Principles on Development of Combination Ophthalmic Solutions for Glaucoma — PMDA Early Consideration Summary

In Plain Language

The document addresses how to plan confirmatory studies of combination eye drops for glaucoma when the products contain active ingredients already approved in Japan for glaucoma or ocular hypertension. It describes a randomized, parallel-group study with a suitable comparator to test whether the combination is more effective than that comparator. It sets out how the comparator and the study population depend on whether the combination brings together first-line drugs, second-line drugs, or one of each. The main efficacy measure should be change in intraocular pressure, with measurement times chosen to reflect how the ingredients work and, where appropriate, variation in pressure over the day. The document also discusses masking, the timing of the primary assessment and circumstances in which sponsors should consider longer-term safety information or consult PMDA.

What This Guidance Covers

The document presents considerations for planning confirmatory studies during development of combination ophthalmic solutions for glaucoma. Its stated scope is combinations containing only active ingredients that are approved in Japan for treatment of glaucoma and ocular hypertension. The discussion mainly concerns combinations of two active ingredients.

The document identifies combinations of first-line drugs, combinations of second-line drugs, and combinations containing one first-line and one second-line drug. The choice of comparator and the patients included in the study are addressed in relation to these categories. It does not provide the same detailed study-design discussion for combinations of three or more active ingredients; sponsors developing those products should consult PMDA.

The document focuses on confirmatory efficacy-study design and related considerations, including comparator selection, target patients, the primary endpoint, evaluation timing and masking. It also discusses possible long-term studies where post-marketing surveillance results for the individual active ingredients do not make it possible to evaluate the efficacy and safety of long-term concomitant administration adequately.

Why It Matters

Glaucoma is described as a progressive optic neuropathy, meaning damage to the optic nerve that can progress over time. The document states that intraocular pressure-lowering therapy is considered the only evidence-based, reliable treatment, and that eye drops are mainly used for this purpose. It also notes that multiple ophthalmic solutions with different mechanisms of action have been approved for glaucoma.

When a single-active-ingredient drug does not achieve the target pressure reduction or adequately control progression of visual field disorder, treatment with multiple drugs may be selected. However, using more eye drops and instilling them more frequently can reduce medication adherence. The document gives this as a reason to consider combination solutions when multiple drugs are used together: combining active ingredients in one solution may help address the adherence issue. Against this background, the document sets out points for evaluating the efficacy of these combinations and for considering safety information when they are used over the long term.

Key Recommendations

1. Use a randomized, parallel-group confirmatory study. Efficacy should be evaluated in a randomized, parallel-group study with an appropriate comparator group, designed to confirm superiority over the comparator. In a parallel-group study, participants are assigned to different treatment groups and assessed according to the group to which they are assigned.

2. Select the comparator according to the ingredient combination. For a combination containing two first-line active ingredients, or two second-line active ingredients, the sponsor should use each single-active-ingredient drug containing one of the combination’s active ingredients as a comparator. For a combination of a first-line and a second-line active ingredient, the sponsor should use only the first-line drug as the comparator. The document explains this choice by noting that it is unlikely that a patient who has not responded sufficiently to a second-line drug would switch to the combination in order to add the first-line drug.

3. Enrol patients with an inadequate response to the relevant comparator. The target patients are people with glaucoma or ocular hypertension who have not responded sufficiently to the comparator single-active-ingredient drug. For a combination of a first-line and a second-line active ingredient, the study population should be limited to patients with an insufficient response to the first-line drug. The document gives the same rationale about the unlikely switch from a second-line drug to a combination that adds a first-line drug. If the study includes patients who have not responded sufficiently to a different active ingredient with a mechanism of action generally similar to that of either ingredient in the combination, sponsors should consult PMDA.

4. Use intraocular pressure change as the primary endpoint. The primary endpoint should be change in intraocular pressure from baseline. The document connects this choice to its view that intraocular pressure-lowering therapy is the only evidence-based, reliable treatment for glaucoma.

5. Choose measurement times with the ingredients’ effects in mind. Appropriate measurement times should be determined from the intraocular pressure-lowering profile of each active ingredient, including the time when its pressure-lowering effect reaches its peak. If the ingredients have different profiles, the primary endpoint should be the mean change in intraocular pressure measurements at multiple time points considered appropriate in light of those profiles. If a single measurement time is used as the primary endpoint, the document says that pressure at multiple times throughout the day, including immediately before instillation, should be investigated as a secondary or exploratory endpoint to assess persistence of the effect throughout the day.

6. Set the primary evaluation time when the effect can be shown to have reached a plateau. The primary evaluation time point should be chosen based on clinical-study results for the single-active-ingredient drugs, at a time when it is at least possible to confirm that the intraocular pressure-lowering effect has reached its plateau.

7. Mask treatment assignments to reduce bias. Confirmatory studies should, in principle, be conducted with double-masking to minimize bias by participants, investigators and others. If double-masking is not feasible, single-masking in which the assessor is masked is acceptable. In that case, appropriate measures should be taken to preserve masking as far as possible. The document gives examples: when the test drug and comparator differ in appearance, use identical, indistinguishable containers or boxes; and ensure the investigator involved in evaluation does not confirm the investigational product’s identity from participants or take part in its supply and collection operations.

8. Consider long-term studies when existing information is not enough. If post-marketing surveillance results for the single-active-ingredient drugs do not make it possible to evaluate the efficacy and safety of long-term concomitant administration adequately, a long-term study of the ophthalmic solutions may be necessary. Sponsors should consult PMDA in such cases. If conducting a long-term administration study of the combination, ophthalmic solutions expected to be used with it in clinical practice should be allowed, and collecting long-term safety information when those concomitant solutions are used with the combination is desirable.

Practical Implications

Interpretation: The design decisions in this document are linked to the product’s ingredients and the treatment setting, rather than being presented as one comparator strategy for every combination. A sponsor planning a two-ingredient combination would first classify its ingredients as first-line or second-line under the approach described in the document, then identify the relevant comparator drug or drugs and the patient group for which the study is intended.

For study planning, the stated inadequate-response definition gives a practical reference point: the comparator is instilled for a certain period, at least 4 weeks, and inadequate response is roughly defined as intraocular pressure of 18 mmHg or higher. The document calls this a rough definition, so it should not be represented as an exact threshold detached from its stated context. The population and comparator remain connected: the first-line/second-line combination is studied in patients with an insufficient response to the first-line drug.

The endpoint provisions also have operational consequences. Study teams need to plan when pressure will be measured, taking account of the active ingredients’ pressure-lowering profiles. Where profiles differ, the primary outcome uses measurements at multiple appropriate times; where the primary endpoint uses one time, the document points to additional measurements across the day, including immediately before instillation, as secondary or exploratory outcomes. The timing of the primary evaluation should be supported by clinical-study results for the single-active-ingredient drugs.

Masking considerations may affect how investigational products are packaged and how study responsibilities are assigned. If the appearance of the test drug and comparator differs, the document’s example is to place them in indistinguishable containers or boxes. For assessor-masked studies, it also describes separating the evaluating investigator from product-identification information and from product supply and collection operations. These are examples of measures to preserve masking as far as possible when double-masking cannot be done.

Finally, sponsors may need to consider whether available post-marketing surveillance information for each ingredient can support evaluation of long-term concomitant use. If it cannot, the document says a long-term study may be necessary and advises consultation with PMDA. When such a study is conducted, allowing other eye drops expected in clinical practice and collecting safety information during their long-term use with the combination are described as desirable.

Technical Details

Several technical points help connect the study design to the intended treatment and the way intraocular pressure changes:

• Baseline change: The primary endpoint is the change in intraocular pressure from baseline. The document does not specify a calculation formula, so this summary does not add one.
• Time of measurement: Each active ingredient has an intraocular pressure-lowering profile, including when its effect reaches its peak. The measurement schedule should be selected in light of those profiles.
• Different profiles: If the ingredients’ profiles differ, the primary endpoint should be the mean change in measurements at multiple time points considered appropriate based on the profiles.
• Diurnal variation: Intraocular pressure varies during the day. If the primary endpoint is a change at one measurement time, multiple daily measurements—including one immediately before instillation—should be examined as secondary or exploratory endpoints to investigate whether the pressure-lowering effect persists throughout the day.
• Evaluation period: The primary evaluation time point should be based on clinical-study results for the single-active-ingredient drugs and occur when it is at least possible to confirm that the pressure-lowering effect has reached a plateau.
• Masking: Double-masking is the principle described for confirmatory studies. Assessor-masked single-masking is acceptable if double-masking is not feasible, alongside appropriate steps to warrant masking as far as possible.

These considerations are interdependent. For example, the endpoint’s measurement schedule is informed by the ingredients’ effects over time, while the evaluation time is informed by evidence from studies of the single-active-ingredient drugs. The document does not specify a sample-size method, numerical superiority margin, or detailed statistical analysis procedure.

Who Should Read It

This document is relevant to sponsors and development teams planning confirmatory studies of glaucoma combination eye drops containing active ingredients already approved in Japan for glaucoma or ocular hypertension. It will also be useful to clinical and statistical teams selecting comparators, defining the target population, setting intraocular pressure assessment schedules, and planning masking procedures.

Regulatory affairs professionals may find the consultation points relevant when a proposed study includes patients who did not respond to a similar-mechanism active ingredient, when developing combinations of three or more ingredients, or when considering a long-term study because existing surveillance information is insufficient. Investigators and clinical operations teams can use the document to understand the rationale for patient selection, measurement timing and masking arrangements.

Official PMDA Source

• Official title: Principles on Development of Combination Ophthalmic Solutions for Glaucoma (Early Consideration)
• Issuing body and office: Pharmaceuticals and Medical Devices Agency, Office of New Drug III
• Date printed on the cover: January 15, 2026
• PMDA PDF: Official PMDA document
• PMDA list page: PMDA Early Consideration documents

Source: Pharmaceuticals and Medical Devices Agency (PMDA) website, PMDA Early Consideration documents. This page was created by editing and summarising the PMDA document.

Consult the official document; this summary does not replace it. PMDA provides the English text for reference purposes; if it differs from the Japanese original, the Japanese original prevails.

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