Delivering the precision oncology paradigm: reduced R&D costs and greater return on investment through a companion diagnostic informed precision oncology medicines approach.

BACKGROUND: Precision oncology medicines represent a paradigm shift compared to non-precision oncology medicines in cancer therapy, in some situations delivering more clinical benefit, and potentially lowering healthcare costs. We determined whether employing a companion diagnostic (CDx) approach during oncology medicines development delivers effective therapies that are within the cost constraints of current health systems. R&D costs of developing a medicine are subject to debate, with average estimates ranging from $765 million (m) to $4.6 billion (b). Our aim was to determine whether precision oncology medicines are cheaper to bring from R&D to market; a secondary goal was to determine whether precision oncology medicines have a greater return on investment (ROI). METHOD: Data on oncology medicines approved between 1997 and 2020 by the US Food and Drug Administration (FDA) were analysed from the Securities and Exchange Commission (SEC) filings. Data were compiled from 10-K, 10-Q, and 20-F financial performance filings on medicines' development costs through their R&D lifetime. Clinical trial data were split into clinical trial phases 1-3 and probability of success (POS) of trials was calculated, along with preclinical costs. Cost-of-capital (CoC) approach was applied and, if appropriate, a tax rebate was subtracted from the total. RESULTS: Data on 42 precision and 29 non-precision oncology medicines from 56 companies listed by the National Cancer Institute which had complete data available were analysed. Estimated mean cost to deliver a new oncology medicine was $4.4b (95% CI, $3.6-5.2b). Costs to bring a precision oncology medicine to market were $1.1b less ($3.5b; 95% CI, $2.7-4.5b) compared to non-precision oncology medicines ($4.6b; 95% CI, $3.5-6.1b). The key driver of costs was POS of clinical trials, accounting for a difference of $591.3 m. Additional data analysis illustrated that there was a 27% increase in return on investment (ROI) of precision oncology medicines over non-precision oncology medicines. CONCLUSION: Our results provide an accurate estimate of the R&D spend required to bring an oncology medicine to market. Deployment of a CDx at the earliest stage substantially lowers the cost associated with oncology medicines development, potentially making them available to more patients, while staying within the cost constraints of cancer health systems.

Cost-effectiveness of precision diagnostic testing for precision medicine approaches against non-small-cell lung cancer: A systematic review.

Precision diagnostic testing (PDT) employs appropriate biomarkers to identify cancer patients that may optimally respond to precision medicine (PM) approaches, such as treatments with targeted agents and immuno-oncology drugs. To date, there are no published systematic appraisals evaluating the cost-effectiveness of PDT in non-small-cell lung cancer (NSCLC). To address this gap, we conducted Preferred Reporting Items for Systematic Reviews and Meta-Analyses searches for the years 2009-2019. Consolidated Health Economic Evaluation Reporting Standards were employed to screen, assess and extract data. Employing base costs, life years gained or quality-adjusted life years, as well as willingness-to-pay (WTP) threshold for each country, net monetary benefit was calculated to determine cost-effectiveness of each intervention. Thirty-seven studies (50%) were included for analysis; a further 37 (50%) were excluded, having failed population-, intervention-, comparator-, outcomes- and study-design criteria. Within the 37 studies included, we defined 64 scenarios. Eleven scenarios compared PDT-guided PM with non-guided therapy [epidermal growth factor receptor (EGFR), n = 5; programmed death-ligand 1 (PD-L1), n = 6]. Twenty-eight scenarios compared PDT-guided PM with chemotherapy alone (anaplastic lymphoma kinase, n = 3; EGFR, n = 17; PD-L1, n = 8). Twenty-five scenarios compared PDT-guided PM with chemotherapy alone, while varying the PDT approach. Thirty-four scenarios (53%) were cost-effective, 28 (44%) were not cost-effective, and two were marginal, dependent on their country's WTP threshold. When PDT-guided therapy was compared with a therapy-for-all patients approach, all scenarios (100%) proved cost-effective. Seven of 37 studies had been structured appropriately to assess PDT-PM cost-effectiveness. Within these seven studies, all evaluated scenarios were cost-effective. However, 81% of studies had been poorly designed. Our systematic analysis implies that more robust health economic evaluation could help identify additional approaches towards PDT cost-effectiveness, underpinning value-based care and enhanced outcomes for patients with NSCLC.

Challenges in the clinical implementation of precision medicine companion diagnostics.

INTRODUCTION: The pace of biomarker discovery has increased exponentially over the last few years, ushering in an era of precision medicine (PM) with a growing arsenal of treatments tailored to specific patient populations. To accurately identify patients, companion diagnostics (CDx) are developed and launched alongside these treatments. However, even with a timely launch of therapies and CDx tests, patients are not guaranteed optimal access to these tests because of the inefficiencies embedded within the clinical diagnostic testing landscape supporting PM. AREAS COVERED: This commentary describes implementation challenges facing CDx tests and delaying clinical uptake. We also assess the 'siloed thinking' perpetuating these challenges and propose steps toward resolution. Our research is based on published literature and findings from the Diaceutics proprietary patient testing database. EXPERT OPINION: The clinical and economic ecosystem underpinning the diagnostic journey of patients remains severely underdeveloped. Patients are denied suitable therapies because of delayed identification or failings in real-world testing deployment. Progress is needed in clinical collaborations, integrator platforms, economic value sharing, and ownership of the patient testing journey to PM. We need to consider that better precision testing will deliver an equal or greater outcome to patients than new precision treatments alone.

Diagnostics Reform and Harmonization of Clinical Laboratory Testing.

Developments in diagnostics reform legislation in the United States are occurring at a rapid pace. The framework for future regulatory oversight of clinical laboratory testing is currently under intensive debate among stakeholders that represent patients, practitioners, laboratories, diagnostic manufacturers, and regulators. The importance of clinical laboratory test standardization is a key component of any plan for regulatory reform. A laboratory-developed test is performed in a specific laboratory setting, often led by clinical laboratory professionals who possess specific expertise for developing and running the test to fill a clinical need. A test commercially marketed as an in vitro diagnostic kit is designed to operate across a spectrum of laboratory settings in laboratories with a range of expertise. Both types of tests are stringently regulated, laboratory-developed tests by the Clinical Laboratory Improvement Amendments and in vitro diagnostic kits by the US Food and Drug Administration. Interlaboratory comparisons of laboratory-developed tests have been published, demonstrating highly reproducible results. Comparisons of laboratory-developed tests with in vitro diagnostic kits have also found high concordance. Several important clinical laboratory test standardization projects are currently under way. The US Food and Drug Administration has acknowledged the need for such standardization. In its most recent draft guidance, the agency requested input from the scientific community as to actions that can be taken to facilitate standardization.

Infusion medication concentrations in UK's critical care areas: Are the Intensive Care Society's recommendations being used?

Following two studies done in 2007 and 2009, a follow-up of the adherence to the suggested guidelines on drug standardisation has been performed with a suggestion for future standards that can be achieved, to complement the recently published Carter report. The Intensive Care Society (ICS) introduced recommendations for infusion concentrations of 16 medications commonly used in critical care areas. The importance being improvement in patient safety and rationalised use of available critical care resources. Five years after publication of these recommendations, a further audit has been undertaken to assess the level of acceptance and application. This revealed that 89.5% of the 133 surveyed units (representing 42.49% critical care units across the UK) have adopted the recommendations. There are further medication concentrations which could also be standardised.

Comparative in vitro analyses of recombinant maize starch synthases SSI, SSIIa, and SSIII reveal direct regulatory interactions and thermosensitivity.

Starch synthases SSI, SSII, and SSIII function in assembling the amylopectin component of starch, but their specific roles and means of coordination are not fully understood. Genetic analyses indicate regulatory interactions among SS classes, and physical interactions among them are known. The N terminal extension of cereal SSIII, comprising up to 1200 residues beyond the catalytic domain, is responsible at least in part for these interactions. Recombinant maize SSI, SSIIa, and full-length or truncated SSIII, were tested for functional interactions regarding enzymatic activity. Amino-terminal truncated SSIII exhibited reduced activity compared to full-length enzyme, and addition of the N terminus to the truncated protein stimulated catalytic activity. SSIII and SSI displayed a negative interaction that reduced total activity in a reconstituted system. These data demonstrate that SSIII is both a catalytic and regulatory factor. SSIII activity was reduced by approximately 50% after brief incubation at 45 °C, suggesting a role in reduced starch accumulation during growth in high temperatures. Buffer effects were tested to address a current debate regarding the SS mechanism. Glucan stimulated the SSIIa and SSIII reaction rate regardless of the buffer system, supporting the accepted mechanism in which glucosyl units are added to exogenous primer substrates.

Removing PEG tubes with 'buried bumpers': Lessons learnt from four patients.

We noted an increase in the number of presentations with dysfunctional PEG tubes due to the 'buried bumper syndrome' (BBS). There is no standard approach to this problem, although case reports exist of endoscopic needle knife excision and forceful pulling. We present a description of our experience in the management of this problem and the lessons learnt by complications or adverse outcomes. Two patients died within 2 weeks of endoscopic therapy. Successful and safe endoscopic removal appears dependent on the depth of the bumper, and this may be gauged by whether or not a wire can be inserted into the gastric lumen via the external portion of the tube. Further experience with radiological estimation of depth is required. The underlying frailty of this group of patients requires careful pre-intervention risk assessment and may favour a conservative approach.

Towards a balanced value business model for personalized medicine: an outlook.

Novel targeted drugs, mainly in oncology, have commanded substantial price premiums in the recent past. Consequently, the attention of pharmaceutical companies has shifted away from the traditional low-price and high-volume blockbuster business model to drugs that command high, and sometimes extremely high, prices in limited markets defined by targeted patient populations. This model may have already passed its zenith, as the impact of more and more high-priced drugs coming to market substantially increases their combined burden on payors and public health finances. This article introduces a new 'balanced value' business model for personalized medicine, leveraging the emerging opportunities to reduce drug development cost and time for targeted therapies. This model allows pharmaceutical companies to charge prices for targeted therapy below the likely future thresholds for payors' willingness to pay, at the same time preserving attractive margins for the drug developers.

The economics of personalized medicine: commercialization as a driver of return on investment.

Optimizing commercialization of drugs is the sine qua non of the pharmaceutical industry and intensive work has been done to characterize fully the drivers of drug adoption and understand the resources required to optimize those drivers for full adoption of drugs. Conversely, while the pharmaceutical industry is actively embracing the new personalized medicine (PM) paradigm, much work remains to be done to understand fully what drives adoption of targeted therapies and how to resource those drivers appropriately. While the industry is slowly learning from its early missteps, progress is still inhibited by a lack of understanding of the specific hurdles that individual development teams face in developing and commercializing targeted therapies and the requirement for budgets specifically aimed at driving test adoption. This article considers the benefits of optimizing commercial planning in the PM space and the potential negative impact in potentially failing to optimize that planning. Real world insights are used to illustrate that a far broader commercial lens is required in the PM space and will touch on functional areas not usually included in the context of 'commercial' decisions.

A retrospective analysis of benzodiazepine sedation vs. propofol anaesthesia in 252 patients undergoing endoscopic retrograde cholangiopancreatography.

BACKGROUND: Historically, hepatopancreatobiliary surgeons and gastroenterologists have undertaken endoscopic retrograde cholangiopancreatography (ERCP) using benzodiazepine sedation (BS). This is poorly tolerated by a substantial number of patients, which leads to its potential premature abandonment and subsequent additional investigations and therapeutics, and hence to the exposure of patients to avoidable risk and the health service to increased costs. Furthermore, concerns have been raised in the recent literature regarding safe sedation techniques. OBJECTIVES: The aim of this study was to compare the completion rates and safety profile of ERCP using BS vs. those of ERCP using light propofol anaesthesia (PA). METHODS: We carried out a retrospective, case-matched comparison analysis of consecutive patients who underwent ERCP with BS vs. PA, in the presence of an anaesthetist, over a 2-year period. Benzodiazepine sedation consisted of midazolam, fentanyl and buscopan. Propofol anaesthesia consisted of propofol, fentanyl and buscopan administered via a mouth guard in a non-intubated patient. Patient demographics, complications and completion rates were recorded. Procedural monitoring included pulse oximetry, non-invasive blood pressure, electrocardiography and end-tidal CO(2) . Statistical analyses used t-tests to compare continuous variables and chi-squared and Fisher's exact tests to compare categorical variables. A P-value of <0.05 was considered significant. RESULTS: Of 252 patients included in the study, 128 (50.8%) received BS and 124 (49.2%) received PA. Median ages in the BS and PA groups were 69 years (range: 20-99 years) and 65 years (range: 26-98 years), respectively (P= 0.07). Median hospital stays in the BS and PA groups were 1 day (range: day case to 61 days) and 1 day (range: day case to 38 days), respectively (P= 0.61). Incidences of mild anaesthesia-related complications in the BS and PA groups were 2.3% and 2.4%, respectively (P= 0.97). There were no severe anaesthesia-related complications. Incidences of mild procedural complications in the BS and PA groups were 2.3% and 1.6%, respectively (P= 0.68). One severe procedural complication occurred in the PA group. Incidences of incomplete ERCP procedures in the BS and PA groups were 10.9% (n= 14) and 4.0% (n= 5), respectively (odds ratio = 2.92, 95% confidence interval 1.02-8.38; chi-squared test, P= 0.04; Fisher's exact test, P= 0.03). CONCLUSIONS: Propofol anaesthesia for ERCP carried out in the presence of an anaesthetist is safe and may improve procedural completion rates.

Towards IV drug standardization in critical care.

Local infusion practice within critical care has evolved over time, and one example of this is the wide variation in concentrations of drug infusions within critical care. While there are many similarities between critical care units, there are also many differences. Often drug infusions are used outside their product licence and, because of the diversity in practice, manufacturers are unlikely to license multiple preparations of even the most commonly used infusions. Critical care nurses spend many hours every day preparing and administering intravenous infusions. Much time could be saved if the infusions were available as a ready-to-use solution. This would also reduce the risk of errors that occur during the preparation and administration of medication infusions. This article describes a national project to achieve consensus on the strengths of drug infusions used within UK critical care units. Having agreed on standard solutions, it is hoped that manufacturers will seek licences for commonly used infusions and work towards mass production of these products. Off the shelf, ready-to-use infusions of commonly used medications could become a reality.

Biochemistry and genetics of starch synthesis.

Enormous progress has been made in understanding the genetics and biochemistry of starch synthesis in crop plants. Furthermore, starch remains at the very epicenter of the world's food and feed chains and has even now become one of the world's most important sources of biorenewable energy (biofuel). Yet, despite this remarkable progress and the obvious economic importance, very little has been achieved in terms of adding value to starch or increasing starch yield, particularly in cereal crops. Here, we review the genetics and biochemistry of starch synthesis in crop plants, particularly maize. With all this know-how in place and a chasm of opportunity ahead, the time is right to see science deliver progress into a new frontier. Thus, in our view the stage is set for a new era of changes in starch synthesis, delivering enhancements in functionality and yield.

Driving personalized medicine: capturing maximum net present value and optimal return on investment.

In order for personalized medicine to meet its potential future promise, a closer focus on the work being carried out today and the foundation it will provide for that future is imperative. While big picture perspectives of this still nascent shift in the drug-development process are important, it is more important that today's work on the first wave of targeted therapies is used to build specific benchmarking and financial models against which further such therapies may be more effectively developed. Today's drug-development teams need a robust tool to identify the exact drivers that will ensure the successful launch and rapid adoption of targeted therapies, and financial metrics to determine the appropriate resource levels to power those drivers. This special report will describe one such benchmarking and financial model that is specifically designed for the personalized medicine field and will explain how the use of this or similar models can help to capture the maximum net present value of targeted therapies and help to realize optimal return on investment.

Proteins from multiple metabolic pathways associate with starch biosynthetic enzymes in high molecular weight complexes: a model for regulation of carbon allocation in maize amyloplasts.

Starch biosynthetic enzymes from maize (Zea mays) and wheat (Triticum aestivum) amyloplasts exist in cell extracts in high molecular weight complexes; however, the nature of those assemblies remains to be defined. This study tested the interdependence of the maize enzymes starch synthase IIa (SSIIa), SSIII, starch branching enzyme IIb (SBEIIb), and SBEIIa for assembly into multisubunit complexes. Mutations that eliminated any one of those proteins also prevented the others from assembling into a high molecular mass form of approximately 670 kD, so that SSIII, SSIIa, SBEIIa, and SBEIIb most likely all exist together in the same complex. SSIIa, SBEIIb, and SBEIIa, but not SSIII, were also interdependent for assembly into a complex of approximately 300 kD. SSIII, SSIIa, SBEIIa, and SBEIIb copurified through successive chromatography steps, and SBEIIa, SBEIIb, and SSIIa coimmunoprecipitated with SSIII in a phosphorylation-dependent manner. SBEIIa and SBEIIb also were retained on an affinity column bearing a specific conserved fragment of SSIII located outside of the SS catalytic domain. Additional proteins that copurified with SSIII in multiple biochemical methods included the two known isoforms of pyruvate orthophosphate dikinase (PPDK), large and small subunits of ADP-glucose pyrophosphorylase, and the sucrose synthase isoform SUS-SH1. PPDK and SUS-SH1 required SSIII, SSIIa, SBEIIa, and SBEIIb for assembly into the 670-kD complex. These complexes may function in global regulation of carbon partitioning between metabolic pathways in developing seeds.

Personalized medicine: the absence of 'model-changing' financial incentives.

This perspective biases on the side that personalized medicine can contribute to a more efficient collective model; however, the hard economics need and deserve significantly more critical analysis and new data input than they are currently being given, to determine their role, or not, in driving change. Put simply, as with the birth of all new and promising developments in healthcare, myth, hope and trend-spotting are driving this market forward, rather than any hard evidence of a sustainable commercial business model for all stakeholders. While there are clear economic benefits to aspects of delivery along the way to personalized care, there may in fact be no compelling economic drivers for radical change for payers and the pharmaceutical industry. The best they can hope to achieve is that the balance sheet is, just that, in balance.

Role of the Opportunity To Test Index in integrating diagnostics with therapeutics.

In theory, the introduction of a novel test to accompany a therapy should be simple and automatic. However, In reality, the marriage of a test with therapy will not be a simple one, since each industry operates with its own distinct business model. Of concern to the pharmaceutical industry is the potential commercial dependency of a drug on the performance and implementation of a diagnostic. These concerns are justified since the history of diagnostic tests is frequently one of under use. One of the factors cited by Rogers is the issue of how complex an innovation is to administer. Rogers demonstrates that an innovation that is difficult to administer will be implemented more slowly or be discontinued by the user group it was intended for. It is the author's view that understanding this micro interaction, experience and barriers of testing with the individual provider, in short the complexity of the test, will, in turn, provide those in the pharmaceutical industry with a methodology to consider their risk or exposure to a test upon which their therapy may become dependent in the US market. Since personalized medicine significantly marries the test and treatment decision, it is the perspective of the provider that will be paramount in determining which, if any, test is ordered and the subsequent clinical decision he or she is enabled to take upon the test response. Therefore, a focus of this perspective is to consider the issues of test implementation from the perspective of the US provider who will order and use the information they provide. The Opportunity To Test Index methodology is introduced, which the authors speculate may help quantify the level of risk a pharmaceutical company has to the complexity of a test upon which its therapy will be dependent. The methodology scores five key elements impacting test implementation: reimbursement, turnaround time, test administration, test interpretation and patient engagement.

Involvement of lysine-193 of the conserved "K-T-G-G" motif in the catalysis of maize starch synthase IIa.

It has been suggested that the lysine residue in the conserved K-T-G-G motif could be the substrate ADP-glucose binding site of Escherichia coli glycogen synthase (GS). Since the K-X-G-G motif is highly conserved between E. coli GS and all the maize starch synthase (SS) isozymes, it has become widely accepted that the lysine in the conserved K-T-G-G motif may also function as the ADPGlc binding site of maize SS. We have used chemical modification and site-directed mutagenesis to study the function of lysine residues in SS. Pyridoxal-5'-phosphate inactivated maize SSIIa activity in a time and concentration dependent manner. ADPGlc completely protected SSIIa from inactivation by pyridoxal-5'-phosphate, indicating that lysine residue(s) could be important for ADPGlc binding and enzyme catalysis. In contrast to E. coli GS, mutation of conserved lysine193 (K-T-G-G) in maize SS did not alter the ADPGlc binding while significantly changing the enzyme activity toward different primers. Our results suggest that lysine-193 (K-T-G-G) is not directly involved in ADPGlc binding, instead mutation in the conserved lysine position affected the primer preference.