PMDA's Perspective on the PMDA's Perspective on the Cli i l E l ti fCli i l E l ti fClinical Evaluation of Clinical Evaluation of

Cell/TissueCell/Tissue Based ProductsBased ProductsCell/TissueCell/Tissue--Based ProductsBased Products

Office of Biologics II, Ph ti l d M di l D i APharmaceuticals and Medical Devices Agency

Kenichi Yanagi, MD, PhDg , ,http://www.pmda.go.jp/

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Today’s TalkToday’s TalkToday s TalkToday s Talk

• Concept of Clinical Development Based• Concept of Clinical Development Based on Characteristics of Cell/Tissue-based Products

• Design of Clinical TrialDesign of Clinical Trial– Target Disease

C t l G– Control Group– Endpoint

• An Example

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Characteristics of Cell/TissueCharacteristics of Cell/Tissue--Based ProductsBased Products• Because of limited clinical experiences of advanced

technology-applied products, estimation of the risk gy pp p ,of these is rather difficult compared to other products.p

• Control of raw materials and avoidance of contamination during manufacturing is critical sincecontamination during manufacturing is critical since inactivation or elimination of infectious agents by heat or chemical treatment or purification procedureheat or chemical treatment or purification procedure.

• Risk of change in characteristics of the cell including transformation cannot be excluded.

• Most cell/tissue products cannot be removed even ifMost cell/tissue products cannot be removed even if severe adverse events is observed in the patients.3

US & EU Trends on the evaluation of cell/tissueUS & EU Trends on the evaluation of cell/tissue--based productsbased productsbased productsbased products

US: Initial Approval (August 22, 1997) -Accelerated approvalIndication: The repair of clinically significant, symptomatic, cartilaginous defects of the femoral condyle (medial, lateral or

Phase IV

cartilaginous defects of the femoral condyle (medial, lateral or trochlear) caused by acute or repetitive trauma

Approval to narrow the Indication (March 2, 2000)Indication: ---second line therapy, for use in patients who have had

i d t t i th i th i lan inadequate response to a prior arthroscopic or other surgical repair procedure, has been approved.

EU

EU regulation for Advanced therapy medicinal products

EU:

4(EC/1394/2007)Each Site →Central Procedure

General Principles GL.General Principles GL.Notification No.1314 (26 Dec. 2000), Appendix 1

Background• It is necessary to prevent introduction, transmission, and

spread of communicable disease through the use ofspread of communicable disease through the use of cell/tissue-based products.

• Problems arising from defective products not properly f t d f i i t h dli d fmanufactured or from inappropriate handling and use of

products should be avoided.Objectivej• To show basic requirements as well as to ensure scientific and

ethical validity in quality, safety and handling of cells/tissues.

Basic principle• The use of cell/tissue-based products should be confined toThe use of cell/tissue based products should be confined to

the medical treatments where the clinical advantage over the other products/treatments is expected, because the potential i k f th t i i f th i f ti t d i d f

5risk of the transmission of the infectious agents derived from the products is not completely ruled out.

Why Are Clinical TrialsWhy Are Clinical Trials Required ? Required ? • To evaluate safety and efficacy of a new medical products.

– Evaluation of efficacy of the product in patientsy p p– Assessing safety is acceptable compared to the benefit

of the productp• To provide scientific information on safety and efficacy of

the product to patients and healthcare professionals

The purpose of clinical trials and medicalThe purpose of clinical trials and medical treatments is different.

Protocol of clinical trials should be appropriately designed so that scientific information required g qfor evaluation of the product can be obtained 6

Concept of Clinical DevelopmentConcept of Clinical DevelopmentConcept of Clinical DevelopmentConcept of Clinical Development

Choose target diseases and population that the benefit of the product is expected to be overcomebenefit of the product is expected to be overcome

Optimize the best usage that offer a greater benefit and a smaller risk at the target population.

Design the clinical trial protocoles g t e c ca t a p otoco

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Priority of the Product in Target Disease and Priority of the Product in Target Disease and Cli i l T i l D iCli i l T i l D i G l C id tiG l C id tiClinical Trial DesignClinical Trial Design——General ConsiderationGeneral Consideration

C 1 Fi t h i th i t i ti• Case 1: First choice therapy: superior to existing ones

show Superiority to the existing therapies.

• Case 2: First-line therapy: non-inferiority to existing ones.

show Non-inferiority to existing therapiesshow Non inferiority to existing therapies.

• Case 3: Limiting: existing therapies cannot be applied.

show Superiority to placebo or conservative therapies in patients other therapies cannot be applied.

• Case 4: Limiting: existing therapy has failed.

(Those who other therapy has failed…) Same as above.

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Control GroupControl Group (1)(1)

• Necessary in most cases• Purpose of control group

To discriminate patient outcomes caused by the testTo discriminate patient outcomes caused by the test treatment from other outcomes caused by other factors (e g natural progression of the disease etc ）factors (e.g. natural progression of the disease, etc.）

• Randomization» Patients are randomized into 2 or more groups.» Controls: Placebo, already approved products, etc., y pp p ,

• Blinding» Double blind if possible» Double blind if possible.

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Control GroupControl Group (2)(2)• External Control (Including Historical Controls)• Acceptable only in limited conditions• Acceptable only in limited conditions

» Comparing with a group of patients external toth t dthe study.

» e.g. Baseline-controlled studies.» Inability to control bias is the major and well-

recognized limitation.g» Difficult to establish comparability of the

treatment and control groups.treatment and control groups.» Should be limited to cases which the effect of

treatment is dramatic and the usual course oftreatment is dramatic and the usual course ofthe disease highly predictable 10

Control Group (3)Control Group (3)p ( )p ( )Basically, control group is needed in all trials, but･･･• In a case it is difficult or inadequate to set a

control group….. g p» Rational reason is required.»Set an index that enables objective evaluation»Set an index that enables objective evaluation without comparative control.

• In a case a subjective index (e g pain feeling• In a case a subjective index (e.g. pain, feeling,etc.) is selected…..

S l t l ti th d/i d hi h» Select an evaluation method/index which ensures more objective (e.g. VAS:visual analog scale).» Evaluation by blinded raters.

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EndpointsEndpoints

• Primary endpoint–should reflect clinically relevant effects–selected based on the principal objective of the p p jstudy

• Surrogate endpointSurrogate endpoint–an indirect measurement of effect in situations where direct measurement of clinical effect is notwhere direct measurement of clinical effect is not feasible or practical

reasonably likely or well known to predict clinical–reasonably likely or well known to predict clinical outcome if used as primary endpoint

• The endpoint should be validated appropriately• The endpoint should be validated appropriately.12

Basic Consideration for Design of Clinical TrialBasic Consideration for Design of Clinical TrialDesign of a clinical trial will be different according to the relationship between indication of the product and existing therapy.

Controlled trialConfirmation of superiority Second choice

①Existing②Existing

therapy①Existing therapy is successful

therapy has failed

③No effective existing therapy

Controlled trial Controlled trialControlled trialConfirmation of superiority/non-inferiority

Controlled trialConfirmation of superiority

First choice / First line First choice13

ICH GuidelinesICH Guidelineshttp://www.pmda.go.jp/ich/ich_index.html

• ICH; The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.

• The regulatory authorities and pharmaceutical industry of EU, Japan and US discuss scientific and technical aspects of product registrationof product registration.

• In addition to 17 efficacy guidelines, many guidelines on quality and safety have been issuedquality and safety have been issued.

• Basic and general principle described in efficacy guidelines such as ICH-E8, E9 and E10 would be helpful to designsuch as ICH E8, E9 and E10 would be helpful to design protocol for cell/tissue-based products for regenerative therapy.

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ICH Efficacy Guidelines (1)ICH Efficacy Guidelines (1)Clinical Safety• E１; The Extent of Population Exposure to Assess Clinical

Safety for Drugs Intended for Long-Term Treatment ofSafety for Drugs Intended for Long Term Treatment of Non-Life-Threatening Conditions

• E2A; Clinical Safety Data Management: Definitions and ; y gStandards for Expedited Reporting

• E2B(M); Data Elements for Transmission of Individual Case Safety ReportsCase Safety Reports

• M2 ; Electronic Transmission of Individual Case Safety Reports Message SpecificationReports Message Specification

• E2C(R1); Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugsy p p g

• E2D; Post-approval Safety Data Management: Definitions and Standards for Expedited Reporting

15• E2E; Pharmacovigilance Planning

ICH Efficacy Guidelines (2)ICH Efficacy Guidelines (2)Cli i l St d R tClinical Study Reports• E3; Structure and Content of Clinical Study ReportsDose-Response Studies• E4; Dose-Response Information to Support Drug RegistrationEthnic Factors• E5(R1); Ethnic Factors in the Acceptability of Foreign Clinical Data( ); p y gGood Clinical Practice• E6(R1); Guideline for Good Clinical PracticeClinical TrialsClinical Trials• E7; Studies in Support of Special Populations: Geriatrics• E8; General Considerations for Clinical Trials• E9; Statistical Principles for Clinical Trials• E9; Statistical Principles for Clinical Trials• E10; Choice of Control Group and Related Issues in Clinical Trials• E11; Clinical Investigation of Medicinal Products in the Pediatric PopulationCli i l E l tiClinical Evaluation• E12A; Principles for Clinical Evaluation of New Antihypertensive DrugsPharmacogenomics

E15 D fi iti f G i Bi k Ph i• E15; Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories 16

Feasibility and Protocol DesignFeasibility and Protocol DesignFeasibility and Protocol DesignFeasibility and Protocol Design

• Protocol should be designed appropriately• Protocol should be designed appropriately according to the principles described in this presentation and in helpful ICH-guidelines.presentation and in helpful ICH guidelines.

• If there is any difficulty in designing protocol as above, choice of the second best and feasible way , ywould be acceptable.

• When protocol was designed without enough p g gconsideration on the principle, it is difficult to obtain scientific information on safety and efficacy of the

d t i d f lproduct required for approval.• PMDA strongly recommend to make the best use of

PMDA ConsultationPMDA Consultation.17

Examples of Clinical Review by PMDAExamples of Clinical Review by PMDA“JACE®” approved on October 29th, 2007

● JACE is autologous cultured epidermis prepared by Green’s technique.

Keratinocytes isolated from patient’s skin are cultured together with

3T3-J2 mouse fibroblast feeders to form a multilayer keratinocyte sheet.

JACE on a carrier The package of JACE 18

Summary of Clinical Study of JACESummary of Clinical Study of JACE• Subjects : Serious Burn with large burn surface area （Burn

Index 30-90）St d D i O l b l i l• Study Design : Open-label, single group

• Sample Size : 2 subjects• Endpoint for Efficacy : % Formation of epidermis 4 weeks• Endpoint for Efficacy : % Formation of epidermis 4 weeks

after application of JACE

• Efficacyhighly effective (100%) ; 1 subjectg y ( ) jeffective (50%) ; 1 subject

• SafetyS i d t hi hl l t d t th d t–Serious adverse events highly-related to the product wasnot observed

–A subject died 62days after application of JACEj y pp–Another subject did not have medical examination after

discharged from hospital 19

Evaluation of JACEEvaluation of JACE• Target Disease; Serious burn with large burn surface area

Highly lethal without established therapy Clinical evaluation; Formation of epidermis• Clinical evaluation; Formation of epidermisDirect and objective

• Supportive informationSupportive informationLarge clinical experience of similar products by Green’s technique with few report of serious adverse events

• Approve JACE to provide a new treatment for serious burnwith large burn surface area.

• Evaluated efficacy and safety information is quite limited.Restricted use in qualified facilities and by qualified doctors. Post-marketing information including additional clinical trial data must be disclosed appropriately. 20

Exploratory Clinical Trial and Exploratory Clinical Trial and C f CC f CConfirmatory Clinical TrialConfirmatory Clinical Trial

• Exploratory clinical trial• Exploratory clinical trial– Explore use for the targeted indication

E ti t d th d f f– Estimate dosage or method of use for subsequent studiesProvide basis for confirmatory study design– Provide basis for confirmatory study design, endpoints, methodologies

• Confirmatory clinical trial• Confirmatory clinical trial– Demonstrate/confirm efficacy

Establish safety profile– Establish safety profile– Provide an adequate basis for assessing the

benefit/risk relationship to support licensingbenefit/risk relationship to support licensing21

Approval is not Final GOALApproval is not Final GOALApproval is not Final GOALApproval is not Final GOAL

Ad d th d t ft till i• Advanced-therapy products are often still in development stage when approved.

• Collection, assessment and disclosure of Post-Marketing information is extremelyPost-Marketing information is extremely important for advanced therapy products.

• Quality control of the products including manufacturing process should be revisedmanufacturing process should be revised according to additional information including obtained in clinical useobtained in clinical use.

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ConclusionsConclusionsConclusionsConclusions

• Adequate and well-designed trials is essential for evaluation of new products.p

• Generally, controlled study data is required for all new drug or device application.application.

• Please consult PMDA at appropriate stage pp p gof development including before you startclinical trialsclinical trials.

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PMDA ConsultationPMDA Consultation• Approx. 14 types of Consultation

– General; Regulatory Framework, Review Process,General; Regulatory Framework, Review Process, Application Dossier Format, etc.

– Development Strategy– Quality– Safety– Clinical Trial; Protocol for each Phase, Critical issues

regarding Clinical Data, GCP, etc.Pre NDA– Pre-NDA

– PMS• Cost; ¥20 000 ~ ¥6 011 500Cost; ¥20,000 ¥6,011,500• 2 hours Meeting• Simple consultation for Venture Business is availableSimple consultation for Venture Business is available

(20min, ¥20,000).24

Tha k f r r att tiThank you for your attention.ご静聴ありがとうございましたご静聴ありがとうございました

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