Lawrence Charles Parish, M.D.
Ever look on the handout that comes with the medicine dispensed by the neighborhood pharmacist? This lengthy document usually lists many dos and don'ts and may even confirm the dosage. How is so much information accumulated? From the clinical trial.
Background
Clinical trials, or I should say formal clinical trials, did not always exist. For example, digitalis was grown in many gardens in the eighteenth century and still is. Only by trial and error did William Withering find that it had an effect on the heart, but there were no full-scale trials conducted. In fact, digitalis was tried for a number of eighteenth century diagnoses, including rheumatism, other types of dropsy, and even gout, but without benefit. When aspirin was introduced in the late nineteenth century, patients tried it but not in an organized fashion and only by chance, or perhaps it was through serendipity, that this wonder drug came to relieve headaches and to diminish joint pain. The formal clinical trial is actually an outgrowth of the Cooperative Clinical Trials of the 1920's for evaluating neoarsphenamine (a later version of Ehrlich's 606) for the treatment of syphilis.
Since 1938, the United States Food and Drug Administration (FDA) has taken an ever-increasing role in overseeing the evaluation of pharmaceutical agents. This developed due to the sulfonamide scandal of the era, when the S. E. Massengill Company formulated an elixir of sulfa drug for pediatric use. They had reasoned that if the new antibacterial agent were useful in pill form, then a liquid form would be fine. Tragically, the reasoning was wrong. The safety steps that we would use today were not in force.
Clinical Trials
Before pharmaceuticals are made available for prescribing by physicians, the drugs must undergo a lengthy trial process. Note that the word trial is used, because not even the most astute pharmaceutical chemist can predict in the laboratory what will happen in the clinic.
Once a drug is synthesized or discovered, a research team will evaluate it in laboratory animals to determine the initial safety and therapeutic potential. When this is established, it enters Phase 1 testing, where healthy volunteers are given various dosages to determine its safety and utility. If the agent passes this step, then it enters Phase 2 testing to see if it will treat the disease or diseases for which it is intended. Dosing and means of administration are evaluated here.
If everything is okay, then it is placed in Phase 3 trials among larger groups of patients. For example, does it work in women as well as men? Until the past few years, women were excluded from being volunteers for fear that they might become pregnant during the trials, but this meant that needed information was not available. A similar situation has occurred with children. Whereas adults generally receive a standard dose of a medicine, children usually are given a dose per weight. Without necessary trials, this information would not be known, and so most appropriate drugs are currently evaluated in children, as well.
Now the drug is ready for approval, but the evaluation process doesn't stop here. Once it is marketed, more studies ‚ post-marketing or Phase 4 trials ‚ are conducted. Why? Despite the sophisticated process of studying the drug and the extensive use of biostatistics, nothing replaces use in large numbers of patients.
Conclusions
Why do so many drugs need to be evaluated? Many years ago, a hospital committee whose approval I needed to conduct an antibiotic study kept delaying their decision. They couldn't understand the need for one more antibacterial. This was shortsighted, as each pharmaceutical agent has its own niche. Bacteria develop different resistance patterns, and new antibacterial agents are continually needed. In addition, just because a family of drugs is labeled as an antibiotic doesn't mean that it won't have other uses. Witness the macrolide family of agents that make up the new immunomodulators (ElidelÆ and ProtopicÆ) for treating atopic dermatitis, as well as for the antibiotics used for treating bacterial sore throats and impetigo (erythromycin, BiaxinÆ, and ZithromaxÆ).
If you want to learn more about clinical trials in the pediatric age group, there is a good website, sponsored by Children's Hospital Boston www.researchchildren.org.
Lawrence Charles Parish, M.D., is a clinical professor of Dermatology and Cutaneous Biology and director of the Jefferson Center for International Dermatology, Jefferson Medical College, Philadelphia, PA. Please send your questions and comments to him care of Pediatrics for Parents, P.O. Box 63716, Philadelphia, PA 19147.
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