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

2. 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

3. University of Miami HSRO October 24, 2008 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.

4. University of Miami HSRO October 24, 2008 4 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

5. University of Miami HSRO October 24, 2008 5 Where is OCP?

6. University of Miami HSRO October 24, 2008 6 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.

7. University of Miami HSRO October 24, 2008 7 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.

8. University of Miami HSRO October 24, 2008 8 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

9. University of Miami HSRO October 24, 2008 9 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

10. University of Miami HSRO October 24, 2008 10 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

11. University of Miami HSRO October 24, 2008 11 You have a combination product

12. University of Miami HSRO October 24, 2008 12 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)

13. University of Miami HSRO October 24, 2008 13 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

14. University of Miami HSRO October 24, 2008 14 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

15. University of Miami HSRO October 24, 2008 15 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)

16. University of Miami HSRO October 24, 2008 16 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?

17. University of Miami HSRO October 24, 2008 17 PMOA - CDER or CDRH?

18. University of Miami HSRO October 24, 2008 18 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?)

19. University of Miami HSRO October 24, 2008 19 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

20. University of Miami HSRO October 24, 2008 20 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

21. University of Miami HSRO October 24, 2008 21 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

22. University of Miami HSRO October 24, 2008 22 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

23. University of Miami HSRO October 24, 2008 23 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

24. University of Miami HSRO October 24, 2008 24 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

25. University of Miami HSRO October 24, 2008 25 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)

26. University of Miami HSRO October 24, 2008 26 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)

27. University of Miami HSRO October 24, 2008 27 “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….”

28. University of Miami HSRO October 24, 2008 28 “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

29. University of Miami HSRO October 24, 2008 29 “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

30. University of Miami HSRO October 24, 2008 30 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

31. University of Miami HSRO October 24, 2008 31 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

32. University of Miami HSRO October 24, 2008 32 Significant Risk (SR) Study Examples

33. University of Miami HSRO October 24, 2008 33 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

34. University of Miami HSRO October 24, 2008 34 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

35. University of Miami HSRO October 24, 2008 35 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

36. University of Miami HSRO October 24, 2008 36 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

37. University of Miami HSRO October 24, 2008 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

38. University of Miami HSRO October 24, 2008 38 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

39. University of Miami HSRO October 24, 2008 39 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

40. University of Miami HSRO October 24, 2008 40 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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42. University of Miami HSRO October 24, 2008 42 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

43. University of Miami HSRO October 24, 2008 43 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

44. University of Miami HSRO October 24, 2008 44 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

45. 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

46. 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

47. 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

48. 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.

49. 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)?

50. 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

51. 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

52. University of Miami HSRO October 24, 2008 52 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.

53. University of Miami HSRO October 24, 2008 53 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%)

54. University of Miami HSRO October 24, 2008 54 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%)

55. University of Miami HSRO October 24, 2008 55 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

56. University of Miami HSRO October 24, 2008 56  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

57. University of Miami HSRO October 24, 2008 57 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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59. University of Miami HSRO October 24, 2008 59 Thank You Stephen P. Rhodes Office of Device Evaluation Center for Devices and Radiological Health Phone: 240-276-4036 FAX: 240-276-4009 stephen.rhodes@fda.hhs.gov www.fda.gov/oc/combination/