Draft Guidance for Industry, 
Clinical Laboratories, and FDA 
Staff  
 
 
In Vitro Diagnostic Multivariate 
Index Assays 
  
DRAFT GUIDANCE 
 
This guidDance documRent is beinAg distributFed for comTment 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of publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 
http://www.fda.gov/dockets/ecomments. All comments should be identified with the docket 
number 2006D-0347.  
 
For questions regarding this document contact Courtney Harper at 240-276-0694 
(courtney.harper@fda.hhs.gov).  For questions regarding this document as applied to devices 
regulated by CBER contact Martin Ruta at 301-827-3518 
 
 
 
 
  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 
Preface  Draft  Not for Implementation 
Contains Nonbinding Recommendations 
 
 
 
Additional Copies 
Additional copies are available from the Internet at: 
http://www.fda.gov/cdrh/oivd/guidance/1610.pdf or http://www.fda.gov/cber/guidelines.htm.   
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 240-276-3151 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
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Draft Guidance for Industry, Clinical 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This draft guidance, when finalized, will represent the Food and Drug Administration's 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 
DRAFT
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:  
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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 "DefinitioDn and RegulatRory Status of IAVDMIAs" oFf this guidanTce, 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 
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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 
DRAFT
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 persons risk of developing a disease or condition.  
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  A device that integrates a patients 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). 
  DRAFT
  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 patients 
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 patients treatment or disease 
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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.  
DRAFT
 
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 
                                                           
 
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. 
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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 http://www.fda.gov/cdrh/devadvice/3132.html 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 
DRAFT
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 
                                                           
 
2 For information regarding approval of such tests, contact the Division of Emerging and Transfusion 
Transmitted Diseases, Center for Biologics Evaluation and Research. 
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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 devDices, IVDMIRAs are subjectA to the QualiFty System reTgulation (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). 
 
                                                           
 
3 For FDA Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human 
Specimens that are Not Individually Identifiable see http://www.fda.gov/cdrh/oivd/guidance/1588.pdf 
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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 guidance.4 
 
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.  
 
DRAFT
                                                           
 
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).    
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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 
DRAFT
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 
                                                           
 
5 For information on Establishment Registration, see, http://www.fda.gov/cdrh/devadvice/341.html. 
6 For information on Listing a device with FDA, see, http://www.fda.gov/cdrh/devadvice/342.html. 
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, http://www.fda.gov/cdrh/devadvice/341.html. 
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, http://www.fda.gov/cdrh/devadvice/342.html. 
9Reserved Class I devices require clearance prior to marketing.  See 63 FR 5387, February 2, 1998, for a listing 
of Reserved Class I devices. 
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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 sponsor.11 
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 
DRAFT
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) 
                                                           
 
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, 
http://www.fda.gov/cdrh/devadvice/314.html. 
12 For additional information on the de novo process, see, http://www.fda.gov/cdrh/modact/clasiii.pdf. 
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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. 
DRAFT
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 
FDAs 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 
                                                           
 
13 http://www.fda.gov/cdrh/ode/510kmod.html. 
14 Final Guidance issued in March 1998, http://www.fda.gov/cdrh/ode/parad510.html. 
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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 itseDlf used in testR development Awill usually Fhave a signiTficant 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.  
 
                                                           
 
15 For additional information, see, http://www.fda.gov/cdrh/ode/guidance/1584.pdf . 
  14 
  Draft  Not for Implementation 
Contains Nonbinding Recommendations 
 
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.  
 
 
 
 
   
 
 
DRAFT
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