FDA and Clinical Drug Trials: A Short History. Suzanne White Junod, Ph. ![]() D. 1. The function of the controlled clinical trial is not the . Discoveries are made in the animal laboratory, by chance observation, or at the bedside by an acute clinician. The function of the formal controlled clinical trial is to separate the relative handful of discoveries which prove to be true advances in therapy from a legion of false leads and unverifiable clinical impressions, and to delineate in a scientific way the extent of and the limitations which attend the effectiveness of drugs. ![]() ![]() William Thomas Beaver 2. Overview. The U. S. Food and Drug Administration has evolved as one of the world's foremost institutional authorities for conducting and evaluating controlled clinical drug trials. Ancient civilizations relied on medical observation to identify herbs, drugs and therapies that worked, and those that did not. ISIS Report 23/05/06 Post Mortem on the TGN1412 Disaster. Peter Saunders raises a number of key questions on the way the drug trial was conducted.Beginning in the early twentieth century, therapeutic reformers in the United States and in other places began to develop the concept of the . This concept, included, for example, laboratory analysis followed by clinical study. As medical historians have pointed out, however, these early reformers' therapeutic vision often far exceeded their clinical and experimental grasp. In 1. 93. 8, a newly enacted U. FDA and Clinical Drug Trials: A Short History: article by Suzanne White Junod, Ph.D. Six men remain in intensive care after being taken ill during a clinical drugs trial in north-west London. The healthy volunteers were testing an anti-inflammatory. S. Food, Drug, and Cosmetic Act subjected new drugs to pre- market safety evaluation for the first time. This required FDA regulators to review both pre- clinical and clinical test results for new drugs. Although the law did not specify the kinds of tests that were required for approval, the new authority allowed drug officials to block the marketing of a new drug formally or delay it by requiring additional data. The act also gave regulators limited powers of negotiation over scientific study and approval requirements with the pharmaceutical industry and the medical profession. A worldwide drug disaster in 1. Drug Amendments, which explicitly stated that the FDA would rely on scientific testing and that new drug approvals would be based not only upon proof of safety, but also on . Increasingly, responsibility for testing standards previously established as voluntary by the American Medical Association's (AMA) Council on Drugs, the U. S. Pharmacopeia and the National Formulary were taken up by the FDA. Since 1. 96. 2, FDA has overseen substantial refinements to the broad legal requirement that post- 1. Medical Observation As Precursor to Clinical Trials. Clinical trials are prospective, organized, systematic exposures of patients to an intervention of some kind (drug, surgical procedure, dietary change). The earliest recorded therapeutic investigations, however, lacked the rigor of a modern clinical trial. Based largely on observations and tested through time by trial and error, ancient medicine such as that practiced by the Egyptians, Babylonians, and Hebrews was closely allied with religion. Nonetheless, some of these early medical investigations did yield some important successes in fields such as minor surgery and orthopedics. The Hebrews, in particular, excelled in public hygiene, but even their public health strictures, so effective in preventing epidemic disease, were observational and experiential rather than experimental. The Babylonians reportedly exhibited their sick in a public place so that onlookers could freely offer their therapeutic advice based on previous and personal experience. The first mention of a paid experimental subject came from Diarist Samuel Pepys who documented an experiment involving a paid subject in a diary entry for November 2. He noted that the local college had hired a . British naval surgeon James Lind (1. Twelve men with similar cases of scurvy ate a common diet and slept together. Six pairs, however, were given different . Two were given a quart of cider daily; two an . One man who received the oranges and lemons recovered within six days, while the other recovered sufficiently that he . Nonetheless, the British Navy did not supply citrus to its ships until 1. Although simple observation may provide a starting point for medical study, however, experience has shown that it is rarely efficient at advancing medical knowledge. As one early proponent of planned experimentation in the form of clinical trials remarked, . Although clinical trials are not the only way to find things out, the clinical trial is unique. Certainly clinical trials in this country have evolved in pursuit of a larger therapeutic goal - - to see that the physicians use the best possible therapies available. It is interesting to note that in the late 1. U. S. In their quest to protect animals, they viewed both animals and human beings as equally vulnerable, and feared that the replacement of the family physician by a . It was the antivivisectionist and playwright George Bernard Shaw, in fact, who first used the term . In 1. 88. 0, patent medicines – a misnomer because nothing but the label and the bottle were actually patented or trademarked – constituted 2. By 1. 90. 0, however, they represented 7. It was popular to blame both the gullible physician and the ignorant laymen for being equally taken in by the advertising excesses of the era. The American Medical Association (AMA) began to push for federal evaluation of new medical products hoping to make a dent in the patent medicine industry, but it was unsuccessful. In 1. 90. 5, the AMA formed its own Council on Pharmacy and Chemistry which levied a fee on manufacturers to evaluate their drugs for quality (ingredient testing) and safety. Drugs accepted by the Council could carry the AMA's Seal of Acceptance and only products with the seal had access to the advertising pages of the Journal of the American Medical Association (JAMA). The AMA's Chemical Laboratory tested commercial statements about the composition and purity of drugs in their labs, while the Council on Pharmacy and Chemistry followed up with safety evaluations and rudimentary efficacy evaluations designed to eliminate exaggerated or misleading therapeutic claims. Although the Council eagerly sought evidence that drugs had an effect on the cause or course of a disease, the Seal was awarded to drugs that merely provided symptomatic relief. Although the Council would have liked to rely upon clinical studies to supplement laboratory studies submitted by drug manufacturers, they lacked the necessary funding to support such studies and the AMA did not authorize the Council to require them. Instead of relying on the anecdotal information provided by private practitioners, however, the Council relied heavily on the opinions and recommendations of Council members who were well- respected medical specialists and scientists, a progressive practice for the era. Once their evaluations became a regular feature in the Journal of the American Medical Association (JAMA) the Council began to make inroads against the commercialism that physicians had felt were . The AMA's drug certification program remained in place until 1. Clinical Trials and the 1. Pure Food and Drugs Act. While the AMA Council on Pharmacy and Chemistry held out a carrot of certification to ethical drug products that met their standards, the first federal food and drug statute, the 1. Pure Food and Drugs Act, wielded little in the way of a stick. The AMA had been unsuccessful in getting any kind of drug review in the new law and the statute merely provided a legal definition for the terms . The law did empower the Bureau of Chemistry (forerunner of the U. S. Food and Drug Administration) to seize adulterated and misbranded products that moved in interstate commerce, but it simply adopted the drug standards as published in the U. S. Pharmacopeia and the National Formulary. The law also prohibited . In the case of drugs, the law listed eleven so- called . This listing requirement alone inspired many manufacturers to abandon use of many dangerous ingredients following passage of the 1. Act. But efforts to prohibit false therapeutic claims on drug labels were defeated both by the Supreme Court and the U. S. Congress. During the 1. Therapeutic experimentation, however, did not begin to gain a true foothold in modern medicine until the U. S. As late as 1. 93. In a landmark state Supreme Court decision in 1. Michigan seemed to recognize and authorize controlled clinical investigations as a part of medical practice without subjecting the researcher to strict liability (without fault) for any injury so long as the patient consented to the experiment and it did not . In particular, the Michigan Supreme Court accepted that experimentation was necessary not just to treat the individual, but also to help medicine progress. Breakthrough drugs such as the first sulfa drug, sulfanilamide, new drugs including amphetamines and barbiturates, and biologics such as insulin were coming onto the market and beginning to transform medicine entirely. Clinical trials and human experimentation were becoming increasingly more important in medical research. Moreover, turn- of- the- century patent medicines with inert ingredients and quirky but quaint labels were becoming a true public health danger when patients relied on them rather than seeking out effective new therapies. The case of Banbar, in particular, convinced regulators early in the 1. Soon after the 1. Act had been enacted, a dispute arose over the meaning and enforcement of the drug labeling provisions of the law. The Supreme Court ruled in U. S. Johnson in 1. 91. Dr. Johnson's Cure for Cancer – it just prohibited . In 1. 91. 2, Congress quickly enacted the Sherley Amendment, a compromise that merely prohibited false therapeutic claims . Proving that a proprietor knew that his drug was worthless in order to demonstrate fraud under the statute, however, could be a daunting task. To cite a single example: an old patent medicine maker created a . Its active ingredients included milk sugar and equisetum (horsetail). Northwick Park drug trial disaster - could it happen again? Before any new medicine can be given to patients, detailed information about how it works and how safe it is must be collected. Clinical trials are the key to getting that data - and without volunteers to take part in the trials, there would be no new treatments for serious diseases such as cancer, multiple sclerosis and arthritis. But one disastrous drug trial at a London hospital in 2. In what became known as the Elephant Man trial, six healthy young men were treated for organ failure after experiencing a serious reaction within hours of taking the drug TGN1. After they were all admitted to intensive care, two became critically ill, the worst affected lost his fingers and toes, and all the men were subsequently told they would be likely to develop cancers or auto- immune diseases as a result of their exposure to the drug. In follow- up interviews, the men described feeling like their brains were . Experts queued up to say the outcome of the trial had been unprecedented and exceptional, but could it happen again? Prof David Webb, professor of therapeutics and clinical pharmacology at the University of Edinburgh and vice president of the British Pharmacological Society, says it is . Then there are four stages of drug testing in humans. Phase I - studies, on a small number of healthy volunteers, to understand what effects a new medicine has on human subjects - what happens to the compound in the body from the time it is swallowed or injected until it is excreted. Study participants are monitored for side effects. Phase II - designed to evaluate the safety and efficacy of a drug in patients who are at the same stage of a specific disease or condition. They are given various doses of a compound and closely monitored. Phase III - used to confirm a new drug's safety and efficacy, while working out the best dosage regimen. Studies are carried out in large numbers of patients with a specific disease or condition. Safety and efficacy is compared to the currently accepted standard treatment. Phase IV - these studies take place after the drug has been approved for marketing. They evaluate the long- term effects of the drug in larger numbers of patients, sub- populations of patients. Less common adverse events may be detected. MHRAThis is particularly important when trials involve drugs that affect the immune system, he says. But is it possible to eliminate the risks entirely? We can never be sure. This is the initial phase in assessing the safety of a drug before moving onto larger- scales studies in patients themselves. The report said Parexel, the company managing the trial, had been unclear about a safe dose to start testing on humans and it should have tested the drug on one person at a time. The MHRA, which regulates clinical trials and medicines in the UK, and which was criticised at the time for giving the green light to the TGN1. It adds that it has simplified and streamlined the regulation of clinical trials and collaborated with other bodies and experts to collect as much information as possible on risk factors before a trial is authorised. Phase- one trials, when drugs are tested on humans for the first time, only happen after extensive testing on tissue samples and animals in the lab. Getting this stage right before moving onto research in humans is crucial. Dr Catherine Elliott, director of clinical research interests at the Medical Research Council, which funds clinical trials in the UK and globally, says there is a move to refine the models used at the pre- clinical stage. We'd get the payback eventually because by the time we're in our 6. It shouldn't be related to risk. People have to be able to give free consent. Prof Webb says he has always found it relatively easy to find volunteers for the . The MHRA is in no doubt about the safety of drug trials, seven years on from Northwick Park. A representative said.
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