Physician perspectives on compassionate use in pediatric oncology.

BACKGROUND: Targeted cancer treatments are almost always first studied in adults, even when there is a biologically plausible potential for efficacy in children. Through compassionate use programs, children who are not eligible for a clinical trial and for whom there are no known effective therapies may obtain access to investigational agents, including drugs under development for adults. However, little is known about pediatric oncologists' experiences with applying for and obtaining compassionate use agents. METHODS: This study surveyed 132 pediatric oncologists to assess awareness and utilization of compassionate use programs, to identify barriers to their use, and to evaluate available institutional support and resources. RESULTS: We found that the process of applying for access to drugs in development is poorly understood, which presents a barrier to obtaining investigational drugs. Fifty-seven percent of the pediatric oncologists applied for compassionate use. Providers from larger institutions or with more than 15 years of clinical experience were more likely to complete an application and obtain investigational agents for their patients. CONCLUSION: Identified perceived and actual barriers to compassionate use application submission suggest pediatric oncologists may benefit from educational resources and support to ensure children with cancer equal access to investigational agents and care.

Enhancing pediatric access to cell and gene therapies.

Increasing numbers of cell and gene therapies (CGTs) are emerging to treat and cure pediatric diseases. However, small market sizes limit the potential return on investment within the traditional biopharmaceutical drug development model, leading to a market failure. In this Perspective, we discuss major factors contributing to this failure, including high manufacturing costs, regulatory challenges, and licensing practices that do not incorporate pediatric development milestones, as well as potential solutions. We propose the creation of a new entity, the Pediatric Advanced Medicines Biotech, to lead late-stage development and commercialize pediatric CGTs outside the traditional biopharmaceutical model in the United States-where organized efforts to solve this problem have been lacking. The Pediatric Advanced Medicines Biotech would partner with the academic ecosystem, manufacture products in academic good manufacturing practice facilities and work closely with regulatory bodies, to ferry CGTs across the drug development 'valley of death' and, ultimately, increase access to lifesaving treatments for children in need.

Before It's Too Late: Multistakeholder Perspectives on Compassionate Access to Investigational Drugs for Pediatric Patients With Cancer.

Patients and their families, physicians, drug companies, and regulatory agencies have common goals: to find effective therapies for life-threatening conditions. In oncology, the lines between clinical research and treatment are often blurred; parents and physicians of patients who have exhausted standard-of-care treatments and cannot participate in a clinical trial are likely to consider seeking compassionate use access to investigational drugs; however, knowledge and perspectives about compassionate use may differ among these groups. There are unique considerations associated with providing compassionate use to children diagnosed with cancer, including evaluation for potential developmental toxicities, the need for pediatric-specific dosing and formulations, informed consent, and, when appropriate, patient assent. Positive impacts of providing access to investigational therapies to children include potential treatment benefits to patients who obtain investigational agents as well as benefits to future patients if data from expanded access support drug development for childhood cancer. Challenges for physicians seeking compassionate use access to investigational drugs for their patients include obtaining the drug sponsor's agreement to provide the investigational drug as well as lack of knowledge about the process and regulatory requirements. Clinical trials in oncology provide the possibility of therapeutic benefit for pediatric patients; when feasible and warranted, these benefits should also be available to patients on a compassionate use basis outside of trials.

Text Messaging to Improve Disease Management in Patients With Painful Diabetic Peripheral Neuropathy.

Purpose The purpose of the study was to determine the impact of educational text messages on diabetes self-management activities and outcomes in patients with painful diabetic peripheral neuropathy (pDPN). Methods Patients with pDPN identified from a large integrated health system who agreed to participate were randomized to 6 months of usual care (UC) or UC plus twice-daily diabetes self-management text messages (UC+TxtM). Outcomes included the Pain Numerical Rating Scale, Summary of Diabetes Self-Care Activities (SDSCA), questions on diabetes health beliefs, and glycated hemoglobin (A1C). Changes from baseline were evaluated at 6 months and compared between groups. Results Demographic characteristics were balanced between groups (N = 62; 53% female, mean age = 63 years, 94% type 2 diabetes), as were baseline measures. After 6 months, pain decreased with UC+TxtM from 6.3 to 5.5 and with UC from 6.5 to 6.0, with no difference between groups. UC+TxtM but not UC was associated with significant improvements from baseline on all SDSCA subscales. On diabetes health beliefs, UC+TxtM patients reported significantly increased benefits and reduced barriers and susceptibility relative to UC at 6 months. A1C declined in both groups, but neither change was significant relative to baseline. Conclusions Patients with pDPN who receive twice-daily text messages regarding diabetes management reported reduced pain relative to baseline, although this change was not significant compared with usual care. In addition, text messaging was associated with increased self-management activities and improved diabetes health beliefs and total self-care. These results warrant further investigation.

Global Development of Anticancer Therapies for Rare Cancers, Pediatric Cancers, and Molecular Subtypes of Common Cancers.

Advances in genetic sequencing and other diagnostic technologies have enabled the use of precision medicine in clinical cancer care, as well as the development of novel therapies that are targeted to specific molecular drivers of cancer. Developing these new agents and making them accessible to patients requires global clinical studies and regulatory review and approval by different national regulatory agencies. Whereas these global trials present challenges for drug developers who conduct them and regulatory agencies who oversee them, they also raise practical issues about patients with low-frequency cancers who need these therapies. A lack of uniform standards in both regulatory approval for marketing and reimbursement for approved agents across countries may make the newly developed agent either unavailable or inaccessible to patients in certain countries or regions, even if patients from those countries or regions participated in the clinical research that established the safety and efficacy of the agent. In an effort to further understand and address this need, we convened an international workshop in 2017 in North Bethesda, MD. After presentations of the individual regulatory pathways for marketing approval and reimbursement for individual nations, participants discussed expedited pathways and specific challenges for uncommon cancers. As a matter of justice, agents being developed for rare cancers, pediatric cancers, or uncommon molecular subsets of common cancers need a pragmatic, science-based regulatory policy framework to clearly specify the type and quantity of evidence needed to demonstrate efficacy from these trials and evidence to support accessibility.

Anti-interleukin-12 antibody for active Crohn's disease.

BACKGROUND: Crohn's disease is associated with excess cytokine activity mediated by type 1 helper T (Th1) cells. Interleukin-12 is a key cytokine that initiates Th1-mediated inflammatory responses. METHODS: This double-blind trial evaluated the safety and efficacy of a human monoclonal antibody against interleukin-12 (anti-interleukin-12) in 79 patients with active Crohn's disease. Patients were randomly assigned to receive seven weekly subcutaneous injections of 1 mg or 3 mg of anti-interleukin-12 per kilogram of body weight or placebo, with either a four-week interval between the first and second injection (Cohort 1) or no interruption between the two injections (Cohort 2). Safety was the primary end point, and the rates of clinical response (defined by a reduction in the score for the Crohn's Disease Activity Index [CDAI] of at least 100 points) and remission (defined by a CDAI score of 150 or less) were secondary end points. RESULTS: Seven weeks of uninterrupted treatment with 3 mg of anti-interleukin-12 per kilogram resulted in higher response rates than did placebo administration (75 percent vs. 25 percent, P=0.03). At 18 weeks of follow-up, the difference in response rates was no longer significant (69 percent vs. 25 percent, P=0.08). Differences in remission rates between the group given 3 mg of anti-interleukin-12 per kilogram and the placebo group in Cohort 2 were not significant at either the end of treatment or the end of follow-up (38 percent and 0 percent, respectively, at both times; P=0.07). There were no significant differences in response rates among the groups in Cohort 1. The rates of adverse events among patients receiving anti-interleukin-12 were similar to those among patients given placebo, except for a higher rate of local reactions at injection sites in the former group. Decreases in the secretion of interleukin-12, interferon-gamma, and tumor necrosis factor alpha by mononuclear cells of the colonic lamina propria accompanied clinical improvement in patients receiving anti-interleukin-12. CONCLUSIONS: Treatment with a monoclonal antibody against interleukin-12 may induce clinical responses and remissions in patients with active Crohn's disease. This treatment is associated with decreases in Th1-mediated inflammatory cytokines at the site of disease.

Affirming At-Risk Minorities for Success (ARMS): retention, graduation, and success on the NCLEX-RN.

Increasing ethnic and racial diversity in the U.S. population combined with inadequate minority representation in the nursing profession requires innovative strategies to recruit, retain, and graduate nurses from diverse ethnic and racial populations. Affirming At-Risk Minorities for Success (ARMS) was funded by a U.S. Department of Health and Human Services Basic Nurse Education and Practice Program grant. Participants (N = 64) were enrolled in a baccalaureate degree nursing program that has been predominantly White/ Anglo and is located in the south-central region of the United States. Research objectives were to increase program retention, graduation rates, and success on the National Council Licensure Examination for Registered Nurses (NCLEX-RN) for minority or educationally disadvantaged students through programmatic interventions, including mentoring and advising, tutoring, and educational seminars. The comparison group was non-ARMS students derived from a comprehensive database (N = 265). Results indicated that interventions positively affected graduation rates (measure of retention = 98%), significantly affected grades in the Leadership-Management capstone course, and eliminated the effects of ethnicity on NCLEX-RN success.

Modernizing Clinical Trial Eligibility: Recommendations of the American Society of Clinical Oncology-Friends of Cancer Research Minimum Age Working Group.

Purpose Children have historically been excluded from first-in-human studies of promising new cancer drugs and later phase adult clinical trials. Delays in evaluation may result in off-label use without dosing information as the only access to new drugs. A multistakeholder workshop was convened in May 2016 by ASCO and Friends of Cancer Research to identify opportunities for when it would be scientifically appropriate to expand trial eligibility to include children younger than age 18 years in first-in-human and other adult cancer clinical trials. Methods This group convened experts from academia, government, and industry to review barriers to enrolling children and adolescents in oncology clinical trials. We evaluated the historical context, published literature, regulatory considerations, and myriad risks and benefits associated with lowering the age of enrollment on oncology clinical trials. Results We conclude that many of the historical concerns about including children early in oncology clinical trials do not apply in the current scientific and clinical environment of pediatric oncology and drug development; we provide specific recommendations for how the inclusion of children in early-phase investigational cancer drug trials might be accomplished. Automatic inclusion of pediatric patients is appropriate in early-phase trials that assess dose, safety, and pharmacokinetics in a variety of tumor types and later phase trials that assess efficacy in a specific disease that spans adult and pediatric populations. Conclusion Including children in appropriately designed adult clinical oncology trials is feasible and can be done in a way that enhances their access to these agents without compromising safety or development strategies.

A real-time PCR assay for DNA-methylation using methylation-specific blockers.

DNA methylation-based biomarkers have been discovered that could potentially be used for the diagnosis of cancer by detection of circulating, tumor-derived DNA in bodily fluids. Any methylation detection assay that would be applied to these samples must be capable of detecting small amounts of tumor DNA in the presence of background normal DNA. We have developed a real-time PCR assay, called HeavyMethyl, that is well suited for this application. HeavyMethyl uses methylation-specific oligonucleotide blockers and a methylation-specific probe to achieve methylation-specific amplification and detection. We tested the assays on unmethylated and artificially methylated DNA in order to determine the limit of detection. After careful optimization, our glutathione-S-transferase pi1 and Calcitonin assays can amplify as little as 30 and 60 pg of methylated DNA, respectively, and neither assay amplifies unmethylated DNA. The Calcitonin assay showed a highly significant methylation difference between normal colon and colon adenocarcinomas, and methylation was also detected in serum DNA from colon cancer patients. These assays show that HeavyMethyl technology can be successfully employed for the analysis of very low concentrations of methylated DNA, e.g. in serum of patients with tumors.

Isolation and sequencing of a putative promoter region of the murine G protein beta 1 subunit (GNB1) gene.

The expression of the heterotrimeric GTP-binding protein beta 1 subunit gene (GNB1) is regulated by psychostimulants such as cocaine and amphetamines. Since the up-regulation appears to be one of the candidate processes of sensitization, it is necessary to elucidate the cellular and molecular mechanism of the GNB1 gene regulation for a better understanding the establishment of sensitization. In the present study, we describe the isolation and nucleotide sequence analysis of the GNB1 gene promoter region. We have isolated approximately 10 kb of the 5'-flanking region of the mouse of GNB1 gene and found potential elements involved in putative transcriptional control of the GNB1, such as AP1, AP2, Sp1, cyclic AMP response element, and nuclear factor kappa B recognition sites, within the sequences 0.3 kb upstream from the putative transcription start site. This region was highly rich in G + C content, but lacked TATA or CATT boxes. Comparing the nucleotide sequence of the cDNA clone with the human genome databases using the BLAST program a region containing putative exon 1 and promoter of the human GNB1 gene in chromosome 1 was found. The cloning and sequence analysis of an extensive portion of the 5'-flanking regulatory region of the GNB1 gene provides new insights into the factors involved in the regulation by psychostimulants of GNB1 expression.