Research Involving the Use of Investigational Devices January 18, 2006

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Research Involving the Use of Investigational
DevicesJanuary 18, 2006

• Presented by the TMHRI Offices of Research
  Compliance and Research Protection

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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

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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").

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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.

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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

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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

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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.

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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.

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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.

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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.

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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.

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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.

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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 subjects 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

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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

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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 investigators part of the
  investigation, submit a final report to the
  Sponsor and the reviewing IRB.

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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 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

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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

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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

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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.

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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.

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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).

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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

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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.

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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

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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

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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

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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

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Routine Care Decision Tree
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Routine Care Decision Tree
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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.

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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

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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

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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 patients 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

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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?

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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

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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.

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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