Title: Combination Products and Sponsor-Investigator IDE Studies
1Combination 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
2Combination 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
3Office 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.
4OCP Common Questions
- OCP answers four questions about products
-
- 1. Type of product
- 2. Lead reviewing Center
- 3. The review process
- 4. Minimize review times
-
5Where is OCP?
6Definition 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.
7Definition 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.
8Definition 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
9What 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
10Examples 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
11You have a combination product
12Primary 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)
13PMOA, 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
14Mode 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
15Primary 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)
16PMOA 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?
17PMOA - CDER or CDRH?
18Request 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?)
19RFD 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
20The 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
21Section 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
22Purpose 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
23Provisions 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
24Definitions
- 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
25Studies 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)
26Studies 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)
27Practice 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.
28Practice 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
29Basic 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
30If 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
31Significant 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
32Significant 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
33Significant 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
34Non-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
35Non-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
36Study 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
37- 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
38Applicable 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
39Sponsor-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
40SPONSOR 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
41A 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
42Significant 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
43Different 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
44Required 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
45Investigator 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
46Investigator 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
47Investigator 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
48Supervision 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.
49FDA 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)?
50Protecting 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
51Protecting 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
52Enforcement 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.
53FY07 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)
54FY07 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)
55Tips 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
56Remember
- 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
-
57Resources
- 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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59Thank You
- Stephen P. Rhodes
- Office of Device Evaluation
- Center for Devices and Radiological Health
- Phone 240-276-4036
- FAX 240-276-4009
- stephen.rhodes_at_fda.hhs.gov
- www.fda.gov/oc/combination/