What is next with C. R. Bard’s Urethral Bulking agent, Tegress: Is It Too Technique Sensitive and Unpredictable for Continued Effective Use?

Armand Rossetti

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I have been reporting about problems with tension-free vaginal tape, and approval of vaginal mesh products without tracing the history of submissions to ensure that the initial predicate device was not itself dangerous and defective. However while researching about these issues, I found another area of concern; a relatively new urethral bulking agent, C. R. Bard, Inc.’s Tegress Urethral Implant.

An Eerie Feeling About How Tegress Works:

In reading about properties associated with Tegress, the first thing that came to mind that the material acted much like spray foam insulation. While I completely understand that there is no biological comparison between the two materials; that they are not interchangeable in application and not even related chemically, the way that each material works is somewhat similar. I focus on: 1) seamless application; 2) dimensionally stable; 3) Does not shrink or settle; and 4) adds structural strength.

The Use of A Special Penetrating Solution:

Something else caught my attention. The carrier fluid used to make the injection less viscous and to set up the reaction once the Tegress is in place is a chemical named dimethyl sulfoxide (DMSO). Of utmost concern is the fact that DMSO can penetrate tissue because it is a “go-between” solvent, a delivery vehicle that can dissolve and transport chemicals through tissue that otherwise would not be able to pass through. Here is a description:

“This colorless liquid is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water. It has a distinctive property of penetrating the skin very readily, so that one can taste it soon after it comes into contact with the skin. Its taste has been described as oyster- or garlic-like.

Use of DMSO in medicine dates from around 1963, when a University of Oregon Medical School team, headed by Stanley Jacob, discovered it could penetrate the skin and other membranes without damaging them and could carry other compounds into a biological system.

Because DMSO increases the rate of absorption of some compounds through organic tissues including skin, it can be used as a drug delivery system.”

Because DMSO easily penetrates the skin, substances dissolved in DMSO may be quickly absorbed. For instance, a solution of sodium cyanide in DMSO can cause cyanide poisoning through skin contact. DMSO by itself has low toxicity. Dimethyl sulfoxide can produce an explosive reaction when exposed to acid chlorides; at a low temperature, this reaction produces the oxidant for Swern oxidation.”

Manufacturer’s Warning:

Tegress instructions carry a warning that DMSO “might be a contributing factor in the causes of erosion of the implant into the urethra or vagina and necrosis of the urethra, which is minimized by strict adherence to the Tegress implant injection described herein.” The procedure seems very technique sensitive.

The FDA’s Involvement in Developing the Device:

Review of Urology 2005; 7(Suppl 1): S22-S26 contained a paper entitled Tegress™ Urethral Implant Phase III Clinical Experience and Product Uniqueness (Domochowski, MD, FACS). One statement caught my eye:

“Upon injection of and exposure to the solution (blood or extracellular space) at physiologic temperatures, the DMSO diffuses from the hydrophobic copolymer and causes the EVOH to precipitate into a complex cohesive spongiform mass. This phase change requires diligent separation of agent and body temperature fluids prior to implantation. The phase transformation takes place rapidly, with the spongiform mass developing within 60 seconds post injection. Based on these unique findings and the demonstrated biocompatibility of the agent, the applicability of Tegress as a urethral bulking agent was analyzed in a large-scale new-device trial supervised by the US Food and Drug Administration (FDA).”

In this case, the FDA actually supervised the large scale new device trial for Tegress involving 15 sites in the United States and Canada, and compared Tegress with Bovine collagen. While the results of the study seemed to indicate success amidst adjustment for delivery technique and area of placement, modified directions for use highlight the fact that investigators reported hundreds of treatment related events. Of the treatment related adverse events, 39% were classified as mild, 58% were classified as moderate, and 3% were classified as severe. The procedural insert for surgical placement contains the following added language (revisions to the original procedural directions are highlighted in green):

“Potential Adverse Events:

Although not reported in the clinical study, other potential adverse events which may occur include erosion, implant extrusion through urethral tissue during injection, necrosis, erythema, embolic phenomena, and vascular occlusion. Erosion, implant extrusion through urethral tissue during injection and necrosis have been observed during post-approval use of Tegress™ Implant in clinical practice. These adverse events have been noted immediately after injection (implant extrusion) or in the period of days to months after injection. Erosion may be an incidental finding during repeat cystoscopy, or patients may complain of urethral pain, dysuria, hesitancy or frequency, usually of mild to moderate but rarely severe intensity.

Urinary tract infection may or may not be present. Bladder neck obstruction by the extruded or eroded material has been reported. Signs and symptoms of eroded material typically resolve within days to 2 weeks. Resolution of the signs and symptoms is typically accompanied by re-epithelialization of the necrotic or eroded urethral mucosa, after elimination by voiding or cystoscopic removal of the extruded/eroded material. Treatment of pain or infection may be required.”

Upon accessing the FDA's Adverse Event Reports (AERs) on the FDA’s Manufacturer and User Facility Device Experience (MAUDE) and entering “Tegress” in the “Brand Name” window, 207 Adverse Events appear. The date range for the reports is from August 30, 2005 to November 21 2007 (post study).

An Outside Opinion Concerning Tegress' Effectiveness:

Recently, a paper appeared in the International Urogynecology Journal(2007) 18:869-873 (Hurtado, E., et al.) entitled The safety and efficacy of ethylene vinyl alcohol copolymer as an intra-urethral bulking agent in women with intrinsic urethral deficiency. The abstract contained the following statement:

“Intra-urethral bulking for the treatment of SID is meant to be minimally invasive and safe with minimal reports of complications. This series of 19 patients show significant percentage of patients experiencing serious complications with Tegress. Additionally, Tegress may be less efficacious than reported in the FDA trials, especially those with prior injections. A long-term prospective study needs to be performed in women with intrinsic sphincter deficiency (ISD) before treatment can be recommended for general use by all gynecologists and urologists.” [Emphasis added}.

GIGNA's Comment:

The following statement appears in the Cigna HealthCare Coverage Position (revised 12/15/2007):

“Based on findings from this multicenter study, the FDA granted the PMA with the following requirements:

• The manufacturer must create and administer a physician training program on the specific injection technique needed for the use of URYX.

• The manufacturer must perform a five-year post-approval study to assess the long-term safety and effectiveness of URYX (e.g., durability of the treatment effect, the impact of re-treatment); and confirm that the incidence of material exposure has been minimized, with modifications to the instructions for use.

• The manufacturer is to conduct a two-year enhanced surveillance program, in which U.S. physicians using URYX will be contacted on a quarterly basis to actively solicit information on adverse events.

In December 2004, the manufacturer submitted their training and post-approval study plans to the FDA.”

Ten Pages of Patient Precautions:

C.R. Bard has also released a 10-page booklet entitled, Tegress for the Treatment of Stress Urinary Incontinence in Women; Information for Patients. The booklet is replete with warnings and contraindications, including a statement that Tegress Implant should only be used by a doctor properly trained in the use of the product.

Hence, the FDA has granted a qualified PMA approval for Tegress, unlike 510(k) approved devices, PMA approved devices are federally preempted.

Conclusion:

Given all of the variables discussed above that are attached to the placement and use of Tegress, it will be interesting to see what develops in the future, regarding this novel, technique sensitive, and somewhat unpredictable implant.

UPDATE:

I received an email from Mr. John Uro, alerting me that Bard had withdrawn Tegress from the marketplace (effective January 31, 2007). During my research on Tegress, I had consulted the FDA Recall Archives and found no evidence of an FDA recall concerning Tegress. Evidently (because I can yet find no evidence of an FDA recall regarding Tegress), Bard had made a decision, on its own, to pull Tegress from the marketplace in 2007.

However, please note that there are many patients who received Tegress implantation, and the controversy about the accuracy of peer rreviewed studies remains in the mainstream of concern.

My conclusion remains the same:

Given all of the variables discussed above that are attached to the placement and use of Tegress, it will be interesting to see what develops in the future, regarding this novel, technique sensitive, and somewhat unpredictable implant. Those patients who received Tegress treatment will still be affected by the dangers associated with Tegress.