Points to consider in the clinical development of drugs for transthyretin amyloid cardiomyopathy — PMDA Early Consideration Summary

In Plain Language

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a heart disease in which amyloid derived from transthyretin (TTR) collects in the heart and impairs its function. The document sets out considerations for developing medicines for this condition, especially how to design confirmatory trials that can show whether treatment improves outcomes that matter to patients. It encourages early participation by Japan in multiregional clinical trials (MRCTs), because it may be challenging to study enough mortality or morbidity events in Japan alone. For a confirmatory trial, PMDA recommends a randomized, double-blind controlled design and recommends that the primary endpoint focus on death or a composite of death and other events related to survival outcomes. The document also explains how to define and assess those events, consider the Japanese population within an MRCT, and choose trial duration and analyses in light of current clinical practice.

What This Guidance Covers

The document outlines current considerations for the clinical development of drugs for ATTR-CM. Its central focus is confirmatory trials: overall development strategy, trial populations, comparators, primary and other efficacy endpoints, evaluation period, and statistical analysis. It does not set out a complete development programme or provide a fixed trial design, sample size, or universal evaluation period; instead, it identifies issues to consider in planning studies for this disease.

The document describes ATTR-CM as a form of systemic amyloidosis characterized by TTR-derived amyloid deposition in the myocardium, leading to functional impairment. TTR occurs as a wild-type form with a normal amino acid sequence and a variant (mutant) form with enhanced fibril formation. The recommendations apply to development of therapeutic drugs for ATTR-CM, including situations in which the intended population includes wild-type and variant TTR patients.

The document notes that diagnostic methods and patient screening have changed, and that diagnosed cases of wild-type ATTR-CM have increased. Accordingly, its considerations about patient eligibility and recruitment are explicitly linked to contemporary clinical practice and epidemiological information. In Japan, the document reports that approved treatments at the time were the TTR tetramer-stabilizers tafamidis and tafamidis meglumine, while other agents were in development. This context is reported as part of the document’s background, rather than as a broader review of available treatments.

Why It Matters

The document describes a condition with a generally poor prognosis, regardless of whether a patient has a TTR gene mutation. It identifies death from sudden cardiac death, heart failure and myocardial infarction among the outcomes of concern. Although ATTR-CM was traditionally considered rare, changing diagnostic techniques and criteria have led to more wild-type cases being identified, suggesting that some cases may previously have gone undiagnosed.

For clinical development, this creates a planning challenge. The goal of treatment is to improve prognosis, but it may be difficult to conduct a confirmatory trial using mortality or morbidity events as the primary endpoint only in Japan. At the same time, changes in diagnosis and screening can affect who is identified as eligible and how many patients can realistically be recruited. The document therefore emphasizes early Japanese participation in MRCTs and planning based on current practice and epidemiological data.

Endpoint selection is another key issue. Measures such as walking performance, quality of life or biomarkers may provide useful information, but the document says their relationship with survival outcomes is not clearly established. It consequently distinguishes these measures from the outcomes recommended for a confirmatory trial’s primary endpoint.

Key Recommendations

1. Plan the overall development strategy around the intended treatment population and the feasibility of event-based evidence. PMDA encourages Japan’s participation in MRCTs from the early stage of development, given the challenge of conducting a Japan-only confirmatory trial with mortality or morbidity events as the primary endpoint. When defining trial inclusion criteria and estimating the number of patients who can be enrolled, it is necessary to consider the latest clinical practice and epidemiological data.

2. Represent both TTR patient groups when both are intended to be treated. If the intended target population includes both wild-type and variant TTR ATTR-CM patients, it is desirable to include both groups in the confirmatory study. Because variant TTR ATTR-CM patients are very few in Japan, the evaluation in these situations would include data from non-Japanese cases.

3. Use a controlled, randomized, double-blind confirmatory trial. The efficacy of ATTR-CM therapeutics should be evaluated in a randomized, double-blind controlled trial with an appropriate control group. Select the comparator in view of the anticipated clinical positioning of the investigational drug. If a placebo is used as the comparator, it is necessary to clarify whether existing ATTR-CM treatment can be used in combination with the investigational drug, so the regimen is evaluated as expected in clinical practice. An existing ATTR-CM therapeutic agent may instead be selected as the comparator, with a design to demonstrate non-inferiority or superiority to that treatment.

4. Focus the primary endpoint on morbidity or mortality outcomes. Because improvement in morbidity or mortality is the true endpoint of efficacy assessment for ATTR-CM treatment, the document recommends that the primary endpoint in a confirmatory trial be death (all-cause or cardiovascular death), or a composite endpoint combining death with “other events related to survival outcomes.” Those other events should be selected with regard to their relationship to morbidity or mortality and their clinical importance. Hospitalization or urgent medical visits resulting from cardiovascular events are examples that could be considered.

5. Define and assess composite-event components carefully. The protocol should define “other events related to survival outcomes” as specifically as possible. In principle, these events should be evaluated based on the results of a blinded central judgment by an independent adjudication committee. This is intended to reduce variation in judgments across study sites, countries or regions and support objective evaluation. If cardiovascular hospitalizations or urgent visits are included, it is also recommended to collect objective supporting information, such as medical records, to validate reported events.

6. Support the composite result with its components and assess population consistency in MRCTs. When a composite endpoint is primary, the investigational drug’s efficacy should be demonstrated not only by the composite result, but also supported by each component. In an MRCT, consistency of results for the composite endpoint between the overall population and the Japanese population must be demonstrated. For clinically significant events within the composite, consistency between those populations is desirable.

7. Consider design strategies in response to changing event rates and diagnostic practice. The document notes increased early diagnosis and reductions in mortality among patients with ATTR-CM as changes to consider in trial design. Including recurrent events, as well as first events, among “other events related to survival outcomes” could be considered; in that case, it is appropriate also to evaluate event incidence rates adjusted for observation period. Enrichment strategies, such as selecting patients with a higher risk of events to accumulate more events, could also be considered. Because of the complexity of trial design, PMDA strongly recommends consultation with the Agency to ensure the appropriateness of the study design.

8. Use other efficacy measures as secondary or exploratory endpoints where useful. Exercise tolerance, such as the 6-minute walk test, quality of life (QOL), and biomarkers such as troponin and N-terminal pro-brain natriuretic peptide (NT-proBNP) are not recommended as components of the primary endpoint because their relationship with survival outcomes is not clearly established. Including them as secondary or exploratory endpoints in confirmatory trials may, however, be valuable for demonstrating efficacy and clinical relevance and assessing consistency of efficacy results between the overall and Japanese populations.

9. Set the evaluation period and statistical approach to suit the study. The evaluation period should be set appropriately based on the investigational drug’s characteristics and the time needed for it to demonstrate therapeutic effects in the target population. For comparing morbidity or mortality between groups, it is generally appropriate to compare event incidence during the evaluation period or conduct a survival analysis of time to event. If a composite endpoint is primary and its components differ in clinical importance, an analytical method that takes account of the clinical importance of each component may be appropriate.

10. Plan the Japanese sample size and study feasibility within an MRCT. In an MRCT, the target sample size for Japanese patients needs to be determined considering the probability of demonstrating consistent results for the primary endpoint and its components between the overall and Japanese populations. Feasibility should also be considered using the number of patients in Japan, the number of study sites, and the time required for the study, taking account of recent clinical practice systems and epidemiological data as needed.

Practical Implications

Interpretation for planning teams: these considerations make the trial question and intended population early design decisions, rather than details to defer until recruitment begins. A team planning an MRCT can use current diagnostic and epidemiological information to assess which patients may be eligible and whether the planned Japanese participation is feasible. If the intended population includes both wild-type and variant TTR disease, the protocol and evidence plan need to reflect the document’s expectation that both groups are desirably included, while recognizing that data from non-Japanese patients would be part of evaluation where Japanese variant cases are very few.

Interpretation for endpoint and operations teams: if a composite primary endpoint is selected, each component needs a clear protocol definition and an assessment process that supports consistent, objective classification across sites and regions. Independent blinded central adjudication is the approach the document says should in principle be used for the relevant events. Collecting records to substantiate reported cardiovascular hospitalizations or urgent visits can help the adjudication process. The document’s call to support the composite result with each component also means that component-level evidence should be considered in the trial’s analysis and reporting plan.

Interpretation for statisticians: analysis planning should reflect the endpoint’s construction and the study’s international setting. Depending on the primary outcome, the document identifies event incidence during follow-up or time-to-event analysis as generally appropriate approaches. If component importance differs, methods that take account of those differences may be appropriate. For MRCTs, planning should address consistency between Japanese and overall results, and the Japanese sample size should be considered in relation to the probability of demonstrating that consistency as well as practical recruitment constraints.

Interpretation for regulatory and clinical teams: the document does not prescribe one duration or a universal enrichment strategy. It asks development teams to tailor the evaluation period to the drug and target population, and says higher-risk patient selection or recurrent-event approaches could be considered in light of current practice and event rates. Given the stated complexity, teams considering these strategies are encouraged to consult PMDA on the study design.

Technical Details

The document’s main technical choices concern endpoint definition, event assessment, analysis and MRCT planning:

• Primary outcome: death may be all-cause or cardiovascular death. Alternatively, the primary outcome may combine death with selected “other events related to survival outcomes.” The document gives cardiovascular hospitalization and urgent medical visits as examples of events that could be considered; it does not say that they must be used.
• Adjudication: define the additional events as specifically as possible in the protocol. In principle, assess them using a blinded central judgment by an independent adjudication committee. Where cardiovascular hospitalization or urgent visits are part of the endpoint, objective supporting information, for example medical records, is recommended to validate reported events.
• Composite interpretation: present the result for the composite endpoint and ensure efficacy is also supported by each component. In an MRCT, demonstrate consistency of the composite result between the total study population and the Japanese population; consistency for clinically significant individual events is desirable.
• Analysis options: compare event incidence during the evaluation period or use survival analysis for time to event. If clinical importance varies across composite components, an analysis method that takes account of the clinical importance of each component may be appropriate. If recurrent events are included, it is appropriate also to evaluate incidence rates adjusted for observation period.
• Evaluation period: choose it based on the characteristics of the investigational drug and the time required for therapeutic effects in the target population. The document notes that previous developments generally used an evaluation period of about 30 months, but this is contextual information about previous developments, not a stated universal duration for future trials.
• MRCT sample size and feasibility: consider the Japanese target sample size in relation to the probability of showing consistent results for the primary endpoint and components between the overall and Japanese populations. Also assess feasibility using the number of Japanese patients and study sites and the time required, with recent practice and epidemiological data taken into account as needed.

For secondary or exploratory endpoints, exercise tolerance, QOL and biomarkers may help demonstrate efficacy and clinical relevance or assess consistency across populations. Their role is distinct from the primary endpoint because the document does not consider their relationship with survival outcomes clearly established.

Who Should Read It

This document is relevant to pharmaceutical developers and clinical teams planning trials of drugs for ATTR-CM, particularly confirmatory studies and MRCTs with Japanese participation. It will also be useful to statisticians developing endpoint and analysis plans; clinical operations teams assessing recruitment, sites and event documentation; investigators and adjudication committees involved in identifying outcome events; and regulatory affairs and medical writing professionals preparing development rationales or study documents. It is especially pertinent when a programme must decide how to represent wild-type and variant TTR disease, choose a primary endpoint, or plan Japanese and overall-population assessments.

Official PMDA Source

• Official title: “Points to consider in the clinical development of drugs for transthyretin amyloid cardiomyopathy (Early Consideration)”
• Issuing body: Pharmaceuticals and Medical Devices Agency, Office of New Drug II
• Date on the cover: December 26, 2024
• PMDA PDF: Official PMDA document (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; this summary does not replace it. PMDA describes Early Consideration documents as reference information reflecting its views at the time of publication, which may change as scientific knowledge develops. PMDA provides the English version for reference purposes, and the Japanese original prevails if the versions differ.

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