An explosion of recent studies from multiple university medical centers recently exposed that the use of the prescription drug Elmiron® can result in patients’ vision failure, up to and including legal blindness. Elmiron® is the brand name for pentosane polysulfate sodium (“PPS”), a drug manufactured and distributed by Janssen Pharmaceuticals. It has been marketed for nearly twenty-five years and resulted in billions of dollars of sales for Janssen. The earliest clinical trials for Elmiron® from the 1990s revealed not only dubious efficacy, but also a host of adverse events including ophthalmologic problems. Now, more than two decades later, multiple studies have revealed a new eye disease, “retinal maculopathy”, in numerous of their patients taking Elmiron®. The research concerning this disease reveals that the disease is not only irreversible, but also progressive and can lead to central vision failure and even blindness.
With anticoagulant properties similar to heparin, Baker Norton Pharmaceuticals originally researched the drug as an anticoagulant but ultimately developed the drug and filed the application for approval with a different indication. The chief indication for the drug is the treatment of a rare condition known as interstitial cystitis (“IC”), also known as bladder pain syndrome. IC is a very poorly understood condition, the symptoms of which include chronic bladder pain, urinary frequency, urinary urgency, and painful sexual intercourse. The United States Food & Drug Administration (“FDA”) approved Elmiron® for the IC indication in September 1996.
Baker Norton ultimately was bought by Teva Pharmaceuticals which licensed Elmiron® to what is now Janssen Pharmaceuticals. The global sales for Elmiron® are, by comparison to other major drugs, relatively modest: approximately $300 million a year in sales. While the use patent for Elmiron® has been expired for nearly a decade, Janssen is the only company which markets PPS and there are no generics available in the United States.
From its inception, Elmiron® has been plagued with problems relating to the efficacy of the drug for its sole indication (IC). On January 27, 1993, the FDA issued its first non-approval letter for Elmiron® citing problems not only with the clinical trial results for Elmiron, but also certain of the clinical trial investigators who conducted the trials. In the November 8, 1991, Statistical Review and Evaluation relating to the clinical trials for Elmiron®, the FDA Reviewer put it quite bluntly: “The evidence of efficacy of Elmiron for the treatment of interstitial cystitis is very weak.” Because of the paucity of efficacy evidence, the FDA requested Baker Norton to conduct an additional clinical trial without those certain investigators who had conducted the previous clinical trials. Baker Norton declined to conduct the additional clinical trial and, instead, re-analyzed the data from the two pivotal clinical trials. After reviewing that re-analysis, the FDA issued a second non-approval letter for Elmiron®, as the information was “inadequate and the application is not approvable” and again requested the sponsor to conduct another clinical trial. Baker Norton again declined to conduct the additional clinical trial. After a meeting with the FDA, the sponsor agreed to conduct a review of the uncontrolled compassionate use database (i.e., not a clinical trial) in its attempt to corroborate its claims of the drug’s efficacy.
This data review was completely unblinded and uncontrolled; as a result, the FDA Reviewer in the third go-round of statistical reviews observed: “Consequently, there are no statistical procedures which can be used to unequivocally assess whether the outcomes seen in this data are a result of the placebo effect or of the use of Elmiron.” The Reviewer determined that it could not be said that the evidence was sufficient to establish that the drug should be approved: “The regulatory decision for this product is not clear cut. After considering the statistical and scientific facts, this NDA is not approvable.” Nonetheless, because there was some evidence of efficacy for a small subset of the studied patients, the Reviewer issued a tepid recommendation for approval in February 1996. The FDA issued its NDA approval for Elmiron® on September 26, 1996.
Once the drug was on the market, its use expanded to a much broader population than studied in the two pivotal clinical trials and the compassionate use database review. As the clinical population grew, it became apparent that Elmiron® in clinical use had questionable efficacy for the treatment of IC. In 2003, a clinical trial comparing Elmiron® to a drug in development determined that neither drug provided any benefit for the majority of patients with IC. More than a decade later, a much larger, multi-center clinical trial also found no statistically significant difference between placebo and Elmiron® with regard to reduction of IC symptoms: “Results in this study in a broad population of patients with symptoms consistent with interstitial cystitis revealed no treatment effect vs. placebo for pentosane polysulfate sodium.”
From 2016 to 2018, ophthalmologists at the Emory University Eye Center observed what they described as a new eye disease, “retinal maculopathy”, in numerous of their patients. There was one overriding commonality among the affected patients: the use of Elmiron®. The Emory Study looked at 6 patients with extensive exposure to Elmiron®. The doctors reviewed advanced retinal imaging of each of the 6 patients, and observed in each patient a form of pattern dystrophy that was not consistent with previously identified forms of maculopathy. They described the observed pattern as having a highly delineated abnormal area in the central region of the macula, characterized by the buildup of lesions. The primary complaints by individuals in the study were a loss of low light vision, generalized dimming of vision, difficulty reading, and general near-vision difficulty. As the Emory researchers dug through the old FDA files relating to the Elmiron® approval process in the 1990s, they discovered that there were numerous adverse event reports from the compassionate use database review in which significant problems with the eyes were reported including optic neuritis, amblyopia, and retinal hemorrhage.
After the Emory Study, numerous other researchers began reviewing the records for their patients and came to similar conclusions including on study which found that nearly 25% of patients with long-term Elmiron® use had evidence of retinal damage. A prevalence study conducted out of the University of California, Los Angeles (UCLA) found a remarkable prevalence of the maculopathy in the studied Elmiron® patients: “A prevalence of 20% in this study cohort suggests a significant risk of macular toxicity for PPS-treated patients.” In another study, the researchers identified 10 patients with Elmiron® exposure who had similar vision problems but also noted that none of the 156 individuals they observed with IC but no Elmiron® exposure developed any vision issues. One publication also described that the retinal maculopathy, once set in course, continued to get worse, even after discontinuation of the Elmiron®.
Researchers from the Cleveland Clinic discussed the biomechanism by which the drug may cause pigmentary maculopathy. The current understanding of how Elmiron treats IC is that it reduces inflammation in the epithelium of the bladder, which can reduce the pressure that causes pain and urinary frequency and urgency. This happens through the effect the drug has on fibroblast growth factors (FGF), which are also involved in the signaling in retinal tissues, especially how the retina repairs itself. Since the primary changes in the eye occur in the retinal epithelium that makes up the macula, it is probable that the drug is either causing direct cellular damage due to its effect on the FGF pathway, or alternatively that it inhibits the mechanism by which the retina naturally repairs itself.
Retinal maculopathy is a very serious, progressive disease which can impair the ability of the patient to focus and result in dark or very blurry areas in the center of vision (“central vision loss”). According to the lead Emory researcher, Dr. Nieraj Jain: “[P]atients tend to suffer from significant subjective visual problems, such as trouble reading or adjusting to dim lighting, glare, and blind spots. In advance stages, the condition can lead to profound disability, with some patients meeting the criteria for legal blindness.” The reason for the visual loss is that the condition causes “severe loss of the retinal epithelium with photoreceptor loss” and can extend beyond the macula to the far periphery of the retina. The condition can continue to progress as the drug may get sequestered in the retinal epithelium or irreversible cellular damage may have begun while the patient was on the drug and the clinical effects of the damage may continue to materialize over time.
The average age of the onset of IC is 51, and it primarily (but not exclusively) occurs in women. “Unfortunately, the vision-threatening pigmentary maculopathy identified in this [Emory] study is irreversible and vision loss of this nature is not recoverable.” Janssen knew or should have known from the very inception of Elmiron® that PPS is “optically active”. Despite knowing of reports of retinal hemorrhage and other very serious ophthalmic adverse events from the mid-1990s, Janssen had no warning in the Elmiron® label until it finally amended the label to include a “Retinal Pigmentary Changes” warning in June 2020.
In a 2018 interview given at the annual conference of the American Academy of Ophthalmology, Dr. Jain gave the following recommendations for physicians treating Elmiron® patients with symptoms of the drug-induced maculopathy:
My recommendation is to be aware of the drug. If you see a patient on it, do the multi-modal imaging; send it to your local retina specialist if you need. And, if they’re on the drug and they have the findings, we’re currently recommending that our patients stop taking the drug.
There is no known treatment to treat the drug-induced maculopathy, according to Dr. Jain.
It is a fundamental principle of ethical drug treatment that physicians be able to weigh the risks versus the benefits of the drug. In the case of Elmiron®, as the FDA observed, the drug had no clinical trials in the FDA-approval process which showed a statistically significant benefit to the arm of patients receiving Elmiron® rather than placebo. Numerous post-marketing studies confirmed what the FDA suspected early on but allowed Elmiron® to be marketed based upon the slivers of efficacy derived from the compassionate use database review. That same database, however, revealed adverse event reports related to the eye and neither Baker Norton nor Janssen ever warned of any problem with the eyes until two years after the publication of the Emory Study. Given the population of patients on the drug, and the prevalence rates seen, the number of Elmiron® patients with this retinal maculopathy is likely to number in the thousands.
Litigation currently is in the very early stages, with a handful of cases having been filed in several different venues across the country. There is not, as of yet, a Multi-District Litigation proceeding for the Elmiron® litigation and it is too early to predict when or if an MDL will be formed. Because mass tort litigation has not been consolidated, it is important for the attorney with a potential Elmiron® client to make sure and order the right records, confirm the correct diagnosis and product use and, if needed, associate co-counsel developing the liability and general causation aspects of the Elmiron® case through robust discovery.
From its very inception, Elmiron® has been a drug with specious efficacy. Numerous researchers from several different academic centers now have uncovered and confirmed very serious risks from the drug which can include significant vision loss and even blindness for those patients who took the drug hoping that it would help with their chronic bladder pain. While Janssen Pharmaceuticals received billions of dollars in revenues from this drug, hundreds of thousands of patients who hoped it would help were exposed to the undisclosed risk of damage to their eyes. Those patients’ loss of vision is the result of the Elmiron® drug sponsors’ failure of vision.
* Author: Timothy M. O’Brien is a senior shareholder at Levin, Papantonio, Thomas, Mitchell, Rafferty & Proctor, P.A. Board-certified in Civil Trial, Mr. O’Brien focuses on complex products liability and environmental litigation and is the Levin Papantonio attorney leading the Elmiron® project.
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