110329P - ISSUES IN RESEARCH ETHICS[1]

Presentation at the Research Ethics Symposium held on 29^th March 2011 at the Faculty of Medicine King Fahad Medical City Riyadh Saudi Arabia 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.

1.0 GENERAL PURPOSES AND PRINCIPLES

1.1 PURPOSES OF HUMAN EXPERIMENTATION

1.1.1 THE PURPOSE OF 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.

1.1.2 THE PURPOSE OF 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.

1.1.3 THE PURPOSE OF 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.

1.1.4 THE PURPOSE OF 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.

1.1.5 THE PURPOSE OF 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.

 

1.2 PRINCIPLES OF HUMAN EXPERIMENTATION

1.2.1 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.

1.2.2 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.

1.2.3 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.

1.2.4 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.

1.2.5 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 OTHER PRINCIPLES RELEVANT TO HUMAN RESEARCH

1.3.1 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.

1.3.2 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.

1.3.3 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 RESEARCH REGULATION BY INSTITUTIONAL REVIEW BOARDS (IRB)

2.1 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.

 

2.2 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.

2.3 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.

2.4 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.

2.5 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.

3.0 POLICY REGULATION OF RESEARCH

3.1 BALANCE OF RISK AND BENEFIT

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.

 

3.2 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.

3.3 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.

 

3.4 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.

 

3.5 DISSEMINATION OF KNOWLEDGE

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.

 

3.6 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.

3.7 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.

3.8 PUBLICATION BIAS

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.

4.0 INTERNATIONAL RESEARCH ETHICAL CODES

4.1 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.

4.3 RESPONSES TO TRANSGRESSIONS

4.3.1 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.

4.3.2 HELSINKI DECLARATION

The World Medical Association drew up the Helsinki Declaration, incorporating the Nuremberg code, in 1964. 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.

4.3.3 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.

4.4 TYPES OF RESEARCH ON HUMANS

4.4.1 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.

4.4.2 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.

 

4.4.3 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

5.0 CLINICAL TRIALS ON HUMANS

5.1 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.

5.2 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.

5.3 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.

5.4  GOOD CLINICAL PRACTICE GUIDELINES

5.4.1 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.

5.4.2 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.

5.4.3 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

5.4.4 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.

6.0 INFORMED CONSENT IN HUMAN RESEARCH

6.1 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.

6.2 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.

 

6.3 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.

6.4 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.

6.5 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.

WORKSHOP I: GENERAL CONSIDERATIONS

1.       What is the moral justification for non-therapeutic research

2.      Discuss issues relating to inclusiveness (hint: include minorities and women in research).

3.      Explain the concept of clinical equipoise

4.      Should hospitals reject all research sponsored by pharmaceutical companies?

5.      Is research based on putting fluorine or iodine in public water ethical?

6.      What are the duties and responsibilities of a patient in research?

7.      Is innovative surgery considered a form of research?  

8.     Is it proper to include a placebo group in a drug trial in the third for a drug licensed in the rich countries?

9.      Describe various forms of fraud in research (hints: failure to follow standards GCP, failure to get consent, data falsification, plagiarism, including as researchers senior professor who did not actually participate in the research, researchers not trained in ethics, falsifying authorship).

10.  Describe methods of avoiding research malpractices (hints: training researchers in GCP and ethics, ethical and scientific review of the research proposal, detailed recording of all research activities, the principal researcher should be personally involved in the research activities, quality assurance and audit programs, whistleblowers on fraud)

11.   Is it proper for a physician to charge a finder's fee for suggesting his patients to be invited as research subjects? Is it proper for a physician to be paid to enroll patients? Should researchers take money and other benefits from pharmaceutical companies that sponsor research?

12.  Is research ethical in poor countries for the benefit of rich countries? Discuss the 10/90 gap: 10% of research money is spent on 90% of the world's health problems. Explain how patenting restricts access to drugs by poor countries

WORKSHOP 2: INFORMED CONSENT and CONFIDENTIALITY

1. Explain the application of the principle of autonomy in clinical research (hint: informed consent reflects autonomy, consent needed even for records based research that is published anonymously if non-health care workers have access before anonymizing).
2. List information items that patients involved in clinical research must be told (hint: what is the treatment, evidence about the treatment and missing information that necessitates research, how the treatment differs from the standard treatment, available alternatives treatments, likely risks and benefits, measures to ensure safety).
3. Explain how informed consent helps protect the patient. Explain why informed consent in clinical research is more important than in normal patient treatment.
4. Is self interest a valid reason for patient consent to participate in research? Is a patient obliged to participate in clinical research in the public interest?  Can the patient be forced to be part of the research if the research drug s the same as the drug he takes normally for his disease? Why should a terminal patient participate in a drug toxicity study? Is it proper to offer poor patients participation in research so that they can have access to expensive drugs?
5. What measures would you take if a research subject says 'I do not understand this research but I will sign anyway because I trust you'
6. Explain ethico-legal guidelines on withdrawal from research at any time.
7. Is it ethical to undertake research  in the emergency room without informed consent
8. Explain the application of confidentiality in clinical research (hints: use anonymized data, no disclosure of subject details to researchers until after consent).
9. What do you do if in the course of your research you discover a sexually transmitted disease unrelated to the subject of your research?
10. What do you do if the course of your questionnaire research on cardiovascular disease you discover severe mental disease in an airline pilot?

WORKSHOP 3: RESEARCH ON HUMAN TISSUES

Using the purposes and principles of research that you have learned, discuss ethical problems and their ethico-legal solutions for the following issues

1. Describe ethico-legal guidelines on genetic testing of biological samples obtained from individuals (hint: informed consent must be obtained if the test is not anonymized).
2. Describe ethico-legal guidelines on research on material from living donors (hints: approval by ethics committee, information on the how long the material will be stored and the benefits and risks of the research, informed consent is needed to take more material than is needed for therapeutic purposes and specific consent to a specific research, rules of confidentiality. There is no need for consent to test surplus anonymized material). 
3. Describe ethico-legal guidelines on research on material from deceased donors (hints: consent by family after full information: what tissues to retain, the purpose and nature of the research, confidentiality).

4.      Describe ethico-legal issues in research on tissues from aborted fetuses.

5.      Discuss dissection of cadavers for research or educational purposes

6. Discuss what to do when a pregnant woman dies with a dead fetus in utero
7. Discuss ethico-legal issues in embalming a dead body
8. Discuss ethico-legal issues in post mortem examination for educational / research purposes
9. Describe 2 sources of embryos for research and explain the difference in ethical consideration between them (hints: embryos can be surplus from IVF procedures or can be created specifically for research. Creation of embryos for the sole purpose of research is a more serious issue).
10. List research that requires use of embryos (hints: conception, contraception, infertility, inherited diseases).
11. Explain ethical guidelines on research on fetal tissue (hints: fetal tissue from spontaneous abortion creates few problems. Fetal tissue from induced abortion created the appearance that the abortion was for purposes of obtaining the tissue, consent is needed, no financial inducements, the timing, place, and type of termination procedure must not be related to the requirements of research).
12. Discuss comparative ethical issues in research on different types of stem: embryonal, fetal, cord, and adult
13. Discuss genetic research involving genetic engineering

WORKSHOP 4: CONTROVERSIAL ISSUES IN HUMAN RESEARCH

Using the purposes and principles of research that you have learned, discuss ethical problems and their ethico-legal solutions for the following issues

1. Discuss ethico-legal issues of pharmacogenomc research
2. Discuss ethico-legal issues of research on ageing, longevity, and immortality
3. Discuss ethico-legal issues of research on enhancement technologies,
4. Discuss ethico-legal issues of research on psychosurgery,
5. Discuss ethico-legal issues of research on neuro-transplantation,
6. Discuss ethico-legal issues of research on gonadal transplantation,
7. Discuss ethico-legal issues of research on xenotransplantation

WORKSHOP 5: RESEARCH ON THE VULNERABLE

Using the purposes and principles of research that you have learned, discuss ethical problems and their ethico-legal solutions for the following issues

1.       Explain ethico-legal guidelines on consent to research by mentally incompetent persons (hint: decision by proxy or advance consent or refusal, benefits must outweigh the harm, extra precautions to prevent abuse,)

2.      Explain ethico-legal guidelines on consent to research on children (hints: consent by competent children endorsed by parents, consent by parents, consider special vulnerability of children’s physiology, research in child’s interests so parents cannot consent to research that is against the child’s interests, benefits must outweigh the harm, extra precautions to prevent abuse, parental consent can be overridden by the child,).

3.      Discuss ethico-legal issues in research on women (hints: neglect of female 'diseases' , under=representation of women in clinical trials)

4.      Discuss ethico-legal issues in research on the elderly (hint: informed consent)

5.      Research on prisoners  (hint: pressure to participate, need to study prison-based disease)

6.      Research on students  (hint: pressure to participate)

7.      Research on employees  (hint: pressure to participate)

8.     Research on members of uniformed services (hint: pressure from the chain of command)

9.      Discuss the obligation of members of the armed forces to be research subjects without consent (study of conditions exclusive to the military, chain of command)

ATTACHMENT 1: RESEARCH APPLICATION FORM

IDENTIFYING INFORMATION 1. Title of the research project. 2. Information on each of the principal investigators: name, address, professional title, qualifications, name and address of employer, experience in clinical research, and recent research projects involved in 3. Information on the person completing the application form: name. Qualifications, address, professional status 4. Name, address, and telephone of person to be contacted about the project in urgent and non-urgent matters 5. Sponsor of the research: name, contact person, address, level of support, conditions attached to the sponsorship, equipment and staff provided by the sponsor, payments to research subjects, restrictions if any on the publication of research results.

DESCRIPTION OF RESEARCH: 1. type of research subjects (healthy volunteers, inpatients, outpatients), 2. scale of the research (single center, national multi-center, international multicenter), 3. Sponsor (commercial or academic institution), 4. commercial research (drug development, testing devices of equipment), 5. academic and non-commercial research (therapeutic study, non-therapeutic study, laboratory research, epidemiological research)

PROTOCOL AND DATES: 1. Study protocol: existing protocol, new protocol submitted with application 2. Dates: starting date, closing date, duration

METHODOLOGY OF RESEARCH 1. background, justification, research subjects, research design, data collection, data analysis, power of the study 2. Research subjects: proposed cases, proposed controls, method of selection including inclusion and exclusion criteria, age range, gender distribution, number anticipated

ETHICO-LEGAL ISSUES: 1. Informed consent: patient/volunteer information sheet, use of a standard consent form, who will seek consent? method of approaching potential research subjects, time given to respondents to make up their mind about participation, 2. Potential benefits 3. Potential hazards and discomforts 3. Methods of assuring confidentiality 4. Insurance 5. Signed declaration

ATTACHMENT 2: PATIENT/VOLUNTEER INFORMATION SHEET

INVITATION AND TITLE: 1. Invitation to participate 2. Full title of the proposed research that is self explanatory to lay readers

PURPOSES OF THE RESEARCH: 1. Purposes

PROCEDURES AND DURATION OF THE RESEARCH: 1. procedures of the research 2. Duration

RISKS and BENEFITS: 1. Description of foreseeable risks and side effects 2. Description of benefits of the research 3. Description of alternative treatments

ETHICAL AND LEGAL ISSUES: 1. Statement on confidentiality 2. Compensation for research subjects in case of injuries 3. Statement that participation is voluntary 3. Contact person for further information

ATTACHMENT 3: INFORMED CONSENT FORM

OVER VIEW: The consent form should be constructed as a series of questions that the research subject answers. Both the research subject and the investigator should sign the statement. The research subject should be given a copy of the consent to keep.

UNDERSTANDING: Have you read and understood the patient information sheet?

FULL / ADEQUATE INFORMATION: Have you received enough information about the study?

VOLUNTARY PARTICIPATION: 1. Do you understand that participation is voluntary? 2. Do you agree to participate in this study?

RIGHT OF WITHDRAWAL: Do you understand that you are free to withdraw from the study at any time and without having to give any reasons and that such withdrawal will not affect your medical care?

ATTACHMENT 4:FOLLOW-UP QUESTIONNAIRES

CONFIDENTIAL QUESTIONNAIRE FOR RESEARCH SUBJECTS: 1. Study Title and study number 2. Information sheet: was it provided? Was it easy/difficult to understand? Did it answer most of your questions? Did someone explain the information sheet to you? 3. Voluntary consent: did you feel pressured to join the study? Were you given enough time to make up your mind?

CONFIDENTIAL REVIEW QUESTIONNAIRE FOR RESEARCHERS: 1. Start and end of the study 2. Protocol amendments 3. Progress of recruitment 4. Provision of information 5. Obtaining consent 6. Withdrawal of consent 7. Adverse events 8. outcome of research

ATTACHMENT 5: STUDY PROTOCOL

Chapters of the protocol: Title page, background and Introduction; Objectives of the trial; Patient Selection Criteria; Trial design; Therapeutic regimen: dose and toxicity; required evaluations: clinical, laboratory, and follow-up; criteria of evaluation; registration and randomization of patients; forms and procedure for data collection; statistical procedures; administrative responsibilities; informed consent; references; regulatory regulations, drug ordering, appendices (consent form etc).

Definition of objectives: A clinical trial is a serious and expensive undertaking that must not be started before defining clear, specific, and attainable objectives.

Literature review: Once objectives are set, literature review is carried out for similar studies or similar outcomes.

Definition of patients: method of randomization, inclusion and exclusion criteria, treatment allocation, and withdrawals. The criteria should not be too rigid to ensure a homogenous population. Registration procedures must be defined explicitly. Rigorous enrollment procedures should ensure that the subject does not have the outcome at the time of enrollment.

Description of treatment: treatments, response assessment (single-blind & double-blind), protocol departures, definition of end-points and criteria of efficacy, duration and frequency of treatment. Treatments may be single agent, combined modality, or adjuvant therapy. Description of treatment administration includes what to do in case of side effects or adverse drug reactions. A schema is a treatment plan in graphic form.

Sample size: The sample size is fixed in advance in fixed sample studies. In sequential sample trial the sample size is not fixed in advance. What really matters is the number of events and not number of subjects. A study of 1000 patients with 5 events is a weak study.

Data Collection: The exact methods of data collection must be described in such detail that any knowledgeable person will be able to carry out the protocol without further instructions. Measurement of effects and end-points must be defined. The data collection section must define the items of data to be collected. The following data items are usually needed: identification data (patient identifier, trial identifier, and institution identifier), administrative data (names of physicians and research associates), regulation data (institution review board approval, informed consent), the case record form (who fills the form and when, standard layout of the form including standard header, number of items, designation of decimal points, unit of measurement used, and definition of alternative responses of unknown, not available or not applicable, not done) coding of the CRF responses (multiple choices, numeric self-coding, non-numeric self coding), The design of the case record form is important for accuracy of data collection. In computerized CRF data is entered directly into the data-base. The choice between online and offline data entry depends on the nature of the study and preferences of the institution. Online data entry has the problem that there is no paper record to check for mistakes. Sometimes direct data capture is possible from laboratory and clinical measuring instruments.

Data-base: The design of the study data-base including details of data retrieval and security features. The database should be designed such that automatic editing checks are made for eligibility criteria and data inaccuracies as data is entered. The system must also be able to check for timely submission of data from the clinical centers. The relational data-base is more commonly used than the hierarchical. Attention must be paid to data security. Audit trails for changes made to the data must be updated and available. Three groups of study files are maintained: the protocol file with all protocol changes, the regulatory file, and the patient file.

Method of analysis: The statistical analytic philosophy must be determined in advance. There are basically 4 approaches: (a) the classical frequentist statistics (b) The Bayesian approach which requires having a prior probability. The prior probability may be subjective or could be objective based on previous data (c) The likelihood approach in which the inference is drawn as the trial progresses. The study is terminated as soon as a significant result is obtained.

Regulatory measures: Information must be obtained on whether the institution where the research is undertaken is in good standing. Is the investigator authorized? Are regulatory requirements met? Are patients eligible? Demographic data. Measures to ensure protocol compliance.

ATTACHMENT 7: DESIGN OF PHASE 3 CLINICAL TRIALS

Completely randomized design: In this design subjects are randomly allocated to treatment groups in such a way that likelihood of belonging to any group is the same for all subjects. It has the advantage of being simple to administer and dealing with the subject only once in allocation. Its disadvantage is that it allows only comparison between subjects and not within subjects.

Stratified design or randomized block design: In a stratified design subjects are randomly allocated to treatment groups separately for each stratum or block. It has the advantage if allowing within-block comparisons and using smaller sample sizes than the completely randomized design. Its disadvantage is that the allocation process is prolonged and patients may drop out. The stratification factors are: histology, performance status etc. Stratification may be carried out to achieve institutional balance. Stratifying on too many factors is not recommended. Imbalances can be adjusted at analysis. The larger the study the less the need for stratification.

Single-stage vs Multi-stage design: the study sample may be selected in one step. It may also be selected in 2 or more stages. Subsequent samples are selected from those first selected.

Factorial design: assess more than 2 treatments at the same time displayed as shown below

	Drug B+	Drug B-
Drug A+
Drug A-

Cross-over design: In a cross-over design, each subject is his own control. Subjects are allocated to sequences and each sequence contains all the treatments. The advantage of the cross-over design is that comparisons are made within subjects rather than between subjects which decreases confounding effects. This design requires a smaller sample size than the completely randomized design. Its advantage is spill-over effects in which treatment effects are carried over into the next treatment sequence. Drop-outs are likely because the allocation process is prolonged.

Sample size determination must take into consideration the number of participants, the total number of end-points, and the differences in compliance. Formulas are used to compute the total number of participants. Since there are many end-points in a study, there must be a method of selecting which ones are used in sample size determination. The general guideline is to use end-points associated with ‘high risk’ and those that can assure an adequate period of follow-up. Difference in compliance between the two groups is difficult to determine. A pilot study may provide some guidance. Results of the pilot study may be used to eliminate potential non-compliers before randomization. In the end analysis of the study may have to be based on ‘intention to treat’.

Study non-participants and participants come from a reference population. The participants, also called the experimental population, are then randomized to a treatment and a comparison group. Participants may differ in systematic ways from non-participants. It is therefore important to obtain minimal information from non-participants in order to assess the potential for bias. Volunteer participants may differ by age, gender, SES, and educational levels.

ATTACHMENT 8: DATA COLLECTION CLINICAL TRIALS

TYPES OF DATA COLLECTED

Patient data: eg performance status, weight

Tumor data: ICD, histopathology, TNM, Measurement (palpation, radiology, phototherapy, CAT scan); tumor markers eg gonadotrophins for trophoblast

Response to treatment: We may talk of response by one organ or response by the whole patient. Response assessment may be qualitative or quantitative. The qualitative assessment is preferred. The response scale is ordinal. The following are normally used for solid tumors: Complete response, Partial response, No response, Disease progression, No Evidence of Disease (NED), Recurrence. Response measurement in non-solid tumors is more difficult and is often measured indirectly. Although not measurable, the response is evaluable. Duration of response is an important parameter, defining the start of response is difficult but the end of response is easy

Survival: disease-free survival, time to recurrence, survival until death

Adverse effects: Type of toxicity, severity, onset, duration (acute/transient vs long-term/chronic). Distinguishing toxicity from medical complications of the disease. The longer the duration of treatment the higher the occurrence of toxicity. More frequent observation increases pick-up of toxicity. Proper toxicity analysis should include all patients even the non-evaluable. Patients whose drug dose was reduced because of toxicity should be analyzed separately. There are patient-related factors for toxicity.

Quality of life: Quality of life is not easy to measure. Quantifiable scales are preferred. Methods of measurement: clinical observation, clinical interview, self report by patient. Levels of inquiry: physical, chemical, anatomical, biochemical, physiological (organs and systems), psychological, social, and socio-psychological. Measuring instruments must have: validity, reliability, norms, and feasibility.

BLINDING

Blinding is used to avoid biases. There three types of blinding: single blinding, double blinding, and triple blinding. Single blinding is when the person assessing the response knows the diagnosis but not the treatment. Double blinding is when the person assessing does not know both the treatment and the diagnosis. This not possible in surgery and similar circumstances. The practical problems of ensuring double-blind status can be avoided by using a panel of physicians to review the outcome while leaving the usual physician to continue his work as usual. Maintaining complete double-blind will prevent early detection of benefits in order to stop the trial. In triple blinding the physician, the subject, and the data analyst are blinded to the treatment and the diagnosis.

STOPPING RULES

Stopping rules must be established from the start. Usually the trial is stopped when there is evidence of a difference or when there is risk to the treatment group.

ATTACHMENT 10: ANALYSIS AND INTERPRETATION OF CLINICAL TRIALS

FIXED SAMPLE VS SEQUENTIAL ANALYSIS

A sequential trial is one designed in such a way that there is continuous assessment of results in order to be able to stop the trial as soon as a difference or no difference has been determined. A pre-determined stopping rule must be used to avoid bias. Sequential trials have the following advantages: (a) economy of time and money since fewer patients are involved (b) Achievement of a specific precision (c) ethical considerations: the trial is not continued beyond what is necessary to establish the result. The disadvantage of sequential trials is that a lower level of statistical significance has to be used. This makes the study too strict.

ANALYTIC METHODS

Compare response proportions: chi-square, exact test, chi-square for trend

Drawing survival curves: K-M & life-table

Comparing survival & remission: Wilcoxon and log-rank tests

Prognostic factors related to response: Cox logistic regression

Prognostic factors of remission, duration, and survival times: Cox proportional hazards model

Meta-analysis: This is a technique of combining data from several related clinical trials. Each study is treated as a treatment block.

CAUSES OF DIFFERENCES BETWEEN THE 2 SERIES

Sampling variation/chance: controlled by statistical tests of significance

Inherent differences between the two series: controlled by randomization

Differences in the handling and evaluation of the 2 series: controlled by double-blinding

True effects of the treatment

Non compliance may cause a difference between the two groups. Non compliance may be overt or covert.

Drop-in is a term used to describe a situation in which patients in one group take the treatment of the other group.

PROBLEMS WITH STUDY DESIGN

Lack of full documentation/accounting for patients

Removing 'bad' cases from series

Not censoring the dead

Retrospective censoring: ‘clean up’ data by removing cases due to ‘competing causes of death’

Retrospective stratification

Publication bias

Ethics: The following ethical issues arise: (a) withholding a potentially beneficial treatment from the controls (b) the new agent may have unknown risks (c) lack of informed consent (d) Is double-blinding proper? (e) is using a placebo proper?

PROBLEMS WITH ANALYSIS

Maturation of data: If study is analyzed later different results are obtained

Misuse of ‘p-value’: no proper substantive or statistical questions and conclusions; use of part of data; use of inappropriate formula

Numerator problems: errors in measuring response

Denominator problems (# at risk): exclusion of the ineligible of non-evaluable, early death, loss to follow-up, failure to complete therapy due to toxicity, refusal of further therapy, inadequate data, major protocol violations. To solve denominator problems several denominators should be used in calculations and results are compared: registered and eligible, registered eligible and treated, registered, eligible, and adequately treated.

Accuracy is lack of bias. Precision is lack of variability. Among methods of controlling or minimizing bias: written protocols, blinding double or single, and minimizing drop out form the study.

[1] This is an adaptation and update of  a paper first presented by the author