PREP Course #27: Medical Device Clinical Trial Management

Transcription

1 PREP Course #27: Medical Device Clinical Trial Management Presented by: Evelyn Huang Jeffrey Revello Office of Research Compliance North Shore-LIJ Health System

2 CME Disclosure Statement The North Shore LIJ Health System adheres to the ACCME s new Standards for Commercial Support. Any individuals in a position to control the content of a CME activity, including faculty, planners, and managers, are required to disclose all financial relationships with commercial interests. All identified potential conflicts of interest are thoroughly vetted by the North Shore-LIJ for fair balance and scientific objectivity and to ensure appropriateness of patient care recommendations. Course Director and Course Planners, Kevin Tracey, MD, Cynthia Hahn, Emmelyn Kim, MPH, Tina Chuck, MPH have nothing to disclose. Evelyn Huang and Jeffrey Revello are the speakers and have nothing to disclose.

3 Learning Objectives Describe the requirements for using and managing medical devices in clinical trials.

4 Contents Discuss the regulations that govern the administration of device research including risk categorization and device classification. Review the basic concepts related to medical device trials Discuss device trial conduct and management Review current device GCP trends for PI s and identify common device GCP risks for investigators / sponsor studies Case study FDA Warning Letter

5 Regulatory Background Any device used in an unapproved manner, not cleared for marketing, or is the subject of a research study must obtain an investigational device exemption (IDE) or be IDE exempt. This serves as an exemption from the law that otherwise requires the device be approved before crossing state lines.

6 Regulatory Environment of Device Trials State NSLIJHS Institutional Policies (GR092) Regulatory Committees (IRB/COI) OHRP 45 part 46 Best Practices GCP, ISO FDA 21CFR 812, 809, 814, 807 etc Investigators Sponsor & Protocol

7 What is a Device? Definition of Medical Device 201 (h) FD&C Act Something being studied or promoted for a medical purpose Cannot interact chemically with the body (compared to a drug) Computer software including mobile apps and programs for medical decision making, dependent on their use may be regulated.

8 FDA Regulations Related to Devices The regulations enforced by the bioresearch monitoring program for medical devices are found in four sections of the CFR 1 : 21 CFR Investigational Device Exemptions 21 CFR 50 - Protection of Human Subjects 21 CFR 56 - Institutional Review Boards 21 CFR 58 - Good Laboratory Practice for Nonclinical Laboratory Studies

9 21 CRF 812 Title 21 CRF 812 Investigational Device Exemption (IDE) Submission process of an IDE application to FDA for significant risk device studies Process for obtaining IDE for non-significant risk device studies Assigns responsibilities to sponsor and investigator for the conduct of a device clinical investigation Provides information about how sponsors should submit an application for an Investigational Device Exemption to the FDA Provides information about device classifications according to risk

10 Device Classifications All devices are given specific classifications ranging from Class I III. The higher the classification, the greater the level of risk, which means the greater the level of assessment required. The classification guidance is located at the FDA website.

11 Marketing Clearance There are two major processes by which medical devices requiring U.S. Food and Drug Administration (FDA) review come to the American market. One process is called Premarket Notification or the 510(k) process. The other major process is called Premarket Approval PMA.

12 Basic Concepts Related to Device Trials Significant Risk and Non-Significant Risk devices Investigational Device Exemption (IDE) Pre-market Approval (PMA) HDE HUD

13 Definition of Significant Risk Device A device that presents a potential for serious risk to health, safety, or welfare of a subject and; is intended as an implant is used in supporting or sustaining human life is of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise prevents impairment of human health otherwise presents a potential for serious risk to the health, safety, or welfare of a subject

14 Non-Significant Risk Device (NSR) An investigational device that does not meet the definition for a significant risk study. Examples: Dental cavity removal solution, daily wear contact lens, gastroenterology and urology endoscopes and/or accessories, externally worn monitors for insulin reactions

15 Difference Between SR and NSR Significant Risk Must follow IDE regulations Must have IDE application approved by FDA before starting Non-Significant Risk Must follow abbreviated IDE regulations No need to report to FDA. Does not need IDE approved by FDA Study may start after IRB approval alone

16 Is an Investigational Device Exemption (IDE) Needed? No if: It is part of clinical care Basic physiological research Is considered IDE Exempt Yes if: Study is being done to support research or marketing applications Study of investigational devices Study of new device indications

17 When is an IDE Required? Significant Risk Device Trial: Submission of an IDE to FDA Follow all of 21 CFR 812 Non-Significant Risk Device Trial: IRB approval, after which the study is considered to have an approved IDE Follow 21 CFR 812.2(b)- abbreviated requirements (labeling, IRB, consent, monitoring, reporting)

18 Examples of Trials that Require an IDE Device trials that collect safety and effectiveness data whether or not the results are intended for FDA review New intended use of an approved device Different population New disease or condition Different placement on/in the body Changing intended use from treatment to prevention for the same disease Significant Design Changes

19 Emergency Use A one-time emergency use of an investigational device without prospective IRB review is allowed if all of the following conditions are met, providing that such use is reported to the IRB within 5 working days. a life-threatening situation necessitating the use of the test article, no standard acceptable alternative treatment is available, and because of the immediate need for the use of the test article, there is not sufficient time to obtain IRB approval

20 Summary

21 Device Trial Conduct and Management Major Responsibilities of Investigator: 1. Ensure that the investigation is conducted according to the signed agreement, the investigational plan (protocol), and applicable regulations 2. Protect the rights, safety, and welfare of subjects under the investigator s care 3. Ensure that the informed consent is obtained from each subject and that the study is not commenced until appropriate approvals are obtained (IRB, FDA if applicable) 4. Control devices under the investigation 5. Ensure the data integrity

22 Qualification of the Principal Investigator 1. Be qualified by education, training and experience to assume responsibility for the proper conduct of the clinical investigation in accordance with the international standard 2. Be experienced in the field of application and trained in the use of the investigational device under consideration 3. Disclose potential COIs, including financial, that may interfere with the conduct of the clinical investigation or interpretation of results 4. Be knowledgeable of obtaining informed consent

23 Investigator Agreements Investigator agreement requirements Sponsors should carefully prepare and institutions, IRBs and participating investigators should carefully review investigator agreements: To avoid FDA compliance actions To avoid later disputes over terms and obligations Make sure participating investigators fully understand what they are agreeing to do under the agreement.

24 Communication with the IRB Comply with the IRB review requirements: Obtain and maintain effective IRB approval (If the study involves a significant risk device, the IDE must be approved by FDA) Promptly report any deviations from the protocol Promptly submit any safety reports as per the IRB requirements Maintain correspondences between the IRB Final reports must be submitted to the IRB within 3 months of termination or completion of the study

25 Compliance with the Clinical Investigation Plan (Protocol) Indicate PI s acceptance of the protocol in writing Conduct the trial in compliance with the protocol Document and explain any deviation from the approved protocol that occurred during the course of the study Comply with any conditions of approval imposed by the reviewing IRB and FDA if applicable

26 Subject Protection -1 Protect the rights, safety, and welfare of subjects under the investigator s care: Appropriately obtain informed consent from subjects Only enroll subjects meeting all study eligibility criteria Inform subjects of any new significant findings/new safety information occurring during the study Provide subjects with the necessary instructions on proper use, handling, storage and return of the device, when it is used or operated by subjects

27 Subject Protection -2 Inform subjects of the nature and possible cause of any adverse events experienced Provide adequate medical care to subject during and after a subject's participation in a trial in the case of AE, as described in the consent

28 Informed Consent Process and Documentation-1 Follow the regulation and institutional policies to obtain informed consent from subjects Only IRB approved qualified personnel (delegated by the PI) can obtain consent Follow the process described in the protocol to obtain consent if applicable

29 Informed Consent Process and Documentation-2 Follow the IRB committee s requirement to obtain consent / re-consent Document the consent process Maintain the informed consent record (PI keeps the original, a copy will be given to subject, and a copy will be placed in the medical record)

30 Device Procurement Devices should be appropriately procured through the sponsor or manufacturer as detailed in the protocol and delivered to the PI after Health System authorized IRB approval is obtained and all other institutional and federal regulatory body approvals are secured. If this is not feasible (e.g., device requires, installation, testing, calibration, etc.) the Investigator should contact the appropriate institutional Biomedical Engineering department for approval to deliver the device to the research site.

31 Investigational Device Management-1 1. Ensure that the investigational device is used solely by authorized uses and in accordance with the protocol and instructions for use 2. Devices should be labeled to reflect Investigational Device Research Use Only. 3. Ensure that maintenance and calibration of the equipment relevant for the assessment of the clinical investigation is appropriately performed and documented, where applicable

32 Investigational Device Management-2 1. Report every observed device deficiency 2. Report to the regulatory agencies/irb/sponsor, without unjustified delay, all device deficiencies that could have led to a serious device effect 3. Storage: Devices must be stored in a locked, secure area. If possible, investigational devices should be kept separately from non-investigational devices.

33 Investigational Device Management-3 Disposal or Transfer: The PI (or Sponsor/Manufacturer) must provide direction for the disposition of unused, damaged or faulty devices and for the disposition of all stock and/or equipment at the termination of the research study. Devices cannot be maintained after the conclusion of the study, unless they have FDA marketing approval and the Investigator has secured institutional approval to maintain the device for a specified purpose. A PI who is exiting the Health System must adhere to NSLIJHS Policy GR088: Principal Investigator Exit Process to facilitate transfer of devices.

34 Investigational Device Accountability -1 The Principal Investigator (PI) must keep accurate, complete, and current records relating to their participation in a clinical investigation. A device accountability log, or equivalent, must be maintained by the Investigator

35 Investigational Device Accountability -2 The log should document records of receipt, use and disposition of a device that relates to the type and quantity of the device, the dates of its receipt, and the batch number or code mark; the names of all persons who received, used, or disposed of each device; and why and how many units of the device have been returned to the Sponsor, repaired, or otherwise disposed of.

36 Device Billing Investigational device studies require slightly different billing processes from investigational drug studies Refer to the most updated HS policy GR 023 and research subject registration forms for more details Contact the CRS Financial Core for any questions related to the device billing PREP education on the device billing will be coming soon

37 Data Integrity and Credibility Protocol compliance Maintain adequate, complete, and accurate study record for each subject: 1. Create and maintain original source documents throughout the study and make them available as requested during monitoring visits or audits 2. Ensure the accuracy, completeness, legibility and timeliness of the data reported to the sponsor in the CRF and in all required reports FDA ALCOA

38 Current GCP Trends of Device Trials GCP trends- ISO has been revised in 2011: 1. More closely aligned with ICH GCP 2. Gaps in ISO 14155: 2003 filled guidance on study conduct and responsibilities in line with ICH GCP 3. Generally accepted as harmonized with ICH GCP, but adapted for device studies 4. More focus on documentation 5. Changes in AE definition to address the different failures modes of devices

39 Common Risks/Issues Identified for Device Trials Failure to ensure proper oversight of the investigation. Failure to follow the protocol and / or regulations Inadequate subject protection including failure to adhere to informed consent requirements Inadequate communication with IRB/regulatory agencies Failure to maintain accurate, complete and current records related to the investigation. Failure to maintain accurate, complete and current records of receipt, use or disposition of the investigational device.

40 Case Study- FDA Warning Letter What Issue Can you Identify? -1 What is in the protocol? The device is intended for use on spine arthroplasty of one cervical disc. In addition, the Exclusion Criteria of the protocol indicates that subjects are to be excluded if there was any prior surgery at the target level.

41 Case Study- FDA Warning Letter What Issues Can you Identify? -1 This is a major safety concern because it placed subject at additional risks of serious harm due to the need for a second surgery only four days after the first. These risks include infection, bleeding, risks associated with anesthesia, and neurological damage including paralysis and death. The subject has therefore been placed at increased risk of developing long-term complications such as worsening pain and disability as a result of the critical error made by PI. Adherence to the investigational protocol assures that research subjects will not be exposed to known hazards that would place them in jeopardy or invalidate the outcome of the research.

42 Case Study- FDA Warning Letter What Issues Can you Identify? -1 What did the FDA inspector find? Physician notes signed by PI on April 17, 2009, and May 8, 2009, indicate that the subject has left C5-C6 disc herniation with chronic radiculopathy. The subject s operative report and discharge summary show that the procedure was performed on May 27, 2009, on the left C6-C7 disc. The physician note signed by PI on June 3, 2009, shows that the procedure was performed on the incorrect level. In addition, four days after the first surgery, you performed a second procedure on the subject on May 31, 2009, on the correct disc level, C5-C6 and did not exclude this subject from the study as required by the protocol.

43 Case Study- FDA Warning Letter What Issues Can you Identify? -2 What did the FDA inspector find? Both the physician note, dated July 6, 2009, and signed by subinvestigator and subject s medical monitor report indicate persistent hand and forearm numbness on the right side. In addition, the medical monitor report indicates that the event is considered device related. However, there is no documentation to show that this SAE was recorded in the ecrf. Inconsistency and inaccurate records of AEs and SAEs are major subject safety and data quality concerns. Discrepancies in reporting AEs may call into question the integrity and reliability of the data you obtained during the course of the study and increase the risk of harm to the participating subjects.

44 Case Study- FDA Warning Letter What Issues Can you Identify? -3 What the FDA inspector found? PI failed to maintain adequate device shipment records and records related to his participation as a clinical investigator in these studies and so could not produce during the inspection the device accountability records, as described above, in the Registry study for at least XX subjects Clinical investigators are responsible for maintaining accurate, complete, and current records of study related matters that include receipt and use of each device with specifics about the type and quantity of the device, dates of receipt, and batch number or code mark. 21 CFR (a)(2).

45 Resources If you have questions about whether your study needs an IDE: CDRH Manufacturer s Assistance Your IRB manager Training modules for persons involved in FDA regulated device clinical research activities: ISO Version

46 Questions??

47 Contact the ORC Office of Research Compliance 3333 New Hyde Park Rd. Suite 317 New Hyde Park, NY

48 References 1. etyourdevice/investigationaldeviceexemptionide/ucm htm 2. HS policy GR ISO Warning letter: 0.htm 5. Sandra Welch, ISO14155 & ICH GCP The Differences & Similarities Highlighted, May, efault.htm 7. lassifyyourdevice/default.htm 8. eneralandspecialcontrols/default.htm 9. rovalsandclearances/510kclearances/default.htm