NCI’s national treatment trial networks: Experience and adaptations during COVID-19.

1562 Background: The National Cancer Institute supports several national trial networks which responded rapidly to the COVID-19 pandemic to overcome operational barriers to clinical cancer research. The National Clinical Trials Network (NCTN) focuses on late phase treatment trials, while the Experimental Therapeutics Clinical Trials Network (ETCTN) conducts early phase treatment trials. We report findings on the experience and adaptations of these networks during COVID-19. Methods: Using 2019 and 2020 accrual data, we analyzed changes in accrual levels and demographics. We also evaluated changes in trial activation numbers and timelines. In July 2020, we surveyed 255 investigators from academic and community sites to assess changes in research practices and get feedback on modified processes implemented by NCI to address trial conduct during the pandemic. Results: Accrual across the NCTN and ETCTN fell significantly in mid-March 2020, dropping from a weekly average of 307 patients in February to 169 the week of March 23-29. Accrual began to recover in June and July but did not return to pre-pandemic levels until September. Accrual in November and December 2020 followed the patterns seen in 2019, with short-term drops around major holidays. Non-White participants were enrolled to NCTN and ETCTN trials at similar monthly rates throughout 2019 and 2020, with slightly higher overall enrollment in 2020 (23.7% vs. 22.7%). New trials continued to be developed and activated throughout 2020. Between 2017 and 2019, an average of 71 trials were activated per year (NCTN = 46, ETCTN = 25), compared to 84 activated in 2020 (NCTN = 58, ETCTN = 26). The average time to trial activation was similar or slightly longer in 2020 compared to 2019. The investigator survey yielded 111 responses (43.5% response rate). 43% of respondents’ sites paused enrollment to phase 1 trials during the pandemic, compared to 18% for phase 3 trials. Many sites temporarily stopped opening new trials and processing specimens. Sites were more likely to keep enrolling to trials offering clear potential benefit and pause complex trials that required more patient contact. Respondents attributed some of the decline in accrual to a reduction in overall patient volume, increased patient concerns, and reduced research staff on site. Respondents were asked to rate the usefulness of modified trial processes NCI put in place during the pandemic. Telehealth was rated most useful (avg. 4.6/5), followed by shipping oral IND agents to enrolled patients (4.5/5), remote informed consent (4.2/5), coordinating care with local providers (3.9/5), and remote auditing (3.7/5). Conclusions: The cancer trials community has an opportunity to learn from working through the challenges of COVID-19. NCI will seek to continue and expand on modifications to clinical trial processes that have the potential to improve operational efficiency, reduce cost, and help bring trials to more patients.

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Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

Advances in Pulmonary Hypertension ◽

10.21693/1933-088x-9.4.214 ◽

2010 ◽

Vol 9 (4) ◽

pp. 214-219

Author(s):

Robyn J. Barst

Keyword(s):

Clinical Trials ◽

Pulmonary Arterial Hypertension ◽

Drug Development ◽

Phase 1 ◽

Preclinical Studies ◽

Phase 2 ◽

Phase 3 ◽

Preclinical Testing ◽

New Drug ◽

Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

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Efficacy and Safety of SOBERANA 02, a COVID-19 conjugate vaccine in heterologous three doses combination

10.1101/2021.10.31.21265703 ◽

2021 ◽

Author(s):

Maria Eugenia Toledo-Romani ◽

Mayra Garcia-Carmenate ◽

Carmen Valenzuela Silva ◽

Waldemar Baldoquin-Rodriguez ◽

Marisel Martinez Perez ◽

...

Keyword(s):

Clinical Trials ◽

Placebo Group ◽

Conjugate Vaccine ◽

Neutralizing Antibodies ◽

Phase 1 ◽

Dose Schedule ◽

T Cell Response ◽

Group 14 ◽

Phase 3 ◽

Double Blinded

Background: SOBERANA 02 is a COVID19 conjugate vaccine (recombinant RBD conjugated to tetanus toxoid). Phase 1 and 2 clinical trials demonstrated its high immunogenicity, promoting neutralizing IgG together with specific T-cell response. A third dose of SOBERANA Plus (SARS-CoV-2 RBD-dimer) further increased the specific anti-RBD neutralizing antibodies. Methods: In a randomized, double-blinded, placebo-controlled, phase 3 trial we randomly assigned 44 031 participants, aged 19-80 years to three groups in a 1:1:1 ratio to receive 28 days apart either a) two doses of 25 microg SOBERANA 02, or b) two doses of 25 microg SOBERANA 02 followed by a third dose of 50 microg SOBERANA Plus, or c) two doses of placebo. Reported study endpoints are vaccine efficacy (VE) evaluated through laboratory-confirmed symptomatic COVID-19 cases and safety. During the trial, the SARS CoV-2 isolates in Havana were predominantly (beta 74.0 %) and shift gradually to delta (100%). Results: Two doses of SOBERANA 02 protects against symptomatic COVID-19: 43 cases in the two-dose group (14 371) vs. 155 in the placebo group (14 403), VE 71.0%, adjusted (CI 95%58.9-79.1). The heterologous three dose combination with SOBERANA Plus protected against symptomatic COVID-19: 15 cases in the vaccine groups (13 833) vs. 155 in the placebo group (14 303), VE 92.4%, adjusted (CI 95% 86.9-95.6%). For two-dose schedule VE against severe COVID-19 was 63.0% and for death 59.0%; for heterologous three-dose schedule, 100% in both cases. Conclusions: This is the first phase 3 study of a three-dose, heterologous vaccine combination against SARS-CoV-2. Two doses of the conjugate vaccine SOBERANA 02 was safe and attained efficacy of 71.0% in adults population 19-80 y/o; incorporating SOBERANA Plus after two doses of SOBERANA 02, increased efficacy from 71.0 % to 92.4% (Clinical Trials IFV/COR/09 number, RPCEC00000354.)

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The race for a coronavirus vaccine

Bionatura ◽

10.21931/rb/2020.05.04.1 ◽

2020 ◽

Vol 5 (4) ◽

pp. 1290-1292

Author(s):

Gerardo Ferbeyre ◽

Nelson Santiago Vispo

Keyword(s):

Clinical Trials ◽

Viral Vectors ◽

Phase 1 ◽

Phase 3 ◽

Antiviral Immune Response ◽

Degree Of Protection ◽

Advantages And Disadvantages ◽

Phases Of Development ◽

Vaccination Campaigns ◽

Short Time

The international race to find a preventive vaccine and effective treatments against COVID 19 has been influenced by two fundamental factors. Firstly, by the molecular characterization of the causative virus and the pathology it produces, and secondly, by access to this information, mostly free of charge by the international scientific community causing a synergy to obtain results in such a short time. Several vaccines preparations against Covid19 have entered Phase 3 clinical trials. Although it is uncertain the degree of protection that they will achieve, preliminary data from Phase 1 and 2 trials and studies in animals indicate that they trigger an antiviral immune response without serious side effects. The current formulations include viral vectors, RNA vaccines, inactivated viruses, and recombinant proteins particles. They all have advantages and disadvantages, but only the results of Phase 3 clinical trials will ultimately decide the best candidates for vaccination campaigns. The tremendous impact of the SARS-CoV-2 in our society has triggered an unprecedented effort to find a vaccine to control the pandemic. Billions of dollars have already been invested in multiple vaccination schemes. According to the WHO, more than 170 vaccines were in different phases of development in August 2020. Here is a summary of the advantages and disadvantages of the front runner strategies categorized according to their delivery method.

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Assessing Sunscreen Protection Using UV Photography: Descriptive Study (Preprint)

10.2196/preprints.24653 ◽

2020 ◽

Author(s):

Caitlin Horsham ◽

Helen Ford ◽

Jeremy Herbert ◽

Alexander Wall ◽

Sebastian Walpole ◽

...

Keyword(s):

Clinical Trials ◽

New Zealand ◽

Phase 1 ◽

Sun Protection ◽

Trial Registration ◽

Phase 2 ◽

Phase 3 ◽

The Public ◽

Uv Photography ◽

Clinical Trials Registry

BACKGROUND Photography using a UV transmitting filter allows UV light to pass and can be used to illuminate UV blocking lotions such as sunscreens. OBJECTIVE The aim of this study is to compare currently available UV photography cameras and assess whether these devices can be used as visualization tools for adequate coverage of sun protection lotions. METHODS This study was conducted in 3 parts: in phase 1, 3 different UV cameras were tested; in phase 2, we explored whether UV photography could work on a range of sun protection products; and in phase 3, a UV webcam was developed and was field-tested in a beach setting. In phase 1, volunteers were recruited, and researchers applied 3 sun protection products (ranging from sun protection factor [SPF] 15 to 50+) to the participants’ faces and arms. UV photography was performed using 3 UV cameras, and the subsequent images were compared. In phase 2, volunteers were recruited and asked to apply their own SPF products to their faces in their usual manner. UV photographs were collected in the morning and afternoon to assess whether the coverage remained over time. Qualitative interviews were conducted to assess the participants’ level of satisfaction with the UV image. In phase 3, a small portable UV webcam was designed using a plug-and-play approach to enable the viewing of UV images on a larger screen. The developed webcam was deployed at a public beach setting for use by the public for 7 days. RESULTS The 3 UV camera systems tested during phase 1 identified the application of a range of sun protection lotions of SPF 15 to 50+. The sensitivity of the UV camera devices was shown to be adequate, with SPF-containing products applied at concentrations of 2 and 1 mg/cm<sup>2</sup> clearly visible and SPF-containing products applied at a concentration of 0.4 mg/cm<sup>2</sup> having lower levels of coverage. Participants in phase 2 reported high satisfaction with the UV photography images, with 83% (29/35) of participants likely to use UV photography in the future. During phase 2, it was noted that many participants used tinted SPF-containing cosmetics, and several tinted products were further tested. However, it was observed that UV photography could not identify the areas missed for all tinted products. During phase 3, the electrical components of the UV webcam remained operational, and the camera was used 233 times by the public during field-testing. CONCLUSIONS In this study, we found that UV photography could identify the areas missed by sun protection lotions with chemical filters, and participants were engaged with personalized feedback. CLINICALTRIAL Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12619000975190; http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377089 ; Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12619000145101; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376672.

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LB7. Ad26.COV2.S-Elicted Neutralizing Activities Against SARS-CoV-2 Variants of Concern in Phase 1/2a and Phase 3 Clinical Trials

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1638 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S804-S805

Author(s):

Mathieu Le Gars ◽

Jerald Sadoff ◽

Mandy Jongeneelen ◽

Dirk Heerwegh ◽

Georgi Shukarev ◽

...

Keyword(s):

Clinical Trials ◽

Single Dose ◽

Phase 1 ◽

Geometric Mean ◽

Wild Type Virus ◽

Original Strain ◽

Wild Type ◽

Serum Samples ◽

Phase 3 ◽

Neutralizing Activity

Abstract Background In a Phase 3 trial, the Janssen COVID-19 vaccine, Ad26.COV2.S, showed robust efficacy against severe–critical COVID-19 in countries where different SARS-CoV-2 variants were circulating. We evaluated Ad26.COV2.S-elicited antibody neutralizing activity against variants of concern (VOC) B.1.1.7 (Alpha), B.1.351 (Beta), and B.1.617.2 (Delta) in sera from participants in clinical trials following a single dose of Ad26.COV2.S. Methods Neutralizing activities of Ad26.COV2.S (given at a dose level of 5 x 1010 viral particles [vp]) against VOC were assessed by wild-type virus neutralizing (wtVNA) and pseudovirion neutralization (psVNA) assays in sera from participants in Phase 1/2a and Phase 3 clinical trials, respectively. Geometric mean titers (GMTs) were determined at Days 29 and 71 after vaccination. Results In serum samples from Phase 1/2a participants (n = 6), at Day 29 after 1 dose of Ad26.COV2.S, wtVNA titers against VOC were lower than for the original strain (GMT = 573), with GMT = 65, 14, and 15 for Alpha, Beta, and Delta, respectively, representing 8.8-, 40.9-, and 37.7-fold decreases. By Day 71 after vaccination (n = 14), fold differences between the original strain (GMT = 375) and VOC (GMT = 113, 27, and 28) were smaller (3.3-, 13.9-, and 13.4-fold) than at Day 29, suggestive of B-cell maturation (Figure 1). Day 71 titers against the Delta variant were maintained for at least 8 months following a single dose of Ad26.COV2.S (5 x 1010 vp). In serum samples from Phase 3 participants (n = 8), psVNA titers against VOC were lower than the original strain at Day 71 after vaccination, with the lowest titers observed for the Beta variant (3.6-fold decrease vs original strain). Smaller reductions in Nab titers for VOC were observed in the psVNA assay compared to wtVNA. Figure 1. Neutralization of B.1.1.7 (Alpha), B.1.351 (Beta), and B.1.617.2 (Delta) lineages in serum samples from participants who received Ad26.COV2.S. n = 6 samples at Day 29 and n = 14 (n = 14 for Alpha and Beta; n = 6 for Delta, comprising the same 6 participants at Day 29) samples at Day 71 after vaccination with a single dose of Ad26.COV2.S (5 x 10^10 vp dose level) were analyzed in wild-type virus neutralization assays against the SARS-CoV-2 Victoria strain (D614, black dots), the B.1.1.7 (Alpha; green dots) the B.1.351 (Beta; blue dots), and the B.1.617.2 (Delta; purple dots) lineages. Dots represent the IC50 (inhibitory concentration) titers per participant. Geometric mean titers (GMTs) and fold decrease in neutralizing activity between the original Victoria strain and each lineage are shown. Conclusion Ad26.COV2.S-elicited serum neutralizing activity against VOC showed an overall decrease in titers relative to the original strain that was largest for the Beta variant, even though vaccine efficacy against severe–critical COVID-19 was maintained in countries where these variants were circulating versus in countries where they were not circulating. Over time, titers against variants increased, suggesting B-cell affinity maturation leading to increasing coverage of VOC. Disclosures Mathieu Le Gars, n/a, Johnson & Johnson (Employee, Shareholder) Jerald Sadoff, MD, Johnson & Johnson (Employee, Shareholder) Mandy Jongeneelen, n/a, Johnson & Johnson (Employee, Shareholder) Dirk Heerwegh, n/a, Janssen Research and Development (Employee) Georgi Shukarev, MD, Janssen (Employee) Carla Truyers, n/a, Janssen Research and Development (Employee) Anne Marit de Groot, n/a, Johnson & Johnson (Employee) Gert Scheper, n/a, Johnson & Johnson (Employee, Shareholder) Jenny Hendriks, n/a, Johnson & Johnson (Employee, Shareholder) Boerries Brandenburg, n/a, Johnson & Johnson (Employee, Shareholder) Frank Struyf, n/a, Johnson & Johnson (Employee, Shareholder) Johan Van Hoof, n/a, Johnson & Johnson (Employee, Shareholder) Macaya Douoguih, MD, MPH, Janssen (Employee) Hanneke Schuitemaker, PhD, Johnson & Johnson (Employee, Shareholder)

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regCOVID: Tracking publications of registered COVID-19 studies

10.21203/rs.3.rs-905657/v1 ◽

2021 ◽

Author(s):

Craig Mayer ◽

Vojtech Huser

Keyword(s):

Clinical Trials ◽

Clinical Studies ◽

Late Phase ◽

Phase 3 ◽

Multiple Study ◽

Vaccine Trials ◽

Study Results ◽

Phase Phase ◽

Trial Phase

Abstract In response to the COVID-19 pandemic many clinical studies have been initiated leading to the need for efficient ways to track and analyze study results. We expanded our previous project that tracked registered COVID-19 clinical studies to also track result articles generated from these studies. We conducted searches of ClinicalTrials.gov and PubMed to identify articles linked to COVID-19 studies, and developed criteria based on the trial phase, intervention, location, and record recency to develop a prioritized list of result publications. We found 760 articles linked to 419 interventional trials (15.7% of all 2 669 COVID-19 interventional trials as of 15 August 2021), with 418 identified via abstract-link in PubMed and 342 via registry-link in ClinicalTrials.gov. Of the 419 trials publishing at least one article, 123 (29.4%) have multiple linked publications. We used an attention score to develop a prioritized list of all publications linked to COVID-19 trials and identified 58 publications that are result articles from late phase (Phase 3) trials with at least one US site and multiple study record updates. For COVID-19 vaccine trials, we found 69 linked result articles for 40 trials (13.9% of 290 total COVID-19 vaccine trials). Our method allows for the efficient identification of important COVID-19 articles that report results of registered clinical trials and are connected via a structured article-trial link.

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An update on targeted therapies in systemic sclerosis based on a systematic review from the last 3 years

Arthritis Research & Therapy ◽

10.1186/s13075-021-02536-5 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Corrado Campochiaro ◽

Yannick Allanore

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Systemic Sclerosis ◽

Targeted Therapies ◽

Observational Studies ◽

Phase 1 ◽

Phase 2 ◽

Inclusion Criteria ◽

Phase 3 ◽

Trial Drug

AbstractNew molecular mechanisms that can be targeted with specific drugs have recently emerged for the treatment of systemic sclerosis (SSc) patients. Over the past 3 years, the achievement of one large phase 3 trial has led to the approval by drug agencies of the first drug licenced for SSc-related interstitial lung disease. Given this exciting time in the SSc field, we aimed to perform a systemic literature review of phase 1, phase 2 and phase 3 clinical trials and large observational studies about targeted therapies in SSc. We searched MEDLINE/PubMed, EMBASE, and ClinicalTrials.gov for clinical studies from 2016 with targeted therapies as the primary treatment in patients with SSc for skin or lung involvement as the primary clinical outcome measure. Details on the study characteristics, the trial drug used, the molecular target engaged by the trial drug, the inclusion criteria of the study, the treatment dose, the possibility of concomitant immunosuppression, the endpoints of the study, the duration of the study and the results obtained were reviewed. Of the 973 references identified, 21 (4 conference abstracts and 17 articles) were included in the systematic review. A total of 15 phase 1/phase 2 clinical trials, 2 phase 3 clinical trials and 2 observation studies were analysed. The drugs studied in phase 1/phase 2 studies included the following: inebilizumab, dabigatran, C-82, pomalidomide, rilonacept, romilkimab, tocilizumab, tofacitinib, pirfenidone, lenabasum, abatacept, belimumab, riociguat, SAR100842 and lanifibranor. All but 3 studies were performed in early diffuse SSc patients with different inclusion criteria, while 3 studies were performed in SSc patients with interstitial lung disease (ILD). Phase 3 clinical trials investigated nintedanib and tocilizumab. Nintedanib was investigated in SSc-ILD patients whereas tocilizumab focused on early diffuse SSc patients with inflammatory features. Two observational studies including > 50 patients with rituximab as the targeted drug were also evaluated. All these studies offer a real hope for SSc patients. The future challenges will be to customize patient-specific therapeutics with the goal to develop precision medicine for SSc.

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The changing atlas of clinical research in cancer: Measuring accessibility to clinical trials.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e14123 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e14123-e14123

Author(s):

Luca Mazzarella ◽

Giulia Tini ◽

Pammolli Fabio ◽

Righetto Lorenzo ◽

Giuseppe Curigliano ◽

...

Keyword(s):

Resource Allocation ◽

Clinical Trials ◽

Clinical Research ◽

Phase 1 ◽

Healthcare Research ◽

Site Location ◽

Middle Income ◽

Trial Conduct ◽

Global Economic Growth ◽

The Impact

e14123 Background: The recent global economic growth produced dramatic social changes that impacted healthcare. Private industries, low and middle income countries increased their interest in clinical research. How these changes impact on accessibility to clinical trials has not been sufficiently studied, an issue becoming more relevant as trials increasingly constitute a relevant source of access to innovative drugs. Methods: We analyzed changes related to funding source, phase and locations involved in all interventional clinical trials on cancer extracted from clinicaltrials.gov from 2005 to 2019. We studied the evolution of accessibility to clinical trials on worldwide scale, by developing a family of indexes weighted on population, distance from the site location, numbers of trials. These indexes were also used to simulate different resource allocation models. Results: The absolute involvement of industry in clinical trials consistently increased (~6 fold over 2005), with a significant bias for phase 1 trials; however, its relative impact has globally remained the same. The geographical distribution of trial sites changed dramatically: some nations (China, Korea) increased their total number of trials 50 fold. The number of countries with ≥10 multicentric studies grew from 3 to 16. Our accessibility index (Table, relative increment on 2005 in parenthesis) shows that Asia had the highest improvement, with Korea and Taiwan as leading countries. The analysis captures significant trends associated with changing policies on trial conduct, such as the introduction in 2012 and abandonment in 2015 of centralized ethical committees in Brazil, or the introduction of EUdract in Europe in 2015. Simulations allowed to identify specific resource allocations to maximize accessibility. Conclusions: Accessibility to clinical trials is improving worldwide, but with important differences across continents and countries, which follow social, economic and political changes. Our accessibility indexes can inform national and continental healthcare/research policies, as they predict the impact of different resource allocation models, representing useful tools to facilitate access to innovative treatments. [Table: see text]

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Levoleucovorin as Replacement for Leucovorin in Cancer Treatment

Annals of Pharmacotherapy ◽

10.1345/aph.1q677 ◽

2012 ◽

Vol 46 (10) ◽

pp. 1349-1357 ◽

Cited By ~ 6

Author(s):

Victor Tuan Giam Chuang ◽

Manabu Suno

Keyword(s):

Clinical Trials ◽

Cancer Treatment ◽

Clinical Studies ◽

English Language ◽

Antitumor Agents ◽

Data Extraction ◽

Phase 1 ◽

Phase 3 ◽

Medline Search ◽

Reasonable Alternative

Objective: To comprehensively review the literature regarding the efficacy, safety, and costs associated with the use of levoleucovorin in cancer treatment and to assess whether levoleucovorin would be a reasonable alternative to the use of racemic leucovorin. Data Sources: A MEDLINE search was conducted for English-language human studies published between January 1980 and April 2012 using the terms I-LV. levoleucovorin, d,I-LV, leucovorin, folinic acid, tolinate, 5-formyltetrahydrofolate, folic acid, folates, methotrexate, 5-fluorouracil, and clinical trials. Study Selection and Data Extraction: Articles pertinent to clinical trials (Phase 1, 2, 3) related to evaluating the efficacy, interchangeability, and safety of levoleucovorin were collected and their contents reviewed. Data Synthesis: From these pharmacokinetics and clinical studies, information on the use of levoleucovorin as a modulator of fluorouracil as well as when combined with other antitumor agents were scrutinized and extracted for comparison with leucovorin whenever possible. Two randomized Phase 3 clinical studies comparing the efficacy and adverse effect profiles of leucovorin and levoleucovorin demonstrated that levoleucovorin is as effective as leucovorin in terms of response, toxicity, and survival. Six randomized Phase 3 clinical studies demonstrated the safety and efficacy of levoleucovorin as a modulator of fluorouracil in combination with/without other antitumor agents in colorectal cancer patients. Levoleucovorin has been studied in other cancers. These clinical Phase 1/2/3 studies demonstrated efficacy and safety of levoleucovorin in combination chemotherapeutic regimens comprising fluorouracil and other antitumor agents. Conclusions: The results of the clinical studies suggest that levoleucovorin is efficacious and can be used safely in combination with fluorouracil and other antitumor agents. Levoleucovorin can be used interchangeably with leucovorin for modulating fluorouracil. The current shortage of the supply of leucovorin centered in North America renders levoleucovorin a reasonable alternative in terms of efficacy and toxicity profile, but from the perspective of cost, leucovorin remains the drug of choice.

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Free of charge medicine schemes in the NHS. A local and regional Drug and Therapeutic Committees (DTC) experience.

10.22541/au.162601445.50513844/v1 ◽

2021 ◽

Author(s):

Simon O'Callaghan ◽

Robin Ferner ◽

Andrew Barron ◽

Katherine Saxby ◽

Reecha Sofat (CURRENTLY UNAVAILABLE)

Keyword(s):

Clinical Trials ◽

Observational Studies ◽

Phase 1 ◽

Clinical Trial Data ◽

Access To Medicines ◽

Pharmaceutical Companies ◽

Phase 3 ◽

Regulatory Oversight ◽

Early Access ◽

Drug And Therapeutics Committee

Introduction: Free-of-charge (FoC) medicine schemes are increasingly available and allow access to investigational treatments outside clinical trials or in advance of licensing or NHS commissioning. Methods: We retrospectively reviewed FoC medicine schemes evaluated between 2013 and 2019 by a single NHS trust and a regional drug and therapeutics committee (DTC). The details of each locally reviewed FoC scheme, and any nationally available MHRA Early Access to Medicines Scheme (MHRA EAMS) in the same period, were recorded and categorised. Results: Most FoC schemes (95%) allowed access to medicines intended to address an unmet clinical need. Over 7 years, 90% were company-FoC schemes and 10% were MHRA EAMS that were locally reviewed. Phase 3 clinical trial data were available for 44% of FoC schemes; 37% had phase 2 data; and 19% were supported only by phase 1, retrospective observational studies, or pre-clinical data. Utilisation of company-FoC schemes increased on average by 50% per year, while MHRA EAMS showed little growth. Conclusion: Company-FoC medicine schemes are increasingly common. This may indicate a preference for pharmaceutical companies to independently co-ordinate schemes. Motivations for company-FoC schemes remain unclear and many provide access to treatments that are yet to be evaluated in appropriately conducted clinical trials, and whose efficacy and risk of harm remain uncertain. There is no standardisation of this practice and there is no regulatory oversight. Moreover, no standardised data collection framework is in place that could demonstrate the utility of such programmes in addressing unmet clinical need or allow generation of further evidence.

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