Rheumatoid Arthritis – Clinical Development
Clinical Development: Working with the product planning and clinical development groups of a large pharmaceutical company, Health Advances identified and interviewed key opinion leaders in rheumatoid arthritis to advise the company on the prospects and clinical trial design of a new molecule in preclinical development and assembled a panel of thought leaders for a six-hour focus group held with representatives from the company. As a result of the project, the company significantly revised its clinical development program to generate more substantial preclinical data prior to proceeding into the clinic.
Rheumatoid Arthritis – Product Strategy
On behalf of a large biotechnology company, Health Advances designed a conjoint study and survey to assess rheumatologists’ anticipated use of novel treatments for rheumatoid arthritis. The study assessed rheumatologist trade-offs between multiple new therapies expected to enter the market in the near future, including new biologics, follow-on biologics, and novel small molecule treatments.
Multiple Sclerosis – Franchise Strategy
Health Advances completed a franchise strategy optimization for a company’s neuro-immunology division. Health Advances worked with senior management to define the vision, strategy, goals, and metrics for the franchise moving forward. As part of this process, Health Advances investigated and prioritized activities within five key strategic initiatives and proposed recommendations along with short and mid-term action plans.
Multiple Sclerosis – Biosimilar Commercialization
Health Advances worked with an emerging biosimilar manufacturer to develop a commercialization strategy for a biosimilar interferon-beta in the US and EU. Health Advances conducted interviews with physicians, payers, pharmacists, wholesalers, regulatory experts, and industry experts to understand the spectrum of issues that will accompany a new biosimilar launch. In particular, we sought to understand the relevant stakeholders in each country and how best to engage with each to ensure success. The end result was the identification and prioritization of market-specific success factors and action steps for our client to use when developing the launch plan for their product.
Psoriasis – Formulation
On behalf of a biotech company, Health Advances assessed the potential impact of delivery format on the roll-out and acceptance of an infused drug for psoriasis. In addition to the US market, hurdles and opportunities relating to the logistics of the product’s potential use in France and Germany were also identified. A detailed understanding of the approval and adoption practices within these countries was crucial to outlining the how the client could maximize adoption of its product in a market that historically had few or no infusion-based therapies.
Crohn’s Disease – Forecasting
Health Advances created a patient flow forecast model of Crohn’s disease in the US, 5EU, and Japan to support a large pharmaceutical company’s clinical development program. Model assumptions were based on market research reports, interviews with gastroenterologist and rheumatologist KOLs, and a detailed analysis of clinical literature, pipeline compounds, and clinical trials. A "lines of therapy" framework was used to define a patient transition matrix with numerous positions for a new therapy to penetrate to allow for a flexible, scenario-based model.
Systemic Lupus Erythematosus – International Market Assessment:
Health Advances worked a large pharmaceutical company to conduct a comprehensive evaluation of the market for systemic lupus erythematosus (SLE) and lupus nephritis therapies in the US, EU, Japan and China. Working with the company we developed a perspective on the opportunity and potential fit for SLE in the broader strategy. Over 75 interviews were conducted in the US, EU, Japan and China with both thought leaders and practicing rheumatologists. “Patient flow” interviews reviewing specific patient charts were utilized to accurately capture real treatment practice. A detailed forecast model was developed and future therapies and clinical development challenges were evaluated in depth.
CAD and PVD
Health Advances was asked to help a client identify key competitors in coronary artery and peripheral vascular diseases. Looking at the client's marketed products and those in development, we outlined clinical trial attributes necessary to position the client's products favorably from both a physician and payer prospective.
Market Sizing for a Novel Mechanical Thrombus Ablation Device
To create a development strategy for a client with a novel mechanical thrombus ablation device, Health Advances explored four target indications: DVT, peripheral arterial disease, hemodialysis clots, and coronary thrombi. Extensive secondary and primary research revealed the unmet needs, referral patterns, decision-making process and reimbursement environment in each clinical area. This allowed the Health Advances team to develop a detailed market segmentation and sizing which, along with clinical development considerations, formed the basis for the strategic plan.
Vascularization in Refractory Angina
Health Advances was asked to assess the unmet needs in induction of vascularization in refractory angina and to determine the relative enthusiasm among physicians toward procedures inducing mechanical injury compared to novel angiogenic therapies. Feedback from cardiologists, interventional cardiologists, and cardiac surgeons informed clinical trial criteria and directed a development plan incorporating both methodologies.
Reformulation of a Beta-Blocker
Health Advances was asked to evaluate the opportunity to enter the large but crowded beta-blocker market with a once-daily formulation of one of the market-leading compounds. A key issue in positioning our client's product was that the branded compound was also being launched in a daily formulation. While our client's product would have some modest advantages, understanding formulary and reimbursement issues was essential in determining the degree to which the proposed advantages would overcome an established brand presence in addition to competition from lower-priced generics.
Cellular Therapies in Cardiac Indications
A large public company sought to develop a clinical trial development plan for cellular therapies in cardiac indications. Health Advances used a thorough investigation of relevant cellular therapy literature to assist application prioritization and benchmarking trial parameters. Extensive interviews with cardiovascular and cell therapy experts were used to determine relevant patient segments for the high-priority indications.
P-Selectin Inhibitor for Vascular Diseases
A start-up company engaged Health Advances to analyze multiple vascular diseases including sickle cell anemia, deep vein thrombosis, ischemic reperfusion injury, and vascular restenosis for potential applicability of a P-selectin inhibitor. The Health Advances team examined market size, unmet need, competition, trial feasibility, and the role of P-selectin in disease etiology in order to determine the best development strategy for our client.
Development of a CNS Entry Strategy
Health Advances assisted a large pharmaceutical company interested in increasing its CNS presence through licensing and acquisition with a comprehensive review of the CNS space and the development of a CNS strategy. After reviewing the spectrum of CNS indications, Health Advances conducted interviews with top thought leaders and completed a scientific/clinical literature review in order to perform a deep and careful investigation into six high-priority areas: Alzheimer's, Parkinson's, schizophrenia, neuropathic pain, insomnia, and depression. This investigation evaluated targets, mechanisms, and pipelines for clinical utility and commercial potential. We also identified key unmet needs and the state of current clinical practice for each disease.
Health Advances assisted a large public company in preparing a commercial development plan for acute ischemic stroke. At the time of the project, the client's product was in late stage clinical development and was expected to receive FDA approval shortly thereafter. Health Advances interviewed numerous cardiologists and neurologists with experience as investigators in clinical trials for ischemic stroke. Integrating unmet needs, competitive positioning, development timing, and possible label claims, the Health Advances team refined the product development plan.
An esoteric reference lab asked Health Advances to investigate the utility of various esoteric lab tests marketed to neurologists to facilitate differential diagnosis of diseases exhibiting similar symptoms such as muscular dystrophy versus ataxia. The project forecasted the demand for the high-margin panels in light of changing referral patterns, managed care pressures, and pioneering therapeutics in development.
Neurotechnology for Brain Stimulation
An early-stage company was developing a neurotechnology device to detect neural signals and stimulate the brain. The primary application was spinal cord injury but the technology was applicable to many other disease areas. The client asked Health Advances to help determine the first group of applications upon which it should initially focus, the most interesting of which was Alzheimer's disease. All potential applications were screened and 10-12 indications were prioritized for initial development.
Health Advances worked with a client on the formation of a new company to complete the development of a novel compound that could potentially slow progression of Parkinson's disease. In addition to examining the market opportunity, we also explored issues around the predictability of preclinical disease models, the utility of disease scores for evaluating clinical performance, and other possible endpoints for clinical development.
Health Advances developed a detailed commercialization plan for a novel agent targeting psoriasis. The plan highlighted the market opportunity, product positioning strategies, clinical trial plans, and sales and marketing requirements for the novel agent. The company used the Health Advances analysis to support business development activities and maximize the value of the program.
Platelet Concentrators for Wound Healing
As part of an acquisition candidate search, Health Advances evaluated the market dynamics surrounding platelet concentration systems in plastics and musculoskeletal surgeries. The study considered use of Platelet Rich Plasma (PRP) as a wound healing sealant, soft-tissue growth factor, and as an agent to augment bone repair.
Laser-Based Acne Therapy
Health Advances investigated both the reimbursed path and the self-pay path for a novel laser-based therapy intended to displace some of the most expensive drug regimens. Although acne is a covered medical necessity, we discovered that it would be better for the company to rely on self-pay patients.
Laser-Based Therapy Onychomycosis
Health Advances evaluated the commercial potential for a novel laser-based treatment for onychomycosis. The project included in-depth physician interviews, rigorous competitor analysis, and market sizing.Health Advances evaluated the commercial potential for a novel laser-based treatment for onychomycosis. The project included in-depth physician interviews, rigorous competitor analysis, and market sizing.
Product for Treatment of Diabetic Foot Ulcers
Health Advances conducted due diligence on a product used in diabetic foot ulcers. Primary research with users focused on determining the decision-making process in choosing wound healing products and identifying current treatment paradigms.
Relationship with Juvenile Diabetes Research Foundation
Health Advances has an ongoing relationship with the Juvenile Diabetes Research Foundation (JDRF), working directly with the Board of Directors and research management team to ensure research investments are optimized and the funding portfolio is properly balanced to achieve JDRF's goals. Health Advances initially developed the long-term strategic plan for JDRF's research team in 2006.
DPP-IVs Inhibitors - Brand Strategy
A large pharmaceutical company asked Health Advances to help it understand how a novel DPP-4 inhibitor in Phase II should be positioned in the marketplace, depending on the outcome of the clinical studies that were still in progress. Health Advances developed a 3x3 matrix with nine different product profiles, reflecting different outcomes from the trial program. For each product profile, a positioning statement and key marketing messages were developed in the form of a "message ladder." This tool helped to illustrate how each one of the nine profiles could be positioned in a way that made the product look attractive and its profile clinically relevant.
Insulin - Lifecycle Strategy
Health Advances worked with a large pharmaceutical company to develop a 10-year perspective and portfolio strategy for its diabetes franchise. Health Advances developed a worldwide insulin market model based on data from 28 countries to understand key product share dynamics and to forecast market opportunities. Implications from this analysis were used to prioritize portfolio initiatives and secure funding for key programs.
Insulin Delivery and Continuous Glucose Monitoring - Growth Strategy
Leveraging its strong foundation in delivery systems and glucose monitoring, Health Advances assisted a major pharmaceutical company with an assessment of the influence of insulin pumps and continuous glucose monitoring (CGM) on the competitive dynamics of the insulin market. Health Advances quantitatively modeled the financial impact of a number of strategies, including potential partnerships with major insulin pump and CGM companies.
Obesity - Customer Analysis and Market Forecast
A clinical-stage biotechnology company developing a product to minimize a common side effect of many obesity drugs asked Health Advances to provide a comprehensive overview of the current and future obesity market. This analysis provided the foundation for developing the clinical trials, brand positioning, and a potential partnership strategy.
Surgical Approach to Obesity and Diabetes Management - Commercialization Strategy
Health Advances developed the commercialization strategy for a venture-backed company developing a less invasive surgical approach to treat obesity. A key finding shifted the strategy of the company towards the segment of obese patients with type 2 diabetes. The business plan has been used by the company to successfully raise $50MM from top-tier venture capital companies.
Diabetic Neuropathy - Development Strategy
A large biotechnology company developing a novel agent for peripheral neuropathy requested that Health Advances review its brand strategy for the diabetic neuropathy indication. This product was one of the first drugs in development with the potential to modify disease progression. Key focal points were a customer segmentation analysis and an assessment of the rational and emotional arguments that could be supported through pivotal and post-market clinical studies.
Tissue-Engineered Product for Bladder Reconstruction
The client asked Health Advances to investigate the market potential for its tissue-engineered product in bladder augmentation and bladder reconstruction. The main indications for these procedures were neurogenic bladder arising from spinal cord injury, multiple sclerosis or spina bifida, and bladder cancer. A pricing analysis was used to determine potential pricing, including current economics for these procedures and associated complications from both the hospital and the payer perspectives. The Health Advances team used several market examples to determine likely adoption rates for this type of product, including cadaveric fascia for pubovaginal sling and InterStim for urge incontinence.
Radiopharmaceutical Diagnostic for Prostate Cancer
Health Advances determined the US commercial potential for a public company's novel radiopharmaceutical used in the diagnosis and monitoring of prostate cancer. We used primary and secondary research to understand the current diagnostic standard of care for prostate cancer, provide details on relevant patient segments, and determine the greatest unmet needs for each segment. We also determined the potential penetration of the radiopharmaceutical into the diagnostic paradigm and developed detailed stacked incidence models of patient segments and preliminary revenue projections.
Health Advances studied the market for a currently marketed medical device to treat prostate cancer to determine how to achieve broader market penetration. Our team assessed product positioning as a first-line alternative treatment versus a second-line therapy for treatment failures. The study involved interviewing both current users and non-users to determine current perceptions of product positioning and use, and assessed the opportunity for growth and the likely requirements for penetration (clinical trials, etc.) in other indications not yet targeted by the client.
Novel Dialysis Product
Health Advances conducted a system economics analysis for a novel product intended to treat dialysis patients. This product would be used in conjunction with current continuous dialysis treatment to augment the performance of dialysis and more closely mimic the true functionality of kidneys. The analysis was built on a large dataset obtained from a major health system. This provided detailed charge and reimbursement information on the major cost drivers of managing dialysis patients and the costs when problems arise and they are hospitalized. Using inputs from physicians involved in the development of the novel product, expected benefits were outlined and modeled into a range of economically justifiable prices to consider for the future introduction. The specific price could be selected once trials were completed and the actual performance was documented.
Outreach Laboratory Testing
Working closely with senior leadership of a health system, our team identified and assessed numerous strategies to grow, partner, or sell a profitable, market-leading hospital outreach laboratory. The engagement required a detailed pro forma P&L valuation model that tested various scenarios including maintaining ownership of the laboratory, establishing an independent reference laboratory, pursuing a joint-venture with various partners, or selling the business. The team vetted assumptions and the underlying strategy through a combination of rigorous analysis of internal laboratory data in addition to primary research with industry leaders and customers.
NGS Program Strategy
Working closely with senior leadership of several academic medical centers and medical school, out team helped the institutions assess whether to initiate an NGS program. The engagement included a thorough qualitative and quantitative evaluation of potential test menu (e.g. tumor or constitutional panels, WES, WGS), local market, current and necessary organizational capabilities, and options such as outsourcing certain NGS workflow components. A detailed pro forma P&L valuation model was constructed to demonstrate the financial consequences of various scenarios and estimate the necessary investment required to initiate and maintain the program.
Specialty Pathology Services Provider Diligence
As part of a rapid diligence effort, our team conducted an evaluation of neuropathology testing paradigms and explored the competitive position of an independent specialty pathology practice. Primary interviews with US clinicians treating patients with suspected small and large fiber peripheral neuropathies were conducted including interviews with endocrinologists, rheumatologists, podiatrists and neurologists. Overall growth prospects for the Target were evaluated and a recommendation on pursuing an acquisition was made to our client.
Outreach Program Strategy
Working closely with senior leadership of a pediatric hospital laboratory, our team assessed numerous strategies for expanding outreach laboratory testing within and outside the laboratory’s healthcare system. The engagement included a thorough qualitative and quantitative evaluation of the impact of service expansion on the laboratory and the healthcare system to arrive at strategic recommendations. A detailed pro forma P&L valuation model based on rigorous analysis of internal data and primary research with potential internal and external customers, laboratory and clinical thought leaders, and payers was demonstrate the financial consequences of various clinician and payer engagement scenarios and was ultimately used to inform selection of the most appropriate strategy for the client.
Genomics Laboratory Diligence
Our team worked with a private equity firm to evaluate a high profile laboratory specializing in esoteric genetic testing. Our team evaluated the target’s key existing offerings across multiple clinical areas including NIPT, pediatric inherited disease, and oncology to understand the market demand, competitive landscape, and expected growth rates in order to forecast their market potential. Additionally, we explored the outlook for the target’s pipeline tests, the potential impact of enhanced sales and marketing efforts, as well as the acquisition of additional capabilities and lab service providers. Based on this evaluation, we made final recommendations to our private equity client on whether or not to pursue this investment.
Applications for an Antimicrobial Product
An early-stage client recognized that an antimicrobial industrial product may possess valuable healthcare capabilities. Health Advances evaluated thirteen applications ranging from oral mucositis to onychomycosis. The evaluation included understanding the role of pathogens, unmet needs, and developmental requirements. Using this analysis, Health Advances developed a blueprint for the client's healthcare enterprise, which led the client's Board to appropriate several hundreds of thousands of dollars for preclinical work.
Identification and Prioritization of Target Medical Devices for a Novel Antimicrobial Coating
A large public client was committed to developing an antimicrobial coating for a broad range of devices. Health Advances initially evaluated dozens of conceivable applications, from coatings on disposable diapers to heart valves. The analysis quickly focused on four applications and these were then further prioritized based upon manufacturability, clinicians' perceptions of the devices' roles in the infection process, and the value-based premiums that each could capture. The initially targeted product has been successfully commercialized and the organization is now working on expanding the core technology and base product into a wide range of related products for analogous indications.
Genomic-Based Infection Detection
With the goal of rapid diagnosis of infectious agents in the hospital setting, our client developed a novel DNA-based bacterial fingerprint system. Health Advances conducted an extensive interview program with hospitals and infectious disease experts to understand how they diagnose and treat many of the major infections seen in the hospital setting. We worked with the client to determine the value of a rapid test from a clinical and economic perspective.
Market Assessment for a Novel Antibiotic Therapy:
Health Advances worked with a private early-stage company focused on developing novel antibiotics using structure-based design. We help our client to identify potentially attractive market opportunities in the hospital and community setting based on unmet needs, market size, and segmentation of the current antibiotic market, antibiotics in the clinical pipeline, anticipated treatment trends, and hospital formulary decisions.
HIV Vaccine Development Planning
Health Advances was asked to take a top-level look at a client's HIV vaccine program as part of a company-wide portfolio reassessment initiated when a new president was appointed to the company. This review examined the client's technical progress versus that of competitors, funding sources, likely continued commitments from those sources, and synergy with the company's other products in development.
Global Diligence for a Novel Serological BGT Technology
Our team was engaged by a leading global diagnostics company to assess the market outlook for a novel blood group typing technology. Qualitative phone interviews and an in-depth, quantitative online survey were used to capture laboratorian and transfusion medicine specialist perspectives on the potential clinical, economic, and workflow impacts of this technology. In conjunction with supporting secondary research, detailed revenue projections and pricing recommendations were developed for the US, Germany, Italy, France, Australia and Brazil.
Global Voice of the Customer Research on a New Integrated Platform and a New Immunochemistry Platform
Our team was tasked with understanding customer needs for clinical chemistry and immunoassay instrumentation. A global survey was conducted to assess features driving purchasing decisions as well as the response to two novel products. Areas of key focus where pricing, competitive outlook, marketing and sales strategy, and future development opportunities. Countries included in this analysis were the US, Germany, France, Italy, Brazil, Hong Kong, South Korea, Australia/New Zealand, and Japan.
Prenatal Testing Business Model & Strategy
Working with a PE-backed diagnostics technology startup company, the team developed a commercialization strategy and proposed business model for a novel lower-cost non-invasive prenatal test (NIPT). The team performed a robust assessment of the market landscape including current treatment paradigm, current and future competitors, and reimbursement and regulatory landscape for prenatal testing in both high-risk and average-risk patient types to understand market potential. This analysis was combined with laboratory customer segmentation business model benchmarking of other complex IVDs to provide a recommendation on business model for our client.
Point-of-Care Diagnostics for Gastroenterology
Seeking new avenues for growth, an established player in gastroenterology engaged Health Advances to outline a strategic approach to point-of-care diagnostic testing. Through clinician and payer interviews, our team articulated the outlook for in vitro testing at gastroenterology practices and defined a platform and menu development roadmap to capture value by addressing clinical, financial, and workflow factors. A dynamic revenue model allowed our client to integrate this work with other opportunities in overarching portfolio planning sessions and move forward with greater clarity.
Cardiac Diagnostic Marketing Message Development
A global, core lab diagnostics player engaged our team to support the launch of a diagnostic cardiac marker in the US and EU by articulating the value messages for the marker. The team conducted interviews with physicians and laboratory directors in the US, France, Germany, Spain, and the UK. The work required the team to have an intimate understanding of hospital protocols. In-depth interviews provided insight into the potential clinical, economic, and logistical implications of implementing the marker and developed the key value messages that would resonate with each specific stakeholder.
Support for Decentralized Testing Initiative
Our team was engaged by a global, core lab diagnostics player to assess the need and overall opportunity for decentralized testing product offerings. Particularly, our team demonstrated the distributed nature of testing in emerging markets such as China and India as well as in rural areas of the developed world. This foundation was used to assess the need for this lab focused company to provide smaller scale instrumentation with specifications ideal for less sophisticated environments.
US Digital Pathology Market Potential
As part of a market assessment, the team worked with a leader in digital pathology to assess the adoption of digital pathology in the US hospital market. The project involved a rigorous primary research program including interviews with anatomical pathologists, oncologists, other clinician stakeholders, and hospital administrators to gauge the opportunity for the novel technology and to identify the key call points in the hospital market. Secondary research was used to quantify and segment the hospital market. Ultimately, the team provided the client with adoption penetration estimates by hospital segment and a forward-looking strategy for penetrating and leading the clinical market.
Africa Life Sciences Strategy
For a large international diagnostics and life sciences company, our team provided strategic support to the clients internal initiative to align business unit strategies across diagnostics and life sciences divisions in Africa. The team conducted primary and secondary research and supported modeling efforts to understand the future outlook for HIV and TB testing technologies and platforms. The team spoke with key stakeholders including lab directors as well as representatives from Ministries of Health and NGOs to understand trends in testing paradigms, technology selection, and funding. One key area of focus was understanding the conversion in HIV monitoring from CD4 testing to viral load testing in sub-Saharan Africa.
Capillary Sample Collection Strategy Development
A global medical technology company enlisted Health Advances to assist in validating the opportunity to provide novel capillary blood sample collection technologies for both point-of-care (POC) and non-POC applications. Our team reviewed the overall trajectory of the POC market including the types of platforms that are most likely to succeed, evaluated POC platforms currently on the market and in development, and assessed the near and long-term potential of capillary blood collection to facilitate overall diagnostic testing. We recommended a roadmap of strategic partnerships in the capillary POC sample collection space and clearly defined the nature and timing of the overall opportunity for improved sample collection in the acute and non-acute settings.
Clinical Workflow Solution Strategy
Working with a global life science and diagnostics company, our team developed a detailed step by step workflow for a component of clinical diagnostic testing that is largely manual today. Key challenges and unmet needs were identified and instrument, reagent, software, and service solutions were proposed and prioritized to meet these needs. Revenue implications were assessed and timeline was proposed for the client to develop and launch a series of workflow solutions for its laboratory customers in order to maintain the company’s market leading position.
LBC System Economics
An economic analysis, comparing liquid based cytology (LBC) to conventional cytology, was conducted. The purpose of this analysis was to demonstrate potential savings to laboratories from adoption of an LBC method and based on this potential savings determine optimal pricing for LBC supplies in various geographies including Germany, Brazil, Japan, China, and Australia. Factors considered in the analysis included level of technology (LBC) automation; technician, pathologist and cytotechnologist time and salaries; indirect cost for space; sample transportation costs; and laboratory testing volume.
US Point of Care Platform Strategy
Health Advances was tasked by the management team of small, point of care (POC) technology company to optimize the company’s strategy in the US. Detailed review of testing needs in a variety of clinical settings coupled with an assessment of the technologies critical advantages lead to the identification of an initial list of test with strong potential. Given business implications including size of call point and competitive dynamics, a number of potential strategies were outlined. A recommendation to focus on specialty physician office settings was provided.
Awareness, Trial, and Utilization Survey for Novel Diagnostic Assay
Health Advances conducted an awareness, trial, and utilization (ATU) survey to assess key customer perceptions of brand equity, perceptions and utilization of molecular diagnostic platforms, and perceptions and utilization of molecular diagnostic assays in order to gauge ROI by the client's marketing division regarding their upcoming assay in the virology space. Using the results of this survey targeting molecular lab directors as key customers, our team assessed the client's current market positioning in the virology space and recommended strategies for increased marketing effectiveness surrounding their upcoming novel assay. Our team will be re-fielding this survey in six months in order to gauge the client's marketing ROI following assay launch.
CMV Diagnostic Strategy
In order to prioritize test menu development decisions on an automated molecular diagnostic testing platform, our team conducted a market opportunity assessment for viral load testing of cytomegalovirus (CMV). Through interviews with key clinical and laboratory decision makers, the team estimated the addressable US market opportunity, identified clinical and laboratory trends, and quantified the value of the test in driving platform adoption and use with a five year incremental revenue model segmented by type of laboratory.
Low Volume Hematology Diligence
For a public global company looking to expand their clinical diagnostics footprint, the team performed due diligence on the hematology clinical diagnostics and contract manufacturing business of a private international IVD company. The team focused on evaluating market drivers, trends and competitive landscape and sizing the market for hematology analyzers suited for low volume labs in hospitals, physician offices, and reference lab settings in the US, 3EU, India, and China. Primary research with lab directors, reimbursement experts, and industry decision-makers was supplemented by secondary research.
WW Market Projection for POC Coagulation Testing Products
Working with the management team of a mid-size diagnostics company, the team built a data-driven estimate of the worldwide market size for the company’s coagulation testing products in the hospital and physician office/clinic to assist with M&A/partnership discussions. The research program included a bottoms up market build of patients and procedures requiring testing and qualitative interviews with primary decision makers to gauge the potential uptake of the company’s novel devices. The team also assessed the potential impact of novel oral anticoagulants, disruptive technologies, and trends in reimbursement, procedure volumes, testing location and use of self or point of care technologies.
POC Diagnostics International Distribution Strategy
A major pharmaceutical company engaged our team to determine if direct sales or third party distribution was the optimal strategy for the commercialization of a novel Point of Care testing platform in the EU5 and Japan. Our team conducted extensive primary research with potential customers in both the outpatient and hospital setting, in order to determine purchasing processes for diagnostic platforms and preferences for how to purchase our client’s platform. In addition, secondary research was conducted on the distributor landscape in the geographies of interest. Finally, the team provided recommendations on how to determine whether to engage a distributor, key criteria in choosing an appropriate distributor, and the most attractive distribution partners in each geography.
Corporate IVD Growth Strategy
A company providing solutions to the Japanese life science research tools market sought our teams input on developing a strategy that would enable the company to establish a foot hold in the US diagnostics market. A mutli-phase project was undertaken beginning with a detailed review of the market landscape in several areas: specialty immunoassay diagnostics, molecular diagnostics, liquid biopsy diagnostics including cell-free DNA, circulating tumor cells, and exosomes, and microbiome diagnostics. Potential opportunities for the client were identified in several of these market domains. Deeper assessment of these domain was completed through a more rigorous primary research program. The company is now seeking avenues for investment in these areas.
Business Unit Strategy
The team worked with the Bio-discovery division of a large life sciences company to help set the division's strategy for the next 3-7 years. In addition to extensive secondary research, the team interviewed academic, CRO and industry researchers in the US, EU, China, and India across a range of disciplines including mass spec, flow cytometry, genomics, biomarker discovery, HTS, and HCS. The team identified target acquisition candidates and developed an execution strategy for building a business that would address major unmet needs from basic research to translational medicine.
Our team conducted commercial diligence on a clinical CRO for a group of private investors. The team participated in several management meetings with the target, conducted in-depth interviews with CRO customers and industry executives and extensive secondary research to understand the trends in clinical outsourcing and the relative positioning of the target to act against these trends. The team developed a robust demand forecast model to assess how the outsourced market would change over time by therapeutic area, phase, molecule and company type. The team combined these analyses to help inform the client's successful bid during the auction process.
Go-to Market Strategy
A large CRO client historically focused on GLP-level preclinical animal studies was interested in understanding the opportunity to offer non-GLP discovery services. Health Advances conducted an extensive internal research program to understand the company's strengths/weaknesses, the current approach to handling such requests, and general organizational opinion of the opportunity. We also conducted interviews with customers, KOLs, and competitors to understand the relative demand for discovery services and the types of models that would be relevant and possible for a CRO to offer. We worked closely with the client to develop a document outlining the key investments to make, services/model to offer, and potential acquisition targets to build the business.
LSR Digital Pathology Strategy
Following a previous assessment of the hospital market for digital pathology (DP) systems, the team worked with a leader in digital pathology to assess the adoption potential of DP in life science research including early basic research, drug discovery and development and medical device development. Through interviews with end users and C-level executives, the team established pathology workflows and identified use cases and value propositions for digital pathology. Based on the value of digital pathology and its near-term applicability in each setting, the team developed a strategy for our client to expand their footprint in life science research.
Positioning of New Cell Analysis Capability in Research
A leading player in life science tools engaged our team to understand how a new technology for high throughput single-cell analysis could augment its current instrument portfolio. Through detailed qualitative interviews with a variety of researchers and core facility staff, we confirmed the potential for the new technology to enable new experiment types and outlined several unique use cases. A subsequent survey of ~120 researchers allowed us to test the adoption potential with various instrument features and price points. The resulting insights provided a foundation for revenue model assumptions under various development scenarios and allowed our client to solidify the business case for investing in the technology.
Research Reagent Due Diligence
Our team was contracted by a global life science company to explore the potential for a novel set of research reagents in a variety of applications. Techniques considered in the analysis include FISH, immunofluorescence, Western blots, PCR, lateral flow, and protein and nucleic acid arrays. Expert interviews were used to identify unmet needs in each area and determine the likely impact of improved fluorescence capabilities. Revenue projects were developed for each area to support valuation of the target product portfolio.
Bioprocessing Due Diligence
As part of a due diligence assignment, the team conducted an evaluation of an opportunity in the cell culture market, including both research and industry applications. Research and insights were driven by an international (US, EU, Asia) primary research program where the team spoke with academics and industry experts in bioprocessing. Competitive threats and broader market trends were synthesized to arrive at recommended competitive positioning for key product segments and a 10 year revenue forecast.
Gene Modulation Reagent Market Opportunity Assessment
To support a strategic transaction in the life science space, our team investigated the market for gene modulation reagents such as RNAi and genome editing tools. Interviews with researchers engaged in academic, translational, and industry research across the globe revealed important shifts in the competitive landscape and drivers of vendor choice as this field has matured. Our team forecasted several realistic opportunities to reverse this trend and drive growth for the target’s business after historically flat to declining share and revenue. As the engagement concluded, we worked closely with our client’s team to integrate our revenue forecast and recommendations with a P&L and final deal rationale.
Business Development Strategy
Health Advances reviewed the basic research portfolio of a medical school and associated academic medical center to evaluate and identify individual translational research programs that could be leveraged to increase the level of industry sponsorship for the institutions. The potential of grouping individual faculty's research programs into multi-faculty platform areas that could provide "bench-to-beside" translational science capabilities was also evaluated. In addition, recommendations were made about the internally and externally focused tactics the university/medical center could pursue to enhance industry funding.
Cellular Immunotherapy CRO/CMO Services Strategy
Our team conducted a detailed assessment of the autologous cell-based therapy (e.g., CAR T cell and TCR therapies) market to characterize future growth, therapeutic uses beyond cancer therapy, and identify the need for support services to enable development and commercialization. Expert interviews informed a detailed production workflow from patient sample collection, manufacturing and quality control of the personalized therapy, through to administration. Points of unmet need where new technologies or services could offer meaningful improvements to the workflow were identified along with recommendations for acquisition targets to help fill gaps.
Go-to-Market Strategy for Novel Immunoassay Platform
Our team was engaged to assist a small startup in identifying and prioritizing ideal life science research customers in academia, BioPharma and CROs for the company’s novel immunoassay platform, and developing a strategy to target these customers with a small internal salesforce. Current unmet needs with immunoassay testing and the ability of the platform to meet these needs was assessed. Recommendations were provided on the target customers, overall market size by research setting, and initial sales force structure and deployment strategy.
Conjoint Analysis of a Novel Assay System
A company with a highly sensitive cell-based assay was considering selling its technology as an instrument to academic and biopharma researchers. Following up on our previous work to determine the opportunity in academic research, our team used a large survey and conjoint analysis to identify a target instrument that balances features and price that was most likely to garner the most interest and have a lasting impact beyond the academic opportunity. The team’s work was also used to help refine forecast assumptions from the prior work.
Opportunity and Business Model Prioritization for Novel LSR Technology
Our client had developed a tool that enables slide based, multiplex nucleic acid and protein detection on tissue samples. With a number of possible research applications, the client required assistance in assessing the overall opportunity for each application and developing an optimal go-to-market strategy. The team conducted interviews across academic and biopharma research settings in the US and EU and considered analogs to determine revenue potential and product specifications required to win. Ultimately, this information was used to recommend, for each application, the launch of the technology as a service offering out of the client’s lab or as an instrument and reagent set sold to other facilities.
Health Advances developed positioning strategies and pricing recommendations for product line extensions in trauma, spine, and degenerative disc disease populations. Qualitative interviews and a quantitative analysis including conjoint were used. The study considered competitive threats from all the existing competitors as well as likely new entrants.
Bioresorbable Bone Cement
A private early-stage company was seeking to better understand the market opportunity for its bioresorbable bone cement. Heath Advances outlined which indications would provide the best lead candidate versus the best overall market opportunity. The assessment covered market sizing in cranio-maxillofacial, dental, spinal, and general musculoskeletal markets.
Musculoskeletal Implant Components
Health Advances worked with a private equity firm to evaluate an acquisition in the musculoskeletal implant component market. The study assessed the evolution of materials and designs likely to grow and shrink in the next ten years. This assessment helped project the market demand for the subset of components made by the target company and provided insights into which OEM customers were best leveraged to target for increased sales and those that were likely to decrease orders due to design and material changes.
Corrective Procedures for Treatment of Damaged Knee Cartilage
Health Advances identified and analyzed a large research database developed by a leading musculoskeletal surgeon to assess the frequency of different corrective procedures for damaged knee cartilage and their outcomes. The Health Advances team captured quantitative and qualitative measures of outcomes, including timing to subsequent treatments. This information was combined with findings from musculoskeletal surgeon interviews to document current clinical pathways by patient segment. Subsequently, the economics of a novel therapeutic procedure were quantified, assuming a range of clinical success rates as documented in the database and published literature. This work was included in the BLA filed with the FDA, which was approved.
Diagnostic for Soft Tissue Musculoskeletal Injuries
Health Advances was asked to assess the annual market size of soft-tissue musculoskeletal injuries in terms of volume of tests, to examine the potential cost effectiveness of the device in different patient populations, and to test the concept of a MDSN strategy, whereby the client would establish provider networks to address patients with musculoskeletal injuries and to boost use of the client's device. This diagnostic was initially being used to evaluate the source of cervical and lumbar pain, both where the problem was and as a way to identify malingerers who really did not have a problem (a concern with prolonged workers' compensation cases).
Osteoporosis and Estrogen Replacement
Working closely with an investor group, Health Advances supported a market evaluation and planning effort for a new company to be formed around breakthrough technology targeting the estrogen receptor and its role in osteoporosis. In addition to addressing some of the technical questions underlying the opportunity, Health Advances also examined the role of estrogen replacement therapy in post-menopausal women, the potential impact of the Women's Health Initiative Study, and competitive product development efforts.
On behalf of a financial investor, Health Advances created a five-year risk-adjusted global revenue forecast for a blockbuster oncology drug. The team conducted in-depth interviews with opinion leaders in the US and Europe to understand the drug’s potential across multiple indications and treatment settings.
Health Advances worked with a major medical device company to conduct an in-depth analysis of the oncology ablation market to inform the client’s strategic options going forward. The project outputs included a market sizing analysis with detailed segmentation in both the US and EU, and an in-depth evaluation of current and emerging technologies.
As a novel cancer agent was completing Phase III studies targeted at three cancers: colon, lung and breast, Health Advances conducted a detailed analysis leading to the recommended launch price taking into consideration the potential product positioning in current and future indications.
Clinical Trial Planning
Health Advances worked with a non-profit disease foundation to identify ways to streamline and enhance the outcomes of clinical trials in multiple myeloma. The team analyzed over 100 ongoing and proposed multiple myeloma trials and spoke with leaders in industry, academia, and the FDA to identify best practices.
Health Advances worked with the business development team at a specialty pharmaceutical company to identify and analyze potential acquisition targets to supplement the company’s early-stage pipeline. The team developed a rigorous set of acquisition criteria and used them to identify attractive assets and prioritize therapeutic markets for entry.
Health Advances was asked to perform strategic due diligence for a large pharmaceutical company looking to grow its oncology franchise through the acquisition of a novel therapeutic cancer vaccine. Health Advances conducted a detailed analysis of the market to predict the competitive position of the therapy, understand the logistical issues surrounding commercialization, and conducted a study of pricing and reimbursement to inform the financial forecast.
The Competitive Intelligence group of a large biotech client asked Health Advances to analyze how three competitive programs in development for hormone refractory prostate cancer would impact the competitive positioning of the client’s molecule. The team developed detailed profiles on each drug, including current clinical trial status, previous results, likely positioning, and expected resources dedicated to further development and marketing.
Health Advances provided a full commercialization strategy for a device for intraoperative margin assessment in breast cancer lumpectomies. The team assessed the potential market by segment and the likely reimbursement for the technology, and recommended clinical, pricing, and sales strategies.
Device-Based Glaucoma Therapy
A client engaged Health Advances to determine the market size and segmentation for a novel device to treat glaucoma. Health Advances quantified the economics of the entire range of glaucoma diagnostics and treatments from the perspectives of payers, doctors, patients, and facilities.
Diagnostic for Diabetic Retinopathy
Health Advances worked for a venture-backed company to assess the state-by-state reimbursement potential for a novel diagnostic with a complex revenue generation model. The Health Advances team developed the investor road show characterizing the opportunity and estimating market potential.
Novel Therapy for Improving Night Vision
Health Advances tested product concepts for a novel therapy for night vision with thought leaders and practitioners, including ophthalmologists and optometrists. A detailed model projected the potential market size, considering likely penetration into different patient segments and pricing potential for the therapy in the US market.
Cataract and Refractive Surgery Devices
Health Advances conducted due diligence for a private equity investor on a manufacturer of equipment and disposables used in cataract and refractive procedures. The Health Advances team also investigated the competitive landscape and emerging technologies through secondary research and primary interviews with ophthalmologists in the US and Germany
Health Advances conducted consumer research with amblyopia patients to assess willingness to self pay for therapy. The market potential was determined considering patients' preferred treatment regimen and pricing threshold among various patient segments for a computer-based treatment for amblyopia.
Ear Infection (Otitis Media)
Many young children experience six or more ear infections per year, and these infections, commonly treated with inexpensive antibiotics, place these young patients at risk for hearing loss and the development of antibiotic resistance. Our client identified a novel, non-vaccine approach to the prevention of ear infections. Health Advances was asked to investigate the potential to change pediatricians' existing treatment paradigm, to determine whether physicians could select patients for treatment before patients entered a cycle of infections, and to project how that would translate into market potential. We went on to assist the client with a strategy for positioning the product and identifying potential commercialization partners.
Orphan Disease Forecasting
Health Advances developed a worldwide market forecast for a cell-based gene therapy targeting an ultra-orphan indication. Countries were classified into segments based on standard of care, reimbursement considerations, and regulatory processes. The team combined epidemiologic data from multiple sources with physician-level patient volumes from interviews to establish the number of eligible patients in each country segment. The resulting flexible model allowed the client to evaluate various commercialization and distribution strategies. In addition, the team advised the client on the unique manufacturing and distribution requirements for their therapy.
LSD Drug Global Market Opportunity
For a university technology transfer office considering the sale of its royalty stream for an orphan drug in development for a lysosomal storage disorder, the team forecasted the global revenue potential of the orphan asset. Assumptions for revenue projections were supported by interviews with key opinion leaders in multiple geographies.
Orphan Disease Launch Road Map
On behalf of a specialty pharmaceutical company, Health Advances developed a comprehensive launch strategy road map for commercialization of what would be the first drug approved for a specific lysosomal storage disease. This involved a detailed examination of how treatment patterns would shift, strategies for different patient segments, and expected adoption rates over time.
International Orphan Drug Pricing Strategy
Using in-depth interviews with KOLs, government agencies, disease foundations, patient groups and various payers across 19 ex-US markets, Health Advances prepared an analysis of key product adoption and market penetration issues that would frame the pricing and reimbursement strategy for this orphan drug. The information informed the clinical trial design strategy and the international pricing strategy.
Hereditary Angioedema Commercial Plan
To support the commercialization plan and options, Health Advances prepared a market forecast for this orphan indication reflecting our assessment of the patient segmentation, product positioning, competitive environment, pricing scenarios and go-to-market options.
Cellular Therapy Strategy
Health Advances worked with a biotechnology company to support the development and commercialization of the company’s cellular therapy for an ultra-orphan enzymatic deficiency. The project consisted of three primary modules: pricing and reimbursement, partnering support, and a US market commercialization roadmap. Health Advances helped the company to develop a framework and argument to support a price in the US market by evaluating the product’s clinical value and assessing orphan drug and cellular therapy price benchmarks. Health Advances also examined reimbursement trends and policies, as well as identified pharmaco-economic rationales that could be compelling to payers. We helped the company’s management team prepare for partnering discussions by identifying and evaluating potential partners, developing and refining a pitch presentation, and benchmarking relevant deal structures. Finally, Health Advances worked with the company’s management team to develop a high level roadmap that addresses the major commercialization activities, timing and investments that are required in order to build infrastructure and execute a launch in the US.
International Orphan Disease Drug Forecast
As part of a deal negotiation, Health Advances prepared a detailed sales forecast for a launched drug for an orphan indication in the US, EU and Japan. Secondary and primary resources were used to verify epidemiology, treatment patterns, market penetration, growth rates, pricing and the future outlook for reimbursement and drug utilization.
LSD Clinical Trial Design and System Economics
Anticipating the complex challenges of developing and pricing a novel, high-priced therapy, Health Advances was engaged to prepare a comprehensive development strategy and system economic analysis of a LSD therapy. The analysis integrated a complex disease management paradigm, actual patient treatment activities and cost data and extensive discussions with thought leaders in the field.
Orphan Disease Strategy
Health Advances completed a comprehensive analysis on behalf of a multinational pharmaceutical company in support of a strategic decision regarding how to pursue orphan drug opportunities. Our work involved extensive benchmarking of orphan drug products, company strategies (including other large pharmaceutical companies, mid-size specialty and orphan drug companies, and emerging venture-backed companies) and the strategies that enabled those companies to be successful.
Cost Effectiveness Assessment in Acute Respiratory Distress Syndrome
Health Advances developed a cost effective assessment and model for a novel therapeutic for Adult Respiratory Distress Syndrome (ARDS) patients. , Specifically, Health Advances was asked to quantify the potential savings to a hospital through the reduction of ventilator ICU, non-ventilator ICU and routine room days, as well as the incidence of multiple organ failure. This quantification involved evaluating discharge data from over 13,000 patient billing records, conducting detailed reviews of daily billing records for 15 ARDS patients. The findings helped focus the client’s planned clinical trial by highlighting critical endpoints important for maximizing value potential.
Indication Prioritization in Allergic Asthma, Rhinitis and Atopic Dermatitis
Health Advances was engaged by a biotech company to assess the commercial potential of a pre-clinical antibody therapeutic with potential applications in allergic asthma, atopic dermatitis, allergic rhinitis, and other atopic indications. The goal of the project was to enable our client to prioritize indications and inform negotiations with potential licensing and commercial partners. Reviewing clinical literature and conducting research with allergists, pulmonologists, and dermatologists, the team built a robust forecast model quantifying peak sales potential by indication and recommended a development and partnership strategy.
Forecast for Alpha-1 Antitrypsin Deficiency
Like many rare diseases, the alpha-1 antitrypsin deficiency market is limited more by diagnosis rates than actual prevalence. To help our client assess the future demand for AATD therapies, Health Advances thoroughly reviewed information on the genetic basis and progression of disease to develop a comprehensive patient-based forecast for AATD prevalence, diagnosis, and treatment rates in the US and EU5. Flexible assumptions allowed our client to understand the impact of positive or negative data from ongoing trials on the number of patients eligible for treatment.
Launch Strategy for Asthma Inhaled Therapy
Health Advances helped a global pharmaceutical company prepare for launch of its inhaled therapy for asthma and COPD. As part of this process, Health Advances investigated the value of branding – for the drug and delivery device – as well as the impact of substitutability and competitor activity in the context of evolving physician and patient needs for management of asthma and COPD. Allergists, pulmonologists, primary care physicians and KOLs were interviewed, as were patients and caregivers in order to identify opportunities to address unmet needs along the patient journey.
Strategic Plan for Bronchiectasis Asset
Health Advances assisted a venture stage biotech with a drug delivery technology platform, with a comprehensive product and corporate strategic plan. The team conducted a comprehensive evaluation of the market for an inhaled antibiotic therapy, including application of the product in bronchiectasis. As a result of this plan, the board approved a major strategic shift toward a product based strategy and a large increase in funding.
Opportunity Evaluation in Chronic Obstructive Pulmonary Disease
For a global biopharmaceutical company, the team analyzed patient segmentation in COPD with a particular focus on identifying and sizing the opportunity for emerging disease modifying therapies. Two product concepts were tested with key opinion leaders, community pulmonologists, and primary care physicians to evaluate patient selection and likely adoption rates in both COPD broadly as well as Alpha-1 Antitrypsin Deficiency.
Opportunity Evaluation in Cystic Fibrosis and NTM
The Health Advances team analyzed multiple orphan infectious disease indications, including pulmonary MRSA in Cystic Fibrosis and non-tuberculosis mycobacterium (NTM). Detailed market landscapes were constructed that included patient journey analysis, treatment paradigm, and pipeline assessment to support understanding market sizing for an acute vs. chronic treatment for the orphan infectious diseases.
Opportunity Evaluation in Food Allergy Prophylaxis
Health Advances helped a large biopharmaceutical client understand the potential opportunity for its portfolio of early stage immunotherapy assets to provide prophylaxis for food allergy. The team developed a detailed understanding of current and future epidemiology, patient segmentation, and diagnosis and treatment paradigms in this evolving landscape. Research informed the development of a forecast model to understand adoption scenarios and help the client make a go/no-go decision for the portfolio.
Market Assessment of Idiopathic Pulmonary Fibrosis (IPF)
A client developing a biologic for use in Idiopathic Pulmonary Fibrosis (IPF) approached us shortly after the launch of two oral drugs to understand the impact on agents in development. The team developed an in-depth understanding of how the standard of care in IPF may evolve and helped the client to understand how next generation agents will need to be positioned for success. Interviews with general and KOL pulmonologists were used to inform the team’s recommendations.
Market Assessment of Interstitial Lung Diseases (ILD)
The team evaluated pulmonary disease opportunities with a specific focus on patients with a particular clinical phenotype in ILD. The team conducted in-depth primary research with ILD KOLs in US and Europe and performed a comprehensive clinical literature review to better understand the disease entities and the phenotype, to assess clinical trial approaches, and to size each opportunity.
Market Assessment of Pulmonary Arterial Hypertension (PAH)
Health Advances conducted an analysis of the Pulmonary Arterial Hypertension (PAH) market in the US, EU, and Japan to assess current and future treatment paradigms, an overall view of the therapy pipeline, and the potential for a novel therapy. Particular attention was given to the impact various clinical trial strategies would have on market acceptance, rate of adoption, and method of use for this novel treatment. Our assessment included the development of a stacked incidence model reflecting the flow of patients in and out of various lines of therapy as well as due diligence on a number of potential partners and acquisition candidates in the PAH space.
HPV Market Assessment
Health Advances conducted a market assessment of the HPV diagnostic and treatment paradigm. Health Advances performed a comprehensive search of the clinical literature and conducted primary research with OB/GYNs, primary care physicians, and pediatricians to assess the impact of the HPV vaccine and co-testing on the treatment market. To identify the optimal product profile and positioning for a novel HPV therapeutic, Health Advances performed a quantitative survey and conjoint analysis. The analytic insights drive a dynamic financial model that estimates sales under various competitive scenarios, providing the client with the information necessary to pursue the optimal clinical strategy.
OB/GYN Practice and Economic Overview
On behalf of a client, Health Advances completed a study of OB/GYN physician offices to assess the relative economic benefits of procedures and various office visits. The study involved site visits to OB/GYN offices to understand a “typical day” and the time involved in each visit. The analysis outlined the contribution margin for the most frequently performed procedures and office visits to dissect the economics of an OB/GYN practice.
Oral Contraceptive Market
Health Advances forecasted the sales of the oral contraceptive (OC) market and the sales of a specific OC in development. Health Advances spoke with OB/GYNs to understand the decision-making process when prescribing OCs and considered the impact of other contraceptive delivery options, generic entrants and PBM tiering to forecast product sales.
Health Advances worked with an early stage company to develop a value based price for a non-invasive maternal blood test that replaces amniocentesis while providing complete and accurate prenatal diagnosis. Health Advances provided a fact-based compelling analysis quantifying the technology’s value proposition to lobby for a value-based price with payers. This analysis integrated both the current costs for prenatal testing and the costs of potential complications of invasive testing.
Breast Biopsy Devices
A client engaged Health Advances to analyze the breast biopsy market. The project involved extensive research with radiologists and breast surgeons to detail the current referral patterns and decision-making processes when selecting the type of biopsy to perform and the specific breast biopsy device. The project also involved understanding the types of procedures performed in each setting and the corresponding economics to physicians and facilities.