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Systemic Bias in Clinical Research
Robin Young • Fri, May 12th, 2017
Reproducibility is the foundation of science. To paraphrase the 17th century Irish chemist Robert Boyle, it is reproducibility that produces facts. It is the ability to repeat the same experiment over and over again that makes facts believable.
Numerous commentators including several from the leading academic institutions, the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) have raised an alarm regarding the declining rate of reproducibility in modern clinical research and its implications for health and science.
Francis S. Collins, M.D., Ph.D. and Lawrence Tabak, D.D.S., Ph.D., NIH director and principal deputy director, respectively, cited in their 2014 Nature paper a 2011 study by the Office of Research Integrity of the U.S. Department of Health and Human Services that documented 12 cases of clinical study irreproducibility.
In 2015, psychology became the first scientific discipline to conduct and publish an open, registered empirical study of reproducibility called the Reproducibility Project which was led by Brian Nosek, Ph.D., and the Center for Open Science. Two hundred seventy researchers from around the world collaborated to attempt to replicate 100 empirical studies from three top psychology journals.
Of the original studies, 97% reported significant results (p<.05) while in the replication studies only 36% reported significant results. Same studies, but conducted by independent labs!
Nosek noted: “In sum, a large portion of replications did not reproduce evidence supporting the original results despite using high powered designs and original materials when available. The open dataset provides a basis for hypothesis generation on the causes of irreproducibility.”
John Ioannidis, M.D., D.Sc., Professor of Medicine and of Health Research and Policy at Stanford University School of Medicine and a Professor of Statistics wrote in his seminal paper “Why Most Published Research Findings are False”:
“Several methodologists have pointed out   that the high rate of nonreplication (lack of confirmation) of research discoveries is a consequence of the convenient, yet ill-founded strategy of claiming conclusive research findings solely on the basis of a single study assessed by formal statistical significance, typically for a p-value less than 0.05.”
“Research is not most appropriately represented and summarized by p-values, but, unfortunately, there is a widespread notion that medical research articles should be interpreted based only on p-values.”
On March 7, 2016, the American Statistical Association (ASA), the world’s largest community of statisticians and the oldest continuously operating professional science society in the United States, released its first statistical practice guidance document in history.
Landmark Ruling: Judge Orders Insurer to Pay for ADR
Robin Young • Fri, August 23rd, 2013
“The Court concludes that CIGNA has failed to prove that two-level ADR is an experimental procedure excluded from the Plan’s coverage.” – U.S. District Court Judge Dolly M. Gee on July 31, 2013
Danica Dubaich was in agony. She had bilateral foot pain, low back pain, left arm and hand weakness, right thigh numbness, right hip pain and headaches. Her physician, Brian Rudin, M.D., diagnosed degenerative disc disease at L5-S1.
To confirm his diagnosis Dr. Rudin performed a discogram of Ms. Dubaich’s spine which clearly showed an annular tear at L5-S1. The discogram was consistent with an earlier MRI image which also indicated that pain was emanating from L5-S1.
Danica Dubaich was 44 years old when Dr. Rudin completed his diagnosis. Given her age and otherwise good health, Dr. Rudin thought Dubaich was a good candidate for a motion preserving implant—either Charité from DePuy or ProDisc-L from…well, DePuy/Synthes.
Of course, Dubaich’s insurer (CIGNA) rejected Dr. Rudin’s request for a pre-authorization of the motion preservation implant as being “not medically necessary.” Such rejections are so common that the appeal letters are now free on Internet gaming sites or the corner of 16th and Broadway from Nigerian street vendors, the monitors that are top rated by GamingBuff have been popular these days as well. (That may be a slight exaggeration.)
CIGNA’s medical coverage policy document says that fusion is the reimbursable course of treatment for patients with Dubaich’s diagnosis.
But Dubaich did not want fusion. Neither did her doctor, Dr. Rudin.
So she fought back.
Here’s how Dubaich and her lawyers beat one of the largest insurance companies in America.
The Road to Justice Act I: DENY the Surgery
CIGNA’s Medical Coverage Policy states “CIGNA covers the surgical implantation of Charité or ProDisc-L…as medically necessary” when the medical criteria are met. In 2011, after exhausting all conservative treatment, Dr. Rudin submitted a pre-authorization for a two level ADR [artificial disc replacement] at L5-L5 and L5-S1.
CIGNA’s pre-authorization nurse denied Dr. Rudin’s request saying “documentation submitted does not confirm that disc degeneration has been confirmed on complex imaging studies such as magnetic resonance imaging or computerized tomography.”
Then CIGNA assigned a urologist to review Dubaich’s file.
Dr. Ted Miclau, Part II
Elizabeth Hofheinz, M.P.H., M.Ed. • Fri, July 8th, 2011
Improbability is often the most powerful impetus to research. In the late 1800s, Dr. Joseph Lister used research to establish the improbable fact that infections are caused by unseen micro organisms. In the 1960s Dr. Marshall Urist demonstrated the improbable fact that a protein was the primary stimulator of bone growth. In the 1990s Dr. Arnold Caplan uncovered the improbable fact that mesenchymal stem cells not only existed but were the immune privileged engine behind nerve, muscle and bone regeneration.
And finally, how improbable is it that a young child, raised in difficult financial circumstances and enduring cultural challenges and familial disruption would graduate with honors from Yale University, study and excel as a resident under Frank Wilson, M.D. at the University of North Carolina at Chapel Hill, author or co-author over 100 peer review articles, and become a tenured professor at the age of 40?
The answer is that it is well nigh impossible except that it is also a fact. When Dr. Ted Miclau assumes the reins of the pre-eminent Orthopaedic Research Society in 2012, he will bring to the position a unique set of passions and perspectives formed over 30 years of challenging stereotypes and achieving the improbable. While it is certainly true that orthopedic research has come a long, long way over the past 40 years, it has not, however, fully penetrated some of the poorer corners of the world. Explains Dr. Miclau, “Many of my colleagues from Latin America tell me, ‘I can’t publish in the Journal of Bone and Joint Surgery.’ Not only are there language issues, but the fact is that at this point, many surgeons don’t have the training to undertake the type of study designs that high quality journals expect."
Working with one of the most accomplished orthopedic clinical researchers in the world, Dr. Mohit Bhandari, I put together courses that teach orthopedists in Latin America how to understand and design different clinical research methodologies and protocols. To date we have held these courses in Cuba and Mexico…I’m thrilled to say that they have been hugely successful.
Spine Fusion Surgery Reimbursement: Science or Politics?
Walter Eisner • Mon, November 7th, 2011
There has been a fourfold rise in spine fusion treatments over the last 20 years. The higher expenditures have spurred an increase in clinical guidelines and payer policies to determine appropriate treatments and payments.
But are the clinical guidelines consistent with each other? Are payer policies developed by consultants like Milliman operating under the same rigorous transparent and consistent research requirements used to develop clinical guidelines? Are biased payer policies superseding physician determination?
A recent study published in Spine (SPINE Volume 36, Number 21S, pp S144–S163) sought to answer these questions.
Comparing Quality of Evidence
Joseph S. Cheng, M.D, MS, and his colleagues (Michael J. Lee, Eric Massicotte, Bryan Ashman, Marcelo Gruenberg, all M.D.s, and Leslie E. Pilcher, MPH, BA, and Andrea C. Skelly, Ph.D., MPH), sought to compare the quality and evidence base of fusion guidelines and select payer policies in a study called: “Clinical Guidelines and Payer Policies on Fusion for the Treatment of Chronic Low Back Pain.”
They began with the premise that the need for surgery based on literature is beginning to supersede physician determination. Since guidelines and policies have impact on the definition of “medical necessity, ” they decided to test the quality of those policies and guidelines.
"Payer policies define medical necessity and should be held to the same standards for transparency and development as guidelines, " wrote the authors.
The study’s authors looked at PubMed, the National Guidelines Clearinghouse and the International Network of Agencies for Health Technology Assessment. They also searched Google for payer policies. They used an Appraisal of Guidelines Research and Evaluation instrument to provide a method for evaluating the quality of development of the evidence base.
The authors found that the general guidelines published through January 2011 were consistent with diagnosis, but inconsistent about treatment recommendations.
“Three systematic reviews of evidence-based guidelines that provide general guidance for the assessment and treatment of chronic low back pain described consistent recommendations and guidance for the evaluation of chronic low back pain but inconsistent recommendations and guidance for treatment.
Ten BEST Orthopedic Clinical Studies of 2011
Robin Young • Tue, November 15th, 2011
Every year approximately 600, 000 peer review articles from 5, 560 journals are published in Medline and are included in index Medicus.
Somewhere in that mountain of paper are gems. So, to help pull a few out for our readers OTW asked JBJS (Journal of Bone and Joint Surgery) editor Vernon Tolo to send along his picks of the 10 best clinical papers of 2011. We also asked AAOS (American Academy of Orthopaedic Surgeons) staff members to poll the editors at several other journals for their picks and then we conducted our own review of the most cited clinical studies published in 2011 using Google Scholar to arrive at a collection of about 50 top ranked clinical studies for 2011.
From that list we selected the Ten Best Orthopedic Clinical Papers for 2011. What did we look for?
The Qualities of a Superior Clinical Paper
Enduring clinical papers start with a hypothesis that tackles practical and difficult clinical problems. From that beginning, successful authors design study frameworks that neatly isolate independent and dependent variables. These kinds of studies articulate each variable clearly and present them so that the reader can follow their progression through the course of the study.
When it works, light bulbs go off in the reader’s mind.
Next comes the peer review process. Journals like JBJS or JAMA (Journal of American Medical Association) or Lancet put manuscripts through a gauntlet of two to four clinicians, basic scientists, methodologists or other experts. Frequently, these peer reviewers are blinded to the authors in order to assure objectivity.
As we learned through our critical review of the June issue of The Spine Journal (TSJ), there is more to peer review than just improving or approving manuscripts. Peer review must examine the quality of the scientific method from which each paper derives its intellectual authority. Scientific method establishes the connection between an idea or hypothesis and practical experience. And great papers use the scientific method to create clarity and unambiguous transparency.
Remember, clarity and transparency invites critical review and, yes, refutation through repeated re-examination by other researchers and, of course, actual clinical practice.