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Evidence Requirements for Innovative Imaging Devices: From Concept to Adoption
Evidence Requirements for Innovative Imaging Devices: From Concept to Adoption Richard A. Frank, MD, PhDa, Donald W. Rucker, MDb, Michael A. Ferguson, PhDc, Terry J. Sweeneyc
Changes in the regulatory and reimbursement environment for advances in imaging in the United States are leading to increasing requirements for formal clinical evidence of efficacy, effectiveness, and safety. The authors describe 5 phases of an imaging product’s lifecycle: design, regulatory clearance and approval, early adoption, reimbursement, and full adoption. Each phase has distinct needs for clinical evidence. With increasing costs of clinical evidence generation, the question of ownership of the responsibility to gather clinical evidence at each successive phase becomes important. Mismatch between the pace of advances in imaging technologies and the time required to do formal clinical trials to clear regulatory and reimbursement evidence requirements threatens patient access to the benefits of innovation such as reduction in exposure to radiation. Public and payer requirements for clinical evidence must also be evaluated for their impact on incremental design improvements, which have historically characterized advances in diagnostic imaging. Key Words: Diagnostic imaging devices, clinical evidence, regulatory affairs, coverage and payment, adoption, comparative effectiveness, cost-effectiveness, public-private partnerships, innovation, infrastructure J Am Coll Radiol 2011;8:124-131. © 2011 Published by Elsevier Inc. on behalf of American College of Radiology
INTRODUCTION The first generations of plain film x-ray, CT, ultrasound, and MRI were so transformative that questions of efficacy and effectiveness were usually nonexistent. Today, with the rise in health care expenditures and advances in computer science fueling growth in technologies throughout the life sciences, innovations in imaging, especially major advances, are coming under increased public policy analysis. Manufacturers deciding to introduce new imaging technologies into the US market must plan for an increasing set of regulatory, reimbursement, and adoption hurdles. Specifically, federal regulators and payers (and their private counterparts) regularly invoke more highly defined requirements for evidence of efficacy and effectiveness, and safety and necessity. We characterize the types of clinical evidence corresponding to the 5 phases in a successful product lifecycle from clinical introduction to a
GE Healthcare, Princeton, New Jersey. Siemens Healthcare USA. c Philips Healthcare. Corresponding author and reprints: Richard A. Frank, MD, PhD, GE Healthcare, 101 Carnegie Center, Suite 124 South, Princeton, NJ 08540; e-mail: [email protected]. b
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full adoption and the appropriate means of generating and using such evidence. We describe (1) product design, (2) FDA clearance and approval, (3) early clinical adoption, (4) reimbursement, and (5) full clinical adoption. This sequence of evidence phases for new applications of novel features in medical devices is driven by the unique US regulatory and reimbursement environment. Although the development of imaging technology is global, the United States has been the largest and most influential adopter of advanced imaging. Therefore, increases in US evidentiary standards may have a global impact on innovation and access to imaging. In general, private markets, whether for health care or other goods, ensure economically valuable and efficient transactions through price signaling as consumers match their personal marginal utility to market prices while at the same time producers are matching their marginal costs to those same prices. In the US health care system, most coverage and payments are effectively set by CMS, heavily influencing private payers. Historically, CMS paid for services that were “medically necessary,” so the discussion of value was not part of this conversation, but new measures of utility or value are increasingly being demanded [1]. © 2011 Published by Elsevier Inc. on behalf of American College of Radiology 0091-2182/11/$36.00 ● DOI 10.1016/j.jacr.2010.06.025
Note: cGCP ⫽ current good clinical practice; EMR ⫽ electronic medical record; HTA ⫽ health technology assessment; PMA ⫽ premarket approval; PPP ⫽ public-private partnership; RCT ⫽ randomized controlled trial; SAP ⫽ SAP. ⴱSome features, such as workflow, may not require formal clinical evidence. †For cost-effectiveness.
PPPs Multi-innovator, co-ops, grantors, PPPs Multi-innovator, grantors Single innovator Sponsor
Single innovator
Standard of care in practice guidelines Coverage and payments Proof of principle in applications adjacent to labeled claims Design history file for dossier Evidentiary standards and consequences
Application and labeled claims
Diagnostic outcomes Reasonable and necessary Peer review, journal criteria Final product specifications Yield
Safety and efficacy
Registries (eg, EMR-based) Modeling† Large prospective studies in community settings, confirmatory RCTs Small prospective studies, exploratory, summary stats Retrospective or prospective multicenter controlled trial to cGCP with a priori SAP Open studies, single-center research collaborations, small-n, summary statistics Methods Logistics and resources
Full Adoption
Peer-reviewed publications to demonstrate appropriate utilization HTA of relevance to therapeutic decisions; to gain reimbursement
Reimbursement Early Adoption
Peer-reviewed publications of relevance to therapeutic decisions; to improve on the standard of care Dossier (510[k] or PMA) to regulators for approval to market
Registration Design
Performance feedback for engineers to refine the technical specifications of featuresⴱ
Unmet clinical imaging needs can be addressed by new devices or novel features in current devices. Whether as additions to existing products or as elements of a completely new product, these features are captured in a design history file with a view to describing the product for which marketing authorization is requested. Clinical evidence gathered during this phase is useful in refining the design, gaining commitment to further investment in
Goals Aims and benefits
PHASE 1: PRODUCT DESIGN AND INTRODUCTION
Phase
Assessment of clinical utility will differ according to the varying perspectives of payers, providers, employers, patients, and politicians. Utility from the vantage point of payers and providers may be driven by cost, each driven by a profit motive, while from the vantage point of employers, the time to return to work would also be considered. Conversely, patients may be less concerned with cost (if they are not paying) but more concerned about quality and quantity of life; for them, the relevant outcome of a diagnostic procedure is change in diagnosis or treatment. That is to say, diagnostics are different from therapeutics; as distinct from the outcome of a therapeutic intervention, a diagnostic outcome is a change in treatment plan. This is clear from the fact that a diagnostic test may result in changing plans for concerted therapeutic intervention to watchful waiting or palliative care. Politicians may be concerned with access across the entire population. These viewpoints can lead to divergent assessments. For example, if a category of expensive imaging procedures enabled a choice of therapy to prevent sudden death, a patient’s perspective might suggest that this is extremely valuable, whereas a payer’s perspective might suggest the opposite because the procedure may now generate an entirely new set of care expenditures in exchange for a relatively small overall improvement in survival. An employer or societal perspective might be influenced by whether the patients are of working age [2]. Changes in the current evidentiary standards are being driven by payers’ perspective, so we will focus on that reasoning. In this paper, we outline the sequential generation of clinical evidence for new imaging technologies. We do so from the point of view of a manufacturer deciding whether to make an investment in research and development of innovative features or applications in imaging. We outline 5 phases of evidence development for imaging applications and technologies (Table 1). Each of the 5 phases of evidentiary development leads to a decision point for investors in and manufacturers of imaging technologies as they weigh opportunity costs. The monetization of investment costs and returns stretches over many years, and therefore investment decisions will be discounted over time using net present value calculations.
Table 1. Clinical evidence strategy integrated across five phases of development of innovative imaging devices, from concept to adoption
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development of the product, and confirming the relationship between design feature and performance. The first phase of evidence development is achieved via small pilot studies, from which the data may not be robust enough for publication because of small sample sizes and limited scope. These clinical investigations are sponsored by innovator companies and usually are performed by clinical imaging experts at a single academic medical center with institutional review boards experienced in assessing the risks and benefits for such trials. The product features in these trials frequently represent serial incremental innovations, which may aggregate to significant gains in performance over time. The evolution of MR and CT hardware and software reflects the impact of such incremental innovation, for example, in the improved resolution gained from field homogeneity with 3-T magnets or the effect of improved detector technology in reducing exposure to radiation. Often technology assessment analysts fail to realize the incremental nature of changes in imaging technology and offer suggestions of global nonreimbursement at an early time in the technology lifecycle, effectively stopping the capital flows that allow significant and progressive improvements [3-5]. PHASE 2: REGULATORY CLEARANCE AND APPROVAL Once a company decides to move forward with market introduction (on the basis of business planning, clinical and bench data, etc), the regulatory strategy and evidence needs are mapped out. The FDA classifies medical devices into 3 groups: classes I, II, and III. Class I devices are considered low risk and primarily exempt from the 510(k) premarket notification clearance route. The 510(k) route (21CFR807.81) is the submission process to the FDA to demonstrate that the medical device is at least as safe and effective as, or substantially equivalent to, a preexisting (“predicate”) device. Traditionally, the 510(k) premarket notification process did not require clinical studies on the device as part of the submission, but this may be changing, as the FDA is currently reviewing 510(k) requirements. Class II devices, which are moderate-risk devices, routinely enter the market via the 510(k) route. The allowance of class II devices into the market on the basis of substantial equivalence to a predicate device is referred to as clearance. Class III devices, which have potential high risk to patient, normally enter the market through a complex premarket approval (PMA) [6]. The PMA submission (21CFR814.20) must demonstrate a device’s safety and efficacy by a thorough performance analysis of bench and clinical evidence data that demonstrates the ability to achieve the new intended use of the device.
Clinical data capture for a PMA is conducted through an investigational device exemption trial. Investigational device exemption studies are required to be conducted under good clinical practices. Investigational device exemption clinical trial requirements such as sample size vary depending on disease and device. High-profile or high-risk device trials may cost millions of dollars and take multiple years to complete. Investigational device exemption trials have targeted patient indications, including primary and secondary end points, a priori subanalysis definitions, and specifically defined follow-up periods. Investigational device exemption data are presented to the FDA for review as part of a panel meeting for product approval. There is an expectation that the data will also be published in the peer-reviewed literature. The allowance onto the market by the FDA of class III devices is referred to as approval. According to the US Government Accountability Office, more than 11,000 510(k) submissions and more than 200 original PMAs were reviewed by the FDA from 2003 to 2007 [7]. With this volume of approval requests, it is not surprising that more than 95% of medical devices are cleared for marketing by the FDA without the need to provide clinical evidence of efficacy. This situation includes clearance applications for imaging modalities. In the United States, the vast majority of imaging devices are cleared for market via the 510(k) premarket notification process [7]. Historically, few PMAs have been required for imaging technologies. The first MR systems and digital mammography systems required PMAs because of their novel technologies. However, this situation may change as imaging manufacturers are able to accelerate functionality driven by advances in computing. As imaging techniques evolve and as diagnosis and treatment are combined, innovations will likely require the submission of randomized clinical trial evidence of safety and efficacy in a PMA document or new drug-device applications. One example of this transformation is high-intensity, focused ultrasound therapy of tumors using MRI guidance and tissue temperature monitoring. At times, the cost of regulation and the state of the science are such that no new technologies are brought to market. For example, there have been very few recent FDA approvals for new CT, MR, or ultrasound contrast agents. With the increase in regulatory oversight, certain 510(k) devices are now being required to provide advanced clinical trial data to support their clearance. This is the current situation for 510(k) submissions of computer-aided diagnosis tools for lung, breast, and colon cancer software. Although not yet specified, additional clinical data likely will be required for select 510(k) submissions required by FDA, but not at the same level as a PMA.
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As regulatory requirements shift from simple 510(k) filings to formal PMA studies, the randomized clinical trials that support the PMA will likely be integrated with trials designed to provide evidence to support early adoption and reimbursement. We characterize evidence generation for early adoption of 510(k) imaging products as the third phase in evidence development, with support for reimbursement typically occurring as the fourth phase. Although there has been discussion about combining the FDA regulatory and CMS reimbursement approval processes, at present they are largely separate [8]. Such combination brings a risk for “mission creep” (for lack of a better term) (Figure 1). For example, patient access to the benefits of innovation would be delayed significantly if the FDA’s criteria for market entry were expanded from “safety and efficacy” to “safety, efficacy, and comparative effectiveness” while CMS’s criteria for coverage were to be simultaneously expanded from “reasonable and necessary” to “reasonable, necessary, and cost effective.” PHASE 3: EARLY ADOPTION Once the FDA has cleared or approved a product for marketing, the device will likely become available for physicians to use. To the extent that the device is innovative, new clinical questions can be answered. For example, when spiral CT scanners became available, radiologists could look for appendicitis; as faster CT scanners and power injectors became available, chest CT could be used to look for pulmonary emboli; and more recently, as 64-slice CT became available, coronary arteries could be reliably imaged. Early research studies with new devices try to match the study to the clinical questions posed by ordering physicians. Furthermore, early research studies tend to focus on the mechanics of how to perform the imaging procedure, the major technical “dos and don’ts.” Studies performed early in the clinical adoption cycle
Fig 1. The risk of “mission creep” is that patient benefit from innovation will be delayed or lost if criteria for successive phases are brought too early in the “concept to adoption” process. CED ⫽ coverage with evidence development.
tend to be small, single-site studies, as researchers are still exploring and learning how to best use the technology. These early-stage studies define bounds primarily on the basis of technology performance, sensitivity, and specificity. These studies often pair the new technology with current modes of answering the same clinical question to provide a comparison. Early studies with cardiac CT angiography typically pared the cardiac CT angiographic study with some combination of single photon-emission CT or cardiac catheterization to compare their sensitivities and specificities. As technologies find their place in clinical practice, the underlying protocols may change as well resulting in better patient selection. For example, one can anticipate a shift from invasive coronary angiography to noninvasive cardiac CT angiography for patients with medium-risk chest pain, reducing the rate of negative angiographic results. Academic researchers or academically inclined experts often are the first to gain access to new technologies. The parameters associated with these early trials are typically controlled and represent “ideal” circumstances. Therefore, studies in this phase of evidence development provide measures of efficacy leaving the effectiveness of the technology in “real-world” settings to be determined later. Funding for these early exploratory studies is commonly provided from clinical radiology departments or from device manufacturers by grants or in-kind support, or formal collaborations with the development team. Publications by early adopters must satisfy the standards of peer-reviewed journals if they are to persuade the wider clinical community of the utility of this application and contribute to the body of evidence for consideration by payers. Billing under fee-for-service reimbursement in the United States requires a Current Procedural Terminology® (CPT®) code owned by the American Medical Association. These codes result from negotiations between various medical specialty societies with compelling guidance from CMS. If manufacturers have not already done so, they should be working with reimbursement experts to obtain one or more CPT codes that could serve as the basis for adequate reimbursement for end users. Once a code has been established, an equally important task is the establishment of coverage and payment. Coverage is dictated by both federal and private payers. Payers reference the concepts of “reasonable” and “necessary” as supported by clinical evidence when making coverage decisions. After initial studies, innovative practitioners in the relevant medical specialties use experiential knowledge to form their own conclusions regarding the value of the new technology. The extent to which early adopters coalesce around consensus that a technology is valuable
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determines the level of interest in further investment and development of evidence. PHASE 4: REIMBURSEMENT Historically, reimbursement for new health care technologies was directly tied to physician adoption. If the technology was “medically necessary,” as loosely defined under the original Medicare enabling statute, it would be covered [1]. From a manufacturer or investor perspective, this reimbursement policy meant that simple product utility to clinicians in clinical decision making was the prime determinant of business success or failure. Congressional concern with spending growth has led to policies that allow CMS to control spending for new technology. An initiative that CMS created to review technology usage and efficacy was the Medicare Evidence Development and Coverage Advisory Committee. In situations in which there is high utilization of technology, but limited published clinical data to support its use, CMS and the Medicare Evidence Development and Coverage Advisory Committee can perform technology assessments and evidence evaluations. Innovations that are identified as promising but lacking sufficient clinical evidence may enter into a program of coverage with evidence development, whereby promising procedures would be covered only if patients are enrolled in a clinical trial or registry to gather evidence, as PET/CT for cancer diagnosis and staging had been in the National Oncologic PET Registry [9,10]. As part of the recent “noncoverage” decision for CT colonography, CMS might have cited the large, multicenter ACRIN® study as a source of promising, yet inadequate, clinical evidence and taken a similar decision to establish coverage with evidence development [11,12]. However, they did not, and fuller analysis of this study, and publication in peer-reviewed journals, will provide additional insight to a number of issues specifically in the Medicare population, such as extracolonic findings. Also, CMS has the ability to make national coverage decisions, or enable local coverage decisions, on the basis of the evidence of its choosing [13,14]. The CMS is concerned with technologies that seem expensive and potentially overutilized [15]. Noninterventional imaging technologies have drawn particular attention, in part because they do not require the concurrent physician time commitment which limits other medical procedures to physician capacity constraints [16]. Innovative technologies that have the potential for broad adoption are the targets for study by health technology assessment experts and are the technologies for which CMS and private payers will require additional clinical research evidence to confirm that they are reasonable and necessary before agreeing to reimbursement. In
contrast, investors in technology are looking at these same technologies as appealing because they offer new diagnostic capabilities or are less labor intensive or less invasive. A consistent goal with high-impact technologies has been to require evidence of effectiveness, to demonstrate value in representative care settings.ⴱ For example, with the national coverage determination for CT coronary angiography in early 2008, even with multiple studies consistently showing specificities for evaluating coronary artery disease to be in the range of 97% to 99%, CMS felt that these studies were not adequate because of the risk for population bias in single-center studies and statistical uncertainty in small trials [17]. Decisions around the evidence requirements for reimbursement may also reflect underlying tension between competing interests. For example, Medicare Evidence Development and Coverage Advisory Committee public hearing testimony on evidence requirements to cover CT colonography for colon cancer screening reflected divergent economic interests of gastroenterologists and radiologists [18]. Innovative technologies may create economic tension with preexisting technologies as well as their respective stakeholders [19]. One can also imagine nonreimbursement for CT colonography adversely affecting the decision to invest in further refinements such as “prepless” CT colonography, in which software removes bowel contents. One method of recent interest for identifying appropriate patients for a given innovation is “comparative effectiveness research” (CER), formally defined as the conduct and synthesis of systematic research comparing different interventions and strategies to prevent, diagnose, treat, and monitor health conditions [20]. Comparative effectiveness research is mainly being used to answer reimbursement questions. Initial funding for CER was explicitly provided for in the 2009 American Recovery and Reinvestment Act with a continuing taxbased revenue stream legislated in the 2010 Patient Protection and Affordable Care Act. Although CER can use a variety of methodologies, such as simulation or modeling, the focus is on multicenter trials. Historically, these large, expensive trials have been paid for by federal grants or, as in the case of the pharmaceutical industry, by the manufacturers themselves. Pharmaceutical manufacturers are able to price their innovative products at high margins because these single molecular entities have strong patent protection. Most imaging advances are incremental and have minimal intellectual property protection. Imaging manufacⴱ
Diagnosis outcomes (change in treatment) are different than therapeutic outcomes (eg changes in survival). In some cases, the outcome of a diagnostic test is the decision not to treat, for example palliative care or watchful waiting. Risks of adverse events also differ significantly in likelihood, impact, and onset.
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turers have had limited ability to subsidize major clinical trials. With the addition of federal funding, more imaging studies may now be considered. A more fundamental challenge in conditioning reimbursement of modern technologies on large clinical trials is the mismatch between the roughly 3 to 4 years it takes to design, execute, analyze, and publish a multisite trial compared with “Moore’s law” of the doubling of computer power innovation every 18 months, which underlies modern imaging innovation [21]. Furthermore, the availability of the skilled researchers to manage large-scale clinical trials is fixed or only slowly growing. Computer science enabled innovation in the life sciences is exponential so matching the time needed to generate evidence with the time that a technology is still current will remain a challenge. With this mismatch between our ability to innovate and our ability to generate clinical trial evidence to support payment for that innovation, we will be forced to make broad policy choices regarding how much innovation we can tolerate. Market economies make allocation choices with price information, but in fundamentally nonmarket economies such as the US health care system, these choices are ultimately political choices. Imaging innovation is an international business with manufacturers globally spreading their costs. A predictable aspect of shifting insurance reimbursement away from innovation in the United States will be either an incremental shift of that innovation to other countries or out of the US insurance market. Such a shift in technology out of the domestic insurance market can be seen with private pay for laser vision treatments such as laser eye surgery or with medical tourism, in which procedures abroad may be available sooner and less expensively. Evidentiary requirements in the reimbursement phase of evidence development are difficult to predict and time. Investors or managers in medical technology companies could easily discount future returns by 10% per year so for delays in waiting 3 to 4 years for multisite, clinical trial results to arrive. The accompanying 30% to 40% reductions in return will correspondingly reduce the incentives to invest in new technology, even if it is believed the technology would eventually be reimbursed. If evidence trials result in approval of only 80% of submitted products, the combination of delay and disapproval would result in greater than a 50% reduction in expected net present value economic return. For context on potential approval rates, Government Accountability Office analysis showed that for 2003 to 2007, 78% of class III PMA submissions were approved [7]. As a complement to, or even in place of, large multicenter trials, community-based registry trials offer the possibility of gathering clinical practice-based (“effectiveness”) data on large numbers of patients. Coverage with evidence development uses registries to simultaneously
gather clinical evidence while providing reimbursement [22], thereby allowing patients access to the benefits of innovation while continuing to gather evidence confirming utility. Although registries can benefit from the intrinsically digital nature of modern images and the framework for storage, shipment, and retrieval represented by PACS, Digital Imaging and Communications in Medicine, and electronic health records, they may impose substantial time costs for capture of other clinical data, in particular on ordering physicians and their practices and, if poorly designed or analyzed, can result in biased data or conclusions [23]. PHASE 5: FULL ADOPTION Widespread adoption of the technology or device is the final hurdle for manufacturers of imaging equipment. Manufacturers and investors perform significant “due diligence” in coming to their prediction of the level of adoption of their products by clinicians. Historically, the evidence the manufacturers used was grounded in market research and expert opinion rather than clinical evidence. Even without any formal clinical trials, the discipline of the marketplace exerted very strong pressure on vendors to offer only those products that clinicians find effective in practice. Few technologies achieve full adoption by the majority of stakeholders. Recently introduced technologies are cannibalized or replaced as competitors introduce disruptive technologies [24]. Reaching full adoption may take several years of successful use by the clinical community and a demonstration of value for clinicians, patients, and payers. Today, full adoption will often require a range of evidence, including randomized clinical trials showing efficacy, broader “real-world” registries or databases showing clinical effectiveness, device safety studies, and measures of utility showing cost-effectiveness. With evolving criteria for success, it is important to distinguish between the various types of studies and end points such as comparative effectiveness or cost-effectiveness (see the Glossary) and to apply the results to the appropriate questions at the appropriate phase of development (Table 1). Following Haynes [25], as adoption increases, questions such as “Can it work?” “Does it work?” and “Is it worth it?” must be answered adequately for each stakeholder. Devices that markedly improve care for challenging illnesses with few diagnostic or treatment options are most likely to be adopted quickly. Less innovative products (cleared through the 510[k] process) may also enjoy early adoption and then widespread use, but these are subject to constant threats from other marginal improvements by competitors or new clinical workflows. It is important to understand that even without formal “health technology assessments” by academics, federal agencies, and payers or CER programs and funding,
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technology is constantly being reassessed in light of new options. Although it has been argued that new technologies often are simply added into care patterns without the elimination of old technologies, imaging offers many counterexamples [26]. Pneumoencephalography, oral cholecystography, gallium scans, and adult skull films are now only of historic interest, and studies such as barium enemas, intravenous pyelography, venography, and ventilation perfusion are plummeting in use, each simply because there was an obviously superior way to answer the clinical questions for which these studies had been used. In addition to strong clinical evidence and perceived patient outcome (social-cognitive theory), factors such as ease of technology use (technology acceptance model), prior training and experiences, impact on care pathway, colleague endorsement, and pricing of devices play roles in deciding if stakeholders will adopt a technology [27]. Rogers [28] described a well-known model of adoption, segmenting users into innovators, early adopters, early majority, late majority, and laggards. Balas and Boren [29] noted that it may take 17 years for clinical practice patterns to be adopted. The experience of imaging manufacturers is that the imaging marketplace readily adopts new generations of technology on the basis of their experience in selling a new generation of product every 2 to 3 years. CONCLUSIONS Many factors influence medical imaging technology adoption with various stakeholders, but the ultimate basis of acceptance and use is strong clinical evidence supporting the diagnostic value. Advances in computer science are driving rapid growth in the capabilities of imaging devices, increasing the adoption of these devices and thus the substitution of precision diagnosis for empiric clinical evaluation. The resulting growth in the proportion of health care dollars spent on imaging has occurred in the absence of market pricing mechanisms that would have, by definition, informed third-party payers of the value of that care [30]. The increased demand for non-market-based funding of diagnostic imaging is leading to a search for accountability in documenting the value of imaging. Politically, it is easier to limit technology spending before the widespread adoption of a new technology rather than once it is in broad use, and therefore patient access to the benefits of innovation in imaging is at great risk in the current payment climate [26]. The availability of further advances in imaging will likely be accompanied by formal requirements for extensive and expensive clinical trials run independently of the clinical consensus of practicing physicians on the value of the technology in daily use, with a risk of “mission creep” for regulatory clearance and coverage decisions
(Fig 1). The recent announcement of a memorandum of understanding between FDA and CMS [http:// www.fda.gov/AboutFDA/PartnershipsCollaborations/ MemorandaofUnderstandingMOUs/DomesticMOUs/ucm 217585.htm] for parallel review to meet “ѧcommon needs for evaluating the safety, efficacy, utilization, coverage, payment, and clinical benefit of drugs, biologics and medical devices,” creates an opportunity to streamline the process between these two steps, but also creates risk of mission creep with resultant delays in regulatory clearance, particularly as the FDA has asked the Institute of Medicine to recommend changes to the 510(k) process [http://iom.edu/ Activities/PublicHealth/510KProcess/2010-JUL-28.aspx]. A particular challenge will be that large randomized clinical trials take at least 3 to 4 years to perform and disseminate, while the underlying computer science doubles every 18 months and the corresponding advances in imaging technology provide new generations of technology every 2 to 3 years. The capacity of the research establishment to increase the numbers of formal trials needed to potentially evaluate the vast array of new life sciences– based innovations is also not clear, as staffing is a linear phenomenon, while the knowledge explosion is exponential. Hence, patient access to the benefits of innovation will be restricted. Balancing the opportunities for improved medical care with modern technology against the need to document value in current, third-party payer reimbursement systems remains a major health policy challenge. GLOSSARY Cost Benefit Analysis: Compares potential monetary costs with benefits of initiative. Cost-Effectiveness: Measures monetary costs relative to a measure of effectiveness (incremental cost per units of blood pressure or cholesterol reduced). Since costs and benefits are measured in noncomparable units, their ratio provides a yardstick with which to assess relative (productive) efficiency. Incremental cost-effectiveness ratio’s (ICER) allow CE comparison between technologies. Cost Utility: Is an adaptation of cost-effectiveness analysis that measures an intervention’s monetary cost per incremental change in patient preference using a utility-based measure such as quality adjusted life years (QALYs). Health Technology Assessment (HTA): A process that summarizes medical and economic information (efficacy, effectiveness, safety) related to the use of a health technology. This process is rooted in strong study design methodology. HTA’s are used to guide health policy decision makers.
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510(k) Pre-Market Notification: This is the submission process to the FDA to demonstrate that the medical device is at least as safe and effective, or substantially equivalent, to a predicate device, meaning a device that is legally marketed and is not subject to a PMA. There are close to 4,000 submissions annually. The 510(k) application would include a description of the device, clinical and preclinical/nonclinical performance data, device labeling and instructions for use, comparative products and/or standard methods documentation, and, if applicable, a description of any software or firmware used in the medical device. The phrase 510(k) refers to the underlying section of the Food, Drug, and Cosmetics Act statute.
10. Tunis SR, Pearson SD. Coverage options for promising technologies: Medicare’s “coverage with evidence development.” Health Aff (Millwood) 2006;25:1218-30.
Pre-Market Approval (PMA): This is the FDA review process to evaluate the safety and effectiveness of Class III medical devices (support or sustain life). A PMA is the most stringent type of device marketing application required by the FDA. Information contained in a PMA submission typically includes a device description and indications for use, manufacturing information, reference to any performance standard or voluntary standard, results of nonclinical laboratory studies, and results of human clinical studies.
15. McClellan MB, Tunis SR. Medicare coverage of ICDs. N Engl J Med 2005;352:222-4.
ACKNOWLEDGMENT We gratefully acknowledge work by Eric Z. Silfen, MD, chief medical officer of Philips Healthcare, in the strategic direction of this paper. REFERENCES 1. Tunis SR. Why Medicare has not established criteria for coverage decisions. N Engl J Med 2004;350:2196-8. 2. Blumenthal D. Part 1: quality of care—what is it? N Engl J Med 1996; 335:891-4. 3. Hillman BJ, Gatsonis CA. When is the right time to conduct a clinical trial of a diagnostic imaging technology? Radiology 2008;248:12-5. 4. Neumann PJ, Tunis SR. Medicare and medical technology—the growing demand for relevant outcomes. N Engl J Med 2010;362:377-9. 5. Dhruva SS, Phurrough SE, Salive ME, Redberg RF. CMS’s landmark decision on CT colonography— examining the relevant data. N Engl J Med 2009;360:2699-701. 6. Buch B. FDA medical device approval: things you didn’t learn in medical school or residency. Am J Orthop (Belle Mead NJ) 2007;36:407-12. 7. US Government Accountability Office. Medical devices—shortcomings in FDA’s premarket review, postmarket surveillance, and inspections of device manufacturing establishments (report GAO-09-370T). Washington, DC: US Government Accountability Office; 2009. 8. Wang SS, Smith JJ. Potential legal barriers to increasing CMS/FDA collaboration: the law of trade secrets and related considerations. Food Drug Law J 2003;58:613-27. 9. Lindsay MJ, Siegel BA, Tunis SR, et al. The National Oncologic PET Registry: expanded Medicare coverage for PET under coverage with evidence development. AJR Am J Roentgenol 2007;188:1109-13.
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16. US General Accountability Office. Medicare Part B imaging services— rapid spending growth and shift to physician offices indicate need for CMS to consider additional management practices (report GAO-08452). Washington, DC: US General Accountability Office; 2008. 17. Baldwin J. NCD for Computed Tomography (220.1), 2008. Available at: http://www.cms.gov/mcd/viewncd.asp?ncd_id⫽220.1&ncd_version⫽ 2&basket⫽ncd%3A220%2E1%3A2%3AComputed⫹Tomography. Accessed May 21, 2010. 18. Re: screening computed tomography colonography (CTC). In: Medicare Evidence Development and Coverage Advisory Committee Hearing November 19, 2008. Woodlawn, Md: Centers for Medicare and Medicaid Services; 2008. 19. Hillman BJ. The diffusion of new imaging technologies: a molecular imaging prospective. J Am Coll Radiol 2006;3:33-7. 20. Conway PH, Clancy C. Charting a path from comparative effectiveness funding to improved patient-centered health care. JAMA 2010;303: 985-6. 21. Moore GE. Cramming more components onto integrated circuits. Electronics 1965;38:114-7. 22. Berliner E. Registries for evaluating patient outcomes: a user’s guide. Rockville, Md: Agency for Healthcare Research and Quality; 2007. 23. Levine MN, Julian JA. Registries that show efficacy: good, but not good enough. J Clin Oncol 2008;26:5316-9. 24. Christenson CM. The innovator’s dilemma: when new technologies cause great firms to fail. Boston, Mass: Harvard Business School Press; 1997. 25. Haynes B. Can it work? Does it work? Is it worth it? The testing of health care interventions is evolving. BMJ 1999;319:652-3. 26. Garber AM. Can technology assessment control health spending? Health Aff (Millwood) 1994;13:115-26. 27. Kukafka R, Johnson SB, Linfante A, Allegrante JP. Grounding a new information technology implementation framework in behavioral science: a systematic analysis of the literature on IT use. J Biomed Inform 2003;36:218-27. 28. Rogers EM. Diffusion of innovations. Glencoe, Ill: Free Press; 1962. 29. Balas EA, Boren SA. Managing clinical knowledge for health care improvement. Yearbook of Medical Informatics 2000: Patient-Centered Systems 2000:65-70. 30. Hackbarth GM. March 17, 2009 report to the Congress: Medicare payment policy. Available at: http://www.medpac.gov/documents/Mar09_ March%20report%20testimony_WM%20FINAL.pdf. Accessed August 28, 2010.
Changes in the regulatory and reimbursement environment for advances in imaging in the United States are leading to increasing requirements for formal clinical evidence of efficacy, effectiveness, and safety. The authors describe 5 phases of an imaging product’s lifecycle: design, regulatory clearance and approval, early adoption, reimbursement, and full adoption. Each phase has distinct needs for clinical evidence. With increasing costs of clinical evidence generation, the question of ownership of the responsibility to gather clinical evidence at each successive phase becomes important. Mismatch between the pace of advances in imaging technologies and the time required to do formal clinical trials to clear regulatory and reimbursement evidence requirements threatens patient access to the benefits of innovation such as reduction in exposure to radiation. Public and payer requirements for clinical evidence must also be evaluated for their impact on incremental design improvements, which have historically characterized advances in diagnostic imaging. Key Words: Diagnostic imaging devices, clinical evidence, regulatory affairs, coverage and payment, adoption, comparative effectiveness, cost-effectiveness, public-private partnerships, innovation, infrastructure J Am Coll Radiol 2011;8:124-131. © 2011 Published by Elsevier Inc. on behalf of American College of Radiology
INTRODUCTION The first generations of plain film x-ray, CT, ultrasound, and MRI were so transformative that questions of efficacy and effectiveness were usually nonexistent. Today, with the rise in health care expenditures and advances in computer science fueling growth in technologies throughout the life sciences, innovations in imaging, especially major advances, are coming under increased public policy analysis. Manufacturers deciding to introduce new imaging technologies into the US market must plan for an increasing set of regulatory, reimbursement, and adoption hurdles. Specifically, federal regulators and payers (and their private counterparts) regularly invoke more highly defined requirements for evidence of efficacy and effectiveness, and safety and necessity. We characterize the types of clinical evidence corresponding to the 5 phases in a successful product lifecycle from clinical introduction to a
GE Healthcare, Princeton, New Jersey. Siemens Healthcare USA. c Philips Healthcare. Corresponding author and reprints: Richard A. Frank, MD, PhD, GE Healthcare, 101 Carnegie Center, Suite 124 South, Princeton, NJ 08540; e-mail: [email protected]. b
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full adoption and the appropriate means of generating and using such evidence. We describe (1) product design, (2) FDA clearance and approval, (3) early clinical adoption, (4) reimbursement, and (5) full clinical adoption. This sequence of evidence phases for new applications of novel features in medical devices is driven by the unique US regulatory and reimbursement environment. Although the development of imaging technology is global, the United States has been the largest and most influential adopter of advanced imaging. Therefore, increases in US evidentiary standards may have a global impact on innovation and access to imaging. In general, private markets, whether for health care or other goods, ensure economically valuable and efficient transactions through price signaling as consumers match their personal marginal utility to market prices while at the same time producers are matching their marginal costs to those same prices. In the US health care system, most coverage and payments are effectively set by CMS, heavily influencing private payers. Historically, CMS paid for services that were “medically necessary,” so the discussion of value was not part of this conversation, but new measures of utility or value are increasingly being demanded [1]. © 2011 Published by Elsevier Inc. on behalf of American College of Radiology 0091-2182/11/$36.00 ● DOI 10.1016/j.jacr.2010.06.025
Note: cGCP ⫽ current good clinical practice; EMR ⫽ electronic medical record; HTA ⫽ health technology assessment; PMA ⫽ premarket approval; PPP ⫽ public-private partnership; RCT ⫽ randomized controlled trial; SAP ⫽ SAP. ⴱSome features, such as workflow, may not require formal clinical evidence. †For cost-effectiveness.
PPPs Multi-innovator, co-ops, grantors, PPPs Multi-innovator, grantors Single innovator Sponsor
Single innovator
Standard of care in practice guidelines Coverage and payments Proof of principle in applications adjacent to labeled claims Design history file for dossier Evidentiary standards and consequences
Application and labeled claims
Diagnostic outcomes Reasonable and necessary Peer review, journal criteria Final product specifications Yield
Safety and efficacy
Registries (eg, EMR-based) Modeling† Large prospective studies in community settings, confirmatory RCTs Small prospective studies, exploratory, summary stats Retrospective or prospective multicenter controlled trial to cGCP with a priori SAP Open studies, single-center research collaborations, small-n, summary statistics Methods Logistics and resources
Full Adoption
Peer-reviewed publications to demonstrate appropriate utilization HTA of relevance to therapeutic decisions; to gain reimbursement
Reimbursement Early Adoption
Peer-reviewed publications of relevance to therapeutic decisions; to improve on the standard of care Dossier (510[k] or PMA) to regulators for approval to market
Registration Design
Performance feedback for engineers to refine the technical specifications of featuresⴱ
Unmet clinical imaging needs can be addressed by new devices or novel features in current devices. Whether as additions to existing products or as elements of a completely new product, these features are captured in a design history file with a view to describing the product for which marketing authorization is requested. Clinical evidence gathered during this phase is useful in refining the design, gaining commitment to further investment in
Goals Aims and benefits
PHASE 1: PRODUCT DESIGN AND INTRODUCTION
Phase
Assessment of clinical utility will differ according to the varying perspectives of payers, providers, employers, patients, and politicians. Utility from the vantage point of payers and providers may be driven by cost, each driven by a profit motive, while from the vantage point of employers, the time to return to work would also be considered. Conversely, patients may be less concerned with cost (if they are not paying) but more concerned about quality and quantity of life; for them, the relevant outcome of a diagnostic procedure is change in diagnosis or treatment. That is to say, diagnostics are different from therapeutics; as distinct from the outcome of a therapeutic intervention, a diagnostic outcome is a change in treatment plan. This is clear from the fact that a diagnostic test may result in changing plans for concerted therapeutic intervention to watchful waiting or palliative care. Politicians may be concerned with access across the entire population. These viewpoints can lead to divergent assessments. For example, if a category of expensive imaging procedures enabled a choice of therapy to prevent sudden death, a patient’s perspective might suggest that this is extremely valuable, whereas a payer’s perspective might suggest the opposite because the procedure may now generate an entirely new set of care expenditures in exchange for a relatively small overall improvement in survival. An employer or societal perspective might be influenced by whether the patients are of working age [2]. Changes in the current evidentiary standards are being driven by payers’ perspective, so we will focus on that reasoning. In this paper, we outline the sequential generation of clinical evidence for new imaging technologies. We do so from the point of view of a manufacturer deciding whether to make an investment in research and development of innovative features or applications in imaging. We outline 5 phases of evidence development for imaging applications and technologies (Table 1). Each of the 5 phases of evidentiary development leads to a decision point for investors in and manufacturers of imaging technologies as they weigh opportunity costs. The monetization of investment costs and returns stretches over many years, and therefore investment decisions will be discounted over time using net present value calculations.
Table 1. Clinical evidence strategy integrated across five phases of development of innovative imaging devices, from concept to adoption
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development of the product, and confirming the relationship between design feature and performance. The first phase of evidence development is achieved via small pilot studies, from which the data may not be robust enough for publication because of small sample sizes and limited scope. These clinical investigations are sponsored by innovator companies and usually are performed by clinical imaging experts at a single academic medical center with institutional review boards experienced in assessing the risks and benefits for such trials. The product features in these trials frequently represent serial incremental innovations, which may aggregate to significant gains in performance over time. The evolution of MR and CT hardware and software reflects the impact of such incremental innovation, for example, in the improved resolution gained from field homogeneity with 3-T magnets or the effect of improved detector technology in reducing exposure to radiation. Often technology assessment analysts fail to realize the incremental nature of changes in imaging technology and offer suggestions of global nonreimbursement at an early time in the technology lifecycle, effectively stopping the capital flows that allow significant and progressive improvements [3-5]. PHASE 2: REGULATORY CLEARANCE AND APPROVAL Once a company decides to move forward with market introduction (on the basis of business planning, clinical and bench data, etc), the regulatory strategy and evidence needs are mapped out. The FDA classifies medical devices into 3 groups: classes I, II, and III. Class I devices are considered low risk and primarily exempt from the 510(k) premarket notification clearance route. The 510(k) route (21CFR807.81) is the submission process to the FDA to demonstrate that the medical device is at least as safe and effective as, or substantially equivalent to, a preexisting (“predicate”) device. Traditionally, the 510(k) premarket notification process did not require clinical studies on the device as part of the submission, but this may be changing, as the FDA is currently reviewing 510(k) requirements. Class II devices, which are moderate-risk devices, routinely enter the market via the 510(k) route. The allowance of class II devices into the market on the basis of substantial equivalence to a predicate device is referred to as clearance. Class III devices, which have potential high risk to patient, normally enter the market through a complex premarket approval (PMA) [6]. The PMA submission (21CFR814.20) must demonstrate a device’s safety and efficacy by a thorough performance analysis of bench and clinical evidence data that demonstrates the ability to achieve the new intended use of the device.
Clinical data capture for a PMA is conducted through an investigational device exemption trial. Investigational device exemption studies are required to be conducted under good clinical practices. Investigational device exemption clinical trial requirements such as sample size vary depending on disease and device. High-profile or high-risk device trials may cost millions of dollars and take multiple years to complete. Investigational device exemption trials have targeted patient indications, including primary and secondary end points, a priori subanalysis definitions, and specifically defined follow-up periods. Investigational device exemption data are presented to the FDA for review as part of a panel meeting for product approval. There is an expectation that the data will also be published in the peer-reviewed literature. The allowance onto the market by the FDA of class III devices is referred to as approval. According to the US Government Accountability Office, more than 11,000 510(k) submissions and more than 200 original PMAs were reviewed by the FDA from 2003 to 2007 [7]. With this volume of approval requests, it is not surprising that more than 95% of medical devices are cleared for marketing by the FDA without the need to provide clinical evidence of efficacy. This situation includes clearance applications for imaging modalities. In the United States, the vast majority of imaging devices are cleared for market via the 510(k) premarket notification process [7]. Historically, few PMAs have been required for imaging technologies. The first MR systems and digital mammography systems required PMAs because of their novel technologies. However, this situation may change as imaging manufacturers are able to accelerate functionality driven by advances in computing. As imaging techniques evolve and as diagnosis and treatment are combined, innovations will likely require the submission of randomized clinical trial evidence of safety and efficacy in a PMA document or new drug-device applications. One example of this transformation is high-intensity, focused ultrasound therapy of tumors using MRI guidance and tissue temperature monitoring. At times, the cost of regulation and the state of the science are such that no new technologies are brought to market. For example, there have been very few recent FDA approvals for new CT, MR, or ultrasound contrast agents. With the increase in regulatory oversight, certain 510(k) devices are now being required to provide advanced clinical trial data to support their clearance. This is the current situation for 510(k) submissions of computer-aided diagnosis tools for lung, breast, and colon cancer software. Although not yet specified, additional clinical data likely will be required for select 510(k) submissions required by FDA, but not at the same level as a PMA.
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As regulatory requirements shift from simple 510(k) filings to formal PMA studies, the randomized clinical trials that support the PMA will likely be integrated with trials designed to provide evidence to support early adoption and reimbursement. We characterize evidence generation for early adoption of 510(k) imaging products as the third phase in evidence development, with support for reimbursement typically occurring as the fourth phase. Although there has been discussion about combining the FDA regulatory and CMS reimbursement approval processes, at present they are largely separate [8]. Such combination brings a risk for “mission creep” (for lack of a better term) (Figure 1). For example, patient access to the benefits of innovation would be delayed significantly if the FDA’s criteria for market entry were expanded from “safety and efficacy” to “safety, efficacy, and comparative effectiveness” while CMS’s criteria for coverage were to be simultaneously expanded from “reasonable and necessary” to “reasonable, necessary, and cost effective.” PHASE 3: EARLY ADOPTION Once the FDA has cleared or approved a product for marketing, the device will likely become available for physicians to use. To the extent that the device is innovative, new clinical questions can be answered. For example, when spiral CT scanners became available, radiologists could look for appendicitis; as faster CT scanners and power injectors became available, chest CT could be used to look for pulmonary emboli; and more recently, as 64-slice CT became available, coronary arteries could be reliably imaged. Early research studies with new devices try to match the study to the clinical questions posed by ordering physicians. Furthermore, early research studies tend to focus on the mechanics of how to perform the imaging procedure, the major technical “dos and don’ts.” Studies performed early in the clinical adoption cycle
Fig 1. The risk of “mission creep” is that patient benefit from innovation will be delayed or lost if criteria for successive phases are brought too early in the “concept to adoption” process. CED ⫽ coverage with evidence development.
tend to be small, single-site studies, as researchers are still exploring and learning how to best use the technology. These early-stage studies define bounds primarily on the basis of technology performance, sensitivity, and specificity. These studies often pair the new technology with current modes of answering the same clinical question to provide a comparison. Early studies with cardiac CT angiography typically pared the cardiac CT angiographic study with some combination of single photon-emission CT or cardiac catheterization to compare their sensitivities and specificities. As technologies find their place in clinical practice, the underlying protocols may change as well resulting in better patient selection. For example, one can anticipate a shift from invasive coronary angiography to noninvasive cardiac CT angiography for patients with medium-risk chest pain, reducing the rate of negative angiographic results. Academic researchers or academically inclined experts often are the first to gain access to new technologies. The parameters associated with these early trials are typically controlled and represent “ideal” circumstances. Therefore, studies in this phase of evidence development provide measures of efficacy leaving the effectiveness of the technology in “real-world” settings to be determined later. Funding for these early exploratory studies is commonly provided from clinical radiology departments or from device manufacturers by grants or in-kind support, or formal collaborations with the development team. Publications by early adopters must satisfy the standards of peer-reviewed journals if they are to persuade the wider clinical community of the utility of this application and contribute to the body of evidence for consideration by payers. Billing under fee-for-service reimbursement in the United States requires a Current Procedural Terminology® (CPT®) code owned by the American Medical Association. These codes result from negotiations between various medical specialty societies with compelling guidance from CMS. If manufacturers have not already done so, they should be working with reimbursement experts to obtain one or more CPT codes that could serve as the basis for adequate reimbursement for end users. Once a code has been established, an equally important task is the establishment of coverage and payment. Coverage is dictated by both federal and private payers. Payers reference the concepts of “reasonable” and “necessary” as supported by clinical evidence when making coverage decisions. After initial studies, innovative practitioners in the relevant medical specialties use experiential knowledge to form their own conclusions regarding the value of the new technology. The extent to which early adopters coalesce around consensus that a technology is valuable
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determines the level of interest in further investment and development of evidence. PHASE 4: REIMBURSEMENT Historically, reimbursement for new health care technologies was directly tied to physician adoption. If the technology was “medically necessary,” as loosely defined under the original Medicare enabling statute, it would be covered [1]. From a manufacturer or investor perspective, this reimbursement policy meant that simple product utility to clinicians in clinical decision making was the prime determinant of business success or failure. Congressional concern with spending growth has led to policies that allow CMS to control spending for new technology. An initiative that CMS created to review technology usage and efficacy was the Medicare Evidence Development and Coverage Advisory Committee. In situations in which there is high utilization of technology, but limited published clinical data to support its use, CMS and the Medicare Evidence Development and Coverage Advisory Committee can perform technology assessments and evidence evaluations. Innovations that are identified as promising but lacking sufficient clinical evidence may enter into a program of coverage with evidence development, whereby promising procedures would be covered only if patients are enrolled in a clinical trial or registry to gather evidence, as PET/CT for cancer diagnosis and staging had been in the National Oncologic PET Registry [9,10]. As part of the recent “noncoverage” decision for CT colonography, CMS might have cited the large, multicenter ACRIN® study as a source of promising, yet inadequate, clinical evidence and taken a similar decision to establish coverage with evidence development [11,12]. However, they did not, and fuller analysis of this study, and publication in peer-reviewed journals, will provide additional insight to a number of issues specifically in the Medicare population, such as extracolonic findings. Also, CMS has the ability to make national coverage decisions, or enable local coverage decisions, on the basis of the evidence of its choosing [13,14]. The CMS is concerned with technologies that seem expensive and potentially overutilized [15]. Noninterventional imaging technologies have drawn particular attention, in part because they do not require the concurrent physician time commitment which limits other medical procedures to physician capacity constraints [16]. Innovative technologies that have the potential for broad adoption are the targets for study by health technology assessment experts and are the technologies for which CMS and private payers will require additional clinical research evidence to confirm that they are reasonable and necessary before agreeing to reimbursement. In
contrast, investors in technology are looking at these same technologies as appealing because they offer new diagnostic capabilities or are less labor intensive or less invasive. A consistent goal with high-impact technologies has been to require evidence of effectiveness, to demonstrate value in representative care settings.ⴱ For example, with the national coverage determination for CT coronary angiography in early 2008, even with multiple studies consistently showing specificities for evaluating coronary artery disease to be in the range of 97% to 99%, CMS felt that these studies were not adequate because of the risk for population bias in single-center studies and statistical uncertainty in small trials [17]. Decisions around the evidence requirements for reimbursement may also reflect underlying tension between competing interests. For example, Medicare Evidence Development and Coverage Advisory Committee public hearing testimony on evidence requirements to cover CT colonography for colon cancer screening reflected divergent economic interests of gastroenterologists and radiologists [18]. Innovative technologies may create economic tension with preexisting technologies as well as their respective stakeholders [19]. One can also imagine nonreimbursement for CT colonography adversely affecting the decision to invest in further refinements such as “prepless” CT colonography, in which software removes bowel contents. One method of recent interest for identifying appropriate patients for a given innovation is “comparative effectiveness research” (CER), formally defined as the conduct and synthesis of systematic research comparing different interventions and strategies to prevent, diagnose, treat, and monitor health conditions [20]. Comparative effectiveness research is mainly being used to answer reimbursement questions. Initial funding for CER was explicitly provided for in the 2009 American Recovery and Reinvestment Act with a continuing taxbased revenue stream legislated in the 2010 Patient Protection and Affordable Care Act. Although CER can use a variety of methodologies, such as simulation or modeling, the focus is on multicenter trials. Historically, these large, expensive trials have been paid for by federal grants or, as in the case of the pharmaceutical industry, by the manufacturers themselves. Pharmaceutical manufacturers are able to price their innovative products at high margins because these single molecular entities have strong patent protection. Most imaging advances are incremental and have minimal intellectual property protection. Imaging manufacⴱ
Diagnosis outcomes (change in treatment) are different than therapeutic outcomes (eg changes in survival). In some cases, the outcome of a diagnostic test is the decision not to treat, for example palliative care or watchful waiting. Risks of adverse events also differ significantly in likelihood, impact, and onset.
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turers have had limited ability to subsidize major clinical trials. With the addition of federal funding, more imaging studies may now be considered. A more fundamental challenge in conditioning reimbursement of modern technologies on large clinical trials is the mismatch between the roughly 3 to 4 years it takes to design, execute, analyze, and publish a multisite trial compared with “Moore’s law” of the doubling of computer power innovation every 18 months, which underlies modern imaging innovation [21]. Furthermore, the availability of the skilled researchers to manage large-scale clinical trials is fixed or only slowly growing. Computer science enabled innovation in the life sciences is exponential so matching the time needed to generate evidence with the time that a technology is still current will remain a challenge. With this mismatch between our ability to innovate and our ability to generate clinical trial evidence to support payment for that innovation, we will be forced to make broad policy choices regarding how much innovation we can tolerate. Market economies make allocation choices with price information, but in fundamentally nonmarket economies such as the US health care system, these choices are ultimately political choices. Imaging innovation is an international business with manufacturers globally spreading their costs. A predictable aspect of shifting insurance reimbursement away from innovation in the United States will be either an incremental shift of that innovation to other countries or out of the US insurance market. Such a shift in technology out of the domestic insurance market can be seen with private pay for laser vision treatments such as laser eye surgery or with medical tourism, in which procedures abroad may be available sooner and less expensively. Evidentiary requirements in the reimbursement phase of evidence development are difficult to predict and time. Investors or managers in medical technology companies could easily discount future returns by 10% per year so for delays in waiting 3 to 4 years for multisite, clinical trial results to arrive. The accompanying 30% to 40% reductions in return will correspondingly reduce the incentives to invest in new technology, even if it is believed the technology would eventually be reimbursed. If evidence trials result in approval of only 80% of submitted products, the combination of delay and disapproval would result in greater than a 50% reduction in expected net present value economic return. For context on potential approval rates, Government Accountability Office analysis showed that for 2003 to 2007, 78% of class III PMA submissions were approved [7]. As a complement to, or even in place of, large multicenter trials, community-based registry trials offer the possibility of gathering clinical practice-based (“effectiveness”) data on large numbers of patients. Coverage with evidence development uses registries to simultaneously
gather clinical evidence while providing reimbursement [22], thereby allowing patients access to the benefits of innovation while continuing to gather evidence confirming utility. Although registries can benefit from the intrinsically digital nature of modern images and the framework for storage, shipment, and retrieval represented by PACS, Digital Imaging and Communications in Medicine, and electronic health records, they may impose substantial time costs for capture of other clinical data, in particular on ordering physicians and their practices and, if poorly designed or analyzed, can result in biased data or conclusions [23]. PHASE 5: FULL ADOPTION Widespread adoption of the technology or device is the final hurdle for manufacturers of imaging equipment. Manufacturers and investors perform significant “due diligence” in coming to their prediction of the level of adoption of their products by clinicians. Historically, the evidence the manufacturers used was grounded in market research and expert opinion rather than clinical evidence. Even without any formal clinical trials, the discipline of the marketplace exerted very strong pressure on vendors to offer only those products that clinicians find effective in practice. Few technologies achieve full adoption by the majority of stakeholders. Recently introduced technologies are cannibalized or replaced as competitors introduce disruptive technologies [24]. Reaching full adoption may take several years of successful use by the clinical community and a demonstration of value for clinicians, patients, and payers. Today, full adoption will often require a range of evidence, including randomized clinical trials showing efficacy, broader “real-world” registries or databases showing clinical effectiveness, device safety studies, and measures of utility showing cost-effectiveness. With evolving criteria for success, it is important to distinguish between the various types of studies and end points such as comparative effectiveness or cost-effectiveness (see the Glossary) and to apply the results to the appropriate questions at the appropriate phase of development (Table 1). Following Haynes [25], as adoption increases, questions such as “Can it work?” “Does it work?” and “Is it worth it?” must be answered adequately for each stakeholder. Devices that markedly improve care for challenging illnesses with few diagnostic or treatment options are most likely to be adopted quickly. Less innovative products (cleared through the 510[k] process) may also enjoy early adoption and then widespread use, but these are subject to constant threats from other marginal improvements by competitors or new clinical workflows. It is important to understand that even without formal “health technology assessments” by academics, federal agencies, and payers or CER programs and funding,
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technology is constantly being reassessed in light of new options. Although it has been argued that new technologies often are simply added into care patterns without the elimination of old technologies, imaging offers many counterexamples [26]. Pneumoencephalography, oral cholecystography, gallium scans, and adult skull films are now only of historic interest, and studies such as barium enemas, intravenous pyelography, venography, and ventilation perfusion are plummeting in use, each simply because there was an obviously superior way to answer the clinical questions for which these studies had been used. In addition to strong clinical evidence and perceived patient outcome (social-cognitive theory), factors such as ease of technology use (technology acceptance model), prior training and experiences, impact on care pathway, colleague endorsement, and pricing of devices play roles in deciding if stakeholders will adopt a technology [27]. Rogers [28] described a well-known model of adoption, segmenting users into innovators, early adopters, early majority, late majority, and laggards. Balas and Boren [29] noted that it may take 17 years for clinical practice patterns to be adopted. The experience of imaging manufacturers is that the imaging marketplace readily adopts new generations of technology on the basis of their experience in selling a new generation of product every 2 to 3 years. CONCLUSIONS Many factors influence medical imaging technology adoption with various stakeholders, but the ultimate basis of acceptance and use is strong clinical evidence supporting the diagnostic value. Advances in computer science are driving rapid growth in the capabilities of imaging devices, increasing the adoption of these devices and thus the substitution of precision diagnosis for empiric clinical evaluation. The resulting growth in the proportion of health care dollars spent on imaging has occurred in the absence of market pricing mechanisms that would have, by definition, informed third-party payers of the value of that care [30]. The increased demand for non-market-based funding of diagnostic imaging is leading to a search for accountability in documenting the value of imaging. Politically, it is easier to limit technology spending before the widespread adoption of a new technology rather than once it is in broad use, and therefore patient access to the benefits of innovation in imaging is at great risk in the current payment climate [26]. The availability of further advances in imaging will likely be accompanied by formal requirements for extensive and expensive clinical trials run independently of the clinical consensus of practicing physicians on the value of the technology in daily use, with a risk of “mission creep” for regulatory clearance and coverage decisions
(Fig 1). The recent announcement of a memorandum of understanding between FDA and CMS [http:// www.fda.gov/AboutFDA/PartnershipsCollaborations/ MemorandaofUnderstandingMOUs/DomesticMOUs/ucm 217585.htm] for parallel review to meet “ѧcommon needs for evaluating the safety, efficacy, utilization, coverage, payment, and clinical benefit of drugs, biologics and medical devices,” creates an opportunity to streamline the process between these two steps, but also creates risk of mission creep with resultant delays in regulatory clearance, particularly as the FDA has asked the Institute of Medicine to recommend changes to the 510(k) process [http://iom.edu/ Activities/PublicHealth/510KProcess/2010-JUL-28.aspx]. A particular challenge will be that large randomized clinical trials take at least 3 to 4 years to perform and disseminate, while the underlying computer science doubles every 18 months and the corresponding advances in imaging technology provide new generations of technology every 2 to 3 years. The capacity of the research establishment to increase the numbers of formal trials needed to potentially evaluate the vast array of new life sciences– based innovations is also not clear, as staffing is a linear phenomenon, while the knowledge explosion is exponential. Hence, patient access to the benefits of innovation will be restricted. Balancing the opportunities for improved medical care with modern technology against the need to document value in current, third-party payer reimbursement systems remains a major health policy challenge. GLOSSARY Cost Benefit Analysis: Compares potential monetary costs with benefits of initiative. Cost-Effectiveness: Measures monetary costs relative to a measure of effectiveness (incremental cost per units of blood pressure or cholesterol reduced). Since costs and benefits are measured in noncomparable units, their ratio provides a yardstick with which to assess relative (productive) efficiency. Incremental cost-effectiveness ratio’s (ICER) allow CE comparison between technologies. Cost Utility: Is an adaptation of cost-effectiveness analysis that measures an intervention’s monetary cost per incremental change in patient preference using a utility-based measure such as quality adjusted life years (QALYs). Health Technology Assessment (HTA): A process that summarizes medical and economic information (efficacy, effectiveness, safety) related to the use of a health technology. This process is rooted in strong study design methodology. HTA’s are used to guide health policy decision makers.
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510(k) Pre-Market Notification: This is the submission process to the FDA to demonstrate that the medical device is at least as safe and effective, or substantially equivalent, to a predicate device, meaning a device that is legally marketed and is not subject to a PMA. There are close to 4,000 submissions annually. The 510(k) application would include a description of the device, clinical and preclinical/nonclinical performance data, device labeling and instructions for use, comparative products and/or standard methods documentation, and, if applicable, a description of any software or firmware used in the medical device. The phrase 510(k) refers to the underlying section of the Food, Drug, and Cosmetics Act statute.
10. Tunis SR, Pearson SD. Coverage options for promising technologies: Medicare’s “coverage with evidence development.” Health Aff (Millwood) 2006;25:1218-30.
Pre-Market Approval (PMA): This is the FDA review process to evaluate the safety and effectiveness of Class III medical devices (support or sustain life). A PMA is the most stringent type of device marketing application required by the FDA. Information contained in a PMA submission typically includes a device description and indications for use, manufacturing information, reference to any performance standard or voluntary standard, results of nonclinical laboratory studies, and results of human clinical studies.
15. McClellan MB, Tunis SR. Medicare coverage of ICDs. N Engl J Med 2005;352:222-4.
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