Clinical Trial in Development and Marketing of Medical Devices

M.D. Director Medial Affairs and Clinical Operations Johnson & Johnson Medical India

Dr. Anish Desai

Introduction
Medical devices, an extremely heterogeneous group of health care products, can use any combination of mechanical, electronic or chemical biochemical action(s) to achieve their purpose Medical Devices are Health-Care products distinguished from Drugs for Regulatory purposes

An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar article, including any component, part, or accessory which is: Recognized in the official National Formulary, or the United States pharmacopeia, or any supplement to them Intended for use in the diagnosis of disease or conditions, or in the cure, mitigation, treatment, or prevention of disease in man or other animals Intended to affect the structure or any function of the body of man or other animals Which does NOT achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is NOT dependent upon being metabolized for the achievement of its intended purposes.

Medical Device Definition

Definition of Device Food Drug and Cosmetic Act 201(h)

The Important Points

Device definition excludes products that: Achieve their primary intended purpose through chemical action within the body Are dependent upon being metabolized for the primary achievement of their primary intended purposes

Devices
Devices are Primarily used by HCPs Devices are subject to frequent incremental innovations Devices can be implanted Devices are manufactured by small companies

Pharmaceutical Development
l va ro pp A nt e D at IN P
P re -c lin ic al

C lin ic al

ea Id

A FD

n nt tio te ra Pa xpi rs) E 7y (1

6 yrs

4.8 yrs

NDA 1.5 yrs

Chemical Synth. Pharmacology Toxicology

Clinical Trials: Phase I Phase II Phase III

Supplemental reporting Phase IV Postmarketing Clinical education

8-10 yrs

Medical Device Development :

Design Controls Waterfall Diagram
User Needs
Desig n Input

R
w Design Proces s Desig n Outpu t

evie

Validation
Clinical evaluation/studies are types of design validation

Verificatio n

Medica l Device

Idea documen ted commitm ent to proceed Will it work, will it Sell ?
Pilot the developme nt , plan for production

PRODUCT DEVELOPMENT PROCESS

Research and Discovery

Clinical Research
Pre clinical safety and efficacy test result ,if applicable

Feasibility

IDE Approval
Pilot/Prototype Manufacturing
Supporting Data

Validation, commercial ization regulatory approval

Full Scale productio n ,Post launch review

Manufacturing Startup
Regulatory approval

Regulatory submission

Product marketing and support / Service Product evaluations

Device Development
Pr ecl in ic ID al E M ar ke tR el ea se

Cl in ic al

D es ig n

Feasibility study

12 - 24 mos

3-9 mos

6 - 36 mos

PMA - 14 mos

Bench Testing & GLP Studies

Human Studies Feasibili ty/pilot Pivotal

FD A

Post market studies Supplemental reporting Clinical education

Regulatory requirements
In India: DCGI IN US: CDRH In EU: Medicines & Healthcare products Regulatory Agency of the Department of Health

Indian Regulatory Environment Regulatory Bodies Governing & Controlling Clinical Trials
Drugs Controller General of India (DCGI) is chief of Central Drugs Standard Control Organization (CDSCO) Location: capital of India and Ministry of Health, New Delhi Directorate General of Foreign Trade (DGFT) Ethics Committees- Local

Regulatory path depends on the class

Medical devices regulation requirements stringency are risk based:

Risk-Based Classification of Medical Devices

Class I: simple, low risk devices
Devices whose safety & effectiveness are well-established Subject only to General Controls (reasonable assurance of the safety and effectiveness) About 40% of all devices are Class I Examples: elastic bandages, scalpels, surgical instruments, contact lenses and wound dressings

Risk-Based Classification of Medical Devices

Class II: Moderate risk
general & special controls (e.g. performance standards, surveillance) Premarket Notification [510(k)] Substantial equivalence 10-15% require clinical data infusion pumps (non-implanted), vascular clamps, sutures, ECGs, urology catheters

Risk-Based Classification of Medical Devices

Class III: Moderate and high risk general & special controls alone

are insufficient, Premarket Application [PMA] Devices that are life-sustaining, life-supporting, or present unreasonable risk of illness or injury Less than 10% of all devices are Class III Examples: heart valves, spinal implants

Research Applications
21 C.F.R. 812

Investigational Device Exemption (IDE)

Approved by an IRB and, if applicable, FDA Informed consent from all subjects Labeling for investigational use only Monitoring of the study Submission of required reports and records

Permits an unapproved device to be shipped lawfully

Device Clinical Research

Significant risk (SR)

IDE submission

Non-Significant risk (NSR)

Abbreviated requirements

IDE exempt

SR vs. NSR Determination

Decision based on use of device in study IDE submission

Sponsor makes initial assignment IRB makes determination FDA can disagree

Overview of MD Approvals
MEDICAL DEVICE IDE Exempt SE NSR Abbreviated Requirements IDE SR Full Requirements

510(k)

PMA

Significant Risk Definition

Decision based on use of device in study

IDE application

Sponsor makes initial assignment IRB makes determination

FDA can disagree

NSR Determination

No IDE application to FDA Considered to have an IDE Abbreviated requirements only

Abbreviated Requirements 812.2(b) 21 C.F.R.

Labels device Obtains IRB approval

Monitors study Maintains records Makes reports

SR vs. NSR determination Ensures informed consent

Ensure CI maintains records and makes reports Refrains from promotion and other practices

IRB may waive documentation of consent if minimal risk

IDE Exempt Device Research 21 C.F.R. 812.2(c)

In commercial use before May 28, 1976

SE to device in commercial use before May 28, 1976 and used or investigated for labeled indication

In vitro diagnostics (IVDs) Consumer preference testing Solely for veterinary or lab animal use

Access to Unapproved

Early/Expanded Access

Emergency Use Compassionate Use Treatment Use Continued Access

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMark

Emergency Use
Life-threatening or serious condition with no alternative

Before or during an IDE

FDA approval not required Report to the IRB within 5 days

Report to the Sponsor http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/Guid and/or FDA

Compassionate Use
Serious condition with no alternative

Before or during an IDE study

FDA approval required

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMark

Treatment Use
21 C.F.R. 812.36

Life-threatening or serious disease No alternative Controlled clinical trial Sponsor pursuing marketing approval FDA approval required

Continued Access

Public health need or

Preliminary evidence that the device will be effective with no significant safety concerns

Occurs after the completion of the clinical trial FDA approval required

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMark

Regulatory Similarities in Trials

FDA approval required before test articles can be shipped
IDE or IND FDA regulations specify sponsor and clinical investigator responsibilities:
21 CFR 812 and CFR 312

Regulatory Differences in Trials

Devices: Investigator agreement generated by the sponsor per 21 CFR 812.43(c) Drugs: Statement of Investigator - Form 1572

 Contract Research Organizations (CRO)

Device regulations are silent about them Drug regulations define transfer of obligations to CRO

Regulatory Differences in Trials

Adverse Event Differences in Trials

Devices
21 C.F.R. 812.150(a)(1)

Drugs
21 C.F.R.312.32

CI report any unanticipated adverse device effects (UADE)

Sponsors report results of an evaluation of a UADE to FDA and all reviewing IRBs within 10 working days

CI report any adverse effects that may reasonably be regarded as caused by, or probably caused by, the drug. Sponsors notify FDA of any unexpected fatal or lifethreatening event

Medical Device Trials

Subject population usually in the 100s rather than 1000s No phases: Feasibility then pivotal study Blinding is less common Controls vary No placebo rather sham, active, historical CI training often critical (e.g. Human Factors) IRBs play a critical role

Clinical Evaluation
Definition The assessment and analyses of clinical data pertaining to a medical device to verify the clinical safety and performance of the device when used as intended by the manufacturer.

NEED FOR CLINICAL EVIDENCE

DATA GENERATION Literature searching and/or Clinical experience and/or Clinical investigation

OVERVIEW

CLINICAL DATA Literature based data and/or Clinical experience data and/or Clinical investigation data

CLINICAL EVALUTION
CLINICAL EVIDENCE Clinical Evalution Report with relevant clinical data

INCLUSION OF CLINICAL EVIDENCE IN THE TECHNICAL DOCUMENTATION

Contents of SG5/N2R8 Stages of Clinical Evaluation

Stage 1 : Identification of clinical data Stage 2 : Appraisal of data

Generate new data

NO Is Clinical Evidence Sufficient

CLINICAL EVALUATION REPORT

Stage 3 : Analysis of Data

YE S

FDA vs EU Requirements
FDA Requirements EU Requirements

Focus on safety and effectiveness Single agency oversees pre and post-market activities, as well as inspections

Focus on safety and Performance

Notified Bodies-approval Competent Authorities- postmarket vigilance and clinical study approval

FDA vs EU Requirements
FDA Requirements MDR Typically requires a prospective , randomized controlled. Adequately powered clinical trial involving hundreds of patients EU Requirements Vigilance Reporting Majority of CE marking trials are non randomized, single arm, feasibility studies involving less than 100 patients for which the primary objective is to demonstrate safety. The EU approval process does not require an evaluation of effectiveness for medium- tohigh risk medical devices

FDA and EU similarities

Clinical data required to support approval Use of harmonized standards strongly encouraged Fee based approvals intended to support cost of review process Medical device reporting is a condition of approval Substantial changes require prior approval before implementation

Impact of Medical Devices on Clinical Trial Design

Impact of Medical Devices on Clinical Trial Design

Classification of Medical device Clinical studies

Elements of the investigational Plan

Device Description Study Objective Study Design Study Population Treatment Regimen Control Group Effectiveness and Safety Evaluation Definition of Trial Success

Elements of the investigational Plan (contd.)

Study Procedures and Duration Sample size calculation and Data Analysis Plan Risk analysis Informed Consent Forms Investigational Sites and IRB approvals DSMB Monitoring Plan

Process Flow
I. Regulatory submissions: DCGI & EC
submissions

II. Study set up costs: Preparation of documents,

insurance policy, Translations ,setting up EDC etc.

III. Site Budgets: Payment to investigator, free

devices, investigation costs, institution costs, patient costs etc.

IV. Cost for managing the study V. Data management and report writing

Summary
Well controlled Clinical trials have become the standard for evaluation of Medical Devices A successful clinical investigation requires careful planning It is important to remember that some questions regarding safety and effectiveness of medical devices are not readily answered in RCTs especially for implanted devices

Questions ???????????? ??