Rare Diseases and Orphan Products Accelerating Research and Development (2010) / Chapter Skim
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7 Medical Devices: Research and Development for Rare Diseases
7 Medical Devices: Research and Development for Rare Diseases
Pages 205-240
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From page 205... ...
To acknowledge the emphasis on drugs for rare diseases is not to imply that devices are not important for many people with rare medical conditions. Some people depend critically on devices targeted at distinctive features of their condition, for example, children who have received the implanted titanium rib described above.
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From page 206... ...
Although medical devices for small populations are grouped under the label orphan products in the grants program created by the Orphan Drug Act and are within the charge of the Office of Orphan Product Development (OOPD) , the term orphan medical device does not appear in legislative or regulatory language.
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. Entrepreneurs at small start-up companies develop many innovative medical devices, including devices that address needs of small patient populations.
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. Because medical device companies are often engaged in a continuous process of product refinement and innovation, patents and similar protections may be less important as a source of competitive advantage for device companies than they are for drug companies.
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. REGULATION OF MEDICAL DEVICES Basic Framework of Medical Device Regulation Although the Federal Food, Drug, and Cosmetic Act of 1938 mentioned therapeutic medical devices, devices were a relatively inconsequential component of FDA's jurisdiction.
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The Center for Biologics Evaluation and Research regulates devices related to blood and cellular products such as blood collection, screening, and processing devices. The OOPD has roles in designation of devices eligible for HDE approval and in awarding product development grants, which are available for device as well as drug development.
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. For Class III devices, which account for a small proportion of all legally marketed medical devices, manufacturers must submit premarket approval (PMA)
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In vitro diagnostic devices include genetic and other tests that are important in diagnosing many rare diseases.7 6 These are the Fujirebio Mesomark Assay (H060004, approved in 2007) , the Heartsbreath test (H030004, approved in 2004)
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. In the past several years, various groups have recommended that FDA should regulate either all genetic tests or all laboratory-developed tests under the medical device authorities (Mansfield and Tezak, 2010)
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. Combination Products Some medical products combine a medical device and a drug or biologic.
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Particularly if FDA requires extensive clinical data for approval of the device, companies may be discouraged from pursuing devices for small markets by the expense and practical challenges of conducting acceptable trials to demonstrate safety and effectiveness. The Safe Medical Devices Act of 1990 authorized the Humanitarian Device Exemption to encourage the development and introduction of complex device technologies to meet the needs of small patient populations.
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In contrast to the orphan drug policy, the HDE policy has no provisions for market exclusivity. This difference reflects the process of ongoing device refinement described earlier and the less significant role of patent or patent-like protection in the medical device industry.
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In general, the costs of clinical trials that are usually needed to support a PMA make small markets unattractive or infeasible, particularly for start-ups and small device companies. Another HDE incentive (and one that parallels that for orphan drugs)
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Like developers of orphan drugs, developers of devices are also eligible for orphan products grants. Seven devices for which grants were awarded have subsequently been approved, five through the HDE process and two through the PMA process (Linda C
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As noted above, the different incentives for orphan drugs and HDE devices could potentially create difficulties for an innovative combination product in some situations. If the testing of safety and effectiveness for an innovative drug required simultaneous use of the innovative device, that clinical testing should provide evidence to support both approval of the drug and clearance or approval of the device.
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From page 220... ...
Incentives for the Development of Pediatric Medical Devices Because children are generally a healthy population, companies often do not find it commercially feasible or attractive to develop devices specific to pediatric diseases or to develop smaller versions of adult devices for relatively small numbers of children who might benefit from them.14 For devices with indications for pediatric use, Congress acted in 2007 to modify 13 For example, in 2006, FDA contacted the manufacturer of a device that had received HDE approval in 2000 for use in closure of a patent foramen ovale (PFO) in patients with recurrent stroke about changes in the patient population.
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MEDICAL DEVICES BOX 7-1 Examples of Devices Approved Under the Humanitarian Device Exemption The Spiration IBV is indicated to control prolonged air leaks of the lung, or signifi cant air leaks that are likely to become prolonged air leaks, following lobectomy, segmentectomy, or lung volume reduction surgery. An air leak present on postop erative day 7 is considered prolonged unless present only during forced exhalation or cough.
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. As described in draft agency guidance, the Pediatric Medical Device Safety and Improvement Act of 2007, this number "is determined by estimating the number of individuals (pediatric and adult patients)
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. The agency has narrowly interpreted the custom device exemption and has brought enforcement actions against certain manufacturers who have sought to rely upon it.15 15 Early in the development of the titanium rib device, FDA approved several uses based on the custom device provisions (Campbell, 2007)
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COVERAGE AND REIMBURSEMENT FOR HDE MEDICAL DEVICES Despite the restriction on profits for devices that have been approved through the HDE process, manufacturers may still set substantial prices for such devices based on the costs that they may legally recover under the law. Thus, in considering whether to pursue development of a device that would fit HDE requirements, manufacturers will also consider whether public and private health plans are likely to cover the device and what they might pay.
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. MEDICAL DEVICE RESEARCH AND DEVELOPMENT In order to lay the foundation for the committee's recommendations for encouraging the development of medical devices for rare diseases, it is useful to review briefly some features of medical device innovation and development.
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Sands, 2010 This man, who has lived for decades with muscular dystrophy, has been assisted by a variety of medical devices. As is the case with many devices used for patients with rare conditions, none were devised specifically for patients with muscular dystrophy but all have helped him survive.
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Figure 7-1 depicts the device development life cycle for more complex devices as beginning with a basic concept to address an unmet need, followed by initial prototype development and test Pr ot ot y Concept pe Preclinical ce en c les so Ob C mercial Use lin ica l Com Manuf g acturing tin ke r Ma FIGURE 7-1 Total product life cycle for medical devices. SOURCE: Feigal, 2002.
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Figure 7-1 draws attention to a key aspect of medical devices, specifically, an "end-of-life" phase. In some cases, a device is supplanted by a radically different product that effectively makes obsolete, or reduces reliance on, the current product.
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For devices such as the titanium rib or the cardiac pacemaker, they devise surgical techniques necessary for safe implantation. Clinicians also participate in clinical trials to support regulatory submissions, and based on research and clinical practice, they may identify clinical and technical problems and suggest refinements to improve performance.
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Although some technological advances in medical devices have taken advantage of government-supported research and development, direct government investment in accelerating medical device research and development was initially limited. One exception is the total artificial heart BOX 7-3 Stanford University Biodesign Program About 10 years ago, faculty at Stanford University developed a systematic ap proach to solving significant medical problems in which invention and innovation were a team activity and were part of a process.
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In addition, the discussion in Chapter 4 of discovery research and diagnostic developments identifies other areas in which scientific and technological advances in biomedicine will likely shape innovation in diagnostic devices. Clinical Studies for Medical Devices As discussed earlier, FDA clears the majority of medical devices for marketing without requiring formal clinical studies.
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RARE DISEASES AND ORPHAN PRODUCTS BOX 7-4 Innovations in Engineering and Biological Sciences and Medical Device Innovation Replacement organs: Using man-made scaffolds and other biomedical tech niques, tissue engineering and regenerative medicine discoveries will permit scientists to "grow" organs in the laboratory to replace patients' failed organs. Tissue-engineered urinary bladders have already been implanted in patients.
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For medical devices that require clinical evaluation, a pilot or feasibility study usually involves an initial clinical evaluation of the safety of a prototype device in individuals with the condition for which the device is designed. Such a study may suggest modifications to the prototype device to improve its performance.
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The other project is preparation of a guidance document on clinical trial design for device trials. In addition, reflecting the characteristics of device trials, CDRH has developed guidance on the use of Bayesian statistics with clinical trials of medical devices, including situations involving confirmatory trials, device modifications, incomplete data, and opportunities for adaptive design strategies.
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Companies will still incur some additional incremental research and development investments to devise any modifications needed for the rare diseases application and to generate data on safety and probable benefit necessary for the HDE application. Although the incremental costs may be relatively modest for an HDE
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. An executive for a company with a device that has both PMA and HDE approvals observed that the HDE process was a means of broadening approved indications for the device that "saved 3 years, recovered $10 million from the initial research and development costs, and established good relationships with many physicians in the field" (p.
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The incentives relevant for drug development, particularly the protections from market competition, are not well matched to the realities of device development. Although recent initiatives to promote the development of pediatric medical devices modify the HDE process by allowing profits, they do not move toward either the marketing protections or the stricter approval requirements applicable to orphan drugs.
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Beyond simplifying some aspects of the HDE process as suggested in Recommendation 7-4, options to encourage device innovation for rare diseases include • the provision of additional orphan products grants and NIH awards for the development of devices to meet priority needs; • the authorization of tax credits for certain research and development costs, similar to those available for companies developing orphan drugs; and • the creation of inducement prizes for the design and initial testing of novel devices in areas of unmet need. In addition, the changes in the HDE incentives for pediatric devices, including the relaxation of the restriction on profits, provide an opportunity to examine the case for similar changes to encourage innovative devices for adults with rare conditions.
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RECOMMENDATION 7-2: Congress should consider whether the rationale for its creation of additional incentives for pediatric device development also supports the use of such incentives to promote the de velopment of devices to meet the needs of adults with rare conditions. A modest step to encourage additional company interest in devices for small populations would involve greater flexibility in the limits on annual shipments of HDE devices.
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From page 240... ...
for sponsors and IRBs on their roles and re sponsibilities related to IRB review of HDEs. In another area, CDRH could also develop new guidance on the use of surrogate endpoints in medical device trials (see discussion in Chapter 5)
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