Why The FDA Removed The Boxed Warning On Regranex

The Food and Drug Administration (FDA) recently removed the boxed warning (often misquoted as a “black box warning”) from Regranex (Smith & Nephew).¹ The FDA placed the warning on Regranex gel in 2008 after a retrospective post-market study based on claims data warned of an “increased rate of mortality secondary to malignancy.”

Smith & Nephew petitioned the FDA for removal of the warning, citing multiple studies that demonstrated no increase in safety risk from the gel.^2,3 The first study focused on patients without prior cancer in the Veterans Affairs (VA) database, comparing 6,429 patients who used Regranex gel to 6,429 patients who did not use Regranex over 11 years.² This data indicated no increased incidence of cancer or cancer mortality with Regranex gel use.

A second retrospective study used medical claims from the VA health care database of patients with prior cancer.³ The study evaluated 477 patients with recently diagnosed malignancy one, two or three years before Regranex gel use in comparison to 1,756 patients who did not use Regranex gel over an 11-year period. The rate of cancer-related death was similar in both groups and researchers indicated no evidence of an increased risk of cancer death with the use of Regranex gel.

The removal of the boxed warning from the Regranex label is the first time a single company was successfully able to argue for the removal of a boxed FDA warning and the associated warnings within the label based on clinical study findings. This removal did not require an advisory committee meeting.

Having been a great believer in Regranex from its initial launch back in the late 1990s and also a previous member of the Smith & Nephew’s Speaker’s Bureau, I have reviewed this subject in a previous DPM Blog.⁴ I attempted to explain the efficacy of the Regranex gel and the reasoning behind the FDA’s initial decision for the boxed warning. To this day, there is no equivalent product to Regranex when it comes to the evidence and approved indications. Regranex gel is still the only recombinant derived growth factor manufactured for use in treating lower extremity diabetic ulcers. 

I have used Regranex in my treatment protocol for over the past 20 years or so but more so in the past three years with my standardized treatment protocols, using the gel as indicated based on the specific patient findings. I have seen an average healing time of six weeks for those diabetic lower extremity ulcers treated with Regranex, weekly thorough sharp debridements, offloading and moist wound healing dressings. What that has translated to is that my patients are back to their normal lives within one and a half months. Patients can return to work, wearing shoes with orthotics and no longer worrying about getting an infection that could lead to a toe or foot amputation.

For now, I am glad I no longer have to raise the issue of cancer with Regranex, words that can often scare patients and may even have caused concern to practitioners. I can now quote the two recent studies that indicate there is no increased associated risk of developing cancer with the use of Regranex. I will continue to biopsy the wound when indicated and do all of the standard tests and plans I have always employed without that dreaded boxed warning discussion.

I invite all of those who do a fair amount of wound care to revisit this product and the new label wording, and see how this product may help you reduce the time to healing with this challenging etiology more often.

I am no longer on the Smith & Nephew’s Speakers Bureau and thus have nothing to disclose.

Dr. Aung is the Chief of the Podiatry Section at St. Joseph’s Hospital in Tucson, Ariz., and a Panel Physician for the St. Mary’s Hospital Outpatient Wound and Hyperbaric Center in Tucson, Ariz. She is a member of the coding committee and the MACRA/MIPS Task Force for the American Podiatric Medical Association. She is on the exam committee of the American Board of Wound Management. Dr. Aung’s website is www.healthy-feet.com .

References

1. Hussain NZ. U.S. FDA removes safety warning from Smith & Nephew’s diabetic gel. Reuters. Available at https://www.reuters.com/article/us-smith-nephew-fda/u-s-fda-removes-safety-warning-from-smith-nephews-diabetic-gel-idUSKBN1O41V7 . Published Dec. 5, 2018.

2. Ziyadeh N, Fife D, Walker A, et al. A matched cohort study of the risk of cancer in users of becaplermin. Adv Skin Wound Care. 2011;24(1):31-39.

3. Regranex gel Prescribing Information.

4. Aung B. A closer look at the evidence for using Regranex. Podiatry Today DPM Blog. Available at https://www.podiatrytoday.com/blogged/closer-look-evidence-using-regranex . Published Oct. 27, 2016.