Transcript 1. Combination Products and Sponsor-Initiated IDE

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
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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:
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4.
Type of product
Lead reviewing Center
The review process
Minimize review times
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Where is OCP?
Commissioners Office
Office of Combination Products
Center for Biologics
Evaluation
and Research
Center for Devices
and
Radiological Health
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Center for Drug
Evaluation
and Research
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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
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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
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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/0516527.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 S&E
questions presented by combination product?
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PMOA - CDER or CDRH?
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Request for Designation (RFD)
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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
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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 FD&C 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 S&E 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 practitionerpatient 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 req’d; 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.html#risk
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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.”
Monitoring Guidance:
http://www.fda.gov/ora/compliance_ref/bimo/clin
guid.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
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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
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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
investigator’s 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 investigator’s part in the
investigation
Maintain accurate/complete/current records related to
participation in investigation, including all correspondence,
receipt/use/disposition of device, each subject’s 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
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
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.
FDA Assessment of Adequacy of
Supervision of a Clinical Investigation
FDA will focus on four major issues:
1) Were delegated individuals qualified to perform the
tasks?
2) Did study staff receive adequate training on doing
delegated tasks and did they have an adequate
understanding of the study?
3)Was there adequate supervision/involvement in ongoing
conduct of the study?
4) Was there adequate supervision/oversight of any third
parties involved in conduct of a study (to the extent such
supervision/oversight reasonably possible)?
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 subject’s 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
Protecting the Rights ,Safety,
and Welfare of Study Subjects (Cont’d)
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
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 CDRH’s Office of
Compliance, Division of Bioresearch Monitoring.
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FY07 Sponsor Deficiencies
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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: 240-276-4036
FAX: 240-276-4009
[email protected]
www.fda.gov/oc/combination/
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