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Letter

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Tyson, Syd L. MD, MPH; Bafna, Shamik MD; Gira, Joseph P. MD; Goldberg, Damien F. MD; Jones, Jason J. MD; Jones, Michael P. MD; Kim, Janet K. MD; Martel, Joseph M. MD; Nordlund, Michael L. MD, PhD; Piovanetti-Perez, Ian K. MD; Singh, Inder Paul MD; Metzinger, Jamie Lynne MS, MPH; Mulani, Deepa MSc; Sane, Swati MS; Talamo, Jonathan H. MD; Goldstein, Michael H. MD, MBA on behalf of the Dextenza Study Group

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Journal of Cataract & Refractive Surgery: April 2019 - Volume 45 - Issue 4 - p 534-535
doi: 10.1016/j.jcrs.2019.02.016
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We are glad that Drs. Grzybowski and Kanclerz recognize that compliance with topical eyedrop therapy is challenging in the real world and that new alternatives, such as intracanalicular inserts that deliver medications, present a potentially interesting option to eyedrops in these patients. After cataract surgery or other ophthalmic surgeries, many patients are physically not able to take topical medications, find eyedrops difficult to use, or fail to remember to take them.1

As the authors note, many different trial designs can be considered when testing a new potential medication. An important choice in any clinical trial design is the selection of the comparator. One option is a placebo-controlled design, such as the comparator placebo intracanalicular insert used in this clinical trial. This type of design is common in ophthalmic studies, including in trials of drugs for ocular allergy, dry eye, glaucoma, and postoperative pain and inflammation, because this type of design is commonly used as part of registration for regulatory approval in the United States. Furthermore, given that it is challenging for a clinical trial to simulate real-world experience by including noncompliant patients, this type of trial design is particularly well suited for indications for which compliance is a significant clinical challenge. As the authors note, an alternative design would be a trial against an active comparator. This design is also commonly used in ophthalmology, in particular in studies in which the disease is vision threatening, such as age-related macular degeneration (AMD). This noninferiority type of trial design typically involves a larger design with more patients exposed to the test article and the comparator. Although we agree that the study design was not dissimilar to that of 2 previous trials, the results are different and rise to the importance of publication in this journal.

We agree that this trial reaffirms the benefit of using the dexamethasone intracanalicular insert for patients having cataract surgery. The trial builds on our previous publication2 and is the largest study to date showing that compared with placebo inserts, the use of the dexamethasone intracanalicular insert leads to a statistically significant difference in the complete absence of ocular pain at 8 days and complete absence of inflammation at 14 days.

Most important, we wish to highlight the importance we place on patient safety in clinical trials. We, as clinicians, value the safety and outcomes of our patients above all. This study adhered to all international laws regarding ethical conduct of clinical trials and was approved by a central (and, if applicable, a local) institutional review board and all patients went through an informed consent process. Patients opting to participate in the study understood the risks; they were extensively educated on the purpose and objective of the trial, the potential risks associated with the use of the trial product and the placebo product, the risks of having cataract surgery, the risks associated with ocular dexamethasone, and unforeseen risks. Furthermore, these patients were arguably followed more closely than patients receiving standard postoperative care because the postoperative visits were more frequent than the standard evaluations, occurring at 1 day, 1 week, and 1 month. Safety assessments were thoroughly performed at each visit, as outlined in our paper. Rescue therapy was allowed at any time throughout the trial based on the patient’s clinical course.

We urge authors Grzybowski and Kanclerz to consider the impact of the conduct of a clinical research study versus real-world clinical outcomes. Our colleagues in retina have shown that their AMD patients improved significantly while receiving antivascular endothelial growth factor medication on a set study protocol; however, after its lapse, patient outcomes declined.3 Researchers acknowledge that trial outcomes are not always exactly predictive of real-world clinical outcomes. Therefore, does the control population in this trial serve as a closer fit to our noncompliant patients? Once a surgery is completed, how can we be certain that prescriptions are filled and that drops are administered correctly and on time as we have prescribed? In short, we cannot. The paradigm shift of Dextenza, a new modality for drug delivery, mitigate this risk for poor patient compliance.

In conclusion, we fully appreciate that several different clinical designs can be used and believe that a superiority study compared with a control intracanalicular insert represents that best path forward in this situation. We look forward to performing additional studies evaluating this dexamethasone intracanalicular insert after cataract surgery, after other ophthalmic surgeries, or in other steroid-responsive ophthalmic conditions.

References

1. An JA, Kasner O, Samek DA, Lévesque V. Evaluation of eyedrop administration by inexperienced patients after cataract surgery. J Cataract Refract Surg. 2014;40:1857-1861.
2. Walters T, Bafna S, Vold S, Wortz G, Harton P, Levenson J, Hovanesia J, Mah F, Gira J, Vroman D, Sampson R, Berdahl J, Elmer T, Noecker RJ. Efficacy and safety of sustained release dexamethasone for the treatment of ocular pain and inflammation after cataract surgery: results from two phase 3 studies. J Clin Exp Ophthalmol. 2016;7:572-582.
3. Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Research Group. Writing committee, Maguire MG, Martin DF, Ying G-s, Jaffe GJ, Ebenezer D, Grunwald JE, Toth CA, Ferris FL III, Fine SL. Five-year outcomes with anti–vascular endothelial growth factor treatment of neovascular age-related macular degeneration; the comparison of age-related macular degeneration treatments trials. Ophthalmology. 2016;123:1751-1761.
© 2019 by Lippincott Williams & Wilkins, Inc.