120228P - ISSUES IN RESEARCH ETHICS[1]

Presentation at the Faculty Development Program of the Faculty of Medicine King Fahad Medical City Riyadh Saudi Arabia on 28^th February 2012 by Professor Omar Hasan Kasule MB ChB (MUK), MPH (Harvard), DrPH (Harvard) Professor of Epidemiology and Bioethics & Chairman of the Institutional Review Board (IRB) King Fahad Medical City, Riyadh Saudi Arabia. EM:  omarkasule@yahoo.com, WEB: http://omarkasule.tripod.com, http://omarkasule-tib.blogspot.com

0.0 BACKGROUND INFORMATION ABOUT RESEARCH

0.1 THERAPEUTIC RESEARCH

Therapeutic trials involve clinical trials of new drugs, clinical trials of new procedures, or clinical trials of new medical devices. Research subjects are either patients (terminal or recovery possible) or healthy volunteers (paid or unpaid). The major ethical issues that arise are: (a) forced participation of the weak (prisoners, children, the ignorant, mentally incapacitated, and the poor), risk to life (short and long term), and lack of informed consent.

0.2 NON THERAPEUTIC EXPERIMENTS

Non-therapeutic experiments have no direct or immediate benefit to the subject of the study but may on the other hand expose him or her to hazards. These experiments are however necessary to generate scientific data on which subsequent therapeutic trials can be based. Phase 1 and phase 2 clinical trials are non-therapeutic trials on terminal patients who are not likely to benefit from the treatment. They however provide pharmacodynamic, pharmacokinetic, and efficacy data used to design phase 3 studies.

0.3 COMMUNITY-BASED EXPERIMENTATION

Experiments in which whole communities and not individuals are inducted into an experiment such as fluoridation of drinking water raises an important issue of informed consent. Many individuals either do not like to participate or are not in a position to give informed consent

0.4 CLINICAL TRIALS ON HUMANS

DESCRIPTION OF CLINICAL TRIALS

Therapeutic clinical trials are controlled experiments to compare the effectiveness of different treatments by random allocation of study participants to treatment and control groups, observing the outcome of interest, and at the same time studying time-varying potential confounding variables. Trials can also be designed to be intervention or preventive trials. They may be accrual or non-accrual. Unadjusted censoring causes bias. Random allocation prevents selection bias. Double blinding prevents observer bias. The primary objective of drug clinical trials is efficacy and the secondary objective is assessing ADR. Complete randomization is simple but requires a large sample size. Stratified randomization balances prognostic factors. Non randomized trials are carried out when randomized ones are not possible. The trial can use historical, concurrent, self, untreated, placebo, negative, or positive controls.

PHASES OF CLINICAL TRIALS

Clinical trials are preceded by screening in vivo in animals and in vitro in human tissues. Phase 1 trials study maximum tolerated doses, drug administration schedules, drug toxicity, and evidence of anti-tumor activity. Phase 2 studies assess therapeutic activity of a drug in advanced disease. Phase 3 trials compare a drug to a placebo or a new drug to an existing drug. Comparability is assured by randomization and equal handling of the 2 groups. Phase 4 studies involve post-marketing surveillance by collecting data on short term and long term effects.

ETHICO LEGAL CONSIDERATIONS IN CLINICAL TRIALS

Clinical trials on humans have several ethico-legal considerations. Search for better treatment justifies clinical trials. The ethical issues of trials are withholding a potentially beneficial treatment from the controls, unknown risks of new agents, lack of informed consent or consent under stress, trials if an effective treatment exists, trial when one treatment is known to be better, testing with no evidence of usefulness, unscientific research, violation of the normal doctor-patient relation, randomization when there is prior knowledge that one treatment is the better one, and failure to stop the study when harmful/beneficial effects appear.

1.0 THE ETHICO-LEGAL-FIQHI OF RESEARCH

1.1.0 PRIORITIZING HUMAN RESEARCH

1.1.1 The general order of priorities is 1. necessities, dharuraat, 2, needs, hajjaat, 3. complimentaries, mukamillaat, and  4. embellishments, tahsinaat. We may add from human experience 5. excesses, israfaat and 6. wastage, tabdhiraat.

1.1.2 Medical research is a necessity for two reasons: (a) discover better ways of treating disease (b) physicians involved in research are intellectually more active and are more likely to practice better medicine that is evidence- based and is up to date. We have to be careful not to undertake non-dharurat research on humans because of the risks involved.

1.2 PURPOSES OF HUMAN EXPERIMENTATION

1.2.1 THE ETHICAL GUIDELINE

For research to be considered ethical, it must conform to or not violate any of the 5 cenessities, dharuraart, of the law otherwise called purposes of the Law, maqasid al shari'at.

1.2.2 PURPOSE 1: PRESERVING MORALITY, hifdh al ddiin

Experiments on humans become unethical when the scientists involved are not guided by morality. Thus violation of the purpose of protecting morality brings cruelty and injustice in its wake.

1.2.3 PURPOSE 2: PROTECTION OF LIFE, hifdh al nafs

Experiments on humans for the purpose of finding new cures for disease fulfill the purpose of protecting health and life. Often the benefit is general for the whole society and not for subjects of the research. Phase 1 and phase 2 clinical trials may have no direct benefit to the patient but they provide basic scientific information. Phase 3 trials have potential benefit for the patient. Phase 4 trials have a general societal benefit. The state has a responsibility for the life and health of its citizens. It therefore must promulgate and enforce laws on the conduct of human experiments in order to prevent abuses. It must be involved in the approval of drugs and devices for experiments as well as ethical approval of protocols.

1.2.4 PURPOSE 3: PROTECTION OF PROGENY, hifdh al nasl

Research on methods of curing infertility fulfils the purpose of protecting progeny. The whole of medicine especially pediatrics and obstetrics also fulfils this purpose. Research on promoting good health of potential parents ensures that they will be healthy enough to bear the next generation. Research on better prenatal and obstetric care ensures delivery of a healthy baby who therefore has more chances of growing into a healthy adult.

1.2.5 PURPOSE 4: PROTECTION OF THE MIND, hifdh al aql

Research on cure of mental conditions fulfills the purpose of protecting the mind. Research on other somatic diseases fulfils the same purpose because any disease will through pain, suffering, and loss of function lead to mental symptoms of depression and anxiety. Research on drugs and nutrients that alter the mind is justified in order to protect humans from such deleterious effects.

1.2.6 PURPOSE 5: PROTECTION OF WEALTH, hifdh al maal

In general good health ensures a healthy workforce that works to generate wealth for the community. Human experimentation may lead to safer, more effective, and cheaper methods of treating disease which saves wealth. Health services research may lead to more efficient health care delivery thus preserving resources.

1.3.0 PRINCIPLES OF HUMAN EXPERIMENTATION

1.3.1 THE 5 GUIDING AXIOMS FOR RESEARCH

Ethical issues and conflicts that arise in the course of carrying out research can be resolved by reference to general or axioms, kulliyaat al shari'at, or also called principles of the Law, qawa'id al fiqh

1.3.2 THE PRINCIPLE OF INTENTION, qasd

The basic principle is that each action is judged by the intention behind it. A research protocol is judged by the underlying objectives of the researcher as manifest in actual implementation and not the stated objectives that may be deceptive. Means are judged with the same criteria as the intentions. If the intention is immoral the means to it is immoral and vice versa. Under this principle a research protocol with beneficial scientific results will be rejected if the methods used are unethical.

1.3.3 THE PRINCIPLE OF CERTAINTY, yaqeen

Human experimentation is carried out because of uncertainty about what is the best treatment. If there is certainty that the current treatment is the best that there can be, an unlikely practical situation, then there is no legal justification for further research. Further research cannot commence on the basis of some doubt about an existing treatment method. There must be some empirical evidence of low efficacy in the current treatment or probable efficacy in the new treatment before an experiment is authorized.

1.3.4 THE PRINCIPLE OF INJURY, dharar

Human experimentation has associated potential hazards and risks. The risk-benefit equation is assessed intuitively or by careful analysis of the protocol items. Decisions to proceed with human experimentation involve a careful balancing of benefits and risks. The easiest situation is when the potential benefit far outweighs the potential risk, in which case the research proceeds in pursuit of the benefit. If the risk is equal to the benefit, we use the principle that prevention of a harm has priority over pursuit of a benefit of equal worth. If the risk is more than the benefit for the individual research subject, but there is a larger societal benefit, we may proceed with the research under the principle that public interest has priority over individual interest.

1.3.5 THE PRINCIPLE OF HARDSHIP, mashaqqat

Hardship mitigates easing of normal regulations and restrictions. If life is at risk, risky experiments that would normally be prohibited would be allowed to seek a cure. Necessity however does not permanently abrogate the patient’s right. No such experiments can be carried out without informed consent by the patient or the research subject. The Law asserts vicarious liability. It is illegal to get out of a difficulty by delegating to someone else to undertake a harmful act. Thus legal action will be brought against all officials in the chain of command for negligence in experiments in their institution even if they did not personally take part.

1.3.6 THE PRINCIPLE OF CUSTOM or PRECEDENT, aadat/urf

The principle of custom is used to define standards of good clinical practice. The basic principle is that custom or precedent has legal effect. What is considered customary is what is consensual, uniform, widespread, and predominant. Thus the standard of clinical care or experimental procedure is what the majority of reasonable physicians consider as reasonable and which constitutes a professional standard. An innovative therapy is departure from the standard care. It is however allowed under the law but the physicians will be held liable for any injuries to the patient. This liability also arises even if standard care were used.

1.3.7 OTHER LEGAL DOCTRINES RELEVANT TO HUMAN RESEARCH

(a) THE DOCTRINE OF CONTINUITY, istishaab

This is continuation of an existing practice. Matters are left as they are until there is evidence to the contrary. In practice this means that existing treatments should continue until there is evidence of a better treatment.

(b) THE DOCTRINE OF PERSONAL PREFERENCE, istihsaan

This is preference for one alternative treatment over another because of evidence that the physician feels more comfortable with. The evidence or reasoning behind the physician's decision may not be obvious. The doctrine operates in a clinical situation in which a physician obtains experimental evidence about the efficacy of a new treatment but continues to use the old treatment because of some inclination in his mind.

(c) THE DOCTRINE OF PUBLIC INTEREST, istislaah

A public interest is recognized in research when the experiment is necessary for serving public and not personal or private interest; and has real and not imaginary benefits. Consideration of public interest arises when we have to compare an existing to a new innovative treatment. The potential benefit from the new treatment must be more than the standard treatment for the experiment to be allowed to proceed. Consideration of public interest also distinguishes a patient as a subject from a healthy volunteer; the former may get some personal benefit from the experiment since experimentation is combined with care whereas the latter has no benefits at all but may be exposed to hazards. Therapeutic research has immediate benefits whereas the benefits of non-therapeutic research are remote. In non-therapeutic research, the subjects are volunteers who may be healthy with or patients. In a randomized trial, subjects who receive a placebo have no benefit and no hazard but of they are patients they are missing the potential benefits of either the traditional or the innovative treatment.

2.0 INTERNATIONAL RESEARCH ETHICAL CODES

2.1 HISTORY OF HUMAN RESEARCH

Experiments on humans are as old as history. Early humans experimented with several plants and by trial and error found some to be useful as medicines and others to be poisonous. Such trials have continued throughout human history giving rise to a corpus of traditional medicine. Many medical systems including some aspects of traditional and complementary medicine represent empirical knowledge accumulated over time by many informal and often un recognized medical experiments. These early experiments were not planned in a systematic way neither were they documented.

Planned medical experiments: are quite recent. Galen is credited with being the founder of experimental medicine before 200 CE. In 1747 CE James Lind found out by experimentation that lemon juice prevented scurvy. Dr Edward Jenner found in 1798 that material from cowpox lesions prevented small pox. In 1914 Goldberger discovered the prevention of pellagra. Experiments were sometimes carried out on whole communities such as the study of vitamin C in the prevention of the common cold, the Salk and HBV vaccine trials, the multiple risk factor intervention trial (MRFIT) against cardiac disease, and fluoridation of community water supplies to prevent dental caries. Some trials are therapeutic such as the randomized study of aspirin myocardial infarction study. One of the earliest clinical trials was the use of streptomycin in the treatment of tuberculosis in 1948. Preventive studies such as the women’s health study in which vitamin C and low dose aspirin were given to prevent cancer and cardiovascular disease or the use of alpha-tocopherol and beta-carotene to prevent lung cancer among smokers.

Modern sophisticated research on humans in search of new drugs is an outgrowth of these early efforts. Modern medicine would not have progressed as it has without some form of experimentation on humans. If a new drug is to be used on humans, it has to be tried on humans because animal experiments are not adequate and may not be relevant to humans.

4.2  HISTORICAL ETHICAL VIOLATIONS

Human transgression has also manifested in several forms of human experimentation. The search for new cures using human experimentation showed extreme forms of human transgression and disrespect for human life in the Nazi and Japanese inhumane medical experiments on prisoners in the Second World War in Europe. These were extreme but not isolated incidents. The horror of the violations led to the emergence of research ethics which were a forerunner for the rest of bioethics.

Despite the horror of the details revealed at the Nuremberg trials of Nazi medical experiments, unethical medical experiments without informing the subjects or getting their consent continued... In the 1950s LSD and other drugs were used in experiments to discover drugs that could control human behavior. In 1953 a CIA employee used in an experiment on LSD without consent developed psychiatric symptoms and committed suicide. In 1953 Harold Blauer, a hospitalized psychiatric patient in a research project funded by the US Army, died after injection of mescaline. In the period 1940s to 1960s the US Atomic Energy Commission conducted experiments on unsuspecting subjects including children to study the effect atomic weapon irradiation. In 1954-56 elderly patients at the Brooklyn Jewish Chronic Diseases Hospital had cancer cells injected directly into their veins. In the period 1932-1972 under the Tuskegee Syphilis Study, 400 Black American men with syphilis were deprived of any treatment in a study of the natural history of syphilis without their informed consent. In 1946-1956 retarded teenage boys in Massachusetts had radioactive iron and calcium put in their breakfast cereals. In the early 1950s in Massachusetts pregnant women had radioactive iron injections to study fetal circulation. Some of the pregnant women involved in the thalidomide disaster were not informed of the experimental nature of the drug.

2.3 RESPONSES TO TRANSGRESSIONS

2.3.1 THE NUREMBER CODE 1946

Twenty-five physicians were charged at Nuremberg after World War II for Nazi inhuman experimentation on humans. Seven were acquitted, 9 were imprisoned, and 9 were sentenced to death. The Nuremberg code was laid down in 1946 in response to the criminal Nazi experiments on humans during the war. The main provisions of the code were: (a) Voluntary informed consent (b) No random or unnecessary experiments (c) Animal experiments and survey of disease natural history before subjecting humans to similar experiments (d) Avoiding unnecessary physical and mental suffering (e) The researchers must be scientifically qualified (f) subjects can withdraw at any time (g) the investigation is stopped if the patient is in danger. There was however no mention of experiments involving children.

2.3.2 HELSINKI DECLARATION

The World Medical Association drew up the Helsinki Declaration, incorporating the Nuremberg code, in 1962. The latest version (1996) was approved by The 48^th Assembly of the World Medical Association held in South Africa in 1996 approved the latest version. The code is divided into three sections: Introduction, Basic principles, clinical research, and non-clinical research.

The introduction asserted that the primary duty of the physician was to act in the best interests of the patient. It pointed out the role of research in advancing knowledge of diagnosis, therapy, or prophylaxis with the caution that such research always carries a risk to the subject. A distinction was made between clinical research involving search for new treatment and diagnostic modalities and purely scientific research that had no direct benefit to the patient. This distinction is however questionable because clinical research in based on prior basic scientific research. The code also alluded to environmental concerns and the welfare of animals used in research.

The following basic principles were included in the code. Research on human subjects must conform to generally accepted scientific principles and must be preceded by laboratory and animal experiments. A competent and independent committee must approve the research protocol, setting out all details of the research and a statement of adherence to the Helsinki declaration. The research is carried out by qualified researchers and under the supervision of a medically qualified person who must assume full responsibility for the welfare of the research subjects. The research must be preceded by careful risk-benefit assessment. The research can be carried out only if its risks are predictable, the objectives are important when considered with the potential risks, and the benefits outweigh the risks. Research subject integrity in the form of privacy, physical, and mental welfare must be respected. Research subjects are entitled to full disclosure that covers the aims, methods, and potential hazards of the research before they give their voluntary informed consent. They should be informed that they are free to abstain from the study or to withdraw at any stage. Proxy consent is obtained for the legally incompetent, children or the mentally retarded. Results of the research will be accepted for publication only if they are accurate and conform to the principles of the Helsinki Declaration.

The declaration defined and approved clinical research as medical research combined with medical care. The physician is free to use a new therapeutic or diagnostic measure that in their judgment has hope of improving life and alleviating suffering. The potential benefits, hazards, and discomfort of the new method must be weighed against the best current and available diagnostic and therapeutic methods. Use of a placebo in a control group is allowed if no better method is available.

The declaration defined non-clinical biomedical research as non-therapeutic research involving humans carried out only on volunteers either healthy volunteers or patient volunteers. In case of patient volunteers the experimental design should not be related to their illness. The lead physician in the research team retains responsibility for subject welfare. The research is terminated as soon as is judged harmful to the research subjects. In any case the interests of science and society should never take precedence over the welfare of the research subjects.

2.3.3 CRITIQUE OF THE INTERNATIONAL ETHICAL CODES

The Nuremberg and Helsinki codes on experimentation have not been successful in stopping unethical research on research subjects who are weak members of society. As mentioned above, many unethical experiments were carried out in the US soon after Nuremberg. The basic failure is that these codes lack a clear identity. They are neither law that is enforceable using the normal legal procedures nor are they moral standards that are enforced by the inner conscience of the experimenter. These codes are a reflection of the secularization of western society in which morality was divorced from law and public affairs. Ethical codes are a bad attempt to mitigate the bad effects of a divorce that should have never been allowed to occur in the first place.

3.0 GOOD CLINICAL PRACTICE GUIDELINES

3.1  DEFINITION OF GCP

Good Clinical Practice (GCP) is an international standard for conducting clinical trials produced by harmonizing European, US, Japanese clinical guidelines. It was also developed in coordination with guidelines of Australian, Canadian, Nordic, and WHO guidelines. Following these guidelines ensures acceptance of study results in many countries of the world. The main purpose of the guidelines is to establish an international ethical and scientific quality benchmark.

3.2 PRINCIPLES OF GCP

GCP requires studies to be conducted according to the ethical principles of the Helsinki declaration. Studies shall be initiated or continued if the anticipated benefits justify the risks involved. The rights, safety, and well being of the research subjects prevail over the interests of science and society in the trial. Before a study is started a determination must be made that it is justified by available clinical and non-clinical information. A study protocol must reflect a sound scientific basis for the investigation. The conduct of the study should not deviate from the approved protocol without specific permission. Medical care and any medical interventions in the study must be carried out by a qualified physician. All participants in the study must have the professional qualifications and experience to undertake their assigned role in the study. Every study subject shall before start of the study give free informed consent. All study data must be recorded carefully and must be available for inspection by regulatory bodies. Strict confidentiality of all records must be observed. Investigational products manufacture, storage, and use must conform to Good Manufacturing Practice (GMP). The research institutions must apply systems with procedures that assure the quality of every stage of the trial.

3.3 SECTIONS OF THE GCP MANUAL

The Institutional Review Board: responsibilities, composition, functions, organization, procedures, records.

The investigator: qualifications, agreement, adequate resources, medical care of trial patients, communication with IRB, compliance with the protocol, investigational products, randomization procedures and un-blinding, informed consent of trial subjects, records, progress reports, safety reporting, premature termination / suspension of the trial.

The sponsor: quality assurance and quality control, contract research organization, medical expertise, investigator selection, allocation of responsibilities, compensation to subjects and investigators, financing, notification of regulatory agencies, confirmation of IRB review, information on investigational products, manufacturing, packaging, labeling, and coding investigational products, supplying and handling investigational products, record access, safety information, adverse drug reaction reporting, monitoring, audit, noncompliance, premature termination / suspension, study reports, multi center trials.

Clinical trial protocol: general information, background information, trial objectives and purposes, trial design, selection / withdrawal of subjects, treatment of subjects, assessment of efficacy, assessment of safety, statistics, direct access to source data /documents, quality control and assurance, ethics, data handling and record keeping, financing and insurance, publication policy, supplements.

Investigator brochure: title page, confidentiality statement, table of contents, summary, introduction, the drug (chemical, physical, and pharmaceutical properties), effects in humans, summary of data and guidance for the investigator

3.4 GCP RESPONSIBILITIES

GCP responsibilities of the local participating site: ethics committee approval, patient recruitment, patient informed consent, collection and record of data required by the protocol,  reporting of adverse effects, ensuring protocol compliance, ordering and storing study drugs.

GCP responsibilities of the study coordination center: confirmation of the ethics committee approval, confirming informed consent, confirming the accuracy of the data by regular visits to the study site, screening qualifications of study personnel, quality control of CRF, monitoring adverse effects, analysis of the trial and report of results.

4.0 MAJOR ETHICAL ISSUES IN RESEARCH:

4.1. INFORMED CONSENT / AUTONOMY

4.1.1 OVERVIEW

The most important ethical issue is to ensure that no research is carried out on a human without informed consent. Informed consent means that the details of the research including benefits and risks were disclosed and that the patient voluntarily consented to be included in the research in the full knowledge that he or she has the right to withdraw from the research at any time and without giving any reason. The autonomous right of the patient falls under the purpose of protecting life, maqsad hifdh al nafs. Of all those involved in research, it is the patient who has his/her best interests at heart. The patient is the best one to protect his or her life. Others may have other motives and biases.

4.1.2 PROBLEM OF CONSENT

The commonest and most serious problem in human experiments is lack of proper informed consent. The following captive populations may be used in research without their knowledge or consent: hospitalized patients, institutionalized children, the mentally abnormal, army or police personnel, laboratory assistants or medical students. The process of full disclosure that precedes patient consent usually creates enough transparency in the research process to prevent fraud and malpractice. Consent to participation in an experiment does not void the duties and obligations of the traditional doctor-patient relationship. Under the doctrine of sadd al dhari’at and in the interest of the public, the subject cannot consent to relieve the physician from liability for negligent medical care or injury from the experimental procedures. The law on the basis that a person with full legal competence would not give consent if all the implications and hazards of the experiment were explained to him or her does not recognize consent to an experiment with a clear preponderance of harm. The Law as a contract under which the patient expects reasonable care as well as expressed or implied warranties and guarantees recognizes the doctor-patient relationship. In an experiment the research protocol is considered part of the contract and any protocol violations are considered a breach of contract for which relief can be sought in a court of law.

4.1.3 CONCEPTUAL BASIS FOR INFORMED CONSENT

Consent is allowed under the doctrine of the human temporary custody of life. Life belongs to Allah but a human has temporary custody during his adult lifetime. It is wrong to argue that a human cannot make any decision to participate in an experiment with potential hazard to life because he has no control over his life. He however is accountable for any decisions made such as consenting to a highly risky experiment that has no potential benefits.

4.1.4 AUTONOMY

The Law is very explicit about the need for consent by a patient. Nobody can be given any medicine or nutrition against his or her will. Human autonomy or privacy is respected even if the refusal of treatment is illogical or is based on false premises. Thus all subjects of a clinical trial must give voluntary consent before being part of the experiment. Consent can be coupled with a contractual relation in which specified conditions of treatment can be detailed and that contract is enforceable by the Law however any clause that exempts the experimenter from liability for harm to the patient is null and void.

4.1.5 SELF INTEREST IN CONSENT

Consent is related to the fine balance between benefit and risk in an experiment. It is only the subject of the experiment who has the most objective assessment of risks because his welfare is at stake. Others may have other interests or pressures that color their judgment. The consent of a minor raises serious problems. The Law allows a guardian to make decisions on behalf of the minor if they are clearly beneficial to the minor. The Law frowns on any decisions that may be disadvantageous to the minor. Since a clinical trial has both benefits and hazards, the decision is very difficult to make. A minor child with insight, mumayyiz, can be allowed to express his or her views but the final decision rests with the guardian.

4.1.6 COMPETENCE TO CONSENT

Consent can only be given by a person judged by the Law to be legally competent. Many experimental subjects in en-ethical research are captive populations who cannot fulfill the conditions of legal competence. Hospitalized patients may not feel free to refuse participation because they feel indebted or under the control of the physicians. Physicians are looked at as authority figures expected not to do harm. Children and the mentally deficient may not have the intellectual competence to evaluate the risks and benefits involved in an experiment in order to make an informed decision. Prisoners, armed forces and police personnel, medical students may have undue pressure from superiors to consent to research that they would normally refuse.

4.2 THE BENEFIT-RISK RATIO

No research is risk-free. Its benefits must be balanced against its risks. According to the principle of injury, qa'idat al dharar, research can be permitted to proceed if the benefits are higher in worth than the potential risks. There is however no easy formula for determining the equipoise point at which benefit and risk are considered equal so that we can know what to do. Under the benefit-risk fall other ethical considerations: (a) protection of the patient's privacy and confidentiality (b) scientific merit of the research and qualification of researchers to avoid exposing patients to risky research of doubtful value (c) due diligence and honest research methods and report of research results.

Research policy aims at minimizing risk to research subjects and achieving a balance between risk and benefit. The risks involved in experimentation may appear to contradict the purpose of preserving life. Research risk is allowed in view of the wider benefit to life protection by finding effective therapies. To minimize risk, the following are considered before approving an experimental drug for experimentation: knowledge about the drug from previous studies, consideration whether further research is needed, benefit and hazards to patients. Death or other forms of injury consequent from an experiment trigger a criminal charge of unintended manslaughter for which compensatory and not punitive damages are awarded, diyat. Informed consent of the victim or his written statement relieving the physician or experimenter from liability is not admissible as defense in this case. The strictness of the law on this matter is intended more for societal benefit to put those engaged in experimentation on their toes so that mistakes are not made.

5.0 REGULATION OF RESEARCH TO PREVENT ETHICAL VIOLATIONS

5.1 APPROVAL AND MONIORING RESEARCH BY IRB

5.1.1 FUNCTIONS OF IRB

IRB assesses research proposals and protocols that have ethical implications. These include research on patients, volunteers, the recently dead, fetal or embryological tissues. It also assesses any research involving access to medical records with a potential to breach confidentiality. It is the duty of IRB to ensure the highest ethical standards in any research. It has to protect the research subjects’ physical and mental well being as stipulated in the Helsinki declaration. It also has the duty to protect the researchers and the institution in which they work by advising them about ethical conduct so that they do not commit mistakes that will lead to criminal prosecution. IRB's role does not end with the approval of the research. It has to continue monitoring the conduct of the study to detect any ethical violations.

5.1.2 MEMBERSHIP OF IRB

Membership of IRB is designed in such a way that all professional and technical competences needed for proper evaluation of a research proposal are included. Membership should comprise representatives of the major medical and surgical specializations practiced in the hospital or region, hospital physicians, hospital nursing staff, general practitioners, pharmacists, statisticians, ethicists, and lay persons from the community. The lay members should not have any connection with medical work. In selecting members attempts should be made to make sure that all genders and age groups are well represented. Members should be selected on their own personal merit as people with knowledge, skills, and sound judgment. They should discuss the proposals as individuals and not representatives of any organization or profession. Members are appointed by the hospital, the health authority in the region or the government. The period of service on the committee is usually three years. Membership may be renewed.

5.1.3 PROCEDURES OF IRB

IRB must be provided with adequate secretarial and logistic assistance to carry out its functions well. A quorum of at least half of the members will be necessary for holding a meeting. Members who cannot attend can send written comments. The proposals, protocols, and reports to be tabled must be sent to the members in advance so that they have a chance to study them. IRB meets in private to preserve confidentiality. Any member of the committee involved in a project will recluse himself when that project comes up for discussion. IRB should normally decide by consensus but where this is not possible, a 2/3 majority carries the decision. Minority views should be recorded. The decision may be full approval, conditional approval, deferment, or rejection. Reasons should be provided for projects approved conditionally or those that are rejected. The chairperson may approve projects that had conditional approval if he is satisfied that the conditions were fulfilled. Any amendments to the protocol must be submitted for committee approval before they are implemented.

5.1.4 CRITERIA OF ASSESSING RESEARCH

IRB will use the following criteria in assessing a submission. To make assessment easier the application is submitted in a standard format. Documentation showing informed consent must be submitted. IRB will look to see whether the research subjects were informed of the objectives of the study and of their rights to participate, abstain, or withdraw from the study. Special scrutiny of proxy consent will be made to ensure there is no abuse. The investigator must submit reasons in writing in cases in which full disclosure is deemed inappropriate. IRB will look to make sure that the objectives are clearly stated and are attainable. The research design and statistical methods must be judged adequate to produce clinically and scientifically useful results. IRB will compare the scientific merit and benefit of the research against risks and costs to patients. The submission must have detailed resumes of the investigators to enable IRB assess their competence to undertake the research successfully. The adequacy of research facilities is also assessed. The proposal must provide details on how confidentiality and security of the data will be assured.

5.1.5 FOLLOW-UP OF RESEARCH

IRB must monitor progress of the research project and must receive reports of all adverse reactions whether related to the drug tested or not. Members of IRB can make on-site inspections to make sure that the approved protocol is adhered to and to inspect research documents and records. Regular monitoring meetings are held to review the following: progress of recruitment of research subjects, changes to the protocol, adverse reactions, the process of informed consent, refusals and withdrawals, and case record forms. IRB keeps full records of all its actions. It submits an annual report listing all proposals considered in the past year, the number approved, and any matters that deserve attention from higher authorities.

5.2 REGULATION OF RESEARCH BY POLICIES AND REGULATIONS

5.2.2 BALANCE BETWEEN RESEARCH AND CARE DELIVERY

Research is a departure from the commonly accepted treatment. Patients who are research subjects may be deprived of effective treatment. They may also be deprived of the full attention of the attending physician who has to devote part of his time to research. A fine balance must be struck between the clinicians duty of care and his role as a researcher. The best way to make sure that this balance is maintained is full disclosure of the dual roles of the physician (treatment vs research) to the patient.

5.2.3 EQUITY AND JUSTICE IN RESEARCH

Recruitment into studies should reflect the community’s ethnic, gender, and age distribution. Results of an unbalanced study may not be applicable to all groups. Minorities and women tend to be under-represented in studies which puts them at risk of being prescribed drugs that were not tested foe safety and efficacy on people who represent them socially or biologically.

5.2.4 FUNDING OF RESEARCH

Decisions on research priorities may be made on a scientific basis or a non-scientific basis (political, socio-cultural, elite interests). The scientific basis is the ideal but in practice non-scientific considerations may dominate. The source of funding may in an indirect and discreet way influence the conduct of research and the report of its findings thus leading to lack of objectivity. Important diseases affecting many people may be neglected in research priorities because the victims are poor or weak politically. The profit motive will dictate research on diseases and drugs that will bring revenue. Examples of neglected diseases / conditions are headache, back pain, PMS, respiratory infections, and tropical diseases. Short-term benefits are usually pursued at the expense of long-term benefits. The pharmaceutical firms that are major funders of research will not put their money in research on diseases of the poor because they see no monetary benefit.

5.2.5 DISSEMINATION OF KNOWLEDGE and PUBLICATION BIAS

Research findings must be disseminated by teaching or by publication. Hiding knowledge and exploiting it as private property is immoral. Drug companies that sponsor research to develop patentable products do not appreciate the type of transparency advocated by Islam. Publication of research results serves scientific communication and scientific networking. Concern about copyright and intellectual property rights limits dissemination of knowledge by publication.

Biases in publication arise at the level of researchers who normally do not submit negative studies for publication. Studies with adverse effects are not reported. Editors prefer publishing positive studies. Biases in selection of papers for publication arise from the peer review process due to old boy networks. Researchers may submit their work more than once treating it each time as new research. Problems in authorship arise when people who made contributions are not acknowledged or people who made insignificant contribution are included as authors. There are problems in published research reports such as: unnecessary research, research poorly designed and poorly conducted, lack of informed consent, lack of IRB approval. The process of peer review does not weed out bad research from publications because reviewers are too trusting. On the other hand reviewers may recommend non-publication of good research because they want to steal ideas or because they are competing with the authors.

5.2.7 RESEARCH MALPRACTICE

Despite the best of efforts to police itself, the scientific research community still has cases of research fraud. Fraud manifests as cooking or doctoring data (fabrication and falsification), selective reporting of data, suppression of negative information, and ‘stealing’ others’ work (plagiarism). Financial gain, reputation, academic promotion, and the pressure to publish or perish are the driving forces behind fraud.

5.2.8 CONFLICT OF INTEREST

The usual cause of research malpractice is conflict of interest. The conflict of interest may involve authors, reviewers, and editors. The conflicts may take various shapes: treatment vs research, personal gain vs patient best interests, organizational interests vs patient interests. A physician who puts research ahead of patient interests is violating his fiduciary duty to the patient. There are many causes of conflict of interest: academic, publication pressure, religious, and financial.. The financial pressures are more marked. For example studies sponsored by drug companies may have results more favorable to industry. The best way to stop conflict of interest is its full disclosure.

6.0 CASES FOR DISCUSSION

6.1 Discussion cases on conflict of interests

1. The local branch of the pharmaceutical companies was very careful not to violate ethical guidelines while sponsoring physicians to conferences overseas. They never required them to say or write anything in favor of the company or any of its products. One day one researcher was surprised when his young daughter complained that the family had gone on company-sponsored summer trips to attend scientific conferences in Europe every year for 3 consecutive years but they had not gone this year. The researcher thought very hard; he remembered his last publication that had generated controversy about a new drug manufactured by the pharmaceutical company. The had made no public comment on the paper.
2. The pharmaceutical company wanted to conduct a 4^th phase study of its new unpopular headache medication and offered SAR500 to physicians in private practice and SAR20 to physicians in public hospitals for every patient recruited into the study. All the physician had to do was to prescribe the drug and complete s short 5-item questionnaire. A company representative would pick up the data sheets at the end of every day’s work.

 6.2 Discussion cases on payment to research subjects

1.      A researcher on cloning advertised in the newspapers with wide distribution in a poor inner city neighborhood for a clinic admitting patients with threatened abortion. If the abortion became inevitable all procedures would be completed for free with USD3000 being given to help in the recuperation phase. The woman would have to sign a statement releasing the abortus for research purposes. No questions were asked about the causes of the abortion.

2.      A researcher interested in the effect of daily aspirin on fine motor activity advertized for volunteers in the local newspaper with a payment of USD50 per 10-minute visit to the study center for completing a questionnaire and undergoing some tests. Volunteers could make as many visits as they liked but no more than 5 in a week. The researchers were overwhelmed by the response. They were also surprised that none of the volunteers had admitted having gastric ulcers or reported any previous gastric problems with aspirin.

3.      Researchers advertised for male obese youths aged 18-25 years to join a randomized study that compared dietary control to surgical control of obesity. The surgery used was innovative including laparatomy and surgical dissection of lipid tissue from the abdominal cavity. Subjects undergoing surgery were each paid USD2000 before operation and USD8000 after 6 months of follow up.

6.3 Discussion cases on the processes of informed consent

1.      A randomized study was carried out among pregnant women to study the impact of iron supplementation on pre delivery hemoglobin levels. Informed consent was obtained after full disclosure of all facts. A questionnaire at the end of the study surprised researchers because the women could not remember that any research was carried out; they knew it was all routine medical care.

2. Parents signed informed consent after full disclosure. Asked after two months they remembered that the research was about finding an effective drug but could not remember the randomization of children to two groups and were not aware that the children received different treatments
3. Patients in a randomized cancer drug trial had to read a 5 page Arabic translation of the disclosure statement and then sign the consent; 2/10 signed without reading but listened to a 2-minute explanation by the principal researcher. 18/20 decided to take it home for study and brought it back fully signed and dated.
4. A terminal cancer patient refused participation in a randomized trial of a new chemotherapeutic agent claiming that he had a right to refuse and that the research was not in his interests and will not contribute to his welfare. The principal investigator was called to convince the patient. He told him that participation was a duty on each citizen and that it was immoral to shirk that duty. He said ‘if everybody refused to participate how can be develop new drugs?’. The patient reluctantly signed the informed consent form.

6.4 Discussion cases on research without consent

1. Researchers wanted to study the effect of restricting teenager’s pocket money on their cigarette addiction. Parents were randomized to various amounts of pocket money for teenagers everyday. Observers acting as spies hanged out with the teenagers and reported on their smoking behaviors. IRB was asked to approve the study without disclosure of its objectives and procedures to the teenagers because that would invalidate the results.
2. The IRB refused to approve a randomized study of the impact of explanation of the mechanisms of drug action on the response to an analgesic because the principal investigator wanted to research without informed consent. He argued that informed consent would involve too much disclosure that that the study would be invalidated.
3. We want to research the impact of an emergency room intervention but all patients are brought in unconscious and we cannot get informed consent. Neither are relatives available. How can we improve our care without research?

6.5 Discussion cases on justice

1. A heated argument arose between the principal investigator who concluded from interim results on 15 patients that the experimental drug made a difference (25% tumor regression in 4/7 treated vs 1/8 controls) and the statistician who wanted to recruit more patients to reach statistical significance. The PI’s conscience was disturbed that those in the control arm were missing out on a useful drug.
2. Patients excluded from a randomized clinical trial on valid exclusion criteria complained to the Ministry of Health because they were denied access to a new experimental therapy available only to those in the randomized trial. They argued that since the drug was brought using public funds they had a right to it They had heard that the drug was known from phase 1 and phase 2 studies to be effective
3. Patients in the control arm of a randomized trial were angry that they had not benefited from the drug that proved to be effective. They planned to take the principal investigator to court. They argued that animal, phase 1 and phase 2 studies had already showed the benefit of the drug. They thought that the principal investigator misled them when he recruited them in the phase 3 study because there was nothing new to fund out.
4. The consultant warmed his resident to make sure no women in the child bearing age are systematically excluded from a randomized study of a new drug whose teratogenic properties were unknown

6.6 Discussion cases on clinical trials in developing countries

1.      A Developing country IRB refused to allow a clinical trial of  a new antibiotic by an international pharmaceutical company. It cited the injustice of the 10/90 gap (10% of world research dollars are allocated to research on 90% of the world problems) and the high cost of drugs due to the unfair patent policies and practices. The IRB argued that the local people will not afford the new antibiotic; why should they be used merely as guinea pigs?.

2.      An angry exchange between a Minister of Health from a developing country and the president of an international pharmaceutical manufacturer. The Minister accused pharmaceutical companies of exploitative and risky research in developing countries because research regulation is weak and standards of care are lower. The president of the pharmaceutical company accused the developing countries of benefiting from drugs developed by exposing first world citizens to risks of clinical trials. He said citizens of developing countries must contribute to the research by taking some of the risk.

3. AZT given in the last trimester, during delivery, and post-natally was shown to prevent neonatal HIV transmission in a developed country. This treatment was too expensive for Africa. A new study was carried out in a modified way. Women were randomized to AZT and placebo in the last week of pregnancy and rates of neonatal transmission were observed in the two groups.

6.7 Discussion cases on publication bias

1. A researcher studying two treatments compared outcome on discharge from the hospital. The outcome results of 10 out of 90 patients were lost due to a computer error and there was no paper back up because all the research was computerized. The patients could also not be traced. The researcher decided on a worst case scenario and assigned all the 10 to the worst outcome and analyzed the results. Fearing confusing the reviewers and readers, he did not mention the assignment of outcome.
2. A systematic literature review carried out before writing the proposal on use of an existing drug for a new indication led to contradictory conclusions. Research overseas of >5 years ago indicated low adverse effects while research <5 years ago indicated high adverse reactions. Local experience with the drug showed it to be very safe. The researchers who already had a grant from the pharrnaceutical company went ahead with the research but decided to exclude the negative information from their literature review in order not to confuse the IRB members who would review the proposal.
3. The editorial board of the faculty journal had an unwritten understanding shared by all members that negative clinical trials would not be published because they would have no new information for the readers. The message trickled through and researchers stopped submitting such trials for publication. As a result the journal became famous for the being the source of breakthrough research on new therapies.
4. The head of department a senior professor of surgery asked his residents to undertake research comparing two surgical techniques. He gave them detailed guidelines on literature survey, study design, and study execution. He never took part in the actual research or the writing of the paper but gave advice on a daily basis whenever they asked him. When the manuscript was ready for publication he asked that his name be put as the first author. The residents wanted him to be the last author.

6.7 Discussion cases on risk-benefit considerations

1.      A resident refused to assist his consultant in a clinical trial on the grounds that from his personal experience the side effects of and reaction to the experimental drug were worse than the migraine headache. The consultant had a different view of the risk-benefit equation. The IRB had approved the study based on similar studies overseas with no reports of severe adverse reactions.

2.      A systematic review of the literature showed that the proposed study had already been carried out in several countries and that the research question had been answered. The researchers still went ahead to submit the study to the IRB which approved it on the basis that the study had not been carried out locally.

6.8 Other Discussion cases

1. Internists were frustrated at the high rate of CVA among male hypertensive patients on regular treatment. On questioning they discovered that most patients were not compliant because medications impaired their sexual function. The physicians decided to carry out a series of studies to compare various hypertensives and select the one with the least impairment of sexual function. They were not sure how to design the study and submit it to IRB.
2. A post approval IRB review revealed that a randomized study of secondary indications for Viagra had recruited 98% of its ‘volunteers’ from men with diabetes mellitus aged 60-65 years. The advertisement had not mentioned any age or gender restrictions.
3. Residents submitted a proposal promptly rejected by IRB for lack of proper consent procedures and inexperience of the investigators. They resubmitted it with a senior consultant as principal investigator, changed the wording of the title, and changed nothing else. The proposal was accepted.