5
The Challenges Ahead

In this session, speakers examined the challenges that lie ahead for medical device innovation, such as identifying areas of clinical medicine in which there are significant unmet needs. Speakers discussed emerging discoveries and technologies that could serve as the basis for developing new medical devices, addressing clinical needs, improving costs, or bettering outcomes of currently available devices.

UNMET CLINICAL NEEDS: CARDIOVASCULAR DISEASE

James E.Muller, M.D.

Center for Integration of Medicine and Innovative Technology

Cardiovascular disease is the largest single cause of medical morbidity and mortality in the United States. It is responsible for over 1.5 million myocardial infarctions annually and over 200,000 sudden cardiac deaths. In addition, the problem of congestive heart failure is one of the leading causes of expenditures for hospitalization.

With progress that has been made in the basic sciences and engineering, it is quite feasible to envision improved devices that are not only more effective but also improve the cost-effectiveness of cardiovascular care. There are many opportunities to extend the use of devices and to improve devices for cardiovascular purposes.

As currently practiced, cardiovascular surgery generally involves thoracotomy, which causes significant morbidity for patients and prolonged hospital



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Innovation and Invention in Medical Devices: Workshop Summary 5 The Challenges Ahead In this session, speakers examined the challenges that lie ahead for medical device innovation, such as identifying areas of clinical medicine in which there are significant unmet needs. Speakers discussed emerging discoveries and technologies that could serve as the basis for developing new medical devices, addressing clinical needs, improving costs, or bettering outcomes of currently available devices. UNMET CLINICAL NEEDS: CARDIOVASCULAR DISEASE James E.Muller, M.D. Center for Integration of Medicine and Innovative Technology Cardiovascular disease is the largest single cause of medical morbidity and mortality in the United States. It is responsible for over 1.5 million myocardial infarctions annually and over 200,000 sudden cardiac deaths. In addition, the problem of congestive heart failure is one of the leading causes of expenditures for hospitalization. With progress that has been made in the basic sciences and engineering, it is quite feasible to envision improved devices that are not only more effective but also improve the cost-effectiveness of cardiovascular care. There are many opportunities to extend the use of devices and to improve devices for cardiovascular purposes. As currently practiced, cardiovascular surgery generally involves thoracotomy, which causes significant morbidity for patients and prolonged hospital

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Innovation and Invention in Medical Devices: Workshop Summary stays. There is an unmet need for methods to perform coronary artery bypass grafting without the need for a full thoracotomy. There are numerous “minimally invasive” approaches that have been taken to bypass surgery and the area is one of rapid experimentation and development. One method that may be useful is that of robotic-assisted, coronary artery bypass grafting. With advanced technology and computer systems it is now possible for a surgeon to manipulate sensors and effectors that permit the anastomosis of an internal mammary artery to the left anterior descending coronary artery without the need for a thoracotomy. Research on such a technique is underway at several institutions and robotic-assisted, coronary artery bypass grafting has been performed in living patients in Europe. This is an area in which further device development is expected and needed. A method has also been proposed to perform coronary artery bypass grafting of total coronary occlusions with the use of the neighboring coronary vein. This method has been developed by Dr. Stephen Oesterle, formerly of Stanford University, and has been entitled percutaneous in situ coronary artery bypass grafting (PICAB). The PICAB method utilizes an approach through the femoral vein, involving puncture of the coronary vein adjacent to the left anterior descending coronary artery. Both distal and proximal punctures are made around a 100% stenosis. Connections are then made to the coronary vein, and the vein is blocked both distal and proximal to the conduit portion. This method could make it possible to perform bypass without the need for thoracotomy. In addition to the methods mentioned above to treat stenosis, there is an urgent need to identify and treat plaques that are not stenotic but that are vulnerable to rupture. Such plaques are the most frequent cause of myocardial infarction and sudden cardiac death. There are multiple technologies capable of characterizing tissue that could be utilized for these purposes. Optical coherence tomography (OCT) has been successfully utilized to obtain very high-resolution images of coronary tissue in living patients. It is also possible to utilize near infrared spectroscopy, both diffuse reflectance and Raman forms, to identify the chemical composition of tissue. Other techniques proposed to identify vulnerable plaque include increased temperature detection, and, in non-invasive tests, ultra fast CT, and magnetic resonance imaging. From this broad range of technology and potential devices, it is highly likely that plaques vulnerable to rupture can be identified before they rupture. This could permit randomized trials of numerous types of plaques stabilization therapy that could be developed. An additional area in which device development is needed is that of electrophysiology. New forms of energy delivery including radio frequency, thermal, and photonic-based energy sources are under development for the ablation of tracts that cause arrhythmia. In summary, the cardiovascular area is one of major importance because of the severity and prevalence of cardiovascular disease. The diseases that are causing the major morbidity and mortality for the country in the cardiovascular area are amenable to therapy with a broad range of devices that can definitely be improved, given the current level of development of technology.

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Innovation and Invention in Medical Devices: Workshop Summary UNMET CLINICAL NEEDS: CLINICAL TRIALS Robert Califf, M.D. Associate Vice Chancellor for Clinical Research Duke University The most important unmet need right now is clinical information systems that will provide information about whether devices are effective and cost-saving. Researchers need rational information that can help them make informed judgments that are ultimately for the best of all involved. Gathering evidence is a challenge. For example, treatment effects are almost always modest. In addition, studies have to be done in the sickest patients to get measurable treatment effects, which raises procedural and ethical issues. Unintended effects are very common, especially when products are combined in a single patient. This is a special problem for devices because the other interaction is between the device itself and the human being who is using the device. This has major implications for the way clinical trials are conducted, especially since it can be difficult to sort out adverse events that are due to the device rather than the underlying condition or interactions with other drugs or devices. While it is easy to be critical of the inventor/investigator and the tinkering that goes on, it is also fair to say that right now researchers are pretty much in their infancy in terms of really understanding how to construct accurate assessment of risk and benefit, even when the raw data are high quality. Without good data, it is almost impossible to construct reasonable evidence-based perspectives on how patients should be treated. Unless researchers develop better methods of keeping practitioners educated and informed and building systems to help them practice, the best inventions in the world are not going to have much of an impact on the public health. This is evidenced in part by the continued—almost unbelievable—variation in the way that medical devices are used. Researchers have no hope of really detecting the kind of important differences that are needed unless they really study them with adequate methodology, and with adequate sample sizes. Five issues face clinical trials of medical devices: informed consent versus tinkering, incentive versus protection from conflict of interest, global markets and standards versus global regulatory standstills, access to medical products versus avoidance of risk, and evolutionary innovation versus regulation. If researchers had ways of collecting the data so they did not spend all the venture capital raised trying to do the clinical trials, one could spend more of it on working on the inventions. The medical profession is going to be forced to develop common clinical data systems that use common nomenclatures so that researchers can ensure the public that they are maintaining privacy and that they know what they are talking about when they prescribe therapies over the long term. Imagine a system where there really were Web-based point-of-care clinical information systems, where doctors use the same names for the same things, with personal patient records that were transportable, where the data could be harvested and aggregated in think tanks. If one had a new device and wanted to

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Innovation and Invention in Medical Devices: Workshop Summary try it out or test it one would not have to spend a fortune building a clinical data system and paying clinical research organizations and academic centers to deal with all these regulations and collect all these data. BARRIERS AND ISSUES IN DEVICE INNOVATION: REIMBURSEMENT Pamela Bailey President, Health Industry Manufacturers Association1 The role of the Health Industry Manufacturers Association (HIMA) is to be an advocate for innovation and to help its member companies move through the regulatory and public policy processes. Because regulation is the result of legislation to affect change either in the regulatory process or within public policy, researchers all need to be players in the broader policy and political debates. For example, FDA is given a budget by Congress, and researchers want to make sure it is adequate for FDA to fulfill its mission. Other issues of prime importance are access to global markets and adequate coverage, globally and in the United States, and adequate payment. Reimbursement and coverage, whether it is at the managed care site or whether it is by Medicare, is like a dark, winding, country road through the woods with no road signs. Over 140,000 pages of regulations embody Medicare. The combination of regulation and payment barriers creates uncertainty, which is a barrier to innovation. In terms of its process for handling the medical devices industry in processing and accelerating technology, Medicare does not innovate. This means that many technologies take years after they are cleared by FDA to be available to the patient and the impact on the patient and on patient care is clear. Delays in assignments of payment codes to FDA-approved products is a tremendous barrier raised by HCFA.2 Even when codes are assigned after long delays, the amount of reimbursement considered acceptable by HCFA can be disastrously low for the innovator. HCFA has begun some reform of the coverage process, but there is only so much they can do. Legislation has to be passed to really fix the process. A crucial problem is that no one has a clear sense of data requirements for proving whether a device is cost-effective or how to adequately demonstrate outcomes or clinical effectiveness for the purposes of payment. Recent legislation considerably reforms the inherent reasonableness authority and the way new technologies, and particularly more expensive innovative technologies, are reimbursed in the outpatient setting. This is a significant achievement because it was a collaborative effort among industry, Congress, and HCFA. Researchers are hopeful that they can use some of that methodology to begin to work on the inpatient setting, particularly in terms of making it easier 1   Now Advanced Medical Technology Association (AdvaMed). 2   Now Centers for Medicare and Medicaid Services (CMS).

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Innovation and Invention in Medical Devices: Workshop Summary for newer technology to be covered and to be adequately paid for so that there are incentives to develop new technology. GENERAL DISCUSSION OF THE CHALLENGES AHEAD David Feigal of FDA opened the discussion by commenting on the synchronization of FDA and HCFA mentioned by Pamela Bailey. He described some recent discussions between FDA and HCFA about imaging innovation for cancer detection and evaluation of extent of cancer, which he characterized as one of the few public forums where FDA and HCFA and companies and NIH have actually all been at the table at the same time. One of the topics that comes up at such meetings is why FDA approval is not good enough for reimbursement. There is apparently a perception that, even in the approval of drugs where clinical trials are much more uniformly required, the evidence that FDA gets does not always address a clinical benefit. HCFA’s mandate, said Feigal, is to look for the value added for their recipients. They are shepherding their recipients’ dollars, which come from their taxes and our taxes. For example, they sometimes will be evaluating a new product comparatively, whereas FDA regulations never require that one establishes one’s comparative efficacy. In fact, FDA usually prefers placebo controls, where that is still ethical. More to the point for the device industry, said Feigal, are products that come in under 510(k) (premarket notifications of intent to market a product that is substantially equivalent to one already legally marketed) without any clinical data, are judged substantially equivalent, and are approved based on performance standards. FDA does not think that those products do not have clinical benefit; they are just linking them to things that have already demonstrated a benefit. But if HCFA then asks the manufacturer of the new medical device to show clinical trial data, all the manufacturer can say is that these performance standards were met and this is how the product is linked to other products. Similarly, even within the same product class over time, FDA is allowed to decrease requirements and down-classify products, but then HCFA may look at them and demand data on clinical benefits. A second point raised by Dr. Feigal concerned the notion that the path to the market is a linear one with everything done in a specific order. Difficult as it is to contemplate deciding on reimbursement at the same time as deciding a code, Feigal claimed that FDA is willing to start the discussions about how to do that. One of the quirks of fate is that the Center for Devices has been given the responsibility to be the liaison to HCFA for all of FDA, and they are eager to work on these problems with HCFA and industry. Pamela Bailey agreed that HCFA could learn much from FDA, but also pointed out that one of the options for reforming Medicare is to establish it almost totally in a private plan choice option, which would put the technology

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Innovation and Invention in Medical Devices: Workshop Summary assessment much more in the context of what is done with private managed care or insurance plans today. There would still be a traditional HCFA, but it would be a much smaller component when it comes to assessing technology. She challenged the clinicians in the audience, or even some of the companies, to comment on how they find the route to market when it goes through a private managed care plan rather than through Medicare. She believes that companies will be the first to say that they have not all figured it out yet either, but in many ways the care plans are much easier to deal with because they are smaller and they have a different set of incentives than HCFA. Nevertheless, she concluded, more and more industry is coming to recognize that when they talk about innovation, it is not just FDA, but the payment folks have to be brought in as well. Robert Califf of Duke University brought up the perception of care providers that anything can be listed and added at a price, but when they add up the cost of providing care relative to what researchers get paid, and Medicare is actually pretty generous compared to most managed care now, available or not, they just cannot afford to do it. Ms. Bailey echoed Dr. Califf s concern, noting that that is just why HCFA has to deal with the cost of technology. Percy Bridger from HCFA pointed out that the 1989 proposed regulations for coverage criteria are just not going to be applicable to today’s world, and a lot of that has to do with the discussions surrounding costs. In fact, he said, HCFA works under a system that was developed and enacted in 1965, a system that does not really work so well in the year 2000. Jeff Lerner from ECRI explained that he often does HCFA technology assessments for the private sector, and gets into a dilemma. Industry often asks him why he does not tell them what the standards are for evaluation, but they also tell him to be careful not to retard innovation. Lerner’s response has generally been that it is not easy to do both. One cannot necessarily say how a device will be evaluated, because if each technology is to be treated on its own merits, it must be evaluated in a unique way. If all technologies are treated exactly the same way, innovation winds up getting cut off. It is impossible to have it both ways. In a routinized process somebody always loses. If the evaluation process is individualized, then it is impossible to specify the evaluation standards in advance. Dr. Califf complimented the FDA for having standards, but always saying that if one sees that a product is going to be different, come in and talk about it and a different plan will be accepted. He pointed out, however, that all the agencies around the world do not always agree on criteria for negotiation. It seems to work pretty well for companies that go in ahead of time and make the case. So, in a way researchers do have it both ways, but that requires thought about the nature of the assessment. Nevertheless, he concluded, maybe some of the things FDA has done, if adopted by HCFA, would speed things up quite a bit and still be fair. Dr. Lerner brought up the idea of journals exclusively for industry-supported research, where it is clear that the work is from industry and everyone

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Innovation and Invention in Medical Devices: Workshop Summary can agree on certain checks on the research. Right now there is a system of journals in which, he said, one is supposed to hide the fact that research might be supported by industry. Dr. Califf responded that research should not be characterized as either industry or academic, although affiliations do need to be acknowledged, and biases and conflicts made public. He conceded that there probably is a way to go with this idea, particularly with some topics. Cost-effectiveness analysis is the most controversial, but in his own field of cardiovascular disease, he estimated that the vast majority of good research is industry-funded, and oftentimes that work is more creative, easier, and more effective because of the absence of all those committees that want to change everything the investigator is trying to accomplish. Mr. Lerner amplified on his earlier thought by pointing out that one can have both, but there should not be a system where one has to pretend that is not going on because that leads to subterfuges. As evidence he cited the Krimsky studies out of Tufts, which, he said, looked at 62,000 articles for conflict-of-interest disclosures and found that only 0.5 percent of them contained any statement of author personal financial interests. Dr. Califf agreed that there is a problem. His analysis was that two trends are contributing. One is industry authors who do not acknowledge that fact out of concern that it would lead to a lower evaluation. The other is the professional writing company, where the authors listed actually do not even know what is in the paper. Robert Anderson of Duke suggested that the manufacturers and HIMA have to take a look at these practices as well as academia, and that perhaps they ought to have an institutional review board. He recalled his experience on a surgery and biomedical engineering study section, where they would get hundreds of grants, 50 percent of which could be thrown out almost immediately as absolute garbage. He suggested that one of the reasons the FDA and HCFA may be so swamped is that they try and treat everything equally; they do not have the right to triage and cull out the obviously poor proposals. Perhaps, he continued, HIMA or some independent group could have an IRB to look at proposals destined for FDA and decide whether they are worth someone at FDA spending time on. Peter Bouxsein of HCFA declined to speak for HCFA, but reminded the group that HCFA and FDA are asked very different questions. FDA is asked whether it is reasonable to put this product into commerce. Will the public be protected at a certain level of safety, and will the product do what it is designed to do so that people can make a decision whether to use it? FDA carries out that mission in a very appropriate way. HCFA is asked a completely different question. The product has already been approved by FDA as safe and effective enough for public commerce. HCFA takes the role of purchaser and copes with the question of whether it is sensible to buy this product. HCFA is representing beneficiaries, including the economic interest of beneficiaries, and the economic interest of the American public and the taxpayers.

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Innovation and Invention in Medical Devices: Workshop Summary Bouxsein closed the session with an anecdote about Uwe Reinhardt that illustrates this difference in the roles of FDA and HCFA. Reinhardt once told an audience like this one that they may not realize it but there are two ways of doing a tonsillectomy, both equally effective. They achieve the same result, the same outcomes, the same risk, but one is far more elegant than the other and costs 20 times as much. Reinhardt asked, “What should HCFA do? Should they just go ahead and pay for both of them or should they make a decision to pay for the cheaper one and not for the more expensive one?” Then he stopped. The audience, of course, was on the edge of their seats saying, well, what is the second procedure. Finally they could not take anymore and called out for Uwe to please tell them what is the second procedure. “Oh”, he said, “I thought you knew. It is transurethral.”