Ethical Issues of Animal and Human Experimentation in the Development of Medical Devices


191.1

191.2

191.3

подпись: 191.1
191.2
191.3

Subrata Saha

Clemson University

Pamela S. Saha

Clemson University

Introduction Clinical Trials

The Reason for Clinical Trials • Dilemmas Presented by Clinical Trials • The Need for Double-Blind Trials Animal Experimentation Animal Testing • The Need for Animal Research • Regulations/Guidelines Related to Animal Research • The Public Debate

Introduction

The number and sophistication of new medical devices is transforming modern medicine at a rate never experienced before. These developments have saved the lives of many more patients and improved their quality of life drastically. Artificial joint replacements alone have transformed the field of orthopaedic surgery, and over 250,000 total hip and total knees are implanted annually in the United States. Ventricular assistive devices (VASs) have extended lives by years, lives that before would have certainly ended at the point the device would have been needed. An estimated two to three million artificial or prosthetic parts, manufactured by hundreds of different companies, are implanted in America each year. The massive production of such devices is not only big science but big business.

New medical devices, however, require thorough testing for safety and efficacy as well as submission for approval by the federal Food and Drug Administration (FDA) before being put on the market for public use. Testing of a new product takes considerable time and expense and is not without problems beyond those of a technical nature. This paper considers the ethical questions that arise when the demands of science, economics, and progress are not entirely compatible with issues raised about the rights and obligations toward human beings and animals.

One of the first levels of testing where ethical debate is more prominent is at the stage when the biomedical scientist is faced with the need to use animal subjects.1 Over the last 30 years there has been a growing debate over whether or not the use of experimental animals is even appropriate. Some animal rights activists have made violent protests and vandalized research facilities where animal experimentation takes place. Increased public sensitivity did help promote an effort by the government, as well as the
Scientific community, to regulate the use of animal subjects and to educate the public as to the importance of such research to the health and well being of both animals and humans. As a result efforts to promote the humane use of experimental animals that are used to advance knowledge of biomedical sciences are to be supported.

Inevitably human beings are involved during the final stages of testing medical devices or systems. While this imposes numerous ethical concerns and has stirred much discussion, clinical trials are nec­essary as the alternative would mean an end of learning anything new for the betterment of medical science and continued use of unsupported practices based on conjecture.2

Consequently, engineers involved with the development and design of medical technology need to become familiar with various aspects of clinical trials and animal research as well as the ethical issues that they raise. Normally, conduction of human experimentation is not a part of the training of an engineer,3 nor are complications presented by ethical concerns a traditional part of engineering educa­tion.4 In this chapter various ethical concerns are examined that are essential elements in the animal testing and the clinical trial of any new treatment modality.

Clinical Trials

The Reason for Clinical Trials

Clinical trials are designed to ascertain the effectiveness and safety of a new medical device as compared with established medical practice. This form of rigorous scientific investigation in a controlled environ­ment for the assessment of new treatment modalities is superior to the is forum of private opinion and individual chance taking. Holding the practice of medicine at the status quo and discontinuing all innovative work would be the only way to prevent exposing patients to some unforeseen risks in new treatments that come with the promise of improved care. Yet, even this does not protect patients from uncontrolled experimentation as conditions change even if the practice of medicine stands still. The changing effectiveness of antibiotics as well as the increase in antibiotic resistant strains through unin­formed overuse of such drugs is a perfect example of how even standard care held stationary can lead to a decline rather than just a status quo in level of medical care. If we wish to continue to seek out new ways to conquer disease or even maintain a current level of care, then we are essentially forced to decide on a manner in which human beings are to shoulder the risks involved.

Total Mastectomies for Stage I and II breast tumors and extracranial-intracranial anastomosis for internal carotid atherosclerosis were once routinely practiced. However, randomized trials have brought the necessity of these surgical procedures under closer scrutiny. Certain procedures which are continually used, such as the now twenty-year-old use of obstetric ultrasonography, are losing support in the battle to cut medical costs as these do not have the benefit of randomized clinical trials to prove their value. Answers are needed to questions concerning health and economic risks and benefits, and the burden of false positive and negative results, especially in this time of multiple options in a profit-driven atmosphere, along with dwindling resources and government aid to the sick, old, and poor.5

A clinical trial is the most reasonable means to test a device as well as control risks and prevent abuse of human subjects because of the following six major factors: (1) A limited number of closely monitored subjects in a controlled environment are in a safer situation than are the same subjects unobserved in relation to one another within the larger population, where the same kinds of risks are imposed by uncertainty about the efficacy of new devices. (2) Clinical trials give conclusive answers to important medical inquiries that otherwise could only be answered by guessing. Medical decisions based on proven results are certainly superior to those dependent on untested clinical opinion. One author has stated that “trials were introduced because personal opinion was so notoriously fragile, biased, and unreliable.” 6 Risks would indeed be greater and potential for harm magnified if doctors are made to make decisions in an environment of general uncertainty and when medical products available are unsupervised by review boards. In an uncontrolled situation, the individual practitioner can be influenced by motives of economic profit, the need to appear knowledgeable and abreast of the new, or by high-pressure sales­manship. In the zeal to argue for individual rights in clinical trials, worry should be placed on how those same rights are threatened in an environment without objective controls. (3) A society that restricts and oversees the advancement of medicine through regulated human experimentation will prevent the sub­jection of people to needless risks brought on by a plurality of devices that may cause harm and offer only a maintenance of the status quo as a benefit. There are a plentitude of types of redundant consumer goods on the market today, e. g., soft drinks that offer multiple ways to relieve one condition—thirst. However, in medicine the concerns are different. The onslaught of numerous types of drugs to relieve nausea during pregnancy should be limited to the testing of a few medicines that offer the greatest benefit. Control of the market place in medicine through government or private testing of the few most promising forms of treatment is a much safer environment than an extensive supermarket full of many possibilities and many potential risks. (4) Clinical trials advance expedient corroboration of medical theories so that research can be channeled in directions that show meaningful results. Promising research is rapidly pinpointed, and harmful products are removed from the hiding place of private opinion and promotional tactics. (5) Clinical trials are the answer to the moral imperative to thoroughly test all new medical devices. Such testing is deficient without a controlled study on human subjects. No researcher can state confidently that a product is safe and effective for human use without such a test. (6) AH clinical trials are evaluated by specialized committees formed for the objective of supervising the ethical conduct of investigators using human beings as subjects. In this manner, individual rights are protected and ethical guidelines effectively imposed in a manner superior to what could be expected in the isolated world of private clinical practice, with its competition for patients and pressures from manufacturers.

Dilemmas Presented by Clinical Trials The Problem of Informed Consent

One of the most controversial issues generated by clinical trials is that of informed consent.7 Informed consent protects certain human rights, such as the patient’s freedom to decide what risks to take with his/her own body, the right to the truth from the doctor in the doctor-patient relationship, and a just distribution of goods in accordance with a standard of equity and access to redress for undeserved harm. These values cannot be sacrificed for any sort of anticipated benefit from research. “The loss of such values is so harmful that benefits become meaningless.”8

Clinical Trials and the Doctor-Patient Relationship

Another issue currently debated is the conflict of clinical trials with the therapeutic obligation. Some authors argue that we must face the fact that if we are to expand the knowledge needed for obtaining high-quality treatment, we must sacrifice our therapeutic obligation. There are others who take a more apprehensive view of clinical trials, stating that trials on healthy subjects are condemned by the Nurem — burg Code, the Tokyo Declaration, and the Helsinki Declaration of the World Medical Association.9

However, outright condemnation of experimentation on healthy human subjects ignores the vital need for progress in preventive as well as remedial medical treatment. For example, the development and use of vaccines carry minimal but real risks to their recipients. Yet few dispute that vaccine research using human subjects is morally justified and may even be compulsory, despite the reality that persons can and do die from experimental as well as FDA approved vaccines. The control of crippling and deadly diseases, and their eventual elimination (i. e., small pox), is due to the study and implementation of vaccines. Those who support clinical trials say that a validated medical practice is a far better alternative for both the individual and society as a whole than subjection to treatments whose effectiveness are not validated by controlled trials.

One article offers several ideas for the elicitation of informed consent and assignment to randomized groups. The best model suggested for general use begins with selection of eligible patients, who are pre­randomized and given the entire protocol with an explanation of benefits and risks of all the options; consent is then sought, the patient knowing his or her group assignment.10

Proposed deviations from the above standard could be defended before review boards; for example, investigations that would be impeded by the patient knowing his or her group’s assignment but that promise the patient major benefits. However, the patient should be informed of any such stipulations and of the relative risks and benefits.

Standards of research require further consideration as a consensus needs to be achieved. For example, in order to test the effectiveness of transplanted embryonic pig cells into the brain for the treatment of Parkinson’s disease, a control group is required in which surgical boring of a hole into the skull occurs without the addition of any cells. This is to remove any placebo effect or any other unforeseeable effect of a mock surgical procedure on Parkinson’s disease. However, the question of simply boring a hole does subject a human being to a procedure with significant risk with little bases for suspecting a beneficial outcome. The design of scientific studies needs to weigh the risks to the human subjects against the need for scientific purity. Such opinions have been voiced by Arthur Caplan, director of the University of Pennsylvania’s Center for Biomedical Ethics who recently told the Boston Herald that, “striving for scientific accuracy is a commendable goal, but asking someone to have a hole drilled in their head for no purpose is putting science ahead of the subject’s interest.”

There has been much effort particularly in recent years toward the protection of individual rights. This is not surprising in this age of rising autonomy and declining paternalism. This concern has led to the consideration of whether or not treatment should be changed mid-course in an experiment due to the “appearance” of a tendency toward one result as opposed to another. At some point in collecting data, the experimenter may begin to surmise a particular outcome or even come to expect it (although he/she may not be certain). In these circumstances, the question arises as to whether the individual subject should be granted the hypothetical benefit of the “good guess,” or should the guess be treated as merely a guess and, hence, a gamble. To do so would mean that the best treatment for the individual might not be one that has been proven valid. In fact, such a choice implies that the best treatment is a perpetual gamble. Nonetheless, treatment methods that maximize the good guess have been presented.11

Another issue that has surfaced from the debate on informed consent is the idea of the “therapeutic misconception,” which refers to an unyielding expectation of personalized care on the part of patients during a clinical trial. This finding shows a need for better communication between the patient and the doctor. However, such “false expectations” could be due to a fundamental trust on the patient’s part believing that through cooperation with the physician in research, personal health needs will eventually be met according to the best available data at any given time. Perhaps, this notion should be addressed during a clinical trial.12

A local newspaper reported that some companies are enticing private physicians to register patients for their studies that have significant fees. What used to be the domain of academic researchers motivated by the drive for new discoveries, fame, and career advancement is now a multibillion dollar industry with numerous companies working with thousands of doctors in private practice having a profound impact on the doctor-patient relationship. Often the patient is unaware that significant amounts of money are involved in their recruitment for a study.13 In addition to the expected problems of human research that have been debated in the past, the influence of a growing industry invites the need for continued inspection and control not only for the prevention of abuse of human subjects but for even the possible effect such methods of recruiting could have on scientific integrity.

The Need for Double-Blind Trials

The double-blind study has magnified the issues concerning clinical trials already mentioned. Obviously, this type of trial means that both the physicians and the patients involved will not be given full information about the experiment. The double-blind study is the best safeguard against biased results. Indeed, the purpose of the double-blind trial is to bring about a treatment plan based on objective fact rather than on biased personal belief or guess work. Even well intentioned and honest researchers can fall victim to seeing their data too subjectively. For instance, an investigator may have a vested interest in the study because of personal prestige, financial gain, or merely normal enthusiasm and faith in his own work.14 These represent obstacles to objective results in research that are not blind. The originator and/or sponsor Of a project may suffer from a conflict of interest when either becomes directly involved in a study. The double-blind approach protects against such conflict. Although some investigators have argued that it is unethical for them to deprive control subjects of their product because they believe so strongly in its efficacy, personal conviction of the usefulness of one’s own work is not a good ethical reason for failing to thoroughly test a new device for safety and effectiveness. The moral imperative to thoroughly test is a basic concept to be followed to achieve a standing of good biomedical engineering.15

The biomedical engineer must face the current debate over the use of medical technology in accordance with the ethical, professional, and scientific imperative to thoroughly test his or her innovation. It is now time for biomedical engineers to stand up and support the sound moral use of clinical trials for the purposes of (1) scientific credibility of the biomedical engineering field, (2) protection of the individual from improper medical care due to unsupervised, unethical market-place forms of human research, and (3) the promotion of medical care based on sound reasoning and scientific fact. These principles are at the heart of the professionalism required of biomedical engineering research.16

Animal Experimentation

Animal Testing

Animal experimentation is an important step in the development of new implants and devices to determine their safety and effectiveness prior to their use in humans. There is no current alternative to the use of animal models to evaluate the biocompatibility of new materials and the response by a host.17 However, animal rights groups have raised important ethical considerations and have challenged the scientific community to justify the use of animals in research. The scientific community should respond and debate these issues. They should help to educate the public and increase understanding of the need for such research. A more proactive approach in this matter is imperative. It is also important that efforts be made by scientists to demonstrate to the public that animal research is done humanely, sparingly, and only when alternatives do not exist.18

The Need for Animal Research

Biomedical engineering has brought remarkable advancement to the field of medicine in a very short time frame. Just in the last quarter of this century we have seen achievements such as (1) pacemakers,

Total joint replacement, (3) artificial hearts, (4) CAT scan machines, and (5) improved surgical techniques made possible through the use of fiber optics, lasers, and ultrasonic devices. Along with these remarkable advances came the need for closer monitoring of the safety and effectiveness of inventions before their release for public use. More regulations, standards, and testing protocols were devised to ensure that each new product is subjected to a uniform system of scrutiny and procedure for approval. As part of that process, the testing of a product in animals is a likely necessary step. For example, NIH Guidelines for the Physicochemical Characterization of Biomaterials outlines a stepwise process for testing blood-contacting devices progressively in animals. A possible hierarchy of testing starting from in vitro to in vivo systems may be as follows:19

Cell culture cytotoxicity (mouse L929 cell line)

Hemolysis (rabbit or human blood)

Mutagenicity [human or other mammalian cells or Ames test (bacterial)]

Systemic injection acute toxicity (mouse)

Sensitization (guinea pig)

Pyrogenicity (limulus amebocyte lysate [LAL] or rabbit)

Intracutaneous irritation (rat, rabbit)

Intramuscular implant (rat, rabbit)

Blood compatibility (rat, dog)

Long-term implant (rat, rabbit, dog, primate)

Animal testing is a necessary means of evaluating a device in the internal environment of the living system. The suggestion that this can be replaced by computer modeling can only be made by one unaware of the lack of knowledge about in vivo conditions.20 The nearly inscrutable chemical pathways, the complex milieu of high chemical, mechanical and electrical activity, and the incalculable number of interactions inside the living organism cannot possibly be modeled theoretically today. Add to this the fact that normal conditions are different from disease states such as thrombosis or inflammation, and we find ourselves still further removed from the prospects of using simulation methods. Yet to thoroughly rule out both long and short-term failure of these products, they must be tested sufficiently to rule out risks of toxicity and even possible carcinogenic effects over many years. In response to questions raised about animal research, the American Association for the Advancement of Science issued a resolution in 1990 that supports the use of animals in research while emphasizing that experimental animals be treated humanely.

Regulations/Guidelines Related to Animal Research

A biomedical engineer must become familiar with regulations with regard to animal research. The National Research Council published a Guide for the Care and Use of Laboratory Animals initially as early as 1963 and most recently in 1996.

In addition to becoming familiar with this Guide, it is important to be aware of all applicable federal, state, and local laws, regulations, and policies such as the Animal Welfare Regulations and the Public Health Service Policy on Humane Care and Use of Laboratory Animals.22

The general objective is to have a cogent reason for conducting a particular experiment. It must be important to the health and well-being of humans or animals.23 It must be demonstrated that alternative means would not achieve the necessary goal. The choice of species must be shown to be essential and that species lower on the evolutionary ladder would not be suitable. An effort must be made to minimize the number of animals required and to prevent unnecessary duplication of tests. Pain and discomfort must be minimized unless important to the conduction of the experiment. Standards must be followed concerning (1) space allotment, (2) type of confinement, (3) availability of food and water, (4) care in transit, and (5) periods of exercise. The experiment must have clear limits and be performed under the close supervision of individuals appropriately trained. Provisions for veterinary care, environmental conditions, and euthanasia must also be made. If palliation of discomfort or pain must be withheld, a detailed explanation must be made available.

In 1985 congress passed The Food Security Act which amended the Animal Welfare Act of 1966. This required that research institutions have a committee of no less than three persons who are qualified to monitor animal care and practices in experimentation.17 These persons are to represent society’s interest in the proper treatment of animal subjects. The committee requires one veterinarian and one other person not connected with the institution. This committee must inspect all animal research and care facilities at the institution twice a year. The institution should in turn keep a report of each inspection on file for 3 years and report any information that notes violation of legal standards on the treatment of animals to federal officials. The committee must review specific areas of treatment of experimental animals, including pain management, veterinary care, and pre — and post-surgical care. A single animal must not be subjected to major survival surgery more than once unless justified scientifically. Dogs must be exercised and envi­ronmental conditions must be conducive to psychological well-being of primates. Note that policies by the National Science Foundation now extend to all vertebrate animals which is broader than the Animal Welfare Act that did not include (1) rats, (2) mice, (3) farm animals, and (4) birds.

The Public Debate

The debate about animal experimentation is marred by extremes on both sides of the issue.24 Scientists have been physically threatened and assaulted and their laboratories vandalized by extremist animal rights groups.25 Unwarranted charges that scientists only conduct animal research for personal gain and that these experiments are cruel and unnecessary demonstrate the extent of misinformation that exists for the public.

The actions of irresponsible activists must not obscure the serious philosophical issues raised by animal rights advocates. Some of them argue that there exists no justification for the claim that animals can be exploited for human benefit. This line of reasoning is that animals have rights equal to that of humans and as animals cannot give informed consent for an experiment they should be precluded from use. This represents a radical change that would have consequences beyond the use of animals in science. When animals are used as beasts of burden for example, should this be considered slavery? What of the use of animals for food, clothing, or even simply in sport. One author noted that a 1990 study showed that although 63% of literature advocating animal rights addresses only their use in research, such use annually is only 0.003% of the number of animals used as food.26 What about protection against pests in the home as well as in agriculture? Even the ownership of pets may be called into question, as a case of imprison­ment. Of all possible targets for basing a case against human exploitation of animals, the use of them in medical experiments is the least worthy. Scientists not only make the least use of animals but do so under strict regulation and with all attempts being made to minimize their use. If we are seriously going to elevate animals to a moral standing equal to human beings, then the research laboratory is not the appropriate place to start. The burden of explaining how all future interaction should take place with the rest of the animal kingdom lies with those who make such a claim.

The other extreme however, is the claim by some scientists that animals have no moral standing or intrinsic value. A report by the National Research Council in 1988 on the Use of Laboratory Animals in Biomedical and Behavioral Research says “Our society does, however, acknowledge that living things have inherent value.”27 This is consistent with society’s tendency to treat animals differently than inanimate objects. Even a mouse merits higher consideration than a stone. That animals have value, moral standing, or even rights is not equivalent to the suggestion that they are equal to human beings in their value, standing, and rights.

Humans are not the only beneficiaries of research on animals. Veterinary medicine would suffer without such research and the care of animals has significantly improved as a result of responsible animal experimentation. Today, human psychoactive drugs are being used for pets with behavioral problems.28

Conclusion

While there is continued consensus within the scientific community on the need for animal research, there is also increased sensitivity and awareness of the need for humane treatment of animals and the intrinsic value and moral standing of non-human animals. This has lead to improved guidelines and regulation on such use as well as much needed discussion on the purpose and ethics of animal research. While the debate will certainly continue, the use of violence, slander, and media sensationalism should be discouraged. This will only lead to further polarization of extreme views. Constructive and responsible discussion will help bring about a consensus on this very important matter that concerns the health and welfare of animals and humans alike.

References

An, Y. H. and Friedman, R. J. Animal Models in Orthopaedic Research, CRC Press, Boca Raton, FL, 1998.

Saha, P. and Saha, S. “Clinical trials of medical devices and implants: Ethical concerns,” IEEE Eng. Med. Y Biol. Mag., 7, 85-87, 1988.

Saha, P. and Saha, S. Ethical responsibilities of the clinical engineer, J. Clin. Eng., 11, 17-25, 1986.

Saha, P. and Saha, S. The need of biomedical ethics training in bioengineering, In Biomedical Engineering I: Recent Developments, S. Saha, Ed., Pergamon Press, New York, 369-373, 1982.

Bracken, M. B. Clinical trials and the acceptance of uncertainty, British Med. J., 294, 1111-1112, London, 1987.

Vere, D. W. Problems in controlled trials: A critical response. J. Med. Ethics, 9(2), 85-89, 1983.

Kaufmann, C. L. Informed consent and patient decision making: Two decades of research, Soc. Sci. Med., 21, 1657-1664, 1983.

Dyck, A. J. and Richardson, H. W. The moral justification for research using human subjects, In Biomedical Ethics and the Law, J. M. Humber and R. F. Almeder, Eds., Plenum Press, New York, 243-259.

Arpzilange, P., Dion, S., Mathe, G. Proposal for ethical standards in therapeutic trials, British Med. J., 291, 887-889, 1985.

Kopelman, L. Randomized clinical trials consent and the therapeutic relationship, Clin. Res., 31(1), 1-11, 1983.

Meler P. Terminating a trial: The ethical problem, Clin. Pharmacol. Therap., 25, 637-640, 1979.

Appelbaum, P., Lidz, C. W., Benson, P., et al. False Hopes and Best Data: Consent to Research and the Therapeutic Misconception, Hastings Center Report, 17(2), 20-24, 1987.

Eichenwald, K. and Kolata, G. Drug trials threaten doctors’ credibility, Anderson Independent Mall, Sunday, May 16, 1999, 13A.

Saha, S. and Saha, P. Bioethics and applied biomaterials, J. Biomed Mat. Res., App. Biomat., 21(A-2), 181-190, 1987.

Saha, S. and Saha, P. Biomedical ethics and the biomedical engineer: A review, Crit. Rev. Biomed. Eng., 25(2), 163-201, 1997.

Mappes, T. A. and Zembaty, J. S. Biomedical Ethics, 2nd ed., McGraw-Hill, New York, 1986.

Saha, P. and Saha, S. Ethical Issues on the Use of Animals in the Testing of Medical Implants, J. Long-Term Effects of Med. Impl., 1(2), 127-134, 1991.

Lukas, V. and Podolsky, M. L. The Care and Feeding of an IACVC, CRC Press, Boca Raton, FL, 1999.

Vale, B. H., Wilson, J. E., and Niemi, S. M. Animal models, In Biomaterials Science, Academic Press, San Diego, CA, 240, 1996.

Malakoff, D. Alternatives to animals urged for producing antibodies, Science, 284, 230, 1999.

National Research Council, Guide for the Care and Use of Laboratory Animals, 2nd ed., 1996.

Rollin, B. E. and Kesel, M. D. The Experimental Animal in Biomedical Research, CRC Press, Boca Raton, FL, 1, 1990.

Saha, S. and Saha, P. Biomedical ethics and the biomedical engineer: A review, Crit. Rev. Biomed. Eng., 25(2), 163-201, 1997.

Saha, S. and Saha, P. Biomedical engineering and animal research, BMES Bulletin, 16(2), 22, 1992.

Kower, J. Activists ransack Minnesota labs, Science, 284:410-411, 1997.

Conn, P. M and Parker, J. Animal Rights: Reaching the Public, Science, 282:1417, 1998.

Herzog, H. A. Jr. Informed Opinions on Animal Use Must Be Pursued, ILAR News, Institute of Laboratory Animal Resources, 31(2), Spring 1989.

Bunk, S. Market Emerges for Use of Human Drugs on Pets, The Scientist, 1 & 10, April 12, 1999.

Bronzino, J. D. “Regulation of Medical, Device Innovation.” The Biomedical Engineering Handbook: Second Edition.

Ed. Joseph D. Bronzino

Boca Raton: CRC Press LLC, 2000

Добавить комментарий

Ваш e-mail не будет опубликован. Обязательные поля помечены *