Regulation of Medical Device Innovation


Introduction

Joseph D. Bronzino

Trinity College/Biomedical Engineering Alliance for Connecticut (BEACON)

подпись: joseph d. bronzino
trinity college/biomedical engineering alliance for connecticut (beacon)
Ethical Issues in Feasibility Studies

Ethical Issues in Emergency Use

Ethical Issues in Treatment Use

The Safe Medical Devices Act

Introduction

Responsibility for regulating medical devices falls to the Food and Drug Administration (FDA) under the Medical Device Amendment of 1976. This statute requires approval from the FDA before new devices are marketed and imposes requirements for the clinical investigation of new medical devices on human subjects. Although the statute makes interstate commerce of an unapproved new medical device generally unlawful, it provides an exception to allow interstate distribution of unapproved devices in order to conduct clinical research on human subjects. This investigational device exemption (IDE) can be obtained by submitting to the FDA “a protocol for the proposed clinical testing of the device, reports of prior investigations of the device, certification that the study has been approved by a local institutional review board, and an assurance that informed consent will be obtained from each human subject” (Bronzino et al., 1990a, b).

With respect to clinical research on humans, the FDA distinguishes devices into two categories: devices that pose significant risk and those that involve insignificant risk. Examples of the former included orthopedic implants, artificial hearts, and infusion pumps. Examples of the latter include various dental devices and daily-wear contact lenses. Clinical research involving a significant risk device cannot begin until an institutional review board (IRB) has approved both the protocol and the informed consent form and the FDA itself has given permission. This requirement to submit an IDE application to the FDA is waived in the case of clinical research where the risk posed is insignificant. In this case, the FDA requires only that approval from an IRB be obtained certifying that the device in question poses only insignificant risk. In deciding whether to approve a proposed clinical investigation of a new device, the IRB and the FDA must determine the following (Bronzino et al., 1990a, b):

Risks to subjects are minimized.

Risks to subjects are reasonable in relation to the anticipated benefit and knowledge to be gained.

Subject selection is equitable.

Informed consent materials and procedures are adequate.

Provisions for monitoring the study and protecting patient information are acceptable.

The FDA allows unapproved medical devices to be used without an IDE in three types of situations: emergency use, treatment use, and feasibility studies.

Ethical Issues in Feasibility Studies

Manufacturers seeking more flexibility in conducting investigations in the early developmental stages of a device have submitted a petition to the FDA, requesting that certain limited investigations of significant risk devices be subject to abbreviated IDE requirements (Bronzino et al., 1990a, b). In a feasibility study, or “limited investigation,” human research on a new device would take place at a single institution and involve no more than ten human subjects. The sponsor of a limited investigation would be required to submit to the FDA a “Notice of Limited Investigation" which would include a description of the device, a summary of the purpose of the investigation, the protocol, a sample of the informed consent form, and a certification of approval by the responsible IRB. In certain circumstances, the FDA could require additional information, or require the submission of a full IDE application, or suspend the investigation (Bronzino et al., 1990a, b).

Investigations of this kind would be limited to certain circumstances: (1) investigations of new uses of existing devices, (2) investigations involving temporary or permanent implants during the early developmen­tal stages, and (3) investigations involving modification of an existing device (Bronzino et al., 1990a).

To comprehend adequately the ethical issues posed by clinical use of unapproved medical devices outside the context of an IDE, it is necessary to utilize the distinctions between practice, nonvalidated practice, and research elaborated in the previous pages. How do those definitions apply to feasibility studies?

Clearly, the goal of this sort of study, i. e., generalizable knowledge, makes it an issue of research rather than practice. Manufacturers seek to determine the performance of a device with respect to a particular patient population in an effort to gain information about its efficacy and safety. Such information would be important in determining whether further studies (animal or human) need to be conducted, whether the device needs modification before further use, and the like. The main difference between use of an unapproved device in a feasibility study and use under the terms of an IDE is that the former would be subject to significantly less intensive FDA review than the latter. This, in turn, means that the responsibility for ensuring that use of the device is ethically sound would fall primarily to the IRB of the institution conducting the study.

The ethical concerns posed here are best comprehended with a clear understanding of what justifies research. Ultimately, no matter how much basic research and animal experimentation has been conducted on a given device, the risks and benefits it poses for humans cannot be adequately determined until it is actually used on humans.

The benefits of research on humans lie primarily in the knowledge that is yielded and the generalizable information that is provided. This information is crucial to medical science’s ability to generate new modes and instrumentalities of medical treatment that are both efficacious and safe. Accordingly, for necessary but insufficient condition for experimentation to be ethically sound, it must be scientifically sound (Capron, 1978; 1986).

Although scientific soundness is a necessary condition of ethically acceptable research on humans, it is not of and by itself sufficient. Indeed, it is widely recognized that the primary ethical concern posed by such investigation is the use of one person by another to gather knowledge or other benefits where these benefits may only partly or not at all accrue to the first person. In other words, the human subjects of such research are at risk of being mere research resources, as having value only for the ends of the research. Research upon human beings runs the risk of failing to respect them as people. The notion that human beings are not mere things but entities whose value is inherent rather than wholly instrumental is one of the most widely held norms of contemporary Western society. That is, human beings are not valuable wholly or solely for the uses to which they can be put. They are valuable simply by being the kinds of entities they are. To treat them as such is to respect them as people.

Respecting individuals as people is generally agreed to entail two requirements in the context of biomedical experimentation. First, since what is most generally taken to make human beings people is their autonomy—their ability to make rational choices for themselves—treating individuals as people means respecting that autonomy. This requirement is met by ensuring that no competent person is subjected to any clinical intervention without first giving voluntary and informed consent. Second, respect for people means that the physician will not subject a human to unnecessary risks and will minimize the risks to patients in required procedures.

Much of the ethical importance of the scrutiny that the FDA imposes upon use of unapproved medical devices in the context of an IDE derives from these two conditions of ethically sound research. The central ethical concern posed by use of medical devices in a feasibility study is that the decreased degree of FDA scrutiny will increase the likelihood that either or both of these conditions will not be met. This possibility may be especially great because many manufacturers of medical devices are, after all, commercial enter­prises, companies that are motivated to generate profit and thus to get their devices to market as soon as possible with as little delay and cost as possible. These self-interested motives are likely, at times, to conflict with the requirements of ethically sound research and thus to induce manufacturers to fail (often unwittingly) to meet these requirements. Note that profit is not the only motive that might induce manufacturers to contravene the requirements of ethically sound research on humans. A manufacturer may sincerely believe that its product offers great benefit to many people or to a population of especially needy people and so from this utterly altruistic motive may be prompted to take shortcuts that compro­mise the quality of the research. Whether the consequences being sought by the research are desired for reasons of self-interest, altruism, or both, the ethical issue is the same. Research subjects may be placed at risk of being treated as mere objects rather than as people.

What about the circumstances under which feasibility studies would take place? Are these not suffi­ciently different from the “normal” circumstances of research to warrant reduced FDA scrutiny? As noted above, manufacturers seek to be allowed to engage in feasibility studies in order to investigate new uses of existing devices, to investigate temporary or permanent implants during the early developmental stages, and to investigate modifications to an existing device. As also noted above, a feasibility study would take place at only one institution and would involve no more than ten human subjects. Given these circum­stances, is the sort of research that is likely to occur in a feasibility study less likely to be scientifically unsound or to fail to respect people in the way that normal research upon humans does in “normal” circumstances?

Such research would be done on a very small subject pool, and the harm of any ethical lapses would likely affect fewer people than if such lapses occurred under more usual research circumstances. Yet even if the harm done is limited to a failure to respect the ten or fewer subjects in a single feasibility study, the harm would still be ethically wrong. To wrong ten or fewer people is not as bad as to wrong in the same way more than ten people but it is to engage in wrongdoing nonetheless. In either case, individuals are reduced to the status of mere research resources and their dignity as people is not properly respected.

Are ethical lapses more likely to occur in feasibility studies than in studies that take place within the requirements of an IDE? Although nothing in the preceding discussion provides a definitive answer to this question, it is a question to which the FDA should give high priority in deciding whether to allow this type of exception to IDE use of unapproved medical devices. The answer to this question might be quite different when the device at issue is a temporary or permanent implant than when it is an already approved device being put to new uses or modified in some way. Whatever the contemplated use under the feasibility studies mechanism, the FDA would be ethically advised not to allow this kind of exception to IDE use of an unapproved device without a reasonably high level of certainty that research subjects would not be placed in greater jeopardy than in “normal” research circumstances.

Ethical Issues in Emergency Use

What about the mechanism for avoiding the rigors of an IDE for emergency use?

“The FDA has authorized emergency use where an unapproved device offers the only alternative for saving the life of a dying patient, but an IDE has not yet been approved for the device or its use, or an IDE has been approved but the physician who wishes to use the device is not an investigator under the IDE (Bronzino et al., 1990a, b).

Because the purpose of emergency use of an unapproved device is to attempt to save a dying patient’s life under circumstances where no other alternative is at hand, this sort of use constitutes practice rather than research. Its aim is primarily benefit to the patient rather than provision of new and generalizable information. Because this sort of use occurs prior to the completion of clinical investigation of the device, it constitutes a nonvalidated practice. What does this mean?

First, it means that while the aim of the use is to save the life of the patient, the nature and likelihood of the potential benefits and risks engendered by use of the device are far more speculative than in the sort of clinical intervention that constitutes validated practice. In validated practice, thorough investiga­tion, including preclinical studies, animals studies, and studies on human subjects of a device has established its efficacy and safety. The clinician thus has a well-founded basis upon which to judge the benefits and risks such an intervention poses for his patients.

It is precisely this basis that is lacking in the case of a nonvalidated practice. Does this mean that emergency use of an unapproved device should be regarded as immoral? This conclusion would follow only if there were no basis upon which to make an assessment of the risks and benefits of the use of the device. The FDA requires that a physician who engages in emergency use of an unapproved device must “have substantial reason to believe that benefits will exist. This means that there should be a body of pre — clinical and animal tests allowing a prediction of the benefit to a human patient” (Bronzino et al., 1990a, b).

Thus, although the benefits and risks posed by use of the device are highly speculative, they are not entirely speculative. Although the only way to validate a new technology is to engage in research on humans at some point, not all nonvalidated technologies are equal. Some will be largely uninvestigated, and assessment of their risks and benefits will be wholly or almost wholly speculative. Others will at least have the support of preclinical and animal tests. Although this is not sufficient support for incorporating use of a device into regular clinical practice, it may however represent sufficient support to justify use in the desperate circumstances at issue in emergency situations. Desperate circumstances can justify des­perate actions, but desperate actions are not the same as reckless actions, hence the ethical soundness of the FDA’s requirement that emergency use be supported by solid results from preclinical and animal tests of the unapproved device.

A second requirement that the FDA imposes on emergency use of unapproved devices is the expectation that physicians “exercise reasonable foresight with respect to potential emergencies and make appropriate arrangements under the IDE procedures. Thus, a physician should not “create” an emergency in order to circumvent IRB review and avoid requesting the sponsor’s authorization of the unapproved use of a device” (Bronzino et al., 1990a, b).

From a Kantian point of view, which is concerned with protecting the dignity of people, it is a particularly important requirement to create an emergency in order to avoid FDA regulations which prevent the patient being treated as a mere resource whose value is reducible to a service of the clinician’s goals. Hence, the FDA is quite correct to insist that emergencies are circumstances that reasonable foresight would not anticipate.

Also especially important here is the nature of the patient’s consent. Individuals facing death are especially vulnerable to exploitation and deserve greater measures for their protection than might oth­erwise be necessary. One such measure would be to ensure that the patient, or his legitimate proxy, knows the highly speculative nature of the intervention being offered. That is, to ensure that it is clearly understood that the clinician’s estimation of the intervention’s risks and benefits is far less solidly grounded than in the case of validated practices. The patient’s consent must be based upon an awareness that the particular device has not undergone complete and rigorous testing on humans and that estima­tions of its potential are based wholly upon preclinical and animal studies. Above all the patient must not be lead to believe that there is complete understanding of the risks and benefits of the intervention. Another important point here is to ensure that the patient is aware that the options he is facing are not simply life or death but may include life of a severely impaired quality, and therefore that even if his life is saved, it may be a life of significant impairment. Although desperate circumstance may legitimize desperate actions, the decision to take such actions must rest upon the informed and voluntary consent of the patient, especially when he/she is an especially vulnerable patient.

It is important here for a clinician involved in emergency use of an unapproved device to recognize that these activities constitute a form of nonvalidated practice and not research. Hence, the primary obligation is to the well-being of the patient. The patient enters into the relationship with the clinician with the same trust that accompanies any normal clinical situation. To treat this sort of intervention as if it were an instance of research and hence justified by its benefits to science and society would be to abuse this trust.

Ethical Issues in Treatment Use

The FDA has adopted regulations authorizing the use of investigational new drugs in certain circumstances where a patient has not responded to approved therapies. This “treatment use” of unapproved new drugs is not limited to life-threatening emergency situations, but rather is also available to treat “serious” diseases or conditions (Bronzino et al., 1990a, b).

The FDA has not approved treatment use of unapproved medical devices, but it is possible that a manufacturer could obtain such approval by establishing a specific protocol for this kind of use within the context of an IDE.

The criteria for treatment use of unapproved medical devices would be similar to criteria for treatment use of investigational drugs: (1) the device is intended to treat a serious or life-threatening disease or condition, (2) there is no comparable or satisfactory alternative product available to treat that condition,

The device is under an IDE, or has received an IDE exemption, or all clinical trials have been completed and the device is awaiting approval, and (4) the sponsor is actively pursuing marketing approval of the investigational device. The treatment use protocol would be submitted as part of the IDE, and would describe the intended use of the device, the rationale for use of the device, the available alternatives and why the investigational product is preferred, the criteria for patient selection, the measures to monitor the use of the device and to minimize risk, and technical information that is relevant to the safety and effectiveness of the device for the intended treatment purpose (Bronzino et al., 1990a, b).

Were the FDA to approve treatment use of unapproved medical devices, what ethical issues would be posed? First, because such use is premised on the failure of validated interventions to improve the patient’s condition adequately, it is a form of practice rather than research. Second, since the device involved in an instance of treatment use is unapproved, such use would constitute nonvalidated practice. As such, like emergency use, it should be subject to the FDA’s requirement that prior preclinical tests and animal studies have been conducted that provide substantial reason to believe that patient benefit will result. As with emergency use, although this does not prevent assessment of the intervention’s benefits and risks from being highly speculative, it does prevent assessment from being totally speculative. Here too, although desperate circumstances can justify desperate action, they do not justify reckless action. Unlike emergency use, the circumstances of treatment use involve serious impairment of health rather than the threat of premature death. Hence, an issue that must be considered is how serious such impairment must be to justify resorting to an intervention whose risks and benefits have not been solidly established.

In cases of emergency use, the FDA requires that physicians not use this exception to an IDE to avoid requirements that would otherwise be in place. This particular requirement would be obviated in instances of treatment use by the requirement that a protocol for such use be previously addressed within an IDE.

As with emergency use of unapproved devices, the patients involved in treatment use would be particularly vulnerable patients. Although they are not dying, they are facing serious medical conditions and are thereby likely to be less able to avoid exploitation than patients under less desperate circumstances. Consequently, it is especially important that patients be informed of the speculative nature of the intervention and of the possibility that treatment may result in little or no benefit to them.

The Safe Medical Devices Act

On November 28, 1991, the Safe Medical Devices Act of 1990 (Public Law 101-629) went into effect. This regulation requires a wide range of healthcare institutions, including hospitals, ambulatory-surgical facilities, nursing homes, and outpatient treatment facilities, to report information that “reasonably suggests” the likelihood that the death, serious injury, or serious illness of a patient at that facility has been caused or contributed to by a medical device. When a death is device-related, a report must be made directly to the FDA and to the manufacturer of the device. When a serious illness or injury is device-related, a report must be made to the manufacturer or to the FDA in cases where the manufacturer is not known. In addition, summaries of previously submitted reports must be submitted to the FDA on a semiannual basis. Prior to this regulation, such reporting was voluntary. This new regulation was designed to enhance the FDA’s ability to quickly learn about problems related to medical devices. It also supplements the medical device reporting (MDR) regulations promulgated in 1984. MDR regulations require that reports of device-related deaths and serious injuries be submitted to the FDA by manufac­turers and importers. The new law extends this requirement to users of medical devices along with manufacturers and importers. This act represents a significant step forward in protecting patients exposed to medical devices.

References

Bronzino, J. D., Flannery, E. J., and Wade, M. L. “Legal and Ethical Issues in the Regulation and Devel­opment of Engineering Achievements in Medical Technology,” Part I IEEE Engineering in Medicine and Biology, 1990a.

Bronzino, J. D., Flannery, E. J., and Wade, M. L. “Legal and Ethical Issues in the Regulation and Devel­opment of Engineering Achievements in Medical Technology,” Part II IEEE Engineering in Medicine and Biology, 1990b.

Bronzino, J. D., Chapter 10 “Medical and Ethical Issues in Clinical Engineering Practice” In: Management of Medical Technology. Butterworth, 1992.

Bronzino, J. D., Chapter 20 “Moral and Ethical Issues Associated with Medical Technology” in: Instruction to Biomedical Engineering. Academic Press, 1999.

Capron, A. “Human Experimentation: Basic Issues.” In: The Encyclopedia of Bioethics vol. II. The Free Press, Glencoe, IL, 1978.

Capron, A. “Human Experimentation.” In: (J. F. Childress, et al., eds.) University Publications of America, 1986.

Further Information

Daniels, N. Just Health Care. Cambridge University Press, Cambridge, 1987.

Dubler, N. N. and Nimmons, D. Ethics on Call. Harmony Books, New York, 1992.

Jonsen, A. R. The New Medicine and the Old Ethics. Harvard University Press, Cambridge, MA, 1990. Murphy, J. and Coleman, J. The Philosophy of Law. Rowman and Allenheld, 1984.

Laxminarayan, S., Bronzino, J. D., Beneken, J. E. W., Usai, S., Jones, R. D.

"Swamy Laxminarayan, Joseph D. Bronzino, Jan E. W. Beneken, Shiro Usai, Richard D. Jones" The Biomedical Engineering Handbook: Second Edition.

Ed. Joseph D. Bronzino

Boca Raton: CRC Press LLC, 2000

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