False Accusations and a Web of Deceit – in a DIABETIC FOOT STUDY?

Is it not even possible to have honesty in MEDICAL RESEARCH?

Here is a link to a petition posted by Canadian physician Dr. Kenneth DeDez, about the false data published in Diabetes Care from a study of hyperbaric oxygen therapy (HBOT) in Wagner Grade 2 diabetic foot ulcers (DFUs). His goal is 1000 signatures. It takes only about a minute to sign.

Why should you do it?

The petition requests that the Toronto University Health Network (UHN) withdraw the paper submitted to Diabetes Care because it was conducted in an unethical manner and the results were not reported honestly. The falsified results will likely impact coverage of HBOT in the most populous region of Canada. When the chief investigator reported the ethics violations to the appropriate entities, he was punished for whistle-blowing (lost his academic position).

Why should you care?

Private payers and Medicare have stated that they intend to make coverage decisions on the basis of the “evidence.” However, the “evidence” has often been selectively evaluated (with even some prospective randomized controlled trials excluded from consideration by some payers). It is even more shocking to think that the government might put its finger on the scales to ensure that the outcome of a clinical trial is negative, manipulating the evidence so it does not have to cover a costly treatment option.

I summarized the situation more than a year ago in an editorial in Today’s Wound Clinic.  Recapping the highlights, Diabetes Care published a prospective, double-blind, randomized controlled trial (RCT) conducted in Canada on the use of hyperbaric oxygen therapy (HBOT) for patients living with diabetes and chronic, nonhealing ulcers of the lower limb. The study claims HBOT does not reduce indications for amputation among these patients. No screening was performed with transcutaneous oximetry (TCOM) to determine whether the wounds were hypoxic. The majority were Wagner Grade 2 ulcers for which HBOT is not recommended per the clinical practice guidelines produced by the Undersea and Hyperbaric Medical Society. Additionally, digital photographs were used to determine the primary endpoint of “amputation,” even though photographic assessment has never been validated as a surrogate for actual amputation — particularly after only 12 weeks of care. Traditionally, studies evaluating the efficacy of HBOT have used the number of amputations actually performed as the definition of “amputated.”  Diabetes Care refused to publish any of the many letters to the editor expressing concern over these issues.

At the time it was published, I thought it was odd that the manuscript failed to mention the institution in which the HBOT was provided, and that none of the authors was a hyperbaric physician. I looked up the trial on “Clinical Trials.gov” and found that Ron Linden, MD, a well-known hyperbaric medicine physician with considerable experience in the treatment of diabetic foot ulcers (DFUs), was listed as a principal investigator of the trial, yet, he wasn’t an author on the Diabetes Care paper. I contacted him to ask about this. Dr. Linden told me that the paper had been published without his consent. He alone had provided all the wound care and hyperbaric oxygen treatments to all subjects (hyperbaric and non-hyperbaric groups). The published paper differed in substantial ways from the protocol approved by Toronto University (the academic institution with which the research ethics board is affiliated). Specifically:

  1. The original protocol required enrolled patients to be examined in person by a vascular surgeon to determine the primary outcome measure (amputation versus limb salvage), but that examination reportedly never happened.
  2. Digital photographs were substituted for a vascular surgeon’s examination to determine the primary outcome measure of amputation, even though photographic assessment was never approved by the ethics committee as the endpoint of the trial.
  3. TCOM was required as part of the original protocol, but patients reportedly did not undergo screening with TCOM and this change to the protocol also was not approved by the IRB.

Dr. Linden informed me that, years before the publication of the paper, he had notified the aforementioned research ethics board (and others) of multiple protocol violations, falsified data, sequestering of research data by one of the authors, and refusal of an author to share trial data when confronted with evidence of misconduct. However, after Dr. Linden reported the possible misconduct, he was exposed to a retaliatory complaint against him by one of the paper’s authors and his 26-year teaching position was eliminated.

Why does this matter? In Canada, healthcare decisions are made at the provincial level. This study was conducted in Toronto (Province of Ontario), the most populous province in Canada. Included in the “detailed description” of the study is the following information: “… the results of the study will be used to make policy decisions regarding the funding and further utilization of HBOT therapy for people with diabetes mellitus with ulcers of the lower limb in the province.” It is clear the original purpose of this study was to decide whether HBOT would be funded for patients living with DFUs in the largest province of Canada.

What really happened to the Canadian HBOT patients?

One major question is, “What was the actual outcome of the subjects — was it the same as determined by photographic assessment or something different?” Dr. Linden claims to have irrefutable evidence that many patients in the Canadian study who were allocated to the outcome of “amputated” on the basis of a photograph actually healed. Among HBOT patients, he states 83% of the vascular surgeon’s adjudications were wrong and many wounds healed within weeks of being adjudicated for amputation. The Diabetes Care paper also did not include the one-year outcome that was part of the approved protocol. When Dr. Linden evaluated subjects at one year, as per the protocol, in the HBOT treatment group 78% of patients were healed and 13% had amputations (mostly minor), and 9% still experienced chronic wounds. In the control group, at 12 weeks there were 40 patients remaining unhealed. As part of the approved protocol, unhealed control subjects could cross over to open-label HBOT and 80% (32 patients) did in fact cross over and received HBOT. More than 60% of those were healed at one year.

Linden’s data jives well with the recent report of the multi-year followup from the prospective RCT by Londahl showing that HBOT is associated with an improvement in 6-Year survival in people with Diabetic Foot Ulcers.

Here’s a video clip of a patient who was reported as “amputated” in the Diabetes Care published study.

Impact on U.S. Patients

In the U.S., the current coverage of Wagner Grade III DFUs by the Centers for Medicare & Medicaid Services (CMS) was made largely on the basis of a rather small randomized trial.  Therefore, it is possible CMS could use the negative conclusions in the Canadian study as a reason to withdraw coverage for HBOT of DFUs in the U.S. I was at the meeting with CMS officials in Baltimore when its decision regarding coverage of Wagner Grade III DFUs was made in the spring of 2002. While one additional RCT published since then has demonstrated the efficacy of HBOT in DFUs, a large retrospective study of effectiveness by Thom and Margolis did not.

Although payers insist on high-level data from randomized trials before they agree to cover treatments, they are willing to withdraw coverage on the basis of lower-level data. Despite the apparent payer bias for accepting negative data, if there really is evidence that HBOT does not improve outcomes in advanced DFUs, then, given our dwindling Medicare budget, those Medicare dollars need to be spent somewhere else. However, if the results of the Canadian study were manipulated by anyone (payer or investigator) to ensure a negative result, not only may many thousands of patients suffer as a result, but the entire fabric of our decision-making process will have been betrayed.

Oxygen is not made by a pharmaceutical company, so HBOT has long suffered from a lack of funding for research. Until the publication of the Canadian study, every prospective trial of HBOT in DFUs had shown that HBOT improved outcomes in Wagner Grade III and/or ischemic DFUs. However, all of these trials have been criticized for their small size and short follow-up periods, and for not making a sufficiently compelling case that HBOT is worth the price tag. The recent trial is the first prospective trial of HBOT funded by a national payer specifically for the purpose of making a coverage decision.

As clinicians, we have agreed to use evidence-based medicine as the guiding principle for clinical practice and for payer coverage. If it turns out that a payer can manipulate the results of a trial in order to produce the result they want for (non)payment purposes, and if a respected, peer-reviewed journal like Diabetes Care is unwilling to shine a light on what happened, then we as an industry will have colluded in one of the greatest betrayals of patient trust since the Tuskegee syphilis study.

I don’t know about you, but I am getting tired of the honest guy who tells the truth being the one who gets punished. I also don’t think we can handle any more people or institutions refusing to follow ethics rules and never being held responsible for their actions. I signed the Canadian petition for the university to follow ethics rules- even if it feels like only a gesture.


Additional Reading:

https://carolinefifemd.com/2016/03/03/when-a-picture-is-not-worth-1000-words-and-why-we-need-patient-reported-outcomes-in-wound-care/