Incorporating FDA Regulatory Thinking into Plans for Medical Devices

Transcription

1 Incorporating FDA Regulatory Thinking into Plans for Medical Devices Ken Holroyd, MD, MBA Medical Director, Center for Technology Transfer and Commercialization Assistant Vice Chancellor for Research June 11, 2015

2 Summary of Learning Objectives MDRAP s mission: promote the success of the faculty s medical device R&D through FDA regulatory affairs support Incorporating regulatory thinking in medical device plans: Understand how IRB and FDA evaluate risk of the device in a human investigation Understand the role of the IRB in evaluating risk/benefit in a human investigation Role and process of risk assessment and management in product commercialization Benefits of regulatory thinking early in device development Understand pathways for FDA device approval

3 Medical Device Regulatory Affairs Program (MDRAP) Established May, 2014

4 MDRAP Mission Promote the success of faculty s medical device R&D through FDA regulatory affairs support

5 MDRAP People Axel Strombergsson Lu Ellen Davie Ken Holroyd

6 MDRAP Functions Early regulatory input into R&D Development of regulatory strategies Assistance with IDE preparation and maintenance Education Information Collaboration

7 MDRAP Implementation VU-wide Town Hall on MDRAP held October 15, 2014 Providing training for all IRB staff and Members at annual IRB education sessions October 21-23, 2014 Meeting individually with R&D teams MDRAP working closely in parallel with the IRB to review and make recommendations for investigator, IRB analyst and IRB committee reviewers, for all medical device IRB submissions from sponsor-investigators (3% of IRB submissions) MDRAP attends IRB committee meetings of reviewed medical devices

8 Plans for Medical Devices Grant Applications Research Development Clinical Testing Technology Commercialization Begin with the End in Mind Stephen Covey

9 Grants with Plans for Medical Devices Grant Application Types --NIH, NSF research may be interested in plans preparing for, or conducting, early feasibility human testing --SBIR, STTR need commercialization plans --NSF icorp program need commercialization plans All of these plans have significant FDA regulatory considerations MDRAP can provide assistance with discussion, information, grant text and/or support letters, as well as participate in grants, as the faculty prefer

10 FDA Design Control regulations include the Design History File and Device Master Record documentation for medical devices Necessary for medical device investigation reaching human testing, and beyond to commercialization MDRAP adapting design control regulations to an academic environment to support early feasibility clinical studies, and assist with commercialization Risk assessment and management an initial and important step

11 Medical Device Development

12 Clinical development stages Exploratory (IDE) Limitations and advantages First in human/early feasibility device not finalized, specific indication, usually up to 10 subjects Traditional feasibility near final or final device design, requires more data, purpose to plan adequate clinical study May overlap Pivotal (IDE) Definitive safety and efficacy for identified intended use One or more studies Post-market Additional study or studies to evaluate device safety/rare adverse events/longterm efficacy Design improvement

13 Regulatory Thinking: Planning for Institutional Review Board The IRB must review all research conducted under Vanderbilt s legal umbrella The IRB serves as the FDA s surrogate in making risk determinations for studies of devices for which the FDA has not already made this determination The IRB must consider the device how the device is to be used in the proposed study additional study procedures that might increase risk the nature of the harm that could result Source: animalpetdoctor.homestead.com

14 Is the Use of the Device in the Investigational Protocol Significant Risk (SR) or Non-Significant Risk (NSR)? SR if potential for serious risk to health, safety or welfare of subject SR = IDE needed from FDA before clinical protocol can be started

15 Role of the IRB If the IRB Committee determines the device is NSR, the study may start upon IRB approval IDE from IRB Source: The SI is responsible for adhering to relevant parts of 21 CFR 812, et. al. If the IRB Committee determines the device is SR, the SI must submit an IDE application to the FDA, the study must have both FDA and IRB approval The SI is responsible for adhering to 21 CFR 812, et. al.

16 Role of the IRB IRB makes risk (SR/NSR) determination for device in the context of the protocol, before and separately from risk/benefit determination for the study SR/NSR determination applies to one potential study, it is not a ruling on the device alone The investigator must supply a recommendation to the IRB for SR/NSR, and supply reasons, as part of the IRB application

17 Role of the IRB FDA is the ultimate arbiter IRB or investigator can go directly to the FDA for a determination, submitting the protocol including study population, and a complete description of the device IRB should in theory reach same decision as the FDA would New program at Vanderbilt can provide faculty in advance an IRB determination of SR/NSR status of a protocol and device before full resources are committed contact MDRAP if of interest

18 Significant Risk Decisions IRBs should understand distinctions between certain important concepts that are frequently confused: A. Difference between NSR and Minimal Risk Determinations IRBs should not confuse their responsibility to make an SR/NSR determination for a device study with the concept of minimal risk. Minimal Risk is a term used in the IRB regulations in part to identify certain studies that IRBs may approve through an expedited review procedure. For a device study to be eligible for expedited review, it must be an NSR study AND present no more than minimal risk to the subject. (See 21 CFR ) B. Difference Between SR/NSR Determinations and Approval Decisions IRBs should not confuse their responsibility to review and approve research for conduct at a clinical site with the SR/NSR determination. IRBs make the SR/NSR determination before the IRB conducts its review of the study under Part 56. The judgment about whether a study poses a significant risk or nonsignificant risk is based on the significance of the potential harm that may result from participation in the study, including the use of the device; whereas the IRB s decision to approve a study for implementation is based on the study s risk-benefit assessment.

19 Significant Risk Decisions Is the medical device in context of the protocol significant risk (= IDE needed) or non-significant risk? dances/ucm pdf FDA Guidance Document 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 use 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.

20 Significant Risk Decisions What is a potential serious risk to health, safety or welfare? Stanford University IRB states it is related directly to the potential for a serious adverse event (which has its own seven point definition): l The risk determination should be based on the proposed use of a device in an investigation, and not on the device alone. In deciding if a study poses an SR, an IRB must consider the nature of the harm that may result from use of the device. Studies where the potential harm to subjects could be life-threatening, could result in permanent impairment of a body function or permanent damage to body structure, or could necessitate medical or surgical intervention to preclude permanent impairment of a body function or permanent damage to body structure should be considered SR. Also, if the subject must undergo a procedure as part of the investigational study, e.g., a surgical procedure, the IRB must consider the potential harm that could be caused by the procedure in addition to the potential harm caused by the device.

21 Significant Risk Decisions What is a potential serious risk to health, safety or welfare? If there is a potential for a serious adverse event listed in the protocol or in the consent form related to the device or the procedure involving the device, it is probably a significant risk device or is there another definition of serious risk? Accessories or components of devices are considered the same SR / NSR status as the overall device / device system needed for the intended use

22 Serious Adverse Event List What is a serious adverse event in a clinical trial, as defined by FDA? 1.Death 2.Life-Threatening 3.Hospitalization (Initial or Prolonged) 4.Disability or Permanent Damage 5. Birth Defect 6. Required Medical or Surgical Intervention to Prevent Permanent Impairment 7. Other Important Medical Events

23 Non-Significant Risk Studies Abbreviated IDE requirements apply Abbreviated requirements. The following categories of investigations are considered to have approved applications for IDE's, unless FDA has notified a sponsor under (a) that approval of an application is required: (1) An investigation of a device other than a significant risk device, if the device is not a banned device and the sponsor: (i) Labels the device in accordance with 812.5; (ii) 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; (iii) 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 (c). (iv) Complies with the requirements of with respect to monitoring investigations; (v) Maintains the records required under (b) (4) and (5) and makes the reports required under (b) (1) through (3) and (5) through (10); (vi) Ensures that participating investigators maintain the records required by (a)(3)(i) and make the reports required under (a) (1), (2), (5), and (7); and (vii) Complies with the prohibitions in against promotion and other practices. MDRAP can work with the IRB to help sponsor-investigators understand their obligations for significant risk and nonsignificant risk medical device studies

24 VU Commercialization Process Around Intellectual Property

25 Commercial Medical Device Development Phases

26 Why Early Regulatory Thinking? Standard practice in industry begin with the end in mind Increase understanding of timeline, tasks, funding for reaching early feasibility human testing, and for reaching marketplace Important for technology commercialization through CTTC licensing or applying for IRB and/ or IDE for early feasibility human testing Start design control documentation, including risk assessment and management, for design history and device master records helpful for such licensing or human testing MDRAP adopting documentation procedures to emphasize core activities of interest to academic faculty

27 Regulatory Thinking: Risk Management using ISO ISO specifies a process for a manufacturer to identify the hazards associated with medical devices, including in vitro diagnostic (IVD) medical devices, to estimate and evaluate the associated risks, to control these risks, and to monitor the effectiveness of the controls The requirements of ISO are applicable to all stages of the life-cycle of a medical device, including initial conception MDRAP has adopted the process to an academic environment, and conducted pilot test

28 Risk Management Risk Analysis Intended use and identification of characteristics related to the safety of the medical device Identification of hazards Estimation of the risk for each hazardous situation Severity and frequency of harm that may result Risk Evaluation Risk control Risk control option analysis Implementation of risk control measures Residual risk evaluation Risk / benefit analysis Risk arising from risk control measures Completeness of risk control Evaluation of overall residual risk acceptability Risk management report Production and post-production information

29 Risk Assessment and Management Document can be provided to funding agencies, IRB, FDA, or commercial partners Will help define testing that should be done to prove the safety of your device Will be used in regulatory submissions A process of defining a device s benefit / risk balance Allows development of tools to minimize risk while preserving benefit Done throughout the product development and life cycle For example, use of the actual device by actual users may highlight new and different levels of risk not considered earlier

30 Risk Management Team Expertise in: How is device constructed How does device work How is device produced How is device used clinically In academia, it is in practice the engineering and clinical investigational team, with input from any outside parties involved in device construction or production Training is conducted on the risk management process

31 Preliminary Hazards Analysis Analysis method often performed early in device development When often little information or history of device use Generic hazardous situations Overview of questions for the preliminary hazard analysis: Intended use of the device? Intended use of the device in the early feasibility clinical protocol? Identification of hazards: how can it fail, break, or hurt someone? Device characteristics Estimation of risks for hazards

32 ISO 14971: Questions for Analysis From ISO Annex C Intended Use? Implanted? In contact with patient or other people? Energy delivered or extracted from patient? Substance delivered or extracted from patient? Are biological materials processed by device for re-use? How sterilized? How cleaned? Will device modify patient environment? Are measurements take? Is device interpretive? Does it work with other devices? Unwanted outputs of energy or substances?

33 ISO 14971: Questions for Analysis From ISO Annex C Consumables? Maintenance or calibration needed? Is there software? Restricted shelf life? Delayed or long term use effects? Subject to mechanical forces? What determines lifetime of device, such as batteries? Single use? How disposed of? Installation or use require special training? How is information for safe use provided? New manufacturing process needed

34 ISO 14971: Questions for Analysis From ISO Annex C Successful use dependent on human factors? User interface can contribute to user error? Distractions can cause errors? Connecting parts or accessories? Control interface? Displays information? Controlled by a menu? Used by a person with special needs? Can user interface initiate user actions? Alarm system? Can be deliberately misused? Hold data critical to patient care? Mobile or portable?

35 Estimating Risk Identify potential hazards based on device characteristics, brainstorming Hazard Hazardous situation Harm Severity of event Probability of event Detection of event

36 Acceptable Risk? A matrix of the likelihood of the risk (five categories, from rare through certain), and the consequence of the risk (five categories, from minor through catastrophic) Unacceptable risks should be addressed to see how they can be modified (risk control) for the planned clinical investigation, and future intended use of the device

37 Risk Control Can the risk be controlled? How best to control? Design of device Protective measures Information on safety Risk control measures would be adopted and evaluated for effectiveness Is the remaining risk acceptable? Risk/ benefit analysis New risks arising from risk control Risk management report as summary document

38 FDA Approval of Medical Devices Class I, II, III Device Classifications 510(k) pathway predicate device, substantial equivalence PMA pathway Average timelines and costs CLIA regulations for in-vitro diagnostics Quality Systems Regulations FDA Audits MDRAP can assist with analysis of these topics for your device

39 A Few Words About Software Recently attended three day AAMI course on software validation with FDA and medical device software instructors Commercial software needs to be written in a controlled process with an initial plan and subsequent review and testing to validate Large companies understand that no medical device software will be released unless it is written under controlled protocols and processes Documentation of research software will facilitate both commercialization, and IRB/ IDE applications As always, the risk analysis will be helpful in identifying approaches to control risk during early human studies all of today s talk applies to medical device software

40 Summary of Learning Objectives MDRAP s mission: promote the success of the faculty s medical device R&D through FDA regulatory affairs support Incorporating regulatory thinking in medical device plans: Understand how IRB and FDA evaluate risk of the device in a human investigation Understand the role of the IRB in evaluating risk/benefit in a human investigation Role and process of risk assessment and management in product commercialization Benefits of regulatory thinking early in device development Understand pathways for FDA device approval

41 Thank you for your attention! Questions / Comments / Discussion?