Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Alternatively, electronic comments may be submitted to http://www.fda.gov/dockets/ecomments. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this document contact Sally Hojvat, Ph.D. in CDRH at (240) 276-0496 or Leonard Wilson in CBER at (301) 827-0373. When final, this document will supersede "Guidance for FDA Staff: Regulating In Vitro Diagnostic Device (IVD) Studies," dated December 17, 1999. |
U.S. Department of Health and Human Services |
Contains Nonbinding Recommendations
Draft - Not for Implementation
Additional Copies
Additional copies are available from the Internet at: http://www.fda.gov/cdrh/oivd/guidance/1587.pdf , or to receive this document via your fax machine, call the CDRH Facts-On-Demand system at 800-899-0381 or 301-827-0111 from a touch-tone telephone. Press 1 to enter the system. At the second voice prompt, press 1 to order a document. Enter the document number (1587) followed by the pound sign (#). Follow the remaining voice prompts to complete your request.
Or, contact:
Office of Communication, Training, and Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448
Internet: http://www.fda.gov/cber/guidelines.htm
Tel: 800-835-4709 or 301-827-1800
I. Background
II. Introduction
III. General Regulatory Issues
IV. Investigational Studies
V. Human Subject Protection
VI. Data Considerations
VII. Glossary
VIII. References
Appendix 1: REGULATORY DECISION TREE (21 CFR PART 812) for IVD INVESTIGATIONAL STUDIES
Appendix 2: Regulatory Framework for IVD Products Regulated as Class I, II, or III Devices
Appendix 3: Sponsor’s Responsibilities for Significant Risk Device Investigations .
Appendix 4: Investigator’s Responsibilities for Significant Risk Device Investigations .
Appendix 5: Suggested Format for IDE Final Report
This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. |
The Investigational Device Exemptions (IDE) regulation, Title 21, Code of Federal Regulations (21 CFR) Part 812, sets forth regulatory requirements for studies of investigational devices. Certain investigational IVD device studies (see the Glossary), however, are exempt from most of the provisions of Part 812 (21 CFR 812.2(c)(3))1. This guidance document, written in question and answer format, is intended to assist you2 (the manufacturer, sponsor, applicant, investigator and the IVD device industry in general) in the development of IVD studies, particularly those exempt from most of the requirements of the IDE regulation and to provide you with a broad view of the regulatory framework pertaining to the development phase of IVD devices. The information in this guidance document is also pertinent to investigators who participate in IVD studies and to institutional review boards (IRB) that review and approve such studies. The document is intended to facilitate the movement of new IVD technology from the investigational stage to the marketing stage.
This guidance document outlines FDA regulations applicable to studies for investigational IVD devices, including those regulations related to human subject protection. The guidance also explains data considerations that ultimately will affect the quality of the premarket submission. This document includes a glossary, a reference list with related web addresses, and a quick-reference table.
The Center for Devices and Radiological Health (CDRH) and the Center for Biologics Evaluation and Research (CBER) each have regulatory responsibilities for IVD devices; information included in this document applies to Class I, II, and III IVD devices regulated by either Center.
Note: Some devices used to test blood donor suitability are regulated as biologics and licensed under biologic regulations (600 series of 21 CFR) rather than under device regulations (800 series of 21 CFR). Examples of biologics IVD devices include licensed blood donor screening tests for human immunodeficiency virus (HIV) and hepatitis B and C tests intended for blood screening. This guidance is written to address only IVD devices that are approved or cleared under device regulations (800 series of 21 CFR), regardless of which Center reviews the submission. If you have questions about a device regulated by CBER, you may go to the CBER website for published guidance ( http://www.fda.gov/cber/guidelines.htm ) or contact CBER for further information on applicable biologic guidance and regulations. (See Introduction, Section II, question # 4, of this guidance for a listing of CBER contact numbers).
FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.” 21 U.S.C. 321(h) (emphasis added).
How do IVD devices differ from other devices?
Most other devices function on or in a patient. In contrast, IVDs include products used to collect, prepare, and examine specimens (e.g., blood, serum, urine, spinal fluid, tissue samples) after they are removed from the human body.
Title 21, Code of Federal Regulations (21 CFR)
Part 11, Electronic Records; Electronic Signatures
Part 50, Protection of Human Subjects
Part 54, Financial Disclosure by Clinical Investigators
Part 56, Institutional Review Boards
Part 99, Dissemination of Information on Unapproved/New Uses for Marketed Drugs, Biologics, and Devices
Part 801, Labeling
Part 803, Medical Device Reporting
Part 807, Establishment Registration and Device Listing for Manufacturers and Initial Importers of Devices
Part 809, In Vitro Diagnostic Products for Human Use
Part 810, Medical Device Recall Authority
Part 812, Investigational Device Exemptions
Part 814, Premarket Approval of Medical Devices
Part 820, Quality System Regulation
Part 860, Medical Device Classification Procedures
Part 862, Clinical Chemistry and Clinical Toxicology Devices
Part 864, Hematology and Pathology Devices
Part 866, Immunology and Microbiology DeviceIn addition, certain sections of Part 610 apply to devices that employ human blood components. For example:
610.40, Test Requirements (Testing Requirements for Communicable Disease Agents)
610.42, Restrictions on Use for Further Manufacture of Medical Devices
We recommend that you begin with the exemptions in 21 CFR 812.2(c). Your proposed IVD study is exempt from most provisions of the IDE regulation if it fits any one of thefollowing three categories:
- The IVD is a pre-amendments device (i.e., a device that was in commercial distribution prior to the enactment of the 1976 Medical Device Amendments to the Act), other than a transitional device (see the Glossary for definition), and is used or investigated according to the indications in the labeling at that time.
- The IVD is a device, other than a transitional device, that has been found to be substantially equivalent to a pre-amendments device and is used or investigated according to the indications in the labeling reviewed by FDA in determining substantial equivalence.
- The IVD
For your study to be exempt from most of the requirements of the IDE regulation under this category, it must meet all of the conditions listed in “c” above. (See also the decision tree in Appendix 1.) You should refer to Parts 50 and 56 for applicable requirements relating to IRBs and informed consent, including for device studies that meet the criteria described in 21 CFR 812.2(c). Additionally, investigators for those studies are still subject to 21 CFR 812.119 (the provision entitled “Disqualification of a clinical investigator.”).
If your proposed study does not fit into one of the three categories listed above, you, the sponsor, must have an approved IDE (21 CFR 812.2) before you may ship your investigational IVD. (Note: A device that is approved under a premarket approval application (PMA) or cleared under a 510(k) and then used in a study in accordance with the approved or cleared labeling is not investigational and, therefore, is not subject to the IDE regulation.) The requirements for an IDE depend on the level of risk that the study presents to subjects. For a significant risk device (see the Glossary for definition), the sponsor must apply to FDA for an IDE approval (see 21 CFR 812.1, 812.20). For a non-significant risk device (see the Glossary for definition), the sponsor must meet the abbreviated requirements of 21 CFR 812.2(b), including review and approval of the investigation by an institutional review board (IRB) and compliance with informed consent requirements. A non-significant risk study is considered to have an approved IDE when the abbreviated requirements are met.
Note: The requirements of the “Protection of Human Subjects” and “Institutional Review Boards” regulations (21 CFR Parts 50 and 56) apply to all clinical investigations regulated by FDA under section 520(g) of the Act, as well as other clinical investigations that support applications for research or marketing permits. (21 CFR 50.1, 56.101; see also Section V, Human Subject Protection, of this guidance.) Therefore, all studies of investigational IVDs that will support applications to FDA are subject to Parts 50 and 56, even if they are not subject to most requirements of Part 812.
A significant risk IVD device is generally one that 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 health, safety, or welfare of a subject. 21 CFR 812.3(m).
For IVDs, we interpret "potential for serious risk" in relation to the nature of the harm that may result to the subject. Misdiagnosis and/or error in treatment caused by inaccurate test results would be considered a significant risk if the potential harm to the subject could be life-threatening, or could result in permanent impairment of a body function or permanent damage to the body structure.
False positive results can lead to unnecessary confirmatory testing, unnecessary treatment that can be invasive or have harmful side effects, and/or unnecessary psychological trauma when serious or life-threatening diseases or conditions are involved. False negative results can lead to a delay in establishing the correct diagnosis, failure to start or continue needed treatment, false security that may prevent timely follow-up and retesting, and contribute to the potential spread of infectious agents to others. If the potential risk does not rise to the level described above, the study is not considered to pose a significant risk. FDA recommends the sponsor consider all these factors when determining the risk associated with your investigational IVD. (See 21 CFR 812.3(m) and also "Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors," available at http://www.fda.gov/oc/ohrt/irbs/, particularly the one on “Significant Risk and Nonsignificant Risk Medical Devices” at http://www.fda.gov/oc/ohrt/irbs/devrisk.pdf.)
To determine whether an invasive sampling technique presents a serious risk, we recommend that you base your risk determination on the nature of the harm that may result from sampling. For example, FDA considers sampling techniques that require biopsy of a major organ, use of general anesthesia, or placement of a blood access line into an artery or large vein (subclavian, femoral, or iliac) to present a significant risk.
A noninvasive device is one that does not, by design or intention:
- penetrate or pierce the skin or mucous membranes of the body, the ocular cavity, or the urethra; or
- enter the ear beyond the external auditory canal, the nose beyond the nares, the mouth beyond the pharynx, the anal canal beyond the rectum, or the vagina beyond the cervical os.
(21 CFR 812.3(k)).
Blood sampling that involves simple venipuncture is considered noninvasive, and the use of surplus samples of body fluids or tissues that are left over from samples taken for non-investigational purposes is also considered noninvasive (21 CFR 812.3(k)).
For an investigational study to be exempt under 812.2(c)(3), clinical investigators must use a medically established means of diagnosis (e.g., another cleared or approved IVD or culture) of the disease or condition as the basis for decisions regarding treatment of all subjects participating in the study. 21 CFR 812.2(c)(3)(iv). Additionally, test results from the exempt IVD investigation should not influence patient treatment or clinical management decisions before the diagnosis is established by a medically established product or procedure.
If there is no medically established diagnostic product or procedure and clinical investigators use the results from the investigational study to decide on treatment, FDA would not consider the study exempt from IDE requirements under 21 CFR 812.2. The sponsor would need to obtain FDA approval of an IDE if the results are used in diagnosis without confirmation (e.g., to assist in determining treatment) (21 CFR 812.1, 812.2) and if a significant risk device is involved.
Yes. (See also Chapter III, “Expanded Access to Unapproved Devices,” of the guidance document “IDE Policies and Procedures.”)3 A physician may use an investigational IVD device in an emergency situation if:
- the patient has a serious disease or condition;
- no generally accepted alternative diagnostic device or treatment for the condition is available; and
- there is no time to use existing procedures to get FDA approval for the emergency use.
FDA recommends that the physician make the determination that the patient's circumstances meet the above criteria, to assess the potential for benefit from the use of the unapproved device, and to have substantial reason to believe that benefits will exist. In the event that a device is used in circumstances meeting the criteria listed above, the physician should follow as many of the patient protection procedures listed below as possible. These include obtaining:
- Informed consent from the patient or a legally authorized representative;
- Clearance from the institution as specified by their policies;
- Concurrence of the IRB chairperson;
- An assessment from a physician who is not participating in the study; and
- Authorization from the IDE sponsor, if an approved IDE exists for the device;
- Authorization from the device company, if no IDE exists.
While prior FDA approval for shipment for emergency use of the investigational device is not required, 21 U.S.C. § 360bbb(a), if an IDE exists, the use should be reported to FDA in a supplemental IDE by the IDE sponsor within 5 working days from the time the sponsor learns of the use (21 CFR 812.35(a)(2)). The IDE supplement should contain a summary of the conditions constituting the emergency, patient outcome information, and the patient protection measures that were followed. If no IDE exists, the physician should follow the above procedures and report the emergency use to the sponsor and to CDRH or CBER, as appropriate.
For additional information on the procedures physicians and IRBs should follow in an emergency use situation, please see Chapter III, "Expanded Access to Unapproved Devices" of the guidance entitled, IDE Policies and Procedures.
Yes, in exceptional situations. CDRH recognizes that there are circumstances when an unapproved or uncleared IVD is the only available option for a patient or small group of patients who do not meet the inclusion criteria and "compassionate use" of the device may be appropriate. Federal Food, Drug, and Cosmetic Act, Section 561. CBER has a similar program termed “single patient exemption.” FDA requires for compassionate use the same patient protection measures required for emergency use, noted above.
Use of an investigational IVD device for one or a small group of patients who do not meet the study inclusion criteria would require a change to the investigational plan. If the study is being conducted under an approved IDE, the sponsor should submit a supplement to the IDE requesting a change to the investigational plan for “compassionate use”. 21 CFR 812.35(a). The review of this supplement can be facilitated by a phone call to the reviewing division and by the submission by facsimile of an advanced copy of the supplement. If the investigational IVD device would require an FDA-approved IDE, but one has not yet been submitted or approved, FDA intends to exercise enforcement discretion where the sponsor submits a compassionate use request to CDRH or CBER, as appropriate, and follows the patient protection measures listed above for emergency use.4
Whether the study is being conducted according to an exemption under 21 CFR 812.2, or a significant or non-significant risk IDE, the sponsor should obtain prior approval for the specific compassionate use for the individual(s) in question from the FDA and the reviewing IRB at the site where the physician proposes to use the device. For CDRH regulated products, the required information can be submitted to the Director of the IDE Program:
Attn: Director, IDE Program
Food and Drug Administration
Center for Devices and Radiological Health
HFZ-403
9200 Corporate Blvd
Rockville , MD 20850Compassionate use information is available on FDA’s web site at http://www.fda.gov/cdrh/devadvice/ide/early.shtml#compassionateuse .
For CBER regulated products, the required information should be submitted to the appropriate reviewing division.
Yes, both are available. See 21 CFR 812.36 and the Glossary for definitions of treatment IDE and continued access.
Yes, it is possible for an IVD device to be approved for marketing under the HDE. See the Glossary for definitions, 21 CFR 814 Subpart H, and Appendix 1 for more information.
IVD devices qualify for an HUD designation when the number of persons tested with the device is fewer than 4,000 per year. FDA recognizes that the number of tests with the device may exceed one per patient. A device that involves multiple patient uses may still qualify for HUD designation as long as the IVD device is designed for diagnosis or treatment of a total of fewer than 4,000 patients per year in the US.
If a device is being developed to diagnose or to help diagnose a disease or condition with an incidence of fewer than 4,000 patients per year, but there are more than 4,000 patients a year “at risk” who would be subject to testing using the device, then the device may not qualify as a HUD. 21 CFR 814.102(a)(5).
No. The goals for IVD studies are the same as the goals for other device studies, even if the IVD study is exempt from most IDE requirements under 21 CFR 812.2(c)(3).
We recommend that the sponsor and the investigators conduct an IVD device study with the goals of
- producing valid scientific evidence (for a definition, see 21 CFR 860.7(c)(2) and answer #1 of section IV) demonstrating reasonable assurance of the safety and effectiveness of the product, as described below, and
- protecting the rights and welfare of study subjects. (See Human Subject Protection, Section V of this guidance).
In addition, the FDA 510(k) substantial equivalence determination summaries and FDA PMA summaries of safety and effectiveness are currently available on the CDRH OIVD web page at http://www.fda.gov/cdrh/oivd/index.html or for CBER products at http://www.fda.gov/cber/efoi/pma.htm and http://www.fda.gov/cber/dap/devlst.htm.
We recommend that the sponsor structure submissions according to the relevant regulations and provide sufficient detail to give the reader an understanding of the scientific data and information supplied. OIVD has issued many device specific guidances that describe FDA’s recommendations for premarket submissions for particular types of IVDs.
CDRH has developed a guidance document entitled “Guidance for Industry; Supplements to Approved Applications for Class III Medical Devices: Use of Published Literature, Use of Previously Submitted Materials, and Priority Review,” which can be found on the CDRH website at http://www.fda.gov/cdrh/modact/evidence.html. CDRH and CBER believe that the principles outlined in this guidance are applicable to other submissions, specifically those for a 510(k), PMA, and HDE. (See the Glossary for definitions of these submission types.)
See Introduction, Section II, question # 4 of this guidance for a list of reviewing divisions in both CDRH and CBER.
A master file (MAF) is a reference source that a person submits to FDA. In general, it is a file of trade secret or confidential commercial/financial information submitted by a third party (i.e., someone other than the applicant) in support of the application as a reference source. FDA will accept MAFs from organizations or persons who have not submitted or will not directly submit the information in a PMA, IDE, 510(k), or other device-related submission to FDA. MAFs may include information on the following:
We recommend that a MAF include a cover letter, preferably on company letterhead, signed by a responsible company official that identifies the submission as a MAF and provides the name of a contact person at the company or a designated agent. For more information concerning MAFs, see Appendix C of the Premarket Approval Manual, which is found on the CDRH website at http://www.fda.gov/cdrh/dsma/pmaman/appdxc.html#P7_2
You, the sponsor, should contact the company that owns the information you would like to incorporate by reference in your premarket submission to FDA, and find out if this information is currently in a master file. If it is, you should obtain a written authorization from the master file holder (or an authorized designated agent/representative) on company letterhead. You should include the original authorization letter in the original copy of the premarket submission to FDA, and a copy of the authorization letter in each subsequent copy of the premarket submission. The master file holder should not send the authorization letter directly to FDA for inclusion in the master file or for inclusion in your premarket submission.
If the information you, the sponsor, would like to incorporate by reference in your premarket submission to FDA is not already in a master file, you should request that the company that owns this information submit a master file to FDA.
For more information on referencing MAFs, see Appendix C of the Premarket Approval Manual, which is found on the CDRH website at http://www.fda.gov/cdrh/dsma/pmaman/appdxc.html#P7_2
Valid scientific evidence is defined in the “Medical Device Classification Procedures” regulation, 21 CFR Part 860, as:
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 (21 CFR 860.7(c)(2)).
The intended use of the IVD, the level and quality of information in the literature relevant to the device use, and FDA knowledge of the technology obtained from reviewing other premarket applications determine the type of study and the level of evidence you may need to demonstrate reasonable assurance of the safety and effectiveness. For example, if you are studying an IVD device that uses a well-characterized technology and has an intended use that falls within a type of device that has been classified into Class I or Class II, the study may consist of a comparison of analytic performance to that of a legally marketed (i.e., predicate) device. On the other hand, if your IVD uses novel or unproven technology or if there is a new intended use, you may need to conduct a well-planned clinical study of the device in the target population defined by your intended use. You may contact the Division in the appropriate Center if you have questions regarding the type of study you need to conduct for your device.
We recommend that sponsors and investigators of all studies, including exempt studies under 21 CFR 812.2(c)(3), conduct the studies with the following goals in mind: producing valid scientific evidence of the product’s safety and effectiveness and protecting the rights and welfare of study subjects. Sponsors and investigators of significant and non-significant risk studies must comply with the regulation requirements in 21 CFR Part 812. FDA recommends that sponsors and investigators of studies exempt from the majority of requirements under 21 CFR Part 812 use the relevant sections of 21 CFR Part 812 regarding the general conduct of device studies as guidance. (General Regulatory Issues, Section III of this guidance, discusses how 21 CFR Part 812 may apply to a particular IVD study.)
Some studies are exempt from most of Part 812 because of the low risk they pose to study subjects. However, studies that will support a PMA or other premarket submission should have the same goals as all other device studies: 1) to produce valid scientific evidence to support reasonable assurance of a product’s safety and effectiveness, and 2) to protect study subjects. Therefore, the information in Part 812 will also be useful to sponsors and investigators of device studies exempt under 812.2(c). In addition, all studies that will support applications to FDA are subject to 21 CFR 812.119(c) as well as to 21 CFR Part 50 and 21 CFR Part 56.
You may use the ICH GCP as a reference regarding the proper conduct of studies. Although the ICH document was written for studies of pharmaceuticals, sections discussing study conduct common to all investigational products are appropriate references.
The draft ISO document specifically states that it does not apply to IVD devices. This proposed ISO document is an international document intended to reflect basic practices appropriate to clinical trials worldwide. It does not include all of FDA’s specific requirements for clinical studies and is not presently a standard that FDA has officially recognized; therefore, we do not recommend that you rely on it.
Yes. (See the Glossary for definition of terms.) A guidance document regarding these meetings, “Early Collaboration Meetings Under the FDA Modernization Act (FDAMA); Final Guidance for Industry and for CDRH Staff,” is available at http://www.fda.gov/cdrh/ode/guidance/310.pdf. CBER also follows this meeting guidance document when determination and/or agreement meetings are requested.
The majority of the sponsor’s and investigator’s responsibilities in a study of a non-significant risk device are found in section 812.2(b)(1) of the IDE regulation and are summarized below:
- Label the device in accordance with 812.5;
- Obtain 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 maintain such approval.
- Ensure 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 56.109(c).
- Comply with the requirements of 812.46 with respect to monitoring investigations;
- Maintain the records required under 812.140(b)(4) and (5) and make the reports required under 812.150 (b)(1) through (3) and (5) through (10);
- Ensure that participating investigators maintain the records required by 812.140(a)(3)(i) and make the reports required under 812.150(a)(1), (2), (5), and (7);
- Comply with the prohibitions in 812.7 against promotion and other practices.
We recommend that all studies have a written protocol as described in 21 CFR 812.25 (b) and a risk analysis as described in 21 CFR 812.25 (c), regardless of the status of the study under 21 CFR Part 812.
We also recommend that all sites participating in the study use identical copies of the protocol and receive protocol amendments simultaneously so that data is collected in a consistent manner. Data collected from different sites otherwise may not be poolable in the final analysis due to inconsistencies in how it was collected. We recommend that protocols describe the study objectives, design, methodology, subject populations, types of specimens, data to be collected and planned data analysis. (See also Data Considerations, Section VI, of this guidance). For information on how to monitor the study, you may refer to the FDA guidance document entitled “Guideline for the Monitoring of Clinical Investigations,” which is available at http://www.fda.gov/ora/compliance_ref/bimo/clinguid.html.
Yes, we recommend that sponsors and investigators follow quality systems methodologies, including accountability and traceability of the investigational device, auditing of data collected and monitoring to make sure the protocol was followed, documentation of training of staff in the use of the device [21 CFR 812.43(a)], and notifying FDA of unanticipated adverse device effects 21 CFR 812.150(b)(1) in the conduct of IVD studies. Also, 21 CFR 812.20(b)(3) requires “A description of the methods, facilities, and controls used for the manufacture, processing, packing, storage, and, where appropriate, installation of the device, in sufficient detail so that a person generally familiar with good manufacturing practices can make a knowledgeable judgment about the quality control used in the manufacture of the device.” This suggestion is consistent with both the need to provide scientifically valid information in support of premarket submissions and the design control requirements. Manufacturers of Class II and Class III IVD devices, and some Class I devices, are requiredto follow design controls, as described in 21 CFR 820.30 of the “Quality System Regulation,” during the development of investigational devices. 21 CFR 812.1(a). See the Glossary for the definition of device classes.
Additionally, electronic spreadsheets of study data are useful. Given the possible need to review or analyze study data at the most detailed level, electronic spreadsheets may help to minimize review time. For information on electronic records, see the guidance document, "Part 11, Electronic Records; Electronic Signatures -- Scope and Application," at http://www.fda.gov/cder/guidance/5667fnl.htm. There is also a more general guidance document available on electronic records for clinical studies that is entitled “Computerized Systems Used in Clinical Trials,” which is in draft format and can be found at http://www.fda.gov/cder/guidance/6032dft.htm. However, because this document is still in draft form, it is not currently in effect.
What does FDA recommend be included in the final report of the investigation from the sponsor to all reviewing IRBs (and to FDA for significant risk studies) ( 21 CFR 812.150(b)(7))?
A final report should be a basic scientific report of the studies conducted, including the results of testing the study hypotheses. This report can be a useful means of providing a simple account of the data collection and study outcome. Such a report can facilitate preparation of the eventual submission for regulatory action, particularly when accompanied by the information included in the investigational plan (see the Glossary for definition).
Note: this glossary is written in plain language and is for use with this guidance document. Definitions that have been taken from the Act, other pertinent laws, or in Federal regulations include the relevant citation.
Accuracy – the closeness of agreement between the result of a measurement and the true value of the measurand, where the measurand is a particular quantity subject to measurement. For additional information, refer to the Harmonized Technology Database, Clinical and Laboratory Standards Institute, available at http://www.clsi.org.
510(k) – See Premarket Notification.
Agreement meeting – a meeting, under § 520(g)(7) of the act 21 U.S.C. § 360j(g)(7) that is available to anyone planning to investigate the safety or effectiveness of a class III device (see definition below) or any implant. Unlike the Determination Meeting, the Agreement Meeting is available to submitters of 510(k)s for eligible devices. The purpose of the meeting is to reach agreement on the key parameters of the investigational plan, including the study protocol. The meeting is to be held within 30 days of the receipt of a written request. FDA will document in writing any agreement reached and make it a part of the administrative record. The agreement is binding on FDA and can only be changed with the written agreement of the applicant or when there is a substantial scientific issue essential to determining the safety or effectiveness of the device. See 21 U.S.C. 360j(g)(7). A guidance document regarding these meetings, “Early Collaboration Meetings Under the FDA Modernization Act (FDAMA); Final Guidance for Industry and for CDRH Staff,” is available at http://www.fda.gov/cdrh/ode/ guidance/310.pdf.
Class I devices – devices for which the general controls of the Act are sufficient to provide reasonable assurance of their safety and effectiveness. They typically present minimal potential for harm to the user and the person being tested. They are subject to general controls, which include registration and listing, labeling, and adverse event reporting requirements (section 513(a)(1)(A) of the Act). Most Class I devices are exempt from premarket notification (see definition below), subject to certain limitations found in section 510(l) of the Act and in 21 CFR § 862.9, 864.9, and 866.9. Some are also exempt from the “Quality Systems Regulation” found in 21 CFR Part 820. IVD examples of Class I devices include complement reagent, phosphorus (inorganic) test systems (21 CFR 862.1580), and E. coli serological reagents (21 CFR 866.3255).
Class II devices – devices for which general controls alone are insufficient to provide reasonable assurance of their safety and effectiveness and for which establishment of special controls can provide such assurances. Special controls may include special labeling, mandatory performance standards, risk mitigation measures identified in guidance, and postmarket surveillance (section 513(a)(1)(B) of the Act). Some Class II devices are exempt from premarket notification (see definition below), subject to limitation in 21 CFR § § 862.6, 864.9, and 866.9. IVD examples of Class II devices include glucose test systems (21 CFR 1345), antinuclear antibody immunological test systems (21 CFR 866.5100), and coagulation instruments (21 CFR 864.5400).
Class III devices – devices for which insufficient information exists to provide reasonable assurance of safety and effectiveness through general or special controls. Class III devices are usually those that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury (section 513(a)(1)(C) of the Act). Most Class III devices require premarket approval (PMA,see definition below). IVD examples of these include automated PAP smear readers, nucleic acid amplification devices for tuberculosis, and total prostate specific antigen (PSA) for the detection of cancer. A limited number of Class III devices that are equivalent to devices legally marketed before enactment of the Medical Device Amendments of 1976 may be marketed through the premarket notification (510(k)) process (see definition below), until FDA has published a requirement for manufacturers of that generic type of device to submit PMA data.
Compassionate use – The compassionate use provision allows access for patients with a serious disease or condition who do not meet the requirements for inclusion in the clinical investigation but for whom the treating physician believes the device may provide a benefit in treating and/or diagnosing their disease or condition. There must be no feasible alternative therapies/diagnostics available. Compassionate use is typically available only for individual patients but also may be used to treat a small group. Prior FDA approval is needed before compassionate use occurs. Further information can be found at http://www.fda.gov/cdrh/devadvice/ide/early.shtml#compassionateuse.
Confidence interval – the range of plausible values for a statistical parameter, consistent with the observed data, which is computed with a sample estimate parameter (e.g., mean) and its standard deviation. For example, a “95% Confidence Interval” is computed such that, if the parameter was determined for repeated experiments, the resulting values would include the true parameter value 95% of the time.
Continued access to investigational devices – FDA may allow sponsors to continue to enroll subjects under an IDE, after the trial has been completed, while a marketing application is prepared by the sponsor and/or reviewed by FDA. To continue enrolling subjects, a sponsor should show that there is a public health need for the device, that preliminary evidence indicates that the device is likely to be effective for the indications proposed, and that no significant safety concerns have been identified for the proposed indication. A guidance document, entitled “Continued Access to Investigational Devices During PMA Preparation and Review,” can be found at http://www.fda.gov/cdrh/d961.html.
Co-variables – data elements relating to a subject that might affect how well a diagnostic test works, such as demographic status (age, gender, etc.), morbidity, or concurrent therapy.
Determination Meeting – A Determination meeting under § 513(a)(3)(D) of the Act is available to anyone anticipating submitting a PMA or PDP and is intended to provide the applicant with the FDA’s determination of the type of valid scientific evidence that will be necessary to demonstrate that the device is effective for its intended use. As a result of this meeting, FDA will determine whether clinical studies are needed to establish effectiveness and, in consultation with the applicant, determine the least burdensome way of evaluating device effectiveness that has a reasonable likelihood of success. The applicant can expect that FDA will determine if concurrent randomized controls, concurrent non-randomized controls, historical controls, or other types of evidence will be acceptable. FDA’s determination is to be written, shared with the applicant within 30 days following the meeting, and is binding upon the FDA, unless it could be contrary to public health. 21 U.S.C. § 360c(a)(3)(D). A guidance document regarding these meetings, “Early Collaboration Meetings Under the FDA Modernization Act (FDAMA); Final Guidance for Industry and for CDRH Staff,” is available at http://www.fda.gov/cdrh/ode/guidance/310.pdf.
Device – as defined in the Act, section 201(h):
an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is
- recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them;
- intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals; or
- intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.
Excess samples – remnants of human specimens collected for routine clinical care or analysis that would otherwise have been discarded, as well as specimens leftover from specimens previously collected for other unrelated research or investigations. Excess samples are also referred to as “surplus samples,” “residual”, “reserved samples,” "library samples," and "leftover specimens."
Expedited review – review by an institutional review board (IRB) that does not require full board review or a convened meeting. Such a review may be carried out by the IRB chairperson or one or more experienced reviewers assigned by the IRB chairperson from among the members of the IRB. Reviewers may exercise all of the authorities of the IRB except they may not disapprove the study. Disapproval may only result through the IRB’s non-expedited review process. Expedited review is reserved for minimal risk studies. (See 21 CFR 56.110.)
General purpose reagents – chemical reagents that have general laboratory application and that are not labeled or otherwise intended for a specific diagnostic application. They are used to collect, prepare, and/or examine specimens from the human body for diagnostic purposes. (Example: reagents used for general staining in microscopic procedures.) General purpose reagents do not include laboratory machinery, automated or powered systems (21 CFR 864.4010(a)).
Gold standard – see truth standard.
Humanitarian use devices (HUDs) –HUDs are devices intended to diagnose a disease or condition in fewer than 4,000 patients in the U.S. per year. Such devices are regulated under 21 CFR Part 814, Subpart H. If a device receives a designation as an HUD, a Humanitarian Device Exemption request (HDE) can be submitted. HUDs that are approved for marketing under an HDE have specific labeling requirements. IRB approval is required for use of a HUD (21 CFR 814.124).
Investigation – a clinical investigation or research involving one or more subjects to determine the safety or effectiveness of a device (21 CFR 812.3(h)). It is often referred to as a clinical trial and is sometimes referred to as a field trial.
Investigational Device Exemption (IDE) – application which, when approved, allows the device to be shipped lawfully for the purpose of conducting studies regarding the safety and effectiveness of the device, without complying with certain requirements of the Act. (See 21 CFR 812.1 for specific exemptions.) For significant risk (SR) device studies (see definition below), a sponsor must apply to FDA to obtain approval for an IDE. (See 21 CFR 812.20.) For non-significant risk (NSR) device studies (see definition below), an IDE is considered approved when a sponsor meets the abbreviated requirements found in 21 CFR 812.2(b), which include approval from the reviewing Institutional Review Board(s) (IRB(s)).
Investigational plan – sponsor’s overall plan regarding the conduct of an investigational study. It includes, but is not limited to, the purpose of the study, a written protocol, a risk analysis, device description, labeling, written monitoring procedures, informed consent materials, and Institutional Review Board (IRB) information. (21 CFR 812.25.) For IVD studies, protocols should describe the study objectives, design, methodology, subject populations, types of specimens, data to be collected and planned data analysis.
Investigational Use in vitro diagnostic (IVD) product – an IVD product being shipped or delivered for product testing prior to full commercial marketing (e.g., for use on specimens derived from humans to compare the usefulness of the product with other products or procedures in current use or recognized as useful). These products must be labeled according to 21 CFR 812.5 for non-significant risk or significant risk devices and according to 21 CFR 809.10(c)(2)(ii) for devices that are exempt under 812.2(c).
Investigator – an individual who actually conducts a clinical investigation, i.e., a person under whose immediate direction the investigational product is administered, dispensed, or used, provided that the investigation involves a subject. In the event of an investigation conducted by a team of individuals, the investigator is the responsible leader of that team (21 CFR 812.3(i)).
In vitro diagnostic (IVD) products – those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body. IVD products are devices as defined in section 201(h) of the Act and may also be biological products subject to section 351 of the Public Health Service Act. The regulatory definition of in vitro diagnostic products is found in 21 CFR 809.3(a).
Leftover specimens -- remnants of specimens collected for routine clinical care or analysis that would otherwise have been discarded, or remnants of specimens previously collected for other unrelated research. These specimens may be obtained from a specimen repository -- a common site for storage of collections of human biological specimens available for study. See also Excess samples.
Non-significant risk (NSR) device – a device that does not meet the definition of significant risk (SR) device (see definition below). An IDE is considered approved for a NSR investigational device study once sponsors meet the abbreviated requirements found in the “Investigational Device Exemptions” regulation at 21 CFR 812.2(b). The risk determination for an investigational device study should be based on the proposed use of the device in the investigation in addition to the characteristics of the device.
Outlier – a data observation whose value appears to be out of line with the main body of data that has been collected.
Pre-amendment in vitro diagnostic (IVD) tests – IVD tests that were in commercial distribution before May 28, 1976.
Precision – the closeness of agreement between independent diagnostic test results obtained under stipulated conditions. For additional information refer to the Harmonized Technology Database, Clinical and Laboratory Standards Institute, available at http://www.clsi.org.
Premarket Approval Application (PMA) – the application for approval required prior to the marketing of most Class III medical devices (section 515 of the Act, 21 USC 360e). (See definitions of Class I, II, and III devices above.) PMA approval is based on a determination by FDA that the applicant’s submission provides sufficient valid scientific evidence to provide reasonable assurance that the device is safe and effective for its intended use(s). The PMA regulation is 21 CFR Part 814. PMA information is available at http://www.fda.gov/cdrh/devadvice/pma/.
Premarket Notification – also referred to as a 510(k), is a submission to FDA that contains information to demonstrate that a device is substantially equivalent (SE) to a legally marketed (predicate) device. Governing regulations regarding premarket notification procedures are found in Subpart E of the “Establishment Registration and Device Listing for Manufacturers and Initial Importers of Devices” regulation (21 CFR Part 807). The 510(k) manual is available at http://www.fda.gov/cdrh/manual/ 510kprt1.html.
Product Development Protocol (PDP) – FDA process of approval for marketing of medical devices, usually reserved for Class III devices (see definitions of device classes above), by which the sponsor and FDA agree on the product design and testing early in the concept and planning stages of a product (section 515(f) of the Act).
Protocol – a document that contains a description of the objectives and design of an investigational study, methodology(s) to be used, and data to be collected. It may also contain information regarding the planned data analysis and study monitoring. For most studies in the development of an IVD product, it also contains information regarding types of specimens and subject populations.
Reserved samples – see excess samples.
Sensitivity – the probability that a diagnostic test will yield a positive result when the disease or the target analyte is present.
Significant risk (SR) device – an investigational device that presents a potential for serious risk to the health, safety, or welfare of a subject and:
The risk determination for an investigational device study should be based on the proposed use of the device in the investigation in addition to the device characteristics. Sponsors of significant risk device studies must apply to FDA for an Investigational Device Exemption (IDE) (see definition above). (21 CFR 812.3(a), 812.3(m); 812.20.)
Simulated specimens – specimens made in the laboratory by adding the analyte of interest in known concentrations to a medium that simulates the natural matrix.
Specificity – the probability that a diagnostic test will yield a negative result when the disease or target analyte is absent.
Sponsor – a person who initiates, but who does not actually conduct, the investigation, i.e., the investigational device is administered, dispensed, or used under the immediate direction of another individual. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-investigator (see next definition), and the employees are investigators (see definition above) (21 CFR 812.3(n)).
Sponsor-investigator – an individual who both initiates and actually conducts, alone or with others, an investigation, i.e., under whose immediate direction the investigational device is administered, dispensed, or used. The term does not include any person other than an individual. The obligations of a sponsor-investigator include both those of an investigator and those of a sponsor (21 CFR 812.3(o)).
Statistical hypothesis – a statement about some state of nature that a proposed study or set of studies will either accept or reject on the basis of the experimental data. The hypothesis is usually broken down into a null hypothesis (a statement of what the testing results will hopefully reject) and an alternative hypothesis (a statement of what the testing results will hopefully accept).
Study – as used in this document, covers the systematic evaluations conducted in the development of an IVD product, including the feasibility, analytical assessments, method comparison, and evaluations to determine clinical utility of a product.
Subject – a human who participates in an investigation, either as an individual on whom or on whose specimen an investigational device is used or as a control. A subject may be in normal health or may have a medical condition or disease (21 CFR 812.3(p)).
Surplus samples – see excess samples.
Transitional device – a product defined as a device as of May 28, 1976, but previously considered by FDA to be a new drug or an antibiotic drug (21 CFR 812.3(r)).
Treatment IDE – use of an unapproved investigational device for the treatment or diagnosis of patients during the clinical trial or prior to final FDA action on the marketing application, if during the course of the clinical trial the data suggest that the device is effective. A treatment IDE may cover a large number of patients that exceeds the number of clinical sites and patients stipulated in the original IDE. The device must be for treatment or diagnosis of a serious or immediately life-threatening disease or condition; there must be no comparable or satisfactory alternative device or therapy available; the device must be under investigation in a controlled clinical study for the same use under an approved IDE, or such clinical studies have been completed; and the sponsor must be actively pursuing marketing approval or clearance of the device. Requirements for an application for a treatment IDE are found in the Investigational Device Exemptions regulation at 21 CFR 812.36.
Truth Standard (“Gold” Standard) - any medical procedure or laboratory method or combination of procedures and methods that the clinical community relies upon for diagnosis, that is accepted by FDA, and that is regarded as having negligible risk of either a false positive or a false negative result. The truth standard result should be definitive (positive/negative, present/absent, or diseased/non-diseased), and should not give an indeterminate result. As science and technology improve, newer, more reliable standards may replace previous standards, particularly in the case of new disease markers.
Note: this listing is presented in the order that the documents are first referred to in this guidance document.
Registration & Listing |
Application | Applicable Labeling 801-Subpart A & 801.119 to all |
Limitations | QSRs | IRB & Informed Consent |
Adverse Event Reporting |
|
---|---|---|---|---|---|---|---|
General Purpose Reagents (Class I) |
No 807.65(c) |
No 864.4010(b) |
809.10(d) |
‘For Laboratory Use’ 809.10(d)(1)(iv) |
Only 820.180 and 820.198 (if not sterile) 864.4010(b) |
N/A |
Yes Part 803 |
ASR's Class I | Yes 807.20(a) |
No 864.4020(b)(1) |
809.10(e) 809.30(c) |
Restrictions on sale, use, distribution, & reporting 809.30 |
Yes 809.20(b) |
N/A |
Yes Part 803 |
Class II | Yes 807.20(a) |
510(k) 807.81 864.4020(b)(2) |
|||||
Class III | Yes 807.20(a) |
PMA, 814.1 | |||||
864.4020(b)(3) | |||||||
Investigational Use: | No 812.1 |
IDE 812.20 |
812.5
[exempt from 809.10(a)&(b)] |
Prohibition on promotion and commercialization
812.7 |
No (except for 820.30) 812.1 But see 812.20(b)(3) |
Yes Parts 50 & 56 |
For SR and NSR:
Investigators report to IRB |
Significant Risk (SR) | |||||||
Non-Significant Risk (NSR) | No 812.1 |
No 812.2(b) |
|||||
Exempt from most requirements of Part 812 Note: 21 CFR 812.119 applies to all |
No 807.20(a) (investigational devices are not in commercial distribution) |
No 812.2(c)(3) |
809.10(c)(2)(ii) |
‘For investigational Use Only. The performance characteristics of this product have not been established’ 809.10(c)(2)(ii) |
No* |
Yes Parts 50 & 56 |
Sponsors may need to report to FDA 812.150(b)(1) |
Research Use |
No 807.65(f) |
No |
809.10(c)(2)(i) |
‘Research Use Only’ 809.10(c)(2)(i) |
No* |
See Parts 50.1 & 56.101 for applicable requirements for clinical research |
No 803.19(a)(2) |
For non investigational commercially marketed in vitro diagnostic devices: |
|||||||
Pre-Amendment device |
Yes 807.20(a) |
No [unless 807.81(a)(3) and unless rule requires PMA, 21 U.S.C. 360e(b)] |
809.10 “For In Vitro Diagnostic Use” 809.10(a)(4) |
See "labeling" |
Yes 809.20(b) |
N/A |
Yes 803.1 |
Premarket Notification* *See 21CFR 862-866 (generic device class regulations) for specific-device exemptions |
Yes 807.20(a) |
510(k) 807.81 (Exemptions subject to limitations in 862.9, 864.9 & 866.9) |
Yes 809.20(b) |
||||
PMA/PDP (Class III) |
Yes 807.20(a) |
PMA 814.20 |
Yes 809.20(b) |
||||
HDE | Yes 807.20(a) |
HUD 814.102 HDE 814.104 |
809.10 814.104(b)(4)(ii) |
Labeling & Cost
814.104(b)(4)(ii) |
Yes 809.20(b) |
IRB approval 814.124 [no informed consent] |
Yes 814.126(a) 803.1 |
* While investigational IVDs exempt from most of the provisions of 812 are not exempt from the QSR requirements, we generally do not intend to enforce such requirements for investigational IVDs that are exempt from most Part 812 requirements; except for design controls.
1. General Duties (21 CFR 812.40)
a. Submitting the IDE application to FDA
b. Obtaining both FDA and IRB approval for the investigation
c. Selecting qualified investigators and providing them with the information they need to conduct the investigation properly
d. Ensuring proper monitoring of the investigation
e. Ensuring that any reviewing IRB and FDA are promptly informed of significant new information about an investigation
2. Selection of Investigators (21 CFR 812.43)
a. Assuring selection of investigators qualified by training and experience
b. Shipping the investigational device only to participating investigators
c. Obtaining a signed investigator's agreement from each investigator containing:(1) investigator's curriculum vitae
(2) statement of investigator's relevant experience, including dates, location, extent, and type of experience
(3) if an investigator was involved in an investigation or other research that was terminated, an explanation of the circumstances that led to the termination
(4) statement of the investigator's commitment to:• conduct the investigation in accordance with the agreement, the investigational plan, Part 812 and other applicable regulations, and any conditions of approval imposed by the IRB or FDA
• supervise all testing of the device involving human subjects
• ensure that the requirements for obtaining informed consent are met (21 CFR Part 50)d. Selecting monitor(s) qualified by training and experience to monitor the progress of the investigation in accordance with FDA regulations.
e. Providing investigators with the investigational plan and report of prior investigations of the device. (21 CFR 812.45)
3. Monitoring (21 CFR 812.46)
a. Securing compliance of all investigators in accordance with the signed investigator's agreement, the investigational plan, the requirements of Part 812 or other applicable FDA regulations, or any condition of approval imposed by the reviewing IRB or FDA. If compliance cannot be secured, shipment of the device to the investigator and the investigator's participation in the investigation must be discontinued
b. Evaluating all unanticipated adverse device effects and terminating the investigation, or portions of it, as soon as possible if that effect presents an unreasonable risk to subjects (Reporting requirements are listed below.)
c. Resuming terminated investigations only after IRB and/or FDA approvals are obtained, as required by this regulation.
4. Controlling Distribution and Disposition of Devices
Although investigators are responsible for ensuring that investigational devices are made available only to persons who are legally authorized to receive them (see 21 CFR 812.110(c)), sponsors also bear responsibility for taking proper measures to ensure that devices are not diverted outside of legally authorized channels. Sponsors may ship investigational devices only to qualified investigators participating in the clinical investigation (§ 812.43(b)). Sponsors must also maintain complete, current, and accurate records pertaining to the shipment and disposition of the investigational device (§ 812.140(b)(2)). Records of shipment shall include the name and address of the consignee, type and quantity of device, date of shipment, and batch number or code mark. Records of disposition shall describe the batch number or code marks of any devices returned to the sponsor, repaired, or disposed of in other ways by the investigator or another person, and the reasons for and method of disposal.
To further ensure compliance with these requirements, sponsors should take appropriate measures to instruct investigators regarding their responsibilities with respect to recordkeeping and device disposition. The specific recordkeeping requirements for investigators are set forth at § 812.140(a). Upon completion or termination of a clinical investigation (or the investigator's part of an investigation), or at the sponsor's request, an investigator is required to return to the sponsor any remaining supply of the device or otherwise to dispose of the device as the sponsor directs (§ 812.110(e)).
5. Prohibition of Promotion and Other Practices (21 CFR § 812.7)
The IDE regulation prohibits the promotion and commercialization of a device that has not been first cleared or approved for marketing by FDA. This prohibition is applicable to sponsors and investigators (or any person acting on behalf of a sponsor or investigator), and encompasses the following activities:
a. Promotion or test marketing of the investigational device
b. Charging subjects or investigators for the device a price larger than is necessary to recover the costs of manufacture, research, development, and handling
c. Unduly prolonging an investigation beyond the point needed to collect data required to determine whether the device is safe and effective, and
d. Representing that the device is safe or effective for the purposes for which it is being investigated.
6. Supplemental Applications (21 CFR 812.35(a) and (b))
Supplemental applications are required to be submitted to, and approved by, FDA in the following situations:
a. Changes in the investigational plan: FDA approval is required for any change that may affect the scientific soundness of the investigation or the rights, safety or welfare of the subjects. IRB approval is also required for changes that may affect the rights, safety or welfare of the subjects. The change in the investigational plan may not be implemented until FDA approval (and IRB approval, if required) is obtained.
b. Addition of new institutions: IRB approval is also required for new institutions. The investigation at the new institution(s) may not begin until both FDA and IRB approval(s) are obtained, and certification of IRB approval is submitted to FDA.
7. Maintaining Records (21 CFR 812.140(b))
A sponsor shall maintain the following accurate, complete, and current records relating to an investigation (also See Table I, next page):
a. Correspondence (including reports) with another sponsor, monitor, investigators, an IRB or FDA
b. Records of shipment, including:(1) name and address of consignee
(2) type and quantity of device
(3) date of shipment
(4) batch numbers or code marksc. Records of disposition, describing:
(1) Batch number or code mark of devices returned, repaired, or disposed of by the investigator or other persons
(2) Reasons for and method of disposald. Signed investigator agreements
e. Adverse device effects (whether anticipated or unanticipated) and complaints
f. Any other records that FDA requires by regulation or by specific requirement for a category of investigation or a particular investigation
TABLE I
RESPONSIBILITIES FOR MAINTAINING RECORDS
FOR A SIGNIFICANT RISK DEVICE STUDY
Records |
Maintained by Investigator |
Maintained by Sponsor |
All Correspondence Pertaining to the Investigation |
X |
X |
Shipment, Receipt, Disposition |
X |
X |
Device Administration and Use |
X |
- |
Subject Case Histories |
X |
- |
Informed Consent |
X |
- |
Protocols and Reasons for Deviations from Protocol |
X |
- |
Adverse Device Effects and Complaints |
X |
X |
Signed Investigator Agreements |
- |
X |
Membership/Employment/Conflicts of Interest |
- |
X |
8. Submitting Reports (21 CFR 812.150(b))
A sponsor shall prepare and submit the following complete, accurate, and timely reports (also see Table II, next page):a. Unanticipated adverse device effects (with evaluation) to FDA, all IRBs, and investigators within 10 working days after notification by the investigator. Subsequent reports on the effect may be required by FDA
b. Withdrawal of IRB approval
c. Withdrawal of FDA approval
d. Current 6 month investigator list
e. Progress reports (at least annual) see attached suggested format for IDE progress report
f. Recall and device disposition (within 30 working days after the request was made)
g. Final report see attached suggested format for progress reports
h. Use of device without obtaining patient informed consent within 5 working days of receipt of notice of such use
i. Significant risk determinations by the IRB when sponsor had proposed nonsignificant risk within 5 working days of receipt of such IRB determination
j. Other reports requested by the IRB or FDA about any aspect of the investigation
TABLE II
RESPONSIBILITIES FOR PREPARING AND SUBMITTING REPORTS
FOR SIGNIFICANT RISK DEVICE STUDIES
Type of Report |
Prepared by Investigators for |
Prepared by Sponsors for |
Unanticipated Adverse Effect Evaluation |
Sponsors and IRBs |
FDA, IRBs and Investigators |
Withdrawal of IDE Approval |
Sponsors |
FDA, IRBs, and Investigators |
Progress Report |
Sponsors, Monitors and IRBs |
FDA and IRBs |
Final Report |
Sponsors and IRBs |
FDA, IRBs, and Investigators |
Emergencies (Protocol Deviations) |
Sponsors and IRBs |
FDA |
Inability to Obtain Informed Consent |
Sponsors and IRBs |
FDA |
Withdrawal of FDA Approval |
N/A |
IRBs and Investigators |
Current Investigator List |
N/A |
FDA |
Recall and Device Disposition |
N/A |
FDA and IRBs |
Records Maintenance Transfer |
Sponsors |
FDA |
Significant Risk Determinations |
N/A |
FDA |
9. Inspections (21 CFR 812.145)
Sponsors are required to permit FDA to enter and inspect (at reasonable times and in a reasonable manner) any establishment where devices are held (including any establishment where devices are manufactured, processed, packed, installed, used, or implanted or where records or results from use of devices are kept). FDA may also inspect and copy all records relating to an investigation including, in certain situations, records which identify subjects.
1. General Responsibilities of Investigators (21 CFR 812.100)
a. Ensuring that the investigation is conducted according to the signed agreement, the investigational plan and applicable FDA regulations
b. Protecting the rights, safety, and welfare of subjects under the investigator's care
c. Controlling devices under investigation
d. Ensuring that informed consent is obtained from each subject in accordance with 21 CFR Part 50
2. Specific Responsibilities of Investigators (21 CFR 812.110)
a. Awaiting IRB approval and any necessary FDA approval before requesting written informed consent or permitting subject participation
b. Conducting the investigation in accordance with:(1) the signed agreement with the sponsor
(2) the investigational plan
(3) the regulations set forth in 21 CFR Part 812 and all other applicable FDA regulations, and
(4) any conditions of approval imposed by an IRB or FDAc. Supervising the use of the investigational device. An investigator shall permit an investigational device to be used only with subjects under the investigator's supervision. An investigator shall not supply an investigational device to any person not authorized under 21 CFR Part 812 to receive it.
d. Financial disclosure. A clinical investigator shall disclose to the sponsor sufficient accurate financial information to allow the applicant to submit complete and accurate certification or disclosure statements under Part 54.
e. Disposing of the device properly. Upon completion or termination of a clinical investigation or the investigator's part of an investigation, or at the sponsor's request, an investigator shall return to the sponsor any remaining supply of the device or otherwise dispose of the device as the sponsor directs.
3. Maintaining Records (21 CFR 812.140)
An investigator shall maintain the following accurate, complete, and current records relating to the investigator's participation in an investigation:
a. Correspondence with another investigator, an IRB, the sponsor, a monitor, or FDA
b. Records of receipt, use or disposition of a device that relate to:(1) the type and quantity of the device, dates of receipt, and batch numbers or code marks
(2) names of all persons who received, used, or disposed of each device
(3) the number of units of the device returned to the sponsor, repaired, or otherwise disposed of, and the reason(s) thereforec. Records of each subject's case history and exposure to the device, including:
(1) documents evidencing informed consent and, for any use of a device by the investigator without informed consent, any written concurrence of a licensed physician and a brief description of the circumstances
(2) justifying the failure to obtain informed consent
(3) document all relevant observations, including records concerning adverse device effects (whether anticipated or not), information and data on the condition of each subject upon entering, and during the course of, the investigation, including information about relevant previous medical history and the results of all diagnostic tests
(4) a record of the exposure of each subject to the investigational device, including the date and time of each use, and any other therapyd. The protocol, with documents showing the dates of and reasons for each deviation from the protocol
e. Any other records that FDA requires to be maintained by regulation or by specific requirement for a category of investigations or a particular investigation.
4. Inspections (21 CFR 812.145)
Investigators are required to permit FDA to inspect and copy any records pertaining to the investigation including, in certain situations, those which identify subjects.
5. Submitting Reports (21 CFR 812.150)
An investigator shall prepare and submit the following complete, accurate, and timely reports:
a. To the sponsor and the IRB:
(1) Any unanticipated adverse device effect occurring during an investigation. (Due no later than 10 working days after the investigator first learns of the effect.)
(2) Progress reports on the investigation. (These reports must be provided at regular intervals, but in no event less often than yearly. If there is a study monitor, a copy of the report should also be sent to the monitor.)
(3) Any deviation from the investigational plan made to protect the life or physical well-being of a subject in an emergency. (Report is due as soon as possible but no later than 5 working days after the emergency occurs. Except in emergency situations, a protocol deviation requires prior sponsor approval; and if the deviation may affect the scientific soundness of the plan or the rights, safety, or welfare of subjects, prior FDA and IRB approval are required.)
(4) Any use of the device without obtaining informed consent. (Due within 5 working days after such use.)
(5) A final report. (Due within 3 months following termination or completion of the investigation or the investigator's part of the investigation. For additional guidance, see the discussion under the section entitled "Annual Progress Reports and Final Reports.")
(6) Any further information requested by FDA or the IRB about any aspect of the investigation.b. To the Sponsor:
(1) Withdrawal of IRB approval of the investigator's part of an investigation. (Due within 5 working days of such action).
6. Investigational Device Distribution and Tracking
The IDE regulations prohibit an investigator from providing an investigational device to any person not authorized to receive it (21 CFR 812.110(c)). The best strategy for reducing the risk that an investigational device could be improperly dispensed (whether purposely or inadvertently) is for the sponsor and the investigators to closely monitor the shipping, use, and final disposal of the device(s). Upon completion or termination of a clinical investigation (or the investigator's part of an investigation), or at the sponsor's request, an investigator is required to return to the sponsor any remaining supply of the device or otherwise to dispose of the device as the sponsor directs (21 CFR § 812.110(e)). Investigators must also maintain complete, current and accurate records of the receipt, use, or disposition of investigational devices (21 CFR § 812.140(a)(2)). Specific investigator recordkeeping requirements are set forth at 21 CFR § 812.140(a).
7. Prohibition of Promotion and Other Practices (21 CFR § 812.7)
The IDE regulations prohibit the promotion and commercialization of a device that has not been first cleared or approved for marketing by FDA. This prohibition is applicable to sponsors and investigators (or any person acting on behalf of a sponsor or investigator), and encompasses the following activities:
a. Promotion or test marketing of the investigational device
b. Charging subjects or investigators for the device a price larger than is necessary to recover the costs of manufacture, research, development, and handling
c. Unduly prolonging an investigation beyond the point needed to collect data required to determine whether the device is safe and effective, and
d. Representing that the device is safe or effective for the purposes for which it is being investigated.
8. Annual Progress Reports and Final Reports
The IDE regulations do not specify the content of the annual progress or final reports. With respect to reports to the IRB, the IRB itself may specify what information it wishes to be included in these reports. Because FDA does require the information listed below, it is suggested that, at a minimum, the annual progress and final reports to the sponsor and the IRB also include the following items:
a. IDE number
b. Device name
c. Indications for use
d. Brief summary of study progress in relation to investigational plan
e. Number of investigators and investigational sites
f. Number of subjects enrolled
g. Number of devices received, used, and the final disposition of unused devices
h. Brief summary of results and conclusions
i. Summary of anticipated and unanticipated adverse device effects
j. Description of any deviations from investigational plan
k. Reprints of any articles published by the investigator in relation to the study
1 As explained below, even if a particular IVD study is exempt from most requirements of Part 812, studies that will support applications to FDA are subject to 21 CFR 812.119 (Disqualification of a Clinical Investigator), 21 CFR Part 50 (Informed Consent), and 21 CFR 56 (Institutional Review Boards).
2 For the purpose of this document, “you” refers to the manufacturer, sponsor, applicant, investigator and the IVD device industry in general. If the text refers only to one or some of these entities, the appropriate entity is referenced by its name.
3 This reference can be found at: www.fda.gov/cdrh/ode/idepolcy.html
4 See Chapter III, "Expanded Access to Unapproved Devices," of the guidance document "IDE Policies and Procedures," http://www.fda.gov/cdrh/ode/idepolcy.html.
Updated November 2, 2007
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