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Frontiers in Pharmacology 2020For patients suffering with chronic neuropathic pain the need for suitable novel therapies is imperative. Over recent years a contributing factor for the lack of... (Review)
Review
For patients suffering with chronic neuropathic pain the need for suitable novel therapies is imperative. Over recent years a contributing factor for the lack of development of new analgesics for neuropathic pain has been the mismatch of primary neuropathic pain assessment endpoints in preclinical vs. clinical trials. Despite continuous forward translation failures across diverse mechanisms, reflexive quantitative sensory testing remains the primary assessment endpoint for neuropathic pain and analgesia in animals. Restricting preclinical evaluation of pain and analgesia to exclusively reflexive outcomes is over simplified and can be argued not clinically relevant due to the continued lack of forward translation and failures in the clinic. The key to developing new analgesic treatments for neuropathic pain therefore lies in the development of clinically relevant endpoints that can translate preclinical animal results to human clinical trials. In this review we discuss this mismatch of primary neuropathic pain assessment endpoints, together with clinical and preclinical evidence that supports how bidirectional research is helping to validate new clinically relevant neuropathic pain assessment endpoints. Ethological behavioral endpoints such as burrowing and facial grimacing and objective measures such as electroencephalography provide improved translatability potential together with currently used quantitative sensory testing endpoints. By tailoring objective and subjective measures of neuropathic pain the translatability of new medicines for patients suffering with neuropathic pain will hopefully be improved.
PubMed: 33628181
DOI: 10.3389/fphar.2020.614990 -
Obesity Research Nov 1995Criteria for the evaluation of new drugs to treat obesity are important as guides for designing clinical trials to test these agents. These criteria must be developed in... (Review)
Review
Criteria for the evaluation of new drugs to treat obesity are important as guides for designing clinical trials to test these agents. These criteria must be developed in relation to the realities of obesity, which is a chronic disease associated with morbidity and mortality that is increased by visceral fat deposits. The observation that patients regain weight after stopping drug treatment for obesity argues for the proposition that drugs work only when taken and NOT that the drugs are ineffective. The analogy between the development of treatments for obesity to those for the treatment of hypertension is used to highlight potential areas for new developments. Several features of an ideal drug for the treatment of obesity are suggested. Criteria for evaluating new drugs include both primary and secondary endpoints. The primary endpoint for an anti-obesity drug should be weight loss, possibly by category of success. Losses of total body fat or visceral fat might be alternative primary endpoints. Secondary endpoints include reduction in risk factors for associated diseases and improvement in the quality of life. In trials where vigorous placebo designs including highly aggressive behavior modification or very-low-calorie diets were used, it may be difficult or impossible to detect a response to a drug.
Topics: Appetite Depressants; Drug Evaluation; Humans; Obesity
PubMed: 8697040
DOI: 10.1002/j.1550-8528.1995.tb00209.x -
Statistics in Medicine Nov 1997Confirmatory clinical trials often classify clinical response variables into primary and secondary endpoints. The presence of two or more primary endpoints in a clinical... (Review)
Review
Confirmatory clinical trials often classify clinical response variables into primary and secondary endpoints. The presence of two or more primary endpoints in a clinical trial usually means that some adjustments of the observed p-values for multiplicity of tests may be required for the control of the type I error rate. In this paper, we discuss statistical concerns associated with some commonly used multiple endpoint adjustment procedures. We also present limited Monte Carlo simulation results to demonstrate the performance of selected p-value-based methods in protecting the type I error rate.
Topics: Algorithms; Clinical Trials as Topic; Computer Simulation; Data Interpretation, Statistical; Humans; Monte Carlo Method; Statistics as Topic
PubMed: 9403954
DOI: 10.1002/(sici)1097-0258(19971130)16:22<2529::aid-sim692>3.0.co;2-j -
AIDS (London, England) Sep 2000At present, many clinical trials of anti-HIV-1 therapies compare treatments by a primary endpoint that measures the durability of suppression of HIV-1 replication....
OBJECTIVES
At present, many clinical trials of anti-HIV-1 therapies compare treatments by a primary endpoint that measures the durability of suppression of HIV-1 replication. Several durability endpoints are compared.
DESIGN
Endpoints are compared by their implicit assumptions regarding surrogacy for clinical outcomes, sample size requirements, and accommodations for inter-patient differences in baseline plasma HIV-1-RNA levels and in initial treatment response.
METHODS
Virological failure is defined by the non-suppression of virus levels at a prespecified follow-up time T(early virological failure), or by relapse. A binary virological failure endpoint is compared with three time-to-virological failure endpoints: time from (i) randomization that assigns early failures a failure time of T weeks; (ii) randomization that extends the early failure time T for slowly responding subjects; and (iii) virological response that assigns non-responders a failure time of 0 weeks. Endpoint differences are illustrated with Agouron's trial 511.
RESULTS
In comparing high with low-dose nelfinavir (NFV) regimens in Agouron 511, the difference in Kaplan-Meier estimates of the proportion not failing by 24 weeks is 16.7% (P = 0.048), 6.5% (P = 0.29) and 22.9% (P = 0.0030) for endpoints (i), (ii) and (iii), respectively. The results differ because NFV suppresses virus more quickly at the higher dose, and the endpoints weigh this treatment difference differently. This illustrates that careful consideration needs to be given to choosing a primary endpoint that will detect treatment differences of interest.
CONCLUSION
A time from randomization endpoint is usually recommended because of its advantages in flexibility and sample size, especially at interim analyses, and for its interpretation for patient management.
Topics: Anti-HIV Agents; Endpoint Determination; HIV Infections; HIV-1; Humans; RNA, Viral; Randomized Controlled Trials as Topic; Treatment Outcome; Viral Load
PubMed: 10997401
DOI: 10.1097/00002030-200009080-00012 -
Neural Regeneration Research Aug 2014Cervical spinal cord injury (SCI) results in partial to full paralysis of the upper and lower extremities. Traditional primary endpoints for acute SCI clinical trials... (Review)
Review
Cervical spinal cord injury (SCI) results in partial to full paralysis of the upper and lower extremities. Traditional primary endpoints for acute SCI clinical trials are too broad to assess functional recovery in cervical subjects, raising the possibility of false positive outcomes in trials for cervical SCI. Endpoints focused on the recovery of hand and arm control (e.g., upper extremity motor score, motor level change) show the most potential for use as primary outcomes in upcoming trials of cervical SCI. As the field moves forward, the most reliable way to ensure meaningful clinical testing in cervical subjects may be the development of a composite primary endpoint that measures both neurological recovery and functional improvement.
PubMed: 25317162
DOI: 10.4103/1673-5374.139470 -
European Journal of Clinical... Oct 2016Healthcare professionals and patients could be negatively influenced in their judgments by articles and meta-analyses presenting selective outcome reporting. Clinical... (Review)
Review
BACKGROUND
Healthcare professionals and patients could be negatively influenced in their judgments by articles and meta-analyses presenting selective outcome reporting. Clinical trials should be transparent from inception to the publication of results. To this end, trial prospective registration is an ethical and scientific requirement that have shown to be effective in preventing selective reporting of outcomes. However, even journals with a clear pre-registration policy publish trial results that were retrospectively registered.
SITUATION
Analyses of registration of randomized clinical trials recently published in top specialty journals and of meta-analyses with suspicion of including trials with outcome reporting bias have shown that retrospective registration is in the range from 56 to 76 %. This translates into publication of primary endpoints that differ from those included in the registry: some 30 % of trials showed discrepancies between the primary endpoint in the trial registry and the article. Furthermore, it has been shown that 8 % of all clinical trials published by 6 high-impact ICMJE-member journals was retrospectively registered after primary endpoint ascertainment could have had taken place, raising concerns that endpoints may not have been pre-specified, or were changed. With regards to meta-analyses, 34 % of Cochrane systematic reviews included one or more trials with a high suspicion of selective reporting bias for the primary outcome.
PROPOSAL
Retrospective registration of trials may foster selective outcome reporting unless journal editors implement specific quality control processes aiming to prevent or minimize this type of bias. Prospective registration of trials-and protocol public disclosure if proven effective in future studies-prevents outcome reporting bias, a must to ensure clinicians and patients have access to reliable clinical trial results. Journal editors should enforce, rather than encourage, appropriate measures to ensure publication of trials free of outcome reporting bias.
Topics: Clinical Trials as Topic; Periodicals as Topic; Publication Bias
PubMed: 27484242
DOI: 10.1007/s00228-016-2112-3 -
Biometrical Journal. Biometrische... Mar 2018The choice of a primary endpoint is an important issue when designing a clinical trial. It is common to use composite endpoints as a primary endpoint because it...
The choice of a primary endpoint is an important issue when designing a clinical trial. It is common to use composite endpoints as a primary endpoint because it increases the number of observed events, captures more information and is expected to increase the power. However, combining events that have no similar clinical importance and have different treatment effects makes the interpretation of the results cumbersome and might reduce the power of the corresponding tests. Gómez and Lagakos proposed the ARE (asymptotic relative efficiency) method to choose between a composite or one of its components as primary endpoint comparing the efficacy of a treatment based on the times to each of these endpoints. The aim of this paper is to expand the ARE method to binary endpoints. We show that the ARE method depends on six parameters including the degree of association between components, event proportion, and effect of therapy given by the corresponding odds ratio of the single endpoints. A case study is presented to illustrate the methodology. We conclude with efficient guidelines for discerning which could be the best suited primary endpoint given anticipated parameters.
Topics: Biometry; Clinical Trials as Topic; Endpoint Determination; Humans; Paclitaxel; Stents; Treatment Outcome
PubMed: 29023990
DOI: 10.1002/bimj.201600229 -
Journal of the National Cancer Institute Mar 2013Surrogate endpoints offer the hope of smaller or shorter cancer trials. It is, however, important to realize they come at the cost of an unverifiable extrapolation that...
Surrogate endpoints offer the hope of smaller or shorter cancer trials. It is, however, important to realize they come at the cost of an unverifiable extrapolation that could lead to misleading conclusions. With cancer prevention, the focus is on hypothesis testing in small surrogate endpoint trials before deciding whether to proceed to a large prevention trial. However, it is not generally appreciated that a small surrogate endpoint trial is highly sensitive to a deviation from the key Prentice criterion needed for the hypothesis-testing extrapolation. With cancer treatment, the focus is on estimation using historical trials with both surrogate and true endpoints to predict treatment effect based on the surrogate endpoint in a new trial. Successively leaving out one historical trial and computing the predicted treatment effect in the left-out trial yields a standard error multiplier that summarizes the increased uncertainty in estimation extrapolation. If this increased uncertainty is acceptable, three additional extrapolation issues (biological mechanism, treatment following observation of the surrogate endpoint, and side effects following observation of the surrogate endpoint) need to be considered. In summary, when using surrogate endpoint analyses, an appreciation of the problems of extrapolation is crucial.
Topics: Biomarkers; Clinical Trials as Topic; Endpoint Determination; Humans; Mathematical Computing; Models, Statistical; Neoplasms; Primary Prevention; Research Design; Time Factors; Treatment Outcome; Uncertainty
PubMed: 23264679
DOI: 10.1093/jnci/djs527 -
Reports of Practical Oncology and... 2020Treatment of bone metastasis using stereotactic body radiotherapy (SBRT) is being widely used in clinical practice. The reported clinical advantages of SBRT include high... (Review)
Review
Treatment of bone metastasis using stereotactic body radiotherapy (SBRT) is being widely used in clinical practice. The reported clinical advantages of SBRT include high pain and local control rates, high response rates against bone metastasis from radio-resistant tumors, and safe re-irradiations. Although most reports in the literature use local control as the primary treatment endpoint, this endpoint is not appropriate because local control does not relate directly to patient benefit. Herein, we proposed five pathophysiology-based patient groups, as well as appropriate endpoints for each group.
PubMed: 32042273
DOI: 10.1016/j.rpor.2019.12.018 -
Journal of Visceral Surgery Feb 2014Endpoints are measurable clinical and biological findings that are used for the development and assessment of treatment options. In the treatment of cancer, endpoints... (Review)
Review
Endpoints are measurable clinical and biological findings that are used for the development and assessment of treatment options. In the treatment of cancer, endpoints can be classified into two categories: "patient-centered clinical endpoints" including overall survival (OS) and health-related quality of life (QoL), and "tumor-centered clinical endpoints" such as progression-free survival. Surrogate endpoints are tumor-centered clinical endpoints that can be used as substitutes for patient-centered clinical endpoints, particularly OS. The choice of endpoints in oncology trials is a major problem. The published Consolidated Standards of Reporting Trials (CONSORT) best-practice guidelines encourage the reporting of clearly defined primary and secondary outcome measures. OS is the gold standard of endpoints but as increasing numbers of effective salvage treatments become available for many types of cancer, much larger numbers of patients are included; this requires a longer follow-up period and increases the cost of clinical trials. Thus, tumor-centered clinical endpoints that can be assessed earlier and used as surrogates for overall survival are increasingly studied, but most of them currently lack standardized definitions to enable cross comparison of results among different clinical trials and they have not been validated as surrogate endpoints. In addition, the variability of their definition can strongly impact the trial's conclusions by affecting both statistical power and estimation. In this context, QoL constitutes an available and useful surrogate endpoint for trials to ensure treatment benefit from both the patient and public health points of view. Methodological research should be pursued to develop standard outcome definitions for use in cancer clinical trials and to define a standardized longitudinal analysis of QoL data.
Topics: Clinical Trials as Topic; Disease-Free Survival; Humans; Neoplasms; Outcome Assessment, Health Care; Quality of Life; Research Design; Survival Rate; Treatment Outcome
PubMed: 24440056
DOI: 10.1016/j.jviscsurg.2013.10.001