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Please note: as of October 1, 2002, FDA charges fees for review of Premarket Notification 510(k)s and Premarket Approvals Clinical Studies
Investigational Device Exemption (§812) Clinical studies on human subjects that is conducted within the United States and U.S. territories must comply with Good Clinical Practices regulations. These regulations include Investigation Device Exemption (IDE) under 21 CFR 812, Protection of Human Subjects under 21 CFR 50, and Institutional Review Boards under 21 CFR 56. Guidance on these requirements can be found on the CDRH website at http://www.fda.gov/cdrh/devadvice/ide/index.shtml Research conducted outside the United States (§814.15) A study conducted under an investigational device exemption (IDE) outside the United States and submitted in support of a PMA must comply with the IDE regulation (21 CFR 812). A study conducted outside the U.S. which was not conducted under an IDE must comply with one of the following:
A PMA based solely on foreign clinical data and otherwise meeting the criteria for approval under this part may be approved if:
Applicants who seek approval based solely on foreign data are encouraged to meet with FDA officials in a presubmission meeting. Additional guidance on FDA policy regarding the acceptance of foreign clinical data can be found in the following documents.
Determination of Safety and Effectiveness (§860.7) Relevant Factors In determining the safety and effectiveness of a device for Premarket Approval of class III devices, FDA will consider the following, among other relevant factors:
Valid Scientific Evidence Although the manufacturer may submit any form of evidence to the FDA in an attempt to substantiate the safety and effectiveness of a device, the FDA relies upon only valid scientific evidence to determine whether there is reasonable assurance that the device is safe and effective. After considering the nature of the device and the rules in §860.7, FDA will determine whether the evidence submitted or otherwise available to the FDA is valid scientific evidence for the purpose of determining the safety or effectiveness of a particular device and whether the available evidence, when taken as a whole, is adequate to support a determination that there is reasonable assurance that the device is safe and effective for its conditions of use. Valid scientific evidence is evidence from well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts, and reports of significant human experience with a marketed device, from which it can fairly and responsibly be concluded by qualified experts that there is reasonable assurance of the safety and effectiveness of a device under its conditions of use. The evidence required may vary according to the characteristics of the device, its conditions of use, the existence and adequacy of warnings and other restrictions, and the extent of experience with its use. Isolated case reports, random experience, reports lacking sufficient details to permit scientific evaluation, and unsubstantiated opinions are not regarded as valid scientific evidence to show safety or effectiveness. Safety There is reasonable assurance that a device is safe when it can be determined, based upon valid scientific evidence, that the probable benefits to health from use of the device for its intended uses and conditions of use, when accompanied by adequate directions and warnings against unsafe use, outweigh any probable risks. The valid scientific evidence used to determine the safety of a device must adequately demonstrate the absence of unreasonable risk of illness or injury associated with the use of the device for its intended uses and conditions of use. Among the types of evidence that may be required, when appropriate, to determine that there is reasonable assurance that a device is safe are investigations using laboratory animals, investigations involving human subjects, and nonclinical investigations including in vitro studies. Effectiveness There is reasonable assurance that a device is effective when it can be determined, based upon valid scientific evidence, that in a significant portion of the target population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warnings against unsafe use, will provide clinically significant results. The valid scientific evidence used to determine the effectiveness of a device shall consist principally of well-controlled investigations. Well-Controlled Clinical Investigation The following principles are recognized by the scientific community as the essentials of a well-controlled clinical investigation. They provide the basis for FDAs determination whether there is reasonable assurance that a device is effective based upon well-controlled investigations and are also useful in assessing the weight to be given to other valid scientific evidence. The plan or protocol for the study and the report of the results of a well-controlled investigation shall include the following:
Where objective measurements of effectiveness are available and placebo effect is negligible, comparison of the objective results in comparable groups of treated and untreated patients; Where there may be a placebo effect with the use of a device, comparison of the results of use of the device with an ineffective device used under conditions designed to resemble the conditions of use under investigation as far as possible; Where an effective regimen of therapy may be used for comparison, e.g., the condition being treated is such that the use of a placebo or the withholding of treatment would be inappropriate or contrary to the interest of the patient;
To insure the reliability of the results of an investigation, a well-controlled investigation shall involve the use of a test device that is standardized in its composition or design and performance. Data Analysis The PMA application must include a discussion of the conclusions drawn from studies conducted with the medical device [814.20(3(vi)]. FDA does not prescribe specific statistical analyses for given devices and/or situations. All statistical analyses used in an investigation should be appropriate to the analytical purpose, and thoroughly documented. The discussion should demonstrate that the data and information in the application constitute valid scientific evidence within the meaning of §860.7 (discussed above) and provide reasonable assurance that the device is safe and effective for its intended use. The indications for use is based on the nonclinical and clinical studies described in the PMA. Indications for use for a device include a general description of the disease or condition the device will diagnose, treat, prevent, cure, or mitigate, including a description of the patient population for which the device is intended. Any differences related to gender, race, ethnicity, or age, etc. should be discussed in the data analysis and included in the labeling. The concluding discussion must present benefit and risk considerations related to the device including a discussion of any adverse effects of the device on health and any proposed additional studies or surveillance the applicant intends to conduct following approval of the PMA. The analysis should include the following:
Additional guidance can be found in the following documents: Clinical Utility and Premarket Approval, Blue Book Memo #P91-1 Statistical Guidance for Clinical Trials of Non Diagnostic Medical Devices Perspectives on Clinical Studies for Medical Device Submissions (Statistical) http://www.fda.gov/cdrh/ode/78.pdf Bioresearch Monitoring Sponsors, IRBs, and investigators, or any person acting on their behalf, are required to permit authorized FDA employees reasonable access at reasonable times to inspect and copy all records relating to clinical and nonclinical investigations. Furthermore, if FDA has reason to suspect that adequate informed consent was not obtained or that reports required to be submitted by the investigator to the sponsor or IRB have not been submitted or are incomplete, inaccurate, false, or misleading, FDA may inspect and copy records that identify subjects. To assure compliance with the IDE and related regulations, FDA inspects sponsors, clinical investigators, and institutional review boards. Nonclinical laboratories that perform animal studies in which the data are used to support research or marketing permits are included in the inspection program. The inspection program is referred to as bioresearch monitoring (BIMO) and is overseen the CDRHs Office of Compliance, Division of Bioresearch Monitoring. The objectives of the bioresearch monitoring program are to ensure the quality and integrity of data and information submitted in support of PMA and IDE submissions and to ensure that human subjects taking part in investigations are protected from undue hazard or risk. This is achieved through site audits of clinical data contained in PMAs prior to approval, data audits of IDE submissions, and inspections of Institutional Review Boards and nonclinical laboratories. Additional guidance on FDA’s biological monitoring program can be found in the documents: §812.145 Bioresearch Monitoring Agreement for PMAs and PDPs Integrity of Data and Information Submitted to ODE May 29, 1991 (I91-2) Device Advice: Clinical Trials and Investigational Device Exemption Office of Compliance - Bioresearch Monitoring Program Application Intregrity Policy Office of Regulatory Affairs; Compliance References; Bioresearch Monitoring
(BIMO) FDA/Office of Regulatory Affairs Form FDA-3674, ClinicalTrials.gov Data Bank Title VIII of the Food and Drug Administration Amendments Act of 2007 (FDAAA) included a provision that all PMA applications are required to be accompanied with certification that all applicable clinical trial information has been submitted to the ClinicalTrials.gov data bank. Information on how to register your clinical trial(s) in the ClinicalTrials.gov data bank is available on the National Library of Medicine (NLM) Protocol Registration System (PRS) website. Updated 01/30/2008
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