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Real World Evidence. Risk-Based Monitoring. Study Start-Up. Therapeutic Areas. Trial Design. Spotlight - Patient Participation Regulatory. Sample Banking for Future Clinical Research November 11, Lina Genovesi, PhD, JD.

Regulatory Considerations Going global in a clinical trial context has its own sets of issues and challenges when it comes to sample collection for future clinical research. There are no uniform regulations and several inconsistencies exists relating to informed consent language, duration of sample storage, sample usage and return of patient level research data, Japan In , the Pharmaceuticals and Medical Devices Agency PMDA issued a guidance outlining the general principles of pharmacogenomics in clinical trials and supporting the collection of future use samples.

USA In January , the US FDA issued a draft guidance with one of its goals, the assistance of parties engaged in new drug development in evaluating the effect of variations in the human genome on the clinical responses of drugs.

Sample Storage To assure sample integrity, the appropriate storage of biological samples is one of the key challenges in sample collections.

Accreditation One of the key issues with facilities involved in sample storage for future clinical research is accreditation.

Case Studies Because biospecimen collections exist to enhance the translation of basic research to the clinical setting, collaborations have formed to make the most of the opportunities presented.

Science of Biobanking Several institutions have provided their investigators access to an extensive repository of biological samples. These biobanks include: The Indiana Biobank IB , which is a repository of blood and saliva samples from Hoosier volunteers.

The Susan G. Komen® Tissue Bank KTB at the IU Simon Cancer Center, which is a repository for normal breast tissue and matched serum, plasma and DNA. The IU Simon Cancer Center IUSCC Tissue Procurement and Distribution Core. The IUSCC Tissue Procurement and Distribution Core includes the IUSCC Tissue Bank and the Hematological Malignancies Biobank.

Going Forward Sample banking for future clinical research will continue to be of utmost importance to develop safe and effective medications.

One of its goals is to work with the FDA, EMEA, regulators and various policy groups to provide information on noncompetitive issues related to pharmacogenetic research. One of its goals is to identify safe and effective drug therapies for individual patients and interact with scientists in academia, industry, and government regulatory agencies.

It includes senior scientists from drug regulatory authorities and pharmaceutical companies, plus experts from WHO and academia. One of its goals is to consider drug development and the regulatory, ethical, educational, and economic issues related to pharmacogenetics. For example, PET with 2-deoxy fluorine fluoro- D-glucose 18 F-FDG PET , a radiolabelled analogue of glucose, is routinely used for cancer staging and evaluation of disease response to cancer therapy and within the context of drug trials.

Although not available as part of standard clinical practice, use of dynamic 18 F-FDG PET scans in research studies may be more sensitive in evaluating metabolic response to therapy and enable assessment of tracer distribution over time.

However, it has been shown to be preferentially taken up into many tumour types and uptake corresponds to mitochondrial membrane potential.

A number of magnetic resonance imaging MRI techniques have now also been developed that can image biomolecules of interest. These techniques have some advantages over PET imaging in that they are typically less invasive and avoid radiation exposure and hence are more suited to several measurements over a short period.

Functional MRI and, in particular, chemical exchange saturation transfer CEST MRI measures the chemical exchange of protons between hydroxyl groups and water. For example, glucoCEST MRI has been shown to be a sensitive technique for detecting glucose uptake into tumours. have described the potential of these techniques to characterise redox state and NADH concentration.

Magnetic resonance spectroscopy MRS allows the non-invasive molecular imaging of many oncometabolites. Most commonly proton MRS 1 H MRS has been used to detect known shifts in the resonance of protons that vary with the concentration of specific metabolites in the tumour environment and hence image the metabolic heterogeneity of cancer tissue.

In addition, 13 C MRS is especially suited to measuring metabolic fluxes although this technique typically requires the infusion of 13 C substrate as natural abundance of 13 C is limited.

Attempts have been made to monitor response to neoadjuvant chemotherapy in breast cancer using choline 1 H MRS to monitor changes in phospholipid metabolism with limited success.

A Phase 1 study using in vivo MRS showed a rapid decrease in 2-HG levels within the tumour following treatment with a novel IDH1 inhibitor, consistent with metabolic response to therapy. Window study designs can be used to evaluate novel imaging and understand how the imaging signature reflects tumour biology.

We have recently conducted a study, the FRONTIER trial, in which we imaged primary breast cancers with 18 F-FACBC, shortly prior to tumour sampling at surgical resection clinicaltrials. gov number: NCT Here, we plan to correlate immunohistochemical, transcriptomic and metabolomic profiling with 18 F-FACBC uptake to characterise the metabolic signature for this tracer with a view to understanding its potential to act as a biomarker for drugs targeting cancer metabolism.

In a similar manner we are also conducting a study, the IMAGO trial, using Amide CEST-MRI, a non-invasive imaging technique that can determine the pH and presence of hypoxia within the brain.

During neurosurgical resection of the tumour, laser guided biopsies are then taken from areas of high and low CEST contrast and to match tissue-based assays to the imaging signature, again using immunohistochemical, transcriptomic and metabolomic approaches ISRCTN identifier: ISRCTN Design of window trials must be undertaken with care and there are particular considerations for cancer metabolism studies.

Consistency of sample handling is critical to success and is a particular issue in surgical trials. For example, it has been shown that the proliferation marker Ki67 can significantly vary between samples taken at surgery and ultrasound-guided breast core biopsy.

Patients undergoing an anaesthetic and major surgery will be undergoing significant physiological stress and often receive glucose infusions that may alter host metabolism.

As soon as a tumour is devascularised during resection, the degree of hypoxia will likely increase with profound metabolic consequences. Hence, samples for metabolomic and functional genomic profiling need to be snap frozen at point of biopsy by a dedicated team to optimise quality.

Drug PK may inform timing of sampling for example, such that biopsies are taken at point of peak plasma concentration. Prior to study set up consideration has to be made as to the choice of molecular target to assay and considerable effort should be expended in development of study assays prior to commencing the study.

Molecular targets are unlikely to be suitable if there is only limited variability from baseline observed with the intervention of interest in preclinical studies or assay sensitivity is limited.

Marked assay replicate variability in assay sampling will require a high magnitude of drug-induced change with regard to the endpoint of interest. Once the assay has been optimised in this fashion biobanked human tissue from the tumour site of interest should then be assayed for further validation.

Similar approaches apply to other techniques, for example using surrogate tissue samples to optimise metabolite or RNA extraction.

Ethical and pragmatic considerations also apply to study design. Giving a very novel drug to patients with curative disease and undergoing major surgery may not be safe. The window prior to definitive surgery has to be relatively short in order that standard of care treatment is not significantly delayed, and the number of interventions should not be too burdensome for patients.

Nuclear medicine interventions using radiolabelled tracers have to be limited in terms of radiation exposure to the patient, particularly in the curative setting. Over the past 15 years there has been growing interest in the potential of repurposing the biguanide drug, metformin, as a cancer therapy.

This was sparked by a series of epidemiological studies suggesting a decrease in cancer incidence for patients with diabetes that were taking metformin compared with those patients on other anti-hyperglycaemic therapies.

This led to the publication of multiple preclinical studies aimed at teasing out the mechanism of anticancer action for biguanide therapy but often with conflicting results.

The one consistent theme in these preclinical studies was that the dose of metformin used in order to elicit antineoplastic activity, either in vitro or using animal models, was typically 10— times peak plasma level in patients.

Firstly, that metformin has a direct anti-mitochondrial effect on tumour cells resulting in reduced tumour growth by a limiting carbon flux through the TCA cycle for anabolic metabolism; and b disrupting energy metabolism leading to activation of AMP-activated protein kinase AMPK and hence a switch from anabolic to catabolic metabolism.

Alternatively, other investigators view that its anticancer effects are most probably driven by modulation of host patient metabolism through AMPK activation in hepatocytes decreasing hepatic gluconeogenesis, with subsequently reduced circulating insulin and glucose levels.

The first of these published by Hadad et al. Following metformin treatment there was a significant fall in Ki67 suggestive of an antiproliferative effect and also increased phosphorylation of AMPK consistent with a direct mitochondrial effect.

Serum insulin levels remained stable pre- and post-metformin. Similarly contrasting observations have been observed in window studies assessing metformin in patients with Type 1 endometrial cancer, a disease strongly associated with obesity and Type 2 diabetes.

Three early studies have been published all of which demonstrated significant falls in Ki67 and evidence of decreased mTOR signalling. No direct evidence of AMPK activation was detected but there was a trend toward a decrease in prostate-specific antigen.

It is not absolutely clear why there was such inconsistency in results from these studies and as such, these results did not move the field much further forward. Recruitment varied between 35 and patients, some with and some without controls, therefore some trials may have been inadequately powered for a highly heterogeneous population.

Differences in sample collection at surgery and pre-treatment biopsy may have influenced expression of sensitive immunohistochemical markers including phosphorylated proteins and Ki67, as well as circulating markers of host metabolism.

The studies may reflect the limitations of relying on a handful of immunohistochemical biomarkers to characterise drug activity. A number of studies have also used metabolomic profiling to assess for mitochondrial targeting by metformin.

Schuler et al. used this technique in a surgical window study of metformin in endometrial cancer comparing the metabolomic profile of patients dependent on Ki67 response with metformin.

Here, they observed an intra-tumoural increase in levels of glucose and glycogen levels, and the ketone body, 3-hydroxybutyrate, in those tumours that had a fall in Ki67 post-metformin. The authors speculated that these changes reflected increased fatty acid oxidation and shunting of glucose to glycogen as a consequence of direct mitochondrial effect.

also carried out metabolomic profiling of historic ovarian cancer samples taken from patients that had received metformin. They reported reduced levels of a number of mitochondria metabolites compared with untreated controls including TCA intermediates and short-chain acyl carnitines, consistent with mitochondrial interference.

A small pilot study of metformin in healthy patients with Li-Fraumeni syndrome, a cancer predisposition disorder associated with germline p53 mutations, has shown the potential of using other mitochondrial assays in drug studies.

Here, Wang et al. showed that the oxygen consumption rate OCR was reduced in extracted peripheral blood mononuclear cells. Additionally, there was an increase in the OCR to extracellular acidification rate ECAR ratio suggestive of a switch from oxidative to glycolytic metabolism in response to metformin in Li-Fraumeni patients.

Skeletal muscle phosphocreatine was also measured using 31 P magnetic resonance spectroscopy with an increased phosphocreatine recovery time after metformin consistent with a mitochondrial effect.

We recently conducted a window study, the NEOMET trial, to profile the bioactivity of metformin in breast cancer and characterise heterogeneity of metabolic response. Shortly after diagnosis with primary breast cancer, patients underwent a baseline and post-metformin dynamic 18 F-FDG PET-CT scan and ultrasound-guided tumour biopsies for mRNA sequencing and metabolomics profiling.

We utilised functional imaging with dynamic 18 F-FDG PET-CT to identify subtle changes in glucose uptake into the primary tumour. This allows for kinetic analysis of tumour FDG uptake generating a flux constant K FDG that describes the rate of intra-cellular FDG phosphorylation.

Additionally, by using an input function, in this case from aortic blood flow, dynamic imaging adjusts for any metformin-induced changes in circulating blood glucose. Using this sensitive methodology, we observed a significant increase in K FDG following metformin treatment but no change in the standard static 18 F-FDG uptake measures SULmax and SULmean standardised uptake values normalised for lean body mass.

We then went on to carry out mRNA sequencing of the tumour samples pre- and post-metformin and identified multiple mitochondrial pathways that were upregulated at the transcriptomic level.

Additionally, metabolomic profiling of the samples demonstrated decreases in the levels of several mitochondrial metabolites including two short-chain acyl-carnitines consistent with findings from another metabolomic study of tumour samples from metformin-treated patients.

By integrating these datasets, we were then able to observe two distinct metabolic responses; a an OXPHOS transcriptional response OTR group for which there is an increase in OXPHOS gene transcription and decreased short-chain acyl-carnitine levels, and b an FDG response group with increased 18 F-FDG uptake.

Ongoing work is aimed at identifying baseline biomarkers that can discriminate between these two groups. This case study describes how the integration of multiple assays including novel molecular imaging, transcriptomics and metabolomics can provide, for drugs that target cancer metabolism, substantial insight into the nature of target engagement, selection of patients and mechanisms of resistance.

Further work is ongoing and, based on this initial characterisation of dynamic response to metformin, we plan to assay for baseline markers of interest with a view to informing future stratification in late-phase clinical trials.

For example, prior preclinical analysis has suggested that mutations in mtDNA encoding for mitochondrial complex 1 may define metabolic response to biguanide therapy. Window study designs can enable detailed characterisation of the pharmacodynamic effects of drugs or the tumour biology that lies behind an imaging signature.

Such studies may occur in the setting of the short window prior to instigation of standard therapy just after diagnosis offering a unique opportunity to study pharmacodynamic response in the setting of a tumour unperturbed by prior therapy. Modern molecular imaging, and metabolomic and functional genomic techniques, can now be applied to pharmacodynamic cancer metabolism studies, and are powerful tools to identify target engagement and understand resistance to therapy.

However, it is important to be attentive to window trial design as flaws in sample handling, choice of assay and insufficient power will compromise a study. Ashton, T. Oxidative phosphorylation as an emerging target in cancer therapy. Cancer Res. Article CAS Google Scholar.

Tabernero, J. et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. Stein, E. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia.

Blood , — Faubert, B. Lactate metabolism in human lung tumors. Cell , — e Fan, T. Altered regulation of metabolic pathways in human lung cancer discerned by 13 C stable isotope-resolved metabolomics SIRM.

Cancer 8 , 41 Article Google Scholar. Hensley, C. Metabolic heterogeneity in human lung tumors. Cell , — van Asselt, S. Everolimus reduces 89 Zr-Bevacizumab tumor uptake in patients with neuroendocrine tumors.

van Kruchten, M. Positron emission tomography of tumour [ 18 F]fluoroestradiol uptake in patients with acquired hormone-resistant metastatic breast cancer prior to oestradiol therapy. Imaging 42 , — Linden, H. Quantitative fluoroestradiol positron emission tomography imaging predicts response to endocrine treatment in breast cancer.

Lord, S. Integrated pharmacodynamic analysis identifies two metabolic adaption pathways to metformin in breast cancer. Cell Metab. McGowan, D. Buparlisib with thoracic radiotherapy and its effect on tumour hypoxia: A phase I study in patients with advanced non-small cell lung carcinoma.

Cancer , 87—95 It is also recommended that applicants check the online version of their funding opportunity within 8 weeks of the due date to ensure it is still appropriate for their application. Notices of funding opportunities specify the allowability of clinical trials in the funding opportunity Title and Section II with the following designations:.

Notices of funding opportunities that accept clinical trials have specific review criteria to ensure that reviewers appropriately consider clinical trial-related information. These studies fall within the NIH definition of a clinical trial and also meet the definition of basic research.

Career Development awards may support either independent clinical trials or a mentored research training experience , depending on the funding opportunity. The NIH encourages fellows to receive training in clinical research; however, NIH supported fellows are not permitted to conduct a clinical trial independently.

Institutional Training awards do not support clinical trials with the exception of some D43 and K12 awards. An official website of the United States government Here's how you know. Department of Health and Human Services link is external National Institutes of Health link is external NIH Grants and Funding.

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In a similar manner opportuniies are also conducting a study, Sample trial opportunities IMAGO trrial, using Amide Sapmle, a Sample trial opportunities imaging technique that can determine the pH and opplrtunities of Wellness product samples within the brain. Effects of metformin on endometrial cancer cell growth in vivo: a preoperative prospective trial. For example, it has been shown that the proliferation marker Ki67 can significantly vary between samples taken at surgery Sa,ple ultrasound-guided breast core biopsy. In vivo imaging of glucose uptake and metabolism in tumors. Romero, Q. What treatments will I receive during the study? Scott E.	External Link Icon and Disclaimers. International Applications. Modern molecular imaging already plays a central role in the diagnosis and staging of cancer patients, and to assess response to drug therapy. The authors speculated that these changes reflected increased fatty acid oxidation and shunting of glucose to glycogen as a consequence of direct mitochondrial effect. For example, glucoCEST MRI has been shown to be a sensitive technique for detecting glucose uptake into tumours.	These clinical trial advertising sample ideas are designed to engage patients while following strict FDA and IRB guidelines Clinical research and trials offer hope for many people and a chance to help researchers find better treatments for others in the future Reach patients who are searching for trial opportunities. Paid search ads can be a great way to connect with patients who are actively looking	opportunities to obtain biological sample collections that will allow it to investigate safety and efficacy in future clinical research and Blood and body tissue samples are vital for cancer research. People taking part in trials may be asked to donate various types of tissue Clinical research and trials offer hope for many people and a chance to help researchers find better treatments for others in the future	UCLA conducts research for a wide range of medical disorders, and offers patients the opportunity to participate in clinical trials and research Missing Career Development awards may support either independent clinical trials or a mentored research training experience, depending on the funding
Questions and Samplle If you have Opportuniities about clinical trials at Penn Medicine or Sapmle like to Free sample program in one, please contact: Office of Clinical Research University of Pennsylvania Perelman School of Medicine psom-ocr pobox. Table 1 Selected agents that target tumour metabolism that are either approved or in clinical trials Full size table. Select Agents. Why is it important? Website Policies and Notices.	Article CAS Google Scholar Chandel, N. Although these applications demonstrate good grantsmanship, time has passed since these grantees applied. Piwnica-Worms, D. Información en español. Excel Word PDF Smartsheet.	These clinical trial advertising sample ideas are designed to engage patients while following strict FDA and IRB guidelines Clinical research and trials offer hope for many people and a chance to help researchers find better treatments for others in the future Reach patients who are searching for trial opportunities. Paid search ads can be a great way to connect with patients who are actively looking	Missing This template also includes a section for situation analysis and risk analysis that asks for inputs on strengths, weaknesses, opportunities, and Reach patients who are searching for trial opportunities. Paid search ads can be a great way to connect with patients who are actively looking	These clinical trial advertising sample ideas are designed to engage patients while following strict FDA and IRB guidelines Clinical research and trials offer hope for many people and a chance to help researchers find better treatments for others in the future Reach patients who are searching for trial opportunities. Paid search ads can be a great way to connect with patients who are actively looking
Sample opportunkties must monitored Sample trial opportunities the opportuniites storage facility supported by multiple backup systems and Smple inventory Snack pack sales system. Related Content. These are like Sample trial opportunities. Welcome to Cancer Chat. Effects of metformin on endometrial cancer cell growth in vivo: a preoperative prospective trial. Types of participation can include: Completing a questionnaire about health or behaviors, or answering questions in an interview with researchers. What are the possible short- and long-term risks or side effects I might experience?	Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome. Threaded Document Discussions: Team members can start and track discussions within documents. Research Compliance Templates. Will my doctor know? Regardless, the point of research is to capitalize on scientific progress and move it along. Article CAS Google Scholar Laskov, I. The study team will also explain the purpose of the study and what will happen while you are in it and will answer any questions you have.	These clinical trial advertising sample ideas are designed to engage patients while following strict FDA and IRB guidelines Clinical research and trials offer hope for many people and a chance to help researchers find better treatments for others in the future Reach patients who are searching for trial opportunities. Paid search ads can be a great way to connect with patients who are actively looking	Reach patients who are searching for trial opportunities. Paid search ads can be a great way to connect with patients who are actively looking A type of intervention model describing a clinical trial in which groups of participants receive two or more interventions in a specific order. For example, two Window of opportunity trials exploit the 'window' of time after cancer diagnosis, typically prior to initiation of cancer therapy	A collection of sample grant applications and other resources provided by NIAID investigators Explore potential opportunities to use digital health tools to engage with patients and potential research participants, facilitate recruitment of participants Most research studies offer compensation. The amount you can get paid for clinical trials is determined by many factors
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