited to questions of moral permissibility, leaving for future research the question of whether expanded access is morally obligatory. We take up this further question and argue that pharmaceutical companies have a moral obligation to expand access. Our defense is not based on beneficence, compassion, or rescue, but instead on a reciprocal moral expectation resulting from existing social commitments that help ensure a robust pharmaceutical practice within the broader healthcare system. Our aim is to give this obligation, along with several others, a coherent and plausible structure within the wider clinical trial process so that one might better explain the sources of the dilemmas and their possible resolutions.

Practical risk management in early phase clinical trials.

PURPOSE: Stopping rules are an essential part of risk management in early phase clinical trials. As well as being necessary for ensuring the safety of participants on clinical trials, they are also a requirement under the revision to the European Medicine Agency's first-in-human and early clinical trial guideline. The increasing complexity and size of modern trial designs (e.g. integrated trials) raise potential issues with risk management, which, if also too complex, presents challenges for both regulators and investigators to implement. Therefore, there is a clear need for a standard, template, or algorithm-based approach to risk management, in particular rules concerning adverse reactions. The purpose of this manuscript is to present template stopping (or adverse reaction, AR) rules that fulfil regulatory requirements and that can be adapted, taking into account trial design, nature of the investigational medicinal product, and anticipated effects. METHODS: The template AR rules that use a systematic, objective and consistent process were developed, taking into account severity (using an objective grading system), seriousness, frequency and reversibility of ARs. These rules control decisions relating to individual trial participants, dosing regimens and dose escalation and/or progression to successive trial parts. For ease of use, the template rules consist of a single, one-page table. RESULTS: The template AR rules have been successfully applied to many early phase adaptive integrated trials that received regulatory authorisation and were performed in the UK. This manuscript presents the template rule table and case studies of some trial-specific adaptations. CONCLUSIONS: This work demonstrates how a systematic, objective and consistent approach to risk management of large integrated trials can be simple yet robust, facilitating effective decision making and trial progression whilst safeguarding participant safety.

A quick scoping review of efficacy, safety, economic, and health-related quality-of-life outcomes of short- and long-acting erythropoiesis-stimulating agents in the treatment of chemotherapy-induced anemia and chronic kidney disease anemia.

Erythropoiesis-stimulating agents (ESAs) are man-made forms of erythropoietin used in the treatment of anemia. This quick-scoping review of systematic literature reviews (SLRs) was conducted to define the clinical, economic, and health-related quality of life (HRQoL) outcomes for short-acting and long-acting ESAs in patients with chronic kidney disease-induced anemia (CKD-IA) and patients with chemotherapy-induced anemia (CIA). Embase, Medline, and the Cochrane Database of Systematic Reviews were searched from their establishment until October 2017. SLRs related to the use of short-acting and long-acting ESAs in the treatment of CIA and CKD-IA were included. Forty-eight studies met the inclusion criteria. The evidence suggests little difference in efficacy, HRQoL, and safety outcomes among ESA types. Cost-effectiveness and market price are likely to become determining factors driving the choice of agent. Comparative studies and costing models accounting for the utilization of biosimilars are needed to establish which ESAs are more cost-effective.

The need for appropriate registration of pregnancy outcomes under newer oral glucose-lowering therapies.

Because of the increase in type 2 diabetes (T2DM) in young adults, women of childbearing age are frequently treated with newer glucose-lowering therapies, and an increase in unintentional exposure to therapies unapproved for use during pregnancy is expected. The clinician is left with the dilemma of deciding between discontinuation of a novel agent that is providing excellent glycaemic control, while switching to other agents may cause deterioration of glycaemia, and continued use of novel agents that may have uncertain effects on the unborn child. For T2DM, pregnancy data are collected only via spontaneous reporting systems. Therefore, we evaluated the available data on pregnancy outcomes under newer glucose-lowering agents in pharmaceutical safety databases. We found that data on pregnancy outcomes with new glucose-lowering agents in T2DM are scarce, with a high risk of bias towards negative outcomes, limiting their usefulness in robustly assessing safety. Because of the lack of information at present, these agents are not recommended for use during pregnancy or when planning pregnancy. To better guide clinical practice, structured systems of assessing pregnancy outcomes in women receiving these novel agents are urgently needed.

Expanded access to investigational drugs: balancing patient safety with potential therapeutic benefits.

INTRODUCTION: Expanded access is the use of an investigational product by patients with serious medical conditions without participation in a clinical trial. It is a complicated process involving the collaboration of many parties and pharmaceutical companies. Ongoing efforts focus on accelerating expanded access procedures in the best interest of patients with cancer. AREAS COVERED: We review the regulatory and ethical challenges encountered in efforts to optimize expanded access. EXPERT OPINION: In the era of personalized medicine, patients may benefit from novel therapeutic agents that demonstrate encouraging results in early studies. However, drug approval is a lengthy and cumbersome procedure that might exceed the time frame of a life-threatening disease. Expanded access provides options to patients with unmet needs. It may provide informative safety and efficacy data to the manufacturers and the scientific and regulatory organizations. Ongoing efforts are being made by global governmental and scientific committees, regulatory agencies, and patient organizations to address the ethical and regulatory issues and to optimize the expanded access process. Their goal is to expand access to promising novel drugs for individual patients and to accelerate the necessary procedures while preserving patient safety.

How Often Are Drugs Made Available Under the Food and Drug Administration's Expanded Access Process Approved?

In this review of individual patient expanded-access requests to the Center for Drug Evaluation and Research for the period Fiscal Year 2010 to Fiscal Year 2014, we evaluated the number of applications received and the number allowed to proceed. We also evaluated whether drugs and certain biologics obtained under expanded access went on to be approved by the Food and Drug Administration. Finally, we considered concerns that adverse events occurring during expanded access might place sponsors at risk for legal liability. Overall, 98% of individual patient expanded-access requests were allowed to proceed. During the study period, among drugs without a previous approval for any indication or dosage form, 24% of unique drugs (ie, multiple applications for access to the same drug were considered to relate to 1 unique drug), and 20% of expanded-access applications received marketing approval by 1 year after initial submission; 43% and 33%, respectively, were approved by 5 years after initial submission. A search of 3 legal databases and a database of news articles did not appear to identify any product liability cases arising from the use of a product in expanded access. Our analyses seek to give physicians and patients a realistic perspective on the likelihood of a drug's approval as well as certain information regarding the product liability risks for commercial sponsors when providing expanded access to investigational drugs. The US Food and Drug Administration (FDA)'s expanded-access program maintains a careful balance between authorizing patient access to potentially beneficial drugs and protecting them from drugs that may have unknown risks. At the same time, the agency wishes to maintain the integrity of the clinical trials process, ultimately the best way to get safe and effective drugs to patients.

The year's new drugs & biologics 2016: Part I.

Nearly 90 new drugs and biologics, including important new line extensions, were approved or launched for the first time globally in 2016, a comparatively lower number with respect to previous years. Forty-four new drugs and biologics reached their first markets worldwide in 2016, nearly 10% fewer than the previous year. Seven of the new launches were first-in-class agents, meaning the first drug with a novel mechanism of action to be approved and launched anywhere in the world. In addition, 23 novel line extensions (i.e., new formulations, new combinations and new indications) were introduced last year. The remaining 21 products discussed in this article were approved for the first time during the year just passed, but had not yet been launched as of December 15, 2016. Information on these new arrivals is covered in depth in part I of our annual review of the pharma and biotech industry.

The year's new drugs & biologics 2016: Part II - Trends and highlights of an unforgettable year.

This eagle's-eye overview of the drug industry in 2016 provides insight into some of last year's top stories, including disease outbreaks that drove R&D, orphan drug development, pipeline attrition, drug pricing, and the ongoing movement in M&A. We also consider recent political events in the U.S. and U.K. and their potential impact on the industry in the years to come, and take a glimpse into the crystal ball to anticipate the new drugs that may be approved in 2017.

Early assessment of proarrhythmic risk of drugs using the in vitro data and single-cell-based in silico models: proof of concept.

BACKGROUND AND PURPOSE: To determine the predictive performance of in silico models using drug-specific preclinical cardiac electrophysiology data to investigate drug-induced arrhythmia risk (e.g. Torsade de pointes (TdP)) in virtual human subjects. EXPERIMENTAL APPROACH: To assess drug proarrhythmic risk, we used a set of in vitro electrophysiological measurements describing ion channel inhibition triggered by the investigated drugs. The Cardiac Safety Simulator version 2.0 (CSS; Simcyp, Sheffield, UK) platform was used to simulate human left ventricular cardiac myocyte action potential models. RESULTS: This study shows the impact of drug concentration changes on particular ionic currents by using available experimental data. The simulation results display safety threshold according to drug concentration threshold and log (threshold concentration/ effective therapeutic plasma concentration (ETPC)). CONCLUSION AND IMPLICATIONS: We reproduced the underlying biophysical characteristics of cardiac cells resulted in effects of drugs associated with cardiac arrhythmias (action potential duration (APD) and QT prolongation and TdP) which were observed in published 3D simulations, yet with much less computational burden.

Barriers to participation in industry-sponsored clinical trials in pediatric type 2 diabetes.

BACKGROUND: The rapid emergence of type 2 diabetes (T2D) in the pediatric population has left pediatric endocrinologists with limited artillery in terms of management. While multiple medications are available for adults, Food and Drug Administration (FDA)-approved medications in children are limited to only metformin and insulin. Additional treatment options require randomized controlled trials, yet heretofore several barriers at the participant and institutional level have impeded these studies from proceeding in children and adolescents. Identification of the most challenging obstacles that pediatric endocrinologists experience in participating in industry-sponsored T2D trials may facilitate development of feasible platforms for future studies. MATERIALS AND METHODS: We conducted an anonymous online survey consisting of 31 questions that assessed potential barriers to industry-sponsored clinical trials in pediatric patients with T2D. The survey was sent to members of the Pediatric Endocrine Society (PES), and members conducted the survey between October and November of 2014. As part of the survey, respondents rated the significance of several possible barriers to participation in industry-sponsored T2D studies. RESULTS: We received a total of 207 responses from members of PES. Baseline demographics showed that 50% of represented institutions care for 50 or fewer T2D patients age 18 years and younger; 70% of institutions diagnose 20 or fewer new T2D cases per year; and 3 racial groups predominated: African American, Hispanic, and Caucasian. A total of 70% of responders have a research infrastructure to participate in clinical trials, but only half have dedicated research nurses. Protocol restrictions on participant recruitment due to current glycemic control or medication use as well as frequent visit schedules were reported to be major obstacles. In addition, the financial support provided to centers to carry out the studies is insufficient. CONCLUSIONS: Efforts must be made to ease the burden of research participation on both pediatric T2D patients as well as pediatric endocrinologists.

Stakeholders' views on the ethical challenges of pragmatic trials investigating pharmaceutical drugs.

BACKGROUND: We explored the views of key stakeholders to identify the ethical challenges of pragmatic trials investigating pharmaceutical drugs. A secondary aim was to capture stakeholders' attitudes towards the implementation of pragmatic trials in the drug development process. METHODS: We conducted semistructured, in-depth interviews among individuals from different key stakeholder groups (academia and independent research institutions, the pharmaceutical industry, regulators, Health Technology Assessment (HTA) agencies and patients' organizations) through telephone or face-to-face sessions. Interviews were structured around the question "what challenges were experienced or perceived during the design, conduct and/or review of pragmatic trials." Respondents were additionally asked about their views on implementation of pragmatic trials in the drug development process. Thematic analysis was used to identify the ethically relevant features across data sets. RESULTS: We interviewed 34 stakeholders in 25 individual sessions and four group sessions. The four perceived challenges of ethical relevance were: (1) less controlled conditions creating safety concerns, (2) comparison with usual care potentially compromising clinical equipoise, (3) tailored or waivers of informed consent affecting patient autonomy, and (4) minimal interference with "real-world" practice reducing the knowledge value of trial results. CONCLUSIONS: We identified stakeholder concerns regarding risk assessment, use of suboptimal usual care as a comparator, tailoring of informed consent procedures and ensuring the social value of pragmatic trials. These concerns increased when respondents were asked about pragmatic trials conducted before market authorization.

The therapeutic potential of new investigational hepatitis C virus translation inhibitors.

INTRODUCTION: Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis, hepatocellular carcinoma and liver-related death worldwide. Currently, the anti-HCV armamentarium encompasses several direct-acting antivirals (DAA) that achieve very high response rates and have an excellent tolerability profile. However, they do not represent a final solution for HCV global eradication for at least these two reasons: i) some patients harbour resistant strains to DAAs and cannot benefit from currently available treatments; ii) the cost of these drugs remains very high. AREAS COVERED: This review summarizes pre-clinical and clinical data regarding HCV translation inhibitors, a new class of drugs currently in the pipeline with novel mechanisms of action. EXPERT OPINION: The availability of DAAs resolved most issues related to HCV treatment compared with the previous interferon-based therapies. However, there are some patients that cannot achieve a viral clearance with currently available treatments. Therefore, there is still room for new drugs in this setting, providing that they demonstrate an advantage in terms of efficacy, safety, cost or or simplicity of use. Based on preliminary results, at least for some promising molecules (e.g. miravirsen and RG-101), studies on safety and efficacy on this intriguing class of drugs are needed.