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Lecture for 4th year medical students at FOM KFMC by Professor Omar Hasan Kasule Sr. on 28th March 2011.
1.0 RESEARCH IN ISLAM
Islam puts emphasis on seeking knowledge. Humans are encouraged to derive empirical knowledge from observation of the earth and their own bodies. The observation referred to is serious and deliberative, al nadhar bi al tadabbur. The prophet taught that there is a cure for every disease. There is an injunction to search for cures by processes of medical research.
2.0 RESEARCH PRACTICE
The Ethics committee approves research proposals and protocols that have ethical implications. It ensures the highest ethical standards in any research and protection of research subjects as stipulated in the Helsinki declaration, and protection of researchers from committing mistakes that lead to criminal prosecution. It monitors the conduct of the study to detect any ethical violations. Membership should include major medical and surgical specializations, hospital physicians, hospital nursing staff, general practitioners, pharmacists, statisticians, ethicists, and lay persons from the community. All genders and age groups must be represented.
3.0 RESEARCH ON HUMANS: HISTORICAL BACKGROUND
Early humans experimented with several plants and by trial and error found some to be useful as medicines and others to be poisonous. These early experiments were not planned in a systematic way neither were they documented. Galen founded experimental medicine before 200 CE. Historical experiments were carried out by James Lind In 1747 on scurvy, Dr Edward Jenner in 1798 on small pox, and Goldberger in 1914 on pellagra. Community trials were carried out on vitamin C, the Salk and HBV vaccines, cardiac disease risk factors, and water fluoridation for dental caries. Clinical trials were on streptomycin in TB 1948, aspirin and vitamin C for cancer prevention, alpha-tocopherol and beta-carotene in lung cancer prevention in smokers.
Unethical experiments without informed consent were carried out in the 1940s, 1950s, and 1960s. The Nuremberg code of 1946 laid down rules on voluntary informed consent, unnecessary experiments, animal before human experimentation, physical and mental suffering, scientific qualification of researchers, freedom of subjects to withdraw, and stopping the investigation if patient are in danger.
The Helsinki Declaration of 1964 incorporated the Nurenberg code. Its basic principles were: conformity generally accepted scientific principles, qualified researchers, risk benefit assessment, research subject welfare, and full disclosure before informed consent.
4.0 PURPOSES OF THE LAW IN HUMAN EXPERIMENTATION
The Islamic ethical theory on research is based on the 5 purposes of the Law, maqasid al shari’at, religion, life, progeny, the mind, and wealth. If any of the 5 necessities at risk permission is given to undertake human experiments that would otherwise be legally prohibited. Therapeutic research fulfills the purpose of protecting health and life. Infertility research fulfils the purpose of protecting progeny. Psychiatric research fulfills the purpose of protecting the mind. The search for cheaper treatments fulfills the purpose of protecting wealth.
5.0 PRINCIPLES OF THE LAW IN HUMAN EXPERIMENTATION
The 5 principles of the Law guide research. Research is judged by its underlying and not expressed intentions. Research is prohibited if certainty exists about beneficial existing treatment. Research is allowed if benefit outweighs the risk or if public interest outweighs individual interest. If the risk is equal to the benefit, prevention of a harm has priority over pursuit of a benefit of equal worth. The Law chooses the lesser of the two evils, injury due to disease or risk of experimentation. The principle of custom is used to define standards of good clinical practice as what the majority of reasonable physicians consider as reasonable. Under the doctrine of istishaab, an existing treatment is continued until there is evidence to the contrary. Under the doctrine of istihsaan a physician can ignore results of a new experiment because of some inclination in his mind. Under the doctrine of istislaah preventing a harm has priority over obtaining a benefit.
6.0 INFORMED CONSENT
Informed consent by a legally competent research subject is mandatory. Informed consent does not legalize risky non-therapeutic research with no potential benefit. It is illegal to force participation of the weak (prisoners, children, the ignorant, mentally incapacitated, and the poor) in clinical trials even if they sign informed consent forms.
7.0 PHASES OF A CLINICAL TRIAL
The screening process is long and systematic but could give false positives and false negatives. A synthetic drug is selected based on some rational criteria. It is screened by in vivo tests in rats or in vitro tests on human tissues before it is tested in animals.
Animal tests: The first stage is to screen drugs using animal tests to reject inactive preparations. There are no formal design requirements at this stage of the study. The design and approach depend on the intuition of the investigator.
Phase 1: Studies in humans start with the phase 1 clinical trials. These are small exploratory investigations that are not comparative. They accomplish 4 objectives: (a) determining the optimal or maximum tolerated dose, MTD. (b) studying drug administration schedules and (c) studying drug toxicity, qualitative and quantitative and (d) evidence of anti-tumor activity. Patients selected for phase 1 trials have disseminated disease that is not amenable to treatment. The patient must have life expectancy of at least 12 weeks. Animal data is used to decide the starting dose, dose schedule, and dose escalation.
Phase 2: Phase 2 studies are small non-comparative studies that assess therapeutic activity of a drug. The objective of phase 2 trials is to screen for anti-tumor activity in advanced disease. There are 2 sub-stages: stage 2a determines whether the drug is effective; stage 2b is a follow-up to determine a precise estimate of effectiveness.
Phase 3: This is the main stage of clinical trials. It is a comparative clinical trial that compares two drug regimens or compares a drug regimen to a placebo. Its objective is to compare the new agent against existing agents by determining relative efficacy in a comparative trial. The trial specifically aims at (a) selecting the better treatment (b) obtaining a precise measure of the effectiveness of the treatment regimen. The following measures are taken to ensure comparability: (a) The 2 groups must be similar with the exception of the treatment being assessed. This is ensured by randomization (b) The 2 groups must be treated in exactly the same way. Double blind techniques are used to prevent the possibility of investigator bias. A phase 3 study has three main stages: study design and protocol development, patient accrual and data collection, and follow up and analysis.
Phase 4: Phase 4 studies involve post-marketing surveillance by collecting data on short term and long term effects.
8.0 DISSEMINATION OF RESEARCH FINDINGS
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. Editors prefer publishing positive studies. Biases in selection of papers for publication arise from the peer review process due to old boy networks.
9.0 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, selective reporting of data, suppression of negative information, and ‘stealing’ others’ work. Financial gain, reputation, and the pressure to publish or perish are the driving forces behind fraud.
10.0 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.
11.0 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.
12.0 OUTSTANDING ETHICO-LEGAL ISSUES
Research on fetal human tissues may encourage abortion. Cadaver dissection and post mortem examination are permitted under necessity. Use of human bodies in auto crass experiments violates human dignity. Genetic experiments may cause diseases hitherto unknown. The Law allows research on ageing as long as the aim is not prolongation of life or preventing death because those aspects are under Allah’s control.