Using analogue data to substantiate long-term durability of gene therapies: a narrative review.

The number of gene therapies in clinical trials and moving toward licensure is increasing. Most gene therapies are designed to achieve long-term effects, but at licensure the data to support claims of long-term durability are often limited, as long-term monitoring studies are often part of post-approval commitments by companies. Health technology assessors must therefore assess the potential for the long-term durability of a product and the potential cost-effectiveness based on the data available. The authors explored the benefit of strengthening the ability to infer durability of effect using analogue category data. Different analogue categories were assessed for the potential to substantiate claims of sustainability of effect for gene therapies by leveraging biological plausibility arguments. The authors propose a pathway for identifying potential analogues. Such a pathway should help establish plausible or theoretical long-term outcomes that can be considered in value assessments of gene therapies.

Many diseases, affecting all parts of the body, can be treated with gene therapy. Gene therapies make changes to a person's genes by either replacing or inactivating a gene that is causing disease or by adding new genes that can fight diseases such as cancers. These therapies have the potential to cure patients of the disease for their lifetime. When decisions are being made over whether gene therapies are safe and work well in patients, it can be difficult to understand if they will maintain their benefits to a person over a lifetime, as they have only been studied in clinical trials for a much shorter amount of time. In this paper, the authors explore whether information around the benefits of therapies that work in a similar way, or target similar diseases, can be used to strengthen an understanding of how well newer therapies work over a long period of time. The authors propose a pathway that can be followed to identify the suitability of a comparison between different therapies and how the evidence of benefit over time can be interpreted. This information will be useful for developers of gene therapies who are trying to generate evidence of long-term benefit to patients, as well as for decision makers who need to understand how well these gene therapies will work over a patient's lifetime.

The use of innovative payment mechanisms for gene therapies in Europe and the USA.

Innovative reimbursement mechanisms have long been considered potential solutions to the data uncertainty associated with one-off, high-value gene therapies that have long-term therapeutic potential, combined with limited supporting evidence at launch. The launches of increasing numbers of such gene therapies in Europe and the USA in the past 5 years provide valuable exemplars of how innovative reimbursement mechanisms are used by healthcare system decision makers in practice. This review details the use of such reimbursement schemes for recently launched gene therapies in key European countries and the USA, and shows that they are more widespread in Europe than in the USA. Although innovative payment schemes are increasingly used across countries, differences in healthcare system structures (e.g., single- vs multi-payer systems) and willingness to pay mean that decision makers in different countries have different incentives to manage uncertainties around long-term, real-world product value.

Clinical Adoption of Advanced Therapies: Challenges and Opportunities.

As the cell and gene therapy field matures the powerful therapeutic potential of these innovative therapies is starting to be shown, particularly in the fields of oncology and childhood immune deficiency diseases. However, as more therapies enter late stage clinical trials, advances and innovation are required in manufacturing, logistics, regulation, reimbursement and the healthcare setting to ensure that systems are in place to support wider clinical adoption of these promising treatments. A window of opportunity exists to implement new methodologies for best practice in both the ability to manufacture products reproducibly at scale, as well as ensuring healthcare systems are not overwhelmed by the variety and complexity of these new therapies and the additional burden they will place on already stretched facilities. If all interested parties work together it will be possible for the sector to develop the necessary processes, skilled staff and infrastructure needed as more treatments move from clinical trial to marketed products.

Outcomes-based reimbursement for gene therapies in practice: the experience of recently launched CAR-T cell therapies in major European countries.

Background: The experience of Kymriah® and Yescarta® provides real-world examples of how health-care systems approach and manage the reimbursement of one-off, high-cost, cell, and gene therapies, and the decision uncertainty and affordability challenges they present. Objective: To provide an overview of the reimbursement schemes used for Kymriah® and Yescarta® in France, Germany, Italy, Spain, and the UK (EU5) as per the final quarter of 2019; to identify challenges and derive learnings for future product launches. Methodology: Secondary research, complemented by primary research with key market access stakeholders. Findings: Kymriah® and Yescarta® have relatively uniform list prices across the EU5, and are reimbursed according to their marketing authorisations. In France and the UK, reimbursement is on the condition of collecting additional data (at the cohort level) and subject to future reassessments; elsewhere, rebates (Germany) or staged payments (Italy and Spain) are linked to individual patient outcomes. Conclusions: The experience of Kymriah® and Yescarta® shows an increased appetite for outcomes-based reimbursement (OBR) in the EU5, with notably novel approaches applied in Italy and Spain (outcomes-based staged payments). Thus, real-world evidence (RWE) has become an increasingly powerful lever for demonstrating the value of health benefits in the clinical setting.

Upgrading the SACT dataset and EBMT registry to enable outcomes-based reimbursement in oncology in England: a gap analysis and top-level cost estimate.

Background: Outcomes-based reimbursement (OBR) can reduce decision uncertainty and accelerate patient access to cell and gene therapies, however, OBR is rarely applied in practice in England. Oncology is the therapy area with the most cell and gene therapies in late-stage development, and the Systemic Anti-Cancer Therapy (SACT) dataset and The European Society for Blood and Marrow Transplantation (EBMT) registry are two data collection infrastructures that could potentially act as conduits for implementing OBR in cancer in England. Objective: To perform a gap analysis to identify the key requirements for upgrading the SACT and EBMT databases for the purposes of enabling OBR, and a top-level estimation of how much this upgrade may cost, using either a manual (staff-heavy) workaround or part automation (technology-heavy) approach. Methodology: The analysis of current data capture and gaps is informed by secondary research, while the assumptions and data used to derive the top-level cost estimates were informed by consensus-based primary research with experts in healthcare information technology (IT) systems integration and platform development, as well as experts of SACT and EBMT. Findings: In its current form, the SACT dataset in isolation is largely unfit for enabling OBR in oncology, whether through clinical, economic or humanistic outcomes. The EBMT registry has a greater potential; however, this relates to key clinical outcomes only, not economic or humanistic outcomes. Part automation requires a higher upfront investment than the manual workaround (~£1.8 million vs. ~£400k); however, lower annual costs (~£200 vs. ~£260k-£850k) mean that part automation becomes a more cost-effective approach over time. Conclusions: An appropriately automated and scalable data collection infrastructure should be implemented, with the ability to integrate clinical, economic and humanistic outcomes with healthcare cost data and payment systems, to enable OBR not only in cancer but also in other therapy areas.

Data collection infrastructure for patient outcomes in the UK - opportunities and challenges for cell and gene therapies launching.

Background: Cell and gene therapies are associated with uncertainty around their value claims at launch due to limitations of supporting clinical data; furthermore, their high costs present affordability issues for payers. Outcomes-based reimbursement can reduce payer decision uncertainty and improve patient access, however, requires data collection infrastructure and practice to be operational. Objective: To identify indications most likely to see launch of cell or gene therapies in the UK over the next five years, and to perform a qualitative assessment of how conducive the existing data collection infrastructure and clinical practice is in facilitating adoption of outcomes-based reimbursement in the corresponding indications. Methodology: Through secondary research, we identified target indications for cell or gene therapies at a mature clinical development stage (Phase III) with EU and/or US trial sites, and assessed availability of relevant data collection infrastructures in the UK. Secondary research findings were validated through primary research (expert interviews). Key parameters considered for the suitability of existing data collection infrastructure in supporting outcomes-based reimbursement include time horizon of data collection, whether data entry is mandatory and whether infrastructure is product or therapy area-specific. Findings: We identified 58 cell or gene therapies, spanning 47 indications, 20 of which are in oncology. Oncology seems well placed for outcomes data collection (through the mandatory Systemic Anti-Cancer Treatment database), however data entry compliance can be an issue (due to resource limitations), and upgrading will be needed for the purpose of outcomes-based reimbursement. Among non-oncology indications ~two-thirds have data collection infrastructures in place, but only three come close to the requirements for outcomes-based reimbursement. Conclusions: Existing data collection infrastructure in indications with potential cell or gene therapies launches in the next five years in the UK is overall not sufficient to facilitate outcomes-based reimbursement.

The potential price and access implications of the cost-utility and budget impact methodologies applied by NICE in England and ICER in the US for a novel gene therapy in Parkinson's disease.

Background: NICE in England, and ICER in the US both use cost-utility analyses (CUA) and budget impact analyses (BIA) to assess value for money and affordability, however the thresholds used differ greatly. Objective: To perform a cross-country comparison of the results of the CUA and BIA and detail the implications for reimbursed price and volumes, for a novel gene therapy for Parkinson's disease (PD). Methods: A Markov model was built to perform country-specific CUAs and BIAs Findings: The US ceiling price identified through CUA is ~ 1.8 times higher than in England (aligning to our previous US/UK price comparison analysis of high-cost drugs). However, the net budget impact corresponding to these price levels would limit number of patients treated in order not to exceed the BIA threshold. Performance-based annuity payments can increase patient access at launch without exceeding the thresholds while reducing payers' data uncertainty. Conclusion: Our cost-utility analysis in PD shows a difference in price potential between the US and England that aligns with what is observed in practice for other high-cost drugs. Furthermore, the budget impact threshold operational in England imposes a greater downwards pressure on price and/or volumes than the one applied by ICER in the US.

Establishing the cost of implementing a performance-based, managed entry agreement for a hypothetical CAR T-cell therapy.

Background: Market access stakeholders consider the adoption of Managed Entry Agreements (MEAs), however a clearly described methodology to quantify their implementation burden is not available in the public domain. Objective: To quantify the cost of implementing a performance-based MEA at the hospital level. Methods: The analysis involved a hypothetical one-off therapy targeting Acute Lymphoblastic Leukaemia. Data collection from five NHS Hospital Trusts in England captured costs by task, job band, personnel time and capital investment. We compared the administrative burden of the standard of care (SoC) to that of adopting the therapy with or without an MEA over 10 years. Findings: The 10-year cost for the activities required to support hospital payments for the target patient population in England varied as follows: for the SoC was £447,353, compared to £1,117,024 for the novel therapy with MEA, and £245,317 without MEA. Conclusions: The higher cost associated with the SoC compared to the novel therapy without an MEA, arises from the higher frequency of infusions requiring payments and the associated mandatory data capturing requirements for oncology therapies. The novel therapy with MEA presents the greatest burden due to increased frequency of monitoring in year one to compensate for the greater uncertainty in clinical data and to inform the performance-based reimbursement.

Annuity payments can increase patient access to innovative cell and gene therapies under England's net budget impact test.

Background: Cell and gene therapies have the potential to provide therapeutic breakthroughs, but the high costs of researching, developing, manufacturing and delivering them translate into prices that may challenge healthcare budgets. Various measures exist that aim to address the affordability challenge, including reducing price, limiting patient numbers and/or linking remuneration to product performance. Objective: To explore how the net budget impact test recently introduced in England can affect patient access to high-value, one-off cell and gene therapies, and how managed entry agreements can improve access. Methods: We use a hypothetical example where a new high-value, one-off therapy launches in an indication where it displaces a relatively low cost chronic treatment. We calculate the number of patients that can be treated without exceeding the £20 million net budget impact threshold, and compare results for scenarios where a full upfront payment is used, and where annuity-based payments are used. Results: Charging a full upfront payment at the time of treatment can lead to suboptimal patient access. Conclusion: Annuity-based payments in combination with an outcomes-based remuneration scheme reduce consequences of decision uncertainty and can increase patient access, without exceeding the net budget impact test.

Concise Review: The High Cost of High Tech Medicine: Planning Ahead for Market Access.

Cellular therapies and other regenerative medicines are emerging as potentially transformative additions to modern medicine, but likely at a staggering financial cost. Public health care systems' budgets are already strained by growing and aging populations, and many private insurer's budgets are equally stretched. The current systems that most payers employ to manage their cash flow are not structured to absorb a sudden onslaught of very expensive prescriptions for a large portion of their covered population. Despite this, developers of new regenerative medicines tend to focus on the demands of regulators, not payers, in order to be compliant throughout the clinical trials phases, and to develop a product that ultimately will be approvable. It is not advisable to assume that an approved product will automatically become a reimbursed product, as examples from current practice in hematopoietic stem cell transplantation in the U.S. demonstrate; similarly, in Europe numerous Advanced-therapy Medicinal Products achieved market authorization but failed to secure reimbursement (e.g., Glybera, Provenge, ChondroCelect, MACI). There are however strategies and approaches that developers can employ throughout clinical development, in order to generate clinical and health economic data which will be necessary to demonstrate the value proposition of the new product and help ensure market access for patients; furthermore, performance based managed entry agreements coupled with post-launch evidence generation can help overcome challenges around product uncertainty at launch and reduce market access delays. Stem Cells Translational Medicine 2017;6:1723-1729.

A price comparison of recently launched proprietary pharmaceuticals in the UK and the US.

OBJECTIVE: To explore the relationship between prices charged by manufacturers of proprietary pharmaceuticals in the US and in the UK in recent years (2013-2016), expressed as a multiplier, and to detail to what extent this relationship differs for high-cost therapies used in smaller patient populations, as compared to lower-cost drugs. METHODOLOGY: Therapies assessed by the Scottish Medicines Consortium (SMC) in the UK between 1 January 2013 and 1 June 2016 were identified; only in-patent therapies were included in the analysis (to avoid the impact of price erosion post patent expiry); results were grouped according to annual cost per patient (whether considered high-cost, i.e., >£2,500 per patient per year, or not) and the size of the UK target population [whether considered orphan (<32,000 patients per year), ultra-orphan (<1,000 patients per year), or not]. Publicly listed prices were obtained in the US and UK and were adjusted where necessary to estimate the prices charged by manufacturers in the respective countries. The difference in price (per unit of the same strength and formulation) was calculated as a multiplier between the US and UK prices for each of the therapies identified. RESULTS: Based on the methodological approach described, 88 therapies were identified and included in the analysis. The multiplier between the US and UK prices was 3.64 for therapies with an estimated annual cost <£2,500; this was reduced to 1.90 for higher-cost therapies. A downward trend was also evident in the subgroup analysis of the higher-cost therapies; as the estimated target patient populations reduced from >32,000 down to <1,000, the US/UK price multipliers reduced from 2.13 for the former to 1.48 for the latter. CONCLUSION: Although pharmaceutical prices have been found to be on average substantially higher in the US compared to the UK, our findings suggest that this price discrepancy is smaller for higher-cost therapies targeting small patient populations. Manufacturers of high-cost products should therefore factor this in when formulating pricing strategies because the potential for higher pricing in the US seems greater for primary care products targeting large patient populations.

Systematic literature review of treatments for management of complications of ischemic central retinal vein occlusion.

BACKGROUND: To understand the clinical and economic outcomes of treatments for managing complications of ischemic central retinal vein occlusion (iCRVO). METHODS: We conducted a systematic literature review by searching multiple databases and ophthalmology conferences from 2004 to 2015. Studies published in English language and populations of age ≥45 years were included. For clinical endpoints, we defined eligibility criteria as randomized controlled trials, prospective before-and-after study designs, and non-randomized studies reporting on treatments in patients with iCRVO. For economic endpoints, all types of study design except cost-of-illness studies were included. We evaluated the definitions of ischemia, clinical and economic endpoints, and rate of development of complications. Risk of bias was assessed for clinical studies using the Cochrane risk-of-bias tool. RESULTS: A total of 20 studies (1338 patients) were included. Treatments included anti-vascular endothelial growth factors (anti-VEGFs), steroids, and procedures primarily targeting macular edema and neovascularization. Ischemia was not defined consistently in the included studies. The level of evidence was mostly low. Most treatments did not improve visual acuity significantly. Development of treatment complications ranged from 11 to 57 %. Incremental cost-effectiveness ratios reported for anti-VEGFs and steroids were below the accepted threshold of GB£30,000, but considering such treatments only ameliorate disease symptoms they seem relatively expensive. CONCLUSIONS: There is a lack of evidence for any intervention being effective in iCRVO, especially in the prevention of neovascularisation. iCRVO poses a significant clinical and economic burden. There is a need to standardize the definition of ischemia, and for innovative treatments which can significantly improve visual outcomes and prevent neovascular complications.

Healthcare costs and outcomes of managing ß-thalassemia major over 50 years in the United Kingdom.

BACKGROUND: The objective was to estimate the incidence-based costs of treating ß-thalassemia major (BTM) to the United Kingdom's National Health Service (NHS) over the first 50 years of a patient's life in terms of healthcare resource use and corresponding costs and the associated health outcomes. STUDY DESIGN AND METHODS: This was a modeling study based on information obtained from a systematic review of published literature and clinicians involved in managing BTM in the United Kingdom. A state transition model was constructed depicting the management of BTM over a period of 50 years. The model was used to estimate the incidence-based health economic impact that BTM imposes on the NHS and patients' health status in terms of the number of quality-adjusted life-years (QALYs) over 50 years. RESULTS: The expected probability of survival at 50 years is 0.63. Of patients who survive, 33% are expected to be without any complication and the other 67% are expected to experience at least one complication. Patients' health status over this period was estimated to be a mean of 11.5 discounted QALYs per patient. Total healthcare expenditure attributable to managing BTM was estimated to be £483,454 ($720,201) at 2013/14 prices over 50 years. The cost of managing BTM could be potentially reduced by up to 37% if one in two patients had a bone marrow transplant, with an ensuing improvement in health-related quality of life. CONCLUSION: This analysis provides the best estimate available of NHS resource use and costs with which to inform policy and budgetary decisions pertaining to this rare disease.

Bringing regenerative medicines to the clinic: the future for regulation and reimbursement.

Significant investments in regenerative medicine necessitate discussion to align evidentiary requirements and decision-making considerations from regulatory, health system payer and developer perspectives. Only with coordinated efforts will the potential of regenerative medicine be realized. We report on discussions from two workshops sponsored by NICE, University of Alberta, Cell Therapy Catapult and Centre for Commercialization of Regenerative Medicine. We discuss methods to support the assessment of value for regenerative medicine products and services and the synergies that exist between market authorization and reimbursement regulations and practices. We discuss the convergence in novel adaptive licensing practices that may promote the development and adoption of novel therapeutics that meet the needs of healthcare payers.

Cell-based therapy technology classifications and translational challenges.

Cell therapies offer the promise of treating and altering the course of diseases which cannot be addressed adequately by existing pharmaceuticals. Cell therapies are a diverse group across cell types and therapeutic indications and have been an active area of research for many years but are now strongly emerging through translation and towards successful commercial development and patient access. In this article, we present a description of a classification of cell therapies on the basis of their underlying technologies rather than the more commonly used classification by cell type because the regulatory path and manufacturing solutions are often similar within a technology area due to the nature of the methods used. We analyse the progress of new cell therapies towards clinical translation, examine how they are addressing the clinical, regulatory, manufacturing and reimbursement requirements, describe some of the remaining challenges and provide perspectives on how the field may progress for the future.

Reimbursement of licensed cell and gene therapies across the major European healthcare markets.

OBJECTIVE: The aim of this research is to identify the pricing, reimbursement, and market access (P&R&MA) considerations most relevant to advanced therapy medicinal products (ATMPs) in the Big5EU, and to inform their manufacturers about the key drivers for securing adoption at a commercially viable reimbursed price. METHODOLOGY: The research was structured following three main steps: 1) Identifying the market access pathways relevant to ATMPs through secondary research; 2) Validating the secondary research findings and addressing any data gaps in primary research, by qualitative interviews with national, regional, and local-level payers and their clinical and economic advisors; 3) Collating of primary and secondary findings to compare results across countries. RESULTS: The incremental clinical benefit forms the basis for all P&R&MA processes. Budget impact is a key consideration, regardless of geography. Cost-effectiveness analyses are increasingly applied; however, only the United Kingdom has a defined threshold that links the cost per quality-adjusted life year (QALY) specifically and methodologically to the reimbursed price. Funding mechanisms to enable adoption of new and more expensive therapies exist in all countries, albeit to varying extents. Willingness to pay is typically higher in smaller patient populations, especially in populations with high disease burden. Outcomes modelling and risk-sharing agreements (RSAs) provide strategies to address the data gap and uncertainties often associated with trials in niche populations. CONCLUSIONS: The high cost of ATMPs, coupled with the uncertainty at launch around their long-term claims, present challenges for their adoption at a commercially viable reimbursed price. Targeting populations of high disease burden and unmet needs may be advantageous, as the potential for improvement in clinical benefit is greater, as well as the potential for capitalising on healthcare cost offsets. Also, targeting small populations can also help reduce both payers' budget impact concerns and the risk of reimbursement restrictions being imposed.

Market access pathways for cell therapies in France.

INTRODUCTION AND OBJECTIVE: Cell therapies can be classified into three main categories of products: advanced therapy medicinal products (ATMPs), ATMPs prepared on a non-routine basis (hospital exemptions), and minimally manipulated cells. Despite the benefits that cell therapies can bring to patients, they are subject to complex pathways to reach the market in France. The objective of this study was to identify and describe routes to market access for cell therapies in France and how these vary by regulatory status. METHODOLOGY: The research was structured following five main steps: (1) identification of the French regulatory framework for cell therapies; (2) identification of the health products categorised as cell therapies in France; (3) mapping of the market access pathways per category of cell therapy; (4) validation of findings by interviewing experts; and (5) development of a roadmap summarising market access pathways for cell therapies in France. The secondary research methodology included a comprehensive literature review conducted on websites of French public health institutions, complemented by a research for peer-reviewed articles, abstracts, and grey literature. RESULTS: Different market access pathways are possible depending on the cell therapy category. For ATMPs, market access pathways depend on the licensing status of the therapy. Licensed ATMPs followed the same market access pathways as 'conventional' pharmaceuticals, whereas not-yet-licensed ATMPs can be funded via a specific financial allowance under the framework of a Temporary Authorisation for Use procedure or various research programmes. For new ATMPs that are associated with a separate medical device (not considered as 'combined ATMPs') or associated with a new medical procedure, additional pathways will apply for the medical device and/or medical procedure to be reimbursed in the ambulatory settings or at hospital. The most likely funding option for ATMPs prepared on a non-routine basis is outside the diagnosis-related group (DRG) system through Missions of General Interest and Support to Contracting (MIGAC). For minimally manipulated cells, four different funding processes are applicable, depending on the type of activity: (1) inclusion in a DRG; (2) inclusion in the list of products and services qualifying for reimbursement (LPPR) (as a medical device); (3) an annual lump sum provided by regional health agencies; and (4) a financial allowance under Missions of General Interest (MIG). CONCLUSION: Cell therapy is a diverse and promising category of medical interventions. Its heterogeneity and complexity mean that several funding options and market access pathways apply. The main challenges facing cell therapies relate to (1) the identification of the most appropriate path to reimbursement, and (2) price setting, whereas high manufacturing costs of these therapies will dictate a high price that could only be achieved by a product that leads to important additional patient benefits compared to available treatment options. More specific funding options could emerge as the number of cell therapies increases and the authorities face the need to structure and stabilise funding. It will be vital for manufacturers to have a clear understanding of the various temporary funding opportunities early in a product's lifecycle for the adoption of a stepwise approach to secure permanent funding. Furthermore, due to the very limited Health Technology Assessment (HTA) bodies experience for cell therapies, manufacturers should enter into dialogues with HTA agencies at an early stage to optimise market access conditions.

CRP2 transcript expression pattern in embryonic chick limb.

Members of the cysteine-rich protein (CRP) family are evolutionary conserved proteins that have been implicated in the processes of cell proliferation and differentiation via the cytoskeletal proteins. In this paper, we present the dynamic expression pattern of CPR2 transcripts during chick limb bud development. CRP2 transcripts are located in various tissues, including muscle, arteries, cartilage, ligaments and digit tendons and also in the apical ectodermal ridge and feather buds.