- Investigational Device Exemption (§812)
- Research conducted outside the United States (§814.15)
- Determination of Safety and Effectiveness (§860.7)
- Data Analysis
- Bioresearch Monitoring
- Form FDA-3674, ClinicalTrials.gov Data Bank
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.
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:
- Research begun on or after effective date November 19, 1986: FDA will accept studies which have been conducted outside the U.S. and begun on or after November 19, 1986, if the data constitute valid scientific evidence (§860.7) and the investigator has conducted the studies in conformance with the "Declaration of Helsinki" or the laws and regulations of the country in which the research was conducted, whichever offers greater protection to the human subjects. If the standards of the country are used, the applicant must state in detail any differences between those standards and the Declaration of Helsinki and explain why the national standards offer greater protection to the human subjects.
- Research begun before effective date November 19, 1986: FDA will accept studies which have been conducted outside the U.S. and begun before November 19, 1986, if the agency is satisfied that the data constitute valid scientific evidence (§860.7) and that the rights, safety, and welfare of human subjects have not been violated.
A PMA based solely on foreign clinical data and otherwise meeting the criteria for approval under this part may be approved if:
- the foreign data are applicable to the U.S. population and medical practice;
- the studies have been performed by clinical investigators of recognized competence; and
- the data may be considered valid without the need for an on-site inspection by FDA or, if FDA considers such an inspection to be necessary, FDA can validate the data through an on-site inspection or other appropriate means.
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.
Declaration of Helsinki
(World Medical Association’s recommendations to every physician in biomedical research involving human subjects)
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:
- The persons for whose use the device is represented or intended;
- The conditions of use for the device, including conditions of use prescribed, recommended, or suggested in the labeling or advertising of the device, and other intended conditions of use;
- The probable benefit to health from the use of the device weighed against any probable injury or illness from such use; and
- The reliability of the device.
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.
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.
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:
- A clear statement of the objectives of the study;
- A method of selection of the subjects that:
- Provides adequate assurance that the subjects are suitable for the purposes of the study, provides diagnostic criteria of the condition to be treated or diagnosed, provides confirmatory laboratory tests where appropriate and, in the case of a device to prevent a disease or condition, provides evidence of susceptibility and exposure to the condition against which prophylaxis is desired;
- Assigns the subjects to test groups, if used, in such a way as to minimize any possible bias;
- Assures comparability between test groups and any control groups of pertinent variables such as sex, severity or duration of the disease, and use of therapy other than the test device;
- An explanation of the methods of observation and recording of results utilized, including the variables measured, quantitation, assessment of any subject`s response, and steps taken to minimize any possible bias of subjects and observers;
- A comparison of the results of treatment or diagnosis with a control in such a fashion as to permit quantitative evaluation. The precise nature of the control must be specified and an explanation provided of the methods employed to minimize any possible bias of the observers and analysts of the data. Level and methods of ``blinding,`` if appropriate and used, are to be documented. Generally, four types of comparisons are recognized:
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;
Active treatment control.
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;
In certain circumstances, such as those involving diseases with high and predictable mortality or signs and symptoms of predictable duration or severity, or in the case of prophylaxis where morbidity is predictable, the results of use of the device may be compared quantitatively with prior experience historically derived from the adequately documented natural history of the disease or condition in comparable patients or populations who received no treatment or who followed an established effective regimen (therapeutic, diagnostic, prophylactic).
- A summary of the methods of analysis and an evaluation of the data derived from the study, including any appropriate statistical methods utilized.
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.
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:
- Summary of results (graphs are helpful)
- Summary of the study subjects including the number of subjects who have prematurely discontinued participation. (Include patient tree and spreadsheets to provide full accounting of all study subjects including controls and drop-outs, as appropriate)
- Description of events potentially affecting study success (e.g., difficulties enrolling patients; changes in key personnel; discontinuation of participation by subjects and investigators)
- Summary of anticipated and unanticipated adverse effects
- Description of any deviations from the investigational plan by investigators
- Discussion of any missing data and how it impacts the study
- Decription of method of statistical analyses used; describe how any assumptions required in the statistical analysis were validated
- Comparison of results to success/failure criteria
- Conclusions drawn from study, relate back to indications for use and how the data supports each indication
Additional guidance can be found in the following documents:
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:
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
Application Integrity Policy Information
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.
Beginning December 26, 2007, PMA applications must include form FDA-3674. If your PMA includes data from a clinical trial, you must determine if your study is applicable for entry into the clinical trial registry data bank at ClinicalTrials.gov. Based on this determination, check box 9.B. or 9.C., and complete the applicable sections of the form. An applicable device clinical trial is a prospective clinical study of health outcomes comparing an intervention with a device against a control in human subjects (other than a small clinical trial to determine the feasibility of a device, or a clinical trial to test prototype devices where the primary outcome measure relates to feasibility and not to health outcomes). See Title VIII - Clinical Trial Databases. Currently, FDA is reviewing the legislation and developing guidance on which clinical trials meet the definition of "applicable" trials and are required to report to ClinicalTrials.gov. Until FDA issues this guidance, the PMA sponsor is responsible for determining whether its studies meet the definition of an applicable trial and, therefore, are subject to reporting requirements.
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.