Ethical Considerations of Biomedical Product Development

Abstract

The importance of ethics can be perceived considering the immorality in terrible history of several projects in the field of biomedical research (e.g., Tuskegee, Willowbrook, Milgram, Stanford Prison, etc.). Tuskegee Syphilis Study, for instance, is conducted by the U.S. Public Health Service (1932–1972). In this study, 400 subjects out of 600 African-American males from a low social economic population were infected with syphilis and observed for 40 years. Free medical check-up was given; however, participants were not aware of their disease. Even though a proven treatment such as penicillin was available in the 1950s, the study continued until 1972 and subjects did not receive treatment. In some cases, when other physicians diagnosed that the participants had syphilis, researchers intervened to stop the treatment. During the research study, many participants died of syphilis. Finally, the study ended in 1973 by the US Department of Health, Education, and Welfare after disclosing its details and a political embarrassment. In 1997, President Clinton under mounting pressure apologized to the study subjects and their families. Because of the advertising from the Tuskegee Syphilis Study, the National Research Act of 1974 was legislated in the United States [1].

Appendices

Appendix 1. The Nuremberg Code (1947)

• 1. The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent, should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs, or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.

• 2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature.

• 3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results justify the performance of the experiment.

• 4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.

• 5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.

• 6. The degree of risk to be taken should never exceed that determined by humanitarian importance of the problem to be solved by the experiment.

• 7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability or death.

• 8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct and engage in the experiment.

• 9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible.

• 10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of good faith, superior skill and careful judgment required of him, that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

Appendix 2. Declaration of Helsinki (1975)

Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended by the 29th WMA General Assembly, Tokyo, Japan October 1975.

13.1.1 Introduction

It is the mission of the medical doctor to safeguard the health of the people. His or her knowledge and conscience are dedicated to the fulfilment of this mission.

The Declaration of Geneva of the World Medical Association binds the doctor with the words: ‘The health of my patient will be my first consideration’, and the International Code of Medical Ethics declares that ‘Any act or advice which could weaken physical or mental resistance of a human being may be used only in his interest’.

The purpose of biomedical research involving human subjects must be to improve diagnostic, therapeutic and prophylactic procedures and the understanding of the etiology and pathogenesis of disease.

In current medical practice, most diagnostic, therapeutic or prophylactic procedures involve hazards. This applies a fortiori to biomedical research.

Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects. In the field of biomedical research, a fundamental distinction must be recognized between medical research in which the aim is essentially diagnostic or therapeutic for a patient, and medical research the essential object of which is purely scientific and without direct diagnostic or therapeutic value to the person subjected to the research.

Special caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research purposes must be respected.

Because it is essential that the results of laboratory experiments be applied to human beings to further scientific knowledge and to help suffering humanity, the World Medical Association has prepared the following recommendations as a guide to every doctor in biomedical research involving human subjects. They should be kept under review in the future. It must be stressed that the standards as drafted are only a guide to physicians all over the world. Doctors are not relieved from criminal, civil and ethical responsibilities under the laws of their own countries.

13.1.2 I Basic principles

• 1. Biomedical research involving human subjects must conform to generally accepted scientific principles and should be based on adequately performed laboratory and animal experimentation and on a thorough knowledge of the scientific tradition.

• 2. The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol which should be transmitted to a specially appointed independent committee for consideration, comment, and guidance.

• 3. Biomedical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given her consent.

• 4. Biomedical research involving human subjects cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject.

• 5. Every biomedical research project involving human subjects should be preceded by careful assessment of predictable risks in comparison with foreseeable benefits to the subject or to others. Concern for the interests of the subject must always prevail over the interest of science and society.

• 6. The right of the research subject to safeguard his or her integrity must always be respected. Every precaution should be taken to respect the privacy of the subject and to minimize the impact of the study on the subject’s physical and mental integrity and on the personality of the subject.

• 7. Doctors should abstain from engaging in research projects involving human subjects unless they are satisfied that the hazards involved are believed to be predictable. Doctors should cease any investigation if the hazards are found to outweigh the potential benefits.

• 8. In publication of the results of his or her research, the doctor is obliged to preserve the accuracy of the results. Reports of experimentation not in accordance with the principles laid down in this declaration should not be accepted for publication.

• 9. In any research on human beings, each potential subject must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study and the discomfort it may entail. He or she should be informed that he or she is at liberty to abstain from participation in the study and that he or she is free to withdraw his or her consent to participation at any time. The doctor should then obtain the subject’s freely given informed consent, preferably in writing.

• 10. When obtaining informed consent for the research project, the doctor should be particularly cautious if the subject is in a dependent relationship to him or her or may consent under duress. In that case, informed consent should be obtained by a doctor who is not engaged in the investigation and who is completely independent of this official relationship.

• 11. In cases of legal incompetence, informed consent should be obtained from the legal guardian in accordance with national legislation. Where physical or mental incapacity makes it impossible to obtain informed consent, or when the subject is a minor, permission from the responsible relative replaces that of the subject in accordance with the national legislation.

• 12. The research protocol should always contain a statement of ethical consideration involved and should indicate that the principles enunciated in the present declaration are complied with.

13.1.3 II Medical research combined with professional care (clinical research)

• 1. In the treatment of the sick person, the doctor must be free to use a new diagnostic and therapeutic measure, if in his or her judgment it offers the hope of saving life, re-establishing health or alleviating suffering.

• 2. The potential benefits, hazards and discomfort of a new method should be weighed against the advantages of the best current diagnostic and therapeutic methods.

• 3. In any medical study, every patient – including those of a control group, if any – should be assured of the best proven diagnostic and therapeutic method.

• 4. The refusal of the patient to participate in a study must never interfere with the doctor–patient relationship.

• 5. If the doctor considers it essential not to obtain informed consent, the specific reasons for this proposal should be stated in the experimental protocol for transmission to the independent committee.

• 6. The doctor can combine medical research with professional care, the objective being the acquisition of new medical knowledge, only to the extent that medical research is justified by its potential diagnostic or therapeutic value for the patient.

13.1.4 III Non-therapeutic biomedical research involving human subjects (non-clinical biomedical research)

• 1. In the purely scientific application of medical research carried out on a human being, it is the duty of the doctor to remain the protector of the life and health of that person on whom biomedical research is carried out.

• 2. The subjects should be volunteers – either healthy persons or patients for whom the experimental design is not related to the patient’s illness.

• 3. The investigator or the investigating team should discontinue the research if in his/her or their judgment it may, if continued, be harmful to the individual.

• 4. In research on man, the interest of science and society should never take precedence over considerations related to the well-being of the subject.

Appendix 3. Guidelines for Ethical Conduct in the Care and Use of Animals

Developed by the American Psychological Association's Committee on Animal Research and Ethics (CARE) ¹

13.1.1 I. General

• A. In the ordinary course of events, the acquisition, care, housing, use, and disposition of animals should be in compliance with relevant federal, state, local, and institutional laws and regulations and with international conventions to which the United States is a party. In accordance with Principle 3(d) of the Ethical Principles of Psychologists of APA, when federal, state, provincial, organizational, or institutional laws, regulations, or practices are in conflict with Association Guidelines, psychologists should make known their commitment to Association Guidelines and, whenever possible, work toward resolution of the conflict.

• B. Psychologists and students working with animals should be familiar with these Guidelines, which should be conspicuously posted in every laboratory, teaching facility, or other setting in which animals are maintained and used by psychologists and their students.

• C. Violations of these Guidelines should be reported to the facility supervisor whose name is appended at the end of this document. If not resolved at the local level, allegations of violations of these Guidelines should be referred to the APA Committee on Ethics, which is empowered to impose sanctions. No psychologists should take action of any kind against individuals making, in good faith, a report of violation of these Guidelines.

• D. Individuals with questions concerning these Guidelines should consult with the Committee on Animal Research and Experimentation.

• E. Psychologists are strongly encouraged to become familiar with the ethical principles of animal research. To facilitate this, the Committee on Animal Research and Experimentation will maintain a list of appropriate references.

13.1.2 II. Personnel

• A. A supervisor, experienced in the care and use of laboratory animals, should closely monitor the health, comfort, and humane treatment of all animals within the particular facility.

• B. Psychologists should ensure that personnel involved in their research with animals be familiar with these Guidelines.

• C. It is the responsibility of the supervisor of the facility to ensure that records of the accession, utilization, and disposition of animals are maintained.

• D. A veterinarian should be available for consultation regarding: housing, nutrition, animal-care procedures, health, and medical attention. The veterinarian should conduct inspections of the facility at least twice a year.

• E. Psychologists should ensure that all individuals who use animals under their supervision receive explicit instruction in experimental methods and in the care, maintenance, and handling of the species being studied. Responsibilities and activities of all individuals dealing with animals should be consistent with their respective competencies, training and experience in either the laboratory or the field setting.

• F. It is the responsibility of the psychologist to ensure that appropriate records are kept of procedures with animals.

• G. It is the responsibility of the psychologist to be cognizant of all federal, state, local, and institutional laws and regulations pertaining to the acquisition, care, use, and disposal of animals. Psychologists should also be fully familiar with the NIH Guide for the Care and Use of Laboratory Animals.

13.1.3 III. Facilities

• A. The facilities housing animals should be designed to conform to specifications in the NIH Guide for the Care and Use of Laboratory Animals.

• B. Psychologists are encouraged to work toward upgrading the facilities in which their animals are housed.

• C. Procedures carried out on animals 128 APA GUIDELINES are to be reviewed by a local institutional animal care and use committee to ensure that the procedures are appropriate and humane. The committee should have representation from within the institution and from the local community. If no representative from the local community is willing to serve, there should be at least one representative on the committee from a non-science department. In the event that it is not possible to constitute an appropriate local institutional animal care and use committee, psychologists should submit their proposals to the corresponding committee of a cooperative institution.

13.1.4 IV. Acquisition of Animals

• A. When appropriate, animals intended for use in the laboratory should be bred for that purpose.

• B. Animals not bred in the psychologist’s facility are to be acquired lawfully. The U.S. Department of Agriculture (USDA) may be consulted for information regarding suppliers.

• C. Psychologists should make every effort to ensure that those responsible for transporting the animals to the facility provide adequate food, water, ventilation, and space, and impose no unnecessary stress upon the animals.

• D. Animals taken from the wild should be trapped in a humane manner.

• E. Endangered species or taxa should be utilized only with full attention to required permits and ethical concerns. Information can be obtained from the Office of Endangered Species, U.S. Department of the Interior, Fish and Wildlife Service, Washington, D.C. 20240. Similar caution should be used in work with threatened species or taxa.

13.1.5 V. Care and Housing of Animals

Responsibility for the conditions under which animals are kept, both within and outside of the context of active experimentation or teaching, rests jointly upon the psychologist and those individuals appointed by the institution to administer animal care. Animals should be provided with humane care and healthful conditions during their stay in the facility. Psychologists are encouraged to consider enriching the environments of their laboratory animals, where appropriate.

13.1.6 VI. Justification of the Research

• A. Research should be undertaken with a clear scientific purpose. There should be a reasonable expectation that the research will a) increase knowledge of the processes underlying the evolution, development, maintenance, alteration, control, or biological significance of behavior, b) increase understanding of the species under study, or c) provide results that benefit the health or welfare of humans or other animals.

• B. The scientific purpose of the research should be of sufficient potential significance as to outweigh any harm or distress to the animals used. In this regard, psychologists should act on the assumption that procedures that would produce pain in humans will also do so in other animals.

• C. The psychologist should always consider the possibility of using alternatives to animals in research and should be familiar with the appropriate literature.

• D. Research on animals may not be conducted until the protocol has been reviewed by the institutional animal care and use committee to ensure that the procedures are appropriate and humane.

• E. The psychologist should monitor the research and the animals’ welfare throughout the course of an investigation to ensure continued justification for the research.

13.1.7 VII. Experimental Design

Humane considerations should constitute one of the major sets of factors that enter into the design of research. Two particularly relevant considerations should be noted:

• 1. The species chosen for study should be well-suited to answer the question(s) posed. When the 129 APA GUIDELINES research paradigm permits a choice among species, the psychologist should employ that species which appears likely to suffer least.

• 2. The number of animals utilized in a study should be sufficient to provide a clear answer to the question(s) posed. Care should be exercised to use the minimum number of animals consistent with sound experimental design, especially where the procedures might cause pain or discomfort to the animals.

13.1.8 VIII. Experimental Procedures

Humane consideration for the wellbeing of the animal should be incorporated into the design and conduct of all procedures involving animals. The conduct of all procedures is governed by Guideline VI.

• A. Procedures which involve no pain or distress to the animal, or in which the animal is anesthetized and insensitive to pain throughout the procedure and is euthanized before regaining consciousness, are generally acceptable.

• B. Procedures involving more than momentary or slight pain not relieved by medication or other acceptable methods, should be undertaken only when the objectives of the research cannot be achieved by other methods.

• C. Procedures involving severe distress or pain that is not alleviated require strong justification. An animal observed to be in a state of severe distress or chronic pain that cannot be alleviated and that is not essential to the purposes of the research, should be euthanized immediately.

• D. When aversive or appetitive procedures appear to be equivalent for the purposes of the research, then appetitive procedures should be used. When using aversive stimuli, psychologists should adjust the parameters of stimulation to levels that appear minimal, though compatible with the aims of the research. Psychologists are encouraged to test painful stimuli on themselves whenever reasonable. Whenever consistent with the goals of the research, consideration should be given to providing the animal with control of painful stimulation.

• E. Procedures involving extensive food or water deprivation should be used only when minimal deprivation procedures are inappropriate to the design and purpose of the research.

• F. Prolonged physical restraint should be used only if less stressful procedures are inadequate to the purposes of the study. Convenience to the psychologist is not a justification for prolonged restraint.

• G. Procedures that entail extreme environmental conditions, such as high or low temperatures, high humidity, modified atmospheric pressure, etc. should be undertaken only with particularly strong justification.

• H. Studies entailing experimentally induced prey killing or intensive aggressive interactions among animals should be fully justified and conducted in a manner that minimizes the extent and duration of pain.

• I. Procedures entailing the deliberate infliction of trauma should be restricted and used only with very strong justification. Whenever possible, without defeating the goals of the research, animals used in such research should be anesthetized.

• J. Procedures involving the use of paralytic agents without reduction in pain sensation require particular prudence and humane concern. Utilization of muscle relaxants or paralytics alone during surgery, without general anesthesia, is unacceptable, and shall not be used.

• K. Surgical procedures, because of their intrusive nature, require close supervision and attention to humane considerations by the psychologist.

  • 1. All surgical procedures and anesthetization should be conducted under the direct supervision of a scientist who is competent in the use of the procedure. 130 APA GUIDELINES

  • 2. If the surgical procedure is likely to cause greater discomfort than that attending anesthetization, and unless there is specific justification for acting otherwise, animals should be maintained under anesthesia until the procedure is ended.

  • 3. Sound post-operative monitoring and care should be provided to minimize discomfort, and to prevent infection and other untoward consequences of the procedure.

  • 4. As a general rule, animals should not be subjected to successive surgical procedures unless these are required by the nature of the research, the nature of the surgery, or for the well-being of the animal. However, there may be occasions when it is preferable to carry out more than one procedure on a few animals rather than to carry out a single procedure on many animals. For instance, there may be experimental protocols where it would be appropriate to carry out acute terminal surgical procedures on animals scheduled for euthanasia as part of another protocol rather than to utilize additional animals.

13.1.9 IX. Field Research

• A. Psychologists conducting field research should disturb their populations as little as possible. Every effort should be made to minimize potential harmful effects of the study on the population and on other plant and animal species in the area.

• B. Research conducted in populated areas should be done with respect for the property and privacy of the inhabitants of the area.

• C. Particular justification is required for the study of endangered species. Such research should not be conducted unless all requisite permits are obtained.

13.1.10 X. Educational Use of Animals

• A. For educational purposes, as for research purposes, consideration should always be given to the possibility of using non-animal alternatives. When animals are used solely for educational rather than research purposes, the consideration of possible benefits accruing from their use vs. the cost in terms of animal distress should take into account the fact that some procedures which can be justified for research purposes cannot be justified for educational purposes. Similarly, certain procedures, appropriate in advanced courses, may not be appropriate in introductory courses.

• B. Classroom demonstrations involving animals should be used only when instructional objectives cannot effectively be achieved through the use of videotapes, films or other alternatives. Careful consideration should be given to the question of whether the type of demonstration is warranted by the anticipated instructional gains.

• C. Animals should be used for educational purposes only after review by a departmental committee or by the local institutional animal care and use committee.

• D. Psychologists are encouraged to include instruction and discussion of the ethics and values of animal research in courses, both introductory and advanced, which involve or discuss the use of animals.

• E. Student projects involving pain or distress to animals should be undertaken judiciously and only when the training objectives cannot be achieved in any other way.

• F. Demonstrations of scientific knowledge in such contexts as exhibits, conferences, or seminars do not justify the use of painful procedures or surgical interventions. Audio-visual alternatives should be considered.

13.1.11 XI. Disposition of Animals

• A. When the use of an animal is no longer required by an experimental protocol or procedure, alternatives to euthanasia should be considered.

  • 1. Animals may be distributed to colleagues who can utilize them. 131 APA GUIDELINES Care should be taken that such an action does not expose the animal to excessive surgical or other invasive or painful procedures. The psychologist transferring animals should be assured that the proposed use by the recipient colleague has the approval of, or will be evaluated by, the appropriate institutional animal care and use committee and that humane treatment will be continued.

  • 2. It may sometimes be feasible to return wild-trapped animals to the field. This should be done only when there is reasonable assurance that such release will not detrimentally affect the fauna and environment of the area and when the ability of the animal to survive in nature is not impaired. Unless conservation efforts dictate otherwise, release should normally occur within the same area from which animals were originally trapped. Animals reared in the laboratory generally should not be released because, in most cases, they cannot survive or they may survive but disrupt the natural ecology.

• B. When euthanasia appears to be the appropriate alternative, either as a requirement of the research, or because it constitutes the most humane form of disposition of an animal at the conclusion of the research:

  • 1. Euthanasia shall be accomplished in a humane manner, appropriate for the species, under anesthesia, or in such a way as to ensure immediate death, and in accordance with procedures approved by the institutional animal care and use committee.

  • 2. No animal shall be discarded until its death is verified.

  • 3. Disposal of euthanized animals should be accomplished in a manner that is in accord with all relevant legislation, consistent with health, environmental, and aesthetic concerns, and approved by the institutional animal care and use committee.