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

University of Miami HSRO October 24, 2008 2

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 products.


OCP – Common Questions

OCP answers four questions about products:

1. Type of product2. Lead reviewing Center3. The review process4. Minimize review times


Where is OCP?

Commissioners Office

Center for BiologicsEvaluation

and Research

Center for Devices and

Radiological Health

Center for DrugEvaluation

and Research

Office of Combination Products


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.


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 bodyand 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

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

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

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


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 product.

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 S&E questions presented by combination product?


PMOA - CDER or CDRH?


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

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


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 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


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


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


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


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)


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 evidence– Maintain records on use and effects

• IDE not req’d; 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 question

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 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


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 begin

• Abbreviated IDE requirements (labeling, IRB, consent, monitoring, reporting, prohibition on promotion)

• No IDE submission to FDA needed


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


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


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 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


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.”

Monitoring Guidance:

http://www.fda.gov/ora/compliance_ref/bimo/clinguid.html




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 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 ParticipationInvestigator should ensure adequate care provided for any adverse eventsInvestigator should inform subject’s primary physician about participation in research if subject has primary physician and agrees to such notificationInvestigator should make every effort to obtain appropriate care, if investigator does not possess necessary skills

2. Reasonable Access to Medical CareInvestigator should be readily available to subjects during conduct of trialAvailability important where subjects receiving intervention with significant toxicity or abuse potentialIf 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 subjectsFailure to follow inclusion’/exclusion criteria specifically intended to exclude subjects for whom study intervention poses unreasonable risksFailure to perform safety assessments intended to detect toxicity/adverse events within protocol-specified time framesInvestigators 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.


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 (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%)


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


• 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

Remember…


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/


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/

combination products and sponsor-investigator ide studies

Documents

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primary intended purposes

primary jurisdiction

growth factorchemotherapy

blood component

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drugthe term drug means

medical device user