Combination Products and Sponsor-Investigator IDE Studies

1
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

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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

3
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
  products.

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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

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Where is OCP?
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Definition of a Drug

• The term "drug" means
• (A) articles recognized in the US Pharmacopoeia,
  Homeopathic Pharmacopoeia, or National
  Formulary
• (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.

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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.

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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

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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
  combinations
• They can be
• Physically or chemically combined
• Co-packaged in a kit
• Separate, cross-labeled products

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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

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You have a combination product
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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)

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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//www.fda.gov/OHRMS/DOCKETS/98fr
  /05-16527.htm

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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

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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
  product.
• 21 CFR 3.2(m)

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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?

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PMOA - CDER or CDRH?
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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?)

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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//www.fda.gov/oc/combination/howtowrite.html

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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

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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

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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

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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

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Definitions

• 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
  distribution
• Investigational Use
• Clinical evaluation of an already legally
  marketed device for a new intended use

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Studies Subject to the Regulation

• To support marketing application PMA, HDE or
  510(k)
• 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)

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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)

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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.

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Practice of Medicine

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

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Basic Physiological Research

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

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If NOT Exempt from Device Regulation, Then

• Need to assess whether proposed study of device
  is considered SIGNIFICANT RISK (SR), or
  NONSIGNIFICANT RISK (NSR)
• IRBs can and do make this assessment most of the
  time
• FDA can assist IRBs and/or investigators by
  making risk determinations this determination is
  final
• See IRB Information Sheet on SR/NSR
  http//www.fda.gov/oc/ohrt/irbs/devices.htmlrisk

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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

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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

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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

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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
  begin
• Abbreviated IDE requirements (labeling, IRB,
  consent, monitoring, reporting, prohibition on
  promotion)
• No IDE submission to FDA needed

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Non-significant Risk Study Examples

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

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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
  final

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• 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

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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

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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
  information
• If not intended to support a marketing
  application, may not need to be as statistically
  robust
• Sponsor-Investigators are responsible for ALL
  requirements of Sponsors and Investigators

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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

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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//www.fda.gov/ora/compliance_re
f/bimo/clinguid.html
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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

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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

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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

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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
  subjects
• 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

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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

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Investigator responsibilities (continued)

• Permit FDA to inspect/copy any records related to
  research
• 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
  investigation

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Supervision of a Clinical Investigation

• In a clinical investigation, the investigator
  commits to conduct and/or supervise the process
  personally.
• 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.

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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
  possible)?

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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
  notification
• 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
  potential
• If investigator unavailable, responsibility for
  subjects should be delegated to a specific
  qualified person readily available to subjects

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Protecting the Rights ,Safety, and Welfare of
Study Subjects (Contd)

• 3. Protocol violations that Present Unreasonable
  Risks
• 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

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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.

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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)

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FY07 Investigator Deficiencies

• Failure to follow investigational plan,
  investigator agreement, or protocol (30)
• Inadequate record of case hx/device exposure
  (17)
• Inadequate subject protection or informed consent
  (14)
• Inadequate device accountability (7)
• Lack of FDA or IRB approval (7)
• Failure to submit progress report (7)

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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
  etc)
• Use CAPA w/management oversight
• Humanize your studies
• Mitigate apparent conflict of interest

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Remember

• 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

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Resources

• 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//www.fda.gov/cdrh/devadvice/

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Thank You

• Stephen P. Rhodes
• Office of Device Evaluation
• Center for Devices and Radiological Health
• Phone [phone]
• FAX [phone]
• stephen.rhodes_at_fda.hhs.gov
• www.fda.gov/oc/combination/