Medical ethics

Chapter 7

Human and Animal research with reference to Islamic ethical values and principles

Medical science is rapidly growing field and largest research is underway in different aspects of clinical and basic medical sciences both in diagnostics and therapeutics. The purpose of research is to advance human knowledge in the hope that it may benefit society for the common good. We are not sure that in spite of the tremendous advances in both medical knowledge and technical sophistication, it is not quite certain that people

are better or happier as a result of research studies, although man may live longer than before. Experiments that involve medical or surgical studies of the human body both in diagnostics and therapeutics involving human and non human biological experimentations including animal experimentation. We have been inclined to surround research with a mantle of sanctity. We can not halt the experimentation because this in other way will lead to challenge progress in medical field but we have to regulate all sort of medication in the best interest of humanity and to protect the dignity and sanctity of life. As for as the experimentation and research is concerned there are many categories and gradations of human and animal experimentation.

7-1 Human Experimentation and research trials on human beings

The types of experimentation range from noninvasive studies such as
demographic analyses of ethnic groups in poverty areas to the experimental transplantation of heart and lungs into a dying patient. Regardless of the category or the quality of the study, the principles involved are the same. We can categorize experiments in to three major inter linked and overlapping types:

a) Pure research, in which experiments are conducted that have no direct commercial application, with a view to advancing knowledge, most often inside universities.

b) Applied research, conducted in order to solve specific biological problems or to develop commercial products, either for medical or non-medical use.

c) Toxicology or safety testing, in which commercial products are tested on animals to measure potential adverse biological reactions to the ingredients.

1. Basic research:

Basic and clinical research is aiming to enhance knowledge about diagnostic and therapeutic methods of curing human sufferings on one hand and better understanding of human life, society, environments, managing and prevention of human disease on the other hand. In summary this type of research help us in understanding better about the way organisms behave, develop, and function biologically. Both the largest number and greatest variety of laboratory animals are used in this type of research.

Examples of the types of animals and experiments used in basic research include: Mutation to study mechanisms in embryonic and developmental biology. Animals are often treated with radiation or with the chemicals which cause mutation during developmental period to generate defective embryos. By studying disrupted development, scientists aim to understand both how organisms develop normally and abnormally The 1995 and 2002 Nobel Prizes in Physiology/ Medicine were awarded for research into developmental processes in animals using a genetic screen for new genes is often referred to as forward genetics as opposed to reverse genetic, the term for identifying mutant alleles in genes that are already known. Mutant alleles that are not tagged for rapid cloning (the process of copying the same copy of an original organism or thing) are mapped and cloned by positional cloning. Embryos used in experiments are often not covered by legislation and therefore not always required to be reported. Consequently, those that believe embryos are de facto animals claim the published number of experimental animals used is an under-representation. Two scientists from the UK and one from USA were awarded Nobel prize for their discoveries concerning 'genetic regulation of organ development and programmed cell death'"

Experiments into behavior, to understand how organisms detect and interact with each other and their environment. Fruit flies, worms, mice and rats are all widely used in research into mechanisms of vision, taste, hearing, touch, and smell. In addition studies of brain function, such as memory and social behavior, often use rats and birds. Less common is the use of larger mammals in these types of studies.

Breeding experiments to study evolutional developments and genetic studies: Various animals like laboratory mice, flies, fish and worms are inbred through many generations to produce strains with defined characteristics. These processes provide scientists with animals of a known genetic background, an important tool for genetic analysis that is currently not available when studying outbreed subjects (such as most human populations). Larger mammals are rarely bred specifically for such studies due to their longer gestational periods, though some scientists take advantage of use of domestic animals like dogs and cats for this purpose. But experiments on mammals are limited.

2. Applied research

Applied research carries problem solving behavior and a miming to achieve the best possible solution of a medical problem. This type of research aims to solve specific and practical problems, often relating to the treatment or cure of disease and disorder in humans and animals. Pure research mainly academic in nature and need lot of funding from research organizations, universities, institutions or states. While applied research is mostly directed to come up solution of existing or impending issue and being funded either by pharmaceutical industry or in universities and research institutions this reset is jointly founded by bio-medical industry and universities. As this type off research needs to be directed for certain health issue/ study of pathological behavior and outcome of proposed treatment process etc. This research may involve the use of animal model of a human disease, allowing the researchers to investigate disease states in ways which would be inaccessible in a human patient, performing procedures on the non-human animal that imply a level of harm that would not be considered ethical to inflict on a human. As the new approach to drug discovery has been to understand how disease or an infection is controlled at physiological and molecular level and to target entities based on this knowledge. Though in certain situations such applied studies may be an early stage in new approach to drug discovery process.

The example of such type of applied research could be:

Animal models of naturally occurring disease and condition: Many wild and domestic animals have natural propensity of developing pathological conditions that are also found in humans. Certain domestic and wild animals have a natural propensity or predisposition for certain conditions Cats, for example are used as a model to develop immunodeficiency virus vaccines due to their natural predisposition to Feline immunodeficiency virus vaccine: Implications for diagnostic testing and disease management. Feline immunodeficiency virus (FIV) is a natural infection of domestic cats, which produces a disease with many similarities to human immunodeficiency virus (HIV) infection in man. The virus is an important cause of morbidity and mortality in cats worldwide. As such an effective vaccine is desirable both for its use in veterinary medicine and also as a model for the development of an HIV vaccine. A large number of candidate vaccines have been tested against feline immunodeficiency virus. These include inactivated virus and infected cell vaccines, DNA and viral vectored vaccines, subunit and peptide vaccines and vaccines using bacterial vectors. Ultimately, the development of inactivated virus and infected cell vaccines led to the release of the first licensed vaccine against FIV, in 2002. This review highlights some of the difficulties associated with the development of antiviral vaccines and some of the lessons that have been learned in the FIV model that are of particular relevance to the development of HIV vaccines.

Their infection with a related feline virus, Feline leukemia virus makes cats a common model for Leukemia research also. Many breeds of dogs suffer fro narcolepsy- a disease cussing excessive day time sleep in spite of good night sleep, the dog model of this disease is used to study this human disease in much more details. Other human diseases can be produced in human models are: Leprosy models in armadillos only a few animal species that naturally suffer from leprosy a human disease. As causative organism (Gram positive bacilli) cannot yet be grown in culture, armadillos are the primary source of bacteria used in leprosy vaccines. Non human primates, being closely related to humans, are applied in the study of a number of human conditions, including dental and visual disorders. Primates are also used extensively in immunology and reproductive studies, a synthesis of which resulted in the discovery of the Rh factor (Rhesus factor)

Transgenic animals have specific genes inserted, modified or removed, with the aim of modeling a specific condition. The aim of these models may be to exactly mimic an already known single genetic disorder like albinism Duchene Muscular dystrophy and development of animal models to investigate and find out more efficient ways of its treatment. More complicated disorders like malignancies and neurological disorders as well as cardiovascular disorders are reproduced in animal model to study the pathology and clinical course of certain disease as well as effects of various drugs and other agents like radiation etc. on these diseases. Pharmaceutical industry< scientific bodies, medical institutions, social and philanthropic workers and professional bodies consider “explosion of research on such disease and widely endorse these techniques.” However animal right groups regularly object the sacrifice of animal lives considering all genetic modification in efficient and animals do not always model human disease accurately and correctly.

Due to worldwide shortage of organs for clinical transplantation about 60% of patients needing new organs die on the waiting list. Scientists are striving to over come this clinical issue and use animal organs to be transplanted in human beings (Xenotransplantation), in the hope of potential treatment for end-stage organ failure, one of the most important health problems facing the industrialized world today. Apart from difference in life span of the animals Disease transmission from animals and permanent change to the genetic code of animals are cause for concern. Certain primates, pigs, monkeys are currently used for experimentation. Some scientists and professional agencies consider xenotransplantation as useless effort.

3. Toxicology or safety testing

Since 1960 all drugs being introduced in clinical practice must undergo animal testing to establish the pharmacological testing including the toxic effects of that particular drug. Thereafter go on clinical trails. Though new drugs are letter under go clinical trails and there after can only be recommended are registered with the drug control authorities even after registration some drugs removed from the formulator due to one or the other reasons.

7-3 Animal research or animal testing of drugs:

Various animals ranging from primitive fruit flee and mice primates are used annually and either killed during the experiments or subsequently scarified. Nearly 50 to 100 million animals are used for experimentation worldwide. The research is carried out inside universities, medical schools, pharmaceutical companies, farms, defense-research establishments, and commercial facilities that provide animal-testing services to industry. Most of these animals are grown in labs for this purpose or caught or being purchased from the market.

History of animal experimentation for the development of medicine is very old and can be traced back when Abu Ali Ibne Seena and Al Zuharvi used animals for such purposes.

In Greek writing as well as Aristotle and physicians in room also performed experiments on living animals. In modern world (1880 ) Louis Pasteur experimented on sheep to develop germ theory of medicine by developing anthrax in sheep, Insulin was isolated from dogs in 1922, anti leprosy antibiotics were developed in 1970 through experimentation on armadillos then in humans. First mammal Dolly sheep was cloned an adult cell in 1996.

Examples of drug testing are

Metabolic test,

Toxicology tests,

Efficacy studies, Specific tests on ''reproductive function'', ''embryonic toxicity'' or ''carcinogenic potential'' can all be required by law, dependent of the result of other studies and type of drug being tested.

. The drug is then administered in a [[Randomized controlled trial double-blind controlled trial]]. This is intended to allow scientists. Various countries have come up with state regulation in the form of ethical acts, for example United Kingdom has promulgated a law to protect the rights of animals used in research. This act is more applied and explained some important issues:

The Animals (Scientific Procedures) Act 1986 requires experiments to be regulated by three licenses: a project license for the scientist in charge of the project, which details the numbers and types of animals to be used, the experiments to be performed, and the purpose of them; a certificate for the institution to ensure it has adequate facilities and staff; and a personal license for each scientist or technician who carries out any procedure. In deciding whether to grant a license, the home office refers to the Act's cost benefit analysis which is defined as "the likely adverse effects on the animals concerned against the benefit likely to accrue as a result of the programme to be specified in the license" (Section 5(4)). A license should not be granted if there is a "reasonably practicable method not entailing the use of protected animals" (Section 5(5) (a)). The experiments must use "the minimum number of animals, involve animals with the lowest degree of Neurophysiological sensitivity, cause the least pain, suffering distress or lasting harm, and [be the] most likely to produce satisfactory results" (Section 5(5) (b) Like UK other western countries and Japan also formulated laws and regulation for the use of animal in the process of experimentation.

For example more comprehensive regulations have been letdown by United State’s regulatory bodies. Merit acknowledging the tremendous efforts put by AAALAC non governmental organization prote4cting the right of Animals used in research.

Accreditation from the Association for Assessment and Accreditation of Laboratory Animal Care International { AAALAC}³⁰ not for profit association, is regarded by the industry as the "gold standard" of accreditation.³¹ Accreditation is maintained through a prearranged AAALAC site visit and program evaluation hosted by the member institution once every three years.³² Accreditation is intended to ensure compliance with the standards in the Guide for the Care and Use of Laboratory Animals, as well as any other national or local laws on Animal welfare.

A more widespread ethical problem although one that has not yet received much attention, is raised by new pharmaceutical products. All new drugs are tested on human volunteers. There is, of course, no way can that subjects be fully apprised of the risks in advance, because that is what the tests are conducted to find out. Monetary compensation makes up for repeated blood tests and the other inconveniences that is routine for test subjects. But, should any serious health problem actually result, monetary compensation cannot begin to make up for the potential results. Manufacturers, of course, hope that animal tests will give a good indication of the potential risks. However, neither animal tests, nor the human pre market tests themselves, reveal the full range of drug risks.

Drug Research: After the drug has been tested on animals and approved for human use, the drug is allowed for use on human beings provided the safety of the drug has been established. Double blind drug research or using placebos is allowed, but the patient must be informed and consent must be taken. Worsening of the disease while in drug research, either due to placebo or an ineffective dosage of the drug must be carefully monitored and the trial should be ended for the safety of the patient.

7.4 Clinical Trials

When the efficacy and safety of the drug/ pharmacological agent etc. is established through all the stages mentioned above, the drug is allowed for limited clinical use on trial bases where the safety of every user (patient or healthy volunteers) is guaranteed. After establishing the efficacy as well as safety of pharmacological agent, it registered with the drug control authorities and thereafter allowed for wider clinical use. The process of evaluation of all drugs should continue even after permitting the drug for clinical use because long term clinical effects, side effects, toxic effects as well as adverse reactions are established only after wider use of the drug.

Clinical trials are scientific research studies designed to find better ways to treat or prevent diseases. There are various ethical issues related to clinical trials and participation of the patients or group of patients regarding participation in one or the other trial. The patients or volunteers must be provided an opportunity to make an educated decision about participating in a clinical trial and they must be clearly made understand the clinical trial process. These clinical research studies rely on patients who volunteer to participate. Some of these drugs have not yet been approved by the Food and Drug Administration (FDA) for sale in the United States and other such authorities in other countries. Sometimes the drugs are currently available for sale, but are being tested for a new disease or additional information.

7-4 Ethics of health care research:

Clinical research has a potential risk of harm, and therefore sound standards of ethics must be observed. Research involving human subjects is based on a moral commitment to advancing human welfare, knowledge and understanding, and to exploring cultural dynamics. This has become prominent especially where large-scale trials conducted in developing countries are concerned. Of fundamental importance is the duty to conduct scientifically sound research while acting in the participant's best interests and respecting and protecting the participant's autonomy. Some guiding principles of ethics are respect for: human dignity, autonomy, informed consent, vulnerable persons, confidentiality, and the lack of harm, maximum benefit, and justice. Issues of informed consent are of particular importance, as specified in the Constitution of the Republic of South Africa. The Geneva declaration of the World Medical Association (1981), binds the physician with the words, "The health of my patient will be my first consideration" and the International Code of Medical Ethics declares that, "A physician shall act only in the patient's interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient." Before embarking any sort of research related to human being certain basic principles needs to be adhere so that no breach of any sort could be demonstrated.

1. Biomedical research involving human beings must 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 his or her consent.

2. Every biomedical research project involving human subjects must be started after having assisted the predictable risks in comparison with foreseeable benefits to the subject or to others. Individual concern must always supersede over the interests of science and society.

3. Every precautionary measure 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.

4. All those participating in the research must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study and the discomfort it may entail. They must have been informed that they have free choice to withdraw or are at liberty to abstain from participation in the study even if they have consented to participate.

5. While taking informed consent to participate in a research project the physician must not influence the patient to participate using his personal relationship with patient. In such event it is better the informed consent should be obtained by a physician who isn't engaged in the investigation and who is completely independent of this official relationship.

6. When legal incompetence exists, informed consent must be obtained from the legal guardian in accordance with the existing national legislation. In case of physical or mental incapacity of the subject and obtaining consent is not possible, or when the subject is a minor, permission from the responsible next to kin must be seeked in accordance with national legislation. Whenever the minor child is in fact able to give consent, the minor's consent must be obtained in addition to the consent of the minor's legal guardian.

7. All research protocols must be approved by the institutional ethical committee which ensure the compliance of the principles enunciated in the present declaration are complied with. Special considerations are given to research project where health research is combined with professional care of the patients (Clinical research).

8. In all those cases of research where informed consent is not required, the physician must elaborate the reasons; the specific reasons for this proposal should be stated in the experimental protocol for transmission to the independent committee.

9. Clinical or basic research can be combined with the professional care of the patients to foster medical knowledge and to seek better understanding of disease course. This type of research is justified by its potential diagnostic or therapeutic value for the patient and for fellow physicians.

10. When biomedical research involving human subjects is neither having diagnostic nor the therapeutic values (non- clinical). The subjects should be volunteers- either healthy persons or patients for whom the experimental design is not related to the patient's illness.

11. In all the research protocols where human subjects are involved, the interest of Medical science and society should never take precedence over considerations related to the well-being of the subject even if he is volunteer or given free consent for the participation in research project, where he/she might consider participation in the best interest of the society at large.

Many additional regulations were added in USA (1999), to improve the quality of informed consent like:

a. A statement that the study involves research, an explanation of the purposes of the

research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental;

b. A description of any reasonably foreseeable risks or discomforts to the subject during or after research process.
c. A disclosure of any appropriate alternative procedures or courses of treatment that might be advantageous to the subject.
d. A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

e. Physician must also state that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently not known and can not be predicted.

f. It should be incorporated in the informed consent that in certain circumstances the participation of the subject can be terminated without being asked to the subject or taking his consent.
g. The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject.
h. Willingness of the subject to continue participation in case, significant new findings developed during the course of the research.

In 1982, the Council for International Organizations of Medical Sciences (CIOMS) issued Proposed International Guidelines for Biomedical Research Involving Human Subjects. "These are guidelines for the application ... of the principles of the Declaration of Helsinki, adopted by the World Medical Association in 1964 and amended in 1975, 1983 and 1989." Respect for persons, especially as regards informed consent, is the central concern and is addressed in the first parts of the code. Excerpts from the International Guidelines for Ethical Review of Epidemiological Studies Respect for persons incorporates at least two other fundamental ethical principles .The basic principles of Autonomy. Beneficence, Non malfeasance and Justice to be met at all levels in the process of research.

Informed Consent: Consent is informed when it is given by a person who has been explained by the investigator and understands the rationale, purpose and nature of the study, what is the nature of his participation in the study, what are its; requirements, what are potential risks and benefits to the individual and society in the result of the study.

In case when informed / individual consent is not possible as in case of certain epidemiological studies, consent to be seeked from the society to participate. Approval given by a community representative should be consistent with general ethical principles.

( The above mentioned recommendations are extracted from Helsinki declaration and followed declarations in USA (1999), Germany and Helsinki declaration of 2000 and in USA in 2001). The additions which were made in recent Helsinki declaration are;

The voluntary consent of the human subject is absolutely essential

Some research populations are vulnerable and need special protection. The particular needs of the economically and medically disadvantaged must be recognized. Special attention is also required for those who cannot give or refuse consent for themselves, [or] for those who may be subject to giving consent under duress. (Declaration of Helsinki, 2000, Section I, paragraph-VIII). In 2001 American Medical Association while revising the document more stress on physician's "responsibility to participate in activities contributing to ... the betterment of public health" and state that "a physician shall, while caring for a patient, regard responsibility to the patient as paramount" and that "a physician shall support access to medical care for all people" (new Principle IX).

In 2002 it was more stressed on dignity and honour of human being by modifying the previously existing guidelines: for institutional ethical review committees:

“All proposals to conduct research involving human subjects must be submitted for review of their scientific merit and ethical acceptability to one or more scientific review and ethical review committees. The review committees must be independent of the research team, and any direct financial or other material benefit they may derive from the research should not be contingent on the outcome of their review. The investigator must obtain their approval or clearance before undertaking the research. The ethical review committee should conduct further reviews as necessary in the course of the research, including monitoring of the progress of the study”

Also Guideline 11 was added to the externally sponsored research project:

“An external sponsoring organization and individual investigators should submit the research protocol for ethical and scientific review in the country of the sponsoring organization, and the ethical standards applied should be no less stringent than they would be for research carried out in that country. The health authorities of the host country, as well as a national or local ethical review committee, should ensure that the proposed research is responsive to the health needs and priorities of the host country and meets the requisite ethical standards.”

More guide lines were given on informed consent, nature and types of study, making more responsible the medical researchers and sharing responsibility by the institutional and external sponsors and safeguarding the interest of human subjects’ voluntarily participating in research project.”(Guideline 1to 21: CIOMS Geneva -2002).

More guidelines and recommendations have been designed by Medico Research council (MRC) for researchers the summary of these guidelines is as follow:

It is obligatory for the ethical board of the institution where research is conducted must design a sound ethical system for protecting research participants otherwise the research process is losing credibility among some investigators, therefore less and less number of participants will be available if frustration and mistrust will unfortunately prevail in near future. These possibilities are real and serious and are made more pressing by the continuing and rapid growth of the research enterprise, without strict ethical bindings. It is the obligation of ethical committees to establish firm trust and reliability of the research. Protecting the rights and welfare of research participants is the major ethical obligation of all parties ethical committees who, to meet this obligation, must demonstrate competence in research ethics by being able to conduct, review, or oversee research involving human participants in an ethically sound manner. Such competence entails not only being knowledgeable about relevant research ethics issues state policies but also ensuring that conflicting interests for institutions, investigators.

Protecting research participants and reliably carrying out their responsibilities in this area. They include measures:

All the participants must be educated about the substantive and procedural requirements of the system with in the frame work competence in research.

Ensure ongoing mechanics the compliance with regulations, guidance, and procedures pertaining to the protection of all research participants.

Evolve and operate a mechanism of managing conflicts of interest of investigators, ethical board and institutions