key: cord-0858085-rwrkc91n authors: Batra, Harshul; Pawar, Shrikant; Bahl, Dherya title: Current clinical trials and patent update on lung cancer: a retrospective review date: 2021-02-15 journal: Lung cancer management DOI: 10.2217/lmt-2020-0029 sha: 842157b93d3a3ee6114722427006916e2797c7a9 doc_id: 858085 cord_uid: rwrkc91n Several clinical trials using different interventions are currently being sponsored to combat lung cancer at its different stages. The purpose of this study was to provide a portfolio of those trials. All active, open and recruiting clinical trials registered at ClinicalTrials.gov up to March 2018 were included. Information related to 6092 registered lung cancer trials was downloaded. Phase II trials were in the majority, comprising nearly 48.7% of total clinical trials with industry the major sponsor (41.3%) followed by NIH (12.3%). Multicenter studies were the norm accounting for 47.9% and the main study location was the USA (50.9%). Common interventions were radiation (26%), surgery (22%) and EGFR inhibitors (17%). Patent information includes major patent filing office and sponsors. The data analysis provides a comprehensive description of lung cancer trials. apy [13] . Additional approaches to immunotherapy for lung cancer have shown promise in early clinical trials and are now in late-phase development. They fall into four main categories: monoclonal antibodies, checkpoint inhibitors, therapeutic vaccines and adoptive T-cell transfer [14] [15] [16] [17] [18] [19] . Various clinical trials have been reported to study the effectiveness of lung cancer screening. The most extensive testing showed a reduction in lung cancer mortality of 16% (95% CI: 5.0-25.0%) and a reduction in all-cause mortality of 6.7% [20] . This trial included 50,000 adults aged 55-74 years with at least 30 pack-year smoking history. When a similar test was combined with a meta-analysis, the relative risk for lung cancer mortality was 0.81 [1] . One European trial, the Multicentric Italian Lung Detection (MILD) study, is an example of such a meta-analysis [21] . Screening trials have been found to be effective yet a few have reported nonbeneficial results. The PLCO (Prostate, Lung, Colorectal and Ovarian) Cancer Screening Trial evaluated more than 150,000 participants from the general population. It found no benefits of screening in this group or in a subgroup that had tobacco smoke exposure, where no benefits were associated with chest radiography screening [22] . Randomized clinical trials are performed to reduce uncertainty over the efficacy and safety of an intervention and should be designed to result in an unbiased information; however, analysis of trial documentation has revealed that some industry-funded drug trials may be done more for marketing purposes than science. We wanted to define characteristics of drug trials and estimate their prevalence. Trials can have varied interests with competing products. The characteristics which we sought to classify are design, intervention type and treatment settings, biomarker analysis, enrollment timeline and patent information. We provide a global overview of the clinical trial statistics in lung cancer. We briefly describe different characteristics for trial design and type of interventional studies used for lung cancer. Finally, we provide a timeline of patient enrollment and registered patents for lung cancer and discuss advantages, challenges and perspectives for the betterment of clinical trial design for lung cancer studies. The methods were performed as in [23] . Data source On 1 March 2018, a dataset of 6092 clinical studies related to lung cancer was downloaded from ClinicalTrials.gov. The dataset was analyzed using various parameters in Microsoft Excel. Information regarding terminologies can be obtained from Clinical Trials Transformation Initiative website [24] . The data were restricted to active recruiting studies. In advanced search the following parameters were selected 'open/recruiting/active' studies for recruitment status, 'all groups' for study and age groups. The data extracted comprised both interventional and observational studies. We wanted to keep this review current, so we excluded all completed/terminated/not recruiting clinical trials from our search. Further clinical trials with no intervention information were excluded. The information contains all active clinical trials on lung cancer until March 2018 available on ClinicalTrials.gov. Each study was manually reviewed by the authors (title, interventions, outcome measures, recruiting status, MeSH terms and the full ClinicalTrials.gov record if necessary) to certain relevance to lung cancer study. After initial screening, 2250 studies were selected for final data extraction for analysis ( Figure 1 ). The following information was extracted from the website: clinical trial phase (early Phase I, I/II, II, II/III, III, IV); recruiting status; location of clinical center; study design; type of study (interventional, observational or others); the number of trial centers; primary sponsor; primary outcome; treatment setting; treatment classes; time relation with phases. Along with that, we also compiled information about patents related to lung cancer from the lens.org website using lung cancer treatment, lung cancer therapeutic, lung cancer diagnostic and 'lung cancer biomarkers.' The information extracted was: number of patents published; patent office location; primary applicant name and; biologicals. Our parameters identified 2385 trials involving lung cancer. One hundred and thirty five had no treatment information or missing information regarding a location of clinical trials and were excluded from the total clinical (Table 2) . Overall survival was the major primary outcome in all phases of trials (Phase I, 64%; Phase II, 61.5%; Phase III, 76%; Phase IV, 44.4%) followed by progression-free survival (Phase I, 17%; Phase II, 8.5%; Phase III, 6.2%; Phase IV, 11.1%), tumor response rate (Phase I, 15.9%; Phase II, 16.5%; Phase III, 5.2%; Phase IV, 3.7%) and quality of life (Phase I, 7.8%; Phase II, 11.5%; Phase III, 10.5%; Phase IV, 18.5%) ( Table 2) . Lung cancer treatment involves several types of therapeutic methods as seen in Figure 2 . Chemotherapy was the most used intervention with EGFR inhibitors being the major class of intervention accounting for nearly 17% of clinical trials. This was followed by microtubule inhibitors (12%) followed by radiation therapy and surgery comprising 26 and 22% of clinical trials, respectively. A recent boom in using immunotherapy as an intervention was also seen in clinical trials (10%). Next, we extracted information regarding the treatment lines for Phase II and Phase III trials. For the advanced stage of disease: first-line therapy was the most common intervention with 177 (22.3%) clinical trials followed by the second-line of therapy with 92 (11.6%). For large datasets, nearly 318 (40.1%) clinical trials no information was provided regarding the line of therapy (Table 3 & Figure 2A ). Figure 2B ). (Figure 3 ). Our search concluded with nearly 34,760 patents registered for lung cancer as of 1 March 2018. The USA was found to be the significant location for filing patents accounting for 21,543 (62%) patents, followed by Europe 7808 (22.5%) and Australia 5069 (14.6%). Merck registered the highest number of patents on clinical trials (632, 1.8%), followed by Novartis (573, 1.6%) and Genentech (503, 1.4%) ( Table 4 ). Our contemporary study provides lung cancer clinical trial including interventional and observational examinations. Different qualities of preliminaries, for example, design, location, type of intervention, patient enrolment and sponsors are discussed. The study demonstrated significant preliminaries on the ClinicalTrials.gov site for stage 2 lung cancer. As setting up clinical preliminaries requires serious use of assets, cash and publicized patient enrolment, lung cancer trials were in the majority multicentered and sponsored by industry, the NIH and universities. In our investigation, a few information focuses were unknown as the preliminary came up short on the data for that particular column. Industry-supported stage 2 clinical preliminaries were open for a more extended time in contrast with college or US government office-supported preliminaries. However, the pattern was reversed for Phase III clinical trials. One of the serious issues with all these clinical trials was the absence of biomarkers in stage 2 lung cancer trials, and a comparable example is followed at stage 3 lung cancer trials. Biomarker examination data was accessible for just 10% of complete clinical trials. In the future, the beginning phase clinical trials focusing on the better comprehension of pathways and atomic level examinations should be embedded prior to pushing ahead. In addition, biomarker investigation is an important step in advancement of precision medicine. In advanced stages of lung cancer tissue biomarker analysis is difficult as tissue is degraded for collection. Thus, selecting more patients for beginning phase clinical trials in the lungs would be a good method to beat this constraint. Almost 49% of clinical preliminaries were performed on the patients with lung cancer at stage I or II, which is a decent advance given the tissues are as yet unblemished for biomarker improvement and examination. Moreover, significant amounts of lung cancer patients undergo relapse at early-stage even after surgery or postoperative therapy [25] [26] [27] . The novel biomarkers utilizing the examinations performed on tissues could drastically improve the success rates in beginning phases of lung cancer. All these previously mentioned steps would forestall significant stage 3 clinical preliminary disappointments and would assist with conquering the study design issues. Another important information discussed in this paper regards currently published patents in lung cancer. In comparison with the clinical trials data, the information provided in patents lacks several major elements. In recent years ClinicalTrials.org has become a prime website to extract clinical trials information, whereas google patents provide the information for patents, but lacks a basic divisional structure like that for clinical trials. So, we utilized lens.org for our patent data analysis as it was better structured and provided the information required for the data analysis. At the country-level finding, the USA was found to be the significant location for filing patents followed by Europe and Australia. Although, we used ClinicalTrials.gov as the primary data source and non-USA trials are registered on EU or Japanese sites, the USA did show a significant patent filling number. Data discrepancy in the analysis due to human error is one of the major issues with such an analysis. We reviewed the data multiple times and blindly among all other authors to overcome this issue. Other than that, there are several limitations to clinical trial data analysis from ClinicalTrails.gov which needs to be considered as we move forward with such data analysis reviews in future. The ClinicalTrials.gov websites consist of information for all trials in the US or sponsored by multinational organizations (e.g., pharmaceutical companies). However, it lacks information for outside US and trials funded by small organizations. Information and links for other clinical trials registries are provided at the US Department of Health and Human Services, Office for Human Research Protections portal. This includes links of nearly 32 registries from different countries and 11 registries from major pharmaceutical companies. The second issue is related to the information provided in the clinical trials. Moreover, most of the Phase II clinical trials had limited patient enrollment (100 or fewer) which leads to an inappropriate conclusion about the therapy due to failing to reject the null hypothesis and high risk of a type II error [28] . At last, as stated before some data were missing for major characteristics such as intervention, primary sponsor, phases and so on. This might be due to the fact we also selected observational studies for our analysis. Moreover, result information regarding the completed clinical trials was not updated (data not shown), and this is in parallel with the previous observation regarding the low compliance result reporting issue at ClinicalTrials.gov [29] . According to the NIH and FDA CFR 11.44(b) guidelines, some regulations provide for the delayed submission of results information under certain conditions, and also some institutions are not under regulation to submit certain types of information, so a future scope of our present study would be to compare studies covered and not covered by regulatory registration. The NIH further states that the trial has one or more sites in the USA, the trial is conducted under an FDA investigational new drug application or investigational device exemption and the trial involves a drug, biological or device product that is manufactured in the USA or its territories and is exported for research. However, some studies listed as outside the USA could enroll both within and without registration and thus requires a clause to distinguish them and classify separately under regulatory registrations. To overcome a missing data elements issue and improve the quality of lung cancer trial protocols, the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 statement with a 33-item checklist should be followed [30] . Based on the data collected from ClinicalTrials.gov, our analysis reveals that the major clinical trials comprised Phase II with industry-sponsored trials lasting for more than 2 years of enrollment and radiation, surgery and chemotherapy being the major intervention. Most of them were randomized-trials with the primary outcome focused on patient survival. Our comprehensive analysis provides useful information regarding lung cancer which may be helpful to industry and investigators for future decisions. With rapid changing dynamics of clinical trials and with ongoing vaccine efforts for the COVID-19 pandemic, the importance and awareness of trials has increased. Clinical trials are extremely important in understanding robustness of the trialed agent; however, it is possible for certain private companies to attempt to gain advantage by cutting corners. 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This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.No writing assistance was utilized in the production of this manuscript. This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/