IDE Regulation 21CFR Part 812

1. IDE Regulation21CFR Part 812 Fall Seminar Series September 17, 2010 Presented by Lorry W Huffman, MT(ASCP), CLS

2. MyRAQA, Inc. • MyRAQA is a boutique regulatory consulting firm focused exclusive on in vitro diagnostics • Headquartered in Redwood City, California • Clients located both in US and Europe • MyRAQA Team Members • Senior team members have at least of 17 years of IVD experience • Our team incorporates experience from both small and large companies • Expertise includes regulatory, quality systems, clinical trial development and execution, development of assays and instruments & project management • Utilize a team approach to ensure client gets the best of all of our experience

3. AGENDA What is an Investigational device IDE Process Types of devices and IDE’s – significant/non-significant risk/abbreviated Contents of an IDE Application Conduct of IDE Trial What is a pre-IDE? pre-IDE process FDA Guidance and Recognized Standards Conclusions

4. Requirements for Investigational Device • Clinical evaluation of devices that have not been cleared for marketing requires: • An IDE approved by an Institutional Review Board (IRB) • Informed consent from allsubjects; • Labeling for investigation use only; • Monitoring of the study and; • Required records and reports.

5. Investigational Device ExemptionIDE • What is an investigational device? • A new device under investigation for safety and effectiveness data/information to support a PMA or 510(k) • An existing device under clinical evaluation of design modifications or changes/new intended use • Exempt from what? • The requirements (FD&C Act) of placing a device in interstate commerce (commercial distribution): • PMA or 510(k) • Establishment registration • Device listing

6. IDE Process – Submitters Obligations • Send 3 copies marked on the outer envelope: • “Application for an Investigational Device Exemption” • Supplemental IDE application IDE #Ixxxxxx. • Etc. • Send to office where your device is regulated • CDRH – Center for Devices and Radiological Health • CBER – Center for Biologics and Research • CDER – Center for Drug Evaluation and Research • Don’t start your clinical trial until FDA IDE and IRB approvals • With the exception of non-significant risk device/abbreviated IDE that requires only the IRB approval

7. IDE Process – FDA Obligations • Have 30 days to review and make decision • If disapproved, complete explanation for the reasons for disapproval. • Reasons to disapprove: • the risks to the subjects are not outweighed by the anticipated benefits to the subjects and the importance of the knowledge to be gained, or • informed consent is inadequate, or • the investigation is scientifically unsound, or • there is reason to believe that the device as used is ineffective.

8. Confidentiality FDA will not disclose content nor the existence of the IDE until after the PMA/510(k) is approved/cleared Data summaries concerning the safety and effectiveness of the device including adverse health effects caused by the device publicly available Subjects of a clinical trial upon whom the device was used may request copies of the report of adverse device effects as they pertain to use of the device as it was used on the subject

9. Significant and Non-significant Risk • Significant Risk Device • Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject; • Is purported or represented 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. • Non-significant Risk Device • None of the above apply.

10. Abbreviated IDE for non-significant risk Requirements: Labels the device in accordance with 812.5; Obtains IRB approval of the investigation after presenting the reviewing IRB with a brief explanation of why the device is not a significant risk device, and maintains such approval; Ensures that each investigator participating in an investigation of the device obtains from each subject under the investigator's care, informed consent under part 50 and documents it, unless documentation is waived by an IRB under 56.109(c). Complies with the requirements of 812.46 with respect to monitoring investigations; Maintains the records required under 812.140(b) (4) and (5) and makes the reports required under 812.150(b) (1) through (3) and (5) through (10); Ensures that participating investigators maintain the records required by 812.140(a)(3)(i) and make the reports required under 812.150(a) (1), (2), (5), and (7); and Complies with the prohibitions in 812.7 against promotion and other practices.

11. IDE Contents

12. IDE Contents (1) The name and address of the Sponsor • The person who initiates, but does not actually conduct the investigation. • Investigational device is used under the immediate direction of another individual.

13. IDE Contents - Investigational Plan (2) Summary – summarize the following sections: • Purpose - name and intended use of device, objectives, duration • Protocol - methodology used and analysis. a.k.a. statistical rationale • Risk analysis – • description and analysis of all increased risks to patients • how will risks be mitigated, • justification for the investigation. a.k.a. unmet clinical need • Patient population description • Device description – describe each component, property, and principle of operation and anticipated change in the device during the course of the investigation • Monitoring procedures – procedures as well as the name and address of the study monitor

14. IDE Content - Investigational Plan – cont’d • Complete plan – includes all of above sections plus…… • Labeling • Consent materials – copies of all forms and information to be provided to subjects to obtain informed consent • IRB information – list of names, locations, chairpersons of all IRB’s. Certificates of any action taken by any of those IRB’s regarding the investigation • Other institutions – name and address of each institution at which a part of the investigation may be conducted • Additional records and reports – a description of records and reports that will be maintained on the investigation in addition to those required in 21CFR812.140

15. IDE Contents - Investigational/Clinical Trial • Clinical trial conducted under the IDE requires that GCP be followed. • Scope of these regulations applies to: • Manufacturers, • Sponsors, • Clinical investigators, • IRB and • The medical device.

16. IDE Contents - Prior Investigations • Clinical, animal, laboratory – comprehensive and adequate to justify the proposed investigation • Bibliography of all publications relevant to an evaluation of safety or effectiveness • Copies of published and unpublished adverse information • Other significant publications requested by IRB or FDA • Nonclinical laboratory studies – statement that all studies have been conducted in compliance with applicable GLP (part 58) • If not, statement of reason not compliant

17. IDE Contents – cont’d (3) A description of the methods, facilities, and controls used for the manufacture, processing, packing, storage, and, where appropriate, installation of the device, in sufficient detail so that a person generally familiar with good manufacturing practices can make a knowledgeable judgment about the quality control used in the manufacture of the device. (4) Investigator agreement - sample • Investigators names and addresses of all investigators who have signed the agreement.

18. IDE Contents – cont’d (5) A certification that all investigators who will participate in the investigation have signed the agreement, that the list of investigators includes all the investigators participating in the investigation, and that no investigators will be added to the investigation until they have signed the agreement. (6) A list of the name, address, and chairperson of each IRB that has been or will be asked to review the investigation and a certification of the action concerning the investigation taken by each such IRB.

19. IDE Contents – cont’d (7) The name and address of any institution at which a part of the investigation may be conducted. (8) If the device is to be sold, the amount to be charged and an explanation of why sale does not constitute commercialization of the device. (9) A claim for categorical exclusion under 25.30 or 25.34 or an environmental assessment under 25.40.

20. IDE Contents – cont’d (10) Copies of all labeling for the device. (11) Copies of all forms and informational materials to be provided to subjects to obtain informed consent. (12) Any other relevant information FDA requests for review of the application.

21. Sample TOC for IDE Application

22. Conduct of IDE Trial - Related Regulations 21 CFR 812, Investigational Device Exemptions, covers the procedures for the conduct of clinical studies with medical devices including application, responsibilities of sponsors and investigators, labeling, records, and reports. 21 CFR 50, Protection of Human Subjects, provides the requirements and general elements of informed consent; 21 CFR 56, Institutional Review Boards, covers the procedures and responsibilities for institutional review boards (IRBs) that approve clinical investigations protocols; 21 CFR 54, Financial Disclosure by Clinical Investigators, covers the disclosure of financial compensation to clinical investigators which is part of FDA’s assessment of the reliability of the clinical data. 21 CFR 820 Subpart C, Design Controls of the Quality System Regulation, provides the requirement for procedures to control the design of the device in order to ensure that the specified design requirements are met.

23. Conduct of IDE Trial – Investigator Records • All correspondence with another investigator, an IRB, the sponsor, a monitor, or FDA, including required reports. • Records of receipt, use or disposition of a device that relate to: • (i) The type and quantity of the device, the dates of its receipt, and the batch number or code mark. • (ii) The names of all persons who received, used, or disposed of each device. • (iii) Why and how many units of the device have been returned to the sponsor, repaired, or otherwise disposed of.

24. Conduct of IDE Trial – Investigator Records (cont’d) 3. Records of each subject's case history and exposure to the device. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. Such records shall include: • (i) Documents evidencing informed consent and, for any use of a device by the investigator without informed consent, any written concurrence of a licensed physician and a brief description of the circumstances justifying the failure to obtain informed consent. The case history for each individual shall document that informed consent was obtained prior to participation in the study. • (ii) All relevant observations, including records concerning adverse device effects (whether anticipated or unanticipated), information and data on the condition of each subject upon entering, and during the course of, the investigation, including information about relevant previous medical history and the results of all diagnostic tests. • (iii) A record of the exposure of each subject to the investigational device, including the date and time of each use, and any other therapy.

25. Conduct of IDE Trial – Investigator Records (cont’d) 4. The protocol, with documents showing the dates of and reasons for each deviation from the protocol. 5. Any other records that FDA requires to be maintained by regulation or by specific requirement for a category of investigations or a particular investigation.

26. Conduct of IDE Trial – Sponsor Records All correspondence with another sponsor, a monitor, an investigator, an IRB, or FDA, including required reports. Records of shipment and disposition. Records of shipment shall include the name and address of the consignee, type and quantity of device, date of shipment, and batch number or code mark. Records of disposition shall describe the batch number or code marks of any devices returned to the sponsor, repaired, or disposed of in other ways by the investigator or another person, and the reasons for and method of disposal. 3. Signed investigator agreements including the financial disclosure information required to be collected under 812.43(c)(5) in accordance with part 54 of this chapter.

27. Conduct of IDE Trial – Sponsor Records (cont’d) 4. For each investigation subject to 812.2(b)(1) of a device other than a significant risk device, the records described in paragraph (b)(5) of this section and the following records, consolidated in one location and available for FDA inspection and copying: • (i) The name and intended use of the device and the objectives of the investigation; • (ii) A brief explanation of why the device is not a significant risk device: • (iii) The name and address of each investigator: • (iv) The name and address of each IRB that has reviewed the investigation: • (v) A statement of the extent to which the good manufacturing practice regulation in part 820 will be followed in manufacturing the device; and • (vi) Any other information required by FDA.

28. Conduct of IDE Trial – Sponsor Records (cont’d) 5. Records concerning adverse device effects (whether anticipated or unanticipated) and complaints and 6. Any other records that FDA requires to be maintained by regulation or by specific requirement for a category of investigation or a particular investigation.

29. Conduct of IDE Trial – IRB Records Maintain records according to 21 CFR Part 56

30. Pivotal IDE Summary FormApril 2010 • Completed by FDA reviewers as part of the IDE review • Intent is to provide an accessible summary of the major trial design elements • Serves as a tool to move FDA closer to their goal of rigorously-designed pivotal studies that will be better able to answer essential questions of safety and effectiveness during the review of marketing applications. • Summary also assists FDA reviewers in maintaining consistency, where appropriate, across clinical trials for devices similar in design and/or intended use.

31. Common Pitfalls of IDE Application Inadequate characterization of the device being investigated Poorly designed clinical trials Inadequate subject protection measures FDA intent to improve the quality of the information derived from the investigations and to protect the well-being of those participating in the clinical trials Thus the creation of the pre-IDE process

32. Pre-IDE

33. “Come early; Come often ” • This quote was used by CDRH Director Dr. Schultz every time he spoke. • How early? • When you have tangible design options • When you have a pipeline/iteration path idea • How often? • When you reach milestones • Forks in the road • Prior to initiation of bench studies • Completion of bench studies to get advise on clinical trial design

34. FDA considerations in establishing the pre-IDE process Conduct trials in US Following FDA guidance the quality of the trials and the data generated should be more congruent with the premarket approval requirements Data resulting from domestic trials will be representative of medical practice in the US US physicians will have earlier access to and experience with these new technologies US patients will also have the potential benefit of these novel therapies

35. Pre-IDE Policies and Procedures • Informal Guidance • The reviewing division can provide any advice/guidance which can be used in the development of supporting pre-clinical data or the investigational plan for incorporation into the IDE application • Can do even if an IDE will not be filed • Minutes from meeting key • Formal Guidance • To reach an agreement with FDA regarding FDA’s review of an investigational plan • Detailed description of the device • Detailed description of the proposed conditions of use of the device • Proposed plan (including a clinical protocol) for determining whether there is a reasonable assurance of effectiveness • If available, information regarding the expected performance of the device • If an agreement is reached regarding the parameters of an investigational plan, the terms of the agreement should be put in writing and made part of the administrative record by FDA.

36. Pre-IDE Process • Informal meeting however it is given a tracking number (I10xxxx) and documented. • Non-binding • Meaningful exchange of information with the Agency to increase understanding of requirements resulting in a more complete IDE application and timely approval. • Get guidance on specific elements of the IDE such as: • Appropriate animal model • Pre-clinical testing plans • Clinical trial protocol including statistics

37. Pre-IDE Process (con’t) • Interactive review process • Deficient information can be addressed within fewer review cycles • New strategies in clinical development may arise • Data does not support the initiation of the substantive (pivotal) clinical trial; FDA should consider the use of feasibility/pilot studies. • Such studies may be used to provide investigators with initial device experience • Help address specific safety concerns • Permit initial assessment of device design • Better define the clinical endpoints • Success/failure criteria • Intended patient population • Appropriate follow-up period • Assess the therapeutic effect of the device and estimate the required patient population size • Clarity the possible medical claims before the multi-centered trial is initiated

38. Pre-IDE Process (con’t) • Clearly state the reason for the submission • Identify those areas on which the sponsor would like the Agency to focus • Appropriate animal model to ensure ready for IDE clinical trial • Comment on proposed model, endpoints and follow-up testing • Proposed clinical trail protocol identify issues such as: • primary/secondary endpoints • Follow-up • Control treatment

39. Pre-IDE Process (cont’d) • Discuss the reasons to disapprove IDE: • the risks to the subjects are not outweighed by the anticipated benefits to the subjects and • the importance of the knowledge to be gained, or • informed consent is inadequate, or • the investigation is scientifically unsound, or • there is reason to believe that the device as used is ineffective.

41. Discussion Questions – Example #1 Does FDA agree with the previous and planned bench testing? Does FDA agree that the existing GLP animal data, along with our existing OUS clinical data, will adequately support the IDE application and future 510(k) clearance? Does FDA agree that our proposed clinical trial protocol will adequately support the IDE application and future 510(k) clearance?

42. Discussion Questions – Example #2 • Does FDA agree with the analytical studies strategy proposed for the expanded specimen lesion source particularly NOT repeating the following test protocols since there are no changes to the product design or test principles for the additional specimen? • Precision/Reproducibility study • Lot-to-lot reproducibility study • Limit of detection (LoD) study • Quantitative Range study • Target Sequence study • Carry over and cross-contamination Study • Product stability • Does FDA agree to the use of using retained (retrospectively collected) clinical specimens for the additional specimen types? • Does FDA agree that 50 specimens per specimen lesion site  are adequate for the performance comparison portion of the data?

43. Example – intravascular ultrasound • Educate and inform • Unmet clinical need • What physicians want • Product idea • Product pipeline • Submission strategy • Step-wise • Basic to more complex • Testing plans and rationale • Follow-up

44. Standards and Guidance Documents • Recognized consensus standards • Usually have to purchase • FDA Guidance documents • http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm • Standards • http://www.document-center.com/home.cfm

47. Conclusions Exercise pre-IDE option early to bring FDA along with you in the process Research device class and product codes to learn FDA recognized consensus standards and guidance documents Be clear and to the point in your IDE application making sure to address each requirement http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/default.htm

48. Questions???? Thank you for time today