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Value-Engineered Translation: Developing Biotherapeutics That Align With Health-System Needs

Tania Bubela, PhD, JD, and Christopher McCabe, PhD
The value-engineered translation (VET) framework was designed to evaluate translational candidate biotherapeutics for their potential to clear value-based reimbursement hurdles.18 It comprises 3 distinct steps along the translational continuum—headroom analysis, macro analyses, and micro analyses—as shown in Figure 1. It provides developers with information at specific points in the process to inform “go-no-go” and research prioritization decisions. For technologies that clear all 3 stages, the framework provides a reimbursement portfolio to incentivize investment in, and inform design of, costly phase 3 clinical trials. The portfolio is a starting point for designing the final evidence package to submit to HTA agencies for reimbursement decisions.

This discussion will focus on the first phase. It comprises a headroom assessment, which integrates considerations of the health and resource impacts of a candidate technology and whether social values might modify our assessments of those impacts. The second and third phases of the VET framework are based on the availability of more specific evidence and comprise increasingly sophisticated economic models to assess the likelihood of clearing market access hurdles, along with the value of alternative R&D investments and their impact on that likelihood.

Headroom Analysis

Headroom analysis evaluates any unmet need for a candidate technology for a specific indication to support a price consistent with an acceptable return on the investment in clinical translation (Figure 2). In other words, it considers the scope for therapeutic or health system benefits of a technology relative to other existing technologies or those expected to be on the market at the time of product launch. This phase may commence as soon as a technology or indication dyad has been specified. It first assesses the maximum health gain that could be achieved if a new therapy restores the affected individual to his or her full health, with consideration for age and gender. However, if existing therapies are successful in restoring a patient’s health, then it will be very difficult for a new therapy to justify a premium price on the basis of health delivered.

Fortunately, in a value-based decision framework, improvements in the cost of care are also valued, as they reflect potential health gain for other people served by the health system. Thus, the second component of the headroom assessment considers whether the candidate technology could achieve savings elsewhere in the system that would be valued by the budget holders, as releasing resources to provide healthcare to others.

The final component of the headroom assessment contemplates whether the characteristics of the technology, the disease, or the affected population would modify the value of the health benefits or resource savings for the decision maker. For example, many jurisdictions incentivize technology development for rare/orphan diseases and for pediatric populations.

The assessment of headroom draws upon insights from clinical landscaping, which maps how the condition is currently managed in target healthcare systems, and technology landscaping, which draws upon patent, clinical trials, and trade and publications databases to identify potential competitor technologies likely to be on the market at the expected time of product launch. The former assessment specifies current headroom and the latter determines the likely headroom at the time of market access. Combined, these analyses determine whether the technology is likely to be a first to market, a fast follower, or a me-too, all of which would influence the ability of a developer to command a premium price.

The final component of the headroom assessment combines the methods of evidence synthesis and Bayesian expert elicitation. It examines the preclinical and early clinical data for evidence of publication bias, which forms the basis for adjusting expectations about the scope of the new technology for “over-confidence” bias.

Why Should Health Technology Developers Consider Headroom?

Here, we present retrospective and prospective examples of how early analysis of headroom may aid in decisions along a translational continuum. The first example illustrates the need for analysis of future market prospects—technologies may fail close to clinical adoption if the expected health benefit shrinks at the time of market entry. Vitravene (fomivirsen), an antisense therapy developed at the National Institutes of Health and licensed by Isis Pharmaceuticals, Inc, was approved by the FDA in August 1998 to treat cytomegalovirus retinitis (CMV-R). During its development in the 1990s, AIDS had transformed CMV-R from a rare disease into one of the most common ocular infections in the United States. When approved for use, Vitravene was a biomedical breakthrough as the first FDA-approved antisense therapy. While Vitravene was in phase 3 clinical trials, Highly Active Anti-retroviral Therapy (HAART) regimen, the “3-drug cocktail”, was developed to suppress HIV replication and allow the immune system to recover. As a consequence, the number of new cases of CMV-R declined by nearly 75%. When Vitravene reached the market, distributed by Novartis Ophthalmics AG, HAART had been standard therapy for about a year. New cases of CMV-R were less common, and many existing cases no longer needed treatment; in other words, the health crisis that Vitravene was designed to address had receded and sales of the product were much lower than predicted. As a result, Novartis no longer markets Vitravene, but Isis Pharmaceuticals still cites Vitravene as evidence of its “ability to meet FDA and European regulatory requirements for safety and efficacy, and for the commercial manufacture of antisense drugs.”19

The second example illustrates that delays in evidence development for regulatory approval and legal rights may lead to a loss of headroom if they enable a competitor to enter the market, making a therapy a fast-follower rather than a first-in-class. In 2008, Abbott Laboratories (now AbbVie) began marketing an anti-TNF-alpha human monoclonal antibody, Humira, as a therapeutic for anti-inflammatory disease, including psoriasis. The antibody was derived from a phage display library obtained from Cambridge Antibody Technology (CAT).20,21 Abbott disputed the royalty payments to CAT on products it developed from antibodies it had licensed. Abbott lost the court case in 2004, resulting in royalty payments to CAT of 5% instead of 2% on net sales.22 At the same time, Abbott was developing another anti-inflammatory therapeutic, anti-IL-12/23 human monoclonal, briakinumab, also obtained from CAT. Despite Abbott’s positive phase 3 results in 2009 for treating psoriasis, the FDA demanded additional data.23 Later that year, Centorcor Ortho Biotech Inc (now Janssen Biotech) received FDA approval for its anti-IL12/23 monoclonal StelaraTM (ustekinumab).24 In 2011, Abbott announced it had withdrawn its application with the FDA and the European Medicines Agency for briakinumab, partly because of a competitor and in part to avoid competing with its existing market for Humira.25

The example of 2 FDA-approved recombinant Lyme disease vaccines from the late 1990s illustrates the potential negative impact of social values on headroom for a technology. While social values can lead decision makers to approve technologies that would otherwise not be considered cost-effective, they can also produce a contrary effect. In 1998, FDA approved SmithKlineBeecham’s (now GlaxoSmithKline’s) LYMErix. Pasteur Merieux Connaught (now Sanofi) conducted phase 3 trials of its vaccine ImuLyme at the same time, but never applied for FDA approval. LYMErix trials demonstrated only 76% efficacy and required 3 doses. Additionally, it was approved for a restricted population: persons aged 15 to 70 years who lived in endemic areas and who engaged in activities with frequent exposure to ticks. After 1 year on the market, reports of adverse events began to appear and the media covered stories about “vaccine victims.” A class action lawsuit was filed against the company. While the FDA did not find a higher rate of adverse reactions among a small group who received the vaccine, some studies suggested HLA DR4+ patients who received the vaccine might be at a higher risk for developing chronic treatment-resistant arthritis. The FDA convened a public meeting in 2001 to discuss the risks and benefits of the vaccine. After a highly contentious discussion, the FDA made no changes to the use and labeling of the vaccine, but required the manufacturer to provide data from a phase 4 (postmarketing) trial. With all the negative publicity, sales fell off and GlaxoSmithKline withdrew the vaccine from the market in 2002.26

Our work with the regenerative medicine community is leading to greater awareness of cost-effective development of related technologies.18 Two current examples in regenerative medicine are Osiris Therapeutics Inc’s Prochymal, a stem cell therapy to treat steroid-refractory graft-versus-host-disease (GVHD), which was the first off-the-shelf regenerative medicine therapy to gain regulatory approval in Canada in 2012. The conditional approval, requiring ongoing collection of evidence, was only for children with the rare condition. No provincial health plan in Canada has approved reimbursement for the therapy—evidence that regulatory approval is no longer equivalent to market access.

The FDA approved Dendreon Corporation’s Provenge (sipuleucel-T) in 2010 as an autologous cellular immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. However, Provenge has struggled since its approval due to its administration procedure and the cost. Physicians balk at the $93,000 cost of a course of therapy for an expected 4 month survival benefit for prostate cancer patients. Research found that 57% of physicians indicated a maximum price of $30,000 for this scale of benefit.27 Physicians were concerned with the ability of patients to pay or copay for expensive therapies, the need for preauthorization from insurance companies, and the minimal benefit to patients. At the time Dendreon sought FDA approval, Provenge was a first-in-class immunotherapy. However, the FDA required further evidence of efficacy, which delayed the launch. Now Provenge struggles for market share against rival drugs: Xtandi, from Astellas and Medivation and Zytiga from Johnson & Johnson. The company’s share price and workforce now reflect its decline in fortunes.

From a prospective standpoint, the key lesson for health technology developers is that reimbursement considerations influence all markets. An HTA framework that starts with an analysis of available headroom is valuable from an R&D investment standpoint only when supported by further economic modeling, as the evidence of safety and efficacy mount. For example, a simple plot of disease burden (patient population and potential health impact of the technology) plotted against existing and prospective technologies, is a valuable basis for R&D investments, from both funding and research career perspectives. For example, the headroom for an expensive stem cell therapy for myocardial infarction—with limited benefits for patient survival and quality of life compared to a plethora of existing technologies—is low when compared with an expensive stem cell therapy for severe sepsis or a treatment for triple-negative breast cancer, which present an increased health gain, especially when alternative therapies are lacking.

Copyright AJMC 2006-2018 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
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