Humanitarian Use Devices/Humanitarian Device Exemptions in Cardiovascular Medicine
http://www.100md.com
《循环学杂志》
the Cardiology Section, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon, NH (A.V.K., H.S., J.F.R.)
Centers for Devices and Radiologic Health, US Food and Drug Administration, Rockville, Md (E.D.H.)
Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (R.E.K.)
Cardiovascular Medicine Section, Stanford University, Stanford, Calif (P.F.).
Abstract
The Second Dartmouth Device Development Symposium held in October 2004 brought together leaders from the medical device community, including clinical investigators, senior representatives from the US Food and Drug Administration, large and small device manufacturers, and representatives from the financial community to examine difficult issues confronting device development. The role of the Humanitarian Use Device/Humanitarian Device Exemption (HUD/HDE) pathway in the development of new cardiovascular devices was discussed in this forum. The HUD/HDE pathway was created by Congress to facilitate the availability of medical devices for "orphan" indications, ie, those affecting <4000 individuals within the United States each year. The HUD/HDE pathway streamlines the approval process and permits less well-characterized devices to enter the market. HDE approval focuses primarily on issues of safety and scientific soundness and does not require demonstration of efficacy. In the 7 years since the first device was approved in 1997, a total of 35 HDEs have been granted (23 devices, 6 diagnostic tests). As the costs to gain regulatory approval for commonly used devices increase, companies often seek alternative ways to gain market access, including the HUD/HDE pathway. For a given device, there may be multiple legitimate and distinct indications, including indications that meet the HUD criteria. Companies must choose how and when to pursue each of these indications. The consensus of symposium participants was for the HUD/HDE pathway to be reserved for true orphan indications and not be viewed strategically as part of the clinical development plan to access a large market.
Key Words: heart disease catheterization surgery catheter
Introduction
The approval pathway for a significant-risk new medical device for treatment of a cardiovascular disorder can be long and expensive, typically requiring a large multicenter, prospective, randomized, controlled trial.1 Gaining approval typically necessitates a large investment of resources and capital and is associated with a high degree of risk. The ability to justify these investments is straightforward when developing therapies addressing large unmet clinical needs associated with substantial market opportunities (eg, drug-eluting stents, automated implantable cardiac defibrillators, biventricular pacing, glucose sensors). When therapies for rare conditions are developed, however, it is often difficult, if not impossible, to attract the necessary resources to address the regulatory requirements for commercialization. Congress created the Humanitarian Use Device/Humanitarian Device Exemption (HUD/HDE) approval pathway to facilitate the availability of medical devices for "orphan" indications. The HUD/HDE pathway streamlines the device approval process and permits less well-characterized devices to enter the market.
The Second Dartmouth Device Development Symposium held in October 2004 in Woodstock (Vt) brought together leaders from the major stakeholders in the medical device community, including clinical investigators, senior representatives from the US Food and Drug Administration (FDA), large and small device manufacturers, and representatives from the venture capital community to examine difficult issues confronting device development. One issue examined during the symposium was the role of the HUD/HDE in the development of new cardiovascular devices. This article is intended to provide a general understanding of the HUD/HDE pathway and its potential impact on device development.
Background
The history of the HUD/HDE dates back to 1990 with passage of the Safe Medical Devices Act.2 Changes to existing regulations were finalized in June 1996.3 These changes established a process for HUD/HDE approval, which was modeled after the premarket approval (PMA) process for regular (non-HUD) devices. The first HUD/HDE device, the Harrison Fetal Bladder Stent, was approved in February 1997. Since then, a total of 35 HDEs have been approved (Table 1).4
Approval to market an HUD is a 2-part process, starting with obtaining an HUD designation, followed by HDE approval. The HUD designation is granted by the FDA’s Office of Orphan Products. The HUD designation is granted for devices designed to treat or diagnose rare conditions when no other comparable devices are available. A rare condition, for the purposes of HUD designation, is defined as a disease or condition affecting <4000 individuals within the United States each year.5 The sponsor formally requests an HUD designation by providing a description of the intended patient population and data to support that there are <4000 of these patients each year within the United States. A description of the device, often in the form of instructions for use, is also submitted for review. Finally, an analysis of available devices is provided to document that a comparable device is not available for the proposed indication. The Office of Orphan Products has 45 days to review the request, at which time it can approve, disapprove, or request additional information.6 If the HUD designation is granted, the sponsor can then seek device approval in the form of an HDE application. The HDE application has format and approval criteria similar to an Investigational Device Exemption (IDE) application. An application for an IDE provides safety data and a rationale to support a specific clinical development plan and study design, including methodology to follow up patients both during and after the procedure. Criteria for IDE approval focus primarily on issues of safety and scientific soundness. Similarly, for HDE approval, the sponsor needs to provide a detailed description of the device, along with appropriate preclinical testing and clinical data (although not required) demonstrating device safety. Manufacturing data qualifying the device for clinical use, eg, destruction testing and sterile validation according to established industry standards, are also provided. Product labeling is also reviewed and must include a statement indicating that the device is an HUD. An additional component of the HUD/HDE process is cost assessment. It must be demonstrated that the amount charged for the device does not exceed the cost of research and development, fabrication, and distribution. If the amount charged for the device exceeds $250, the sponsor must include certification from an independent accountant that the charged amount does not exceed these costs.6
HDE applications are submitted to the Office of Device Evaluation at the Center for Devices and Radiologic Health (CDRH), which has 75 days to review the application. Criteria for HDE approval focus on safety, probable benefit, and lack of a comparable device. The application needs to provide data and a rationale supporting the probable benefit of the device and is exempt from the effectiveness requirements for a PMA device. During the initial 30 days, CDRH/FDA determines whether the application is complete enough to permit substantive review. If all the data appropriately support the HDE, the application is approved. If deficiencies are noted, the FDA notifies the sponsor as to their nature. As with other approved devices, the sponsor is required to manufacture and distribute the device according to established industry standards. In addition, the sponsor is required to maintain records of the names and addresses of facilities to which HUDs are shipped, in addition to correspondence with the Institutional Review Boards (IRBs) at each institution.6
As with sponsors, there are additional responsibilities for clinicians and facilities as well. Use of an HUD requires local initial and continuing IRB approval. When an HUD device is used in a manner outside the limits of FDA approval, ie, for "off-label" or "compassionate" use, it is strongly recommended that the user first notify FDA, except in cases of an emergency or life-threatening nature. In the case of emergency or compassionate off-label use, the user should provide a description of the circumstances of the case, a copy of the informed consent document, concurrence of the IRB chair, documentation of institutional clearance, an independent assessment by an uninvolved physician, and approval of the manufacturer. A report should be filed with FDA promptly (within 5 working days) after emergency off-label use.6 If an HUD device receives a PMA approval, the HDE approval for that device and other HDE-approved devices with that indication may be rescinded.
There are important differences in the rules and regulations associated with the HUD/HDE pathway compared with the PMA pathway for general-use devices. These differences emanate from the different effectiveness standards for HDE compared with PMA approval. HDE approval is based on demonstrating a reasonable assurance of safety and probable benefit; PMA approval is based on demonstrating a reasonable assurance of safety and effectiveness. Demonstration of probable benefit may be accomplished from the literature and may not require submission of any clinical data. If clinical data are required, they may be limited to a small single-arm study focused on feasibility and safety. This is in contrast to PMA approval, which for a significant-risk device in a new class more commonly requires large multicenter, prospective, randomized controlled trials to demonstrate safety and effectiveness. These trials can be extremely expensive and time consuming. Current trials designed to demonstrate the safety and effectiveness of a patent foramen ovale closure device for the prevention of recurrent stroke cost approximately $24 million and >4 years to complete (Table 2).8
Discussion
As the costs to obtain device approval continue to rise, companies (especially start-up companies devoted to developing a single device) are under extreme pressure to quickly obtain evidence of the clinical benefit of a device and its market acceptance and to generate revenues. The HUD/HDE pathway provides a way for a product to quickly enter the marketplace, allowing the company to obtain early performance data and realize revenue from device sales. For a given device, there may be multiple legitimate and distinct indications, including indications that meet the HUD criteria. Companies must choose how and when to pursue each of these indications. When contemplating the strategic use of the HUD/HDE, one must note the following limitations. First, a strategy using the HUD/HDE pathway as a stepping stone in the development of a device intended for large markets/populations is inconsistent with the intent of this legislation and may interfere with the PMA process. Second, HDE approval restricts the commercial opportunity by confining legal marketing and promotion to the orphan indication and by limiting the amount charged for the device as detailed above. Recent changes emanating from the Medicare Modernization Act of 2003, allowing for reimbursement of routine costs for clinical trials for some IDE devices, are being implemented to relieve some of the financial burden and to encourage adequately sized trials.9 Third, device availability as a result of HDE approval may interfere with the ability to run large multicenter, randomized clinical trials designed to evaluate safety and effectiveness when the device is used for broader indications. The current problems of recruiting patients into clinical trials evaluating the risks and benefits of patent foramen ovale closure to prevent recurrent stroke provide a vivid illustration of the difficulties encountered in recruiting patients when a device is available for another indication.10–12 Nonetheless, for devices with multiple potential indications, it may be possible to limit these difficulties by delaying the HUD/HDE process until after completion of the enrollment phase of a PMA trial.
At the Second Dartmouth Device Development Symposium, it was the consensus among the discussants—clinical investigators, large and small medical device manufactures, senior staff from CDRH/FDA, and the venture capital community—that the HUD/HDE pathway should be reserved for true orphaned indications. This pathway should not be viewed strategically as part of the clinical development plan to access a large market.
Appendix
The Second Dartmouth Device Development Symposium Discussion Subgroup focused on HUD/HDE and included John Ahern (NMT Medical, Inc); Peter Fitzgerald, MD, PhD (Stanford University); Elisa Harvey, DVM (CDRH/FDA); Rick Hillstead (The Innovation Factory); Bob Hopkins (Lehman Brothers); Aaron V. Kaplan, MD (Dartmouth Medical School/Dartmouth-Hitchcock Medical Center); Richard, Kuntz, MD (Harvard/Brigham and Women’s Hospital); Jim O’Donnell (Cordis Corp); Jean Paul Rasschaert (Epitek, Inc); John F. Robb, MD (Dartmouth Medical School/Dartmouth-Hitchcock Medical Center); Stanton Rowe, PhD (Edwards Laboratories); Hadas Shiran, BS (Dartmouth Medical School); Charles Warden (Versant Ventures); and Jack Wennberg, MD (Dartmouth Medical School).
Acknowledgments
We thank Jason Kahn for his help in the preparation of this manuscript.
Footnotes
This article resulted in part from sessions at the Second Dartmouth Drug and Device Development Symposium (3D2), Woodstock, Vt, October 14–15, 2004.
This article reflects the opinions of the authors and does not necessarily reflect the official policies of the institutions where they are employed.
References
Kaplan AV, Baim DS, Smith JJ, Feigal DA, Simons MS, Jefferys D, Fogarty TJ, Kuntz RE, Leon MB. Medical device development: from prototype to regulatory approval. Circulation. 2004; 109: 3068–3072.
Post Safe Medical Devices Act (SMDA) of 1990, Public Law 91-4243.
21 CFR 814, subpart H.
Snider S. Fetal stent receives first "humanitarian use" approval. HHS News. US Department of Health and Human Services February 14, 1997. Available at: http://www.fda.gov/bbs/topics/NEWS/NEW00556.html. Accessed January 15, 2005.
Section 520(m), Food, Drug and Cosmetic Act.
Humanitarian Device Exemption (HDE) Regulation: Questions and Answers: Final Guidance for Industry. Rockville, Md: Centers for Devices and Radiologic Health, US Food and Drug Administration; July 12, 2001.
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfHDE/HDEInformation.cfm. Accessed January 15, 2005.
Annual Report 2003. NMT Medical, Inc. Page 16.
Medicare Modernization Act of 2003.
Ruiz CE, Austin EH III, Cheatham JP, Danford DA, Latson LA, Mayer J, Mullins CE, Sanders S. First Food and Drug Administration approval under Humanitarian Device Exemption of a septal occluder for fenestrated fontan and muscular ventricular septal defects. Circulation. 2000; 101: e9042.
www.closurei.com. Accessed January 3, 2005.
www.amplatzer.com/us/medical_professionals/respect_trial.html. Accessed January 3, 2005.(Aaron V. Kaplan, MD; Elis)
Centers for Devices and Radiologic Health, US Food and Drug Administration, Rockville, Md (E.D.H.)
Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (R.E.K.)
Cardiovascular Medicine Section, Stanford University, Stanford, Calif (P.F.).
Abstract
The Second Dartmouth Device Development Symposium held in October 2004 brought together leaders from the medical device community, including clinical investigators, senior representatives from the US Food and Drug Administration, large and small device manufacturers, and representatives from the financial community to examine difficult issues confronting device development. The role of the Humanitarian Use Device/Humanitarian Device Exemption (HUD/HDE) pathway in the development of new cardiovascular devices was discussed in this forum. The HUD/HDE pathway was created by Congress to facilitate the availability of medical devices for "orphan" indications, ie, those affecting <4000 individuals within the United States each year. The HUD/HDE pathway streamlines the approval process and permits less well-characterized devices to enter the market. HDE approval focuses primarily on issues of safety and scientific soundness and does not require demonstration of efficacy. In the 7 years since the first device was approved in 1997, a total of 35 HDEs have been granted (23 devices, 6 diagnostic tests). As the costs to gain regulatory approval for commonly used devices increase, companies often seek alternative ways to gain market access, including the HUD/HDE pathway. For a given device, there may be multiple legitimate and distinct indications, including indications that meet the HUD criteria. Companies must choose how and when to pursue each of these indications. The consensus of symposium participants was for the HUD/HDE pathway to be reserved for true orphan indications and not be viewed strategically as part of the clinical development plan to access a large market.
Key Words: heart disease catheterization surgery catheter
Introduction
The approval pathway for a significant-risk new medical device for treatment of a cardiovascular disorder can be long and expensive, typically requiring a large multicenter, prospective, randomized, controlled trial.1 Gaining approval typically necessitates a large investment of resources and capital and is associated with a high degree of risk. The ability to justify these investments is straightforward when developing therapies addressing large unmet clinical needs associated with substantial market opportunities (eg, drug-eluting stents, automated implantable cardiac defibrillators, biventricular pacing, glucose sensors). When therapies for rare conditions are developed, however, it is often difficult, if not impossible, to attract the necessary resources to address the regulatory requirements for commercialization. Congress created the Humanitarian Use Device/Humanitarian Device Exemption (HUD/HDE) approval pathway to facilitate the availability of medical devices for "orphan" indications. The HUD/HDE pathway streamlines the device approval process and permits less well-characterized devices to enter the market.
The Second Dartmouth Device Development Symposium held in October 2004 in Woodstock (Vt) brought together leaders from the major stakeholders in the medical device community, including clinical investigators, senior representatives from the US Food and Drug Administration (FDA), large and small device manufacturers, and representatives from the venture capital community to examine difficult issues confronting device development. One issue examined during the symposium was the role of the HUD/HDE in the development of new cardiovascular devices. This article is intended to provide a general understanding of the HUD/HDE pathway and its potential impact on device development.
Background
The history of the HUD/HDE dates back to 1990 with passage of the Safe Medical Devices Act.2 Changes to existing regulations were finalized in June 1996.3 These changes established a process for HUD/HDE approval, which was modeled after the premarket approval (PMA) process for regular (non-HUD) devices. The first HUD/HDE device, the Harrison Fetal Bladder Stent, was approved in February 1997. Since then, a total of 35 HDEs have been approved (Table 1).4
Approval to market an HUD is a 2-part process, starting with obtaining an HUD designation, followed by HDE approval. The HUD designation is granted by the FDA’s Office of Orphan Products. The HUD designation is granted for devices designed to treat or diagnose rare conditions when no other comparable devices are available. A rare condition, for the purposes of HUD designation, is defined as a disease or condition affecting <4000 individuals within the United States each year.5 The sponsor formally requests an HUD designation by providing a description of the intended patient population and data to support that there are <4000 of these patients each year within the United States. A description of the device, often in the form of instructions for use, is also submitted for review. Finally, an analysis of available devices is provided to document that a comparable device is not available for the proposed indication. The Office of Orphan Products has 45 days to review the request, at which time it can approve, disapprove, or request additional information.6 If the HUD designation is granted, the sponsor can then seek device approval in the form of an HDE application. The HDE application has format and approval criteria similar to an Investigational Device Exemption (IDE) application. An application for an IDE provides safety data and a rationale to support a specific clinical development plan and study design, including methodology to follow up patients both during and after the procedure. Criteria for IDE approval focus primarily on issues of safety and scientific soundness. Similarly, for HDE approval, the sponsor needs to provide a detailed description of the device, along with appropriate preclinical testing and clinical data (although not required) demonstrating device safety. Manufacturing data qualifying the device for clinical use, eg, destruction testing and sterile validation according to established industry standards, are also provided. Product labeling is also reviewed and must include a statement indicating that the device is an HUD. An additional component of the HUD/HDE process is cost assessment. It must be demonstrated that the amount charged for the device does not exceed the cost of research and development, fabrication, and distribution. If the amount charged for the device exceeds $250, the sponsor must include certification from an independent accountant that the charged amount does not exceed these costs.6
HDE applications are submitted to the Office of Device Evaluation at the Center for Devices and Radiologic Health (CDRH), which has 75 days to review the application. Criteria for HDE approval focus on safety, probable benefit, and lack of a comparable device. The application needs to provide data and a rationale supporting the probable benefit of the device and is exempt from the effectiveness requirements for a PMA device. During the initial 30 days, CDRH/FDA determines whether the application is complete enough to permit substantive review. If all the data appropriately support the HDE, the application is approved. If deficiencies are noted, the FDA notifies the sponsor as to their nature. As with other approved devices, the sponsor is required to manufacture and distribute the device according to established industry standards. In addition, the sponsor is required to maintain records of the names and addresses of facilities to which HUDs are shipped, in addition to correspondence with the Institutional Review Boards (IRBs) at each institution.6
As with sponsors, there are additional responsibilities for clinicians and facilities as well. Use of an HUD requires local initial and continuing IRB approval. When an HUD device is used in a manner outside the limits of FDA approval, ie, for "off-label" or "compassionate" use, it is strongly recommended that the user first notify FDA, except in cases of an emergency or life-threatening nature. In the case of emergency or compassionate off-label use, the user should provide a description of the circumstances of the case, a copy of the informed consent document, concurrence of the IRB chair, documentation of institutional clearance, an independent assessment by an uninvolved physician, and approval of the manufacturer. A report should be filed with FDA promptly (within 5 working days) after emergency off-label use.6 If an HUD device receives a PMA approval, the HDE approval for that device and other HDE-approved devices with that indication may be rescinded.
There are important differences in the rules and regulations associated with the HUD/HDE pathway compared with the PMA pathway for general-use devices. These differences emanate from the different effectiveness standards for HDE compared with PMA approval. HDE approval is based on demonstrating a reasonable assurance of safety and probable benefit; PMA approval is based on demonstrating a reasonable assurance of safety and effectiveness. Demonstration of probable benefit may be accomplished from the literature and may not require submission of any clinical data. If clinical data are required, they may be limited to a small single-arm study focused on feasibility and safety. This is in contrast to PMA approval, which for a significant-risk device in a new class more commonly requires large multicenter, prospective, randomized controlled trials to demonstrate safety and effectiveness. These trials can be extremely expensive and time consuming. Current trials designed to demonstrate the safety and effectiveness of a patent foramen ovale closure device for the prevention of recurrent stroke cost approximately $24 million and >4 years to complete (Table 2).8
Discussion
As the costs to obtain device approval continue to rise, companies (especially start-up companies devoted to developing a single device) are under extreme pressure to quickly obtain evidence of the clinical benefit of a device and its market acceptance and to generate revenues. The HUD/HDE pathway provides a way for a product to quickly enter the marketplace, allowing the company to obtain early performance data and realize revenue from device sales. For a given device, there may be multiple legitimate and distinct indications, including indications that meet the HUD criteria. Companies must choose how and when to pursue each of these indications. When contemplating the strategic use of the HUD/HDE, one must note the following limitations. First, a strategy using the HUD/HDE pathway as a stepping stone in the development of a device intended for large markets/populations is inconsistent with the intent of this legislation and may interfere with the PMA process. Second, HDE approval restricts the commercial opportunity by confining legal marketing and promotion to the orphan indication and by limiting the amount charged for the device as detailed above. Recent changes emanating from the Medicare Modernization Act of 2003, allowing for reimbursement of routine costs for clinical trials for some IDE devices, are being implemented to relieve some of the financial burden and to encourage adequately sized trials.9 Third, device availability as a result of HDE approval may interfere with the ability to run large multicenter, randomized clinical trials designed to evaluate safety and effectiveness when the device is used for broader indications. The current problems of recruiting patients into clinical trials evaluating the risks and benefits of patent foramen ovale closure to prevent recurrent stroke provide a vivid illustration of the difficulties encountered in recruiting patients when a device is available for another indication.10–12 Nonetheless, for devices with multiple potential indications, it may be possible to limit these difficulties by delaying the HUD/HDE process until after completion of the enrollment phase of a PMA trial.
At the Second Dartmouth Device Development Symposium, it was the consensus among the discussants—clinical investigators, large and small medical device manufactures, senior staff from CDRH/FDA, and the venture capital community—that the HUD/HDE pathway should be reserved for true orphaned indications. This pathway should not be viewed strategically as part of the clinical development plan to access a large market.
Appendix
The Second Dartmouth Device Development Symposium Discussion Subgroup focused on HUD/HDE and included John Ahern (NMT Medical, Inc); Peter Fitzgerald, MD, PhD (Stanford University); Elisa Harvey, DVM (CDRH/FDA); Rick Hillstead (The Innovation Factory); Bob Hopkins (Lehman Brothers); Aaron V. Kaplan, MD (Dartmouth Medical School/Dartmouth-Hitchcock Medical Center); Richard, Kuntz, MD (Harvard/Brigham and Women’s Hospital); Jim O’Donnell (Cordis Corp); Jean Paul Rasschaert (Epitek, Inc); John F. Robb, MD (Dartmouth Medical School/Dartmouth-Hitchcock Medical Center); Stanton Rowe, PhD (Edwards Laboratories); Hadas Shiran, BS (Dartmouth Medical School); Charles Warden (Versant Ventures); and Jack Wennberg, MD (Dartmouth Medical School).
Acknowledgments
We thank Jason Kahn for his help in the preparation of this manuscript.
Footnotes
This article resulted in part from sessions at the Second Dartmouth Drug and Device Development Symposium (3D2), Woodstock, Vt, October 14–15, 2004.
This article reflects the opinions of the authors and does not necessarily reflect the official policies of the institutions where they are employed.
References
Kaplan AV, Baim DS, Smith JJ, Feigal DA, Simons MS, Jefferys D, Fogarty TJ, Kuntz RE, Leon MB. Medical device development: from prototype to regulatory approval. Circulation. 2004; 109: 3068–3072.
Post Safe Medical Devices Act (SMDA) of 1990, Public Law 91-4243.
21 CFR 814, subpart H.
Snider S. Fetal stent receives first "humanitarian use" approval. HHS News. US Department of Health and Human Services February 14, 1997. Available at: http://www.fda.gov/bbs/topics/NEWS/NEW00556.html. Accessed January 15, 2005.
Section 520(m), Food, Drug and Cosmetic Act.
Humanitarian Device Exemption (HDE) Regulation: Questions and Answers: Final Guidance for Industry. Rockville, Md: Centers for Devices and Radiologic Health, US Food and Drug Administration; July 12, 2001.
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfHDE/HDEInformation.cfm. Accessed January 15, 2005.
Annual Report 2003. NMT Medical, Inc. Page 16.
Medicare Modernization Act of 2003.
Ruiz CE, Austin EH III, Cheatham JP, Danford DA, Latson LA, Mayer J, Mullins CE, Sanders S. First Food and Drug Administration approval under Humanitarian Device Exemption of a septal occluder for fenestrated fontan and muscular ventricular septal defects. Circulation. 2000; 101: e9042.
www.closurei.com. Accessed January 3, 2005.
www.amplatzer.com/us/medical_professionals/respect_trial.html. Accessed January 3, 2005.(Aaron V. Kaplan, MD; Elis)