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GlobeCitizen · 2021-10-04

Below is an article to be published in one of the prestigious medical journals regarding using external data (real-life data) in the design and analyzing of clinical trial data, which is directed by DI who is the vice president of PR for the company when asked by an investor for direction (as if it's something new, instead it's not):

https://www.dr-bala.net/NWBO/Lancet/Rahman_Lancet_102021.pdf

Cancer Trials and Design Principles 4Leveraging external data in the design and analysis of clinical trials in neuro-oncology
Rifaquat Rahman, Steffen Ventz, Jon McDunn, Bill Louv, Irmarie Reyes-Rivera, Mei-Yin C Polley, Fahar Merchant, Lauren E Abrey, Joshua E Allen, Laura K Aguilar, Estuardo Aguilar-Cordova, David Arons, Kirk Tanner, Stephen Bagley, Mustafa Khasraw, Timothy Cloughesy, Patrick Y Wen, Brian M Alexander*, Lorenzo Trippa*
Integration of external control data, with patient-level information, in clinical trials has the potential to accelerate the development of new treatments in neuro-oncology by contextualising single-arm studies and improving decision making (eg, early stopping decisions). Based on a series of presentations at the 2020 Clinical Trials Think Tank hosted by the Society of Neuro-Oncology, we provide an overview on the use of external control data representative of the standard of care in the design and analysis of clinical trials. High-quality patient-level records, rigorous methods, and validation analyses are necessary to effectively leverage external data. We review study designs, statistical methods, risks, and potential distortions in using external data from completed trials and real-world data, as well as data sources, data sharing models, ongoing work, and applications in glioblastoma.
IntroductionDrug development is associated with inefficiency, long timelines, and poor success rates in oncology, in which less than 10% of drug candidates are ultimately approved by the US Food and Drug Administration (FDA).1,2 As new unproven therapies emerge at an accelerated pace, there has been an increasing interest in novel approaches to clinical trial design that could improve efficiency.3,4Within neuro-oncology, the use of trial designs with potential for increased efficiency is of interest, particularly in the study of glioblastoma, a disease with an unmet need for better therapies because of its poor prognosis.5 There are several distinctive challenges in drug development for glioblastoma, such as the inability to completely resect tumours, difficulty in crossing the
blood–brain barrier, tumour heterogeneity, imaging challenges for monitoring disease course, and a unique immune environment.6,7 With few treatment advances over the past two decades, the clinical trial landscape in glioblastoma has been characterised by long development times, low patient participation, problematic surrogate outcomes, and poor decision making.8,9 Indeed, poor early phase decision making has been repeatedly high-lighted as a major problem in the development of therapeutics10 and continues to increase interest in novel clinical trial designs.Randomised controlled trials (RCTs) are the gold standard for clinical experimentation and evaluation of therapies. RCTs control for systematic bias from known and unknown confounders by randomly assigning
patients to receive an experimental therapy or standard of care, which allows for the evaluation of treatment effects. However, RCTs can be difficult to conduct in some neuro-oncology settings. A small percentage of patients with cancer participate in clinical trials,11 and RCTs can have slow patient accrual because of patient reluctance to enrol in studies with a control group, which is a pronounced problem in settings with ineffective standards of care, such as recurrent glioblastoma.12–14 Precision medicine further complicates this issue by focusing trials on biomarker-defined subgroups of patients who might benefit from targeted therapies.15 These subgroups are often small, resulting in substantial challenges to conducting RCTs with adequate sample sizes to detect treatment effects.15,16The design and implementation of clinical trials that leverage external datasets, with patient-level information on pretreatment clinical profiles and outcomes to support testing of experimental therapies and study decision
making, has attracted interest in neuro-oncology.17,18 A phase 2b trial in recurrent glioblastoma19 used a prespecified, eligibility-matched, external control group (including individual pretreatment profiles and outcomes), with data from patients with glioblastoma from major neurosurgery centres as a comparator group to evaluate MDNA55. After implementation of this trial design, investigators reported improved survival in patients receiving MDNA55 compared with the external control group.19 Several ongoing neuro-oncology trials are actively exploring similar approaches to use external data in the design and analysis of clinical studies.The Society of Neuro-Oncology hosted the 2020 Clinical Trials Think Tank on Nov 6, 2020, with a virtual session dedicated to trial designs leveraging external data. Experts in the field of neuro-oncology were paired with experts in data science and biostatistics, and representatives from industry, patient advocacy, and the FDA. The interdisciplinary session focused on challenges in drug development, data sharing and access, regulatory considerations of novel trial designs, and emerging methodological approaches for using external data. Although participation was broad in terms of expertise, most participants were from the USA and provided a US perspective on the topic. The discussion from the Clinical

e457 www.thelancet.com/oncology Vol 22 October 2021SeriesCalifornia Los Angeles, Los Angeles, CA, USA (Prof T Cloughesy MD); Foundation Medicine, Cambridge, MA, USA
(B M Alexander)Correspondence to: Dr Rifaquat Rahman, Department of Radiation Oncology, Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, MA 02215, USA
rrahman@bwh.harvard.edu
Trials Think Tank serves as a framework for this Series paper, which focuses on the use of external data to design, conduct, and analyse clinical trials with an emphasis on possible applications in neuro-oncology. We review trial designs, methodologies, approaches, regulatory considerations, and current barriers in data sharing and access.
Early phase trial designs
Early phase trials are typically designed to obtain preliminary estimates of treatment efficacy and toxic effects, which will inform the decision to pursue a phase 3 trial or stop drug development. Often in neuro-oncology, these early phase studies are single-arm trials that test the superiority of an experimental therapeutic compared with an established benchmark for the current standard of care (eg, median overall survival or other point estimates).20 Importantly, there can be substantial differences between populations or standards to assess outcomes across trials,21 which can lead to inappropriate comparisons and inadequate evaluations of the experimental therapy. Another major challenge with single-arm trials is the choice of a primary endpoint. Response rate might not correlate with overall survival and is difficult to interpret in glioblastoma,22 and single-arm studies are suboptimal for reliable inference on improvements in time-to-event endpoints, such as survival. On the basis of these known limitations, single-arm designs have been posited as a possible reason for poor decision making and unsuccessful phase 3 trials in glioblastoma.23,24The risk of biased conclusions from single-arm trials has been examined extensively and frameworks have been developed to help guide the choice between RCTs versus single-arm designs for glioblastoma.10,25 Despite well documented limitations, single-arm trials remain the most common early phase trial design in glioblastoma.25 Alternative trial designs have been proposed, including the incorporation of randomisation, seamless phase 2/3 study designs,26 and Bayesian outcome-adaptive trials to overcome limitations and
improve the evaluation of therapeutic candidates in the early phase of development.27–29
Overview of trial designs that include external data
Trial designs that leverage external data can generate valuable inferences in settings in which single-arm trials are suboptimal and RCTs are infeasible.30 External data can play a role in supporting key decisions in the drug development process, including regulatory approvals and decision making in early phase trials. The use of external patient-level datasets has the potential to improve accuracy of trial findings and inform decision making (eg, determining the sample size of a subsequent confirmatory phase 3 trial or selecting the phase 3 patient population). External data can also be incorporated into RCTs31—eg, within interim analyses18—although these designs remain largely unexplored.Externally augmented clinical trial design refers to the broad class of designs that leverage external data for decision making during a study or in the final analysis. These designs rely on access to well curated patient-level data for the standard of care from one or more relevant data sources to allow for adjustment of differences in pretreatment, covariates between enrolled patients and external data, and to derive treatment effect estimates. Given the need for statistical adjustments, the external dataset ideally includes a comprehensive set of potential confounders.32 Pretreatment covariates have been thoroughly studied for adult primary brain tumours.33,34An example of an externally augmented clinical trial design consists of a single-arm study combined with an external control group (ie, an external dataset with patient-level outcomes and pretreatment profiles), which is used as a comparator to evaluate the experimental treatment. This design (figure 1A), an externally controlled single-arm trial, infers the treatment effect by using adjustment methods to account for differences in patient pretreatment profiles between the external control group and the experimental group.35 In this design, the external control group is used to contextualise the outcome data from a single-arm study. Instead of using benchmark estimates (eg, median survival) for the standard of care, data analyses and treatment effect estimates are based on patient-level data from an external dataset.Hybrid randomised trial designs constitute another type of externally augmented clinical trial. With adequate external data and statistical planning,36 these designs have the potential of reducing sample size while maintaining the benefits of randomisation. An example of a two-stage hybrid design is shown in figure 1B. The study has an initial 1:1 randomisation to an internal control group and an experimental group. If the interim analysis does not identify differences between adjusted primary outcome distributions in the internal randomised control group and the external control group, then different randomisation ratios (eg, 2:5) can be used in the second stage of the study. If there is evidence of inconsistencies between the external and internal control groups (eg, unmeasured confounders or different measurement standards of outcomes and prognostic variables), the trial can continue with 1:1 randomisation. In the outlined example, the potential increase of randomisation probability for the experimental group can be attractive and might accelerate trial accrual. Indeed, patients with a brain tumour and an inadequate standard of care might be more likely to enrol in a trial if the probability of receiving the experimental therapy is higher.25
Externally augmented clinical trial designsAlong with high quality and complete data, a statistically rigorous study design is the most important element of an externally augmented clinical trial. As with any clinical trial, the design, including the sample size, a detailed

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plan for interim decisions, and statistical methods for data analyses should be prespecified. Additionally, a plan for how missing data in the trial and external data sources will be handled is important. Potential distortion mechanisms that can bias treatment effect estimates and undermine the scientific validity of externally augmented clinical trial findings have been carefully examined and include unmeasured or misclassified confounders and data quality issues, such as the use of different standards to capture or measure outcomes.37–39Risks of introducing bias (table) and compromising the control of false positives and false negatives when using external patient-level data can differ substantially across externally augmented clinical trial designs, which span from single-arm studies (figure 1A) to hybrid randomised studies (figure 1B). Quantitative analyses of these and other risks (eg, exposure of patients to inferior treatments) are necessary before trial initiation. The decision to use external data should take account of several factors in addition to the study population and available patient-level datasets, including the stage of drug development (eg, early phase 2 vs confirmatory trials); the specific decisions (eg, early stopping of a phase 2 study for futility40 or sample size re-estimation during the study41) that will be supported by external data; resources (including maximum sample size); and the potential trial designs and statistical methods for data analysis.Candidate externally augmented clinical trial designs and statistical methods for data analysis can present markedly different trade-offs between potential efficiencies (eg, discontinuing early randomised trials of ineffective treatments by leveraging external data) and risks of poor operating characteristics (eg, bias and poor control of false positive results). The value of integrating external data is context specific and strictly dependent on the trial design and methods selected for data analysis and decision making.We describe three examples of externally augmented clinical trials with markedly different risks of poor operating characteristics. The purpose of these examples is to illustrate how external information can be used for making different decisions during or at completion of a trial.The first example is a single-arm trial with an external control group. We consider either binary primary out-comes (eg, tumour response) or time-to-event outcomes with censoring (eg, overall survival). This design uses procedures developed for observational studies,42 such as matching, propensity score methods,43,44 or inverse
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Figure 1: Clinical trial designs
(A) A clinical study with patient enrolment to a single experimental group and an external control group (externally controlled single-arm trial). (B) A two-stage hybrid randomised trial design. (C) A randomised trial design that uses external data for interim futility analyses to support the decision to continue or discontinue the study. If the trial is not discontinued, the final analysis does not use external data.

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probability weighting,45 which are applicable to the comparison of single-arm trial data (experimental treatment) with external patient-level data representative of the standard of care treatment (external control; figure 1A). These procedures have been developed to estimate treatment effects in non-randomised studies and have generated numerous contributions to the statistical literature.46 They compare outcome data Y in the experi-mental and control treatment groups with adjustments that account for confounders X.The literature on adjustment methods applicable to externally augmented clinical trial designs (eg, matching)43,44 is largely based on assumptions that are difficult to demonstrate,42 including the absence of unmeasured confounders.47 In the context of externally controlled single-arm trial designs, in which these assumptions might be violated, the investigator can attempt to evaluate the risk of bias and other statistical properties of treatment effect estimates (eg, the coverage of confidence intervals) computed using adjustment methods. Patient-level data from a library of completed RCTs in a specific clinical setting—eg, newly diagnosed glioblastoma patients—facilitate the comparison of externally controlled single-arm trial, RCT, and single-arm trial designs. For example, a treatment effect estimate computed using only data from a previously completed RCT can be compared with a second treatment effect estimate, computed using the experi-
mental group of the same RCT and external data (figure 2).48 This method can be repeated considering different RCTs, adjustment methods, and external datasets. These comparisons describe the consistency between RCT results and hypothetical results obtained from a smaller externally controlled single-arm trial (ie, the experimental group of the RCT, or part of it) leveraging external data; similar evaluation frameworks have been discussed elsewhere.49,50The leave-one-out algorithm is an alternative evaluation approach that requires a collection of completed RCTs with the same control treatment.17 The algorithm has been used to compare the application of candidate causal inference methods in externally controlled single-arm trials. This approach has been applied to a collection of studies in newly diagnosed glioblastoma and requires pretreatment profiles and outcomes from patients receiving standard of care (radiotherapy and temozolomide). This aspect is relevant because data access barriers can be substantially different for the control and experimental groups. The algorithm17 iterates the following three operations for each RCT in the data collection: (1) randomly selects n (the sample size of a hypothetical externally controlled single-arm trial) patients (without replacement) from the radiotherapy and temozolomide group (control) and uses patient pretreatment profiles (X) and outcomes (Y) of these
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Figure 2: Validation schema
A treatment effect estimate computed using only data from a previously completed randomised controlled trial is compared with a second treatment effect estimate, computed using the experimental group from the same randomised controlled trial and external control data.
Description Example Methods to avoid or reduce bias
Measured confounders The distributions of pretreatment patient characteristics that correlate with outcomes in the trial population and in the external control group are differentThe external control group has a higher Karnofsky performance status or age on average than the trial populationMatching; inverse probability weighting; marginal structural modelsUnmeasured confoundersThe distributions of unmeasured pretreatment patient characteristics that correlate with outcomes in the trial population and in the external control group are differentSupportive care (not captured in the datasets) differs between patients in the clinical trial and in the external control groupValidation analyses can indicate the risk of bias before the trial beginsDifferences in defining prognostic variables or outcomesThe definition of clinical measurements might vary between datasets, leading to differences in the definitions of outcomes or prognostic variables between the clinical trial and the external control groupMeasurement of tumour response with different response criteria or at different intervals in external control armsData dictionaries and validation analyses can reveal these discrepancies
before the trial beginsImmortal time bias In the external dataset the time-to-event outcome cannot occur during a time window because of the study design or other causesIn glioblastoma, different real-world datasets capture patient survival from diagnosis or from other timepoints, such as surgeryExplicit and detailed definitions of the time to event outcomes for the trial and external dataset can reveal the risk of bias
Table: Potential causes of bias in clinical trials with an external control group

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patients to define a fictitious single-arm study (the experimental group); (2) the data on patients receiving radiotherapy and temozolomide in the remaining studies are used as external data, these datasets are combined into a single data matrix (the external control group); and (3) a treatment effect estimate is computed by comparing the fictitious externally controlled single-arm trial (step 1) and the external data (step 2), using a candidate adjustment method, which is also used to test the null hypothesis (H0—ie, the treatment does not improve the primary outcome).For each study in the data collection, steps 1–3 (similar to cross-validation) can be repeated to evaluate bias, variability of the treatment effect estimate, and the risk of false positive results. By design, the treatment effect in this fictitious comparison is null, because patients receiving radiotherapy and temozolomide are being compared with those receiving radiotherapy and temozolomide from different studies. This facilitates interpretability and produces bias summaries for the statistical plan of an externally controlled single-arm trial. An analysis using this leave-one-out algorithm approach in patients with newly diagnosed glioblastoma showed high false positive error rates in standard single-arm clinical trials (higher than the α level),10 which can be considerably reduced (up to 30%) by using external control data from previously completed trials.17The first validation approach (figure 2) attempts to replicate results of a completed RCT, whereas the leave-one-out algorithm approach is based on subsampling a control group. Both approaches are valuable strategies that can detect potential distortion mechanisms (eg, unmeasured confounders or inconsistent definitions of primary outcomes), which undermine the scientific validity of externally controlled single-arm trials. These approaches require patient-level data from several RCTs with adequate sample sizes to produce reliable analyses of
the risk of bias and false positive results in future externally controlled single-arm trials. Importantly, positive findings from retrospective analyses should not be overinterpreted using either approach because relevant changes in available treatments and technologies, or other factors, can rapidly make the entire data collection obsolete and inadequate.51The second type of externally augmented clinical trials are hybrid randomised trial designs that combine external and randomised control data to estimate potential treatment effects.52 Figure 1B represents a two-stage hybrid design. In the first stage, patients are randomly assigned to the experimental group and the internal control arm. Interim analysis can be used for early stopping for futility and to determine sample sizes for the experimental and control groups in the second stage. These decisions are based on a similarity measure comparing estimates of conditional outcome distributions (Pr[Y|X]) of the external and internal control groups and preliminary treatment effect estimates. The proportion of patients randomised to the internal control group during the second stage can be reduced or increased on the basis of a prespecified interim analysis, which involves sum-maries in support of or against the integration of external data to estimate the effects of the experimental treatment.On the basis of results from a phase 2 study of MDNA55,19 investigators are planning an open-label, phase 3 registration study with implementation of a hybrid randomised design in patients with recurrent IDH-wild-type glioblastoma. The study team is considering a 3:1 (experimental to control) randomisation ratio with a final comparison of overall survival between patients receiving MDNA55 and the control groups (external and internal).53The third type of externally augmented clinical trials incorporates external data to support futility analyses. External data can be incorporated into RCTs for use in interim decisions.18,31 In such a design (figure 1C), interim analyses use predictions based on early data from the RCT combined with external data. These predictions express the probability that the trial will generate significant evidence of positive treatment effects. The trial is discontinued by design if the predictive probability becomes smaller than a fixed threshold. After completing the enrolment and follow-up phases, the final analysis does not use external data. The primary endpoint of the trial is positive (indicating improved outcomes with the experimental treatment) if the p value, computed using only RCT data (excluding external information), has a value lower than the targeted control of false positive results α.In ideal settings, without unmeasured confounders and other distortion mechanisms, leveraging external data for interim futility analyses can reduce the expected sample size when the experimental treatment is ineffective and can reduce early stopping probability
when the experimental therapy is superior, thus increasing the power.18 Additionally, the outlined design maintains a rigorous control of type I error probability, even in the presence of unmeasured confounders, because the external data are excluded from the final data analyses. The efficiency gains and risks associated with integration of external data into interim decisions have been quantified for trials of patients with newly diagnosed glioblastoma using evaluation analyses that built on a collection of datasets from completed RCTs, the leave-one-out algorithm, and other similar procedures.18As externally augmented clinical trials require numerous context-specific considerations, from relevant aspects of the external datasets to the feasibility of alternative designs, a discussion with regulatory agencies in early stages of trial planning is strongly recommended.
External data sourcesThe use of external controls to evaluate new treatments is
dependent on the availability of high-quality external data. Selecting appropriate datasets is crucial and checklists have been developed to provide guidance on data quality.54

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Data considerations for external controls include appropriate capture of patient-level data,55 consistent definition of covariates and endpoints, and adequate temporality of the data, as small temporal lags can substantially affect the trial analysis.49 Investigators should consider potential biases that occur if the endpoint definitions are inconsistent across studies. For example, survival can be measured from the date of diagnosis, randomisation, or adjuvant treatment start. The definition of the outcome should be explicit and consistent during the trial and in the external datasets.56 Missing data are another important consideration in analyses with external data.57,58 Although there are methods to address missing data (eg, multiple imputation and likelihood-based methods), their use within externally augmented clinical trial designs has not been extensively studied. In general, the external control population and trial population should be similar to reduce the risk of bias. Potential unmeasured confounders, inconsistencies in definitions, and different measurement standards of covariates and outcomes across datasets need to be scrutinised using data dictionaries and study protocols. Contemporaneous controls are ideal, but historical controls with patient-level data might be helpful in appropriate contexts. For example, disease settings without a recent change in the standard of care (eg, glioblastoma) or a long track record of time-stable outcomes might have more flexibility in the temporality of data, but this benefit should be weighed against the possibility of unmeasured aspects of care such as advances in imaging, radiotherapy, surgical techniques, and supportive care that might change over time.59 Additionally, the data should be traceable (ie, an audit trail should be available to document data management processes) to support a marketing application.54The two most relevant sources of external data are previously completed clinical trials and real-world data derived from clinical practice. The use of data from clinical trials can be advantageous, given that the data are typically collected in a rigorous environment with vetting procedures. Clinical trials are often done in specialised institutions and enrol clearly defined patient populations. Data from patients previously enrolled on RCTs and given standard of care might be more likely than real-world data cohorts to contain pretreatment profiles similar to those of patients who will be enrolled in future trials. The use of data collection forms, intensive monitoring, and specialised personnel enable adherence to clear protocols to produce standardised data.15 Data from previous trial participants exist, as there have been several negative phase 3 randomised trials in glioblastoma, sponsored by cooperative groups and industry, with many patients receiving the current standard of care (radiotherapy and temozolomide).60–63 Data access, however, can be challenging because of impediments to data sharing64 and contemporary trial data might not be made available by trial sponsors.Real-world data is derived from registries, claims and billing data, personal devices and applications, or electronic health records. Because real-world data is generally not collected for research purposes, there can be concerns about data organisation and quality, confounding, selection mechanisms, and ultimately, bias.65–67 Advances in the quality of electronic health records data have created opportunities, and new curated datasets can be linked to molecular or radiological data with high fidelity. Efforts to harmonise real-world data from disparate data sources and novel methods to incorporate such data into clinical studies provide an avenue to inform trial design68 and regulatory decision making,69 but further work is required to validate these approaches.Although differences between real-world data and data from clinical studies have been reported,70 methodological work on the use of joint models and analyses to compensate for the scarcity of trial data and the potential distortions of real-world data (eg, measurement errors or unknown selection mechanisms) is in early stages.Methodological work has primarily focused on overall survival,17,48 which is more likely to be adequately captured in external datasets relative to other outcomes. Radiological endpoints, such as progression-free survival, require caution because of the risk of inconsistent assessments across datasets. In real-world data, radiological outcomes might not be determined by standardised response assessment criteria and central radiological review would probably not be routinely implemented. Although brain tumour trials71,72 often use consensus guidelines by the Response Assessment in Neuro-Oncology working group, these criteria include subjective components,73 and datasets of previously completed trials can still include misclassification errors. Quality of life, neurological function, and neurocognitive outcomes are increasingly incorporated into clinical trials.72,74 These non-survival outcomes can provide meaningful measures of the clinical benefit of a therapy and serve as valuable endpoints in neuro-oncology trials.75 Nevertheless, missing measurements of these outcomes are common across datasets from completed trials and real-world data. Exploration of the use of external data to analyse radiographical outcomes, patient-centred outcomes, and safety outcomes in neuro-oncology trials remains scarce.
External control groups beyond neuro-oncologyCarrigan and colleagues48 leveraged a curated real-world data dataset of 48 856 patients (electronic health records from a Flatiron database) to reanalyse 11 completed trials in advanced non-small-cell lung cancer. In this study, the external control groups were defined with matching methods. The external control groups were able to recapitulate treatment effect estimates (hazard ratios) for ten of 11 RCTs. This finding suggests that real-world data can potentially be used as external controls partly because of the large number of patients

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in these datasets, as many patient records can meet the RCT inclusion and exclusion criteria and be used as comparators. Notably, the external control groups derived from electronic health records did not recapitulate the results for one RCT. On inspection, the authors of the study felt this discordance was associated with a biomarker subgroup population that was not sufficiently represented in the electronic health record dataset. These findings underscore the need to account for biomarkers and well represented sub populations in external control groups.A study by Ray and colleagues76 provides an example of the use of external data to contextualise a single-arm trial. In an FDA led retrospective analysis, the outcome of invasive disease-free survival from a single-arm study77 of adjuvant paclitaxel and trastu zumab in patients with HER2-positive early breast cancer was analysed using an external control group derived from clinical trials (control therapies included anthracycline, cyclophosphamide, taxane, and trastuzumab; or taxane, carboplatin, and trastuzumab).78 The de-escalated regimen that combines adjuvant paclitaxel and trastuzumab had been adopted in clinical practice on the basis of initial single-arm trial results.77 This retrospective analysis used propensity score matching to adjust for differences in pretreatment patient profiles in the single-arm trial and the external control dataset. The analysis estimated similar outcome distributions for adjuvant paclitaxel and trastuzumab and the control, which supported the use of a de-escalated regimen, particularly in light of higher toxic effects with the control regimens.
Considerations and implications for regulatory decision makingIn the USA, the 21st Century Cures Act directed the FDA to develop guidance for evaluation and use of real-world data, and to consider the potential role of real-world data in drug development and regulatory decision making. For example, real-world data could be used to support approvals for new indications or be integrated into existing monitoring requirements after approval.79 Accordingly, the FDA launched a real-world data programme to lay the foundation for rigorous use of such data in regulatory decisions.80 Several ongoing initiatives are providing guidance on data quality, data standards, and study designs that incorporate real-world data.81 Also, other regulatory institutions, such as the European Medicines Agency and Health Canada, have shown an openness towards better understanding and potentially leveraging real-world data for drug development.82,83Within a regulatory scope, the use of external control data can support expedited approval, extend on-label use of a therapy to a new indication or subgroup, and more generally support regulatory decision making.84 For example, in terms of rare diseases, the FDA approved blinatumomab for adults with relapsed or refractory acute lymphocytic leukaemia on the basis of a study that used data from a previous clinical trial as a comparator.85In a regulatory context, there is a high burden of proof for investigators to show the scientific rigor of study designs and analyses that leverage external control data with an appropriate risk level. Comparative analyses with standard RCT designs are fundamental to evaluate robustness and efficiencies of externally augmented clinical trial designs. The external data, study design, and analysis should be tailored to each specific clinical context and intended regulatory use. Each element should be carefully considered and scrutinised when evaluating the risks of biased treatment effect estimates and inadequate control of false positive findings.
Data sharing modelsDespite the appeal of patient-level data from previous clinical trials, data access is a barrier to studying and implementing externally augmented clinical trial designs in early phase and late phase trials. Data sharing efforts from industry funded RCTs are increasing, but substantial room for improvement remains.86,87 Beyond implications for externally augmented clinical trials, clinical trial data sharing allows investigators to carry out analyses that generate new knowledge and which have been deemed “essential for expedited translation of research results into knowledge, products, and procedures to improve human health” by the National Institutes of Health.88 Substantial challenges and appropriate concerns about data sharing remain,89 including the need to ensure patient privacy and academic credit; the use of adequate standards for combining data from different sources; and the allotment of resources required to deidentify patient records and provide infrastructures for data sharing. The patient perspective serves as an important counterpoint, assuming that privacy is protected; studies indicate that patients are in favour of data sharing for purposes that can help to advance clinical outcomes.90Advances towards simpler data access could transform the ability to do secondary analyses91 and leverage external data in future clinical studies. For many data sharing platforms, a gatekeeper model is used, often with long approval processes, restrictive criteria for data access, and limitations on data use. These requirements act as a mechanism of passive resistance and delay access to data from completed trials. An increasing number of data sharing platforms such as Vivli,92 YODA,93 and Project Data Sphere,94 are aligned with more open sharing models for clinical trial datasets.95 Nonetheless, most data from previously completed neuro-oncology trials remain difficult to access.New policies might be necessary for data sharing and to accelerate the study of new therapeutics. An important consideration is the modification of incentives for data sharing.96 A systematic effort from cooperative groups, industry, academia, and other stakeholders could help to achieve this goal. Regulatory requirements that ensure

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timely data sharing and patient advocacy groups could play key roles in hastening this process. Additionally, initiatives and agreements to prospectively share patient-level data from the control groups of multiple cooperative RCTs could be beneficial to participating studies and create opportunities to extend data sharing.
ConclusionAt the end of our Clinical Trials Think Tank session, there was a strong interest and desire to continue to collaborate and investigate, validate, and implement externally augmented clinical trial designs in glio-blastoma and, on a broader level, in neuro-oncology. Efforts to form industry cooperative group partnerships and selection of datasets and statistical methods were set as goals to continue towards an advancement in understanding the role of externally augmented clinical trials for drug development in neuro-oncology.The use of external data to design and analyse clinical studies has the potential to accelerate drug development and can contribute to rigorous evaluation of new
treatments. RCTs will remain the indisputable gold standard for evaluation of treatments, but external datasets can supplement information gathered from RCTs and single-arm studies. Further methodological work can help to identify the appropriate clinical contexts, data, and statistical designs for externally augmented clinical trials that generate inference on treatment effects of experimental therapies, with well controlled risks regarding their their accuracy and scientific validity.There is a continuum of approaches for leveraging external data, and use of externally augmented clinical trial designs should be tailored to the disease context. An emphasis on high-quality patient-level data, rigorous methods, and biostatistical expertise are crucial in the successful implementation of externally augmented clinical trials. Data access to previously completed clinical
trials and real-world data is improving, but new policies and initiatives for data sharing could further unlock the value of external data. Continued collab orations between stakeholders, including indus try, academia, biostatisticians, clinicians, regulatory agencies, and patient advocates, are crucial to understand the appropriate use of externally augmented clinical trial designs in neuro-oncology.
Search strategy and selection criteria
We searched PubMed for articles using the search terms “external control arms”, “synthetic control arms”, “neuro-oncology trial design”, “glioblastoma trial design”, published from Jan 1, 2000, to May 1, 2021. Articles were also identified through searches of the authors’ own files. Only papers published in English were reviewed. The final reference list was generated on the basis of relevance to the scope of this Series paper.
Contributors
RR, PYW, BMA, and LT conceptualised this Series paper and wrote the first draft. All authors contributed to the interpretation of findings and editing. All authors approved the final manuscript.
Declaration of interests
RR received research support from the Project Data Sphere, outside of submitted work. IR-R reports employment and owns stocks of Roche and Genentech. FM reports employment at Medicenna Therapeutics. LEA reports employment and owns stocks of Novartis. JEA reports employment and owns stocks of Chimerix. LKA and EA-C report employment at Candel Therapuetics. SB reports grants and personal fees from Novocure; grants from Incyte, GSK, and Eli Lilly; and personal fees from Bayer and Sumitomo Dainippon. MK reports personal fees from Ipsen, Pfizer, Roche, and Jackson Laboratory for Genomic Medicine and research funding paid to his institution from Specialised Therapeutics. TC reports personal fees from Roche, Trizel, Medscape, Bayer, Amgen, Odonate Therapeutics, Pascal Biosciences, DelMar Pharmaceuticals, Tocagen, Karyopharm, GW Pharmaceuticals, Kiyatec, AbbVie, Boehinger Ingelheim, VBI Vaccines, Dicephera, VBL Therapeutics, Agios, Merck, Genocea, Puma, Lilly, Bristol Myers Squibb, Cortice, Wellcome Trust; and stock options from Notable Labs. TC has a patent (62/819,322) with royalties paid to Katmai and is a board member for the 501c3 Global Coalition for Adaptive Research. PYW reports personal fees from Abbvie, Agios, AstraZeneca, Blue Earth Diagnostics, Eli Lilly, Genentech, Roche, Immunomic Therapeutics, Kadmon, Kiyatec, Merck, Puma, Vascular Biogenics, Taiho, Tocagen, Deciphera, and VBI Vaccines; and research support from Agios, AstraZeneca, Beigene, Eli Lily, Genentech, Roche, Karyopharm, Kazia, MediciNova, Merck, Novartis, Oncoceutics, Sanofi-Aventis, and VBI Vaccines. BMA reports employment at Foundation Medicine; personal fees from AbbVie, Bristol Myers Squibb, Precision Health Economics, and Schlesinger Associates; and research support from Puma, Eli Lilly, Celgene. SV, JM, BL, M-YCP, DA, KT, and LT declare no competing interests.
Acknowledgments
We thank Amy Barone, Pallavi Mishra-Kalyani, and the Food and Drug Administration for contributing and helping with preparation of this Series paper. We also thank the Society for Neuro-Oncology and their staff for arrangements and coordination of the 2020 Clinical Trials Think Tank meeting. We thank Johnathan Rine for help with preparation of the figures. RR was supported by the Joint Center for Radiation Therapy Foundation grant. LT and SV were supported by the National Institutes of Health (grant 1R01LM013352–01A1).
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GlobeCitizen · 2021-10-08

Unbelievable so late in the game, this stock has had to struggle for direction. Scumbags do exist in the Wall Street.

GlobeCitizen · 2021-10-15

Below is a blogger's analysis which actually just summarizes some known/published information. Nonetheless for a newbie, it's a good start.

Northwest Bio: Imminent Catalysts, Highly Compelling Upside, Significant Improvement To Brain Cancer Survival Rate (OTCMKTS:NWBO)

Northwest Bio has developed a platform vaccine technology that personalizes a cancer vaccine based on the patients own tumor bio-markers, significantly improved survival rates in 16 solid...

seekingalpha.com

Northwest Bio: Imminent Catalysts, Highly Compelling Upside, Significant Improvement To Brain Cancer Survival Rate

Oct. 14, 2021 2:32 PM ETNorthwest Biotherapeutics, Inc. (NWBO)
Please Note: Blog posts are not selected, edited or screened by Seeking Alpha editors.

Summary

Northwest Bio has developed a platform vaccine technology that personalizes a cancer vaccine based on the patients own tumor bio-markers, significantly improved survival rates in 16 solid tumor cancers.
Its 15+ year Phase 3 Trial in Glioblastoma brain cancer is about to read out its top-line results- potential significant improvement over the current standard of care (Chemotherapy + Radiation).
Company has built out proprietary manufacturing system, able to address future market demand for this vaccine. Final GMP certification in the UK an imminent catalyst.
The standard of care for Glioblastoma (the hardest to treat, violent brain cancer) has not changed since the addition of chemo to radiation in the early 2000's, the 5 year overall survival rate is less then 5%, and 400+ trials have been conducted and failed in this indication.
NWBO's vaccine is potentially showing upwards of 15-30%+ 5 year survival with an imminent top-line readout, total addressable market in the US & UK for only GBM between 20k-40k patients per year at $100-250k/per treatment course, and orphan drug status giving the firm 7-10 years of exclusivity upon approval. Total Addressable market $2-10 Billion in ANNUAL sales, vs current ~$1.5b Enterprise Value.

UW Medicine Conducts Novavax COVID-19 Vaccine Clinical Trial

Karen Ducey/Getty Images News
Blinded Data Readout: ~90% of the trial received the vaccine either through original randomization (2/3rds of patients) or crossover after progression on chemo + radiation. The data is so compelling that even including the progressed patients, the survival figures below show significant improvement over standard of care.
Given that 90% of the trial received the vaccine at some point and so few patients in this trial were left in the strictly placebo arm, regulators have proposed new guidelines approving the use of external control arms (see endpoints below) in cancer studies with high-unmet needs. It would be unethical to not allow a progressed patient to crossover to an experimental arm, and therefore it wouldn't make sense to statistically compare the large ~220 patient originally randomized arm of the trial to the only ~30 patients left on strictly chemo + radiation.
Updated Interim Data from Phase 3 Trial of DCVax®-L for Glioblastoma - Northwest Biotherapeutics

Source:

Source:
Trial Endpoints: https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-001977-13/GB#summary
Primary Endpoint:

The primary endpoint of this study is overall survival (OS) compared between patients randomized to DCVax-L and control patients from comparable, contemporaneous trials who received standard of care therapy only, in patients with newly diagnosed glioblastoma.

Secondary Endpoint (Even greater market opportunity:
The first secondary endpoint is overall survival (OS) compared between patients randomized to placebo who received DCVax-L treatment following disease recurrence, and control patients from comparable, contemporaneous clinical trials, in patients with recurrent GBM

Further Research Piece:
Cash Burn/Financial Analysis: Cash Burn per Month in $5-6mm range. The company, through a recent debt offering and warrants remains fully funded.

Bottom Line: NWBO stock is significantly undervalued at its current price. The addressable market in Glioblastoma alone is $2-10 billion in annual sales. The company would, upon approval, receive 7-10 years of market exclusivity with orphan drug status. Comps in the space trade at 10x+ revenue multiples. This should imply a 20-100 billion market cap vs ~1.5 billion today, and does not include sales from other solid tumor cancers. Given the compelling data shown above, high unmet need in a cancer that still uses the same chemo and radiation from 2005, large addressable market, and manufacturing in place, the stock should be SIGNIFICANTLY higher then it is today......

Deck: https://nwbio.com/wp-content/uploads/Boston-Presentation-v0.2.pdf

Recent Press Releases:
Northwest Biotherapeutics Announces Data Lock of Phase III Trial - Northwest Biotherapeutics
Northwest Biotherapeutics Announces Development Completed for Initial Production Capacity of Sawston, UK Facility - Northwest Biotherapeutics
UK Manufacturing Facility & Phase III Trial Updates From Northwest Biotherapeutics (OTCQB: NWBO) - Northwest Biotherapeutics

Disclosure: I/we have a beneficial long position in the shares of NWBO either through stock ownership, options, or other derivatives.
I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article.

GlobeCitizen · 2021-10-27

Two factors contribute to today's price:

1) It seems most warrants have been exercising and converted to stocks of which some have been sold, suppressing the price; on the other hand all insiders warrants still restricted; and

2) the quiet period relating to topline data release still intact, and nobody knows when the topline data will be released in whatever forms.

It may be tomorrow or by the end of year, but for those who believes in the science behind the DCVax, and have done their DD based on all known data, this stock at present is a strong buy, if temporary up and downturn is ignored.

GlobeCitizen · 2021-10-28

Nothing new but at least it's a goodwill communication with shareholders.

Northwest Biotherapeutics Announces HTA License Issued and MHRA Inspection Conducted for Sawston, UK Facility

/PRNewswire/ -- Northwest Biotherapeutics (OTCQB: NWBO) ("NW Bio"), a biotechnology company developing DCVax® personalized immune therapies for solid tumor...

www.prnewswire.com

Northwest Biotherapeutics Announces HTA License Issued and MHRA Inspection Conducted for Sawston, UK Facility

News provided by
Northwest Biotherapeutics
Oct 28, 2021, 11:42 ET

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BETHESDA, Md., Oct. 28, 2021 /PRNewswire/ -- Northwest Biotherapeutics (OTCQB: NWBO) ("NW Bio"), a biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, today announced the completion of two key milestones which are required for production of DCVax products at the Company's manufacturing facility in Sawston, UK, and which have been a major focus since the completion of initial construction last year.
First, a license to work with human tissues for medical products at Sawston has been issued by the UK Human Tissue Authority (HTA) to the Company's contract manufacturer and operator of the facility, Advent BioServices. Second, the comprehensive regulatory inspection of the facility has been conducted by the UK Medicines and Health Products Regulatory Authority ("MHRA").
In the UK, an HTA license is required for the collection, processing and storage of human tissues and cells for medical purposes. This includes the tumor tissues used to prepare the lysate for DCVax-L products, and the immune cells that comprise the active ingredient of DCVax-L. Obtaining such a license requires an application, inspection and certification process. This process has now been completed and the HTA license allowing the relevant activities to be conducted at Sawston for DCVax-L has been issued.
The Sawston facility must also be certified and licensed by MHRA in order to be able to manufacture products such as DCVax-L. The process involves an extensive application process, comprehensive inspection of all aspects of the physical facility, its construction and equipment, and all aspects of the facility's operations, including all operating systems, flow of materials and activities, sterility, quality control, staffing and other factors. It also includes extensive scrutiny of the quality management system that comprises approximately 1,000 regulatory documents, including standard operating procedures (SOPs) for the facility and for the product, validation records, data from practice manufacturing runs and other required documents.
Intensive preparations have been under way all year for this comprehensive inspection. A detailed application package and data were submitted to MHRA to qualify for the inspection. The original inspection timing was delayed by MHRA due to their caseload; however, the week-long onsite review by two MHRA inspectors was recently completed. The final phase of the process involves receiving an official MHRA inspection report and taking any responsive actions that may be required. The Company currently anticipates that this process will be completed before year-end.
About Northwest Biotherapeutics
Northwest Biotherapeutics is a biotechnology company focused on developing personalized immunotherapy products designed to treat cancers more effectively than current treatments, without toxicities of the kind associated with chemotherapies, and on a cost-effective basis, in both North America and Europe. The Company has a broad platform technology for DCVax® dendritic cell-based vaccines. The Company's lead program is a 331-patient Phase III trial of DCVax®-L for newly diagnosed Glioblastoma multiforme (GBM). GBM is the most aggressive and lethal form of brain cancer, and is an "orphan disease." This Phase III trial reached data lock and the Company is actively continuing to move toward announcement of top line data. The Company has also developed DCVax®-Direct for inoperable solid tumor cancers. It has completed a 40-patient Phase I trial and, as resources permit, plans to pursue Phase II trials. The Company previously conducted a Phase I/II trial with DCVax-L for advanced ovarian cancer together with the University of Pennsylvania.
Disclaimer
Statements made in this news release that are not historical facts, including statements concerning future treatment of patients using DCVax and future clinical trials, are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as "expect," "believe," "intend," "design," "plan," "continue," "may," "will," "anticipate," and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. We cannot guarantee that we actually will achieve the plans, intentions or expectations disclosed in our forward-looking statements and you should not place undue reliance on our forward-looking statements. Actual results may differ materially from those projected in any forward-looking statement. Specifically, there are a number of important factors that could cause actual results to differ materially from those anticipated, such as risks related to the Company's ability to achieve timely performance of third parties, risks related to whether the Company's products will demonstrate safety and efficacy, risks related to the Company's ongoing ability to raise additional capital, and other risks included in the Company's Securities and Exchange Commission ("SEC") filings. Additional information on the foregoing risk factors and other factors, including Risk Factors, which could affect the Company's results, is included in its SEC filings. Finally, there may be other factors not mentioned above or included in the Company's SEC filings that may cause actual results to differ materially from those projected in any forward-looking statement. The Company assumes no obligation to update any forward-looking statements as a result of new information, future events or developments, except as required by securities laws.

CONTACTS

Dave Innes	Les Goldman
804-513-4758 dinnes@nwbio.com	240-234-0059 lgoldman@nwbio.com

SOURCE Northwest Biotherapeutics

4 Promising OTC Stocks: IPIX NWBO RGBP SYSX | Insider Financial

insiderfinancial.com

4 Promising OTC Stocks: IPIX NWBO RGBP SYSX

Investors are in a good mood as stock market indices are at their record highs. Both S&P 500 and Nasdaq updated their all-time highs on Thursday, sending positive vibes to OTC stocks. Investors have ignored the Fed’s decision to start tapering its bond-buying program later this month, as the move has been already priced in. Instead, the focus has been on the earnings season that saw companies share better-than-expected results.

Shares of Qualcomm and Nvidia surged over 11% and almost 10%, respectively, on positive reports.

Randy Frederick, managing director of trading and derivatives for Charles Schwab, told Reuters:

“We have had a very strong earning season and the Fed has followed through on what it was preparing markets for and investors generally get happy if they get what they expect. The last time the Fed tapered, it took more than a year for it to hike rates and it looks like that’s what is going to happen going ahead too, with only one-third of the market factoring hikes next year.”

Meanwhile, government data showed that US citizens filing applications for unemployment benefits dropped to a 19-month low last week, which suggests a significant improvement in the job market. Nevertheless, the Nonfarm Payrolls report scheduled for Friday will set the tone.

OTC STOCKS THE PLACE TO BE

Smart investors know that if you want to make the big money off a small account, the place to be is the OTC Markets. There are many good OTC stocks that can boost your portfolio’s value in the long term. For investors, we preach the key to trading penny stocks is finding momentum BEFORE it happens and ahead of the crowd.

We alert our subscribers with our best ideas before our regular readers. This is the value of having a subscription to Insider Financial, which you can sign up for here.

If you watch the Insider Financial YouTube channel, you can get a sense of the ideal time to book profits. We warned our subscribers not to get greedy or get caught up in the diamond hands/paper hands BS.

We also recommend you own a portfolio of penny stocks. For some, that can be as many as 10 to 20 or more OTC stocks. This provides diversification and allows one to manage the market’s moods much easier. It also helps to own shares in the following 4 hot OTC stocks.

In this article, we look at 4 OTC stocks that will greatly reward patient investors, three of which are biotech companies. They are Innovation Pharmaceuticals Inc (OTCQB: IPIX), Northwest Biotherapeutics, Inc (OTCQB: NWBO), Regen BioPharma, Inc (OTCPK: RGBP), and Sysorex, Inc (OTCQB: SYSX).

OTC stocks #1 IPIX

OTC stocks #2 NWBO

OTC stocks #3 RGBP
OTC stocks #4 SYSX

OTC STOCK #1 IPIX

Innovation Pharmaceuticals Inc has been gaining traction lately, hitting the highest level since the summer of 2018. The share price has increased by over 130% to $0.52, and momentum is still there. The OTCQB stock has been bullish since bottoming out in May.

IPIX is an early-stage developmental biotech firm with six pharmaceutical compound candidates that are designed for the treatment of diseases that may be either existing or diseases identified in the future. The company will initially spend most of its efforts and resources on its anti-cancer compound, Kevetrin, for the treatment of head and neck cancers.

Another drug candidate is Brilacidin, a therapeutic for the treatment of oral mucositis, inflammatory bowel disease, acute bacterial skin and skin structure infection, and… COVID-19. Yes, IPIX is a COVID play, and we first paid attention to this OTC stock in October 2020, when its price traded below 20 cents.

In fact, the latest price surge is related specifically to Brilacidin. The company said last week that it was expecting results for its Phase 2 clinical trial of Brilacidin to be revealed on November 8. The study data is presently blinded at the data management vendor, with final checks and approvals in progress.

The company also reported Brilacidin has been shipped to two academic laboratories for planned in vitro testing of Brilacidin in over 20 acutely infectious viruses, including Ebola, Marburg, Nipah, West Nile, and Zika, through a collaboration with US government scientists. The goal of this testing is to further inform the spectrum of Brilacidin’s antiviral properties.

Brilacidin is the only non-peptidic defensin-mimetic drug candidate currently in a clinical trial as a treatment for SARS-CoV-2. IPIX is developing Brilacidin for the treatment of COVID-19 under the US FDA Fast Track designation. A dual-acting inhibitor able to target viral proteins and host factors, while also exhibiting robust anti-inflammatory and antibacterial properties, Brilacidin has shown potent and consistent inhibition in vitro against coronaviruses, alphaviruses, and bunyaviruses (with lab testing against other viruses also underway), supporting Brilacidin’s development as a broad-spectrum antiviral.

Two independent Machine Learning studies identified Brilacidin as one of the most promising inhibitors of SARS-CoV-2, based on Brilacidin’s molecular properties.

$IPIX #Brilacidin has been chosen by two AI systems to be a top compound to combat #COVID19. The drug was created and tested over 50k computing hours at UPENN. Let’s see if machine learning works!Innovation Pharma’s COVID-19 Drug Candidate Brilacidin Ranked in Top Three Percent of Compounds Predicted to Be Most Effective Against SARS-CoV-2 — Innovation Pharmaceuticals Inc.$PFE $JNJ $GILD $AZN $MRNA $INO $VIR $AMGN $GSK $NVAX https://t.co/oJAOxOokzj
— DrBones (@BoneyestSteak) October 29, 2021

The $200 million company has a great share structure and is really onto something. There is a great probability that IPIX will report promising results of its Phase 2 trial, and it would make sense to already hold the stock when it’s ready to move to the Phase 3 trial.

OTC STOCK #2 NWBO

Unlike IPIX, Northwest Biotherapeutics, Inc has been correcting since mid-May, when it hit a YTD high at almost $2. However, the $1 billion biotech company has some great value and solid fundamentals. We first covered Northwest Biotherapeutics in September 2020, well before the price surge that led to the highest level in years.

NWBO develops personalized immune therapies for cancer in the US and internationally. The company develops its products based on DCVax, a platform technology that uses activated dendritic cells to mobilize a patient’s own immune system to attack cancer. Its lead product, DCVax-L that is in Phase III clinical trials to treat Glioblastoma multiforme brain cancer. It also develops DCVax-Direct, which is in Phase I/II clinical trials to treat inoperable solid tumors.

At the end of October, the company said that it had completed two key milestones which are required for the production of DCVax products at its manufacturing facility in Sawston, UK, and which have been a major focus since the completion of initial construction last year.

First, a license to work with human tissues for medical products at Sawston has been issued by the UK Human Tissue Authority (HTA) to NWBO’s contract manufacturer and operator of the facility, Advent BioServices. Second, the comprehensive regulatory inspection of the facility has been conducted by the UK Medicines and Health Products Regulatory Authority (MHRA).

In the UK, an HTA license is required for the collection, processing, and storage of human tissues and cells for medical purposes. This includes the tumor tissues used to prepare the lysate for DCVax-L products, and the immune cells that comprise the active ingredient of DCVax-L.

The Sawston facility must also be certified and licensed by MHRA in order to be able to manufacture products such as DCVax-L. The process involves an extensive application process, comprehensive inspection of all aspects of the physical facility, its construction and equipment, and all aspects of the facility’s operations, including all operating systems, flow of materials and activities, sterility, quality control, staffing and other factors.

While the full results of NWBO’s Phase 3 trial are not available, the company wouldn’t have gone that far if it wasn’t confident about its treatment. As the company said in May, it has been in a quiet period while the trial is underway. NWBO appreciates shareholders’ patience, and their understanding that it cannot make partial disclosures during this process and cannot comment on the Phase III trial schedule or its data until the announcement of the results.

Investing in NWBO is not about chasing after quick returns. This can be a smart investment with long-term potential. The company can easily become a target of a pharma giant that would pay billions for it.

10% of successful stock picking is picking great stocks. The other 90% is not selling them.
— Ian Cassel (@iancassel) October 31, 2021

OTC STOCK #3 RGBP

Our subscribers are familiar with Regen BioPharma, Inc, as it’s one of the biotech stocks that we think can provide great value in the long term. The share price has increased by 30% during the last five trading days, which is a decent move for an OTC stock that hasn’t been showing wild fluctuations. You can buy the RGBP stock for $0.022, a bargain price for a company that sits on a pile of patents.

RGBP is focused on the immunology and immunotherapy space. At the moment, RGBP is focused on small molecule therapies for treating cancer and autoimmune disorders. On top of that, Regen is working on translational medicine platforms for the commercialization of stem cell therapies. The company produces stem-based medicines for diabetes, heart-related illness, circulatory issues, and Chronic Obstructive Pulmonary Disease. The stem cell industry is expected to exceed $15 billion by 2027.

Earlier this year, RGBP signed two deals with Oncology Pharma. One deal focuses on treating pancreatic cancer, and the other one is for the treatment of colon cancer.

Recently, the company revealed a new patent that it had received. Thus, it said that on October 12, the United States Patent and Trademark Office (USPTO) issued Patent Number 11,141,471 B2 to Regen Biopharma, Inc. for “UNIVERSAL DONOR CHECKPOINT INHIBITOR SILENCED/GENE EDITED CORD BLOOD KILLER CELLS.” The invention encompasses compositions of matters, cells, and treatment protocols useful for the induction of anticancer responses in a patient suffering from cancer.

$RGBP 8-K Out
On October 12, 2021 the United States Patent and Trademark Office ( “USPTO”) issued Patent Number 11,141,471 B2 to Regen Biopharma, Inc. for “UNIVERSAL DONOR CHECKPOINT INHIBITOR SILENCED/GENE EDITED CORD BLOOD KILLER CELLS” pic.twitter.com/ZQ77BIPGR1
— Stock Pop (@Stock_Pop) November 4, 2021

In another 8-k published at the end of October, Regen said it had provided a Scope of Work (SOW) order to Biotech Research Group directing it to perform an independent assessment of work conducted to date on behalf of RGBP by the company’s Contract Research Organization in order to assist RGBP in determining what would be the most efficient actions to undertake in order to commercialize its NR2F6 intellectual property as well as assist it with regulatory strategy with regard to its NR2F6 intellectual property.

@Rgbpharma $RGBP $RGBPP hired Biotech Research Group in Oct to provide a valuation of their patents. $RGBP ALSO hired BGG last may to revive an inactive Investigational New Drug application. 6 months of this process is November 12. Only takes 30 days for an application with FDA pic.twitter.com/xw48oMoEEH
— Chris P. Tendies (@Chris_P_Tendies) November 4, 2021

Things are moving at Regen, and we expect more and more updates to come soon. Eventually, RGBP can be acquired by a larger company, like Oncology or Precigen, but even on its own Regen is a great OTC stock to hold.

OTC STOCK #4 SYSX

Sysorex, Inc is yet another OTCQB stock, although it’s not a biotech company. Its share price has gained almost 60% since last week to trade at $0.47. On Tuesday, SYSX bounced back to a monthly high at $0.54. Larger timeframes show that the stock has been correcting from a YTD high at over $14 reached in April. It means that the price has lost over 96% of its value in a matter of months, but it also means that you can buy the dip, especially when the recent price spike was accompanied by record volumes.

SYSX is a data center owner and operator and is the largest US-based, publicly-traded Ethereum mining and blockchain technology company. Following the company’s reverse triangular merger with TTM Digital Assets & Technologies, Inc. (TTM), SYSX shifted its primary business focus to the mining of Ethereum and opportunities related to the Ethereum blockchain.

The company currently owns and operates thousands of NVIDIA Graphics Processing Units (GPUs) generating approximately 500 Gigahash of computing power, as well as a large number of specialized crypto-mining processors. These GPUs are currently online and securing the Ethereum blockchain and generating ETH around the clock with industry-leading efficiency.

In addition to the mining of Ethereum, SYSX continues to operate its wholly-owned subsidiary, Sysorex Government Services, Inc, a business that provides information technology products, solutions, and services to federal, state, and local government, including system integrators. Recently, the company had been awarded multiple government contracts totaling more than $16 million during Q3. These new orders are from the US Department of Justice, Bureau of Prisons (BOP), and the US Department of Agriculture (USDA).

In the future, the company plans to explore potential strategies to leverage the Ethereum blockchain and distributed ledger technology to SGS’s business opportunities.

On Thursday, SYSX announced that it had completed the acquisition of the remaining 50% of the upstate New York data center that houses the majority of its approximately 500 Gigahash of compute capacity.

Up North Hosting LLC, a data center owner and operator in upstate New York, was previously jointly owned by businesses controlled by Sysorex’s recently appointed CTO, cryptocurrency industry veteran Brian Raymond, and Sysorex. Sysorex now owns 100% of the data center, which offers the company immediate access to additional capacity to expand its mining operations. The purchase also included approximately 1000 GPUs, which presently increases mining capacity by approximately 10%.

Brian Raymond, CTO of Sysorex, said:

“With a consolidated facility, Sysorex is well positioned to grow its Ethereum mining business with a better than industry average cost to support operations.”

Ethereum mining has suddenly become profitable thanks to a surge in the price of ETH itself, which just hit a record high at over $4,600. It also trades not far from a YTD high versus Bitcoin, surging in value by about 300% versus the largest cryptocurrency by market cap. In fact, Ethereum mining outpaced Bitcoin mining this year, and the upgrade that will make Ethereum mining unprofitable has been delayed.

We’re quite bullish on SYSX. SYSX used to trade above $10. Current prices make SYSX a discount entry opportunity.

THE FINAL NOTE

All of the 4 OTC stocks discussed today are on the rise and are good stocks to hold. Nevertheless, our best advice is to be patient and enter the market during corrections. Buying dips and selling rips as swing trades remains the best strategy in the penny stock market. Still, whenever a penny stock is in the middle of a bull run, we recommend our subscribers to book profits.

It’s very important to eye the best OTC stocks that have room for growth and have yet to make their explosive move. There are plenty of opportunities, and we take our time to monitor hundreds of penny stocks to buy each week, trying to find the best alerts for our subscribers.

Remember, all you need is one or two penny stocks to succeed in order to crush the market averages.

As always, good luck to all (except the shorts)!

WHEN INSIDER FINANCIAL HAS A STOCK ALERT, IT CAN PAY TO LISTEN. AFTER ALL, OUR FREE NEWSLETTER HAS FOUND MANY TRIPLE-DIGIT WINNERS FOR OUR SUBSCRIBERS. WE SPECIALIZE IN FINDING MOMENTUM BEFORE IT HAPPENS!

Disclosure: We have no position in any of the securities mentioned. We wrote this article ourselves and it expresses our own opinions. We are not receiving compensation for it. We have no business relationship with any company whose stock is mentioned in this article. Insider Financial is not an investment advisor and does not provide investment advice. Always do your own research and make your own investment decisions. This article is not a solicitation or recommendation to buy, sell, or hold securities. This article is meant for informational and educational purposes only and does not provide investment advice.
Investors are in a good mood as stock market indices are at their record highs. Both S&P 500 and Nasdaq updated their all-time highs on Thursday, sending positive vibes to OTC stocks. Investors have ignored the Fed’s decision to start tapering its bond-buying program later this month, as the move has been already priced in. Instead, the focus has been on the earnings season that saw companies share better-than-expected results.
Shares of Qualcomm and Nvidia surged over 11% and almost 10%, respectively, on positive reports.
Randy Frederick, managing director of trading and derivatives for Charles Schwab, told Reuters:

“We have had a very strong earning season and the Fed has followed through on what it was preparing markets for and investors generally get happy if they get what they expect. The last time the Fed tapered, it took more than a year for it to hike rates and it looks like that’s what is going to happen going ahead too, with only one-third of the market factoring hikes next year.”

Meanwhile, government data showed that US citizens filing applications for unemployment benefits dropped to a 19-month low last week, which suggests a significant improvement in the job market. Nevertheless, the Nonfarm Payrolls report scheduled for Friday will set the tone.

OTC STOCKS THE PLACE TO BE

Smart investors know that if you want to make the big money off a small account, the place to be is the OTC Markets. There are many good OTC stocks that can boost your portfolio’s value in the long term. For investors, we preach the key to trading penny stocks is finding momentum BEFORE it happens and ahead of the crowd.
We alert our subscribers with our best ideas before our regular readers. This is the value of having a subscription to Insider Financial, which you can sign up for here.
If you watch the Insider Financial YouTube channel, you can get a sense of the ideal time to book profits. We warned our subscribers not to get greedy or get caught up in the diamond hands/paper hands BS.
We also recommend you own a portfolio of penny stocks. For some, that can be as many as 10 to 20 or more OTC stocks. This provides diversification and allows one to manage the market’s moods much easier. It also helps to own shares in the following 4 hot OTC stocks.
In this article, we look at 4 OTC stocks that will greatly reward patient investors, three of which are biotech companies. They are Innovation Pharmaceuticals Inc (OTCQB: IPIX), Northwest Biotherapeutics, Inc (OTCQB: NWBO), Regen BioPharma, Inc (OTCPK: RGBP), and Sysorex, Inc (OTCQB: SYSX).

OTC stocks #1 IPIX

OTC stocks #2 NWBO

OTC stocks #3 RGBP
OTC stocks #4 SYSX

OTC STOCK #1 IPIX

Innovation Pharmaceuticals Inc has been gaining traction lately, hitting the highest level since the summer of 2018. The share price has increased by over 130% to $0.52, and momentum is still there. The OTCQB stock has been bullish since bottoming out in May.
IPIX is an early-stage developmental biotech firm with six pharmaceutical compound candidates that are designed for the treatment of diseases that may be either existing or diseases identified in the future. The company will initially spend most of its efforts and resources on its anti-cancer compound, Kevetrin, for the treatment of head and neck cancers.
Another drug candidate is Brilacidin, a therapeutic for the treatment of oral mucositis, inflammatory bowel disease, acute bacterial skin and skin structure infection, and… COVID-19. Yes, IPIX is a COVID play, and we first paid attention to this OTC stock in October 2020, when its price traded below 20 cents.
In fact, the latest price surge is related specifically to Brilacidin. The company said last week that it was expecting results for its Phase 2 clinical trial of Brilacidin to be revealed on November 8. The study data is presently blinded at the data management vendor, with final checks and approvals in progress.
The company also reported Brilacidin has been shipped to two academic laboratories for planned in vitro testing of Brilacidin in over 20 acutely infectious viruses, including Ebola, Marburg, Nipah, West Nile, and Zika, through a collaboration with US government scientists. The goal of this testing is to further inform the spectrum of Brilacidin’s antiviral properties.
Brilacidin is the only non-peptidic defensin-mimetic drug candidate currently in a clinical trial as a treatment for SARS-CoV-2. IPIX is developing Brilacidin for the treatment of COVID-19 under the US FDA Fast Track designation. A dual-acting inhibitor able to target viral proteins and host factors, while also exhibiting robust anti-inflammatory and antibacterial properties, Brilacidin has shown potent and consistent inhibition in vitro against coronaviruses, alphaviruses, and bunyaviruses (with lab testing against other viruses also underway), supporting Brilacidin’s development as a broad-spectrum antiviral.
Two independent Machine Learning studies identified Brilacidin as one of the most promising inhibitors of SARS-CoV-2, based on Brilacidin’s molecular properties.

$IPIX #Brilacidin has been chosen by two AI systems to be a top compound to combat #COVID19. The drug was created and tested over 50k computing hours at UPENN. Let’s see if machine learning works!Innovation Pharma’s COVID-19 Drug Candidate Brilacidin Ranked in Top Three Percent of Compounds Predicted to Be Most Effective Against SARS-CoV-2 — Innovation Pharmaceuticals Inc.$PFE $JNJ $GILD $AZN $MRNA $INO $VIR $AMGN $GSK $NVAX https://t.co/oJAOxOokzj
— DrBones (@BoneyestSteak) October 29, 2021

The $200 million company has a great share structure and is really onto something. There is a great probability that IPIX will report promising results of its Phase 2 trial, and it would make sense to already hold the stock when it’s ready to move to the Phase 3 trial.

OTC STOCK #2 NWBO

Unlike IPIX, Northwest Biotherapeutics, Inc has been correcting since mid-May, when it hit a YTD high at almost $2. However, the $1 billion biotech company has some great value and solid fundamentals. We first covered Northwest Biotherapeutics in September 2020, well before the price surge that led to the highest level in years.
NWBO develops personalized immune therapies for cancer in the US and internationally. The company develops its products based on DCVax, a platform technology that uses activated dendritic cells to mobilize a patient’s own immune system to attack cancer. Its lead product, DCVax-L that is in Phase III clinical trials to treat Glioblastoma multiforme brain cancer. It also develops DCVax-Direct, which is in Phase I/II clinical trials to treat inoperable solid tumors.
At the end of October, the company said that it had completed two key milestones which are required for the production of DCVax products at its manufacturing facility in Sawston, UK, and which have been a major focus since the completion of initial construction last year.
First, a license to work with human tissues for medical products at Sawston has been issued by the UK Human Tissue Authority (HTA) to NWBO’s contract manufacturer and operator of the facility, Advent BioServices. Second, the comprehensive regulatory inspection of the facility has been conducted by the UK Medicines and Health Products Regulatory Authority (MHRA).
In the UK, an HTA license is required for the collection, processing, and storage of human tissues and cells for medical purposes. This includes the tumor tissues used to prepare the lysate for DCVax-L products, and the immune cells that comprise the active ingredient of DCVax-L.
The Sawston facility must also be certified and licensed by MHRA in order to be able to manufacture products such as DCVax-L. The process involves an extensive application process, comprehensive inspection of all aspects of the physical facility, its construction and equipment, and all aspects of the facility’s operations, including all operating systems, flow of materials and activities, sterility, quality control, staffing and other factors.
While the full results of NWBO’s Phase 3 trial are not available, the company wouldn’t have gone that far if it wasn’t confident about its treatment. As the company said in May, it has been in a quiet period while the trial is underway. NWBO appreciates shareholders’ patience, and their understanding that it cannot make partial disclosures during this process and cannot comment on the Phase III trial schedule or its data until the announcement of the results.
Investing in NWBO is not about chasing after quick returns. This can be a smart investment with long-term potential. The company can easily become a target of a pharma giant that would pay billions for it.

10% of successful stock picking is picking great stocks. The other 90% is not selling them.
— Ian Cassel (@iancassel) October 31, 2021

OTC STOCK #3 RGBP

Our subscribers are familiar with Regen BioPharma, Inc, as it’s one of the biotech stocks that we think can provide great value in the long term. The share price has increased by 30% during the last five trading days, which is a decent move for an OTC stock that hasn’t been showing wild fluctuations. You can buy the RGBP stock for $0.022, a bargain price for a company that sits on a pile of patents.
RGBP is focused on the immunology and immunotherapy space. At the moment, RGBP is focused on small molecule therapies for treating cancer and autoimmune disorders. On top of that, Regen is working on translational medicine platforms for the commercialization of stem cell therapies. The company produces stem-based medicines for diabetes, heart-related illness, circulatory issues, and Chronic Obstructive Pulmonary Disease. The stem cell industry is expected to exceed $15 billion by 2027.
Earlier this year, RGBP signed two deals with Oncology Pharma. One deal focuses on treating pancreatic cancer, and the other one is for the treatment of colon cancer.
Recently, the company revealed a new patent that it had received. Thus, it said that on October 12, the United States Patent and Trademark Office (USPTO) issued Patent Number 11,141,471 B2 to Regen Biopharma, Inc. for “UNIVERSAL DONOR CHECKPOINT INHIBITOR SILENCED/GENE EDITED CORD BLOOD KILLER CELLS.” The invention encompasses compositions of matters, cells, and treatment protocols useful for the induction of anticancer responses in a patient suffering from cancer.

$RGBP 8-K Out
On October 12, 2021 the United States Patent and Trademark Office ( “USPTO”) issued Patent Number 11,141,471 B2 to Regen Biopharma, Inc. for “UNIVERSAL DONOR CHECKPOINT INHIBITOR SILENCED/GENE EDITED CORD BLOOD KILLER CELLS” pic.twitter.com/ZQ77BIPGR1
— Stock Pop (@Stock_Pop) November 4, 2021

In another 8-k published at the end of October, Regen said it had provided a Scope of Work (SOW) order to Biotech Research Group directing it to perform an independent assessment of work conducted to date on behalf of RGBP by the company’s Contract Research Organization in order to assist RGBP in determining what would be the most efficient actions to undertake in order to commercialize its NR2F6 intellectual property as well as assist it with regulatory strategy with regard to its NR2F6 intellectual property.

@Rgbpharma $RGBP $RGBPP hired Biotech Research Group in Oct to provide a valuation of their patents. $RGBP ALSO hired BGG last may to revive an inactive Investigational New Drug application. 6 months of this process is November 12. Only takes 30 days for an application with FDA pic.twitter.com/xw48oMoEEH
— Chris P. Tendies (@Chris_P_Tendies) November 4, 2021

Things are moving at Regen, and we expect more and more updates to come soon. Eventually, RGBP can be acquired by a larger company, like Oncology or Precigen, but even on its own Regen is a great OTC stock to hold.

OTC STOCK #4 SYSX

Sysorex, Inc is yet another OTCQB stock, although it’s not a biotech company. Its share price has gained almost 60% since last week to trade at $0.47. On Tuesday, SYSX bounced back to a monthly high at $0.54. Larger timeframes show that the stock has been correcting from a YTD high at over $14 reached in April. It means that the price has lost over 96% of its value in a matter of months, but it also means that you can buy the dip, especially when the recent price spike was accompanied by record volumes.
SYSX is a data center owner and operator and is the largest US-based, publicly-traded Ethereum mining and blockchain technology company. Following the company’s reverse triangular merger with TTM Digital Assets & Technologies, Inc. (TTM), SYSX shifted its primary business focus to the mining of Ethereum and opportunities related to the Ethereum blockchain.
The company currently owns and operates thousands of NVIDIA Graphics Processing Units (GPUs) generating approximately 500 Gigahash of computing power, as well as a large number of specialized crypto-mining processors. These GPUs are currently online and securing the Ethereum blockchain and generating ETH around the clock with industry-leading efficiency.
In addition to the mining of Ethereum, SYSX continues to operate its wholly-owned subsidiary, Sysorex Government Services, Inc, a business that provides information technology products, solutions, and services to federal, state, and local government, including system integrators. Recently, the company had been awarded multiple government contracts totaling more than $16 million during Q3. These new orders are from the US Department of Justice, Bureau of Prisons (BOP), and the US Department of Agriculture (USDA).
In the future, the company plans to explore potential strategies to leverage the Ethereum blockchain and distributed ledger technology to SGS’s business opportunities.
On Thursday, SYSX announced that it had completed the acquisition of the remaining 50% of the upstate New York data center that houses the majority of its approximately 500 Gigahash of compute capacity.
Up North Hosting LLC, a data center owner and operator in upstate New York, was previously jointly owned by businesses controlled by Sysorex’s recently appointed CTO, cryptocurrency industry veteran Brian Raymond, and Sysorex. Sysorex now owns 100% of the data center, which offers the company immediate access to additional capacity to expand its mining operations. The purchase also included approximately 1000 GPUs, which presently increases mining capacity by approximately 10%.
Brian Raymond, CTO of Sysorex, said:

“With a consolidated facility, Sysorex is well positioned to grow its Ethereum mining business with a better than industry average cost to support operations.”

Ethereum mining has suddenly become profitable thanks to a surge in the price of ETH itself, which just hit a record high at over $4,600. It also trades not far from a YTD high versus Bitcoin, surging in value by about 300% versus the largest cryptocurrency by market cap. In fact, Ethereum mining outpaced Bitcoin mining this year, and the upgrade that will make Ethereum mining unprofitable has been delayed.
We’re quite bullish on SYSX. SYSX used to trade above $10. Current prices make SYSX a discount entry opportunity.

THE FINAL NOTE

All of the 4 OTC stocks discussed today are on the rise and are good stocks to hold. Nevertheless, our best advice is to be patient and enter the market during corrections. Buying dips and selling rips as swing trades remains the best strategy in the penny stock market. Still, whenever a penny stock is in the middle of a bull run, we recommend our subscribers to book profits.
It’s very important to eye the best OTC stocks that have room for growth and have yet to make their explosive move. There are plenty of opportunities, and we take our time to monitor hundreds of penny stocks to buy each week, trying to find the best alerts for our subscribers.
Remember, all you need is one or two penny stocks to succeed in order to crush the market averages.
As always, good luck to all (except the shorts)!

WHEN INSIDER FINANCIAL HAS A STOCK ALERT, IT CAN PAY TO LISTEN. AFTER ALL, OUR FREE NEWSLETTER HAS FOUND MANY TRIPLE-DIGIT WINNERS FOR OUR SUBSCRIBERS. WE SPECIALIZE IN FINDING MOMENTUM BEFORE IT HAPPENS!

Disclosure: We have no position in any of the securities mentioned. We wrote this article ourselves and it expresses our own opinions. We are not receiving compensation for it. We have no business relationship with any company whose stock is mentioned in this article. Insider Financial is not an investment advisor and does not provide investment advice. Always do your own research and make your own investment decisions. This article is not a solicitation or recommendation to buy, sell, or hold securities. This article is meant for informational and educational purposes only and does not provide investment advice.

GlobeCitizen · 2021-11-20

Dan88	Saturday, 11/20/21 11:52:46 AM
Re: None
Post # of 419836

We are all golden now ladies and gentlemen given SNO self-inflicted, manipulators executed bear raid had been behind us:

Looking back, we must give Linda a genuine compliment for her very careful efforts of not giving any shreds of information which might have been mistaken by some shareholders that the company and related party would be presenting in this year's SNO. Despite that, unfortunately it seems she has failed, because some people may have been intentionally spreading misinformation, tossing around tea leaves to suggest otherwise, coupled with those usual one-line posters on social media yapping dismal price prediction day in and day out preceding the conference, hoping it would stick on investors mind.

Because of those bad actors, it validates company's strategy to painstakingly work on journal publication, not going the usual way to release short TLD, followed by journal publication several months or years after.

It's great it has gone, and it's great we don't need to look forward to next conference or ASCO. According to DI, the publication is now in peer reviews, which means the six huge steps outlined in the consistent company's news releases since included 5 October 2020 news have been successfully accomplished. Now we are in autopilot indeed!

Be patient ladies and gentlemen, this may take some times for the reviewers to complete their job and make their decision based on the nature of this 15-year long trial with an indication so heterogeneous.

However, since we don't know exactly when the company submitted the draft to journal, and whether there is already some back and forth interaction between the authors and the journal, so timing wise, it could be in very short time (one or two weeks) or some more time before publication. Nonetheless, be happy the big task of analyzing the trial data has been accomplished!

Lastly, as always we have reasons to believe DCVax-L is both efficacious and safe in treating GBM, one of the most difficult to treat cancers based on what we have known so far;

Due to the unique MOA of DCVax-L, it is most likely the therapeutic vaccine will usher in a new era of cancer cares and treatments. It will truly be personalized in which each individual patients own immune cells will be mobilized to kill cancer cells; and

During this long, difficult and rewarding journey, beware of those bad actors, and those who would exploit in any ways via any means!

Gook luck, I seeing the light!

GlobeCitizen · 2021-11-22

strong buy still

GlobeCitizen · 2021-11-22

GlobeCitizen · 2021-11-28

Dan88	Saturday, 11/27/21 11:57:23 AM
Re: None	0
Post # of 422194

After a reflective Thanksgiving, please settle any uneasiness, preoccupation and most of all confusion resulted from the question: what on earth is "the reason behind the long delayed" TLD/publication. Today it has been well known about the phenomena of pseudo-progression and cross-over associated with most immunotherapeutic clinical trials.

As a result, the trials today can follow related regulatory guidance in design to circumvent the potential unfavorable effects of pseudo-progression and cross-over. But for a 15-year old trial which was data locked on 5 October 2020, its sponsor NWBio had no luxury back then. In light of the endless confusion still existing today, please allow me for a quick rehashing on what has been going on:

About in 2014-2015, the company finally realized its initial endpoints might be compromised due to recently known pseudo-progression phenomenon. Despite pseudo-progression in and by itself may actually indicate stronger than expected immunogenicity, i.e., it's inherently a good thing, it may wreak havoc with PFS as the primary endpoint.

Evidently, FDA halted the trial prohibiting the company from screening new patients in order to protect new patients from being harmed. Note any regulatory agency would not wait for the company to prove otherwise if they deem patients may experience harm. To get the trial halt lifted, the burden obviously fell upon NWBio to prove. NWBio's opinion obviously is there is no harm to any participated patients for the reason of pseudo-progression. Evidently in Feb 2017, FDA agreed with the company. As a result, it lifted the halt.

Concurrently with pseudo-progression, by the time the company also realized its initial overall survival secondary endpoint might also be compromised because by design patients in the trial would switch (cross over) to receiving DCVax-L vaccine at disease progression so that about 90% of all the patients enrolled have received DCVax-L. That may make accurately measuring the efficacy of vaccine problematic between both the control and treatment arms of patients.
In order to solve the two potential problems (pseudo-progression and crossover) above, it became natural and necessary for the company to revise its initial SAP in which trial endpoints are significant parts. Today we know both UK and Germany have accepted the changes, evidenced with their respective government responsible update in their clinical trial registries:

"The primary endpoint of this study is overall survival (OS) compared between patients randomized to DCVax-L and control patients from comparable, contemporaneous trials who received standard of care therapy only, in patients with newly diagnosed glioblastoma.

Secondary end point(s)

The first secondary endpoint is overall survival (OS) compared between patients randomized to placebo who received DCVax-L treatment following disease recurrence, and control patients from comparable, contemporaneous clinical trials, in patients with recurrent GBM.

The second secondary endpoint, confirmed progression-free survival (cPFS), is confirmed disease progression (cPD) compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study.

The third secondary endpoint, PFS, is progression-free survival compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study.

The fourth secondary objective, OS, is overall survival compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study.

The fifth secondary objective is tumor response compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study."

Please note the initial primary and secondary endpoints are still part of the revised endpoints. It just now they are ranked the third and fourth endpoints (see above above).

So obviously NWBio will have plenty of explanation work to do to persuade and convince those who have doubts due to a variety of reasons. As a commercial company with only one product in the late stage development, it may not be rational and reasonable for the company to proceed in the direction of what seems familiar for most people: release TLD shortly after data lock, followed by publication/conference presentation, months if not years thereafter, considering the potential relentless malicious attacks the company had received in the past, because the trial results upon and after published will be most likely diced and spun in any negative way possible regardless how good the results will be.

This I think is the fundamental reason why we have been heading in this direction of making the trial data go through the multi-step reviews by "the Company, the Principal Investigator, the Steering Committee of the Trial, the Scientific Advisory Board, and a panel of independent brain cancer experts, who will analyze the data with the statisticians in preparation for public announcement and scientific publication"

Obviously the well analyzed and reviewed trial results published in a peer reviewed journal will be hard to rebuff; In terms of getting the vaccine approved, it may, by carefully making the preparation of data now, save time in the end.

Recently we have known the publication is in the stage of journal peer reviews. Hopefully it will not take long to get the publication out to the public.

Personally, I have been a buyer, even recently having taken a loan since I don't see any other reason not doing so for myself of course. I can accept delayed rewards from my investment after carefully reviewing what we are at and the share price which I consider it close to the price if the trial would fail its primary endpoint. As I have stated many times on this board, it's highly probable the trial will readily meet its primary and key secondary endpoints significantly based on what have been known to the public.

All the above are just my humble opinions. Good luck and be happy everyone!

GlobeCitizen · 2021-11-28

Dan88	Saturday, 11/27/21 10:34:12 PM
Re: biosectinvestor post# 422023	0
Post # of 422202

Appreciated very much for your well-thought out replies biosectinvestor. I understand where you are coming from. Yours is obvious a possible reason, though I think it may be somewhat a stretch.

There are different perceptions and perspectives on the same issue of pseudo progression from different parties. At the time of the partial halt, pseudo progression was already a known phenomenon for NWBio, clinicians running the trial, and regulatory agencies. The problem is when it happened to a patient there seemed to having no ways to distinguish either right on the spot or very shortly the event was in effect due to pseudo progression. So for the regulatory agencies, they had to assume it was a disease progression upon it was approved otherwise; for NWBio it could argue such events were most likely and mostly pseudo progressions, suggested by the underlining patients as a whole have instead lived longer than the rest of the patients in aggregate. So despite seemingly quick disease progressions (one characteristic for pseudo progression events) , these patients have also lived longer than those patients who have experienced disease progressions later (after the exclusion of rapid progression patients from the trial during the 3-month screening process, a characteristic for true disease progression events) which obviously contradicted to the known fact that disease progression normally correlates to underlining overall survival, i.e., the more delayed in disease progression, the longer the overall survival of underlining patients.

In light of the above, I don't think FDA when it initiated the partial halt would consider the halt a straight-forward safety halt. It might just want to give the company time to fix the problem or later provide it with more persuasive and convincing data that would indicate most such suspected events were indeed not harmful to the patients who have experienced the events. Since the halt was lifted by FDA, I do think NWBio was later able to provide to the FDA such data which not only has it showed the underlining patients have lived longer, but they also have experienced better quality of life.

It is in this sense and circumstance I also don't think the partial halt had anything to do with safety at the time. Today it can be said with almost certainty that both NWBio and FDA are on the same page regarding pseudo progressions, i.e., the more than expected disease progression events experienced in the trial are indeed mostly due to pseudo progressions; and it is also suggested NWBio may have found ways to distinguish between pseudo progressions and true progressions, evidenced by the listed second secondary endpoint in the now revised SAP, i.e., cPFS.

All in all, pseudo progression may be a strong indication that DCVax-L is not only safe by also very efficacious. It causes no harm to patients; instead it is a blessing.

GL and best wishes !

[There are not posts left for me today. Thank all]

NWBO: Once In A Decade Best Stock Investment -- Regulatory Approvals Coming! [Dec10, 2022 在第一页加了中文简述]

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Northwest Bio: Imminent Catalysts, Highly Compelling Upside, Significant Improvement To Brain Cancer Survival Rate​

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Northwest Bio: Imminent Catalysts, Highly Compelling Upside, Significant Improvement To Brain Cancer Survival Rate

Summary

Northwest Biotherapeutics Announces HTA License Issued and MHRA Inspection Conducted for Sawston, UK Facility

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