April 1996 Bulletin

New technologies need clinical trials

Need validation before put into public use, say researchers

There is a normal progression from research to clinical practice, said Victor M. Goldberg, MD. "First, you have to define the base science, then apply it in vivo in lower-order animals, then higher-order animals, then apply it in clinical medicine in well-documented prospective randomized studies either in a single institution or a multicenter study," he said. "Ultimately, it goes to the Food and Drug Administration (FDA).

"This process can be as long as a decade. For certain diseases, such as HIV, there might be an accelerated process for FDA approval of drugs, but the vast majority of research requires lengthy research which could last 10 years or longer.

"One of the problems facing FDA today is how to deal with new technologies such as cell therapy, growth factors. The FDA is trying to develop the appropriate definitions."

Richard D. Coutts, MD, believes that "in an ideal world, no treatment should move to uncontrolled widespread usage until it has been thoroughly validated. That certainly was the intent of the government when it established the FDA with the mandate to validate the proof of efficacy and safety of first drugs and then devices before they are released to the medical community and the general public, and then only for specific indications for which the drug or device has been tested.

"However, the FDA does not have oversight of treatments that do not involve a drug or device (and now more recently biologicals), leaving the medical profession to set the standards for the validation of safety and efficacy for such treatments. Surely, the profession requires as high or higher a standard of proof of safety and efficacy for treatments as does the government for drugs and devices? If this be the case, then the next logical question is what constitutes proof?"

Dr. Coutts said that when a new treatment is developed as a result of basic laboratory or animal research, "there ultimately arrives a time when the investigator must decide that the new treatment is ready for human testing. There are clear and obvious limitations of bench top and animal studies that make it impossible to translate their results to the human with accuracy. The surgeon/scientist must exercise careful judgment and objective evaluation of the evidence before deciding to progress to human studies. It is extremely important that the human testing be as scientifically rigorous as possible."

Once the initial human testing has been completed, the orthopaedic surgeon should be given the evidence that the treatment is safe, and that it is effective. "This evidence should measure up to a scientific standard that would give confidence that the new treatment is a true improvement," Dr. Coutts said. "This means that the new treatment must be compared to the current standard treatment(s) using measurable and quantifiable methodology. And ideally, the new treatment will have been validated by others who have likewise studied that treatment and obtained results comparable to those of the innovators. These confirmatory studies must be performed just as rigorously as the initial studies and under Institutional Review Board auspices."

Although developing proof of safety and efficacy is time consuming, and may delay a potentially important treatment from reaching general application quickly, Dr. Coutts said "the needless suffering and disappointment that results from a bad idea reaching general use far outweighs this disadvantage. The patients' welfare must be the principle concern of the physician, and accepting unproven methods does not serve to protect the welfare of the patient.

Gary E. Friedlaender, MD, believes that the transfer of basic research accomplishments to clinical practice is not only desirable and anticipated "but, more importantly, is critical to our collective well-being. It is, therefore, necessary to establish patterns (processes) that encourage the timely and sufficiently meaningful evaluation of emerging science with potential clinical relevance."

Dr. Friedlaender points out that novel approaches to non-life-threatening disorders "for which current treatment is woefully inadequate represents an exciting aspect of our professional life and an important expectation of society. Our inability to reliably regenerate or repair (or, best of all, preserve) articular cartilage remains an unmet challenge. Our approach to evaluating potential solutions must be sufficiently rigorous to provide credible assessment. Well-conceived, appropriately implemented and necessarily controlled studies are conceptually within our grasp.

"The journey from basic science to the bedside must proceed in a step-wise, or phased fashion, wherein we clearly understand the fate of an appropriate number of individuals over a sufficient period of time in a well-planned clinical trial before offering our patients an approach that engenders the confidence we now enjoy and must continue to strive to achieve as their trusted health care provider."


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