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Clinical Trials
Pages 20-33

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From page 20...
... Clinical trials are of vital importance in the development of new drugs for use in humans. Preliminary experimentation in animals is important in identifying potentially effective interventions in animal models human diseases and in identifying the efficacious and nontoxic amounts of a pharmaceutical to be given.
From page 21...
... Similar considerations must apply as well in defining therapeutic efficacy for a new drug and markers of adverse effects during clinical trials. If too stringent a requirement for efficacy is applied, ultimately useful drugs may be discarded prematurely.
From page 22...
... One of the things that sets clinical trials apart from other members of the class of trials is the obligation for care. Investigators undertaking them have obligations to ensure that the patients enrolled in the trial are adequately cared for, even if doing so conflicts with or is at odds with required data collection and treatment procedures set forth in the protocol for the trial.
From page 23...
... The period of treatment may consist of a single exposure to the drug or repeated exposures. The exposures may involve use of the same dose administered according to a specified schedule or differing dose administered according to some scheme (e.g., as in a crossover trial in which each person enrolled receives a low or a high dose followed by a high or a low close)
From page 24...
... That evaluation is relatively straightforward in randomized controlled trials involving comparison of one or more test treatments versus a control treatment. The control treatment in the case of drug trials may be a placebo, or it may be a standard medical treatment or another test treatment.
From page 25...
... Testing of new drugs in human beings typically proceeds in three, and sometimes four phases, defined as follows: Phase I: Usually the first stage in testing performed as part of an TND application to FDA, the trial is done primarily to generate preliminary information on the chemical action and safety of the new drug and is usually not controlled; that is, it is done without the benefit of a concurrently observed comparison group that does not receive the drug. Subjects are most often normal volunteers, but sometimes patients with the target disease.
From page 26...
... As a rule, they are controlled, have fixed sample size designs, parallel treatment structure, and protocols involving a fixed dosage schedule. All trials, regardless of phase, are subject to review and approval by a local institutional review board (IRB)
From page 27...
... In each written IND safety report, the sponsor shall identify all safety reports previously filed with the IND concerning a similar adverse experience, and shall analyze the significance of the adverse experience in light of the previous, similar reports. In regard to telephone reports the regulations specify that: The sponsor shall also notify FDA by telephone of any unexpected fatal or lifethreatening experience associated with use of the drug in the clinical studies conducted under the IND no later than 3 working days after receipt of the information.
From page 28...
... With respect to results from tests in laboratory animals, a serious adverse drug experience includes any experience suggesting a significant risk for human subjects, including any finding of mutagenicity, teratogenicity, or carcinogenicity. ETHICAL CONSIDERATIONS Ethical justification of research involving human subjects requires responsiveness to the ethical norms or rules that are embodied in ethical codes and regulations.
From page 29...
... Substantive Norms The leading international codes and guidelines in the field of research involving human subjects, The Nuremberg Code, The Declaration of Helsinki, and the International Ethical Guidelines for Biomedical Research Involving Human Subjects (promulgated in 1993 by the Council of International Organizations of Medical Sciences in collaboration with the World Health Organization each clearly presents the requirements for good scientific design and competent investigators as ethical requirements (Levine, ~ 9861. This point notwithstanding, it is customary to dissociate the discussion of these matters from discussion of the other substantive ethical norms.
From page 30...
... to ensure the timely identification of adverse reactions so that appropriate interventions can be implemented in time to minimize injury to individual subjects; such interventions are exemplified by discontinuation of a subject's participation in the study and by the administration of antidotes to toxic agents; and (2) to ensure accurate estimates of the nature, probability and magnitude of side effects and adverse events (a)
From page 31...
... Accordingly, one must be especially attentive to avoid what are commonly called "undue inducements." A frequently used guideline calls for limiting cash payments to vulnerable research subjects to the minimum wage for the actual time spent plus reimbursement for out-of-pocket expenses such as parking fees and stipends for baby-sitter (Levine, 19861. Compensation for Research-Relatect Injury Several prestigious groups advisory to the federal government have recommended that there should be "no-fault compensation" for research-induced injury (Levine, 19861.
From page 32...
... SUMMARY Clinical trials are of vital importance in the development of new drugs for use in humans. Preliminary animal experimentation is important in identifying potentially effective interventions and eliminating potentially dangerous ones, but no amount of animal testing can substitute for carefully planned and carefully conducted human studies in which a particular medication or intervention is administered to individuals with a specific disease under conditions where beneficial or detrimental effects can be identified during a reasonable period of observation.
From page 33...
... Investigators undertaking them have obligations to ensure that patients enrolled are adequately cared for, even if doing so is at odds with required data collection and treatment procedures set forth in the protocol for the trial. We have therefore include in our overview not only the FDA regulations governing reporting of adverse events, but also an ethical framework which we found useful in evaluating the FlAC\FlAU trials.


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