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Is the latest always the greatest?

Issue: August 2012

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To the Editor:

It was with great interest that we read the Commentary, “Reproduction of published research results remains a challenge for physicians” in the June 2012 issue of Orthopedics Today. The confirmation of results and conclusions from one study obtained independently in another is considered the scientific gold standard and is a hallmark of modern evidence-based medicine. Douglas W. Jackson, MD, carefully highlights not only that several published studies have reported results not reproducible in independent clinical settings, but also how financial conflicts of interest can potentially serve to impact study results.

The reproduction of original research also may present a particular challenge in the context of medical innovation. The word innovation derives from the Latin word innovare, meaning “to renew or to change” and can be defined as the creation of a novel method or idea with the intent to revolutionize current standards.

While innovation is essential in optimizing patient care and raising clinical standards, we must first seek to benefit the patient before considering the prospect of financial return. The April 2012 issue of Nature featured the topic of rewardable innovation in drug therapy. In nine studies, while almost all referred to an innovative drug as new, novel and generally useful, a favorable benefit-to-harm balance was never mentioned. The different perspectives were described as an imbalance between benefitting the patient and improving health care on one hand, while aiming to increase their profit on the other.

President Eisenhower once had a theory that a researcher’s need to please their superiors and secure funding for future projects contained an inherent drive to obtain positive results. However, the opposite is also true in that there is typically a lag in publishing negative results. A substantial aspect of this may be industry-driven, as companies are reluctant to declare an innovative product ineffective for fear it will jeopardize an expected return on investment. John P.A. Iodannidis, MD, PhD, head of Stanford University’s Prevention Research Center, found that “positive” trials (defined as those in which a treatment is deemed effective) and “negative” trials (where a drug is found ineffective) take the same amount of time to conduct. However, negative trials take an extra 2 years to 4 years to be published, during which time patients may continue to receive expensive treatments that are ineffective or harmful.

Unfortunately, there are several examples where treatments, when first introduced seemed promising as a result of good short-term results and keen marketing campaigns. One such example is the arthritis drug Vioxx, which was backed by a $200 million marketing campaign and introduced to the market in 1999 after receiving approval from the FDA. Despite this and only a year after its approval, researchers began to warn about possible cardiovascular risks associated with the drug. These warnings were largely ignored and it remained on the market for an additional 4 years before being removed. Similar examples are the use of Chymopapain for back pain and Avastin for breast cancer. Chymopapain was introduced as a cure for back pain in the 1980s and was rapidly implemented at the community level. However, in most physicians’ hands it was ineffective. It disappeared from general use and was removed from the U.S. market in 2003.

Avastin had been successfully used in the treatment of colon cancer and was therefore fast-tracked through the approval process as a treatment for breast cancer by the FDA. Unfortunately, this costly treatment appeared to be ineffective for breast cancer and its approval was revoked 3 years later.

While innovative research is often industry-sponsored and reported findings potentially biased, researchers themselves also tend to be biased because it is easier to publish positive results in high-level journals. Important steps toward the reduction of bias would be to conduct research in a blinded manner and to encourage the reporting of challenging or negative results. In the meantime, we are forced to wonder if the latest is always the greatest? Innovation is not synonymous with improvement. Initially promising results do not always hold up in the long-term.

Our objective as physicians is to progress toward the improvement of patient outcomes. Fundamental principles to achieve this goal are summarized in the “evidence-based triad,” which combines the best available clinical evidence with the clinical expertise of the physician and the expectations and values of the patient. However, in orthopedic surgery, we have another important triad to remember in cases with limited or no evidence to support a new treatment: the “orthopedic triad” by John A. Bergfeld, MD. The orthopedic triad summarizes how new treatments in our field become popularized – “famous surgeon, famous athlete, untested treatment.”

Both physicians and patients often seek a “quick-fix” or “cure-all” solution for their injuries, including platelet-rich plasma (PRP), stem cells, growth factors and autologous conditioned plasma. Many modalities are regarded as standard of care by athletes and coaches and have been or are used for a variety of ailments, such as tennis elbow, hair loss, lower back pain, meniscal tears, skin rejuvenation, tendinitis and spine instability. The reality with these treatments is that they are being used in many cases where there is a lack of basic science evidence to justify extrapolation to a clinical setting. Even then, the complexity of many orthobiological treatment modalities contributes to a general lack of quality control. Numerous websites selling unproven “miracle” stem cell treatments for incurable illnesses are just one sad example.

Recently, the use of PRP has gained increased popularity in the field of sports medicine. PRP is an autologous blood product produced by centrifuging whole blood to obtain a concentrated platelet product containing numerous growth factors, cytokines and other proteins, thereby aiming to stimulate bone and soft tissue healing. With approximately 1,100 different growth factors identified in PRP to date, an important question is as to whether all growth factors are beneficial in all type of injuries and at all time points.

One study by Huard and colleagues demonstrated that transforming growth factor beta 1 has the potential to cause fibrosis in the treatment of muscle injuries. Furthermore, numerous variables will affect the ultimate composition of PRP, which include the system used for preparation, whether the platelets are activated, age of the patient and time of day blood is drawn. Despite this variability, the drive of popular culture and positive mainstream media after PRP use for the treatment of high-profile athletes estimates that the market value of PRP will increase to $126 million by 2016. Nevertheless, the clinical validation of PRP remains in the early stages.

Innovation is an essential aspect of science and health care. We, as researchers, strive for it every day. However, many different factors should be taken into account when evaluating exactly what we define as “innovation.” Ezekiel Emmanuel, MD, of the University of Pennsylvania may have summed it up best: “…we need to stop glorifying every new technology as an innovation. ‘New’ matters only when it’s proved better than we had before.” In this regard, we not only need scientific advancement, but we need sophisticated and objective outcome measurements whereby results can be evaluated and compared to the current standard of care in the absence of any potential industry or marketing bias. In 1955, Jonas E. Salk, MD, developed a safe and effective vaccine to treat polio. He filed no patents on his development work, had no interest in personal profit and had one goal in mind – the betterment of the patient. As Albert B. Ferguson, MD, chairman of the Department of Orthopaedic Surgery at the University of Pittsburgh from 1953 to 1986 always said, “Just do the right thing” and “Take good care of your patients, and they will take good care of you.”

Innovation is necessary for continued advances in health care, but needs to be supported by evidence – both basic science and clinical – and must not be market-driven. The progress in health care requires publication of positive and negative results, that should be independently verified.

— Bart Muller, MD;
Marcus Hofbauer, MD;
Christopher D. Murawski, BS; and
Freddie H. Fu, MD, DSc (Hon), DPs (Hon)
University of Pittsburgh