I have conducted numerous unblinded clinical trials, mostly evaluating cellular or tissue-based Products (CTPs). These trials do not easily lend themselves to blinding. However, when I slated this topic with the title “Unblinding the Blind" for my Association for the Advancement of Wound Care lecture track at next year’s spring Symposium on Advanced Wound Care, the organizers removed it and cited the lecture’s controversial nature. I thought that scientific research was the last frontier of free-wheeling discourse in the private sector, but here lurks the most challenging aspect of contemporary research in wound care: we woundologists do not demand increasing rigor in our trials. Outside of hyperbaric oxygen (HBOT) studies, we have not critically evaluated trial results.

I contested the organizers’ response, but to preserve peace among the members of the planning committee and the North American Center for Continuing Medical Education, the continuing education provider, I conceded, although removing the lecture seemed short-sighted to me. The time has come for the wound healing community to critically examine the evidence supporting the use of a growing array of products. There is no downside in this inspection or introspection.

Using GRADE to Evaluate Wound Research Studies

Recently, several negative studies on HBOT for diabetic foot ulcers (DFU) appeared in the literature. Interestingly, they were all published in the same journal, Diabetes Care. In response, the Undersea and Hyperbaric Medicine Society (UHMS) decided to examine the evidence for HBOT in DFUs by using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. This validated system, used throughout medicine, scores the evidence for an intervention in a specific disease. The results published last year supported the use of HBOT in Wagner III DFUs. The poorly designed studies with negative results did “not make the grade”: their low GRADE scores had little if any impact on the final conclusions and recommendations. I applaud the UHMS for their effort separating the wheat from the chaff.

Buoyed by the success of the UHMS, I proposed in my intended presentation submission that the wound care community apply the GRADE criteria to all of its interventions starting with CTPs. First of all, I find choosing among a wide array of CTPs challenging. Typically, I start with only those products with randomized controlled trials (RCTs). This limits the field, but it hardly makes the choice simple. All the CTP trials have a common bias: they are unblinded. The investigators and patients know who receives the active treatment or standard of care alone. This leads to an unconscious prejudice in favor of the CTP. This inherent bias lowers the GRADE score significantly for CTP studies. In addition, industries standing to benefit commercially from the research conducted many of their own RCTs, thus potentially introducing further bias.

Extensive experience and numerous clinical trials have taught me that CTPs promote healing. However, I believe we should apply the GRADE criteria to this research. In addition, I remember the days when numerous growth factors failed to demonstrate efficacy in double-blind investigations. Is it time to ask for blinded studies for advanced therapies such as CTPs? I believe we will find the holy grail of wound treatment research in “bias-busting” blinding. Who will have the courage to conduct the first? Who will heal the unblinded?

About The Author
Dr. Thomas E. Serena is the Founder and Medical Director of The SerenaGroup®, a family of wound, hyperbaric and research companies. Dr. Serena has been the lead or Principal investigator in over 100 clinical trials, including gene therapy, antimicrobial dressings, growth factors, topical and parenteral antibiotics and CTP therapy. He has more than 200 published papers and has authored several medical textbooks and numerous book chapters. He has given over 1000 invited lectures throughout the world. He has been a member of the Board of Directors of the Wound Healing Society and served two terms on the board of the Association for the Advancement of Wound Care (AAWC) and is now the President.