fulfilling the promise of medicine together preparing for an ide application john mclane, ph.d. coo...

Fulfilling the Promise of Medicine Together

Preparing for an IDE Application

John McLane, Ph.D.COO & Vice President Clinical and Regulatory AffairsClinquest, Inc. [email protected]

Fulfilling the Promise of Medicine Together2

Importance of Medical Devices

11,000,000 Americans have at least one medical device implant

In the U.S. annually:

• >290,000 hip replacement surgeries

• >300,000 knee reconstructive implants

• >151,000 pacemaker implants

• >2,000,000 lens implant surgeries

Hippocrates


IDE Preparation

Do your homework CYA – avoid possible liabilities Budget appropriately for R&D

• Lawsuits cost more Form a solid team of experts –

• Scientific advisory Board


Differences between Drugs and Devices

Pharmaceuticals Molecular entities Limited shelf life Long life cycle Long development

time Potential for

interactions with other drugs

Wrong drug/dose issues

Devices Complex

components Many = durable

equipment Short product cycles

– “tweaking” of design

Device malfunctions User errors


FDA 1976 Medical Device Regulations

Prompted by Dalkon Shield IUD contraceptive device – caused injury, miscarriage, infertility

Established three classes of medical devices Required safety and efficacy of all medical

devices including diagnostic products Required manufacturers to register with FDA

and follow quality control procedures Required pre-market approval for devices


Classification Basis

• Classification depends on intended use and indications for use, and level of risk

• Intended use- What disease, symptom, or condition is the device intended to treat? How will the device be used?

• Indications for use- What kinds of patients should this be used on? Can be based on age, disease state, medical history, allergies, etc.

• Level of risk-Is the device life-saving? Is the device life-sustaining? Is there an unreasonable risk of illness or injury associated with use of the device?


Device Classification

Class I Safety & effectiveness are well-established Subject only to “General Controls” (registration, device

listing, GMPs)

Class II Need “Special Controls” (guidances, postmarket

surveillance, labeling, preclinical testing) Class III General and special controls are insufficient to assure

safety and effectiveness Devices that are life-sustaining, life-supporting, or

present unreasonable risk of illness or injury


General Routes for FDA Approval

For a new device: Pre-market Approval or PMA:

• Manufacturer must show safety and effectiveness of new device

Laboratory and Animal Research Clinical Research

For a “Me Too” device:510(k) Notification:

• Manufacturer must show substantial equivalence to marketed device


Valid scientific evidence

Well-controlled investigations• Human factor testing

• Animal testing

• Component testing

Partially controlled studies or studies without matched controls

Well-documented case histories by qualified experts

Reports of significant human experience with a marketed device


Why an IDE?

Studies on “significant risk” devices require an Investigational Device Exemption (IDE) (21 CFR 812)

Sponsors must usually complete bench, animal testing before proceeding to human IDE trials

An IDE helps assure good study design Data from IDE studies are used to

support PMAs and sometimes 510(k)s


Medical Device Clinical Paths


Studies Exempt from IDE Regulation

Legally marketed device when used in accordance with its labeling

Diagnostic device if it complies with the labeling requirements in §809.10(c) and if the testing:• Noninvasive

• Does not require an invasive sampling procedure

• Does not introduce energy into a subject

• Has “back-up” approved confirmatory diagnostic tests

Consumer preference testing, testing of a modification, or testing of a combination of devices if the device(s) are legally marketed device(s)

Device intended solely for veterinary use or laboratory animal use


Type of IDE Devices: Risk Based

Significant Risk (SR) Devices (21 CFR 812.3M)

• Requires FDA approval

• Presents potential for serious risk

• Use for support or sustain life

• Substantial importance diagnosing, or treating Non-significant Risk Devices (812 and 812.2(b)

• Abbreviated IDE

• Sponsor to provide rationale for NSR

• IRB can act as FDA surrogate

• IRB usually asks FDA for ruling on SR/NSR

FDA Guidance


Test for Safety

Biocompatibilty• ISO 10993

• Rabbit epidural study

Implant – Tissue interface Mechanical Performance

• ASTM testing

Biomechanical Performance• Cadaveric, animal??

• Expulsion, subsidence, catastrophic failure


Example: Implant Assessments

Static / Fatigue – endurance – 10M Wear debris – amount & characterization Long term creep Quantity of Motion Quality of Motion How much work does the implant have to do – will

affect lifespan of implant Interface with tissue


Pre IDE FDA Meetings

Informal Guidance Meeting

• Meeting with ODE to discuss IDE development plans Significant and non-significant categories ODE team

Formal Guidance Meetings

• Determination Meeting Broad outline of clinical design

• Agreement Meeting Request and summary information

On-going preclinical programs Protocol design Risk assessments


FDA Meeting Preparation

Prepare a target product profile• Key efficacy and safety objectives

• Potential pt and user group description

Plan on submission questions• Keep questions focused

• Don’t ask question of what you can easily find in the regulations

Can ask question to clarify approach to a regulation

Plan on providing support documentation• Evidence-based information most persuasive

• Be prepared


Non-significant Risk Device IDE Applications Abbreviated IDE application submitted to IRB:

• Device Labeling : CAUTION - Investigational Device. Limited by Federal (or

United States) law to investigational use

• Informed Consent –Investigators must obtain and document informed consent from each subject

• Monitoring - All investigations must be properly monitored to protect the human subjects and assure compliance

• Records and Reports - Sponsors and Investigators are required to maintain specific records and make certain reports as required by the IDE regulation

• Prohibitions –Commercialization, promotion, test marketing, misrepresentation of an investigational device, and prolongation of the study are prohibited (§812.7)


Complete IDE Application Name and address of sponsor Complete report of prior investigations of device Summary and completed investigational plan Description of methods, facilities, and controls used

for manufacture, processing, packaging, storage , installation of device (Quality System Regulations)

Example of investigator agreements Names and addresses of investigators List of names, address, and chairperson IRB Institution(s) participating Investigational labeling for device Reimbursement charges for device Patient informational materials and forms provided

to patients to obtain consent Clinical protocol


Reports of Prior Investigations Provide all data that is relevant (whether

adverse of supportive)• Including laboratory/animal data

Provide data on previous versions (models) of the device.

Explain what conclusions where reached from the clinical experience with previous device designs.

For each clinical investigation: Rationale for subject selection Statistical justification for N Description of the study methods and endpoints Efficacy and safety results (summary table AEs)


Good Manufacturing Processes and Systems Material controls Design controls Production and process Equipment and facility controls Records, documents, and change

controls Risk assessments

• Hazard Identification Risk management programs


Quality System Regulations


Investigational Plan

Purpose Protocol Risk analysis Description of device

• Label to be on device Monitoring Procedures CRF Patient information materials Informed consent template


Device Description

Description of each important component, property and principle of operation of the investigational device

Identify Human Factor tests If applicable, state any anticipated change(s)

in the investigational device during the course of the study

Identify potential device-related risks • Differentiate from clinical risks

Investigational use instructions


Feasibility IDE clinical Study

Simple trial design to provide • Support for a future pivotal study• Answer basic research questions

Often not primary support for a marketing application

May be required by FDA prior to pivotal study to assess basic safety and potential for effectiveness

Endpoints and sample size generally not statistically driven• N=10-50 subjects


Pivotal study

Generally intended as the primary clinical support for a marketing application

Endpoints and sample size statistically driven Assess both safety and effectiveness

• Reasonable study conceptually? • Adequate preclinical validation of device?• Appropriate mitigation of potential risks?• Appropriate enrollment criteria?• Patients adequately informed?• Sample size appropriate?


Key Components of Clinical Protocol General study design Proposed subject population Anticipated number of subjects Inclusion criteria Exclusion criteria Screening procedures Study treatment (allocation, breaking the

blind) Follow-up assessment methods including the

schedule of testing


Biometrics Sections of Protocols

Identify primary effectiveness endpoint• Avoid composite or ambiguously defined terms

• Describe how measured

How will safety be assessed and monitored (safety endpoint)• Not just well tolerated

• Objective performance criteria

Sample size determination Data and Safety Monitoring Committee


Objective Performance Criteria Type of comparison in medical device trials

• Requires statistical pooling of prior investigations

• Underlying disease and pt population well described and stable

Fixed Target(s) Positive Tx effect expected Objective and Meaningful Standard Provides Comparison in Evaluating Safety and Effectiveness Usually a Rate Surrogate for Control Group Benchmark for Minimally Acceptable Values Not a Control Group


Statistical Analysis Plan

Justification for sample size calculations Type-1 error and multiplicity Missing data handling Assessment of critical endpoint covariates Interim analyses and early stopping rules Data handling Contingency analysis Provide enough detail to avoid ambiguity


Anticipated and Unanticipated Safety Events Use prior studies to clearly identify potential

and anticipated risks• Similar devices

• Engineering, animal, and human factor testing

Define how study design mitigates risk• Clinical training necessary?

Define how different safety events to be reported• Patients

• Patient’s Investigator and all investigators

• IRB

• FDA


Shared regulations with drugs

Part 50 – Protection of Human Subjects Part 56 – Institutional Review Boards Part 54 – Financial Disclosure by

Clinical Investigators Part 58 – Good Laboratory Practices for

Nonclinical Laboratory Studies Part 11 – Electronic Records; Electronic

Signatures


Adequate Monitoring

Trained monitors Qualified investigator sites Following the written procedures in the protocol

• Collection of essential documents

Obtaining a signed investigator agreement from each participating investigator (can use FDA form 1572)

Provide investigators with the information they need to conduct the investigation properly

• Documented training of all study personnel

• Delegation log Ensuring subjects sign informed consent form Device quality check and accountability


IDE Supplements

Required if changes significantly affect:• Validity of data

• Scientific soundness of study

• Rights, safety, or welfare of subjects

Examples:

• Different type of study control

• Alternative primary endpoint

• Reduction in study population size

• Change in method of evaluation

• Early termination of the study


5-Day FDA Notice to Protocols

• Additional measurements• More targeted subject criteria• More frequent follow-ups• Change in secondary endpoints


Protocol Deviations

CFR 812.150(a)(4) require prior approval from the sponsor of all planned deviations, including administrative and minor deviations.

Planned deviations requested of a sponsor must be submitted for IRB review as a “Change in Research” prior to instituting any IDE research planned deviations

For device research, the PI must keep on file a copy of the written approval document from the sponsor and IRB when a deviation is granted.


Conclusion

Consider the IDE as a comprehensive process• Get Experts (Reliance Medical Association)

Know your target product profile Be prepared

• Have the evidence Preclinical QSR

Work with the FDA and IRBs Be realistic on potential risks

fulfilling the promise of medicine together preparing for an ide application john mclane, ph.d. coo...

Documents

device slide

promise of medicine

device listing

device lifesustaining

medical device implant

medical device regulations

device classification

injury slide