Research Involving the Use of Investigational Devices January 18, 2006

1. Research Involving the Use of Investigational DevicesJanuary 18, 2006 Presented by the TMHRI Offices of Research Compliance and Research Protection

2. Presentation Overview • Regulatory Background • Significant Risk versus Nonsignificant Risk Medical Devices • Investigator Responsibilities • Investigator Reports • Humanitarian Use Devices • Off Label Use of Investigational Devices • Emergency Use of Investigational Devices • Financial Implications of Device Studies

3. Regulatory Background • Medical Device - any health care product that does not achieve its primary intended purposes by chemical action or by being metabolized. Medical devices include, among other things, surgical lasers, wheelchairs, sutures, pacemakers, vascular grafts, intraocular lenses, and orthopedic pins. Medical devices also include diagnostic aids such as reagents and test kits for in vitro diagnosis (IVD) of disease and other medical conditions such as pregnancy. • Clinical investigations of medical devices must comply with the Food and Drug Administration (FDA) informed consent and Institutional Review Board (IRB) regulations [21 CFR parts 50 and 56, respectively]. • Except for certain low risk devices, each manufacturer who wishes to introduce a new medical device to the market must submit a premarket notification to FDA. FDA reviews these notifications to determine if the new device is "substantially equivalent" to a device that was marketed prior to passage of the Amendments (i.e., a "pre-amendments device").

4. Regulatory Background • Investigational device - a medical device which is the subject of a clinical study designed to evaluate the effectiveness and/or safety of the device. • Clinical investigations undertaken to develop safety and effectiveness data for medical devices must be conducted according to the requirements of the Investigational Device Exemption (IDE) regulations [21 CFR part 812]. • A sponsor shall submit an IDE application to FDA if the sponsor intends to use a significant risk device in an investigation, intends to conduct an investigation that involves an exception from informed consent, or if FDA notifies the sponsor that an application is required for an investigation. • A sponsor shall not begin an investigation for which FDA's approval of an application is required until FDA has approved the application.

5. Significant Risk vs Nonsignificant Risk Medical Device Studies • Significant Risk (SR) Device Study. A study of a device that presents a potential for serious risk to the health, safety, or welfare of a subject and (1) is intended as an implant; or (2) is used in supporting or sustaining human life; or (3) is of substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents impairment of human health; or (4) otherwise presents a potential for serious risk to the health, safety, or welfare of a subject. • Nonsignificant Risk (NSR) Device Study. A study that does not meet the definition for a significant risk study • FDA has the ultimate decision in determining if a device study is SR or NSR

6. Significant Risk vs Nonsignificant Risk Medical Device Studies • NSR device studies have fewer regulatory controls than SR studies and are governed by abbreviated requirements [21 CFR 812.2(b)] • The assessment of whether or not a device study presents a NSR is initially made by the sponsor • The IRB may agree or disagree with the sponsor's initial NSR assessment. If the IRB agrees with the NSR assessment and approves the study, the study may begin without submission of an IDE application to FDA. If the IRB disagrees, the sponsor should notify FDA that an SR determination has been made and submit an IDE application to the FDA • Both SR and NSR studies require full board IRB review and approval, as well an informed consent from all study participants

7. Investigator Responsibilities • An investigator is responsible for ensuring that an investigation is conducted according to the signed agreement, the investigational plan and applicable FDA regulations, for protecting the rights, safety, and welfare of subjects under the investigator's care, and for the control of devices under investigation. An investigator also is responsible for ensuring that informed consent is obtained in accordance with 21 CFR 50.

8. Investigator Responsibilities • Awaiting approval. An investigator may determine whether potential subjects would be interested in participating in an investigation, but shall not request the written informed consent of any subject to participate, and shall not allow any subject to participate before obtaining IRB and FDA approval.

9. Investigator Responsibilities • Compliance. An investigator shall conduct an investigation in accordance with the signed agreement with the sponsor, the investigational plan, this part and other applicable FDA regulations, and any conditions of approval imposed by an IRB or FDA.

10. Investigator Responsibilities • Supervising device use. An investigator shall permit an investigational device to be used only with subjects under the investigator's supervision. An investigator shall not supply an investigational device to any person not authorized under this part to receive it.

11. Investigator Responsibilities • Financial disclosure. A clinical investigator shall disclose to the sponsor sufficient accurate financial information to allow the applicant to submit complete and accurate certification or disclosure statements required under 21 CFR 54 of this chapter. The investigator shall promptly update this information if any relevant changes occur during the course of the investigation and for 1 year following completion of the study.

12. Investigator Responsibilities • Disposing of device. Upon completion or termination of a clinical investigation or the investigator's part of an investigation, or at the sponsor's request, an investigator shall return to the sponsor any remaining supply of the device or otherwise dispose of the device as the sponsor directs.

13. Investigator Records • A Principal Investigator shall maintain the following accurate, complete, and current records relating to his/her participation in an investigation: • All correspondence with another investigator, an IRB, the Sponsor, a Monitor, or FDA; • Records of receipt, use or disposition of a device, e.g. type and quantity of the device, names of all persons who received, used, or disposed of each device, why and how many units of the device have been returned to the Sponsor; • Records of each subject’s case history and exposure to the device; • The protocol, with documents showing the dates of an reasons for each deviation from the protocol; • Any other records that FDA requires to be maintained

14. Investigator Reports • A Principal Investigator shall prepare and submit the following complete, accurate, and timely reports: • Unanticipated Adverse Device Effects. An investigator shall submit to the Sponsor and reviewing IRB a report of any unanticipated adverse device effect occurring during an investigation as soon as possible, but in no event later than 10 working days after the PI first learns of the effect; • Withdrawal of IRB Approval. An investigator shall report to the Sponsor, within 5 working days, a withdrawal of approval by the reviewing IRB; • Progress. An investigator shall submit progress reports on the investigation to the Sponsor, the Monitor, and the reviewing IRB at regular intervals, but in no event less often than yearly;

15. Investigator Reports • Deviations from the Investigational Plan. An investigator shall notify the Sponsor and the reviewing IRB of any deviation from the investigational plan to protect the life or physical well-being of a subject in an emergency. Such notice shall be given as soon as possible, but in no event later than 5 working days after the emergency occurred. In non-emergent cases, prior approval by the Sponsor is required for changes in or deviations from a plan. If these changes or deviations may affect the scientific soundness of the plan or the rights, safety, or welfare of human subjects, FDA and IRB approval is also required. • Informed Consent. If an investigator uses a device without obtaining informed consent, he/she shall report such use to the Sponsor and the reviewing ORB within 5 working days after the use occurs. • Final Report. An investigator shall, within 3 months after termination or completion of the investigation or the investigator’s part of the investigation, submit a final report to the Sponsor and the reviewing IRB.

16. Humanitarian Use Devices: General Criteria • Does not constitute research • A medical device that has received HDE approval by the FDA that is intended to benefit patients by treating or diagnosing a disease or condition that affects or is manifested in < 4,000 individuals in the US per year • No comparable device already available • No exposure to “unreasonable or significant risk of illness or injury” • Potential benefits of the device outweigh the risks

17. Humanitarian Use Device: IRB Requirements • Initial submissions require full board review by the IRB • Federal regulations do not require informed consent, however, TMHRI requires the use of an IRB approved consent form for all HUD cases • IRB continuing review (at least annual) is required, just as for other devices under development

18. Off Label Use of Investigational Devices • The use of a drug in a manner that is not listed in the FDA approved labeling • Off label use may be for 1) the practice of medicine, i.e. strictly limited to a therapeutic purpose or 2) in the context of conducting a clinical investigation • If the off label use is within the context of the practice of medicine, IRB review and approval is not required • If the off label use is within the context of research, IRB review and approval is required • If unsure as to whether the off label use constitutes research or not, call the Office of Research Protections for guidance

19. Emergency Use of Investigational Devices • The FDA recognizes that emergencies arise where an unapproved device may offer the only possible life-saving alternative, but (1) an IDE for the device does not exist, (2) the proposed use is not approved under an existing IDE, or (3) the physician or institution is not approved under the IDE. • Each of the following conditions must exist to justify emergency use: 1. the patient is in a life-threatening condition that needs immediate treatment; 2. no generally acceptable alternative for treating the patient is available; and 3. because of the immediate need to use the device, there is no time to use existing procedures to get FDA approval for the use.

20. Emergency Use of Investigational Devices • FDA would expect the physician to follow as many subject protection procedures as possible. These include: 1. obtaining an independent assessment by an uninvolved physician; 2. obtaining informed consent from the patient or a legal representative; 3. notifying institutional officials as specified by institutional policies; 4. notifying the IRB; and 5. obtaining authorization from the IDE holder, if an approved IDE for the device exists. • After an unapproved device is used in an emergency, the physician should: 1. report to the IRB within five days [21 CFR 56.104(c)] and otherwise comply with provisions of the IRB regulations [21 CFR part 56]; 2. evaluate the likelihood of a similar need for the device occurring again, and if future use is likely, immediately initiate efforts to obtain IRB approval and an approved IDE for the device's subsequent use; and 3. if an IDE for the use does exist, notify the sponsor of the emergency use, or if an IDE does not exist, notify FDA of the emergency use (CDRH Program Operation Staff 301-594-1190) and provide FDA with a written summary of the conditions constituting the emergency, subject protection measures, and results. • Subsequent emergency use of the device may not occur unless the physician or another person obtains approval of an IDE for the device and its use.

21. Informed Consent during an Emergency Use • Even for an emergency use, the investigator is required to obtain informed consent of the subject or the subject's legally authorized representative unless both the investigator and a physician who is not otherwise participating in the clinical investigation certify in writing all of the following [21 CFR 50.23(a)]: (1) The subject is confronted by a life-threatening situation necessitating the use of the test article. (2) Informed consent cannot be obtained because of an inability to communicate with, or obtain legally effective consent from, the subject. (3) Time is not sufficient to obtain consent from the subject's legal representative. (4) No alternative method of approved or generally recognized therapy is available that provides an equal or greater likelihood of saving the subject's life. • If, in the investigator's opinion, immediate use of the test article is required to preserve the subject's life, and if time is not sufficient to obtain an independent physician's determination that the four conditions above apply, the clinical investigator should make the determination and, within 5 working days after the use of the article, have the determination reviewed and evaluated in writing by a physician who is not participating in the clinical investigation. The investigator must notify the IRB within 5 working days after the use of the test article [21 CFR 50.23(c)].

22. Financial Implications of Device Studies • Informed Consent: • Must clearly delineate Routine care from Research Services • Must clearly outline who will be financially responsible for the services provided: • Study • 3rd Party Payor • Hospital • Medicare • Patient

23. Why is the routine care definition important? • In 2000, Medicare (CMS) issued a coverage decision which allows and encourages Medicare beneficiaries to participate in clinical trials • Medicare will only cover services which are part of an “approved” clinical trial and meet the Medicare definition of routine care or medical necessity.

24. Financial Implications of Device Studies • In 1996, Medicare coverage was expanded to include certain investigational medical devices and related medical procedures that are reasonable and necessary for the diagnosis or treatment of an illness or injury, or to improve the functioning of a malformed body member • FDA regulations generally allow sponsors to charge investigators for investigational devices and these costs can usually be passed on to the patients

25. What is routine care? The Methodist Definition: Medicare has determined that usual patient care be defined as: “the care which is medically reasonable, necessary, and ordinarily furnished (absent any research programs) in the treatment of patients by providers under the supervision of physicians as indicated by the medical condition of the patients”

26. Routine Care Includes • Items or services typically provided absent a clinical trial (i.e., medically necessary conventional care) • Services required for the provision of the investigational item (i.e., administration of a non-covered chemotherapeutic agent) • Services required for the clinically appropriate monitoring of the effects of the item or service or the prevention of complications • Services that are medically necessary for the diagnosis and treatment of complications arising from the provision of an investigational drug

27. Routine Care DOES NOT Include • The investigational item itself • Exception - Commercially sponsored category B investigational device trials are not under this National Coverage Determination • Items and services: • For which there is no Medicare benefit or • Are statutorily excluded or • Fall under a national non-coverage policy • Items and services provided solely to satisfy data collection and analysis needs that are not used in direct clinical management of the patient (i.e., monthly CT scan for a condition usually requiring only one scan) • Items and services customarily provided by research sponsors free of charge • Items and services provided solely to determine eligibility

28. Would the patient receive the item or service if they were not enrolled in a clinical trial? STANDARD OF CARE The item is covered Considered “Routine Costs” It can be billed on the UB92 or HCFA 1500 Yes No Is the item or service required to provide a research item or service?Example: Administration of a non-covered chemotherapeutic agent, or a medically necessary inpatient admission for an investigational surgery Yes No Is the service rendered required for the monitoring of the effects of the investigational item or service? Yes No Is the service rendered for the prevention ofcomplications related to the investigational item or service? Yes No Is the item or service medically necessary for the diagnosis or treatment of complications arising from the investigational service? Example: Patient in placebo arm of study develops a complication requiring a medically necessary admission Yes Routine Care Decision Tree

29. Is the item or service excluded by Medicare statute, or is it in a local or national non-coverage Medicare policy? May not be covered and not billable. Yes No Is the item or service reimbursable by the sponsor? Not Covered Not included in “Routine Costs” Yes No Is the item or service provided “free of charge” by the sponsor Yes No Is the item or service provided only for research and not for the patient’s clinical care? Yes Routine Care Decision Tree

30. What is a Category A or Category B Device? • Category A – Experimental/investigational is an innovative device for which “absolute risk” of the device type has not been established (i.e. the initial questions of safety and effective have not been resolved and the FDA is unsure whether the device type can be safe and effective). • Category B - Non-experimental/Investigational is a device for which the incremental risk is the primary risk in question (i.e. the underlying questions of safety and effectiveness of that device type have been resolved), or it is known that the device type can be safe and effective because other manufacturers have obtained FDA approval for that device type.

31. Investigational Device Billing • Category A devices are not covered under Medicare as they do no satisfy the statutory requirement that Medicare pay for devices determined to be reasonable and necessary. • Category B devices are eligible for coverage under Medicare if they are considered reasonable and necessary and if all other applicable Medicare coverage requirements are met

32. Investigational Device Billing • Before 2005, Medicare would not let us bill for services provided with Category A devices. • But, as of January 2005, Medicare will cover the routine costs for clinical trials involving Category A devices so long as we ensure that the devices are intended for use in: • Diagnosis, Monitoring, or Treatment of an Immediately Life-Threatening Disease or Condition

33. Investigational Device Billing Medicare Coverage Criteria • The device must be used within the context of an FDA approved clinical trial and according to approved patient protocols • The device must follow established national or local policies for similar FDA approved devices • The device must be medically necessary for the patient • The device must be furnished in a setting appropriate to the patient’s medical needs and condition Medicare Payment Criteria • Applies to both inpatient and outpatient claims • Deductible and coinsurance do apply • Inpatient payment for the IDE is bundled into the DRG or non-PPS payment

34. How does this affect you? • TMH will do a financial analysis on each device trial to answer these questions: • Who is responsible for paying for the device? • Will we be responsible for paying for the device? • If not, what is the financial risk of the study? • How can we mitigate this risk? • What is the expectation of the study and sponsor in terms of billing and device procurement? • i.e. will the study pay for denied claims?

35. How does this affect you? • TMH Financial Operations will meet with the study coordinator and the department materials coordinator: • Discuss device storage location • Procurement & tracking procedure • Charge set-up • Discuss routine care vs. research • Which services (if any) will the study pay for, and how will those services be identified to the department billing coordinator

36. How does this affect you? • You will need to complete the Medicare coverage request letter and submit to TMH Financial Ops • Why? • The Medicare Fiscal Intermediary (FI) must agree to cover the device in order for TMH to reimbursed for the device. • Category A devices are not covered; however, related services are covered and must notify the FI of intent to submit claims for these services.

37. Questions? Office of Research Protection Lee Seabrooke, Director 713.441.7548 Office of Research Compliance Mariana Pope, Manager 713.441.1791 TMH Financial Services Mark Amox, Project Manager II 713.441.5566