Redefining Durability in nAMD: How nAMD Clinical Trials are Evaluating Durability in New Ways

Over the past two decades, anti-VEGF (vascular endothelial growth factor) therapy has transformed treatment and improved outcomes for patients with neovascular age-related macular degeneration (nAMD).¹ Early detection and prompt treatment of nAMD with intravitreal anti-VEGF agents has been shown to improve visual outcomes.^2,3 Results from pivotal clinical trials in nAMD have demonstrated that treatment with intravitreal anti-VEGF agents has been shown to improve visual outcomes.^4,5

While acknowledging this progress, work remains to improve the current treatment of a disease that affects 1.8 million Americans.⁶ 90% of patients require injections every 1-3 months, impacting and disrupting their lives, and leading to decreased adherence.^7,8 Further, frequent injections may result in retinal fluid fluctuations, which over time lead to fibrosis and atrophy, and ultimately could result in permanent vision loss.⁹ These and other aspects of treatment burden help explain why long-term disease control with treatment burden reduction has become a major focus of current nAMD development.

Treatment interval remains one of the most visible outcomes reported in nAMD studies.^10,11 It is easy to communicate and often serves as a headline result when durability data are presented. Yet interval duration alone does not necessarily describe what occurred during that interval.¹² A patient may go for several months without treatment while still experiencing recurrent disease activity, anatomical fluctuations, or progressive changes that become apparent only when imaging or visual outcomes are evaluated more closely.¹³

At the same time, two therapies might achieve similar treatment intervals while producing very different patterns of disease control.¹² This distinction has implications for clinical practice as retina specialists consider the quality of visual and anatomical disease control alongside the ability to extend treatment intervals.¹⁴ When evaluating durability, many clinicians are interested not only in how long patients go between treatments, but also what happens between visits.¹⁴

As a result, additional questions are needed in assessing durability: Was disease activity truly controlled? Was retinal fluid consistently suppressed? Was inter-visit fluid fluctuation controlled? Were visual gains maintained? Were supplemental treatments required?

When assessing durability, several measures may provide context when evaluating claims of sustained disease control, including fluid fluctuations, supplemental treatment requirements, visual acuity maintenance, and anatomical stability over time.^9,12,15 Together, these data points may offer a more complete view of whether disease remained controlled throughout the treatment cycle.

In the measurement of retinal fluid fluctuation, for example, several studies have generated evidence where greater anatomical fluctuation is associated with poorer visual outcomes, increased fibrosis, persistent disease activity, and a greater likelihood of macular atrophy development over time.^9,16,17

Several post hoc analyses have contributed to growing discussion within the retina community regarding anatomical stability and long-term disease control.^16,17 Notably, these analyses have demonstrated associations between greater retinal thickness fluctuation, poorer visual outcomes, and increased fibrosis, and have explored relationships between anatomical variability, persistent disease activity, and long-term outcomes.^9,16,17

These findings have drawn attention to anatomical stability as a potentially meaningful way of assessing disease control during extended treatment intervals. Rather than focusing solely on OCT findings at scheduled visits, investigators have examined the degree of fluctuation that occurs and whether disease remains consistently controlled between treatments.¹⁶

These findings raise the question: if two therapies achieve similar treatment intervals, but one produces more stable retinal anatomy and fewer fluctuations in disease activity, should those therapies be viewed as equally durable?

Trial design can also influence how durability is measured, reported, and ultimately interpreted. These include treatment intervals, patient-selection criteria, endpoint definitions, supplemental-treatment criteria, and statistical analysis plans.^18,19

Not all durability studies are designed to answer the same question. Superiority studies evaluate whether a therapy performs better than the comparator on a predefined endpoint, while noninferiority studies evaluate whether efficacy can be maintained within an accepted margin while potentially offering other patient benefits, such as reduced treatment burden or increased durability, although reduced treatment frequency alone is not sufficient to demonstrate efficacy to FDA.^18,20 A study reporting superior durability and a study demonstrating noninferior efficacy may arrive at very different clinical conclusions, even when evaluating similar treatment approaches.

The FDA's 2023 draft guidance highlights several considerations relevant to nAMD clinical studies, including comparator selection, masking strategies, efficacy endpoints, and study design.¹⁸ Durability outcomes can also be influenced by how disease activity is defined, what supplemental treatment criteria are used, how treatment intervals are structured, and which endpoints are selected for analysis. As a result, durability outcomes reported across trials are not always directly comparable. While reduction in treatment frequency is an important assessment, the guidance also outlines that reduced treatment frequency alone is not sufficient to establish efficacy, reinforcing a broader assessment of treatment frequency with visual and anatomic based data points.¹⁸

A practical question clinicians ask when reviewing durability data is whether additional intervention was needed to maintain disease control.¹⁰ The therapy may achieve an extended treatment interval while still requiring supplemental injections in a meaningful percentage of patients.^10,21 For that reason, supplemental-treatment outcomes are an important measure in assessing durability claims.

The discussion of supplemental treatment is particularly relevant in the new paradigm of sustained disease control. Unlike today’s treatment approaches, where durability is viewed mainly as the length of time between scheduled treatments, emerging durable therapies have introduced a different way of thinking about long-term disease management.^10,11 Rather than viewing durability solely through the lens of extending treatment intervals, some late-stage development programs are evaluating whether a foundational treatment can provide sustained disease control while requiring only occasional supplemental intervention when disease activity recurs.²² In this setting, supplemental treatment becomes part of the durability story.

The timing of supplemental treatment is also particularly informative. A supplemental injection required within the first several weeks or months of treatment suggests that disease control was not fully maintained in a particular patient. In contrast, supplemental injections occurring later, such as beyond six months after therapy initiation, reflect a different clinical scenario, such as gradual loss of treatment effect, need for redosing, or use of supplemental therapy to maintain disease control. For that reason, timing of supplemental injections provides important context that interval length alone cannot capture.^19,22

The FDA's 2023 draft guidance recommends that comparative treatment arms be designed so that dosing schedules, intervention criteria, and dosing adjustment criteria are similar across groups so that they can be evaluated appropriately.¹⁸ The role of sham procedures has therefore become a recurring consideration in durability-focused trial design.

Historically, sham procedures have often been used in retinal clinical trials to maintain masking when investigational therapies and comparator treatments are administered on different schedules.^11,23 FDA reviewers have noted situations in which sham procedures may not provide optimal masking, particularly when patients and investigators can distinguish between treatment experiences over time.^24,25,26

In some circumstances, direct durability comparisons may require dosing schedules that differ from currently labeled treatment regimens to ensure that treatment intervals and durability data points are evaluated consistently across study arms.²² Study design choices, including the use of sham controls, can also affect the interpretation of efficacy and durability outcomes by the Agency.^25,27,28

Much of the current durability discussion centers on a practical question: what happens between treatments? Treatment interval remains an important measure, but recent analyses suggest that retinal fluid fluctuations, anatomical stability, and the timing of supplemental treatment provide insight into long-term disease control.^9,21 The growing use of these measures reflects the increasing emphasis on understanding disease control throughout the treatment cycle.