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Combination Products and Sponsor-Investigator IDE Studies


Combination Products and Sponsor-Investigator IDE Studies Stephen P. Rhodes Product Jurisdiction Officer Director, IDE and HDE Programs Center for Devices and ... – PowerPoint PPT presentation

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Title: Combination Products and Sponsor-Investigator IDE Studies

Combination Products and Sponsor-Investigator
IDE Studies
  • Stephen P. Rhodes
  • Product Jurisdiction Officer
  • Director, IDE and HDE Programs
  • Center for Devices and Radiological Health
  • University of Miami
  • Human Subjects Research Office (HSRO) Conference
  • October 24, 2008

Combination Products - Background
  • Combination products statutorily recognized in
    Safe Medical Devices Act of 1990
  • Required assignment to lead center based on
    primary mode of action
  • Implemented by Chief Mediator and Ombudsman

Office of Combination Products (OCP)
  • Created by Medical Device User Fee and
    Modernization Act (MDUFMA)
  • Office established on December 24, 2002
  • OCP given broad oversight responsibilities
    covering the regulatory life cycle of combination

OCP Common Questions
  • OCP answers four questions about products
  • 1. Type of product
  • 2. Lead reviewing Center
  • 3. The review process
  • 4. Minimize review times

Where is OCP?
Definition of a Drug
  • The term "drug" means
  • (A) articles recognized in the US Pharmacopoeia,
    Homeopathic Pharmacopoeia, or National
  • (B) articles intended for use in the diagnosis,
    cure, mitigation, treatment, or prevention of
    disease in man or other animals
  • (C) articles (other than food) intended to affect
    the structure or any function of the body of man
    or other animals.

Definition of a Device
  • Instrument, apparatus, implement, machine,
    contrivance, implant, in vitro reagent, or other
    similar or related article, including any
    component, part, or accessory, which is -
  • (3) intended to affect the structure or any
    function of the body
  • and which does not achieve its primary intended
    purposes through chemical action within or on the
    body and which is not dependent upon being
    metabolized for the achievement of its primary
    intended purposes.

Definition of a Biological Product
  • Virus
  • Therapeutic Serum
  • Toxin or Antitoxin
  • Vaccine
  • Blood, Blood Component or Derivative
  • Allergenic Product
  • applicable to the prevention, treatment, or cure
    of diseases or injuries of man

What is a Combination Product?
  • Combinations of different types of products
  • Drug-device
  • Device-biologic
  • Drug-biologic
  • Drug-device-biologic
  • NOT drug-drug, device-device or biologic-biologic
  • They can be
  • Physically or chemically combined
  • Co-packaged in a kit
  • Separate, cross-labeled products

Examples of Combination Products
  • Drug-eluting coronary stent
  • Controlled-release drug delivery implant
  • Spinal fusion cage with growth factor
  • Chemotherapy drug and monoclonal antibody
  • Wound scaffold seeded with autologous cells
  • Interferon and ribavirin for hepatitis C
  • Assay/drug pairing

You have a combination product
Primary Mode of Action (PMOA)
  • Primary mode of action is the statutory criterion
    FDA must use to determine the agency component
    with primary jurisdiction for the review and
    regulation of a combination product.
  • 21 U.S.C. 503(g)

PMOA, continued
  • PMOA not defined in statute, now defined in
    regulations 21 CFR 3.2(k) and (m).
  • Final Rule issued on August 25, 2005 and can be
    accessed at http//

Mode of Action
  • Mode of Action the means by which a product
    achieves an intended therapeutic effect or
    action. 21 CFR 3.2(k)
  • Three types of modes of action biological
    product, device, drug
  • Combination products typically have more than one
    identifiable mode of action

Primary Mode of Action
  • Primary mode of action is the single mode of
    action of a combination product that provides the
    most important therapeutic action of the
    combination product. The most important
    therapeutic action is the mode of action expected
    to make the greatest contribution to the overall
    intended therapeutic effects of the combination
  • 21 CFR 3.2(m)

PMOA algorithm
  • If unable to determine most important therapeutic
    action with reasonable certainty, consider
  • Consistency is there an agency component that
    regulates other combination products presenting
    similar questions of S E with regard to
    combination product as a whole?
  • Safety and Effectiveness which agency component
    has the most expertise related to most
    significant SE questions presented by
    combination product?

Request for Designation (RFD)
  • Voluntary Formal Process
  • 21 CFR Part 3
  • Classification (what am I?)
  • Assignment (where do I go?)
  • Clarification of Regulatory Pathway (what do I
    do when I get there?)

RFD Content
  • Sponsor information
  • Product description
  • Proposed use and indications
  • Description of primary mode of action
  • Recommendation on product classification and
    Center with primary jurisdiction
  • 21 CFR 3.7 (c)
  • Also, see Guidance Document on How to Write a
    Request for Designation at
  • http//

The Future
  • Numbers and Types of Combination Products Will
    Continue to Grow
  • Consultation Process More Systemized
  • Clearer, More Predictable Process for Assignment,
    Premarket Review, and Postmarket Regulation

Section 520(g) of the FDC Act
  • Purpose of an IDE
  • To encourage discovery and development of
    useful medical devices for human use, to the
    extent consistent with the protection of the
    public health and safety and with ethical
    standards, while maintaining optimum freedom for
    scientific investigators in their pursuit of that

Purpose of an IDE
  • An approved Investigational Device Exemption
    (IDE) allows
  • an investigational device to be used in a
    clinical study in order to collect SE data
    required to support a Premarket Approval (PMA)
    application, a Humanitarian Device Exemption
    (HDE), or a Premarket Notification 510(k)
    submission to FDA.
  • a device to be shipped lawfully for the purpose
    of conducting investigations

Provisions of the IDE Regulation
  • All clinical investigations subject to the
    regulation must be approved before they can begin
  • Assigns responsibilities to all participants in
    clinical investigation
  • All subjects in the investigation must give
    informed consent

  • Investigational Device
  • Is still in the developmental stage
  • Object of a clinical investigation is to
    determine safety and efficacy
  • Is not considered to be in commercial
  • Investigational Use
  • Clinical evaluation of an already legally
    marketed device for a new intended use

Studies Subject to the Regulation
  • To support marketing application PMA, HDE or
  • Collection of safety and effectiveness
    information (e.g., for a new intended use of a
    legally marketed device)
  • Sponsor-investigator studies of unapproved
    devices or new intended use of approved device
    (even if no marketing application planned)

Studies Exempt from need for IDE
  • Preamendments (pre-1976) devices
  • 510(k)-cleared or PMA-approved devices, if used
    in accordance with approved labeling
  • In vitro diagnostic devices (most of the time)
  • Consumer preference testing
  • Combinations of legally marketed devices
  • Custom devices (NARROWLY defined)

Practice of Medicine
  • Nothing in this Act shall be construed to limit
    or interfere with the authority of a health care
    practitioner to prescribe or administer any
    legally marketed device to a patient for any
    condition or disease within a legitimate health
    care practitioner-patient relationship.

Practice of Medicine
  • Physician should
  • Be well informed about the product
  • Use firm scientific rationale and sound medical
  • Maintain records on use and effects
  • IDE not reqd Institution may require IRB
    review/approval and IC
  • Other prohibitions still apply

Basic Physiological Research
  • Investigating a physiological principle
  • No intent to develop the device for marketing
  • Only using the device to address the research
  • ? No IDE needed IRB approval and
  • IC should be obtained

If NOT Exempt from Device Regulation, Then
  • Need to assess whether proposed study of device
    is considered SIGNIFICANT RISK (SR), or
  • IRBs can and do make this assessment most of the
  • FDA can assist IRBs and/or investigators by
    making risk determinations this determination is
  • See IRB Information Sheet on SR/NSR

Significant Risk (SR) Study
  • Presents a potential serious risk to the
    health, safety, and welfare of a subject and is
  • an implant or
  • used in supporting or sustaining human life or
  • of substantial importance in diagnosing, curing,
    mitigating, or treating disease or preventing
    impairment of human health

Significant Risk (SR) Study Examples
  • Evaluation of a marketed biliary stent for use in
    the peripheral vasculature
  • Evaluation of unapproved radiofrequency ablation
    device for treatment of primary hepatic neoplasia

Significant Risk IDEs
  • Sponsor submits IDE application to FDA
  • FDA approves, conditionally approves or
    disapproves IDE within 30 calender days
  • Sponsor obtains IRB approval
  • After both FDA and IRB approve the investigation,
    study can begin

Non-significant Risk IDEs
  • Sponsor presents protocol to IRB and a statement
    why investigation does not pose significant risk
  • If IRB approves the investigation as NSR, it can
  • Abbreviated IDE requirements (labeling, IRB,
    consent, monitoring, reporting, prohibition on
  • No IDE submission to FDA needed

Non-significant Risk Study Examples
  • Most functional MRI studies
  • Study of non-invasive blood pressure measuring
  • Electroencephalography studies
  • Studies of wound dressings
  • Contact lens studies
  • Studies of conventional laparoscopes

Study Determination Inquiries
  • If an IRB is uncertain whether a study is exempt,
    significant risk or nonsignficant risk, FDA will
    make a determination
  • E-mail me a draft or outline of the study and a
    clear description of the devices
  • FDAs will issue a letter the determination is

  • What do ALL clinical studies of unapproved or
    investigational medical devices conducted in U.S.
    have in common?
  • Same basic applicable regulations
  • REGARDLESS of whether sponsor is a manufacturer
    or clinical investigator

Applicable Regulations
  • 21 CFR Part 50 Informed Consent,
  • Human Subject Protections
  • 21 CFR Part 54 Financial Disclosure
  • 21 CFR Part 56 Institutional Review Boards
  • 21 CFR Part 812 Investigational Device
  • Exemptions

Sponsor-Investigator Studies
  • May be done to answer a scientific question not
    of interest to manufacturer
  • Right of Reference from company may be needed
    for supporting preclinical data and manufacturing
  • If not intended to support a marketing
    application, may not need to be as statistically
  • Sponsor-Investigators are responsible for ALL
    requirements of Sponsors and Investigators

SPONSOR Responsibilities
  • Ultimately LEGALLY responsible for
  • IRB approval
  • Conduct and monitoring of study
  • Reporting to IRB and FDA (initial, continuing,
    final, unexpected AEs, study suspension, device
    recall, emergency use, IRB withdrawal, etc.)
  • Device disposition
  • Investigator agreements
  • Informing other investigators as needed
  • Adequate record-keeping
  • Labeling
  • Prohibition of promotion/marketing

A sponsor is responsible for assuring, through
personal contact between the monitor and each
investigator, that the investigator clearly
understands and accepts the obligations incurred
in undertaking a clinical investigation. Monitori
ng Guidancehttp//
Significant Risk IDEs
  • Sponsor submits application to FDA
  • FDA approves, conditionally approves or
    disapproves IDE within 30 calender days
  • Sponsor obtains IRB approval
  • After both FDA and IRB approve the investigation,
    study can begin

Different Types of IDEs
  • Feasibility Study, Single Center
  • Pivotal Study, Multi-Center
  • Randomized vs. Non-Randomized
  • Double Blind vs. Single Blind vs. Unblinded
  • Concurrent Control vs. Historical Control
  • Sponsor-Investigator Open-Label, Single Center
  • Treatment Use, Multi-Center
  • Continued Access, Multi-Center
  • Emergency/Compassionate Use, Single Center

Required Elements of an IDE
  • U.S. Sponsor (manufacturer or investigator)
  • Report of Prior Investigations
  • Investigational Plan
  • Manufacturing Information
  • Investigator and IRB Information
  • Sales Information
  • Labeling
  • Informed Consent

Investigator responsibilities
  • Conduct the research in compliance with the
    signed agreement with the sponsor, the
    investigational plan, applicable regulations, and
    any conditions imposed by reviewing IRB or FDA
  • Supervise all testing of the device on human
  • Ensure requirements for obtaining IC are met
  • Use investigational device only with subjects
    under investigators supervision and supply
    investigational device only to persons authorized
    to receive them

Investigator responsibilities (continued)
  • Return any remaining devices to sponsor or
    dispose of them as sponsor directs after the
    completion/termination of the investigation or
    the investigators part in the investigation
  • Maintain accurate/complete/current records
    related to participation in investigation,
    including all correspondence, receipt/use/disposit
    ion of device, each subjects case history and
    exposure to the device, protocol with records
    related to any deviations, and any other records
    required by regulations or specific requirement

Investigator responsibilities (continued)
  • Permit FDA to inspect/copy any records related to
  • Prepare/ submit to sponsor and, when required by
    regulation, reviewing IRB and monitor,
    complete/accurate/timely reports, including
    reports on unanticipated device effects,
    progress, deviation from investigational plan,
    any use of device without informed consent, a
    final report, and any additional information
    requested by FDA or IRB about any aspect of the

Supervision of a Clinical Investigation
  • In a clinical investigation, the investigator
    commits to conduct and/or supervise the process
  • The investigator who delegates tasks related to
    the research is responsible for providing
    adequate supervision to whomever the task is
    delegated and is accountable for regulatory
    violations caused from failure to supervise the
    conduct of the study.

FDA Assessment of Adequacy of Supervision of a
Clinical Investigation
  • FDA will focus on four major issues
  • Were delegated individuals qualified to perform
    the tasks?
  • Did study staff receive adequate training on
    doing delegated tasks and did they have an
    adequate understanding of the study?
  • Was there adequate supervision/involvement in
    ongoing conduct of the study?
  • Was there adequate supervision/oversight of any
    third parties involved in conduct of a study (to
    the extent such supervision/oversight reasonably

Protecting the Rights ,Safety, and Welfare of
Study Subjects
  • 1. Reasonable Medical Care Necessitated by
    Research Participation
  • Investigator should ensure adequate care provided
    for any adverse events
  • Investigator should inform subjects primary
    physician about participation in research if
    subject has primary physician and agrees to such
  • Investigator should make every effort to obtain
    appropriate care, if investigator does not
    possess necessary skills
  • 2. Reasonable Access to Medical Care
  • Investigator should be readily available to
    subjects during conduct of trial
  • Availability important where subjects receiving
    intervention with significant toxicity or abuse
  • If investigator unavailable, responsibility for
    subjects should be delegated to a specific
    qualified person readily available to subjects

Protecting the Rights ,Safety, and Welfare of
Study Subjects (Contd)
  • 3. Protocol violations that Present Unreasonable
  • Situation where failure to follow protocol may be
    considered a failure to protect rights, safety,
    and welfare of subjects
  • Failure to follow inclusion/exclusion criteria
    specifically intended to exclude subjects for
    whom study intervention poses unreasonable risks
  • Failure to perform safety assessments intended to
    detect toxicity/adverse events within
    protocol-specified time frames
  • Investigators should seek to minimize risks by
    adhering close to study protocol

Enforcement of Good Clinical Practices (GCPs)
  • Inspection Program
  • Sponsors, IRBs, and investigators are required to
    permit authorized FDA employees reasonable access
    at reasonable times to inspect and copy all
    records relating to an investigation.
  • To assure compliance with the IDE and related
    regulations, FDA inspects sponsors, clinical
    investigators, and institutional review boards.
  • The inspection program is referred to as
    bioresearch monitoring (BIMO) and is overseen the
    CDRHs Office of Compliance, Division of
    Bioresearch Monitoring.

FY07 Sponsor Deficiencies
  • Inadequate monitoring (39)
  • Failure to submit Progress Report (36)
  • Failure to secure investigator compliance (27)
  • Inadequate UADE analysis and reporting (27)
  • Failure to inform investigators (21)
  • Inadequate device accountability (15)
  • Failure to obtain signed Inv Agreement (15)
  • Failure to obtain FDA/IRB approval (12)
  • Unqualified monitors (12)

FY07 Investigator Deficiencies
  • Failure to follow investigational plan,
    investigator agreement, or protocol (30)
  • Inadequate record of case hx/device exposure
  • Inadequate subject protection or informed consent
  • Inadequate device accountability (7)
  • Lack of FDA or IRB approval (7)
  • Failure to submit progress report (7)

Tips for a Successful Study
  • Adopt a quality system approach to clinical
    studies (GCPs)
  • The data lifecycle
  • Cradle to grave
  • Risk management
  • FMEA
  • Risk reduction
  • Adopt written SOPs and follow them
  • Qualify and train your suppliers (CI sites, CROs
  • Use CAPA w/management oversight
  • Humanize your studies
  • Mitigate apparent conflict of interest


  • Correct issues before they jeopardize submissions
    and/or subject safety
  • Minimize recurring issues
  • Provide an accountable organizational culture
  • Focus on good ethics and research practices
  • Protect your reputation

  • Information Sheet Guidance For IRBs, Clinical
    Investigators, and Sponsors
  • Frequently Asked Questions About Medical Devices
  • Significant Risk and Nonsignificant Risk Medical
    Device Studies
  • Device Advice http//

(No Transcript)
Thank You
  • Stephen P. Rhodes
  • Office of Device Evaluation
  • Center for Devices and Radiological Health
  • Phone 240-276-4036
  • FAX 240-276-4009
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