Company-sponsored Trials Research Articles

Pooled Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone in Patients With Advanced Melanoma.

Nivolumab (NIVO) + ipilimumab (IPI) combination and NIVO monotherapy have demonstrated durable clinical benefit in patients with unresectable/metastatic melanoma. This analysis describes long-term overall survival (OS) with the combination or monotherapy pooled across all major company-sponsored trials, as well as clinical factors associated with survival, in patients with immune checkpoint inhibitor (ICI) treatment-naïve unresectable/metastatic melanoma. Data were pooled from six CheckMate studies in ICI treatment-naïve patients receiving NIVO + IPI (NIVO 1 mg/kg + IPI 3 mg/kg or NIVO 3 mg/kg + IPI 1 mg/kg) or NIVO monotherapy (3 mg/kg). OS was assessed for each treatment, as well as in select subgroups. Cox proportional multivariate analysis (MVA) and classification and regression tree (CART) analyses were performed within treatment arms. Median follow-up for OS was 45.0 months for patients treated with NIVO + IPI (n = 839) and 35.8 months for patients treated with NIVO (n = 536). OS was longer with NIVO + IPI versus NIVO monotherapy (hazard ratio, 0.78 [95% CI, 0.67 to 0.91]), with 6-year OS rates of 52% versus 41%, respectively. Consistent benefit was observed in BRAF-mutant and BRAF-wild-type patients and those with normal and elevated lactate dehydrogenase (LDH). Numerical difference in OS was also observed across PD-L1 expression levels, although more pronounced with no/low PD-L1 expression. Clinical factors associated with decreased survival in both the MVA and CART analyses were LDH > upper limit of normal with either treatment, age ≥65 years with NIVO + IPI, and the presence of liver metastases with NIVO monotherapy. In this large, pooled nonrandomized retrospective analysis, we observed that NIVO + IPI provides longer OS than NIVO in patients with ICI treatment-naïve advanced melanoma and identifies clinical factors that appear to be associated with survival for each treatment, which may assist with treatment decision making.

Publication of neurology clinical trials registered with clinical trial registry of India: A cross-sectional study.

Unbiased and full disclosure of trial results is vital to evidence-based medicine. Non-publication and selective publication leads to publication bias and unrealistic risk-benefit ratio. In the present study, we aim to determine the publication rate of clinical trials related to neurology registered with the Clinical Trial Registry of India (CTRI), compare the characteristics of published and unpublished trials, and evaluate the adherence of investigators to ethics-approved criteria and outcomes. A cross-sectional search using the keyword "neurology" was carried out in CTRI registry. Two independent investigators searched Pubmed, Medline, Scopus, and Google Scholar for published manuscripts. The final literature search occurred in November 2021. Out of 325 trials, 102 trials were published (31.4%). Ninety-one trials were beyond 3 years of expected time of trial completion and were still unpublished. Randomized trials had a slightly higher publication rate than non-randomized ones (56% vs. 46%, p= .223); however the difference was not statistically significant. Majority of trials sponsored by pharmaceutical companies were not published, while majority of those sponsored by non-pharmaceutical institutions were published (34.5% vs. 69.3%, p< .001). Feedback to CTRI about trial status was particularly poor (31.5% - informed vs. 68.5% - not informed, p< .001). 52 (50.9%) and 65 (63.7%) of the 102 published trials had changed the registered inclusion and exclusion criteria, respectively, in the CTRI registry compared to those in the published manuscript. In 29 (28.3%) of the 102 trials, the primary outcome did not match with that registered in the CTRI andin73 (57.8%) trials, the secondary outcomes did not match. A large proportion of neurology registered trials are still unpublished, with a majority of pharmaceutical company-sponsored trials not being published. There is scope for improving the provisions in CTRI for enlisting trial results, that may prevent publication bias and also ensure the investigators adhere to the pre-specified ethics approved trial procedures and outcomes.

Medications for daytime sleepiness in individuals with idiopathic hypersomnia.

Idiopathic hypersomnia is a disorder of excessive daytime sleepiness, often accompanied by long sleep times or pronounced difficulty in awakening, in the absence of a known cause. The optimal treatment strategy for idiopathic hypersomnia is currently unknown. To assess the effects of medications for daytime sleepiness and related symptoms in individuals with idiopathic hypersomnia and, in particular, whether medications may: 1. reduce subjective measures of sleepiness; 2. reduce objective measures of sleepiness; 3. reduce symptoms of cognitive dysfunction; 4. improve quality of life; and 5. be associated with adverse events. We searched the following databases on 4 February 2021: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to 1 February 2021), and reference lists of articles. CRS Web includes randomized or quasi-randomized controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialized registers of Cochrane Review Groups, including the Cochrane Epilepsy Group. We previously searched the WHO ICTRP separately when loading of ICTRP records into CRS Web was temporarily suspended. Randomized studies comparing any medication to placebo, another medication, or a behavioral intervention. Two review authors independently extracted data and assessed trial quality. We contacted study authors for additional data. We collected data on adverse events from the included trials. We included three trials, with a total of 112 participants. Risk of bias was low for the included studies. Two pharmaceutical company-sponsored trials compared modafinil with placebo, involving 102 participants, nearly all of whom had idiopathic hypersomnia without long sleep time. Modafinil significantly improved self-reported sleepiness on the Epworth Sleepiness Scale by 5.08 points more than placebo (95% confidence interval (CI) 3.01 to 7.16; 2 studies, 101 participants; high-certainty evidence). Modafinil also significantly improved disease severity on the Clinical Global Impression of Severity scale by 1.02 points (95% CI 0.11 to 1.93; 1 study, 30 participants; moderate-certainty evidence) and resulted in a greater proportion of participants who were "much improved" or "very much improved" on the Clinical Global Impression of Change (odds ratio (OR) for improvement 5.14, 95% CI 1.76 to 15.00; 1 study, 70 participants; moderate-certainty evidence). Ability to remain awake on the Maintenance of Wakefulness Test was significantly improved with modafinil, by 4.74 minutes more than with placebo (95% CI 2.46 to 7.01; 2 studies, 99 participants; high-certainty evidence).Ratings of exhaustion and effectiveness/performance were improved with modafinil compared to placebo in one study.Number of naps per week was no different between modafinil and placebo across two studies. Participants receiving modafinilexperienced more side effects, although the difference did not reach statistical significance (OR 1.68, 95% CI 0.28 to 9.94; 2 studies, 102 participants; low-certainty evidence). One trial studying 20 participants with different disorders of sleepiness included 10 participants with idiopathic hypersomnia, with or without long sleep time, and compared clarithromycin to placebo. We only included the subset of trial data for those participants with idiopathic hypersomnia, per our protocol. There were no significant differences between clarithromycin and placebo for the Epworth Sleepiness Scale, psychomotor vigilance testing, sleep inertia, other subjective ratings, or side effects. Modafinil is effective for the treatment of several aspects of idiopathic hypersomnia symptomatology, based on studies predominantly including participants with idiopathic hypersomnia without long sleep times, with low risk of bias, and evidence certainty ranging from high to low.There is insufficient evidence to conclude whether clarithromycin is effective for the treatment of idiopathic hypersomnia. There is a clear need for additional studies testing interventions for the treatment of idiopathic hypersomnia.

Abstract 4344: Racial representativeness of cancer clinical trials sponsored by the National Cancer Institute compared to pharmaceutical companies

Abstract Purpose Many clinical trials supporting new drug applications underrepresent minority patients. Trials conducted by the NCI's clinical trial network (NCTN) have greater outreach to community sites, potentially allowing better representation. We compared the representation of black patients in pharmaceutical company-sponsored cancer clinical trials to NCTN trials and the U.S. cancer population. Procedures We established a large cohort of study publications representing the results of pharmaceutical-company sponsored trials that supported new U.S. Food and Drug Administration (FDA) drug approvals from 2008-2018. NCTN trial data were from the SWOG Cancer Research Network. U.S. cancer population rates were estimated using Surveillance, Epidemiology, and End Results (SEER) survey data. We compared the proportion of black patients by enrollment year for each cancer type and overall. Comparisons between groups were conducted using tests of proportions. Results 227 trials (pharmaceutical company-sponsored trials, 74; SWOG trials, 153) comprised of 79,592 patients (pharmaceutical company-sponsored trials, 43,567; SWOG trials, 36,025) for nine specific cancer types were analyzed. Overall, the proportion of black patients was 2.9% for pharmaceutical company-sponsored trials, 8.3% for SWOG trials, and 12.1% for the U.S. cancer population (p&amp;lt;.001 for each pairwise comparison). For each cancer type, the proportion of black patients was statistically significantly lower for pharmaceutical company-sponsored trials compared to SWOG trials (except for melanoma) and compared to the U.S. cancer population. Conclusions The poor representation of minority groups in pharmaceutical company-sponsored trials is of vital scientific concern. These trials could support the use of new drugs with little data about efficacy or side effects in key populations. Because pharmaceutical company-sponsored trials test the newest available therapies, limited access to these trials represents a disparity in access to potential breakthrough therapies. Pharmaceutical companies could improve racial/ethnic diversity in their trials - and expand access to all patients - through increased outreach to community sites, as suggested by the findings for the NCTN trials. These results have the potential to directly influence policy, as the FDA, in partnership with the American Association for Cancer Research, is currently examining ways to improve representation of black patients in FDA registration trials. Citation Format: Joseph M. Unger, Dawn L. Hershman, Raymond U. Osarogiagbon, Anirudh Gothwal, Seerat Anand, Arvind Dasari, Michael Overnman, Jonathan M. Loree, Kanwal Raghav. Racial representativeness of cancer clinical trials sponsored by the National Cancer Institute compared to pharmaceutical companies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4344.

Utility of circulating tumor DNA (ctDNA) versus tumor tissue genotyping for enrollment of patients with metastatic colorectal cancer (mCRC) to matched clinical trials: SCRUM-Japan GI-SCREEN and GOZILA combined analysis.

4071 Background: We recently reported that ctDNA genotyping had advantages compared with tumor tissue testing in terms of enrollment to matched clinical trials across a wide range of GI cancers (Nakamura Y, et al. ASCO-GI 2020). Here, we investigated the utility of ctDNA genotyping in mCRC in a SCRUM-Japan GI-SCREEN and GOZILA combined analysis. Methods: In GI-SCREEN, tumor tissue genotyping was performed using a next generation sequencing (NGS)-based assay, Oncomine Comprehensive Assay since Feb 2015. In GOZILA, NGS-based ctDNA genotyping was performed using Guardant360 since Feb 2018. All tests were conducted centrally in a CLIA-certified and CAP-accredited laboratory. Patients with actionable alterations were enrolled into matched company-sponsored or investigator-initiated interventional clinical trials. Results: As of Apr 2019, 2,791 mCRC patients (2,754 eligible for analysis) in GI-SCREEN and 470 (464 eligible for analysis) in GOZILA were enrolled. There were no significant differences in baseline patient characteristics between GI-SCREEN and GOZILA. Most of trials affiliated with GI-SCREEN (81%) or GOZILA (78%) targeted the RTK/RAS/RAF pathway. Compared with tumor testing, ctDNA genotyping significantly improved turnaround time (median, 12 vs. 34 days, P &lt; 0.0001), sequencing success rate (96.1 vs. 92.3%, P = 0.002), and detection rate of actionable alterations (73.3 vs. 62.2%, P = 0.02). Among patients with actionable alterations, enrollment to matched clinical trials was achieved in 5.0% in GI-SCREEN and 12.1% in GOZILA ( P &lt; 0.0001). Median time from enrollment in the respective screening study to enrollment in a matched clinical trial was 6.5 months in GI-SCREEN and 0.9 months in GOZILA, respectively ( P &lt; 0.0001). Objective response rate and progression-free survival were similar in both groups (tissue vs. ctDNA; ORR: 18.8 vs. 17.1%, P = 1.00; median PFS: 2.2 vs. 2.2 months, HR=1.05 [95% CI, 0.71–1.55], P = 0.79). Conclusions: For patients with mCRC, ctDNA genotyping had advantages over tissue genotyping with shorter turnaround time and higher sequencing success and actionable alteration detection rate, which were associated with improved clinical trial enrollment without compromising the efficacy. Funding: SCRUM-Japan Funds. Clinical trial information: UMIN000029315 .

Seeding trials: Marketing gimmick or credible scientific research.

The pharmaceutical sector has become extensively competitive over the years across the world and India is no exception. While the World Health Organization (WHO) recommends 433 ‘essential medicines’ around 110,329 brands of registered pharmaceuticals, many of which are ‘me-too’ agents.[1,2] Competition in the industry fuels research and development, keeps prices of medicines in check and provides alternative therapeutic agents for the patients. However, in an overcrowded competitive market, enhancing or even sustaining sales volume and profit margins becomes increasingly difficult. Therefore, pharmaceutical companies often adopt aggressive and innovative marketing and positioning strategies aimed at influencing the prescribing habits of the physicians and try to usher them towards new medicines.[3,4] While prescribing new drugs, physicians often try to balance a range of factors, such as potential benefits and risk, long-term effects, cost and range of therapeutic indications. For quick assessment of these factors relatively little information is available in public domain and physicians have little or no prior experience with the use of the drug in a new indication. Under such circumstances, prescribing may be more ‘an act of faith’ than a rational process. In order to ‘educate’ and familiarise the prescriber with the new drug or a new indication of an old drug, manufacturer(s) often adopt various techniques.[3] Prominent among them are detailing by professional sales representative, distribution of promotional literature and physician's sample, conducting programmes such as continuing medical education (CME) activities, symposia and conferences, etc.[3,5] Another lesser-known method of drug promotion is ‘seeding trials’ or ‘marketing trials’.[6] What are seeding trials? Seeding trials are clinical studies designed by pharmaceutical companies with primary intention to promote the use of drugs that were recently approved or are under review by regulatory authorities.[6,7,8] Such trials have been described by Kesseler and colleagues as ‘company-sponsored trials of approved drugs that appear to serve little or no scientific purpose”. Many believe this as a marketing strategy in the guise of science. They are done to get physicians prescribe the new drug being marketed by the company rather than finding the safety and effectiveness of the drug.[6] The company promotes the new drug by sponsoring a clinical trial in which physicians participating as investigators are familiarised with the drug as they follow the trial protocol. It attempts to gratify the participating physicians by engaging them in the research team with the title of ‘investigator’. This honorable and supposedly academic involvement with the pharmaceutical industry for the cause of advancing science is often perceived as qualification for a physician to become ‘an opinion leader’ among their colleagues.[9] While the apparent purpose of such a study is to test a scientific hypothesis, the true purpose is to ‘seed’ the habit of prescribing the new drug into the trial investigators.[8] The company puts its new product in the hands of physicians, hoping that the experience of treating patients with the study drug and the pleasant interaction with the company will translate into increased prescription of the drug in their routine practice.[7] Early experience of using a new drug during its clinical development strongly influences its future use by the physician.[10] Andersen et al. had checked the association between physician participation in a clinical trial of fixed-dose combination of formoterol and budesonide, an asthma drug, and the prescribing patterns of their practices in the 2 years following the trial. The control group comprised general practitioners who did not participate as investigators in the clinical trial. They found that conducting the trial led to a significant increase in the use of the trial sponsor's drug by the investigators in their own daily practice as compared with the control group.[11] Seeding trials are also employed to trigger a ‘switch’ of brands from a competitor product to the new drug, thereby increasing volume of sales.[8] Another possible objective of conducting such trials is to convert the investigators into brand ambassadors of the new drug and use their research experience as testimonial for promoting the drug.[6]

1367P - Quality of life (QoL) in elderly NSCLC patients (pts) treated with nab-paclitaxel/carboplatin (nab-P/C) in the ABOUND.70+ trial

Background: Treatment of elderly pts with advanced NSCLC remains challenging, and the impact of therapies on QoL can be an important factor in clinical decisions. nab-P/C demonstrated efficacy in a subset of pts ≥ 70 yrs with NSCLC in a phase 3 trial. ABOUND.70+ was designed to determine whether a 1-wk break can further improve tolerability of nab-P/C in these patients. QoL outcomes are reported here. Methods: Pts ≥ 70 yrs with locally advanced/metastatic NSCLC were randomized 1:1 to first-line nab-P 100 mg/m2 on d 1, 8, and 15 + C AUC 6 on d 1 of a 21-day cycle (Arm A) or the same regimen with a 1-week break between cycles (Arm B). Primary endpoint: percentage of pts with grade ≥ 2 peripheral neuropathy or grade ≥ 3 myelosuppression. Key secondary endpoints: PFS, ORR, OS for which statistical analyses do not control for type I error (P values unadjusted). QoL (exploratory endpoint) was assessed using Lung Cancer Symptom Scale (LCSS) and EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) at d 1 of each cycle. Results: At interim evaluation, primary endpoint was similar across arms, resulting in early closure of enrollment. In Arms A and B, 78% and 79% completed a baseline and ≥ 1 postbaseline QoL assessment. LCSS item of cough improved with each cycle; at the end of cycle 6, mean change from baseline in Arms A and B was 25.4 and 13.8 mm (visual analog scale). For cough, median time to deterioration (TTD) was 4.4 and 4.7 mos (P = 0.7003). For the composite LCSS pulmonary symptom items of cough, shortness of breath, and hemoptysis, the median TTD was 4.4 and 6.0 mos (P = 0.3347). Mean maximum improvement (at any point during treatment) in EQ-5D-5L visual analog scale was 10.1 and 12.8 points. Table lists key safety, efficacy and QoL data.Table1367PArm A n = 71Arm B n = 72SafetyPrimary endpoint, n (%)52/68 (76)54/70 (77)P value0.9258Grade ≥ 2 peripheral neuropathy25/68 (37)25/70 (36)Grade ≥ 3 myelosuppression48/68 (71)45/70 (64)Neutropenia39/68 (57)39/70 (56)Anemia14/68 (21)17/70 (24)Thrombocytopenia17/68 (25)12/70 (17)EfficacyConfirmed ORR, %2440P value0.0376PFS, median, months3.67.0P value0.0019HR (95% CI)0.48 (0.30 - 0.76)OS, median, months15.216.2P value0.1966HR (95% CI)0.72 (0.44 - 1.19)QoLMean maximum improvement from baseline, mmLCSS Total score5.811.7LCSS Pulmonary symptom9.214.9 Open table in a new tab Conclusions: These results support nab-P/C as a treatment option in elderly pts with NSCLC. Safety (primary endpoint) and OS were similar across the two arms, while there was a signal of improvement in ORR, PFS, and QoL with a 1-wk break. NCT02151149. Clinical trial identification: NCT02151149 Legal entity responsible for the study: Celgene Corporation Funding: Celgene Corporation Disclosure: C.J. Langer: Consultant/Advisor Role: Celgene. J. Goldman, E. Kim: Research funding: Celgene. K. Konduri: Consultant/Advisory Role: Celgene, Boehringer Ingelheim, DAVA – Pharmaceuticals. A. Sanford, K. Amiri: Employment and stock ownership: Celgene. J. Weiss: Astellas: CME & company sponsored trials (CST); AZ, Biodesix, Clovis, Oncoples: consulting; Celgene: IIT support, CST support, SC; EMD Serono: DSMB member; GSK: IIT support; Medimmune, Pfizer: CST support, IIT support; Merck: CS Tsupport, IIT support. All other authors have declared no conflicts of interest.

Medications for daytime sleepiness in individuals with idiopathic hypersomnia

Background Idiopathic hypersomnia is a disorder of excessive daytime sleepiness, often accompanied by long sleep times or pronounced difficulty in awakening, in the absence of a known cause. The optimal treatment strategy for idiopathic hypersomnia is currently unknown. Objectives To assess the effects of medications for daytime sleepiness and related symptoms in individuals with idiopathic hypersomnia and, in particular, whether medications may: 1. reduce subjective measures of sleepiness; 2. reduce objective measures of sleepiness; 3. reduce symptoms of cognitive dysfunction; 4. improve quality of life; and 5. be associated with adverse events. Search methods We searched the following databases on 4 February 2021: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to 1 February 2021), and reference lists of articles. CRS Web includes randomized or quasi-randomized controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialized registers of Cochrane Review Groups, including the Cochrane Epilepsy Group. We previously searched the WHO ICTRP separately when loading of ICTRP records into CRS Web was temporarily suspended. Selection criteria Randomized studies comparing any medication to placebo, another medication, or a behavioral intervention. Data collection and analysis Two review authors independently extracted data and assessed trial quality. We contacted study authors for additional data. We collected data on adverse events from the included trials. Main results We included three trials, with a total of 112 participants. Risk of bias was low for the included studies. Two pharmaceutical company-sponsored trials compared modafinil with placebo, involving 102 participants, nearly all of whom had idiopathic hypersomnia without long sleep time. Modafinil significantly improved self-reported sleepiness on the Epworth Sleepiness Scale by 5.08 points more than placebo (95% confidence interval (CI) 3.01 to 7.16; 2 studies, 101 participants; high-certainty evidence). Modafinil also significantly improved disease severity on the Clinical Global Impression of Severity scale by 1.02 points (95% CI 0.11 to 1.93; 1 study, 30 participants; moderate-certainty evidence) and resulted in a greater proportion of participants who were "much improved" or "very much improved" on the Clinical Global Impression of Change (odds ratio (OR) for improvement 5.14, 95% CI 1.76 to 15.00; 1 study, 70 participants; moderate-certainty evidence). Ability to remain awake on the Maintenance of Wakefulness Test was significantly improved with modafinil, by 4.74 minutes more than with placebo (95% CI 2.46 to 7.01; 2 studies, 99 participants; high-certainty evidence). Ratings of exhaustion and effectiveness/performance were improved with modafinil compared to placebo in one study. Number of naps per week was no different between modafinil and placebo across two studies. Participants receiving modafinil experienced more side effects, although the difference did not reach statistical significance (OR 1.68, 95% CI 0.28 to 9.94; 2 studies, 102 participants; low-certainty evidence). One trial studying 20 participants with different disorders of sleepiness included 10 participants with idiopathic hypersomnia, with or without long sleep time, and compared clarithromycin to placebo. We only included the subset of trial data for those participants with idiopathic hypersomnia, per our protocol. There were no significant differences between clarithromycin and placebo for the Epworth Sleepiness Scale, psychomotor vigilance testing, sleep inertia, other subjective ratings, or side effects. Authors' conclusions Modafinil is effective for the treatment of several aspects of idiopathic hypersomnia symptomatology, based on studies predominantly including participants with idiopathic hypersomnia without long sleep times, with low risk of bias, and evidence certainty ranging from high to low. There is insufficient evidence to conclude whether clarithromycin is effective for the treatment of idiopathic hypersomnia. There is a clear need for additional studies testing interventions for the treatment of idiopathic hypersomnia.

Abstract 2305: Comparative evaluation of peripheral blood T cells and resultant engineered anti-CD19 CAR T cell products from relapsed/refractory non-Hodgkin's lymphoma (NHL) patients

Abstract Introduction: Administration of autologous anti-CD19 CAR T cells prepared from peripheral blood mononuclear cells (PBMC) of patients with various B cell malignancies have mediated high rates of objective response (Kochenderfer et al. Blood 2012, J Clin Onc 2014, Mackall et al, Blood 2013). We analyzed characteristics of the starting material (PBMC) and resultant CAR T cells derived from 14 patients with relapsed/refractory NHL at the NCI Surgery Branch. Methods: After apheresis collection, the T cell-containing PBMC fraction was enriched, activated with anti-CD3 antibody and cultured in serum-free medium for 2 days. Activated T cells were transduced with a retroviral vector encoding the anti-CD19 CAR gene and further expanded with IL-2 to achieve a target dose of CAR T cells. The CAR T cells and starting PBMC population were cryopreserved and analyzed after thawing by flow cytometry. Differences in cell composition between the starting PBMC population and CAR T cells were evaluated with paired t-tests, adjusted for multiplicity. Results: Biologically active autologous CAR T cells were successfully prepared from all 14 NHL subjects. Each product was comprised of both CD4+ and CD8+ T cells, but showed considerable inter-subject variability. The CD4/CD8 ratio in the PBMC and product CAR T cell population were correlated (Pearson correlation coefficient = 0.74, p = 0.0027). While the starting T cell population generally showed a T cell profile comprised of similar proportions of effector T cells (Teff) ($\bar{x}$ = 20%, std = 16%) and naïve T cells (Tn) ($\bar{x}$ = 20%, std = 14%), there was a shift towards a less differentiated T cells population after CAR T cell production, with a decreased Teff (paired t test p = 0.0151) and elevated Tn (p = 0.0031). The percent of juvenile cells (Tn+Tcm) was higher in the final product ($\bar{x}$ = 64%, std = 21%) than in the starting T cell population ($\bar{x}$ = 43%, std = 20%, p* = 0.0031, *stepdown Bonferonni). These products were active in vitro and in subjects with NHL. Clinical responses occurred regardless of product characteristic differences such as CD4/CD8 T cell ratio and juvenile / differentiated T cells. Additional analyses are ongoing, including evaluation of PD-1 expression,% of myeloid cells and gene expression profile. Conclusions: CAR T cells were successfully prepared from all subjects enrolled in the study notwithstanding the diverse nature of the subject starting lymphocyte population. The CAR T cells showed a less differentiated profile, compared to the starting lymphocytes. CAR T cell production by essentially the same process described here is currently being utilized in company-sponsored multicenter trials (NCT02348216, NCT02601313). Citation Format: Timothy Langer, Emily Lowe, Arianne Perez, Steven Rosenberg, Steven A. Feldman, Lily Lu, John M. Rossi, Edmund Chang, Marika Sherman, Marc Better, James N. Kochenderfer, Adrian Bot. Comparative evaluation of peripheral blood T cells and resultant engineered anti-CD19 CAR T cell products from relapsed/refractory non-Hodgkin's lymphoma (NHL) patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2305.

Beyond confusion and controversy, can we evaluate the real efficacy and safety of cholesterol-lowering with statins?

A strong controversy has emerged about the reality of safety and efficacy of statins as stated by company-sponsored reports. However, physicians need credible data to make medical decisions, in particular about the benefit/harm balance of any prescription. This study aimed to test the validity of data on the company-sponsored statin trial by comparing them over time and then comparing statins with each other. Around the years 2005/2006, new stricter Regulations were introduced in the conduct and publication of randomized controlled trials (RCTs). This would imply that RCTs were less reliable before 2006 than they were later on. To evaluate this, we first reviewed RCTs testing the efficacy of statins versus placebo in preventing cardiovascular complications and published after 2006. Our systematic review thereby identified four major RCTs, all testingrosuvastatin. They unambiguously showed that rosuvastatin is not effective in secondary prevention, while the results are highly debatable in primary prevention. Because of the striking clinical heterogeneity and the inconsistency of the published data in certain RCTs, meta-analysis was not feasible. We then examined the most recent RCTs comparing statins to each other: all showed that no statin is more effective than any other, including rosuvastatin. Furthermore, recent RCTs clearly indicate that intense cholesterol-lowering (including those with statins) does not protect high-risk patients any better than less-intense statin regimens. As for specific patient subgroups, statins appear ineffective in chronic heart failure and chronic kidney failure patients. We also conducted a MEDLINE search to identify all the RCTs testing a statin against a placebo in diabetic patients, and we found that once secondary analyses and subgroup analyses are excluded, statins do not appear to protect diabetics. As for the safety of statin treatment – a major issue for medical doctors – it is quite worrisome to realize that it took 30 years to bring to light the triggering effect of statins on new-onset diabetes, manifestly reflecting a high level of bias in reporting harmful outcomes in commercial trials, as has been admitted by the recent confession of prominent experts in statin treatment. In conclusion, this review strongly suggests that statins are not effective for cardiovascular prevention. The studies published before 2005/2006 were probably flawed, and this concerned in particular the safety issue. A complete reassessment is mandatory. Until then, physicians should be aware that the present claims about the efficacy and safety of statins are not evidence based.

Kaleidoscope.

Antidepressant effectiveness is a topic seldom out of the scientific or popular press, with claim and counter-claim about the disclosure, reporting, and interpretation of data. Hieronymus and colleagues1 have thrown their hats into the ring: noting that about half of company-sponsored trials failed to show any superiority over placebo, they challenge that most studies evaluated changes in total scores on the 17-point Hamilton Rating Scale for Depression (HRSD-17), but that this might mask improvement in important subcomponents. Not all items equally correlate with illness burden, so they undertook patient-level post hoc analyses focusing on the four-point depressed mood subcomponent in 18 placebo-controlled industry trials of various selective serotonin reuptake inhibitors (n = 6669). The choice of this question was based on its diagnostic importance and the fact it had the highest baseline severity in the pooled sample. The result was that 91% of comparisons showed superiority of the active drug over placebo, compared with 46% where the summed scale was used (P&lt;0.001). The authors argue that the summed scale is insensitive, and clouds current views on medications. The end of the debate? We think not …

Invited Commentary

Imagination is more important than knowledge. For knowledge is limited, whereas imagination embraces the entire world.–Albert Einstein, 1929 While Einstein wanted to describe imagination as the driving force behind the search for knowledge, the widespread use of a transcatheter aortic valve replacement (TAVR) is an example for the replacement of knowledge by imagination. It is quite astonishing that a novel technique like TAVR with at first a non-inferiority status [1Smith C.R. Leon M.B. Mack M.J. et al.Transcatheter versus Surgical Aortic-Valve Replacement in High-Risk Patients.N Engl J Med. 2011; 364: 2187-2198Crossref PubMed Scopus (4768) Google Scholar] over the established methods, shown in only 1 prospective randomized trial (by the way, sponsored by the same company selling the novel devices) with a very limited number of participants, could gain such relevance in patient treatment as well as in the scientific discussion. The superiority [2Adams D.H. Popma J.J. Reardon M.J. et al.Transcatheter aortic-valve replacement with a self-expanding prosthesis.N Engl J Med. 2014; 370: 1790-1798Crossref PubMed Scopus (2023) Google Scholar] of TAVR over conventional AVR could only later be shown in an, again, company-sponsored trial. The paper of Ribeiro and colleagues [3Ribeiro H. Dahou A. Urena M. et al.Myocardial injury after transaortic versus transapical transcatheter aortic valve replacement.Ann Thorac Surg. 2015; 99: 2001-2009Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar] deals with 2 different TAVR techniques (transaortic versus transapical approach) regarding myocardial injury and ventricular function after the procedure. A clear message can be read between the lines, although very cautiously phrased: transaortic (TAO) TAVR is superior to transapical (TA) TAVR because TAO TAVR leads to less myocardial injury and to a better left ventricular recovery. Interestingly, this does not lead to better clinical outcomes after 30 days or 12 months in the TAO TAVR group, as one would expect knowing the influence of high cardiac biomarkers on long-term outcomes after valve surgery [4Paparella D. Guida P. Caparrotti S. et al.Myocardial damage influences short- and mid-term survival after valve surgery: a prospective multicenter study.J Thorac Cardiovasc Surg. 2014; 148: 2373-2379Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar]. One important detail to be found in Supplemental Table 3 is not mentioned by the authors. Moderate or severe aortic valve regurgitation occurs nearly 4 times more often (nearly significantly more often) in the TAO TAVR group. Although there are data available on how high-degree aortic regurgitation worsens long-term survival [5Abdel-Wahab M. Zahn R. Horack M. et al.Aortic regurgitation after transcatheter aortic valve implantation: incidence and early outcome. Results from the German transcatheter aortic valve interventions registry.Heart. 2011; 97: 899-906Crossref PubMed Scopus (440) Google Scholar], the clinical outcomes of the 2 patient groups in this study are similar. Is it possible that higher biomarkers in the TA TAVR group and more aortic regurgitation in the TAO TAVR group balance each other? Clearly, the hypotheses of Ribeiro and colleagues [3Ribeiro H. Dahou A. Urena M. et al.Myocardial injury after transaortic versus transapical transcatheter aortic valve replacement.Ann Thorac Surg. 2015; 99: 2001-2009Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar] have to be proven “by future studies with larger sample size … to determine whether or not differences in myocardial injury … translate into significant differences in mortality…”, as the authors state themselves. Ribeiro and colleagues are to be congratulated on an excellent study inspired by their imagination, but they still have to contribute to the “limited knowledge.” Einstein again: “It’s important to go on asking questions.” Myocardial Injury After Transaortic Versus Transapical Transcatheter Aortic Valve ReplacementThe Annals of Thoracic SurgeryVol. 99Issue 6PreviewThe release of cardiac biomarkers of myocardial injury after transcatheter aortic valve replacement (TAVR) is common, but no data exist on patients undergoing TAVR through a transaortic approach. We aimed to evaluate the incidence and prognostic significance of the increase in cardiac biomarkers in nontransfemoral TAVR candidates, comparing transaortic and transapical approaches. Full-Text PDF

Consistent superiority of selective serotonin reuptake inhibitors over placebo in reducing depressed mood in patients with major depression.

The recent questioning of the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs) is partly based on the observation that approximately half of company-sponsored trials have failed to reveal a significant difference between active drug and placebo. Most of these have applied the Hamilton depression rating scale to assess symptom severity, the sum score for its 17 items (HDRS-17-sum) serving as effect parameter. In this study, we examined whether the negative outcomes of many SSRI trials may be partly caused by the use of this frequently questioned measure of response. We undertook patient-level post-hoc analyses of 18 industry-sponsored placebo-controlled trials regarding paroxetine, citalopram, sertraline or fluoxetine, and including in total 6669 adults with major depression, the aim being to assess what the outcome would have been if the single item depressed mood (rated 0–4) had been used as a measure of efficacy. In total, 32 drug-placebo comparisons were reassessed. While 18 out of 32 comparisons (56%) failed to separate active drug from placebo at week 6 with respect to reduction in HDRS-17-sum, only 3 out of 32 comparisons (9%) were negative when depressed mood was used as an effect parameter (P<0.001). The observation that 29 out of 32 comparisons detected an antidepressant signal from the tested SSRI suggests the effect of these drugs to be more consistent across trials than previously assumed. Further, the frequent use of the HDRS-17-sum as an effect parameter may have distorted the current view on the usefulness of SSRIs and hampered the development of novel antidepressants.

Exclusion Criteria In The Dasision and Enestnd Trials: Which Could Their Impact Be On The Front-Line Treatment Of a “Real-life” Patient Population With Chronic Myelogenous Leukemia?

The DASISION and ENESTnd controlled clinical trials have changed the front-line treatment of Chronic Myelogenous Leukemia (CML) leading to the advent of dasatinib and nilotinib in this setting: however, both these company-sponsored trials had many exclusion criteria, with a possible selection bias compared to the real-life CML population. To address the impact of these exclusion criteria on the 1st line treatment in the current clinical practice, we revised 207 unselected newly diagnosed chronic phase CML patients [M/F 108/99, median age 58.8 years, interquartile range (IR) 42.3 – 70.2] treated with front-line imatinib from June 2002 to June 2013 at our Institution and evaluated how many of them would have been excluded from enrolment in the 2 trials. Among these 207 patients, 28 patients should have been excluded by both trials due to polycomorbidities (12 cases), severe cardiopathy (5 cases), age > 80 with frailty (3 cases), drug abuse (2 cases), severe liver impairment, Rendu-Osler disease, active prostatic cancer, chronic obstructive broncopulmonar disease (COPD) + peripheral arterial obstructive disease (PAOD), COPD + arrhythmia, refusal to any marrow examination (1 case each). In addition, 8 patients should have been considered not eligible only for the DASISION due to isolated COPD and 19 patients should have been considered not eligible only for the ENESTnd due to isolated diabetes (10 cases), arrhythmia (4 cases), acute myocardial infarction > 6 months before CML diagnosis (2 cases), chronic pancreatic disease (2 cases), PAOD (1 case). On the whole, 36/207 patients (17.4%) would have been considered not eligible for the DASISION trial and 47/207 (22.7%) for the ENESTnd trial. As expected, these patients potentially not eligible for DASISION and ENESTnd were significantly older and with the imatinib treatment had a worse follow-up in terms of Complete Cytogenetic Response (CCyR), Major Molecular Response (MMolR) and Overall Survival (OS) compared to patients potentially eligible, as shown in the Table.DASISION ELIGIBLEDASISION NOT ELIGIBLEpENESTnd ELIGIBLEENESTnd NOT ELIGIBLEpMedian age (IR)54.7 (41.1-67.6)71.1 (62.5-79.6)<0.00153.7 (40.6-67.2)70.5 (59.6-78.5)<0.001CCyR (%)151/171 (88.3%)26/36 (72.2%)0.002143/160 (89.3%)34/47 (72.3%)0.002MMolR (%)126/171 (73.6%)19/36 (52.7%)0.001119/160 (74.3%)26/47 (55.3%)<0.0015-year OS96.3%82.8%<0.00196.8%84.8%0.008In conclusion, our data highlight that an important fraction of newly diagnosed patients in a real-life setting would have been excluded by the 2 controlled trials whose results are the current mainstay of the 1st line treatment in CML: thus, an automatic transposition of those results into the current clinical practice should be regarded with caution. Disclosures:No relevant conflicts of interest to declare.

4-Year Outcome Of 215 Patients With Newly Diagnosed Chronic Myeloid Leukemia (CML) Treated Frontline With Nilotinib In Investigator-Sponsored Studies. A Report From The Gimema CML Working Party

BackgroundNilotinib is a potent and selective BCR-ABL inhibitor approved for the frontline treatment of CML. The latest update (4-yr follow-up) of the ENESTnd study demonstrated sustained superiority of nilotinib vs. imatinib (Hochhaus et al, EHA 2013, abstract 712). The CML Italian Registry of Nilotinib is the largest series of patients treated frontline with nilotinib-based regimens, outside of Company-sponsored trials. Therefore, it represents an important resource for an independent evaluation of the outcome of such patients. Aimsto analyze the response rates and outcome in an independent cohort of patients treated frontline with nilotinib-based regimens in Italy. MethodsThe CML Italian Registry of Nilotinib includes 215 patients, enrolled in 2 multicenter phase II studies conducted by the GIMEMA CML WP (ClinicalTrials.gov. NCT00481052 and NCT00769327) with nilotinib 300 mg or 400 mg BID as initial treatment; 123 patients received a sequential treatment with nilotinib and imatinib, with a 3-mo rotation period. The median age was 53 years (range 18–86). Ten out of 215 patients (5%) had a high EUTOS score. The median follow-up was 43 months (range 18–69 months). We analyzed: the rates of Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR); the overall survival (OS; any death included), progression-free survival (PFS; progression to accelerated/blast phase [AP/BP] and deaths for any cause), failure-free survival (FFS; failures according to ELN 2013 recommendations and deaths for any cause), and event-free survival (EFS; events: failures, permanent discontinuation of nilotinib for any cause, including deaths). ResultsRates of CCyR were 72% and 92% by 3 months and 12 months, respectively. Rates of MMR were 56% and 83% by 3 months and 12 months, respectively. The cumulative rates of CCyR and MMR were 93% and 92%, respectively. Overall, events were recorded in 64 (30%) patients: 31 (14%) patients permanently discontinued nilotinib for adverse events or intolerance; 22 (10%) patients failed therapy according to ELN 2013 recommendations, including 8 (3.7%) patients that progressed to AP/BP; 11 (5%) patients permanently discontinued nilotinib for other reasons. All progressions to AP/BP occurred within the first year of therapy, and all patients subsequently died. Nilotinib-resistant mutations were identified in 5 of these patients (4 T315I; 1 Y253H). No difference in the rate of progression to AP/BP was observed between patients receiving nilotinib alone or nilotinib and imatinib in sequential schedule. Overall, 15 (7%) patients died, in 7 cases for reasons unrelated to CML progression. The 4-year OS, PFS, FFS, and EFS were 93%, 93%, 86%, and 69%, respectively. ConclusionThese Italian nilotinib registry data provide an independent and unbiased overview of the therapeutic effects of nilotinib, with high and early rates of complete cytogenetic and major molecular response. All progressions (3.7%) to AP or BP occurred within the 1st year of therapy; however, all cases were fatal, emphasizing how crucial is the prevention of AP/BP. With a median follow-up of 43 months, 69% of patients were still on nilotinib, and 93% were alive and progression-free. AcknowledgmentsEuropean LeukemiaNet, COFIN, Bologna University, BolognAIL [Display omitted] Disclosures:Gugliotta:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Castagnetti:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Bocchia:Novartis and Bristol Mayer Squibb: Honoraria. Soverini:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; ARIAD: Consultancy. Saglio:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Cavo:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Baccarani:Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Pfizer: Honoraria; Ariad: Honoraria. Rosti:Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Ariad: Consultancy; Roche: Speakers Bureau.

Clinical trial transparency: an assessment of the disclosure of results of company-sponsored trials associated with new medicines approved recently in Europe

Background:Previous studies have raised concerns around the transparency and disclosure rates of clinical trial results on clinical trial registries and in the scientific literature. The objective of this study was to assess the timely disclosure in the public domain of results of company-sponsored clinical trials related to all new medicines approved by the European Medicines Agency (EMA) over a recent 3 year period.Methods:The study surveyed various publicly available information sources for both clinical trial registration and disclosure of results (including clinical trial registries, the International Federation of Pharmaceutical Manufacturers and Associations [IFPMA] Clinical Trials Portal, EMA European Public Assessment Reports and PubMed), searched from 27 December 2012 to 31 January 2013. The study covered all 53 new medicines (except vaccines and fixed-dose combinations) approved for marketing by 34 pharmaceutical companies by the EMA in 2009, 2010 and 2011. It included all completed company-sponsored clinical trials conducted in patients and recorded on a clinical trial registry and/or included in an EPAR.Outcome measure and results:The main outcome measure was the proportion of trials for which results had been disclosed on a registry or in the scientific literature either within 12 months of the later of either first regulatory approval or trial completion, or by 31 January 2013 (end of survey). Of the completed clinical trials associated with all 53 new medicines approved by the EMA between 2009 and 2011, 77% had results disclosed within 12 months. By 31 January 2013, this had increased to 89%. Rates of results disclosure within 12 months were 71%, 81% and 86% for new medicines approved in 2009, 2010 and 2011 respectively. Disclosure increased to 86%, 93% and 91% respectively by 31 January 2013. Although this was a purely quantitative study which did not aim to assess the content of disclosure against any specific requirements, limitations relating to a number of difficulties in finding all relevant data from multiple sources in the public domain were captured.Conclusions:Results of over three-quarters of all company-sponsored clinical trials related to new medicines recently approved by the EMA were disclosed within a year of completion or regulatory approval, and almost 90% were disclosed by 31 January 2013, suggesting transparency is now better than has sometimes been reported previously.

An Analysis of Guidance for Proper Usage Documents for Oncology Drugs in Japan

Pharmaceutical companies in Japan often provide a unique document called the Guidance for Proper Usage (GPU) to medical oncologists, in order to promote the proper use of an approved drug. The aim of the study was to examine the content of and current trends in the efficacy and safety data provided in GPU documents, in order to understand what pharmaceutical companies regard as important information for an oncologist to ensure proper usage of oncology drugs in Japan. Furthermore, this study analysed the influence of route of administration (oral or injection), drug class (cytotoxic or other), type of malignancy (haematological or solid malignancy) and the period of GPU publication (before and after April 2004) on the content of the GPU document. For the 103 oncology drugs approved for use in Japan, 59 GPU documents, covering 50 drugs, were distributed to medical oncologists and were compared by multivariate analysis over two consecutive time periods, from October 1994 to March 2004 and April 2004 to December 2010. For each document, we determined the total number of pages and the proportion of pages that provided drug and toxicity information and the results of registration trials, including postmarketing surveillance. The median number of pages in the GPUs was 48 (range, 11–98). The proportion of pages providing toxicity information, drug information (e.g. warnings, contraindications, instructions, and directions for indications and usage, dosage and administration) and the results of registration trials were 30%, 26% and 11%, respectively. After April 2004, the publication of GPU documents doubled, and the proportion of pages discussing the results of registration trials significantly increased (p = 0.002). The proportions of pages discussing toxicity information and the results of registration trials in molecular-targeted drugs were significantly greater than those for other types of drugs (p < 0.001 and p = 0.008, respectively), while the proportion of pages discussing drug information was significantly lower (p = 0.001). The number and length of GPU publications distributed by pharmaceutical companies in Japan has increased since 2004. Significant changes in content have included a reduction in the amount of information about drug administration and an increase in information on the results of pharmaceutical company-sponsored registrational trials. A further study is warranted to evaluate how often oncologists actually access GPU documents and what type of information could be most useful in medical practice in Japan.

Abstract PL03-02: Current status of recombinant pox-viral vaccines

Abstract PL03-02: Current status of recombinant pox-viral vaccines

Grundlagen, Planung und Durchführung nichtkommerzieller klinischer Studien

The proof of a drug's efficacy in randomized controlled trials is fundamental to therapeutic concepts determined by evidence-based medicine. Clinical trials according to the German Medicinal Products Act are performed by the pharmaceutical industry as company-sponsored trials (CST) driven by commercial interests or by non-commercial facilities as investigator-initiated trials (IIT), typically implemented by University Hospitals. In areas with no commercial interest, IITs are the driving force that generate scientific progress leading to treatment optimization. Therefore, non-commercial or investigator-initiated clinical trials are indispensable for improving medical care. To ensure the safety of trial participants and the quality of the data obtained, clinical trials are controlled by many legal regulations and internationally accepted quality standards. Therefore implementation of a clinical trial requires profound knowledge, qualified personnel, appropriate infrastructure, and substantial financial resources. In IITs unlike CSTs this has to be accomplished by the University without the assistance of the pharmaceutical industry. Since teaching of skills needed to perform clinical trials is still largely neglected in medical school and during residency this review addresses the (in clinical trials) inexperienced physician and outlines the characterization of a clinical trial, the range and division of responsibilities and the performance of clinical trials according to the German Medicinal Products Act.

Bone pain from granulocyte colony stimulating factor: does clinical trial sponsorship by a pharmaceutical company influence its reporting?

It is alleged that pharmaceutical companies sometimes unfairly present clinical trial results. To our knowledge, studies have not explored whether such alleged unfair reporting also occurs in the testing of palliative care agents in cancer patients, a particularly vulnerable group. Therefore, a systematic search was conducted to retrieve all published, prospective clinical trials that used granulocyte colony stimulating factor starting in 2003. Because granulocyte colony stimulating factor can cause severe bone pain - a concerning but historically under-reported symptom in cancer patients - this symptom was assessed to determine whether differences in reporting occurred based on pharmaceutical company-sponsorship. A total of 239 published clinical trials met the present study's eligibility criteria and were retrievable. Within this entire group of studies, 65 (27%) were pharmaceutical company-sponsored, and only 31 (13%) reported on bone pain. However, pharmaceutical company-sponsored trials reported on bone pain at a higher rate compared with other studies: 23% versus 9% (P= 0.005), and this conclusion did not change after adjusting for dose, use of the slow release formulation and year of publication. The reporting of adverse events from cancer symptom control and palliative care interventions should be improved - especially in trials not sponsored by pharmaceutical companies.