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Draft Guidance for Industry, Clinical Laboratories, and FDA Staff - In Vitro Diagnostic Multivariate Index Assays

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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Document issued on: July 26, 2007

Comments and suggestions regarding this draft document should be submitted within 30 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.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 Regulations.gov. All comments should be identified with the docket number 2006D-0347.

For questions regarding this document contact Courtney Harper at 301-796-5458 (courtney.harper@fda.hhs.gov). For questions regarding this document as applied to devices regulated by CBER contact Martin Ruta at 301-827-3518

CDRH logo

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health
Office of In Vitro Diagnostic Device Evaluation and Safety

Center for Biologic Evaluation and Research

Contains Nonbinding Recommendations
Draft - Not for Implementation 

Preface

Additional Copies

Additional copies are available from the Internet. You may also send an e-mail request to dsmica@fda.hhs.gov to receive an electronic copy of the guidance or send a fax request to 301-847-8149 to receive a hard copy. Please use the document number (1610) to identify the guidance you are requesting. Copies of the guidance are also available from:

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
Phone: 800-835-4709 or 301-827-1800

Draft Guidance for Industry, Clinical Laboratories, and FDA Staff
In Vitro Diagnostic Multivariate Index Assays

This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current thinking on this topic.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.

 Introduction

This draft guidance addresses the definition and regulatory status of a class of In Vitro Diagnostic Devices referred to as In Vitro Diagnostic Multivariate Index Assays (IVDMIAs).

The draft guidance also addresses premarket pathways and postmarket requirements with respect to IVDMIAs. As is true for all medical devices, regulatory classifications are driven by intended use(s) and device risk.

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

Background

The definition of a device is set forth at section 201(h) of the Food, Drug and Cosmetic Act ("the Act"). It provides in relevant part: "The term 'device' . . . means an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is . . . (2) 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 . . . ." (21 USC 321(h)). As described further in this guidance document, an IVDMIA is a device that:

  1. Combines the values of multiple variables using an interpretation function to yield a single, patient-specific result (e.g., a “classification,” “score,” “index,” etc.), that is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment or prevention of disease, and
  2. Provides a result whose derivation is non-transparent and cannot be independently derived or verified by the end user.

An IVDMIA is a device within the meaning of the Act.

Some IVDMIAs are laboratory-developed tests (LDTs). LDTs are tests that are developed by a single clinical laboratory for use only in that laboratory. Laboratory developed IVDMIAs are a specific subset of LDTs. While FDA has stated that "clinical laboratories that develop [in-house] tests are acting as manufacturers of medical devices and are subject to FDA jurisdiction under the Act," 62 FR 62249, the Agency has generally exercised enforcement discretion over standard LDTs, e.g., LDTs that use primarily analyte specific reagents, general purpose reagents (21 CFR 864.4010), general purpose laboratory equipment (21 CFR 862.2050), other laboratory instrumentation (21 CFR Part 864, subpart D), and controls (21 CFR 862.1660). IVDMIAs include elements, as described in the section on "Definition and Regulatory Status of IVDMIAs" of this guidance, that are not among these primary ingredients of LDTs (e.g., complex, unique interpretation functions). IVDMIAs thus do not fall within the scope of LDTs over which FDA has generally exercised enforcement discretion.

IVDMIAs raise significant issues of safety and effectiveness. These types of tests are developed based on observed correlations between multivariate data and clinical outcome, such that the clinical validity of the claims is not transparent to patients, laboratorians, and clinicians who order these tests. Additionally, IVDMIAs frequently have a high risk intended use. FDA is concerned that patients are relying upon IVDMIAs with high risk intended uses to make critical healthcare decisions when FDA has not ensured that the IVDMIA has been clinically validated and the healthcare practitioners are unable to clinically validate the test themselves. Therefore, there is a need for FDA to regulate these devices to ensure that the IVDMIA is safe and effective for its intended use.

With this draft guidance document, FDA seeks to identify IVDMIAs as a discrete category of device, and to clarify that, even when offered as LDTs, IVDMIAs must meet pre- and post-market device requirements under the Act and FDA regulations, including premarket review requirements in the case of most class II and III devices.

The Least Burdensome Approach

This guidance document reflects our careful review of what we believe are the relevant issues related to IVDMIAs and what we believe would be the least burdensome way of addressing these issues. If you have comments on whether there is a less burdensome approach, however, please submit your comments as indicated on the cover of this document.

Definition and Regulatory Status of IVDMIAs

Definition

An IVDMIA is a device that:

  1. Combines the values of multiple variables using an interpretation function to yield a single, patient-specific result (e.g., a “classification,” “score,” “index,” etc.), that is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment or prevention of disease, and
  2. Provides a result whose derivation is non-transparent and cannot be independently derived or verified by the end user.

While the input variables, alone or in combination, might have meaning to the clinician, the clinician could not verify the clinical significance of the IVDMIA result on his or her own. In addition, the ordering physician cannot reach the IVDMIA result on his or her own, nor could he or she independently interpret that result. The ordering clinician requires information from the test developer, rather than generally accepted information from the clinical community, in order to interpret the IVDMIA result for use in the management of the patient. For an IVDMIA, it is the single patient-specific result that is associated with the intended use of the device. The IVDMIA device includes all elements necessary for obtaining the result.

Examples

The following are examples, real or hypothetical, of devices that would meet the definition of an IVDMIA because these types of devices combine data from a number of input variables to generate a classification or a score (usually a univariate result) and the clinician could not independently analyze the input variables to arrive at the same interpretation. In general, an IVDMIA might use measured or observed values of multiple variables, such as a patient's age, weight, metabolite level, and gene expression levels. A unique interpretation function specific to the IVDMIA would then combine and analyze these variables to yield a score. The intended use of the IVDMIA would, for example, be to diagnose disease or predict risk of disease based upon this score. The following are more specific examples of IVDMIAs:

  • Devices classified under 21 CFR 866.6040, Gene expression profiling assay for breast cancer prognosis
  • A device that integrates quantitative results from multiple immunoassays to obtain a qualitative “score” that predicts a person’s risk of developing a disease or condition.
  • A device that integrates a patient’s age, sex, and genotype of multiple genes to predict risk of or diagnose a disease or condition.

The IVDMIA result may be expressed in many ways, including, for example, as a binary result (e.g., yes or no), a classification (e.g., disease type or grade, disease positive or disease negative), an ordinal result (e.g., low, average, or high risk), or a continuous result (e.g., score of “18” on a scale of 0 – 50).

In contrast, FDA would not consider devices with a function that simply facilitates the interpretation of multiple variables that health care practitioners could otherwise interpret themselves to be IVDMIAs. The following are examples of devices that FDA does not consider to meet the definition of an IVDMIA and that are outside the scope of this guidance document:

  • Devices that combine multiple variables into a single patient-specific result that facilitates an interpretation of the variables that clinicians could otherwise interpret themselves because of extensive experience and training in use of the device (e.g., standard maternal Triple Screen testing- measurement in the second trimester of AFP, hCG, and estriol).
  • Genotype determination (e.g., CFTR genotyping) – This type of device provides genotype identification that has an established association with the phenotype of interest. Even though multiple variables (loci, alleles, mutations) are measured and a single result (genotype or predicted phenotype) is generated, the device does not incorporate a unique interpretation function but rather provides standard interpretation of the individual variables that clinicians could do themselves.
  • Chromosomal copy number determination – This type of device is intended to identify abnormal or pathologic numerical changes (gains and losses) in a patient’s chromosomal DNA. Even though multiple variables may be measured, the device does not incorporate a unique interpretation function but rather provides standard interpretation of the individual variables that clinicians could do themselves.
  • Common clinical calculations (e.g., creatinine clearance, determination of cholesterol ratios, estimated glomerular filtration rate) - Even though multiple variables are measured and a single result is calculated, the device does not incorporate a unique interpretation function but rather provides standard interpretation of the individual variables that clinicians could do themselves.
  • Devices such as Clinical Decision Support tools that analyze stored clinical information to, for example, flag patient results based on specific clinical parameters (e.g., out of range results, potential drug interactions, opportunities for complementary tests, etc.), create disease registries, summarize patient-specific information in an integrated report, and/or track a patient’s treatment or disease outcome. The analysis performed by these software platforms does not represent a unique interpretation function but rather summarizes standard interpretation of individual variables that clinicians could do themselves.
  • Common, public demographic1 risk calculations (e.g., Gail Index, Framingham Risk Score) – These types of calculations are generally freely available to the clinical community, through wide dissemination in peer-reviewed publications, practice guidelines, etc. Clinicians are able to use and interpret this type of calculation in the context of their own clinical knowledge and generally accepted information from the clinical community.

The examples above are intended to provide general illustrations to help manufacturers understand the properties that, when found in combination, would indicate that the device is considered an IVDMIA. The list is not intended to be exhaustive, and variations in the devices described above could further affect whether the device is considered an IVDMIA. Manufacturers should take care to determine whether a multivariate device would be considered an IVDMIA based on the definition above. Manufacturers may consult with the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) if they are unsure whether a device is an IVDMIA.

Premarket and Postmarket Requirements for IVDMIAs

Regulation of IVDMIAs

As with all devices, including all IVDs, FDA will take a risk-based approach to the regulation of IVDMIAs. (21 USC 360c(a)(1)). The following is general information about pre- and post-market requirements for FDA regulated devices. For more information on such requirements see the Appendix.

1. 510(k) or PMA?

Medical devices, including IVDMIAs, are assigned to one of three regulatory classes based on the level of control necessary to assure the safety and effectiveness of the device. The three classes are designated as Class I (low risk), Class II (moderate risk), and Class III (high risk). 21 USC § 360c. Classification of an IVDMIA would depend on its intended use(s) and on the level of control necessary to assure the safety and effectiveness of the device. Although certain technologies, e.g., gene expression profiling, yield types of data that are likely to be combined and used as IVDMIAs, IVDMIAs, like all devices, are classified based upon the level of risk of the intended use and not based upon the class of technology involved. Class I medical devices are usually exempt from premarket review and rely on general controls such as registration, listing and good manufacturing practices to assure the safety and effectiveness of low risk devices. Class II medical devices typically require FDA clearance of a premarket notification submission (a 510(k)). 21 U.S.C. § 360k. Class III devices require the submission of an application for Premarket Approval (PMA). 21 U.S.C. § 360e. [see "Device Classification" for additional information on device classifications].

We believe most IVDMIAs will be either class II or III devices, although it is possible that an IVDMIA for a low-risk indication could be class I. For example, a device intended as an indicator of a patient's risk of cancer recurrence may be a class II device (e.g., devices classified under 21 CFR 866.6040, Gene expression profiling assay for breast cancer prognosis), while the same device intended to predict which patients should receive chemotherapy might require premarket approval. See the Appendix for more information on how devices with novel intended uses are classified and regulated.

FDA believes that any safety and effectiveness determinations that are part of the premarket review process should include review of the performance of the entire system, including the accurate measurement of the input variables, directions for use, and expected analytical or clinical performance, rather than a review of only certain subcomponents of the test. This is because use of the entire system (e.g., patient demographics, adjunctive clinical information, sample procurement, preparation, analyte measurement, analysis, and reporting) is necessary to obtain a meaningful result. Regulation of the IVDMIA as a whole is consistent with the regulation and classification of other devices, including clinical chemistry test systems (21 CFR Part 862, Subpart B) and clinical toxicology test systems (21 CFR Part 862, Subpart D). Although not IVDMIAs, FDA has regulated as complete devices those laboratory-developed tests used in donor screening for HIV and HCV to assure the safety of blood products under section 351 of the Public Health Service Act2 .

Analytical and clinical performance data in a premarket submission that supports the intended use and indications for use of an IVDMIA should be obtained from studies that include the intended use population and that are performed according to the intended use of the device. If data from clinical studies are necessary to support the intended use, carefully designed prospective studies are ideal. However, we will consider alternative methods to evaluate the performance of the IVDMIA for its specific intended use if the sponsor can demonstrate that the alternative method will provide adequate assurances of safety and effectiveness. For example, the use of archived samples and/or retrospective data may sometimes be used to support clearance or approval, provided the study design and sample composition reflect the intended use of the device in the intended population. If using retrospective data, sample selection biases should be avoided, and studies should be designed using archived samples that were properly collected and stored.

2. Investigational Use of IVDMIAs
Clinical investigations using human specimens3 conducted in support of premarket submissions for IVDMIAs are subject to the human subject investigations requirements of 21 CFR Part 50. During this investigational phase, the safety and effectiveness of the product are being studied; i.e., the clinical performance characteristics and expected values are being determined in the intended patient population(s). These products must be labeled, "For Investigational Use Only. The performance characteristics of this product have not been established.” 21 CFR 809.10(c)(2)(ii). Depending on the nature of the study initiated, sponsors may require an approved investigational device exemption (IDE) (21 CFR Part 812), although many IVD studies, such as those using blinded or retrospective data, may be exempt from certain IDE requirements including prior FDA approval.

FDA recommends sponsors interact with the Agency early and often in the development of these diagnostic methods and utilize appropriate scientific, medical, and statistical expertise to assure that thresholds of safety and effectiveness are addressed in submissions provided to FDA. OIVD recommends use of the pre-IDE process (protocol review) to help facilitate the regulatory process.

3. Postmarket Requirements

Like most devices, IVDMIAs are subject to the Quality System regulation (QS regulation) set forth at 21 CFR Part 820. FDA recognizes that some Clinical Laboratory Improvement Amendments of 1988 (CLIA) requirements may partially fulfill corresponding QS regulation requirements. FDA intends to issue guidance to assist laboratories that manufacture IVDMIAs in complying with the QS regulation. Until such a final guidance is published, FDA intends to exercise enforcement discretion with regard to post-market enforcement of QS requirements for such laboratories. For the QS portion of PMA applications for class III devices, see the PMA section of the Appendix.

IVDMIA manufacturers must also comply with the requirements of the Medical Device Reporting (MDR) regulation. (21 CFR Part 803) Laboratories are currently subject to certain provisions of the MDR regulation in their capacity as device user facilities. (21 CFR 803.3) User facilities are required to report to FDA and the device manufacturer information that reasonably suggests that a device has caused or contributed to the death of a patient. (21 CFR 830.30(a)(1)) User facilities must also report to the device manufacturer or, if the manufacturer is not known, to the FDA, information that reasonably suggests a device may have contributed to a serious injury. (21 CFR 803.30(a)(2)) Manufacturers have some additional reporting requirements, including submission of reports of serious injury and device malfunction to FDA. (21 CFR 830.50(a)) Laboratories that manufacture IVDMIAs should follow the MDR requirements for manufacturers for their IVDMIA device(s).

Timeline for Submitting IVDMIAs for FDA Review

In order to assist IVDMIA manufacturers in complying with device regulatory requirements, FDA intends to exercise enforcement discretion with respect to certain requirements during an initial transition period following publication of the final version of this guidance. For 12 months following publication of the final guidance document, FDA intends to exercise enforcement discretion with respect to all regulatory requirements for currently marketed, laboratory-developed IVDMIAs. FDA intends to exercise enforcement discretion for an additional 6 months for currently marketed, laboratory-developed IVDMIAs if the manufacturer submits a 510(k) or PMA within the initial 12 month period following publication of the final guidance4.

FDA intends to enforce regulatory requirements for all currently marketed, laboratory-developed IVDMIAs that do not receive marketing clearance or approval within 18 months of publication of the final guidance document.

Appendix: General Information on Device Regulation

Registration and Listing
As with all regulated devices, IVDMIA manufacturers are required to register5 with FDA and to list6 , or identify to FDA, the IVDMIAs they are marketing. 21 USC § 360, 21 CFR Part 807. The registration and listing requirement is a means of keeping FDA advised of who is manufacturing devices, and of the types of devices an establishment is manufacturing or marketing.

To register an establishment, form FDA 2891, "Registration of Device Establishment" must be completed by the official correspondent designated on the form and submitted to FDA.7 21 CFR 807.22(a). Listing of a medical device is done by completing form FDA 2892, Device Listing8 within 30 days of marketing the device. 21 CFR 807.22(b).

Submitting IVDMIAs for Premarket Review
Premarket Notification

Each manufacturer who intends to market a Class I or Class II device that is not otherwise exempt9 , 21 USC § 360(l)-(m), must submit a 510(k) to FDA. A 510(k) is a premarket submission made to FDA to demonstrate that the device to be marketed is "substantially equivalent" (SE) to a legally marketed device with the same intended use (a predicate device). 21 USC § 360c(i), 21 CFR 807.92(a)(3). There is no 510(k) “form,” however, 21 CFR Part 807 Subpart E describes requirements for a 510(k) submission. Submitters must compare their device to one or more similar legally marketed devices. A legally marketed device, as described in 21 CFR 807.92(a)(3), is a device that was legally marketed prior to May 28, 1976 (preamendments device), or a device which has been reclassified from Class III to Class II or I, or a device which has been found SE through the 510(k) process. Although devices recently cleared under 510(k) are often selected as the predicate to which equivalence is claimed, any legally marketed device for the same intended use may be used as a predicate. Class III devices approved under the PMA process cannot be used as predicates for Class II devices.

Substantial equivalence is established with respect to intended use, design, performance, safety, effectiveness, labeling, standards, and other characteristics, as applicable, but does not require that devices be identical. 21 USC § 360c(i). In addition, OIVD posts Class II device review summaries on the internet10 . These documents summarize the data used to establish substantial equivalence of the class II device to its predicate device. It may be helpful for manufacturers to review the information and types of data shown in these summaries to get a better understanding of the usual submission elements.

Until the manufacturer receives an order declaring a device substantially equivalent, the manufacturer may not proceed to market the device. 21 USC § 352(o). Once the device is determined to be substantially equivalent, it can then be marketed in the U.S. This "clears" the device for commercial distribution. The substantial equivalence determination is usually made within 90 days and is made based on the information submitted by the sponsor11.

De Novo Classification

The de novo process12 is a mechanism that can be applied to new devices that have been automatically classified as Class III and that have no identifiable predicate device. The process allows manufacturers to petition for risk-based downclassification from Class III to Class I or II for devices that have moderate or low risk profiles that meet the definition of a Class I or II device. 21 USC § 360c(f)(2).

When a device is classified via the de novo process, a new regulation describing the device type and, for class II devices, generally a Special Controls Guidance Document, are published. 21 USC §§ 360c(a)(1)(B), 360c(e)(2). The Special Controls guidance document specifies the scope of the device type and the recommendations for submission of subsequent devices for the same intended use.

Devices classified into Class II via the de novo process may be used as predicates for other devices with the same intended use. 21 USC § 360c(f)(2)(B). Note that if a device is determined to be a Class III, high risk device, as described below, a de novo petition will not be granted, and the device manufacturer will be required to submit a PMA. 21 USC § 360c(f)(2)(B)(ii). For this reason, we recommend that any manufacturer who believes that its new device may be eligible for downclassification consult with FDA prior to submitting a de novo 510(k).

Premarket Approval (PMA)

Premarket approval is the FDA process of scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices. Class III devices are 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. 21 USC § 360c(a)(1)(C). Most Class III devices require FDA approval of a premarket approval application (PMA) under section 515 of the Act prior to marketing 21 USC § 360e(a). PMA approval is based on a determination by FDA that the application contains full reports of investigations that provide a reasonable assurance that the device is safe and effective for its intended use(s). 21 USC § 360e(c)(1). For the section of the PMA application that addresses QS requirements, FDA will work with the applicant to determine the least burdensome approach to developing such systems.

Humanitarian Use Exemption for Rare Disease Diagnosis

A Humanitarian Use Device (HUD) (21 CFR 814 Subpart H) is a device that is intended to benefit patients by treating or diagnosing a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year. The HUD provision of the regulation provides an abbreviated regulatory pathway as an incentive for the development of devices for use in the treatment or diagnosis of diseases affecting these populations.

FDA plans to continue to exercise enforcement discretion with regard to regulatory requirements for laboratory-developed IVDMIAs that meet the definition of an HUD.

Modifications to Cleared or Approved IVDMIAs

FDA has a series of established mechanisms to accommodate the iterative nature of all medical devices (including IVDs).

Device manufacturers making minor changes in Class II product design should refer to FDA’s Guidance entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device13 ." This document's recommendations allow for minor changes to be made to cleared devices without new 510(k) submissions as long as device performance is not significantly changed. OIVD believes that ongoing improvement to IVDs is necessary, and that many changes to 510(k)-cleared IVDs may safely be made, validated by the manufacturer, and documentation supporting the change kept on-site without FDA review prior to implementing the change.

Manufacturers of Class II IVDs who make significant changes in product design but not intended use or fundamental technology can submit a streamlined submission called a "Special 510(k)" as described under the "New 510(k) Paradigm -- Alternate Approaches to Demonstrating Substantial Equivalence in Premarket Notifications14 .” This allows for a streamlined (30 day) review process based on focused information related to the device modification, including a concise summary of the design control activities being used to make the device, an identification of the risk analysis used to assess the impact of the device modification, an identification of the verification and/or validation activities, and a declaration of conformity with design controls.

Changes to Class III, PMA-approved devices are handled in different ways depending on the extent of the device modification. Manufacturers of Class III IVDs who modify the manufacturing procedure or method of manufacturing can submit a streamlined submission called a 30 day PMA Supplement. Minor modifications to Class III devices are reviewed in a type of PMA Supplement called a Real-time supplement, which provides for a focused and efficient review by FDA “in real time.” Major modifications, including modifications that alter the intended use or the fundamental technology of the device, are reviewed in the context of other types of PMA Supplements. However, these supplements do not always require a new review of manufacturing information or a new facility inspection15.

OIVD recognizes that IVDMIAs, by their very nature, pose unique technical or bioinformational challenges that may require carefully considered approaches to device changes. For example, the cohort of patient data used to derive the device and the derivation processes itself used in test development will usually have a significant impact on final test results. Even minor modifications in test inputs can potentially have a profound impact on test performance. By considering how changes to an IVDMIA might affect test performance, interpretation, and results early in the life cycle of the new product, we believe sponsors can work with FDA to develop mechanisms for assuring that changes to IVDMIAs are regulated in a manner that best addresses public health needs.

Labeling

IVDs, including IVDMIAs, are subject to labeling requirements, "except where such information is not applicable." 21 CFR § 809.10. Information that is required to be on the label and that is applicable in the case of IVDMIAs includes the proprietary name and established name of the test, if any, the intended use or uses of the test, a statement of warnings and precautions, and the name and place of business of the manufacturer. 21 CFR § 809.10(a). FDA does not consider a lot or control number to be an applicable requirement with respect to IVDMIAs.

We recommend that laboratories that manufacture IVDMIAs establish and maintain electronic labels that meet such requirements, make such labels publicly available, and indicate the internet address for such electronic labels on IVDMIA laboratory reports. We also recommend that laboratories that develop IVDMIAs maintain such labels at the laboratory and include language in IVDMIA laboratory reports that indicates such labels are available upon request.

IVDs are also subject to additional labeling requirements. 21 CFR 809.10(b). When FDA issues a special controls guidance document for a specific type of IVDMIA or approves a specific IVDMIA, the Agency will address the applicable labeling requirements for that product or type of product, as it does for all devices. FDA encourages IVDMIA manufacturers to indicate in their premarket submissions where they believe that CLIA requirements will meet FDA labeling requirements.


 1 Here, demographic means that only clinical variables (e.g., age, race, family history), rather than information from the in vitro measurement of analytes, are used as inputs.

 2 For information regarding approval of such tests, contact the Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research

 3 FDA Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable

 4 As stated above under "Postmarket Requirements," FDA also intends to continue to exercise enforcement discretion with respect to postmarket QS regulation enforcement for laboratories that manufacture IVDMIAs until the Agency issues QS guidance for such laboratories. For the QS portion of PMA applications for class III devices, see the PMA section of the Appendix. As stated in the Appendix under "Humanitarian Use Exemption for Rare Disease Diagnosis," FDA also intends to continue to exercise enforcement discretion with respect to laboratory developed IVDMIAs that meet the definition of a Humanitarian Use Device, 21 CFR § 814.3(n).

 5 Establishment Registration

 6 Listing a device with FDA

 7 To access the PDF enabled version of form FDA 2891, go to http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRL/printforms.cfm and select ‘Complete Form’ for form FDA 2891. Read the instructions, complete the form online and then print the completed form. For additional information on device listing see Device Registration and Listing.

 8 To access the PDF enabled version of form FDA 2892, go to: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRL/printforms.cfm and click on ‘Complete Form’ for form FDA 2892. Read the instructions, complete the form online and then print the completed form. For additional information on device listing, see Device Registration and Listing.

 9 Reserved Class I devices require clearance prior to marketing. See 63 FR 5387, February 2, 1998, for a listing of Reserved Class I devices.

 10 For a searchable database of cleared Class II devices, see http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm?IVDProducts=on.

 11 For additional information regarding the premarket notification process, see Premarket Notification 510(k).

 12 For additional information on the de novo process, see "New Section 513(f)(2) - Evaluation of Automatic Class III Designation, Guidance for Industry and CDRH Staff".

 13 "Deciding When to Submit a 510(k) for a Change to an Existing Device". 

 14 The New 510(k) Paradigm - Alternate Approaches to Demonstrating Substantial Equivalence in Premarket Notifications - Final Guidance issued in March 1998.

 15 For additional information, see Modifications to Devices Subject to Premarket Approval (PMA) - The PMA Supplement Decision-Making Process.