1. IMDMC Reg 101 Course Clinical Research and IDEs
Amy B. Judge-Prein
Counsel
Faegre Baker Daniels
June 25, 2015

2. Agenda Research vs. Practice of Medicine IDE Requirements
IDE Exemptions
Informed Consent

3. Research vs. Clinical Practice
What makes an activity “research” instead of “clinical practice?”
Research is defined as “a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.” 45 CFR § (d)
Research requires IRB review and subject consent 45 CFR § 46
For research subject to federal regulation
This can be a fine distinction

4. Differences Between Research and Clinical Practice
Clinical Research
Medical Treatment
Primary Goal: Create generalizable knowledge
Primary Goal: Provide medical care
Individualized treatment
Systematic investigation
Standard of care guidelines
Protocol and investigator’s brochure
Existing treatment used for existing indication
Testing experimental treatment (may or may not be commercially available)
Potential publication of only case study
Potential publication of scientific article in peer-reviewed journal
Commercially available product

5. Research in General
Must identify all appropriate governing regulations
Must identify “roles” and “responsibilities”
Most issues come down to fundamental confusion on governing regulations, roles, and responsibilities

6. Key Statutory and Regulatory Structures
Food Drug and Cosmetic Act
Oversight of clinical research
INDs, IDEs, etc.
Safety reporting
Data requirements
Protection of Human Subjects 21 CFR 50
Accuracy of submissions
Record keeping
Patient enrollment
Informed consent
IRB roles 21 CFR 56
Financial disclosures
Inspection rights

7. Investigator Responsibilities
Ensure IRB review and continuing review
Conduct study in accordance with all applicable regulatory requirements
Report study changes and unanticipated problems to IRB
Obtain IRB approval for any protocol changes
Record keeping, record retention, and reporting obligations
21 CFR 312, 21 CFR 812

8. Sponsor Responsibilities
Selecting qualified investigators and providing them with the information they need to conduct the investigation properly
Ensuring proper monitoring of the investigation
Ensuring that IRB review and approval are obtained, submitting appropriate application to FDA, and
Ensuring that any reviewing IRB and FDA are promptly informed of significant new information about an investigation

9. CRO Responsibilities
CRO (“Contract Research Organization”) is defined as “a person that assumes, as an independent contractor with the sponsor, one or more of the obligations of a sponsor, e.g., design of a protocol, selection or monitoring of investigations, evaluation of reports, and preparation of materials to be submitted to the [FDA].” 21 CFR 312.3(b)
“A sponsor may transfer responsibility for any or all of the obligations To a [CRO]. Any such transfer shall be described in writing. If not all obligations are transferred, the writing is required to describe each of the obligations being assumed by the contract research organization. If all obligations are transferred, a general statement that all obligations have been transferred is acceptable. Any obligation not covered by the written description shall be deemed not to have been transferred.” 21 CFR (a)

10. CRO Responsibilities (cont.)
“A [CRO] that assumes any obligation of a sponsor shall comply with the specific regulations applicable to this application and shall be subject to the same regulatory action as a sponsor for failure to comply with any obligation assumed under these regulations. Thus, all references to “sponsor” in [the regulations] apply to a [CRO] to the extent that it assumes one or more obligations of the sponsor.” 21 CFR (b)

11. Sponsor-Investigators
All the responsibilities of Sponsors and Investigators
Liability for adverse events from the use of the test article
Obtaining an IND or IDE when necessary
Charging for test article
Oversight of sub-investigators
Proper monitoring of clinical trial
Reports to FDA
Recordkeeping and record retention

12. IRB Responsibilities IRB Responsibilities 21 CFR 56.108
(1) Conduct initial and continuing review of research and report findings to the investigator and institution;
(2) Determine which projects require review more often than annually and which projects need verification from sources other than the investigator that no material changes have occurred;
(3) Ensure prompt reporting to the IRB of changes in research activity; and
(4) Ensuring that changes in approved research may not be initiated without IRB review and approval except where necessary to eliminate apparent immediate hazards to the human subjects

13. IRB Responsibilities
Follow written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the Food and Drug Administration of:
(1) Any unanticipated problems involving risks to human subjects or others;
(2) any instance of serious or continuing noncompliance with these regulations or the requirements or determinations of the IRB; or
(3) any suspension or termination of IRB approval

14. Full IDE Requires application to FDA
Description of investigational plan
Must include risk analysis
Report of prior investigations
Must wait for 30 days before starting investigation (to give FDA opportunity to review and comment)
21 CFR

15. Full IDE For Significant Risk Device
Implant that presents a potential for serious risk to the health, safety, or welfare of a subject;
Purported to be for a use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject;
Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or
Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject

16. Treatment IDE
Requires less information to be submitted to FDA (no investigational plan, for example)
Still must wait 30 days before beginning
Only if:
Device is intended to treat or diagnose a serious or immediately life-threatening disease or condition;
No comparable or satisfactory alternative device is available to treat or diagnose that stage of the disease or condition in the intended patient population;
Device is under investigation in a controlled clinical trial for same use under an approved IDE, or such clinical trials have been completed; and
The sponsor is actively pursuing marketing approval/clearance of the investigational device

17. Humanitarian Use Device
Alternative to PMA for certain devices intended for use in rare conditions 21 CFR 814
Must apply for HUD designation
For devices designed to treat or diagnose a disease or condition that affects or is manifested in fewer than 4,000 people in the US per year
Must submit HDE (similar to PMA)
Reasonable assurance of safety
Exemption from requirement of demonstrating reasonable assurance of effectiveness

18. Abbreviated IDEs
Considered by FDA to have approved applications for IDEs
Non-significant risk devices
Labeled in accordance with 21 CFR 812.5;
Investigation is IRB approved and informed consent requirements are met (IRB stands in for FDA);
Monitored as required under ;
Records are maintained and reports are made as required under and ;
No pre-approval promotion (812.7)

19. Investigational Device Exemptions
Request for exemption for experimental use of a device. 21 CFR 812
Categories of device investigations
Exempt
Must still comply with IRB and informed consent requirements
Abbreviated IDE for Non-significant risk devices
Full IDE for significant risk devices

20. Exempted Investigations
Some investigations of diagnostic devices, if the testing:
Is noninvasive,
Does not require an invasive sampling procedure that presents significant risk,
Does not by design or intention introduce energy into a subject, and
Is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure
21 CFR 812.2

21. Exempted Investigations
Devices undergoing consumer preference testing, testing of a modification, or testing of a combination of two or more devices in commercial distribution, if the testing is not for the purpose of determining safety or effectiveness and does not put subjects at risk
Devices intended solely for veterinary use or for research on laboratory animals
Custom devices, unless being used to determine safety or effectiveness for commercial distribution
IDE exempt does not necessarily mean consent not required

22. Informed Consent With very few exceptions, all IDE research requires
Legally effective informed consent
Of the subject (or the subject’s legally authorized representative)
Informed consent
Must provide the subject sufficient opportunity to consider whether to participate (so as to minimize the possibility of coercion or undue influence)
Must be in understandable language
Must not include any exculpatory language

23. Informed Consent Elements
Basic Elements (required for all)
A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject’s participation, a description of the procedures to be followed, and identification of any procedures which are experimental.
A description of any reasonably foreseeable risks or discomforts to the subject.
A description of any benefits to the subject or to others which may reasonably be expected from the research.
A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject.
A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the Food and Drug Administration may inspect the records.
For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained.
An explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights, and whom to contact in the event of a research-related injury to the subject.
A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

24. Informed Consent Elements
Additional Elements (to be provided as appropriate)
A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable.
Anticipated circumstances under which the subject’s participation may be terminated by the investigator without regard to the subject’s consent.
Any additional costs to the subject that may result from participation in the research.
The consequences of a subject’s decision to withdraw from the research and procedures for orderly termination of participation by the subject.
A statement that significant new findings developed during the course of the research which may relate to the subject’s willingness to continue participation will be provided to the subject.
The approximate number of subjects involved in the study.
When seeking informed consent for applicable clinical trials, as defined in 42 U.S.C. 282(j)(1)(A), the following statement shall be provided to each clinical trial subject in informed consent documents and processes. This will notify the clinical trial subject that clinical trial information has been or will be submitted for inclusion in the clinical trial registry databank under paragraph (j) of section 402 of the Public Health Service Act. The statement is: “A description of this clinical trial will be available on as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”

25. SUPPORT Trial
This was a large multicenter clinical trial conducted on preterm infants, comparing outcomes of two different airway support systems.
Lawsuit filed against researchers and the University of Alabama IRB, contending that the consent form did not fully explain the risks
OHRP issued a determination letter stating that the consent forms did not fully outline the risks
“Some commentators, in discussing the risks involved in the SUPPORT study, have attached great importance to the fact that all the oxygen levels to which the infants were assigned were within the range of the standard care. But they draw inappropriate conclusions from that fact. Medicine is an imperfect science. When considerable uncertainty exists about the best way to treat a particular medical problem, the range of what can be considered standard care often is quite broad, to allow physicians to exercise clinical judgment on behalf of their patients. Indeed, a core principle of medical ethics requires physicians to make such judgments, even in the face of uncertainty. All of us, as patients, rely on our doctors to do precisely that.”

26. Selected Enforcement and Warning Letters
Clinical Trials
Synthes, Inc. and four top executives charged with conducting clinical device trials without FDA authorization
Label of bone cement contained a warning against the use being studied
All 4 executives were sentenced to prison time in 2011
Sentences exceeded the sentencing guidelines
St. Jude Medical
$16 million settlement in 2011
Post-market studies used as inducements and kickbacks
Whistleblower recovery over $2 million

27. Selected Enforcement and Warning Letters
May 2011 letter to LifeCell, sponsor of surgical mesh device study
Sponsor failed to submit IDE for study; FDA warning letter because investigation did not meet the requirements of an exempted investigation under 21 CFR 812.1(c)
Link to Letter: htm

28.
Amy Judge-Prein