Active control equivalence trials

Article Abstract:

Active control trials are a type of clinical trial which compares the effectiveness of a new drug with a control treatment. In AIDS, where there is treatment available that enhances survival or prevents sickness, a placebo (an inactive substance) is not an acceptable control, because it provides no benefits to the patients who receive it. An active control equivalence study is a trial in which a new drug is compared with a drug whose effectiveness is known (the latter is the active control). The test is devised to see if the experimental treatment is at least as effective as the standard therapy. There can be problems when active control equivalence trials are designed. One of the problems is the lack of a statistical test for significance between the two groups. Statistics show the chances of differences, not similarities, existing between two groups. Larger groups of patients must be used to determine if the two treatments are equivalent, and it takes longer periods of time to measure the effectiveness. The control therapy must be known to be effective, otherwise the test cannot distinguish whether the new drug is effective in comparison. The patient population receiving the test therapy must be equivalent to that receiving the active control. There are active control trials in existence which are comparing the effectiveness of two drugs, such as 2',3'-dideoxyinosine (ddI) versus zidovudine. Zidovudine has been found to be effective in the treatment of HIV infections and AIDS. Other active control studies include the comparison of trimethoprim-sulfamethoxazole with the standard treatment of pentamidine for the treatment of Pneumocystis carinii pneumonia, and amphotericin B versus fluconazole for the treatment of cryptococcal meningitis. Therefore, although the active control equivalence study is an attractive alternative for the evaluation of drugs to treat fatal diseases such as AIDS, there are problems with the design, implementation, and interpretation of results from these types of trials. (Consumer Summary produced by Reliance Medical Information, Inc.)

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Statutory and regulatory framework for drug approval

Article Abstract:

The Food and Drug Administration (FDA) must be certain that a drug is safe and effective before it can be approved for marketing. The procedure for getting a drug approved begins with the identification of active compounds and preclinical testing, including studies in tissue culture and in animals. The next stage is applying for an Investigational New Drug permit so that the drug can be tested in humans; this is followed by phased clinical trials. Small, well-controlled phase I trials are used for establishing the dosage and safety of the drug, larger phase II trials focus on effectiveness and activity of the drug, and large-scale phase III trials evaluate both safety and effectiveness. Effectiveness is proven by "adequate and well-controlled investigations". This is generally done by five types of controlled studies: placebo-concurrent; no treatment-concurrent; active treatment-concurrent; dose comparison; and historically controlled trial. In 1988, the FDA reevaluated its approval procedures and new regulations were issued so that drugs could be developed, reviewed, and approved more rapidly, especially in life-threatening and severely debilitating diseases such as AIDS. The new regulations include early consultation, in which the FDA will meet with sponsors of the drugs before they are ready to submit an application for approval, and meetings after phase I trials, instead of phase II trials. Although the new regulations allow faster development and approval of drugs, the approval is based on adequate but limited data, with some questions still unanswered. The goal is to design clinical trials so that the safety and effectiveness of drugs can be established as efficiently as possible, and yet to still provide the data that are required by the FDA for drug approval. (Consumer Summary produced by Reliance Medical Information, Inc.)

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The need for early randomization in the development of new drugs for AIDS

Article Abstract:

There has been a rapid development of new agents for the treatment of individuals infected with the human immunodeficiency virus (HIV) and for those whose infection has progressed to the disease state of AIDS. Because AIDS is fatal, there is a need to distinguish as quickly as possible between drugs that could be helpful and drugs that would do more harm than good. It is important that clinical trials which give the drug to randomly assigned patients are conducted, as early as possible in the drug testing procedure. In such studies, subjects are randomly (by chance) assigned to receive either the new drug or the standard therapy. The new drug can be given at random in this way if its outcome and side effects have been evaluated in other clinical trials. Early randomization would yield results on the effectiveness of the drug, before a bias could be formed about the value of the drug based on inaccurate information from uncontrolled trials. There are both ethical and scientific reasons why patients should be randomized to receive (or not receive) a new drug. The ethical reasons include that a new drug may or may not be more effective than the standard treatment (and the drug may turn out to be toxic). This point is often missed by those who are not informed about clinical research, who may mistakenly assume that the new treatment is always better than the established therapy. The scientific reasons for randomization include that the state of health of the individual patient affects the outcome of the treatment. (Consumer Summary produced by Reliance Medical Information, Inc.)

Testing, Antiviral agents

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