TECHNOLOGY EXPLAINER
Biomarkers and Clinical Endpoints
— Using what can be measured quickly as a proxy for what really matters
In the end, whether a new drug is really useful"How the patient feels, how it works, and how it lives?"However, it takes a long time to check it. HomeReduction of tumors on blood content and imagesLike, Quickly measure indicators—we will organize where this “substitute” is allowed and where it can be removed.
- Biomarkers and clinical evaluation indicators (3 lines)
- Definition of BEST - Types of Biomarkers
- “Measuring” and “What you want to see” – 3 stages of alternative endpoints
- Indicators of cancer area - OS, PFS, response efficiency
- Definition: The smaller the effect, the faster the required number of events
- When the substitute endpoint is removed - CAST Lessons
- Material Technician Perspective 1: The substitute endpoint is similar to the accelerated test
- Quick approval and alternative endpoints
- Companion Dia —Approving Drugs and Testing in Set
- Material Technician Perspective 2: Measurement is a “Material System”
- Issues and things that have not yet been determined
- Glossary/Reference Materials/Reference Table
Facts= Contents described in the publication material (with source link)
The calculation of this paper= The value calculated based on the specified premise
Undetermined / Future= Items that have not been confirmed as a plan and goal
In addition, reading on structure arrangement, materials and measurement design is"Description"is distinguished.
About this articleExplanation of "Measuring" of clinical development and the mechanism of regulationHome not to evaluate the effectiveness and safety of individual medicines and tests, No medical advice. We do not discuss the superiority of testing. Tests and products that appear in the body are treated only as examples for determining the idea of evaluation indicators. Please be sure to consult your health care professional for your treatment and examination decisions.
1. Biomarkers and clinical evaluation indicators (3 lines)
- Biomarkers:FDA and NIH Joint Working Group"Defined characteristics, measured as an indicator of biological reaction to exposure and interventions, including normal biological processes, pathological processes, or medical interventions"FactsHome Including characteristics, tissues, images, and physiological properties
- What is:The same definition is the biomarker“How individuals feel, how they work, and how they live”It is written clearlyFactsHome Measure thisClinical OutcomeHome
- Why?Clinical outcomes take time to make sure. HomeBiomarkers expected to predict clinical benefitsTest evaluation items (Alternative Endpoints) HomeExchange of speed and accuracyis born
The substitute endpoint is a measurement value that predicts real answers rather than “real answers”. About BEST“It does not affect the clinical benefits that are the primary interest in itself.”definedFactsHome So in the U.S. system, alternative endpointsHow far has been verified?Depending on the stage and If the verification is not sufficient,Test to confirm genuine benefits after approvalContact UsFacts。
2. Definition of BEST – Types of Biomarkers
BEST (Biomarkers, EndpointS, and other Tools) Final revision on January 16, 2025It is a glossaryFactsHome There is a role of "common dictionaries" to prevent the meaning of the term from being distracted by researchers, companies, and regulators. The current glossary lists the following eight types of biomarkers:Facts。
| Type | Definition of BEST |
|---|---|
| Sensitivity/Risk | For those who have no clinically obvious disease,Possibility of developing diseases |
| DiseaseDetect and confirm existenceor diseaseTypeIdentify a person with | |
| Monitoring | To evaluate the condition of the disease or exposure to medicines or environmental factors (or its impact)Repeat measurement |
| Home | Clinical events, recurrence and progression in patients with diseaseEase of occurrenceIdentify |
| Compared to those who do not have biomarkers, exposure to pharmaceuticals, etc.T who are more likely to experience favorable (or preferable) effectsIdentify | |
| Reaction | People exposed to drugs, etc.Biological reactionsPharmacological BiomarkersHomeBiomarkers as an alternative endpointInclude |
| Safety | Measure before and after exposure and as a harmful actionPossibilities of toxicity |
| Multi | Two or more individual biomarkersed in a manner determinedInterpreting |
AllFacts(BEST Glossary [Reference 1]). Japanese expression is a summary of this article.
Pharmacological BiomarkersBEST"Indicates the biological activity of pharmaceuticals without necessarily leading conclusions about efficacy and disease outcomes"and ApplicationConceptual demonstration, dosage selection assistance, reaction measurementHomeFacts。 "Evidence that the drug has reached the body rather than the evidence that the drug is effective"——This distinction is the foundation of the following story.
3. “Measuring” and “What you want to see” – 3 stages of alternative endpoints
BESTEndpointHome"Precisionally defined variables that are statistically analyzed to answer specific research challenges, intended to avoid interest outcomes"FactsHome 、Alternative Endpointsis defined as follows:
"In clinical trials, endpoints that can be used instead of directly measuring how patients feel, how they work and how they live. The substitute endpoint does not reflect clinical benefits, which are the primary interest in itself, but is also considered to be epidemiological, the eutic, pathophysiological, or other scientific grounds, predicting its clinical benefit or harm.”Facts
In addition, from US regulationsDegree of clinical verificationis divided into three phasesFacts。
| Stage | Definition of BEST | How to use with approval |
|---|---|---|
| Verified （validated） | with a clear foundation and strong evidence of clinical data,The effect on the indicator predicts specific clinical benefitsHome | Without additional trials that directly indicate clinical benefits in the defined contextSupport approval |
| Reasonable prediction （reasonably likely） | Although there is a strong foundation on the aircraft and epidemiology,There is no clinical data that is shownHome | Quick approvalcan be used. After approvalation TestContact Us |
| Search （candidate） | The ability to predict clinical benefitsRECRUITHome | — |
AllFacts(BEST Glossary [Reference 1]). BEST is a regu、 replacement endpoint in the United States"In most cases point to biomarkers"
U.S. law (FD&C law 507(e)(9))"Clinical test values, images, physical findings, and other measure markers, which are not direct measurement of clinical benefit."HOME Normal approval if it is known to predict clinical benefits、Fast approval if you can reasonably predictIt is divided into two things that can supportFactsHome FDA is based on this article,List of alternative endpoints based on approval and permissionPublishUpdated every 6 monthsIt isFactsHome for example:High blood pressure、Type 2 diabetes "Serum HbA1c"、"Serum LDL cholesterol" of high cholesterol serumis usually based on approval.Facts。
4. Indicators of cancer area - OS, PFS, response efficiency
The most frequently discussed alternative endpoints is the area of cancer. The FDA organizes evaluation indicators used to approve cancer drugs in December 2018.Facts。
| Index | Definition (Guidance description) | Place (table of guidance) | Cons (table of guidance) |
|---|---|---|---|
| Total survival （OS） | From randomly assigned to deathTime. ITT Group | Easy and precise measurement. Based on objective and quantitative evaluation | It is possible to switch from the control group to the treatment group, and to prevent post- ment.Long tracking requiredHome Includes deaths other than cancer |
| Unexpected survival （PFS） | From random discountAny early person with an objective tumor or deathClose | Survival TestNumber of casescan be evaluated. Stable status also included in evaluation | Non-biased test can be performed for evaluation. The definition is different for each test. Frequent image evaluation is requiredmay not correlate with survival |
| Performance （ORR） | Predefined amountAllows tumor shrinkage to patients with minimal durationHome The FDA generally defines the sum of partial response and complete response | It can be evaluated in a few cases.The effect on the tumor can be attributed to the drug(not natural course) | The definition is different for each test. Fre t image evaluation is required.may not correlate with survival |
AllFacts(FDA Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics) Sorry, this entry is only available in Japanese.
About OS“It is usually a favorable endpoint if the most reliable cancer endpoint is regarded and it is possible to conduct tests that can properly evaluate survival.”FactsHome HomeLong tracking period for large-scale testingicultyFacts。
About PFS“The size of the effect on PFS can be greater than the effect on the overall survival period under certain cases.”HOME Close"The data that can be evaluated stubbornly in the correlation between overall survival and PFS is usually insufficient."It is writtenFactsHome Performance“It’s most commonly used as an alternative endpoint that supports rapid approval.”Contact UsFacts。
Dance is ORR and PFSAlternative endpoints that support rapid approvalHOMEAlternative endpoints that support normal approvalHOME SometimesClinical benefits themselvesIt can beRelationship between disease and use context, effect size, available treatment, risk and benefitsIt is determined by etc.Facts。 The name of the indicator does not determine what it is proofThat is This article explains.
5. Calculation of this paper: The smaller the effect, the fewer the required number of events.
Why is OS testing large and long? Comparison of survival timeThe number of "events" observed (death or worsening) than the number of patients themselvesComment Schoenfeld (Survival) is a formula that seeks the necessary number of observations to test whether two survival distributions are equal under the proportional hazard model.Facts。
approximate type that is commonly used in two groups of 1:1 discount D ＝ 4 ×（zα/2 ＋ zβ）² ÷（ln HR）² ulation usingThe calculation of this paper。
- Premise:Both sides significantly water level (z=1.960), detection force 80% (z=0.842). 4 ×(1.960+0.842)² ≈ 31.4
- Premise:Hasad ratio (HR) is constant (proportional hazard). If the survival time follows the index distribution, the median ratio becomes 1 ÷ HR
- HR 0.50(equivalent to double the center value): 31.4 ÷ (ln 0.50)2 = 31.4 ÷ 0.480 ≈ 66 Events
- HR 2/3(≈0.67) Central 6 months to 9 months): 31.4 ÷ 0.164 ≈ 191 Events
- HR 0.75：31.4 ÷ 0.0828 ≒ 380 Events
- HR 0.80：31.4 ÷ 0.0498 ≒ 631 Events
Premises and Limits:This is a textbook approximation. In actual test design, we consider intermediate analysis, de。s, assignment ratio, non-proprietary hazards. The value of HR has been writtenT numbersnot a specific drug or test result. "Chuo 6 months to 9 months" is a response when the index distribution is assumed, and it is not possible to have a real survival curve.
Read from hereTo show a small difference in OS, you need to wait until many death events occurIt is. And the OS pointed out by guidanceEffects of post- mentContact UsFactsHome This is the background where alternative endpoints are requiredWaiting Time and Mixed ItemsThere is a problem with this article.
6. When the substitute endpoint is removed: Lessons from CAST
A classic example that shows the dangers of alternative endpointsCardiac Arrhythmia Suppression Trial（CAST）Comment 1991 yearNew England Journal of MedicineAccording to the paper abstract, this test is A hypo that "restriction of extra-oc contraction after myocardial infarction suddenly reduces death"Planned to verifyFacts。
Centrifugal contractionPatients with medicine suppressionrandomly assigned to the drug or placebo. Then, there are two types of medicines (enkanid, flexionid):"For excessive death"CanceledFacts。
857 of 1,498 people (432 real drugs, 425 placebos), 661 people (323 real drugs, 318 placebos) 89 deaths on average 10 monthsThe death of an arrhythmia is 43 people.There were 17 cardiac deaths other than arrhythmias, 5 placebos, and 5 placebos.Facts。
- Drugs:432+323 = 755 people. Death 43+17+3 = 63 people. 63 ÷ 755 ≈ 8.3%The calculation of this paper
- placebo group:425+318 = 743 people. Death 16+5+5=26 people. 26 ÷ 743 ≈ 3.5%The calculation of this paper
- Size:8.3% ÷ 3.5% ≒ 2.4 timesThe calculation of this paper
Premises and Limits:It is not an analysis considering the difference of the tracking period, etc. in the rough proportion of the number of abstracts simply combined with two drugs. This result is for the subject of the trial (patients with extra-oclinary contractions after myocardial infarction) and does not evaluate the current use or safety of these drugs.
7. Material Technician Perspective 1: Substitute Endpoint is similar to "Ac ration Test"
In order to see the deterioration that takes 10 years in actual use,Accelerated testing of high temperature and high humidityuse. The material passed in the accelerated test will last long even in real use — the response isThe same mechanism of deteriorationIt is based on the premise of this article.
The substitute endpoint is similar to this. BEST is expected to predict clinical benefits for alternative endpoints Epidemiological, the therapeutic, pathological, or other scientific basisHomeFactsHome In other words“If the indicators move, the outcome of the patient will move”
CASTThe measured value (extra-term contraction) was moved as intended, but the drug refused to re in another routeSorry, this entry is only available in Japanese. Acceleration TestAnother deterioration mode that does not appear in accelerated conditions became dom by actual useContact Us
- Correlation is only guaranteed in the scope of its mechanism:Even with the same indicators, new drugs with different effect can change their prediction. FDA cancer guidance positions ORR and PFS"The size of the context and effect of the disease and use"This is what we judge.Facts
- The FDA list has a "acting mechanism" field:FDA replacement endpoint list (Adults and non-cancer)「Drug Mechanism of Action」「Mechanism agnostic」HbA1c「Glucose-lowering」LDL cholesterol「Lipid-lowering」It is writtenFactsHome The same page is acceptedDisease, target population, mechanism of action of treatment, presence of existing treatmentdepends onIt should not be assumed that the appropriate alternative endpoints in one development plan are also appropriate for another clinical situation planFactsHome In addition, the alternative endpoints that were not shown to be expected in the confirmation test after being used for quick approval are"No longer accepted, not included in the table"It is writtenFacts
- Determines whether the data has been verified:Three stages of BEST (candidates, rationally predicted,、d) have an accelerated coefficient"Estimated value" to "value confirmed by actual measurement"Corres s to the process of becoming (explanation by this article)
Even in the world of materials, it is always a discussion whether you can apply an existing accelerated test to a new material system. “Can existing alternative endpoints be used for new modalities?”The question is the same type of question. This article explains.
8. Quick approval and alternative endpoints
USAAccelerated ApprovalIt is a mechanism to quickly approve the drug of heavy diseases using an alternative endpoint that can reasonably predict. The draft guidance of the FDA in December 2024 organizes the systemFacts。
| Year | Events (Guidance description) |
|---|---|
| 1992 | FDAQuick Approval Rules21 CFR 314 subpart H, 601 subpart E |
| Year 1997 | The parliament positioned the system in the FDA Modernization Act (FDAMA) as a law,Article 506Add |
| Year 2012 | FDASIAWeight, scarcity, prevalence, or alternative treatment of diseaseto consider and amend |
| 2023 year | Revised by the Integrated Ageing Law ( 20 3210) in 2023. When approvedmilestone test conditions (milestones such as registration goals, protocols, and completion target dates)The confirmation test must be "in progress" before approvalContact Us Prog ReportAbout 180 daysSubmitQuick cancellation procedureOpen |
AllFacts“Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics” The rule of 1992 is described in the cancer area guidance [Reference Material 2].The draft guidance is not the final versionUndetermined / Future。
The confirmation test may not be able to confirm the benefits of the confirmation test, or if the confirmation test was not carried out with sufficient effort FDA may cancel approval in a prompt processFactsHome So how much is "confirm" and how much is "revocation"? The FDA has published a list of quick approvals based on alternative endpoints.
"CDER Drug and Biologic Accelerated Approvals Based on a Surrogate Endpoint"Total 350HomeFactsHome Counting the "Conversion-Withal Status" of each line is as follows:The calculation of this paper。
- Converted:210 = 60.0%
- Not Yet Converted:87 = 24.9%
- With)n:53 founded 15.1%
- Decided:53 ÷ 263 ≒ 20.2%
Premises and Limits:The number simply counts the line per adaptation, and multiple indications of the same drug are counted separately. The reason for "reduction" is not distinguished (e.g. failure of confirmation test, corporate judgment). What happens in the future?Undetermined / Future。
9. Companion Dia —Approving Drugs and Testing with Set
BiomarkersPredictive Biomarkersis used to select "people whose medicine is easy to work". The inspection is approved as a product.Companion diagnosisComment
FDA：Companion diagnosis"It is a medical device that provides essential information for safe and effective use of the corresponding drug or biological formulation, and is often IVD."FactsHome For useIdentification of Patients with Benefit、Identification of patients with high risk of heavy side effects、Monitoring of treatment reactionsContact UsFactsHome FDA"If the diagnosis test is inaccurate, treatment decisions based on the examination may not be optimal."It is writtenFacts。
Japan:Notice of the Ministry of Health, Labour and Welfare on July 1, 2013, companion diagnostics, etc."Use for the purpose of improving the effectiveness or safety of certain drugs"Home "Extra-dia。stic drugs or medical devices that are essential for the use of such drugs (。ing external diagnostic drugs or medical devices that simply measure diagnosis of diseases, etc.)"FactsHome In addition, as a rule, for drugs that have not been approved for companion diagnostics, etc.Application for approval of pharmaceutical products and approval of companion diagnostics should be made at the same timeFacts。
In the United States, Immune System、 Testing to Investigate Overexpression of HER2HercepTestPMA P980018September 25, 1998Home Compatible anti-HER2 antibodyHerceptin(BLA 103792)September 25, 1998HomeFactsHome Authorized documents are inspected"Auxiliary of Evaluation of Patients Considered by Herceptin"to useFacts。 The drug and examination were approved on the same day(The two publication dates are reflected). In Vitro Companion Diagnostic DevicesAugust 6, 2014HomeFacts。
FDA-Authorized Companion Diagnostic Devices When this document was confirmed (updated on July 23, 2026)226 linesCommentFactsHome One line is a combination of "Inspection × Corres ing Medicine × Adaptation". Indication - Sample TypeThe calculation of this paper。
- Organization:153 lines = 67.7%
- Plasma:42 lines = 18.6%
- Whole blood, bone marrow, serum, saliva, etc.:23 lines = 10.2%
- tissue or plasma:6 lines = 2.7%／No sample description:2 lines = 0.9%
If you simply count the biomarker field, it will be in many order. EGFR 30 lines, HER2 29 lines, BRAF 19 lines, KRAS 16 lines, PD-L1 15 linesCommentThe calculation of this paper。
Premises and Limits:This article is integrated when the list is notation swaying (bla and uppercase letters). Because the same examination is separate by multiple medicines and indications,Not the number of inspection productsHome The list is updated from time to time.
10. Material Technician Perspective 2: Measurement is a “Material System”
Test, tool, or instrument3 essential elementsIt is defined as a system of evaluation. "1) Materials for measurement, 2) Assays (for biomarkers), 3) Methods and criteria for interpreting measurement values"Facts。 1 material definition of the materialPlease note.
There are two tests. Analy ValidityHomeSensitivity, specificity, trueness, accuracysuch performance,Procedures for collection, handling, and preservation of specimensDetermined by technical procedures, BEST"Not validation of the validity of the item"and pushing in mindFactsHome What is useful?Clinical Validation——Confirm whether or not to properly identify, measure or predict the concept of interestFacts。
Bioanaly Method Validation for Biomarkers "How the collection, handling, and storage of specimens affect the reliability of data obtained from the analysis method"Home The effect of operation on the material, which needs to be frozen during transportation, storage temperature and storage periodExampleFactsHome If the data used to determine approval,Complete validation along with ICH M10Seeking forFacts。
From here, you can see the view of materials and materials (in this article).
- "keeping" material of specimen:blood , preservatives, frozen containers. Figure 6: Companion diagnosistissue and plasmais the main specimen. In a test to measure slight nucleic acid in plasma, the result is that the specimen does not change between the collection and analysis.
- "Read" material of specimen:Standard substances that increase antibodies and nucleic acid used for immunostaining. Used for dyeing HER2 in the list of FDAMono Primary Antibodybut it is on itself as companion diagnosisFacts
- Var Source:The “Bre” of the measured value is filled with differences (HR in Chapter 5) in clinical trials.Preventing material lot differences protects clinical trial detectionContact Us
In the world of materials,Analy Validity ation is "Calibration of Measuring Instruments and Gauge R&R" and "Clinical Validity ation"Close The former is solidified with materials and procedures, but the latter can only be shown in clinical data (in this article).
11. Challenges and things that have not yet been determined
(1) The "validation" of the substitute endpoint is re ted every time the drug type changes
FDA Cancer dance treats ORR and PFSDetermine the size of the disease, context, and effectHomeFactsHome No rules. How long does an existing alternative endpoint apply to a new mechanism of action? The primary information indicating the general answer was not confirmed at the time of the survey (September 2026).Undetermined / Future。
(2) The new rules of rapid approval are at the stage where the operation is becoming solid.
As of December 2024DraftHomeFactsHome What are the criteria for "in progress" of the confirmation test?Undetermined / FutureComment
(3) Relationship with Japan’s rapid approval and conditional approval
This article focuses on the U.S. system. Comparison of the Japan-U.S. speed system is handled in detail in this series "Approval Application and Real World Data".
- Biomarkers are "indices", not "feeling, function, and survival"(BEST definition)Facts
- Substitute endpoints are divided into "candidates, rationally predictable and verified" in the degree of validationFacts
- OS is the most reliable, while long tracking costs.Just change HR from 、 to 0.80, the required number of events is about 1.7 timesThe calculation of this paper
- Even if an alternate indicator is improved, there is an example that the outcome has worsened (CAST)Facts
- 350 350 FDA approvals, the conversion to normal approval is 60.0%, and the reduction is 15.1%.(As of June 30, 2014)The calculation of this paper
- Companion diagnostic specimens are approximately two-、rds of tissue and about 20% of plasmaFDA ListThe calculation of this paper
12. Glossary
- Biomarkers
- Defined characteristics as an indicator of response to biological processes and interventions. It is not a measure of feeling, function, and survival.
- BEST
- Biomarkers and endpoint glossaries of FDA and NIH working groups.
- Predictive Biomarkers
- Biomarkers that identify the person who is likely to have a favorable (or unfavorable) effect on a specific drug.
- Predictive Biomarkers
- Biomarkers that show the ease of recurrence and progression of people with disease.
- Pharmacological Biomarkers
- Reactive biomarkers that show biological activity of the drug. Not limited to validity conclusions.
- Endpoint
- Precisely defined evaluation items for statistical analysis in clinical trials.
- Alternative Endpoints
- Evaluation items used instead of directly measuring clinical benefits. It is expected to predict benefits.
- Clinical Outcome
- The outcome that indicates how the patient feels, how it works and how it lives.
- Total survival (OS)
- Time from random assignment to death.
- Unexpected survival (PFS)
- Time from random allocation to tumor increment or death.
- Efficacy (ORR)
- Allows patients with prescribed tumor reduction for a certain period of time. Partial response and full response.
- Hazard ratio (HR)
- The ratio of the ease of occurrence of two groups of events. Less events than 1 in the treatment group.
- Quick approval
- In the United States, it is a mechanism that approves early based on alternative endpoints that can be reasonably predicted. Test conditions
- ation Test
- Tests to confirm actual clinical benefits after rapid approval.
- Companion diagnosis
- A test that gives you the essential information to use certain drugs safely and effectively. For external diagnosis.
- Analy Validity
- Technical performance of inspection (sensitivity, specificity, trueness, accuracy, etc.). Not validation of usefulness.
- Clinical Validation
- Check whether or not to properly identify, measure or predict the concept of interest in inspection.
- fit-for-purpose
- The idea that the degree of validation is sufficient to support the proposed application.
13. Reference materials (primary information)
- FDA-NIH Biomarker Working Group"BEST (Biomarkers, EndpointS, and other Tools) Resource — Glossary" released on January 28, 2016, January 16, 2025 (NCBI Bookshelf) — ncbi.nlm.nih.gov
- FDA"Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics" December 2018 (PDF) — fda.gov
- FDA“Table of Surrogate Endpoints That Were the Drugis of Drug Approval or Licensure” — fda.gov
- FDA“Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics —ancedance for Industry (Draft)” December 2024 (PDF) — fda.gov
- FDA（CDER）「NDA and BLA Accelerated Approvals — CDER Drug and Biologic Accelerated Approvals Based on a Surrogate Endpoint」As of June 30, 2026（PDF） — fda.gov
- Echt, D.S. (CAST)「Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial」New England Journal of Medicine 324(12), 781–788 (1991). doi:10.1056/NEJM199103213241201 — pubmed.ncbi.nlm.nih.gov
- Schoenfeld, D.A.「Sample-size formula for the proportional-hazards regression model」Biometrics 39(2), 499–503 (1983). doi:10.2307/2531021 — pubmed.ncbi.nlm.nih.gov
- FDA")anion Diagnostics" (updated on June 20, 2023) — fda.gov
- FDA"List of FDA-Authorized Companion Diagnostic Devices (In Vitro and Imaging Tools)" (Updated on July 23, 2026) — fda.gov
- FDA「Premarket Approval (PMA) — DAKO HERCEPTEST, P980018」 — accessdata.fda.gov
- FDA「Drugs@FDA — BLA 103792（HERCEPTIN）」 — accessdata.fda.gov
- Director, Pharmaceutical Food Bureau, Ministry of Health, Labour and Welfare"Notes on the application of companion diagnostics and related drug approval application" Drug Examination No. 0701 No.10, July 1, 2013 (PDF) — pmda.go.jp
- FDABioanaly) Method Validation for Biomarkers —ancedance for Industry, April 2026 — fda.gov
14. Response Table of Claim and Sources (Audit)
| Content | Home | |
|---|---|---|
| Definition of biomarkers (not a measure of feeling, function, and survival, which is defined as an indicator of response to normal biological processes, pathological processes, and interventions). 8 types (sensitivity, risk, diagnosis, monitoring, prediction, safety) Definition and use of pharmacokinetic biomarkers (demonstration of concept, dose selection, and reaction). It is expected that the definition of endpoints, clinical outcomes, and alternative endpoints are predicted based on the epidemiological, etiological and pathological basis. Three stages of validation, reasonably predictable, candidates, and fast-approved verification tests have been required, and in most cases the biomarker alternative endpoint refers to biomarkers. Definition of companion diagnostics. Testing, tools, and measuring instruments consist of three elements: “materials, assays, interpretation methods and standards for measurement.” Defining clinical validity checks with analytical validity (not validation of usefulness, which can be used for sensitivity, specificity, trueness, accuracy, specimen collection, handling, and storage procedures). fit-for-purpose definition. Published: January 28, 2016, Last revised: January 16, 2025 | NCBI Bookshelf[Reference 1]https://www.ncbi.nlm.nih.gov/books/NBK338448/ | Facts |
| The definition of OS, PFS and ORR and the pros and cons described in Table 2. The effects of post-ment, if the OS is the most reliable endpoint of cancer and can be evaluated properly, usually favorable, long-tracking of large-scale trials is difficult. Normally insufficient data that is more effective for PFS and has a strong correlation evaluation. ORR is the most commonly used alternative endpoint for fast approval. ORR and PFS become a clinical benefit to the substitute endpoint of rapid approval and normal approval by context, etc. The rules for rapid approval were established in December 2018 | FDA Cancer Endpoint Dance[Reference 2]https://www.fda.gov/media/71195/download | Facts |
| 21st Century Cures Act Article 3011 has set Article 507 of the FD&C Act, and the definition of the substitute endpoint of Article 507 (e) (9) (usually two categories of approval and fast approval). The table is updated every 6 months. High blood pressure, type 2 diabetes serum HbA1c, and high cholesterol serum LDL cholesterol are listed as "Type of Approval Appropriate for" and "Drug Mechanism of Action" column is Mechanism a。stic・G。ose-lowering・Lipid-lowering respectively. It should not be assumed to be appropriate in different clinical situations, depending on disease, target population, mechanism of action, and existing treatment. The alternate endpoints that did not show benefit in the confirmation test are not included in the table | FDA Replacement Endpoint List Page[Reference 3]https://www.fda.gov/drugs/development-resources/table-surrogate-endpoints-were-basis-drug-approval-or-licensure | Facts |
| FDA Rules: Article 506 was added by FDAMA in 1997, amended by FDASIA in 2012, and further amended by Article 3210 in 2023. Specify the conditions for the confirmation test (including registration targets, protocols, and completion target dates), the authority to request that the confirmation test is ongoing before approval, progress reports every 180 days, and the prompt cancellation procedure and its requirements. The draft must be completed by December 2024. | FDA Quick approval draft guidance[Reference 4]https://www.fda.gov/media/184120/download | Facts |
| As of June 30, 2026, the CDER’s quick approval list is 350. | FDA (CDER)[Reference 5]https://www.fda.gov/media/151146/download | Facts |
| CAST was planned to verify the hypothesis of sudden death due to the suppression of ventricular contractions after myocardial infarction. Patients who had a suppressed periodontal contraction were randomly assigned. The enkanid and flexionid were discovered to be associated with excessive death. The number of people per group: 257 = 432 + 425, 641 = 323 + 318, total: 1,498. The average follow-up period was 10 months. The number of deaths by cause (43 to 16, heart death other than arrhythmia 17 to 5). | Echt et al[Reference Material 6]https://pubmed.ncbi.nlm.nih.gov/1900101/ | Facts |
| Schoenfeld led the observation formula required for the equivalent test of two survival distributions under the proportional hazard model. | Schoenfeld[Reference Material 7]https://pubmed.ncbi.nlm.nih.gov/6354290/ | Facts |
| The final guidance "In Vitro Companion Diagnostic Devices" was issued on August 6, 2014, that the definition of companion diagnostics by the FDA and the three uses, if the diagnosis test is inaccurate, treatment decisions may not be optimal. | FDA Companion Diagnostics Page[Reference 8]https://www.fda.gov/medical-devices/in-vitro-diagnostics/companion-diagnostics | Facts |
| Indication - Sample Type and Biomarker field of each line. The first table contains 226 antibodies, and the PATHWAY anti-Her2/neu (4B rabbit monoclonal primary antibody) has been published as a companion diagnostic. The method for validating the biomarker analysis must be fully compliant with ICH M10 and confirmed to be necessary for verification. Validation of the biomarker analysis method must be completed by April 2026. | FDA Companion Diagnostics List[Reference 9]https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-fda-authorized-companion-diagnostic-devices-in-vitro-and-imaging-tools | Facts |
| HercepTest (PMA P980018) is a semi-quantitative immunoassay that determines the HER2 overexpression on September 25, 1998. It is a supplement to the evaluation of patients who are considering treatment with Herceptin. | FDA PMA Database[Reference Materials 10]https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P980018 | Facts |
| Herceptin (BLA 103792) initial approval (ORIG-1) is on September 25, 1998 | Drugs@FDA[Reference Materials 11]https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=103792 | Facts |
| The scope of companion diagnostics, etc. in Japan (use for the purpose of improving the effectiveness or safety of certain drugs, and for the purpose of use of such drugs) and the approval of companion diagnostics, etc. should be applied at the same time as the application for approval of pharmaceuticals. Notification number and date | Notice of Ministry of Health, Labour and Welfare (No. 0701)[Reference Material 12]https://www.pmda.go.jp/files/000213148.pdf | Facts |
| If you are using the biomarker analysis method for validation in fit-for-purpose, you must fully comply with ICH M10 and confirm that it is necessary to verify it. Validation of the biomarker analysis method must be completed by April 2026. | FDA Biomarker Analysis Method Validation.[Reference 13]https://www.fda.gov/media/185276/download | Facts |
| The number of events required (HR 0.50, 66, 2/3 (≈ 0.67), 191, 380, 0.80, 631) and 1.7 times. CAST mortality rate (actual drug 8.3%, placebo 3.5%, about 2.4 times). Quick approval breakdown: 350 (conversion 210 60.0%, unconverted 87 24.9%, down 53 15.1%, down 20.2%). Companion Diagnostics list breakdown: 226 (67 15.3%, plasma 42 18.6%, blood 23 10.2%, tissue or plasma 6 2.7%, unlisted 2 0.9%). The biomarker column aggregation breakdown (EGFR 30, HER2 29, BRAF 19, KRAS 16, PD-L1 15). HercepTest and Herceptin were approved on the same day. | Detection power is 80%, 1:1 discount, proportional hazard, index distribution is assumed to have this article, HR is a temporary . CAST is a coarse proportion of the number of abstracts. The summary of the list is a simple number of lines, and the notation is integrated. Neither evaluates the effectiveness and safety of individual drugs or tests. | The calculation of this paper |
| In the future, 87 of “uns uled” with quick approval. Fast approval draft guidance finalization and operation | The results are not confirmed at the time of the survey (September 2026). The draft dance is not the final version.[Reference 4]https://www.fda.gov/media/184120/download | Undetermined / Future |
| A common answer to how long an existing alternative endpoint applies to a new mechanism of action | The primary information indicating the general answer was not confirmed at the time of the investigation (September 2026). | Undetermined / Future |
| Effectiveness and effect of individual medicines and testing, evaluation of clinical results, superiority of products | This article explains the mechanism of evaluation indicators and regulations, and does not evaluate the efficacy or safety. CAST cited only the description of the abstract of the paper as a historical example of the idea of the alternative endpoint (explanation) | |
| Biomarkers are arranged for each scene. Read substitute endpoints for accelerated testing of materials (that the correlation is only guaranteed, the three-stage accelerated coefficients have been estimated to the actual measurement process). I read that CAST is “the situation where another deterioration mode was controlled by actual use”. The measurement was considered as a "system of materials", and it was organized into the source of materials, reading materials, and variations that keep the specimen. Analy Validity Verification and Clinical Validity Verification for gauge R&R and lifetime prediction. OSing the waiting time and mixture of OS | and commentary of this article based on the publication content. FDA, NIH, Ministry of Health, Labour and Welfare | |
| Fig. 1 - Fig. 6 is a diagram for explanation, not the actual data screen or test record. Hero image is an AI generation image | Notes by this article |
Last Updated: September 26, 2026 / Source is limited to primary information (FDA-NIH Working Group Glossary, FDA dance/Published List/Approved Database, Ministry of Health, Labour and Welfare Notifications, Review Papers). They are distinguished from the facts as 'explanation' because they include the design and reading of evaluation indicators. The new mechanism of action applies to existing substitute endpoints, the final operation of rapid approval draft guidance, and the method of unchanged quick approval are "undetermined / future". This article explains the mechanism of evaluation indicators and regulations,It is not an evaluation of the effectiveness and safety of individual medicines and tests, but not medical advice. All diagrams are illustrations for explanation. Fig. 1 - Fig. 6 is a vector drawing, and the image is an AI-generated image.We do not show the actual test data screen or product.