Considerations for clinical development of intravenous formulations containing the same active ingredient as oral products for patients who are temporarily unable to receive oral administration in epilepsy treatment — PMDA Early Consideration Summary

In Plain Language

The document addresses development of an intravenous medicine for epilepsy patients who temporarily cannot take an oral medicine containing the same active ingredient. It starts from the premise that the oral formulation’s efficacy and safety have already been confirmed in clinical studies in people with epilepsy. Developers should assess whether the oral and intravenous forms have similar pharmacokinetic profiles—that is, how the body absorbs, distributes and handles the medicine—and consider the potentially higher maximum concentration, or C max, after intravenous administration. The document describes ways to evaluate safety and efficacy, including a possible before-and-after assessment when specified conditions are met, rather than assuming a randomized, double-blind comparison is always needed. It also addresses endpoints, the people studied, study duration and development in children, with the aim of making the evaluation relevant to the intended use and avoiding conclusions based on unplanned interpretation.

What This Guidance Covers

The document presents basic considerations for clinical development of intravenous formulations that contain the same active ingredient as oral formulations, for epilepsy treatment when patients are temporarily unable to receive oral administration. It focuses on clinical studies: their general approach, pharmacokinetic analysis, efficacy endpoints, study population and treatment period. A separate section addresses development in pediatric populations.

The considerations apply in the context described by the document: the oral formulation’s efficacy and safety have been confirmed in clinical studies in epilepsy patients, and the intravenous formulation is being developed as an alternative when oral administration is temporarily not possible. The document does not set out a general development approach for intravenous epilepsy medicines with a different active ingredient, nor does it provide a universal study protocol, numerical pharmacokinetic acceptance limits, or a single required treatment duration. It says study details should be considered in light of the product, study objectives and circumstances.

Why It Matters

The introduction explains the clinical concern behind the development question. Epilepsy is described as a chronic disease involving repetitive, sudden-onset brain symptoms, with seizures thought to arise from excessive excitation of nerve cells in the cerebrum. The document notes that abruptly stopping antiepileptic drugs raises concerns about recurrence of seizures and status epilepticus, and that gradual tapering is the principle even when treatment is being discontinued. When oral administration is temporarily difficult, administering the medicine already being used or an alternative intravenously is considered desirable.

That context creates a specific development challenge: how to evaluate an intravenous alternative when there is already clinical evidence for the oral formulation, while taking account of differences between routes of administration. In particular, the document flags that C max is thought to be higher with intravenous than oral administration. It therefore calls for consideration of dose and infusion rate as well as whether safety and efficacy are similar. The document’s approach links the design of the studies to the intended clinical situation instead of treating route conversion as a question of efficacy alone.

Key Recommendations

1. Start from the oral formulation’s clinical evidence. As a prerequisite for developing an intravenous formulation as an alternative when oral administration is temporarily not possible, efficacy and safety should have been confirmed in clinical studies of the oral formulation in epilepsy patients.

2. Evaluate pharmacokinetics and route-related considerations. It is necessary to confirm that the pharmacokinetic profiles of the oral and intravenous formulations are similar. Because C max is thought to be higher with intravenous administration, the appropriateness of the intravenous dose and infusion rate should also be considered, along with similarity in safety and efficacy. The document says both switching from oral to intravenous administration and administering the intravenous formulation before the oral formulation need to be examined.

3. Choose an appropriate clinical evaluation; a randomized double-blind comparison is not always necessarily required. When similar pharmacokinetics have been demonstrated and changes in pharmacokinetics before and after switching are clinically judged to have “no impact,” it is not necessarily required to plan and conduct randomized double-blind comparative studies for development of an intravenous formulation containing the same active ingredient as an approved oral formulation. One option given is to compare seizure frequency before and after switching from oral to intravenous treatment and examine adverse-event occurrence. In switching studies, the switch to the intravenous formulation should occur after the oral formulation has been administered for a certain period.

4. Plan pharmacokinetic analysis to match the study objective. The analysis should be designed according to the objectives of the clinical study. Analytical methods and success criteria should be specified in advance to avoid arbitrary interpretation of results. Use of population pharmacokinetic models may be considered as one possible approach.

5. Select efficacy endpoints and success criteria deliberately. For efficacy evaluation, it is appropriate to use clinical endpoints such as seizure frequency over a certain period. To compare oral and intravenous formulations, it is desirable to use the efficacy endpoints used in confirmatory studies of the oral formulation. Success criteria should be specified in advance. Surrogate markers, such as changes in electroencephalogram (EEG) findings, can be considered as efficacy endpoints, but the document says it is currently difficult to evaluate the efficacy of intravenous formulations based solely on surrogate-marker results.

6. Define the study population in relation to the oral formulation’s indication. The clinical-study population for evaluating efficacy and safety of the intravenous formulation should be within the indication range of the oral formulation. If the oral formulation has multiple indications, such as partial seizures and tonic-clonic seizures, the efficacy and safety of the intravenous formulation should in principle be evaluated in patients with each indicated disease. If conducting studies with the intravenous formulation in patients with particular indications is difficult from a feasibility perspective, it may be acceptable not to conduct those studies when the rationale for expected efficacy is scientifically confirmed. That rationale should be based on pharmacokinetic similarities or differences among patients with indicated diseases and clinical study results of the oral formulation.

7. Set the evaluation period to fit the use and design. The study evaluation period should be established in light of the intravenous administration period and the study design, including the specified endpoints. If efficacy and safety have been confirmed for the oral formulation and pharmacokinetic studies demonstrate similarity between the formulations, short-term evaluation may be acceptable.

8. Consider pediatric development individually. The basic approach for developing the intravenous formulation in pediatric populations is the same as for adults. For pediatric patients with specific indications, the development strategy should consider whether results from other populations, such as adults, can be extrapolated, taking clinical-trial feasibility into account. When extrapolating results, consideration should be given to “Clinical Investigation of Medicinal Products in the Pediatric Population” (ICH E11) and its addendum. The clinical data needed by the time of an approval application should be considered case by case for each product. The document recommends using PMDA’s clinical trial consultations from early in planning studies.

Practical Implications

Interpretation: The development logic described here begins with evidence for the oral product, then asks what needs to be established about the intravenous route and the transition between routes. Teams can use that logic to organize planning: state the study objective, specify the pharmacokinetic analysis and success criteria in advance, and make clear how the selected safety and efficacy assessments address the proposed use. The document does not supply a one-size-fits-all design or define numerical criteria for deciding that pharmacokinetics are similar or that a change has “no impact.”

For statisticians and pharmacokinetic scientists, the stated expectation to prespecify analytical methods and success criteria is a practical protection against interpreting results after seeing them. The possibility of a population pharmacokinetic model is presented as an approach that may be considered, not as the required method. For clinical operations and investigators, the description of switching studies highlights that participants should receive the oral formulation for a certain period before switching, and that the design should reflect the period of intravenous use and chosen endpoints.

For regulatory and clinical teams, the conditions attached to less intensive study approaches matter. The document does not simply say that a randomized double-blind comparative study can be omitted whenever an oral product exists. Its statement is conditional on demonstrated pharmacokinetic similarity and a clinical judgment that pharmacokinetic changes before and after switching have no impact. Likewise, omission of a study in a particular indicated population is described as potentially acceptable only when feasibility is difficult and a scientific rationale for expected efficacy is confirmed using the specified sources of evidence.

For pediatric planning, the document points to case-by-case decisions about data needed by the approval application and recommends consultation with PMDA from early study planning. This makes early discussion relevant when teams are considering extrapolation from adults or other populations, while the document leaves product-specific data needs to be determined individually.

Technical Details

The technical concepts in the document are chiefly about matching evidence and study design to the development question. “Pharmacokinetic profiles” refer to the patterns of drug concentration in the body over time. C max is the maximum concentration; the document specifically notes that it is thought to be higher after intravenous administration than after oral administration. It does not provide a numerical C max threshold or a formula for defining similarity.

The document’s example of a possible efficacy and safety assessment is a comparison of seizure frequency before and after switching from oral to intravenous treatment, together with examination of adverse-event occurrence. This is presented as one option, not a universal design. The text also distinguishes clinical endpoints from surrogate markers: EEG changes may be considered, but surrogate-marker findings alone are currently difficult to use to evaluate intravenous-formulation efficacy.

For a product with more than one indication, the default described is evaluation of the intravenous formulation in patients with each indicated disease. The stated feasibility exception depends on scientific confirmation of expected efficacy, informed by pharmacokinetic similarities or differences among patients with indicated diseases and clinical study results for the oral formulation. These conditions keep a decision not to study a specific group connected to evidence rather than feasibility alone.

For pediatric populations, the document sets out no separate fixed pathway. It says the basic approach is the same as for adults, while the development strategy for specific pediatric indications should consider the possibility of extrapolating results from other populations and the feasibility of clinical trials. The application-stage clinical data are considered product by product.

Who Should Read It

This document is relevant to sponsors and development teams working on an intravenous formulation that contains the same active ingredient as an oral epilepsy product, particularly when the intended role is temporary use because oral administration is not possible. It may also be useful to clinical pharmacologists, pharmacokinetic and biostatistical teams, clinical operations staff, investigators, medical writers and regulatory affairs professionals who plan or interpret the related studies. Pediatric development teams may find the section on extrapolation and early PMDA consultation especially relevant.

Official PMDA Source

• Official title: Considerations for clinical development of intravenous formulations containing the same active ingredient as oral products for patients who are temporarily unable to receive oral administration in epilepsy treatment (Early consideration)
• Issuing body: Pharmaceuticals and Medical Devices Agency, Office of New Drug III
• Date on the cover: March 3, 2026
• PMDA PDF: Official English PDF
• 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 for the complete text; this summary does not replace it. PMDA provides its English version for reference, and if it differs from the Japanese original, the Japanese original prevails. PMDA describes Early Consideration documents as reference information reflecting the Agency’s views at the time of publication, which may change as scientific knowledge develops.

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