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counterpoint, legal perspective
Point/Counterpoint, Legal Perspective Ellen J. Flannery, Esq Covington & Burling, Washington, District of Columbia
t is a pleasure to be with you today. As Dr Copeland indicated, I am a lawyer and I represent medical Idevice manufacturers. I have also advised certain institutions where clinical investigators perform investigations of medical devices. Doctor Copeland asked me to provide an executive summary of the legal requirements relating to clinical investigations and marketing approvals of devices, and to provide a few editorial comments about how the regulatory requirements have been evolving. That could be a major talk, and my time is limited, so I will try to hit some highlights.
Regulatory Themes I think that there are four overarching themes of Food and Drug Administration (FDA) regulation of devices: (1) to protect the public, which is interpreted as to protect the patient, (2) to police manufacturers, (3) to restrain physicians, and (4) to placate Congress. This is what drives the FDA's medical device regulation. In implementing these themes, the FDA would rather do nothing than to do something and have a problem arise. It is when the FDA does something and a problem arises that the public, the Congress, and the media start attacking agency officials. The FDA is motivated by its desire to avoid approving devices or permitting studies that could result in death or disability. Agency personnel are driven by the experiences of thalidomide on the drug side, and the Dalkon shield and Shiley heart valve on the device side. The FDA pays virtually no attention to deaths and disabilities that could result when regulatory delays cause lack of patient access to devices. This may not be solely the FDA's fault, because Congress has also placed little importance on lack of access.
D i s t i n g u i s h i n g B e t w e e n Law and Policy When criticized, the FDA often says that it must do what it does because of the law it administers. I want to evaluate the FDA's assertion in light of the three sources of medical device regulation. First is the statute. Congress enacted the statute, and only Congress can change it. The statute both empowers Presented at The Third International Conferenceon CirculatorySupport Devices for SevereCardiac Failure, Pittsburgh, PA, Oct 28-30, 1994. Address reprint requests to Ms Flannery, Covington & Burling, 1201 Pennsylvania Ave NW, PO Box 7566, Washington, DC 20044-7566. © 1996 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
the FDA to regulate devices, and constrains the FDA to act within certain parameters. Second are the regulations. The FDA issues regulations to implement the statute. They are promulgated by notice-and-comment rulemaking, so there is public participation in the process. They are readily accessible, because they are published in the Code of Federal Regulations; you can go to the book and there they are. Regulations change infrequently; this could be good because you know what they are, but bad because they cannot easily adapt to new technologies. The third source of device regulation is policy. The FDA makes policy. Policy can change daily. It can change office to office and person to person within the FDA. Regulation by policy allows the FDA flexibility, such as to deal with new technology, but usually the flexibility is used by the FDA to tighten regulation rather than to loosen it. Policy is hard to find, and it takes many forms. It could be in the guidance documents that Dr Burlington mentioned. For example, guidance documents may specify the data required to support a marketing application for interventional devices. Policy could come in the form of speeches. Industry regularly monitors Dr Burlington's speeches to learn the regulatory policy applicable to specific types of devices. Policy can come in letters to manufacturers or physicians that indicate when the FDA finds certain practices objectionable. Lawyers like me comb through these "warning letters" to industry and physicians to discern enforcement trends. Usually policy is made internally by the FDA with no input from industry or physicians. There are some rare exceptions to this, and, hopefully, there will be more exceptions as we all get involved. But so far policy is mostly made internally and gets set to paper before anybody has an opportunity to comment.
Policy Relating to Marketing Approvals Let us compare the statute and the policy using a few examples. The statute establishes two routes to market for medical devices. One is the 510(k) notification, and the other is the premarket approval application. The statute says that a device can be marketed under a 510(k) notification if it is "substantially equivalent" to a predicate device, meaning an already lawfully marketed device. If the new product has the same intended use and the same technological characteristics, it is defined as substantially equivalent to the predicate. If it has the same intended use and different technological characteristics, it can still be substantially equivalent if the 510(k) Ann Thorac Surg 1996;61:487-9 • 0003-4975/96/$15.00 SSDI 0003-4975(95)00946-9
488
CIRCULATORY SUPPORT FLANNERY FDA REGULATION: LEGAL PERSPECTIVE
has data, including clinical data, to demonstrate that the device is as safe and effective as the predicate. Through "policy," the FDA engrafts new requirements onto these statutory conditions. For example, the FDA sometimes requires clinical data in 510(k)s for devices that have the same technological characteristics as the predicate. The FDA sometimes requires that a new device be more safe and effective than the predicate. The FDA requires manufacturers to show that a device has "clinical utility," a term not even mentioned in the statute, and this requirement is imposed in addition to safety and effectiveness. The FDA's "clinical utility" policy requires not only that the device works as intended, but also that it be shown to have a beneficial effect on patient outcome, such as improved survival or fewer surgical interventions. (I will return to this issue later.) The route to market for devices that are not substantially equivalent is the premarket approval application. The statute requires that a premarket approval application contain a complete description of the device and its principles of operation, and valid scientific evidence that demonstrates safety and effectiveness for the intended use.
Now consider FDA policy. The FDA's view of valid scientific evidence is moving toward more use of randomized, controlled clinical trials and away from historical controls. The FDA says that this will give it higher quality data on which to make decisions. With this policy, the FDA wants to push devices more toward the drug approval model. Maybe this approach of randomized, controlled trials can give better data in some cases, but it may not always be appropriate given the diverse kinds of medical devices. Consider another example of policy. The statute allows a device to be approved based on premarket data and a promise to generate additional data after marketing. The FDA implements these provisions by requiring more data at the preapproval stage rather than relying on additional data from postmarketing studies and surveillance. Consider again the issue of clinical utility. The FDA requires the manufacturer to show not only that the device performs as intended but also that there is an identifiable effect on patient outcome. Let me give you an example. A guidance document issued by the FDA's Division of Cardiovascular Devices states that it might find implied claims of clinical utility for some devices. The guidance document used the example of a stentless heart valve, which is expected to have less calcification. The FDA said that the manufacturer would have to show that a lack of calcification achieves a long-term benefit to the patient, because this conclusion can be implied from the fact that it is a stentless valve. It is not enough to show that the valve works as a valve, and it does not matter that the manufacturer is making no explicit claim about any such long-term benefit. This kind of policy goes beyond the statute, and this is how the FDA is moving.
Ann Thorac Surg 1996;61:487-9
Policy Relating to Clinical Studies Let me turn to investigational device exemptions. The regulations differentiate between significant and nonsignificant risk devices. Significant risk devices include cardiology catheters, implants, and ventricular assist devices. A clinical investigation of such devices requires institutional review board approval, informed consent, and FDA approval of an investigational device exemption application. An abbreviated investigational device exemption procedure exists for nonsignificant risk devices, under which FDA approval of an investigational device exemption application is not required. One thing that many investigators and institutional review boards do not understand, however, is the definition of a nonsignificant risk device. This term does not mean that the device to be studied does not pose more risk than the procedure or device that would ordinarily be used. Rather, it means that the device itself presents a nonsignificant risk to the subject. If it is an implant, or a life-supporting or lifesustaining device, it is generally a significant risk device, even if the study presents the same risk as the established procedure. Under FDA policy, approved devices can become investigational very quickly. If you have an approved implantable defibrillator, but you use it with leads not approved for use with that defibrillator, the whole system becomes investigational according to FDA. If a device has a 510(k), but it is modified significantly such that FDA determines it should have had a new 510(k), that device is considered investigational. Traditionally, a physician's use of an approved device for off-label use has been the practice of medicine and within the physician's domain. The FDA has been moving away from that principle in certain ways. The FDA is asking manufacturers to police your use, and not to give the device to you if they know it is going to be used for an unapproved use. In some instances, the FDA has taken direct action against physicians, such as with regard to the use of liquid silicone for injection. If you wander over the line from medical practice to investigation, or you fail to adhere to the investigational device exemption requirements, it can lead to FDA sanctions. These sanctions can include injunctions (and consent decrees), civil penalties, and criminal penalties. The FDA has also proposed to issue regulations for disqualification of clinical investigators. It therefore is important for you to know the changing regulatory landscape, but that may be hard to do when regulatory requirements are only being announced in policy statements. T h e R e g u l a t o r y Balance
There are two different perspectives with regard to the evolving tightening of regulatory requirements. The FDA says that patients are protected from disasters caused by unproven technology. Industry and some clinical investigators say that patients are denied access to medical technologies available outside the United States with resulting death and disability.
Ann Thorac Surg 1996;61:487-9
The FDA says there should be more randomized, controlled clinical trials, and that the quality of data for decision-making will thus be enhanced. Industry says the FDA is demanding data that are unreasonable for many kinds of devices. The FDA says that delays in the review of marketing applications are often caused because the agency must force industry to provide better data and more thorough data in amendments to applications. Industry says that FDA reviewers do not understand some of the breakthrough technologies, and that they are asking inappropilate questions and making unreasonable data demands. The FDA says that the approach of "let the doctors decide" whether a device is effective is an approach that invites disaster, citing the Dalkon shield and silicone breast implants, and that the agency must restrain physicians. Physicians say they have the right to practice medicine and to use all available data to select medical interventions appropriate for their patients. T h e N e e d for M o r e Public Participation If you do not like where device regulation has been heading, what can you do? You must first determine the source of what you perceive to be the problem. Is it the statute? If so, then you must go to Congress. Is it the FDA's regulations or agency policy? Then you have to go to the FDA, or to Congress, or both. A few examples may be useful. Consider the statute. Many believe that legislative changes are needed because of the FDA's restrictive interpretation of the statutory requirements. Some people have proposed that the statute should be amended so that the FDA could approve devices only for safety, and the medical profession can decide whether devices are effective. The FDA does not like this proposal. The FDA has always looked at safety and effectiveness as a relative
CIRCULATORYSUPPORT FLANNERY FDA REGULATION:LEGALPERSPECTIVE
489
determination, and it wants to retain its authority to review both. Congress may not like this kind of amendment if it will be perceived as amending the statute to provide less protection to the patient and little corresponding benefit. The FDA's rulemaking, or lack thereof, has also been criticized. For example, Congress enacted a humanitarian use exemption in 1990, so that patients could get prompt access to devices for rare diseases or conditions. But Congress also said the exemption would not be effective until the FDA promulgates regulations to implement it. Four years later, there are no humanitarian use regulations. The FDA does not move quickly to loosen regulatory requirements. As to policy, the FDA is trying to develop policies and guidance documents on issues such as how to conduct clinical studies, and what kinds of data are required in marketing applications for specific types of devices. You must get more actively involved in that process. The FDA has begun to invite public participation, and it is important that practicing physicians and clinical investigators be at the table. In addition, if FDA employees are demanding data that seem to be unreasonable, or if they do not understand the technology, that has to be brought to the attention of FDA supervisors. The FDA and Congress both have to be given facts-real, specific facts---on instances in which patients may be unreasonably denied access to breakthrough technologies because of regulatory delay. It is not enough simply to claim that this is happening; you must prove it is. The FDA has a list of device disasters, and you must have a list of examples where patients are being hurt by delay or unreasonable demands. If the FDA is to keep pace with changes in medical technology, there must be better consultation among the manufacturers, clinical investigators, medical practitioners, and the agency. I hope that this is on its way to being accomplished.
t is a pleasure to be with you today. As Dr Copeland indicated, I am a lawyer and I represent medical Idevice manufacturers. I have also advised certain institutions where clinical investigators perform investigations of medical devices. Doctor Copeland asked me to provide an executive summary of the legal requirements relating to clinical investigations and marketing approvals of devices, and to provide a few editorial comments about how the regulatory requirements have been evolving. That could be a major talk, and my time is limited, so I will try to hit some highlights.
Regulatory Themes I think that there are four overarching themes of Food and Drug Administration (FDA) regulation of devices: (1) to protect the public, which is interpreted as to protect the patient, (2) to police manufacturers, (3) to restrain physicians, and (4) to placate Congress. This is what drives the FDA's medical device regulation. In implementing these themes, the FDA would rather do nothing than to do something and have a problem arise. It is when the FDA does something and a problem arises that the public, the Congress, and the media start attacking agency officials. The FDA is motivated by its desire to avoid approving devices or permitting studies that could result in death or disability. Agency personnel are driven by the experiences of thalidomide on the drug side, and the Dalkon shield and Shiley heart valve on the device side. The FDA pays virtually no attention to deaths and disabilities that could result when regulatory delays cause lack of patient access to devices. This may not be solely the FDA's fault, because Congress has also placed little importance on lack of access.
D i s t i n g u i s h i n g B e t w e e n Law and Policy When criticized, the FDA often says that it must do what it does because of the law it administers. I want to evaluate the FDA's assertion in light of the three sources of medical device regulation. First is the statute. Congress enacted the statute, and only Congress can change it. The statute both empowers Presented at The Third International Conferenceon CirculatorySupport Devices for SevereCardiac Failure, Pittsburgh, PA, Oct 28-30, 1994. Address reprint requests to Ms Flannery, Covington & Burling, 1201 Pennsylvania Ave NW, PO Box 7566, Washington, DC 20044-7566. © 1996 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
the FDA to regulate devices, and constrains the FDA to act within certain parameters. Second are the regulations. The FDA issues regulations to implement the statute. They are promulgated by notice-and-comment rulemaking, so there is public participation in the process. They are readily accessible, because they are published in the Code of Federal Regulations; you can go to the book and there they are. Regulations change infrequently; this could be good because you know what they are, but bad because they cannot easily adapt to new technologies. The third source of device regulation is policy. The FDA makes policy. Policy can change daily. It can change office to office and person to person within the FDA. Regulation by policy allows the FDA flexibility, such as to deal with new technology, but usually the flexibility is used by the FDA to tighten regulation rather than to loosen it. Policy is hard to find, and it takes many forms. It could be in the guidance documents that Dr Burlington mentioned. For example, guidance documents may specify the data required to support a marketing application for interventional devices. Policy could come in the form of speeches. Industry regularly monitors Dr Burlington's speeches to learn the regulatory policy applicable to specific types of devices. Policy can come in letters to manufacturers or physicians that indicate when the FDA finds certain practices objectionable. Lawyers like me comb through these "warning letters" to industry and physicians to discern enforcement trends. Usually policy is made internally by the FDA with no input from industry or physicians. There are some rare exceptions to this, and, hopefully, there will be more exceptions as we all get involved. But so far policy is mostly made internally and gets set to paper before anybody has an opportunity to comment.
Policy Relating to Marketing Approvals Let us compare the statute and the policy using a few examples. The statute establishes two routes to market for medical devices. One is the 510(k) notification, and the other is the premarket approval application. The statute says that a device can be marketed under a 510(k) notification if it is "substantially equivalent" to a predicate device, meaning an already lawfully marketed device. If the new product has the same intended use and the same technological characteristics, it is defined as substantially equivalent to the predicate. If it has the same intended use and different technological characteristics, it can still be substantially equivalent if the 510(k) Ann Thorac Surg 1996;61:487-9 • 0003-4975/96/$15.00 SSDI 0003-4975(95)00946-9
488
CIRCULATORY SUPPORT FLANNERY FDA REGULATION: LEGAL PERSPECTIVE
has data, including clinical data, to demonstrate that the device is as safe and effective as the predicate. Through "policy," the FDA engrafts new requirements onto these statutory conditions. For example, the FDA sometimes requires clinical data in 510(k)s for devices that have the same technological characteristics as the predicate. The FDA sometimes requires that a new device be more safe and effective than the predicate. The FDA requires manufacturers to show that a device has "clinical utility," a term not even mentioned in the statute, and this requirement is imposed in addition to safety and effectiveness. The FDA's "clinical utility" policy requires not only that the device works as intended, but also that it be shown to have a beneficial effect on patient outcome, such as improved survival or fewer surgical interventions. (I will return to this issue later.) The route to market for devices that are not substantially equivalent is the premarket approval application. The statute requires that a premarket approval application contain a complete description of the device and its principles of operation, and valid scientific evidence that demonstrates safety and effectiveness for the intended use.
Now consider FDA policy. The FDA's view of valid scientific evidence is moving toward more use of randomized, controlled clinical trials and away from historical controls. The FDA says that this will give it higher quality data on which to make decisions. With this policy, the FDA wants to push devices more toward the drug approval model. Maybe this approach of randomized, controlled trials can give better data in some cases, but it may not always be appropriate given the diverse kinds of medical devices. Consider another example of policy. The statute allows a device to be approved based on premarket data and a promise to generate additional data after marketing. The FDA implements these provisions by requiring more data at the preapproval stage rather than relying on additional data from postmarketing studies and surveillance. Consider again the issue of clinical utility. The FDA requires the manufacturer to show not only that the device performs as intended but also that there is an identifiable effect on patient outcome. Let me give you an example. A guidance document issued by the FDA's Division of Cardiovascular Devices states that it might find implied claims of clinical utility for some devices. The guidance document used the example of a stentless heart valve, which is expected to have less calcification. The FDA said that the manufacturer would have to show that a lack of calcification achieves a long-term benefit to the patient, because this conclusion can be implied from the fact that it is a stentless valve. It is not enough to show that the valve works as a valve, and it does not matter that the manufacturer is making no explicit claim about any such long-term benefit. This kind of policy goes beyond the statute, and this is how the FDA is moving.
Ann Thorac Surg 1996;61:487-9
Policy Relating to Clinical Studies Let me turn to investigational device exemptions. The regulations differentiate between significant and nonsignificant risk devices. Significant risk devices include cardiology catheters, implants, and ventricular assist devices. A clinical investigation of such devices requires institutional review board approval, informed consent, and FDA approval of an investigational device exemption application. An abbreviated investigational device exemption procedure exists for nonsignificant risk devices, under which FDA approval of an investigational device exemption application is not required. One thing that many investigators and institutional review boards do not understand, however, is the definition of a nonsignificant risk device. This term does not mean that the device to be studied does not pose more risk than the procedure or device that would ordinarily be used. Rather, it means that the device itself presents a nonsignificant risk to the subject. If it is an implant, or a life-supporting or lifesustaining device, it is generally a significant risk device, even if the study presents the same risk as the established procedure. Under FDA policy, approved devices can become investigational very quickly. If you have an approved implantable defibrillator, but you use it with leads not approved for use with that defibrillator, the whole system becomes investigational according to FDA. If a device has a 510(k), but it is modified significantly such that FDA determines it should have had a new 510(k), that device is considered investigational. Traditionally, a physician's use of an approved device for off-label use has been the practice of medicine and within the physician's domain. The FDA has been moving away from that principle in certain ways. The FDA is asking manufacturers to police your use, and not to give the device to you if they know it is going to be used for an unapproved use. In some instances, the FDA has taken direct action against physicians, such as with regard to the use of liquid silicone for injection. If you wander over the line from medical practice to investigation, or you fail to adhere to the investigational device exemption requirements, it can lead to FDA sanctions. These sanctions can include injunctions (and consent decrees), civil penalties, and criminal penalties. The FDA has also proposed to issue regulations for disqualification of clinical investigators. It therefore is important for you to know the changing regulatory landscape, but that may be hard to do when regulatory requirements are only being announced in policy statements. T h e R e g u l a t o r y Balance
There are two different perspectives with regard to the evolving tightening of regulatory requirements. The FDA says that patients are protected from disasters caused by unproven technology. Industry and some clinical investigators say that patients are denied access to medical technologies available outside the United States with resulting death and disability.
Ann Thorac Surg 1996;61:487-9
The FDA says there should be more randomized, controlled clinical trials, and that the quality of data for decision-making will thus be enhanced. Industry says the FDA is demanding data that are unreasonable for many kinds of devices. The FDA says that delays in the review of marketing applications are often caused because the agency must force industry to provide better data and more thorough data in amendments to applications. Industry says that FDA reviewers do not understand some of the breakthrough technologies, and that they are asking inappropilate questions and making unreasonable data demands. The FDA says that the approach of "let the doctors decide" whether a device is effective is an approach that invites disaster, citing the Dalkon shield and silicone breast implants, and that the agency must restrain physicians. Physicians say they have the right to practice medicine and to use all available data to select medical interventions appropriate for their patients. T h e N e e d for M o r e Public Participation If you do not like where device regulation has been heading, what can you do? You must first determine the source of what you perceive to be the problem. Is it the statute? If so, then you must go to Congress. Is it the FDA's regulations or agency policy? Then you have to go to the FDA, or to Congress, or both. A few examples may be useful. Consider the statute. Many believe that legislative changes are needed because of the FDA's restrictive interpretation of the statutory requirements. Some people have proposed that the statute should be amended so that the FDA could approve devices only for safety, and the medical profession can decide whether devices are effective. The FDA does not like this proposal. The FDA has always looked at safety and effectiveness as a relative
CIRCULATORYSUPPORT FLANNERY FDA REGULATION:LEGALPERSPECTIVE
489
determination, and it wants to retain its authority to review both. Congress may not like this kind of amendment if it will be perceived as amending the statute to provide less protection to the patient and little corresponding benefit. The FDA's rulemaking, or lack thereof, has also been criticized. For example, Congress enacted a humanitarian use exemption in 1990, so that patients could get prompt access to devices for rare diseases or conditions. But Congress also said the exemption would not be effective until the FDA promulgates regulations to implement it. Four years later, there are no humanitarian use regulations. The FDA does not move quickly to loosen regulatory requirements. As to policy, the FDA is trying to develop policies and guidance documents on issues such as how to conduct clinical studies, and what kinds of data are required in marketing applications for specific types of devices. You must get more actively involved in that process. The FDA has begun to invite public participation, and it is important that practicing physicians and clinical investigators be at the table. In addition, if FDA employees are demanding data that seem to be unreasonable, or if they do not understand the technology, that has to be brought to the attention of FDA supervisors. The FDA and Congress both have to be given facts-real, specific facts---on instances in which patients may be unreasonably denied access to breakthrough technologies because of regulatory delay. It is not enough simply to claim that this is happening; you must prove it is. The FDA has a list of device disasters, and you must have a list of examples where patients are being hurt by delay or unreasonable demands. If the FDA is to keep pace with changes in medical technology, there must be better consultation among the manufacturers, clinical investigators, medical practitioners, and the agency. I hope that this is on its way to being accomplished.