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MEDICAL DEVICE CLINICAL RESEARCH AND REIMBURSEMENT CONFERENCE Q1 PRODUCTIONS JANUARY 11-12, 2010 PHOENIX, ARIZONA
A Nonsignificant (NSR) Risk Device is generally a device that does not meet the criteria listed above.
RESPONSIBILITIES OF THE SPONSOR Ensure that the participating investigator(s) in the study obtains informed consent under 21 C.F.R. Part 50 from each study subject and documents the consent; Comply with the requirements of 812.46 with respect to monitoring investigations; Maintain certain records and submit certain reports to FDA, the IRB or investigators under 812.140 and 812.150 respectively; and Comply with the prohibitions in 812.7 against promotion and commercialization of, and certain other practices relative to, investigational devices.
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Monitoring ( 812.46)
A sponsor who discovers that an investigator is not complying with the signed agreement, the investigational plan, the IDE or other applicable FDA regulations, or any conditions of approval imposed by the reviewing IRB or FDA, must promptly either a) secure compliance, or b) discontinue shipments of the device to the investigator and terminate the investigators participation in the investigation. A sponsor must also require that the noncompliant investigator dispose of or return the device, unless this action would jeopardize the rights, safety, or welfare of a subject.
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Labeling ( 812.5)
An investigational device or its immediate package must bear a label with the following information:
The name and place of business of the manufacturer, packer, or distributor of the investigational device; The statement, CAUTION Investigational device. Limited by Federal (or United States) law to investigational use; The quantity of contents, if appropriate; and
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The labeling also must not contain any false or misleading statements nor imply that the device is safe or effective for the purposes being investigated.
However, the sponsor may advertise for research subjects and investigators to solicit their participation in a study. FDA has issued guidance on how this is to be appropriately done, without promoting the investigational device. The guidance states that advertisements for research subjects should be reviewed and approved by the IRB to assure that they are not unduly coercive and do not promise a certainty of result. Moreover, the guidance states that no claims should be made, either explicitly or implicitly, that the device is safe or effective for the purposes under investigation, or that the test article is known to be equivalent or superior to any other device.
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RESPONSIBILITIES OF INVESTIGATORS
The investigator must protect the rights, safety, and welfare of subjects. An investigator must conduct the investigation in accordance with the signed agreement with the sponsor, the investigational plan, the IDE and other applicable FDA regulations, and any conditions of approval imposed by the reviewing IRB and FDA ( 812.100). An investigator may determine whether or not potential subjects would be interested in participating in an investigation, but cannot request written informed consent or allow any subjects to participate before obtaining IRB approval (and FDA approval in the case of an SR device) ( 812.110).
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RESPONSIBILITIES OF INVESTIGATORS
An investigator is responsible for obtaining informed consent from each study subject under 21 C.F.R. Part 50 ( 812.100). In general, an investigator can permit use of the investigational device only with subjects under his/her supervision and cannot supply an investigational device to any person not authorized to receive it ( 812.110(c)). Upon completion or termination of a clinical investigation, or the investigators part of the investigation, or at the sponsors request, an investigator must return to the sponsor any remaining supply of the device or dispose of the device as the sponsor directs ( 812.110(e)).
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RESPONSIBILITIES OF INVESTIGATORS
The investigator must disclose to the sponsor sufficient accurate financial information to allow the sponsor to submit certification or disclosure of financial interests under 21 C.F.R. Part 54 ( 812.110(d)). The investigator must maintain certain accurate and complete records relating to the investigation as detailed in the regulation ( 812.140). The investigator must provide certain reports in a timely manner to the sponsor and/or the IRB as detailed in the regulation (812.150).
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RESPONSIBILITIES OF IRBs
In accordance with FDA regulations, an IRB has the authority to approve, require modifications in (to secure approval), or disapprove research. The purpose of IRB review is to assure, both in advance and by periodic review, that appropriate steps are taken to protect the rights, safety and welfare of humans participating as subjects in research. To accomplish this purpose, IRBs use a group process to review research protocols and related materials (e.g., informed consent documents). The IRB must monitor and review an investigation throughout the clinical study.
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RESPONSIBILITIES OF IRBs
If an IRB determines that an investigation involves an SR device that the sponsor thought was an NSR device, it must notify the investigator and, if appropriate, the sponsor. If this occurs, the sponsor may not begin the investigation until an IDE application is approved by FDA. An IRB must comply with all applicable requirements of the IRB regulation (Part 56) and applicable portions of the IDE regulation (Part 812) in reviewing and approving device investigations involving human testing.
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RESPONSIBILITIES OF IRBs
Criteria for IRB Approval of Research (21 C.F.R. 56.111) Risks to subjects are minimized. Risks to subjects are reasonable in relation to the anticipated benefits to subjects and the importance of the knowledge that may be expected as a result. Selection of subjects is equitable. Informed consent is obtained and documented for each subject. The research plan makes adequate provision for data monitoring, if required. There are adequate provisions to protect the privacy of subjects and confidentiality of data. No coercion or undue influence is used to include subjects in the study.
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INVESTIGATOR AGREEMENTS
Investigator agreement requirements 21 C.F.R. 812.43(c). 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. Review of agreement by legal counsel.
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INFORMED CONSENT Informed consent form requirements 21 C.F.R. 50.25. Sponsors and investigators should carefully prepare and institutions, with their IRBs, should closely scrutinize informed consent forms: To avoid FDA compliance actions. To avoid liability problems.
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INFORMED CONSENT
Investigators, institutions, and their IRBs should closely scrutinize model forms if provided by the sponsor for compliance with regulatory requirements; no one should just accept them. All relevant parties should closely evaluate modifications to model informed consent forms to assure continuing compliance. Review of form by legal counsel.
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OTHER KEY CONSIDERATIONS Make sure the clinical investigation protocol and plan will generate the data needed to support PMA approval or 510(k) clearance. Use the pre-IDE meeting process or more informal mechanisms (e.g., telephone calls to ODE) to pin down as best you can what the PMA or 510(k) data requirements will be and whether the protocol will generate that data. Determine whether your study involves an SR or NSR device it affects whether you are subject to full or abbreviated IDE requirements. Make sure all relevant parties (sponsor, investigator, IRB, monitor, etc.) understand and carry out their responsibilities.
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HOT TOPICS AND ENFORCEMENT Mandatory registration and results reporting of certain device clinical trials.
Applies to controlled product trials with health outcomes which are subject to FDA regulation as well as pediatric postmarket surveillance studies. Excludes small feasibility studies. Trial sponsor or designated principal investigator must register at ClinicalTrials.gov. Required by U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007, Title VIII, Section 801).
Proposed rule to require statement in informed consent regarding the requirement (74 Fed. Reg. 68750 (Dec. 29, 2009)).
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HOT TOPICS AND ENFORCEMENT August 2009 FDA announces enhancement of speed and transparency of actions against misconduct in the development of drugs and devices. September 2009 GAO report critical of FDA oversight of clinical investigators and recommends action to improve timeliness and enhance scope of FDAs debarment and disqualification processes for medical product investigators, including device investigators.
FDA agreed with GAOs recommendations.
HOT TOPICS AND ENFORCEMENT Bioresearch monitoring compliance continues to be an area of high enforcement activity for FDA, including CDRH. Many Warning Letters issue to sponsors, investigators and IRBs each year for clinical trial regulatory noncompliances. 2008/2009 Warning Letter Issues for Device Trial Sponsors
Failure to secure investigator compliance with the signed investigator agreement, the investigational plan, applicable FDA regulations and/or any other conditions of approval imposed by the reviewing IRB or FDA.
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FDA ENFORCEMENT
Form FDA-483/Warning Letter. Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) Letter Initiation of a proceeding to determine whether an investigator should be disqualified from receiving investigational products. Notice of Opportunity for Hearing If an investigators written or oral response to a NIDPOE letter is deemed unsatisfactory, a consent agreement cannot be reached or the investigator fails to respond to the NIDPOE letter, the investigator is given the opportunity for a hearing on the disqualification action held before an FDA presiding officer.
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All clinical investigators who agreed to certain restrictions, which have now been removed. All clinical investigators who, under regulations in effect until 1987, have provided FDA with adequate assurances of their future compliance with requirements.
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QUESTIONS?
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