scholarly journals Statins as Potential Chemoprevention or Therapeutic Agents in Cancer: a Model for Evaluating Repurposed Drugs

2021 ◽  
Vol 23 (3) ◽  
Author(s):  
Nalinie Joharatnam-Hogan ◽  
Leo Alexandre ◽  
James Yarmolinsky ◽  
Blossom Lake ◽  
Nigel Capps ◽  
...  
Keyword(s):  
Drug Development ◽  
Controlled Trial ◽  
Randomised Trial ◽  
Drug Repurposing ◽  
Cancer Chemoprevention ◽  
Cost Effective ◽  
Evidence Base ◽  
Phase Iii ◽  
Epidemiological Research ◽  
Repurposed Drugs

Abstract Purpose of Review Repurposing established medicines for a new therapeutic indication potentially has important global and societal impact. The high costs and slow pace of new drug development have increased interest in more cost-effective repurposed drugs, particularly in the cancer arena. The conventional drug development pathway and evidence framework are not designed for drug repurposing and there is currently no consensus on establishing the evidence base before embarking on a large, resource intensive, potential practice changing phase III randomised controlled trial (RCT). Numerous observational studies have suggested a potential role for statins as a repurposed drug for cancer chemoprevention and therapy, and we review the strength of the cumulative evidence here. Recent Findings In the setting of cancer, a potential repurposed drug, like statins, typically goes through a cyclical history, with initial use for several years in another disease setting, prior to epidemiological research identifying a possible chemo-protective effect. However, further information is required, including review of RCT data in the initial disease setting with exploration of cancer outcomes. Additionally, more contemporary methods should be considered, such as Mendelian randomization and pharmaco-epidemiological research with “target” trial design emulation using electronic health records. Pre-clinical and traditional observational data potentially support the role of statins in the treatment of cancer; however, randomised trial evidence is not supportive. Evaluation of contemporary methods provides little added support for the use of statin therapy in cancer. Summary We provide complementary evidence of alternative study designs to enable a robust critical appraisal from a number of sources of the go/no-go decision for a prospective phase III RCT of statins in the treatment of cancer.

Old Drugs with New Tricks; Paradigm in Drug Development Pipeline for Alzheimer’s Disease

2020 ◽  
Vol 20 ◽  
Author(s):  
Tanay Dalvi ◽  
Bhaskar Dewangan ◽  
Rudradip Das ◽  
Jyoti Rani ◽  
Suchita Dattatray Shinde ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Molecular Targets ◽  
Drug Repurposing ◽  
Phase Iii ◽  
Complex Nature ◽  
New Drug ◽  
Development Pipeline ◽  
Old Drugs

: The most common reason behind dementia is Alzheimer’s disease (AD) and it is predicted to be the third lifethreatening disease apart from stroke and cancer for the geriatric population. Till now only four drugs are available in the market for symptomatic relief. The complex nature of disease pathophysiology and lack of concrete evidences of molecular targets are the major hurdles for developing new drug to treat AD. The the rate of attrition of many advanced drugs at clinical stages, makes the de novo discovery process very expensive. Alternatively, Drug Repurposing (DR) is an attractive tool to develop drugs for AD in a less tedious and economic way. Therefore, continuous efforts are being made to develop a new drug for AD by repursing old drugs through screening and data mining. For example, the survey in the drug pipeline for Phase III clinical trials (till February 2019) which has 27 candidates, and around half of the number are drugs which have already been approved for other indications. Although in the past the drug repurposing process for AD has been reviewed in the context of disease areas, molecular targets, there is no systematic review of repurposed drugs for AD from the recent drug development pipeline (2019-2020). In this manuscript, we are reviewing the clinical candidates for AD with emphasis on their development history including molecular targets and the relevance of the target for AD.

The cost-effectiveness of atezolizumab in first-line for metastatic triple negative breast cancer is heavily linked to PD-L1 level

2021 ◽  
pp. 107815522110194
Author(s):  
Jacopo Giuliani ◽  
Beatrice Mantoan ◽  
Andrea Bonetti
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Controlled Trial ◽  
Metastatic Breast ◽  
Cost Effective ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Pivotal Phase ◽  
First Line Treatment

The present analysis was conducted to assess the pharmacological costs of atezolizumab as first-line treatment in triple negative metastatic breast cancer (mBC). Pivotal phase III randomized controlled trial (RCT) was considered. Nine hundred and two patients were included. Differences in costs between the 2 arms (atezolizumab plus nabpaclitaxel versus placebo plus nab-paclitaxel) was 17 398 €, with a cost of 7564 €per month of OS-gain in the overall population and 2485 €per month of OS-gain in PD-L1-positive (≥1) population. Combining pharmacological costs of drugs with the measure of efficacy represented by the OS, atezolizumab could be considered cost-effective in first-line treatment for triple-negative mBC only in PD-L1-positive population, but a reduction of costs is mandatory.

OP02 A Managed Access Approach To Appraising New Cancer Drugs In England

2017 ◽  
Vol 33 (S1) ◽  
pp. 1-2
Author(s):  
Linda Landells ◽  
Martyn Burke ◽  
Meindert Boysen
Keyword(s):  
Cost Effective ◽  
Integrated Approach ◽  
Evidence Base ◽  
Phase Iii ◽  
Appraisal Committee ◽  
Cancer Drugs ◽  
Cancer Treatments ◽  
Considerable Uncertainty ◽  
Health Technologies ◽  
Current Price

INTRODUCTION:The changing regulatory landscape brings new challenges to Health Technology Assessment (HTA). Marketing authorizations are being granted as the evidence base evolves to facilitate timely patient access to promising health technologies. Consequently, some products come to HTA bodies sooner in their development cycles with less evidence, which ultimately leads to greater uncertainty in decision making. A key challenge for payer and HTA bodies is providing access to promising medicines while the evidence is still emerging, in a financially sustainable way.METHODS:Changes to the Cancer Drugs Fund (CDF) have resulted in a managed access fund for cancer medicines in England. The National Institute for Health and Care Excellence (NICE) can now recommend a treatment for use within the CDF if there is plausible potential to satisfy the criteria for routine use in the National Health Service (NHS) at its current price, but the evidence is not robust enough and associated with significant uncertainty. Further evidence is then generated in clinical trials, through observational data collection, or a combination of the two, while the drug's price reflects the decision uncertainty. At the end of the managed access period, NICE reviews the guidance to determine if the treatment can be recommended for routine commissioning.RESULTS:The first treatment recommended for use within the new CDF was osimertinib for non-small cell lung cancer (1). At the time of NICE appraisal, there was considerable uncertainty in osimertinib's clinical and cost effectiveness because only short-term phase II trial results were available. NICE's independent appraisal committee considered there was plausible potential for osimertinib to be cost effective and identified that an ongoing phase III trial would provide longer-term data addressing the key uncertainties.CONCLUSIONS:An integrated approach between payer and HTA decision-maker has significantly changed how cancer treatments in England are appraised. This collaborative way of working heralds a more sustainable approach to introducing promising cancer treatments.

scholarly journals Protocol for the DisCoVeRy trial: multicentre, adaptive, randomised trial of the safety and efficacy of treatments for COVID-19 in hospitalised adults

BMJ Open ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. e041437
Author(s):  
Florence Ader
Keyword(s):  
Controlled Trial ◽  
Clinical Status ◽  
Antiviral Agents ◽  
Randomised Trial ◽  
Phase Iii ◽  
Ordinal Scale ◽  
Control Group ◽  
National Agency ◽  
Open Label ◽  
Hospitalised Patients

IntroductionTo find effective and safe treatments for COVID-19, the WHO recommended to systemically evaluate experimental therapeutics in collaborative randomised clinical trials. As COVID-19 was spreading in Europe, the French national institute for Health and Medical Research (Inserm) established a transdisciplinary team to develop a multi-arm randomised controlled trial named DisCoVeRy. The objective of the trial is to evaluate the clinical efficacy and safety of different investigational re-purposed therapeutics relative to Standard of Care (SoC) in patients hospitalised with COVID-19.Methods and analysisDisCoVeRy is a phase III, open-label, adaptive, controlled, multicentre clinical trial in which hospitalised patients with COVID-19 in need of oxygen therapy are randomised between five arms: (1) a control group managed with SoC and four therapeutic arms with re-purposed antiviral agents: (2) remdesivir + SoC, (3) lopinavir/ritonavir + SoC, (4) lopinavir/ritonavir associated with interferon (IFN)-β−1a + SoC and (5) hydroxychloroquine + SoC. The primary endpoint is the clinical status at Day 15 on the 7-point ordinal scale of the WHO Master Protocol (V.3.0, 3 March 2020). This trial involves patients hospitalised in conventional departments or intensive care units both from academic or non-academic hospitals throughout Europe. A sample size of 3100 patients (620 patients per arm) is targeted. This trial has begun on 22 March 2020. Since 5 April 2020, DisCoVeRy has been an add-on trial of the Solidarity consortium of trials conducted by the WHO in Europe and worldwide. On 8 June 2020, 754 patients have been included.Ethics and disseminationInserm is the sponsor of DisCoVeRy. Ethical approval has been obtained from the institutional review board on 13 March 2020 (20.03.06.51744) and from the French National Agency for Medicines and Health Products (ANSM) on 9 March 2020. Results will be submitted for publication in peer-reviewed journals.Trial registration numberNCT04315948 Eudra-CT 2020-000936-23.

scholarly journals The Role of Nicotinamide in Cancer Chemoprevention and Therapy

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 477 ◽  
Author(s):  
Ilias P. Nikas ◽  
Stavroula A. Paschou ◽  
Han Suk Ryu
Keyword(s):  
Clinical Trials ◽  
Cancer Chemoprevention ◽  
Cost Effective ◽  
Water Soluble ◽  
Sirtuin 1 ◽  
Phase Iii ◽  
Soluble Form ◽  
Vitamin B3 ◽  
Preclinical Research ◽  
Phase Iii Clinical Trials

Nicotinamide (NAM) is a water-soluble form of Vitamin B3 (niacin) and a precursor of nicotinamide-adenine dinucleotide (NAD+) which regulates cellular energy metabolism. Except for its role in the production of adenosine triphosphate (ATP), NAD+ acts as a substrate for several enzymes including sirtuin 1 (SIRT1) and poly ADP-ribose polymerase 1 (PARP1). Notably, NAM is an inhibitor of both SIRT1 and PARP1. Accumulating evidence suggests that NAM plays a role in cancer prevention and therapy. Phase III clinical trials have confirmed its clinical efficacy for non-melanoma skin cancer chemoprevention or as an adjunct to radiotherapy against head and neck, laryngeal, and urinary bladder cancers. Evidence for other cancers has mostly been collected through preclinical research and, in its majority, is not yet evidence-based. NAM has potential as a safe, well-tolerated, and cost-effective agent to be used in cancer chemoprevention and therapy. However, more preclinical studies and clinical trials are needed to fully unravel its value.

scholarly journals When is a randomised controlled trial health equity relevant? Development and validation of a conceptual framework

BMJ Open ◽  
2017 ◽  
Vol 7 (9) ◽  
pp. e015815 ◽  
Author(s):  
J Jull ◽  
M Whitehead ◽  
M Petticrew ◽  
E Kristjansson ◽  
D Gough ◽  
...  
Keyword(s):  
Conceptual Framework ◽  
Health Equity ◽  
Controlled Trial ◽  
Randomised Trial ◽  
Evidence Base ◽  
Social Disadvantage ◽  
Randomised Trials ◽  
Individual Level ◽  
International Research Team ◽  
Randomised Controlled

BackgroundRandomised controlled trials can provide evidence relevant to assessing the equity impact of an intervention, but such information is often poorly reported. We describe a conceptual framework to identify health equity-relevant randomised trials with the aim of improving the design and reporting of such trials.MethodsAn interdisciplinary and international research team engaged in an iterative consensus building process to develop and refine the conceptual framework via face-to-face meetings, teleconferences and email correspondence, including findings from a validation exercise whereby two independent reviewers used the emerging framework to classify a sample of randomised trials.ResultsA randomised trial can usefully be classified as ‘health equity relevant’ if it assesses the effects of an intervention on the health or its determinants of either individuals or a population who experience ill health due to disadvantage defined across one or more social determinants of health. Health equity-relevant randomised trials can either exclusively focus on a single population or collect data potentially useful for assessing differential effects of the intervention across multiple populations experiencing different levels or types of social disadvantage. Trials that are not classified as ‘health equity relevant’ may nevertheless provide information that is indirectly relevant to assessing equity impact, including information about individual level variation unrelated to social disadvantage and potentially useful in secondary modelling studies.ConclusionThe conceptual framework may be used to design and report randomised trials. The framework could also be used for other study designs to contribute to the evidence base for improved health equity.

scholarly journals RESPIRE 1: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis

2018 ◽  
Vol 51 (1) ◽  
pp. 1702052 ◽  
Author(s):  
Anthony De Soyza ◽  
Timothy Aksamit ◽  
Tiemo-Joerg Bandel ◽  
Margarita Criollo ◽  
J. Stuart Elborn ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Incidence Rate Ratio ◽  
Controlled Trial ◽  
Randomised Trial ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Dry Powder ◽  
Effective Treatment Option ◽  
Double Blind ◽  
Treatment Regimens

We evaluated the efficacy and safety of ciprofloxacin dry powder for inhalation (DPI) in patients with non-cystic fibrosis bronchiectasis, two or more exacerbations in the previous year and pre-defined bacteria in sputum.In this phase III, double-blind, placebo-controlled trial, patients were randomised 2:1 to twice-daily ciprofloxacin DPI 32.5 mg or placebo in two treatment regimens consisting of on/off treatment cycles of 14 or 28 days for 48 weeks. The primary end-points were time to first exacerbation and frequency of exacerbations.A total of 416 patients were randomised to the 14-day on/off regimen (ciprofloxacin DPI (n=137) and placebo (n=68)) or the 28-day on/off regimen (ciprofloxacin DPI (n=141) and placebo (n=70)). Ciprofloxacin DPI 14 days on/off significantly prolonged time to first exacerbationversuspooled placebo (median time >336versus186 days; hazard ratio 0.53, 97.5% CI 0.36–0.80; p=0.0005) and reduced the frequency of exacerbations compared with matching placebo by 39% (mean number of exacerbations 0.6versus1.0; incidence rate ratio 0.61, 97.5% CI 0.40–0.91; p=0.0061). Outcomes for ciprofloxacin DPI 28 days on/off were not statistically significantly different from placebo. The safety profile of ciprofloxacin DPI was favourable.Ciprofloxacin DPI was well tolerated and has the potential to be an effective treatment option in non-cystic fibrosis bronchiectasis.

scholarly journals Cost-effectiveness of a stepped care intervention to prevent depression and anxiety in late life: randomised trial

2010 ◽  
Vol 196 (4) ◽  
pp. 319-325 ◽  
Author(s):  
Petronella van't Veer-Tazelaar ◽  
Filip Smit ◽  
Hein van Hout ◽  
Patricia van Oppen ◽  
Henriette van der Horst ◽  
...  
Keyword(s):  
Primary Care ◽  
Cost Effectiveness ◽  
Preventive Intervention ◽  
Controlled Trial ◽  
Randomised Trial ◽  
Cost Effective ◽  
Stepped Care ◽  
Depression And Anxiety ◽  
Care Programme ◽  
Randomised Controlled

BackgroundThere is an urgent need for the development of cost-effective preventive strategies to reduce the onset of mental disorders.AimsTo establish the cost-effectiveness of a stepped care preventive intervention for depression and anxiety disorders in older people at high risk of these conditions, compared with routine primary care.MethodAn economic evaluation was conducted alongside a pragmatic randomised controlled trial (ISRCTN26474556). Consenting individuals presenting with subthreshold levels of depressive or anxiety symptoms were randomly assigned to a preventive stepped care programme (n = 86) or to routine primary care (n = 84).ResultsThe intervention was successful in halving the incidence rate of depression and anxiety at €563 (£412) per recipient and €4367 (£3196) per disorder-free year gained, compared with routine primary care. The latter would represent good value for money if the willingness to pay for a disorder-free year is at least €5000.ConclusionsThe prevention programme generated depression- and anxiety-free survival years in the older population at affordable cost.

scholarly journals A Functional Threshold for Long-Term Use of Hand and Arm Function Can Be Determined: Predictions From a Computational Model and Supporting Data From the Extremity Constraint-Induced Therapy Evaluation (EXCITE) Trial

2009 ◽  
Vol 89 (12) ◽  
pp. 1327-1336 ◽  
Author(s):  
Nicolas Schweighofer ◽  
Cheol E. Han ◽  
Steven L. Wolf ◽  
Michael A. Arbib ◽  
Carolee J. Winstein
Keyword(s):  
Controlled Trial ◽  
Hand Function ◽  
Cost Effective ◽  
Phase Iii ◽  
Future Research ◽  
Therapy Evaluation ◽  
Effective Interventions ◽  
Term Change ◽  
Number Of Patients

Background Although spontaneous use of the more-affected arm and hand after stroke is an important determinant of participation and quality of life, a number of patients exhibit decreases in use following rehabilitative therapy. A previous neurocomputational model predicted that if the dose of therapy is sufficient to bring performance above a certain threshold, training can be stopped. Objective The aim of this study was to test the hypothesis that there exists a threshold for function of the paretic arm and hand after therapy. If function is above this threshold, spontaneous use will increase in the months following therapy. In contrast, if function is below this threshold, spontaneous use will decrease. Methods New computer simulations are presented showing that changes in arm use following therapy depend on a performance threshold. This prediction was tested by reanalyzing the data from the Extremity Constraint-Induced Therapy Evaluation (EXCITE) trial, a phase III randomized controlled trial in which participants received constraint-induced movement therapy for 2 weeks and were tested both 1 week and 1 year after therapy. Results The results demonstrate that arm and hand function measured immediately after therapy predicts, on average, the long-term change of arm use. Above a functional threshold, use improves. Below this threshold, use decreases. Limitations The reanalysis of the EXCITE trial data provides a “group” threshold above which a majority of patients, but not all, improve spontaneously. A goal of future research is to provide the means to assess when patients reach their individual threshold. Conclusion Understanding of the causal and nonlinear relationship between limb function and daily use is important for the future development of cost-effective interventions and prevention of “rehabilitation in vain.”

scholarly journals Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
L. Guglielmetti ◽  
E. Ardizzoni ◽  
M. Atger ◽  
E. Baudin ◽  
E. Berikova ◽  
...  
Keyword(s):  
Study Protocol ◽  
Controlled Trial ◽  
New Drugs ◽  
Phase Iii ◽  
Current Standard ◽  
Open Label ◽  
Randomized Controlled ◽  
Resistant Tuberculosis ◽  
Repurposed Drugs ◽  
Quality Evidence

Abstract Background Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings. Methods endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations. Discussion The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide. Trial registration ClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.

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