Preclinical Trials, Translation to Humans, and ... · 1 Preclinical Trials, Translation to Humans, and Commercialization Mark S Humayun, MD, PhD Professor of Ophthalmology, Biomedical

1

Preclinical Trials, Translation to Humans, and Commercialization

Mark S Humayun, MD, PhDProfessor of Ophthalmology, Biomedical Engineering,

Cell and Neurobiology

Doheny Eye InstituteUniversity of Southern California

DOE Artificial Retina Project

2

Neural Prostheses: A National Effort

3

Vision: Neural Prostheses

2

4

Strategic Plan

5

Model 1 IRP (16 electrodes)


6

Moving visual stimulus

Blind patient performing visual task with Retinal Implant


On the webcast a movie plays here

3

7

Inventions and Patents in Related AreasOver 120 inventions to date82 patents issued or pendingMost in medical products and technologies

Product DevelopmentLicenses to 15 companies75 commercialized products

A History of Successful Technology Transfer

8

PreclinicalResearch

ClinicalStudies

PMAReview

Industry time FDA time

IDE submission

Postmarket

•Design History File•Good Mfg. Practices•Risk Analysis

Animal Testing

Device development

Institutional Review Boards

Feasibility

Pivotal

PMA submission Approval

Rev

isio

ns Surveillance

Marketing

Device Development Path for FDA


9

Outline

Background Smart Prosthetics (wearable/implantable)

Device (definition/classification)

Benchtop to Bedside/Concept to MarketConcept stage Preclinical developmentClinical developmentCommercialization


4

10

NY Times Headline – Oct 19, 1937

DRUG PREPARATION BLAMED IN DEATHS; Nine Fatalities in Tulsa Laid to Elixir of Sulfanilamide--Maker Recalls Shipments


11

Key Legislation

1938: Federal Food, Drug & Cosmetic ActIn response to Sulfanilamide scandalRequired that a drug be safe before going on marketDefined a device


12

NY Times Headline – Aug 30, 1962

THALIDOMIDE TOLL PLACED AT 10,000; West German Survey Finds 5,000 Infants Still Alive


5

13

Key Legislation

1962: Kefauver-Harris Drug AmendmentIn response to Thalidomide tragedyRequired proof of safety & efficacy for a drug to be marketed

New York Times Oct 26, 1962SHAKE-UP ASKED FOR DRUG AGENCY; A Stronger

Science Role Is Urged by Citizen Panel


14

Lack of Device Regulation

Quack Products

Orgone Accumulator: To collect an ethereal substance in the atmosphere vital to health and longevity

.


15

Key Device Legislation

1976: Medical Device AmendmentsIn response to thousands of women being injured by Dalkon Shield IUDNow devices must demonstrate safety & efficacyEstablished device classification system

1990: Safe Medical Devices Act (SMDA)Expanded & strengthened law

1997: Food & Drug Administration Modernization Act (FDAMA)

Make FDA more efficientMake it easier for patients to get early access to medical products

2002: Medical Device User Fee & Modernization Act (MDUFMA)

User fees for applicationsAllows 3rd party inspections


6

16

Types of Regulatory Documents

LawsPassed by Congress & President“Statutory law”Food, Drug,& Cosmetic Act

RegulationsEstablished by agencies (e.g. FDA)“Administrative law”Code of Federal Regulations (CFR) Part 800-1299

Guidance DocumentsWritten by agencies (e.g. FDA)Guidelines – no legal requirement to follow them


17

Definition of Device

An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:

Recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them, Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or Intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of 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 any of its primary intended purposes


21

Device Classification

Class I - General Controls Most common, low riskMost exempt from 510(k) notificationSome also exempt from most GMPs

Class II - Special Controls More complex, higher riskGeneral controls + additional special controlsMost require 510(k)

Class III - Premarket Approval Most complex, highest risk


7

22

Class II Devices

Additional rules to ensure that a product is and stays safe, eg:

Special labelingPost-market surveillancePerformance standards

Most require 510(k) clearance 43% of medical devices


23

Class III Devices

Sustain or support life, are implanted, or present potential unreasonable risk of illness or injury. Most require PMA approval with clinical data10% of medical devices


24

Class III Device examples

PacemakersArtificial heartsRetinal prosthesisSilicone gel-filled breast implants


8

25

Concept Stage

1. Make sure your product meets definition of a “device”

2. Determine the classification and the appropriate marketing application

Exempt: None510KPMA


26

Which Marketing Application?

1. Check FDA Classification website2. Consult with FDA if uncertain

III

II

I

PMA510(k)ExemptClass


27

Preclinical Testing/Biocompatibility

In Vitro testing: cytotoxicitygenotoxicity

In Vivo testing: toxicitysensitizationirritationimplantationhemocompatibility


International Organization for StandardizationISO 10993-1/EN 30993-1 standard

9

33

Pre-market Approval

Most Class III devicesDesign History File- an analysis of product development

Safety & EffectivenessDevice does no harmDevice does what it is intended to doBenefits outweigh the risks

Typically need Clinical Data to support the application…


34

Clinical Trial Risk Assessment

Significant riskImplant, life-sustaining or life-supporting, presents a potential serious risk to patientIRB approvalFDA IDE approval

Non-significant riskIRB approval only


35

Investigational Device Exemption (IDE)

21 CFR 812Allows a device to be shipped lawfully without being in full compliance with FD&C Act

Must comply with design control (21 CFR 820)

Purpose: To collect clinical data


10

36

Contents of IDE Application

Describe clinical study designDevice DescriptionReport of prior investigations

Prior researchAnimal studiesBench testing & Qualification Testing

Hazard AnalysisManufacturing & Quality ControlLabeling


38

IDE Typical Study Phases

Phase I: Feasibility, Pilot StudyConfirm design & operating specificationsEstablish parameters for pivotal study (e.g. sample size, success criteria)Must have valid scientific objective

Phase II: Pivotal trialDemonstrate safety & effectiveness of deviceConfirm Indication for UseTypically multi-center, randomized controlled trial

-------------------------------------------------Phase III: Post-Market Surveillance


39

Clinical Trials: Key Elements

Good Clinical Practices (GCP)Financial Disclosure of InvestigatorsProtection of Human SubjectsWell-controlledProduce scientifically valid evidence


11

40

IRB/Ethics Committee

Mission is to protect human subjectsApproval necessary prior to start of any clinical study

Review Study Protocol, Informed Consent Form and other study materialsMake sure that subjects will not be improperly influenced or induced to participate in studyReview compensation of study procedures, treatment of adverse events, and compensation to subjects

Also performs ongoing review of studyAnnual progress reportsReview of serious and unanticipated adverse eventsReview changes to study materials (e.g. protocol, consent)


41

Adverse Event Reporting

Definition of Serious Adverse Event:a) Is life-threatening; orb) Results in permanent impairment of a body function or permanent damage to body structure; orc) Necessitates medical or surgical intervention to preclude permanent impairment of a body function or permanent damage to a body structure.

Permanent means irreversible impairment or damage to a body structure or function, excluding trivial impairment or damage.


42

Adverse Event (AE) Reporting

All Adverse Events reported to IRB/Ethics Committee and regulatory agency (e.g. FDA) in annual progress reportsIn addition:

Unanticipated Adverse Events reported to IRB and FDA within 10 working days. Includes:

AEs not identified in study protocol risk analysisAEs identified in protocol risk analysis, but occurring at a rate higher than anticipated

Serious Adverse Events (Outside US)Reported to Ethics Committee and Regulatory Agency within 10 days


12

43

Data Safety & Monitoring Boards

Certain studies employ a Data Safety & Monitoring Board (DSMB)Board Composition

Independent from participating investigatorsAdequate representation in areas of clinical study conduct, biostatistics, bioethics, therapeutic area

ResponsibilitiesMonitor patient safety through review of aggregate clinical study data and adverse eventsAdjudicate adverse events (e.g. device related or not)Act as an advisory panel on study design, study materials, study conduct, and patient safety issuesMake recommendations for continuation, early termination due to futility or safety concerns, early attainment of study objects, or protocol modifications


44

Reporting of Outcomes

Reports prepared for:Publication/Presentation Regulatory AgenciesIRBs/Ethics Committees

Final Report ContentsDevice descriptionStudy design and methodsDeviations from investigational planResults, including statistical analysis of dataDiscussion and Conclusions

Participating investigators should review the report prior to submissionNote: Many journals require that studies be registered with www.clintrials.gov prior to start of study to be accepted for publication


45

Clinical Trials Outside the US

Increasingly common practiceFacilitates patient recruitmentFacilitates marketing approval of device if have in-country subjectsDistributes regulatory risk

Typically requiresEthics Approval – very similar to IRBMinistry of Health notification or approval (varies from country to country)For non-Tier 1 countries – requires FDA export approval to export the device


13

46

PMA Submission

Modular PMAPre-ClinicalManufacturingClinical

TraditionalExpanded IDEFull description of clinical results

Streamlined PMA, Product Development Protocol, Humanitarian Device Exemption (HDE)

Device intended use for <4000 US pts/yearOnly need to show safety


47

What Happens After Submit a PMA?

Filing decision – within 45 daysReview cycle – technically 180 days

In-depth ReviewPanel Meeting possible

AuditsBioresearch Monitoring (BIMO)

Clinical site & IRBPre-clinical Site

Quality System inspectionTypical Review Time: 300-350 days (2000-2002)


48

Now that I’m approved, let’s go SELL!

Who’s paying??Patients – out of pocket Reimbursement from:

Insurance CompanyMedicare


14

49

Reimbursement

Already existing devices: pathways for reimbursement already establishedNew devices (and some improved devices), need to establish reimbursement. Must have established:

Codes (e.g. CPT, ICD9, etc.)Coverage

PayorsGovernment: Medicare (CMS)Private insurers


50

Getting Device to Market…and staying there

Premarket Notification or Premarket ApprovalReimbursementEstablishment Registration & Medical Device ListingQuality System RegulationLabelingMedical Device Reporting (MDR)Other requirements

Post-market surveillanceMedical device trackingEtc.
