Benefit-risk Considerations Research Articles

A Benefit-Risk Conceptual Framework for Biologic Use During Pregnancy: A Mini-Review.

Recent reports related to in utero exposure of marketed immunosuppressive biologics led to clinical recommendations to delay live vaccinations for infants due to the concern of reduced vaccine effectiveness and/or increased risk of vaccine-related disease. These delays can increase the risk of children contracting vaccine preventable diseases, yet the alternative cessation of biologics during pregnancy may result in increased autoimmune disease activity for the pregnant person, raising complex benefit-risk (B-R) considerations and trade-offs. Our goal is to develop a conceptual framework for B-R assessment based on the key benefits and risks pregnant people would consider for themselves and their children when continuing (vs. discontinuing) a biologic during pregnancy. The proposed framework defines the decision contexts, key domains and attributes for potential benefits, and risks of biologic use during pregnancy, informed by a literature review of indications for biologics and refined with key clinical stakeholders. The framework includes both the pregnant person taking the biologic and the infant potentially exposed to the biologic in utero, with potential benefit and risk domains and attributes for each participant. To advance this conceptual framework, there are considerations of potential biases and uncertainty of available data that will be imperative to address when quantifying the B-R framework. For these reasons, we recommend the formation of a consortium to ensure development of a robust, validated framework that can be adopted in the healthcare setting.

Seamless phaseII/III design: a useful strategy to reduce the sample size for dose optimization.

The traditional more-is-better dose selection paradigm, originally developed for cytotoxic chemotherapeutics, can be problematic when applied to the development of novel molecularly targeted agents. Recognizing this issue, the US Food and Drug Administration initiated Project Optimus to reform the dose optimization and selection paradigm in oncology drug development, emphasizing the need for greater attention to benefit-risk considerations. We identify different types of phase II/III dose-optimization designs, classified according to trial objectives and endpoint types. Through computer simulations, we examine their operating characteristics and discuss the relevant statistical and design considerations for effective dose optimization. Phase II/III dose-optimization designs are capable of controlling family-wise type I error rates and achieving appropriate statistical power with substantially smaller sample sizes than the conventional approach while also reducing the number of patients who experience toxicity. Depending on the design and scenario, the sample size savings range from 16.6% to 27.3%, with a mean savings of 22.1%. Phase II/III dose-optimization designs offer an efficient way to reduce sample sizes for dose optimization and accelerate the development of targeted agents. However, because of interim dose selection, the phase II/III dose-optimization design presents logistical and operational challenges and requires careful planning and implementation to ensure trial integrity.

Statins may increase diabetes, but benefit still outweighs risk.

Data have been accumulating on the risk of developing type 2 diabetes in patients receiving statins and on the potential adverse effects of these drugs on glycemic control in patients who already have type 2 diabetes. This article reviews data linking statin use and new-onset diabetes mellitus, the effects of statins on glycemic control in type 2 diabetes, the benefit-risk considerations of statin use and type 2 diabetes, and how these factors affect patient management.

Global Landscape of Benefit-Risk Considerations for Medicinal Products: Current State and Future Directions.

In the last decade there has been a significant increase in the literature discussing the use of benefit-risk methods in medical product (including devices) development. Government agencies, medical product industry groups, academia, and collaborative consortia have extensively discussed the advantages of structured benefit-risk assessments. However, the abundance of information has not resulted in a consistent way to utilize these findings in medical product development. Guidelines and papers on methods, even though well structured, have not led to a firm consensus on a clear and consistent approach. This paper summarizes the global landscape of benefit-risk considerations for product- or program-level decisions from available literature and regulatory guidance, providing the perspectives of three stakeholder groups-regulators, collaborative groups and consortia, and patients. The paper identifies key themes, potential impact on benefit-risk assessments, and significant future trends.

Does cefiderocol heteroresistance explain the discrepancy between the APEKS-NP and CREDIBLE-CR clinical trial results?

Does cefiderocol heteroresistance explain the discrepancy between the APEKS-NP and CREDIBLE-CR clinical trial results?

Impact of the Coronavirus Disease 2019 Pandemic on an Ongoing Pragmatic Pediatric Clinical Trial

Background: The coronavirus disease 2019 (COVID-19) pandemic has a significant negative impact on clinical trials. Therefore, maintaining an optimal trial conduct should be considered to minimize risks to trial integrity while ensuring the safety of trial staff and participants. In this study, we aimed to describe the impact of the COVID-19 pandemic on conducting an ongoing clinical trial, along with challenges and solutions encountered and required to continue the trial. Methods: This Phase IV pragmatic randomized superiority controlled open-label trial included children with epilepsy receiving Vitamin D supplementation at King Saud University Medical City, Riyadh, Saudi Arabia (clinicaltrials.gov registration number: NCT03536845). Children with epilepsy receiving chronic antiepileptic medications and with normal baseline 25-hydroxyvitamin D level were randomized to receive cholecalciferol 400 IU/day versus 1000 IU/day for 6 months. The primary outcome was the percentage of children with Vitamin D insufficiency at 6 months. The secondary outcomes included seizure control, bone mineral density, and safety. Results: Under COVID-19 public health emergency measures, exceptional methods were used, such as telemedicine, home visit for blood extractions, shipping of the study medication to the patient's home, using reminder text messages to follow patients' compliance, and using privacy-compliant platforms to connect the research team members. Conclusion: During the widespread pandemic, ethical dilemmas are of major concern, especially when conducting trials on vulnerable age groups. Therefore, actions should be proportionate and based on benefit-risk considerations, affecting the risk of bias from protocol deviation and overall results.

A Boxed Warning for Montelukast: The FDA Perspective

The U.S. Food and Drug Administration (FDA) became aware of postmarketing reports of neuropsychiatric adverse events with Singulair (montelukast) use in 2007. Over the years, the FDA has conducted reviews of the clinical trial safety data, focused analyses of postmarketing reports, and reviews of the published literature. These activities have resulted in successive labeling updates and public communications. However, there has been continued concern among stakeholders about the risk of neuropsychiatric events and the lack of awareness among prescribers and patients/caregivers. On the basis of these concerns, the FDA embarked on another comprehensive review and also conducted a new observational study using claims data in the Sentinel Distributed Database. In September 2019, the FDA held a public Advisory Committee meeting to discuss its review and solicit recommendations from the panel regarding labeling and communication strategies. After careful consideration of the available data and feedback received during the FDA Advisory Committee meeting, the FDA required a boxed warning and a revision specifically for the allergic rhinitis indication to reserve use of montelukast to patients who have an inadequate response or intolerance to alternative therapies. Based on benefit-risk considerations, the asthma indication was not changed. To provide insight into the process and rationale for the required labeling changes, we provide an overview of the decision-making framework we used.

Review of pharmacological options for the treatment of Chagas disease.

Chagas disease (CD) is a worldwide problem, with over 8 million people infected in both rural and urban areas. CD was first described over a century ago, but only two drugs are currently available for CD treatment: benznidazole (BZN) and nifurtimox (NF). Treating CD-infected patients, especially children and women of reproductive age, is vital in order to prevent long-term sequelae, such as heart and gastrointestinal dysfunction, but this aim is still far from being accomplished. Currently, the strongest data to support benefit-risk considerations come from trials in children. Treatment response biomarkers need further development as serology is being questioned as the best method to assess treatment response. This article is a narrative review on the pharmacology of drugs for CD, particularly BZN and NF. Data on drug biopharmaceutical characteristics, safety and efficacy of both drugs are summarized from a clinical perspective. Current data on alternative compounds under evaluation for CD treatment, and new possible treatment response biomarkers are also discussed. Early diagnosis and treatment of CD, especially in paediatric patients, is vital for an effective and safe use of the available drugs (i.e. BZN and NF). New biomarkers for CD are urgently needed for the diagnosis and evaluation of treatment efficacy, and to guide efforts from academia and pharmaceutical companies to accelerate the process of new drug development.

US Food and Drug Administration (FDA): Benefit-Risk Considerations for Cefiderocol (Fetroja®).

In November 2019, the Food and Drug Administration (FDA) approved cefiderocol for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by susceptible gram-negative bacteria in adults with limited to no alternative treatment options based on a randomized, double-blind, noninferiority cUTI trial (APEKS-cUTI). In a randomized, open-label trial (CREDIBLE-CR) in patients with cUTI, nosocomial pneumonia, bloodstream infections, or sepsis due to carbapenem-resistant gram-negative bacteria, an increase in all-cause mortality was observed in patients treated with cefiderocol as compared to best available therapy. The cause of the increased mortality was not established, but some deaths were attributed to treatment failure. Preliminary data from a randomized, double-blind trial (APEKS-NP) in patients with nosocomial pneumonia due to carbapenem-susceptible gram-negative bacteria showed a similar rate of mortality as compared to meropenem. We describe the uncertainties and challenges in the interpretation of the CREDIBLE-CR trial and some benefit-risk considerations for the use of cefiderocol in clinical practice. Clinical Trials Registration: NCT02321800.

Progress in the treatment of multiple sclerosis

Progress in the treatment of multiple sclerosis Abstract. Especially the immunotherapy of multiple sclerosis demonstrates that neurology has developed into a specialty with multiple therapeutic options. Progress in basic science, translational research but also innovative clinical study designs were pivotal for this advancement. Whereas the disease is still not curable, especially in early stages stabilization is often feasible. The multitude of available immunotherapies often facilitate individualized treatment approaches. However, due to rare but potentially severe side effects patients and MS-therapists alike are confronted with new dimensions of critical benefit-risk considerations. Wheras also for chronic progressive disease immunotherapeutic options are increasing, neuroprotective or -regenerative approaches are still in developmental stages. Thus, further effort is also needed for the optimization of symptomatic therapy.

Patient-Centered Therapy Development for Myotonic Dystrophy: Report of the Myotonic Dystrophy Foundation-Sponsored Workshop.

Myotonic dystrophy (DM) is an autosomal dominant, repeat expansion, progressive disorder with no drug therapies. Consequently, to better define a regulatory pathway in anticipation of new treatment strategies under investigation, the Myotonic Dystrophy Foundation convened a workshop entitled "Patient-Centered Therapy Development for Myotonic Dystrophy" in September 2015. Participants included representatives from academia, industry, the patient community, the National Institutes of Health (NIH) and the Food and Drug Administration (FDA). Presenters described the symptom burden of the disease, and existing data on DM biomarkers, endpoints, natural history, and benefit-risk considerations. FDA participants helped clarify the regulatory requirements for new drug treatment approvals and DM-specific issues such as variability, slow progression, and low prevalence. Workshop attendees gained a better understanding of DM and the current status of existing data and tools to support therapeutic drug research and development.

The Impact of Psychiatric Practice Guidelines on Medication Costs and Youth Aggression in a Juvenile Justice Residential Treatment Program.

Stakeholders have expressed concern over the appropriate use of psychiatric medications and adequacy of mental health services for youths involved with the juvenile justice system. This study assessed the impact of implementing psychiatric practice guidelines on medication costs and youth aggression in a juvenile justice facility. The study examined whether implementing psychiatric practice guidelines in a facility with an organized psychosocial treatment program would reduce psychiatric medication costs, compared with two other facilities, and whether lower psychotropic medication costs would be associated with increases in youth aggression. Administrative data from three state-run juvenile justice facilities were analyzed to determine psychiatric medication costs and rates of youth aggression. Psychiatric practice guidelines that involved screening, shared decision making, psychosocial treatments, medication prescribing, and monitoring of side effects were implemented in only one of the three facilities, with a goal of applying evidence-based psychopharmacology and benefit-risk considerations. Over the ten-year study period (2003-2012), psychiatric medication costs decreased 26% at the facility implementing the psychiatric practice guidelines, whereas costs at the two comparison facilities increased by 104% and 152%. As psychiatric medication costs decreased at the facility implementing the guidelines, youth aggression there did not increase. Implementing psychiatric practice guidelines in juvenile justice facilities can reduce psychotropic medication costs without an increase in youth aggression. Implementation of the guidelines requires an organized psychosocial treatment program to help deter an inappropriate focus on psychotropic treatments.

World health organization approaches to evaluating the potential use and quality of hepatitis e vaccine.

World health organization approaches to evaluating the potential use and quality of hepatitis e vaccine.

Asthma in Pregnancy

Asthma is a common disease among pregnant women. Uncontrolled asthma may increase the risk of maternal and foetal complications, thus optimal asthma management is elemental during pregnancy. Therapy must aim to control the disease; asthmatic women with controlled asthma should continue taking their medications during pregnancy, and maintenance therapy should be increased if asthma is not controlled. Most of the asthma medications have no effects on foetal growth. Although oral corticosteroids may confer an increased risk of lower birth weight and congenital malformations, benefit-risk considerations still favour their use in patients with asthma exacerbations during pregnancy. This review summarises immunological changes characterising asthmatic pregnancy and the clinical implications of asthma management during pregnancy.

Vigabatrin 35 years later - from mechanism of action to benefit-risk considerations

Shields WD, Pellock JM. Vigabatrin 35 years later — from mechanism of action to benefit–risk considerations. Acta Neurol Scand: 2011: 124 (Suppl. 192): 1–4. © 2011 John Wiley & Sons A/S.

Japanese encephalitis: update on vaccines and vaccine recommendations

Japanese encephalitis is the most common vaccine-preventable viral encephalitis in Asia. In view of the production cessation of the inactivated mouse brain-derived Japanese encephalitis vaccine, it is timely to provide an update on new Japanese encephalitis vaccines and revised vaccine recommendations. A new inactivated, adjuvanted, Vero cell-culture-based Japanese encephalitis vaccine, IC51, was licensed in Europe and the United States in 2009. Administered in a two-dose regimen at 0 and 28 days, it was shown to be well tolerated and produce high seroconversion rates. In addition, Chimerivax Japanese encephalitis, a novel live-attenuated one-dose chimeric vaccine comprising the structural genes of SA 14-14-2 virus and nonstructural genes of yellow fever 17D virus, is in the process of getting licensed in Australia and in south east Asia. Previous recommendations for Japanese encephalitis vaccination of travelers were predicated on minimizing exposure to a mouse-brain-derived vaccine with a poorly understood and worrisome safety profile, whereas the risk of acquiring Japanese encephalitis itself during travel was assessed to be relatively low. With the availability of a new cell-culture-derived vaccine IC51 with an excellent safety profile, it is appropriate to reconsider benefit-risk considerations for the vaccination of travelers. These considerations are reflected in the March 2010 revised recommendations by the United States Advisory Committee on Immunization Practices.

Fetal Safety of Drugs Used in the Treatment of Allergic Rhinitis

Allergic rhinitis is the most common allergic disease. Pharmacological interventions are often not used in pregnancy because of alarming information in drug labels and patient information, even when evidence for safety exists.Low-risk therapies could include immunotherapy, intranasal sodium cromoglycate (cromolyn sodium), beclometasone, budesonide and first-generation antihistamines. In a meta-analysis examining the safety of first-generation antihistamines in pregnancy, 200 000 first trimester exposures failed to show increased teratogenic risk. Loratadine is the most studied second-generation antihistamine (with a total patient cohort of 2147 women who were exposed) and does not appear to increase the risk of major congenital malformations; however, it has not been as well studied as the earlier antihistamines. Since desloratadine is the principal metabolite of loratadine, it can be assumed that a similar safety profile would fit for desloratadine as was described for loratadine although no direct human studies have been done. Decongestants have not been conclusively proven to affect the fetal outcome and may be used for short-term relief when no other safer alternatives are available. Intranasal corticosteroids have not been associated with an increase in congenital malformations in humans. Based on efficacy and the fact that there would be little systemic absorption, they can be considered a first-line treatment over oral antihistamines, decongestants and mast cell stabilisers; however, the number of controlled trials in pregnancy is limited. Intranasal corticosteroids are associated with minimal systemic effects in adults and are the most effective therapy for allergic rhinitis. Benefit-risk considerations must, therefore, be done but favour their first-line use during pregnancy. Because fetal safety is paramount, recommendations should be based both on the safety of the drugs during pregnancy and the comparative efficacy of the agent in the treatment of the underlying condition. This review exemplifies the fact that there are many safe treatment options for the clinician when dealing with allergic rhinitis during pregnancy.

Benefit-Risk Considerations in the Treatment of Dementia with Lewy Bodies

Dementia with Lewy bodies (DLB) is a relatively recently characterised syndrome with clinical and pathological features that distinguish it from classical Alzheimer's disease. These characteristics include more rapid decline, spontaneous features of parkinsonism, visual hallucinations and fluctuating cognition. This article reviews the clinical syndrome of DLB and the agents used to treat its cognitive, motor and behavioural manifestations. Benefit-risk issues regarding the treatment of DLB are discussed based upon limited randomised, controlled clinical trials with some speculative conclusions being drawn from case reports and case series. We conclude that patients with DLB may respond better to cholinesterase inhibitors than patients with Alzheimer's disease on both cognitive and behavioural measures. Cholinesterase inhibitor therapy may result in reduced caregiver burden and less time institutionalised. These agents are well tolerated with the majority of adverse effects being gastrointestinal in nature. Although neuropsychiatric manifestations are numerous in patients with DLB, antipsychotics should be used infrequently and with caution, although atypical antipsychotics are better tolerated than conventional antipsychotics. Physicians should exhibit caution when prescribing these agents because of the increased risk of extrapyramidal adverse effects. Limited data suggest that the use of levodopa or other dopaminergic agents may be of benefit for the treatment of the parkinsonism that is associated with DLB. However, the increased risk of hallucinations and neuropsychiatric symptoms may negate the potential benefits of increased mobility. There is insufficient evidence to draw conclusions about the use of antidepressants; however, selective serotonin reuptake inhibitors may be of benefit.

The efficacy and safety of asthma medications during pregnancy

Asthma may be the most common potentialy serious medical problem to complicate pregnancy. Because severe uncontrolled asthma may cause both maternal and fetal morbidity and mortality, pharmacological asthma therapy is often necessary during pregnancy. Only 1 published randomized controlled clinical trial has evaluated the efficacy of an asthma medication (inhaled beclomethasone) during pregnancy. Human data bearing on the safety of medications during pregnancy are usually limited to observational studies, because experimental studies on the use of medications during human pregnancy would generally be unethical. Existing observational cohort data do not associate an increased risk of preeclampsia, total congenital malformations, preterm birth, or low birth weight infants with maternal exposures to inhaled beta agonists, theophylline, cromolyn, or inhaled corticosteroids. Maternal use of oral corticosteroids has been associated with reduced birth weight, an increased risk of preeclampsia, and an increased risk of oral clefts (first trimester use). Based on this information, benefit-risk considerations suggest that inhaled asthma medications and theophylline should be used when indicated for the treatment of asthma during pregnancy. Moreover, although some increased risks may be associated with the gestational use of oral corticosteroids, these risks are probably still less than the potential risks to the mother and the fetus of severe uncontrolled asthma. This articles describes recently published consensus recommendations regarding the pharmacological management of asthma during pregnancy.

ASTHMA AND PREGNANCY

Review of the literature suggests that asthma may improve, worsen, or stay the same during pregnancy. Review of the literature also suggests that asthmatic women may be at increased risk of adverse perinatal outcomes, especially preeclampsia, preterm or low birthweight infants. Although the mechanisms of these increased risks are not fully defined, optimal control of asthma during pregnancy appears to improve perinatal outcome. Although no asthma medications can be considered proven safe during pregnancy, benefit-risk considerations suggest that inhaled beta, agonists, cromolyn, theophylline, inhaled corticosteroids, and systemic corticosteroids should be used when indicated in the treatment of gestational asthma. Management of asthma during pregnancy should include effective patient education, careful and frequent monitoring of asthma status, avoidance of asthma triggers, appropriate preventative therapy, and aggressive treatment of increased symptoms. Such management should maximize the health of both the asthmatic pregnant woman and her baby.