Change In Route Of Administration Research Articles

Clinical Presentation and Management of Malignant Psoas Syndrome: A Scoping Review of Case Reports and Case Series.

Malignant psoas syndrome (MPS) is a rare and underreported clinical syndrome that significantly impacts the quality of life of cancer patients throughmetastatic infiltration of the iliopsoas muscle. Patients suffering from MPS often present with painful hip flexion, loss of mobility, and immense pain in their legs and back. The current literature describing the clinical presentation, management, and prognosis of MPS is limited primarily to case reports and outdated literature reviews. There remains a gap in the current knowledge of MPS and in the management of this complex cancer-related pain syndrome. Thus, this scoping review aimed to map current case reports and case series on MPS for clinical presentation, treatment modalities, and resulting prognoses of MPS in late-stage cancer patients. A systemized search using the databases Embase and PubMed (Medline) was conducted to access case reports and case series published between January 1990 and October 2022 that met the study's inclusion criteria: (1) adult patients with metastatic cancer; (2) MPS symptoms secondary to infiltration of iliopsoas; (3) clinical presentation, treatment modality, and prognosis; and (4) English-language text. Our search strategy yielded 1926 citations. After removing 629 duplicates, 1,283 reports were excluded due to failure to meet eligibility criteria (n=1,271) or inaccessibility (n=12). Using the JBI appraisal tools for case reports and case series, a total of 14 articles remained for the final review. With histories of either genitourinary, hepatic, gastric, or skin cancer, each case reported new onset intense pain in the legs, back, abdomen, or pelvis with associated symptoms such as flexion of the hip or gait disorder. A computerized tomography (CT) scan, magnetic resonance imaging (MRI), orpositron emission tomography (PET) scantypically confirmed metastasis into the iliopsoas causing these symptoms, which suggested MPS. Each case utilized two to seven different pain management strategies to alleviate MPS symptoms. Many cases first used opioids for pain relief. Following a necessitated increase in morphine equivalent daily dose, a subsequent increase in the strength of analgesic, change in route of administration, and integration of combination drug therapy were generally added to the treatment regime. Many cases reported successful management of symptoms through utilizing methadone, radiation therapy, botulinum toxin injection, increased opioid dosage, or epidural catheter administration of opioids. A unified clinical definition of MPS may be required to inform physicians of this syndrome to help support clinical decisions regarding treatments for patients. The studies indicated that a clearer guideline for treatment protocol may be warranted as most cases reported utilizing various treatment medication dosages and procedures with vastly differing results.

Treatment preference among patients with spinal muscular atrophy (SMA): a discrete choice experiment

ObjectiveTo examine patient/caregiver preference for key attributes of treatments for spinal muscular atrophy (SMA).BackgroundIn the rapidly evolving SMA treatment landscape, it is critically important to understand how attributes of potential treatments may impact patient/caregiver choices.Design/methodsA discrete choice experiment survey was developed based on qualitative interviews. Patients with SMA (≥ 18 years) and caregivers of patients were recruited through a U.S. patient organization. Respondents made choices in each of 12 sets of hypothetical treatments. The relative importance of five treatment characteristics was compared (measured by regression coefficients [RC] of conditional logit models): (1) improvement or stabilization of motor function, (2) improvement or stabilization of breathing function, (3) indication for all ages or pediatric patients only, (4) route of administration [repeated intrathecal (IT) injections, one-time intravenous (IV) infusion, daily oral delivery] and (5) potential harm (mild, moderate, serious/life threatening).ResultsPatient ages ranged from less than 1 to 67 years (n = 101, 65 self-reported and 36 caregiver-reported) and 64 were female. Total SMA subtypes included: type 1 (n = 21), type 2 (n = 48), type 3 (n = 29), other (n = 3). Prior spinal surgery was reported in 47 patients. Nusinersen and onasemnogene abeparvovec-xioi use were reported in 59 and 10 patients, respectively. Improvement in motor and breathing function was highly valued [RC: 0.65, 95% confidence interval (CI): 0.47–0.83 and RC: 0.79, 95% CI: 0.60–0.98, respectively]. Oral medication and one-time infusion were strongly preferred over repeated IT injections (RC: 0.80, 95% CI: 0.60–0.98 and RC: 0.51, 95% CI: 0.30–0.73, respectively). Patients least preferred an age-restricted label/approved use (≤ 2 years of age) (RC: − 1.28, 95% CI: − 1.47 to − 1.09). Cross-attributes trade-off decision suggested a lower willingness for a high-risk therapy despite additional efficacy gain. For some patients, there may be willingness to trade off additional gains in efficacy for a change in route of administration from repeated intrathecal administration to oral medication.ConclusionsImprovements in motor/breathing function, broad indication, oral or one-time infusion, and minimal risk were preferred treatment attributes. Treatment decisions should be made in clinical context and be tailored to patient needs.

Synthesis of Novel Macrocyclic Compounds Derived from Ceftriaxone

Macrocyclization can help improve pharmacological activity, metabolic stability, cell permeability and oral absorption to create better drug candidates. For example, enhancing the oral absorption of the compounds can allow a change in administration route. We tried to improve the oral bioavailability of ceftriaxone, a third-generation cephalosporin having a unique side chain with a 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group at the C-3 position of the cephem nucleus. We prepared novel macrocycles of ceftriaxone by valuable synthetic methods and confirmed their oral bioavailabilities.

P0379BION-1301, A FULLY BLOCKING ANTIBODY TARGETING APRIL FOR THE TREATMENT OF IGA NEPHROPATHY: ASSESSMENT OF SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS IN LONG-TERM NONCLINICAL STUDIES

Abstract Background and Aims IgA Nephropathy (IgAN) is a common form of glomerulonephritis and its pathogenesis is thought to consist of sequential pathogenic hits, including the production of auto-antigen galactose-deficient IgA1 (Gd-IgA1) and auto-antibody formation ultimately resulting in immune complex deposition, inflammation and functional deterioration of the kidney. Serum levels of APRIL (A PRoliferation Inducing Ligand, TNFSF13) and levels of Gd-IgA1 are correlated with severity of disease (Zhao et al, 2012). As a ligand for the receptors BCMA and TACI, APRIL is thought to regulate differentiation and proliferation of B cells and plasma cells and IgA class switching. BION-1301 is a humanized antibody neutralizing APRIL. In nonhuman primates, BION-1301 reduced serum levels of IgA, IgM, and IgG with no drug-related toxicity (Dulos J, et al. ASN Annual Meeting. 2018). Here we describe the nonclinical safety assessment of BION-1301, to support its continued clinical development for the treatment of IgA Nephropathy. Method A 14-week repeat-dose toxicity and toxicokinetic/pharmacodynamic (TK/PD) study in non-human primates (NHP) was performed by biweekly intravenous bolus (IV) administration of BION-1301 at three different dose levels. To support a potential change in route of administration, a 4-week repeat-dose NHP bridging study was conducted with weekly subcutaneous (SC) administration of BION-1301 at three different dose levels. Results In both the 14-week IV study and the 4-week SC study, BION-1301 was evaluated for safety, TK and PD. For TK and PD, BION-1301 levels, uncomplexed APRIL levels and immunoglobulin levels (IgA, IgG, IgM) were quantified in serum. Immunophenotyping was performed on peripheral blood to assess the impact of BION-1301 on the B cell compartment. In both studies BION-1301 was well tolerated with no test-article related findings. 14-week IV dosing as well as 4-week SC dosing of BION-1301 reduced serum APRIL levels as well as serum immunoglobulin levels. Conclusion Results of these nonclinical toxicity studies with toxicology, TK and PD endpoints demonstrate that BION-1301 is well tolerated for up to 14 weeks of dosing, corroborates pharmacodynamic proof-of-mechanism and support prolonged dosing and SC administration of BION-1301 in patients with IgA Nephropathy.

A Phase 1 study comparing subcutaneous and intramuscular routes of administration of peginterferon beta-1a: macrophage-producing neopterin levels as biomarker

Abstract Background Developing effective therapies for patients can be difficult as many fail due to safety concerns. Changes in route of administration (ROA) for approved therapies offers options to patients while mitigating known side effects. Peginterferon beta-1a (PEG) is approved for subcutaneous (SC) administration at 125 mcg every 2 weeks for patients with relapsing forms of multiple sclerosis. Intramuscular (IM) administration is associated with a different safety profile from SC and could offer patients receiving PEG an additional treatment option. To confirm efficacy is maintained, neopterin – a reliable pharmacodynamic measure for IFN therapies that is produced by macrophages – was tested in a bioequivalence study. Methods A two-period, crossover study with healthy volunteers who received a single dose of PEG administered SC followed by a single dose administered IM (or vice versa) was conducted. Blood samples were collected up to 504 hours post dose to evaluate pharmacokinetic and pharmacodynamic measures, including neopterin. Results The study enrolled 136 participants. Serum neopterin concentrations following SC and IM administration were similar, with maximal concentrations (Epeak) reached at a median ETmax of 40.1 hours and 44.0 hours, respectively. Geometric mean neopterin levels increased from baseline to maximum concentration similarly between both routes, with an increase from 8.0 to 22.6 nmol/L for SC and from 8.1 to 23.2 nmol/L for IM. The overall exposure to neopterin was also similar between both routes. Conclusion These results demonstrate no major difference in PEG activity; therefore, PEG administered SC or IM is expected to have a comparable pharmacological impact on the body.

Methotrexate Central Nervous System Toxicity Identified in a Pharmacogenomics Pharmacist Consult Patient

OBJECTIVE: To report a possible pharmacogenomics (PGx)-related, cognitive dysfunction, adverse drug reaction from methotrexate (MTX) that may be multifactorial in origin. SUMMARY: The patient subject is a 76-year-old Caucasian female of Russian ancestry suffering from rheumatoid arthritis and treated with MTX who presented to the diagnostic and consultative physician service in a medical clinic with advancing cognitive dysfunction, manifesting as memory loss, dizziness, and confusion. Components of this possible adverse drug reaction (ADR) may include ancestry, pharmacogenomics (PGx) characteristics of the patient, and a change in route of administration, among others. The case demonstrates how patients referred to a pharmacist consult service for a suspected ADR with possible PGx implications may uncover other contributory factors to the ADR. CONCLUSION: PGx testing may increase clinical pharmacist referrals to identify a PGx etiology to an ADR. However, they may also identify other non-PGx contributory factors to an ADR.

P14 The Irish National Centre for Paediatric Rheumatology experience of moving from IV to SC tocilizumab (TCZ)

Abstract Background Tocilizumab (TCZ) is a monoclonal antibody that targets the interleukin 6 receptor. It is approved for use in children over the age of 2 years with systemic onset juvenile idiopathic arthritis (SoJIA) and polyarticular juvenile idiopathic arthritis (pJIA) who have not responded to treatment with non-steroidal agents, corticosteroids and methotrexate mono-therapy. Previous studies from our centre have shown a positive response to IV TCZ with high rates of remission. TCZ has recently been licensed for administration via the SC route. The aim of this study is to determine how many patients receiving IV TCZ were successfully changed to SC TCZ in the first 6 months after SC TCZ paediatric licensing was obtained and to document any adverse events. Methods Retrospective review of patients with SoJIA or pJIA who were on IV TCZ and changed to S/C TCZ over a 6 month period from October 2018 to April 2019. Patients were identified from an in-house aseptic pharmacy database Clinichemo®. All patients on IV TCZ were identified and cross checked against the Hibernian patient referral system for home SC TCZ administration. Criteria for changing included fulfilling Wallace Criteria for clinical remission and appropriate JIA subtype. Results were analysed using Microsoft Excel. Results 28 patients receiving IV TCZ in October 2018 were identified. 8 were excluded due to either a diagnosis other than SoJIA/pJIA or changing to an alternative biologic. Of the 20 eligible patients, 10 had successfully changed by April 2019. Of those who did not change, 1 is due to change in May 2019, 2 did not wish to change, indicating personal preference as their reason. A total of 7 were deemed unsuitable for medication change due to ongoing active disease. Of the 10 patients who successfully changed, 2 had SoJIA and 8 had pJIA. All were commenced on a dose of 162mg with frequency varying from 1 to 4 weekly as per Summary of Product Characteristics. There was no significant change in ESR, CRP, LFT or WCC demonstrated pre or post change in administration route. No adverse events were reported. 1 patient subsequently changed back to IV administration due to patient preference. Conclusion Our experience to date has been positive, with 50% of patients changed to SC administration within 6 months of approval. A number of other patients have been identified for a change to SC TCZ within the next 6 months. While 1 patient subsequently elected to change back to IV TCZ, to date, no patient has come off SC TCZ due to an increase in disease activity. We hope to follow this study with a patient questionnaire to determine the patient perspective of changing to SC administration of TCZ. Conflicts of Interest The authors declare no conflicts of interest.

The natural history of prescription opioid abuse: A pilot study exploring change in routes of administration and motivation for changes.

The purpose of this retrospective, observational pilot study was to explore change in route of administration (RoA) and motivation for changing RoA during the course of opioid abuse. This retrospective pilot study involved collecting and analyzing semistructured interview data. Interviews were conducted with patients undergoing outpatient substance abuse treatment at a buprenorphine clinic. Twenty adult patients (50 percent male) participated in the interviews. Interview data were qualitatively and quantitatively analyzed to evaluate trends and motivations for changing RoA. In this sample, RoA varied over time. Most patients (75.0 percent) began abusing prescription opioids by swallowing intact pills, and 53.3 percent of patients eventually progressed to chewing. All patients who initiated abuse through chewing or insufflation (ie, intranasal use) progressed to injection. However, several patients (20.0 percent) did not exhibit a linear progression from RoAs with lesser to greater risk for serious adverse events. Of the eight motivations for changing RoA identified in the current study, the most frequently cited (38.2 percent) motivation was to achieve a desired effect (eg, euphoria). This pilot study is one of the first to investigate natural history of RoA in prescription opioid abuse and motivations for changing RoA. Results suggest that a defined pathway of RoA progression may not exist, and that achieving a desired effect is a common motivation for changing RoA. Although these findings need to be replicated in a larger sample, this research may help support the development of opioid risk mitigation strategies.

(228) Natural history of prescription opioid misuse/abuse: a qualitative investigation

There is significant interest in understanding factors associated with the growing opioid epidemic so that meaningful prevention efforts can be implemented. We conducted a qualitative study to explore the natural history of opioid misuse and abuse, looking specifically at changes in route of administration (ROA) over time. 20 adult outpatients from a buprenorphine naloxone clinic in Kentucky participated in one-hour, semi-structured interviews about their opioid abuse history. Interviewers created timelines to track the sequence of “progression events” in a participant’s ROA, preferred product, and/or dosage. The sample was 90% white and 50% female with a mean age of 36.2 years; 12 participants had a history of pain. On average, there were 11 years between the first opioid misuse/abuse event and the current treatment episode. 70% of participants reported illicit use of non-opioid substances prior to opioid misuse/abuse. 85% of participants reported manipulating opioids prior to administration (oral, intranasal, or intravenous). A majority (n=11) engaged in chewing at some point when using the oral ROA. Participants who manipulated prescription opioids at first use tended to employ alternative ROAs over time (intranasal or intravenous). Several participants (n=6) went back and forth between ROAs. Less than half of patients injected (n=7) or snorted (n=5). This study provides preliminary evidence that there may not be a “typical” pattern of ROA progression for opioid misuse and abuse. Many participants alternated between ROAs over time and others did not progress from oral to intranasal or intravenous use. In this study, manipulation (including chewing) of opioids was common prior to opioid misuse and abuse. Confirmation of the findings from this small study is warranted. Funded by Egalet Corporation.

Longer Term Efficacy and Safety of Subcutaneous Compared with Intravenous Rituximab: Updated Results of the Phase 3 SABRINA Study

Longer Term Efficacy and Safety of Subcutaneous Compared with Intravenous Rituximab: Updated Results of the Phase 3 SABRINA Study

Could chest wall rigidity be a factor in rapid death from illicit fentanyl abuse?

Background: There has been a significant spike in fentanyl-related deaths from illicit fentanyl supplied via the heroin trade. Past fentanyl access was primarily oral or dermal via prescription fentanyl patch diversion. One factor potentially driving this increase in fatalities is the change in route of administration. Rapid intravenous (IV) fentanyl can produce chest wall rigidity. We evaluated post-mortem fentanyl and norfentanyl concentrations in a recent surge of lethal fentanyl intoxications. Methods: Fentanyl related deaths from the Franklin County coroner’s office from January to September 2015 were identified. Presumptive positive fentanyl results were confirmed by quantitative analysis using liquid chromatography tandem mass spectrometry (LC/MS/MS) and were able to quantify fentanyl, norfentanyl, alfentanyl, and sufentanyl. Results: 48 fentanyl deaths were identified. Mean fentanyl concentrations were 12.5 ng/ml, (range 0.5 ng/ml to >40 ng/ml). Mean norfentanyl concentrations were 1.9 ng/ml (range none detected to 8.3 ng/ml). No appreciable concentrations of norfentanyl could be detected in 20 of 48 cases (42%) and were less than 1 ng/ml in 25 cases (52%). Elevated fentanyl concentrations did not correlate with rises in norfentanyl levels. In several cases fentanyl concentrations were strikingly high (22 ng/ml and 20 ng/ml) with no norfentanyl detected. Discussion: The lack of any measurable norfentanyl in half of our cases suggests a very rapid death, consistent with acute chest rigidity. An alternate explanation could be a dose-related rapid onset of respiratory arrest. Deaths occurred with low levels of fentanyl in the therapeutic range (1–2 ng/ml) in apparent non-naïve opiate abusers. Acute chest wall rigidity is a well-recognized complication in the medical community but unknown within the drug abuse community. The average abuser of illicit opioids may be unaware of the increasing fentanyl content of their illicit opioid purchase. Conclusion: In summary we believe sudden onset chest wall rigidity may be a significant and previously unreported factor leading to an increased mortality, from illicit IV fentanyl use. Fentanyl and norfentanyl ratios and concentrations suggest a more rapid onset of death given the finding of fentanyl without norfentanyl in many of the fatalities. Chest wall rigidity may help explain the cause of death in these instances, in contrast to the typical opioid-related overdose deaths. Intravenous heroin users should be educated regarding this potentially fatal complication given the increasingly common substitution and combination with heroin of fentanyl.

Cost-minimization Analysis of IgPro20, a Subcutaneous Immunoglobulin, in Japanese Patients With Primary Immunodeficiency

PurposeIgPro20, Hizentra® an L-proline−stabilized 20% human subcutaneous immunoglobulin (SCIG), has been shown in a Phase III pivotal study to be well tolerated and efficacious in adult and pediatric Japanese patients with primary immunodeficiency. Economic aspects of SCIG treatment in comparison with previous intravenous immunoglobulin (IVIG) therapy were analyzed in this Phase III study in Japan. MethodsTwenty-four Japanese patients with primary immunodeficiency on IVIG treatment were switched to IgPro20 at an equivalent dose (full analysis set). The study consisted of a screening period, an IVIG treatment period with 3 planned infusions every 3 or 4 weeks, a 12-week SCIG wash-in and wash-out period, and a 12-week SCIG efficacy period. The difference in medical cost and productivity loss resulting from changes in hospital frequency between the SCIG and IVIG treatment was evaluated. Information about treatment cost was collected as part of the Life Quality Index questionnaire. In addition, productivity loss and hospital-related absenteeism were evaluated. FindingsLife Quality Index scores for all domains were higher with SCIG than with IVIG in this patient population. In the full analysis set, the mean (SD) Life Quality Index score of the Costs domain increased from 45.1 (26.34) at Week 1 (IVIG period) to 71.9 (18.52) at Week 24 (end of the SCIG efficacy period), representing a mean change of 26.74 and a large score improvement effect size (1.01). Median productivity loss was reduced by 60% from baseline to Weeks 12 and 24. This resulted in a reduction in costs of JPY 10,875 per patient per month at Weeks 12 and 24. Subcutaneous treatment with IgPro20 also reduced hospital-related absenteeism. The number of patients, parents, or guardians who were not absent from work or housework duties and had no reduction in working time increased from 4 (17.4%) at Week 1 to 9 (39.1%) at Week 24. Similar results were obtained in the per-protocol set (n = 21). ImplicationsSwitching from IVIG to SCIG reduced markedly productivity loss and hospital-related absenteeism. The reduction in hospital visit frequency due to the use of home-based IgG therapy enabled by the change in administration route is expected to produce an important pharmacoeconomic benefit in Japan. Study Code: ZLB06_002CR, ClinicalTrials.gov identifier: NCT01199705.

La «intervención del tercer día»: análisis de los factores asociados al seguimiento de recomendaciones sobre la prescripción de antibióticos

IntroductionStewardship programs on the use of antibiotics usually include interventions based on non-compulsory recommendations for the prescribers. Factors related to the adherence to expert recommendations, and the implementation of these programmes in daily practice, are of interest. MethodsA randomized, controlled, multicentre intervention study was performed in 32 hospitalization units. Antibiotic prescriptions were evaluated by an infectious disease specialist on the third day. We describe the implementation of the intervention, the factors associated with adherence to recommendations, and the impact of the intervention. ResultsA total of 3,192 interventions were carried out. Information sources used to prepare the recommendations varied significantly between centres. A modification was recommended in 65% of cases: withdrawal (47%), change in administration route (26%), change of drugs or number of antibiotics (27%), and change in dose (5%). Simplification of treatment accounted for 75% of all recommendations. Adherence was 68%, with significant differences between hospitals, and higher when the recommendations consisted of a dose adjustment or change of route, during the first intervention period, and also when recommendations were personally commented on, in addition to writing a note in the clinical chart.We did not find any reduction in antibiotic consumption or variation in the incidence of resistant pathogens. ConclusionsAn important proportion of antibiotic prescriptions may be susceptible to improvement, most of them towards simplification. The adherence to the intervention was high, but significant variations at different centres were observed, depending on the type of recommendation, and the study period. Those recommendations that were personally commented on were more followed more than those only written

Assessing safety and immunogenicity of post-exposure prophylaxis following interchangeability of rabies vaccines in humans

Rabies post exposure prophylaxis with cell culture vaccines by either intramuscular route or intradermal route spans over a period of one month. World Health Organization recommends completing post exposure prophylaxis against rabies with the same cell culture or embryonated egg rabies vaccine and with same route of administration and any deviation from this shall be an exception. In the present study, the safety and immunogenicity of rabies post-exposure prophylaxis was studied prospectively in 90 animal bite cases that had interchangeability of rabies vaccines either by route of administration or brand/type and such changes had occurred due to logistical/financial problems. Among them, 47 had change in route of administration from intramuscular to intradermal or vice versa and 43 had change in the brand/type of cell culture rabies vaccine. All of them had category III rabies exposure and received equine rabies immunoglobulin along with the rabies vaccine. None of the study subjects had any adverse reactions. The rabies virus neutralizing antibody titers was assessed by rapid fluorescent focus inhibition test and all the vaccinees had titers ≥0.5 IU per mL on day 14 which is considered as adequate for protection against rabies. Thus, the present study showed that, rabies post-exposure prophylaxis was safe and immunogenic despite changes in the route of administration and brand/type of rabies vaccine.

Minimizing Carry-Over Effects After Treatment Failure and Maximizing Therapeutic Outcome

According to experimental and clinical evidence, the experiences of previous treatments are carried over to different therapeutic approaches and impair the outcome of subsequent treatments. In this behavioral pilot study we used a change in administration route to investigate whether the effect of prior treatment experience on a subsequent treatment depends on the similarity of both treatments. We experimentally induced positive or negative experiences with a topical analgesic treatment in two groups of healthy human subjects. Subsequently, we compared responses to a second, unrelated and systemic analgesic treatment between both the positive and negative group. We found that there was no difference in the analgesic response to the second treatment between the two groups. Our data indicate that a change in administration route might reduce the influence of treatment history and therefore be a way to reduce negative carry-over effects after treatment failure. Future studies will have to validate these findings in a fully balanced design including larger, clinical samples.

Drug repurposing in pharmaceutical industry and its impact on market access: market access implications

BackgroundDrug repurposing is a group of development strategies employed in order to overcome some of the hurdles innate to drug research and development. Drug repurposing includes drug repositioning, reformulation and combination.ObjectiveThis study aimed to identify the determinants of successful market access outcome for drug repurposing in the United States of America (USA) and in Europe.MethodsThe case studies of repurposing strategies were identified through a systematic review of the literature. Price information and reimbursement conditions for all the case studies were collected mainly through access of public datasources. A list of attributes that could be associated with market access outcome (price level and reimbursement conditions) was developed, discussed, and validated by an external expert group. Detailed information for all attributes was researched and collected for each case study. Bivariate regression models were conducted to identify factors associated with price change for all repurposing cases. A similar analysis was performed for reformulation and repositioning cases, in the USA and in Europe, separately. A significance level of 5% was used for all analyses.ResultsA total of 144 repurposing case studies were included in the statistical analysis for evaluation of mean price change. Combination cases (the combination of two or more individual drug components) were excluded from the statistical analysis due to the low number of cases retrieved. The main attributes associated with a significant price increase for overall repurposing cases were ‘change in administration setting to hospital’ (374%, p<0.0001), ‘addressing unmet needs’ (69%, p<0.05), ‘reformulations belonging to Group 3’—that is, change in administration route (117%, p<0.001), and being a repurposed product with the ‘same brand name’ as the original product (65%, p<0.05).ConclusionWe found that the ability of the repurposed product to address unmet needs, a reformulation where the target product had a different administration route than the source product, and having a similar brand name for repurposed and original products, were variables that impacted a positive price change for repurposed drugs overall. Our research results also suggested that orphan designation could have a positive impact for repositioning in the USA, in particular. Although a change of administration from ambulatory to hospital setting seemed to be significantly correlated with a price increase for the target product, only one case was retrieved for this parameter; as such, it was not possible to infer a firm correlation between this parameter and a change in price.

Mandatory Palliative Care Education for Surgical Residents: Initial Focus on Teaching Pain Management

BackgroundKnowledge concerning palliative care and the associated skills, including effective pain control, is essential for surgeons who treat cancer patients in daily practice. This study focuses on a palliative care training course that has been mandatorily conducted for all surgical residents of our hospital since 2009.MethodsWe evaluated the effectiveness of our mandatory palliative care training course by conducting a retrospective study of the patients' medical records and participants' questionnaire results and discussed the importance of palliative care education for surgical residents.ResultsAll 12 surgical residents who participated in the course in 2009 had graduated 4–9 years back. They were assigned to look after a total of 92 cases (average, 7.66 cases per resident) during the course. The purpose of care in most cases (92.3%) was to mitigate pain. Introducing analgesic adjuvants such as gabapentin or amitriptyline accounted for the largest part of initial interventions (23.9%) aimed at controlling cancer pain, followed by changes in route of administration or doses of prior opioid analgesics (21.7%). Interventions with opioid analgesics were conducted most frequently (47.7%). The overall pain improvement rate was 89.1%. We used a questionnaire after the course to evaluate its effectiveness.ConclusionsThe surgical residents stated that it was a meaningful course through which they gained practical knowledge on palliative care and that the experience would change their approach to home care.

Success in Meeting the Primary Endpoint in Phase III Trials: A Comparison of Industry and Cooperative Group Trials

Abstract 508 Background:Evaluation of research effort, especially estimation of the proportion of treatment successes in randomized clinical trials (RCTs), has important ethical, scientific, and public policy implications. Whether commercial or public sector research programs generate higher discovery rate of new successful treatments when tested in cancer RCTs is not known.These research programs are postulated to be governed by two competing hypotheses. The “equipoise/uncertainty hypothesis” assumes that investigators cannot predict trial results in advance, and as a consequence, the rate of discovering new treatments is about 50%. In contrast, the “design bias hypothesis” assumes that researchers conduct only those RCTs which have high likelihood of success. We hypothesize that the public sector RCTs are governed by the equipoise hypothesis while the industry-sponsored (IS) RCTs are based on the design bias hypothesis. Here we conduct the comparative systematic assessment to investigate if IS RCTs are associated with higher success rates than publicly-sponsored trials (PS) according to design bias versus equipoise/uncertainty hypothesis, respectively. Methods:All consecutive, published and unpublished, phase III cancer RCTs assessing treatment superiority and conducted by Canada's NCIC Clinical Trials Group (NCIC CTG) and GlaxoSmithKline (GSK) from 1980 to June 2010 were included. All trial protocols from GSK and NCIC CTG were reviewed independently by two reviewers to determine their eligibility. Two reviewers independently extracted data from eligible study protocols and publications using a standardized form. Three metrics were extracted to determine treatment successes: (1) the proportion of statistically significant trials favoring new or standard treatments, (2) the proportion of the trials in which new treatments were considered superior according to the original investigators, and (3) quantitative synthesis of data for primary outcomes as defined in each trial. An experimental regimen (drug compound or combinations or procedures), which was not tested previously in an RCT involving a specific cancer population or for alleviation of symptoms was classified as a major innovation. If a drug or regimen was already tested in a specific cancer population and testing involved dose modifications or changes in route of administration, it was classified as a minor innovation. Results:Between1980 to 2010 NCIC CTG conducted 77 RCTs enrolling 33,260 patients while GSK conducted 40 cancer RCTs accruing 19,889 patients. Forty two percent (99%CI 24 to 60) of the results were statistically significant favoring experimental treatments in GSK versus 25% (99%CI 13 to 37) in the NCIC CTG cohort (p=0.04). Investigators concluded that new treatments were superior to standard treatments in 80% of GSK versus 44% of NCIC CTG RCTs (p<0.0001) The GSK investigators deemed 32% (99%CI 14 to 50; 14/44) of interventions as “breakthroughs” versus 10% (99%CI 1 to 18; 8/82) by NCIC CTG investigators (p=0.002). Pooled analysis for the primary outcome indicated higher success rate in GSK trials (odds ratio: 0.61 [99%CI 0.47–0.78]) versus NCIC trials (odds ratio: 0.86 [99%CI 0.74–1.00]) (p=0.003). Experimental treatments were considered as major innovations in 32% (99%CI 15 to 49; 16/50) of GSK vs. 93% (99%CI 86 to 100; 78/84) of NCIC CTG trials (p<0.0001). Increased success rate in IS RCTs was mainly due to testing of new palliative agents, while the research program of NCIC CTG largely focused on development of therapies to improve survival. Conclusions:This first study evaluating the treatment success and pattern of therapeutic discoveries in IS versus PS research showed that industry discovers more successful new treatments compared with public sector. However, industry appears to undertake RCTs with high likelihood of success. PS research had significantly high proportion of major innovations compared with IS research. Disclosures:No relevant conflicts of interest to declare.

Epoetin in haemodialysis patients: impact of change from subcutaneous to intravenous routes of administration.

Cases of erythroblastopenia, as an adverse effect to epoetin (EPREX), led to its use being restricted in Europe to the intravenous route (i.v.) since July 2002, in patients with chronic renal insufficiency. This work aimed at investigating the biological, pharmaceutical and economic impacts of this change in policy. We retrospectively compared the characteristics of 99 haemodialysis patients treated with epoetin at the time of the recommendation (July 2002) and 5 months after the policy change (November 2002). In July 2002, 69 patients who were receiving EPREX subcutaneously (s.c./i.v. group) changed to the i.v. route of administration. Thirty other patients were already on i.v. epoetin (i.v. group). During the study period, the dose of epoetin increased significantly in the s.c./i.v. group but not in the i.v. group (46.83 +/- 10.20 UI/kg/week vs. 2.17 +/- 20.14 UI/kg/week respectively). This increased dosage was accounted for by a subgroup of 42 patients in the s.c./i.v. group while the others had dosage variations similar to those observed in the i.v. group. There were no significant clinical and biological changes associated with this change in route of administration. However, the change in policy led to the haemodialysis ward incurring an additional cost of 265,905 Euro (+32.7%) or an average annual extra cost of 1841 +/- 401 Euro per patient. Changing the route of administration of EPREX from the i.v. to the subcutaneous route required an increase in dosage and in substantial additional cost.

Changes in route of drug administration among continuing heroin users: Outcomes 1 year after intake to treatment

This study investigates the type and extent of changes in route of drug administration among heroin users after treatment: whether injectors move to other routes of use; whether changes in route for one drug influence routes used for other drugs; and associations between changes in route of administration and other substance use outcomes. The sample comprised 641 heroin users recruited to 54 UK treatment programmes. At intake, the main routes of heroin use were injecting (61%) and “chasing the dragon” (37%). After 1 year, 81% of those using heroin took it by the same route as at intake, while 19% reported a change, with 14% switching from injecting to chasing. Changes from injecting to chasing were associated with improvements in other substance use behaviours. Changes in route represent an important aspect of drug-taking behaviours. Interventions to prevent the change to injecting should be developed and offered to noninjectors. “Reverse transitions” (from injecting to chasing) may represent a useful intermediate treatment goal for drug injectors who cannot achieve abstinence.