1

Guidance for Industry and FDA 

Staff 

In Vitro Diagnostic (IVD) Device 

Studies -Frequently Asked 

Questions 

 Document issued on: June 25, 2010

The draft of this document was issued on October 25, 2007. 

This document supersedes "Guidance for FDA Staff: Regulating In Vitro 

Diagnostic Device (IVD) Studies," issued December 17, 1999. 

For questions regarding this document, contact Sally Hojvat, Ph.D. in CDRH at 301-796-5455 or 

the Office of Communication, Outreach and Development in CBER at 1-800-835-4709 or 301-

827-1800. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Devices and Radiological Health

Center for Biologics Evaluation and Research 

 
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Preface 

Additional Copies 

Additional copies are available from the Internet at: 

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocu

ments/ucm071230.pdf, 

Or, contact: 

Office of Communication, Outreach and Development, 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/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/defaul

t.htm

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

 
 

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Table of Contents 

I. Background................................................................................................................................ 4 

II. Introduction.............................................................................................................................. 5 

III. General Regulatory Issues..................................................................................................... 7 

IV. Investigational Studies......................................................................................................... 18 

V. Human Subject Protection .................................................................................................... 22 

VI. Data Considerations............................................................................................................. 25 

VII. Glossary ............................................................................................................................... 28 

VIII. References .......................................................................................................................... 35 

Appendix 1: REGULATORY DECISION TREE (21 CFR PART 812) for IVD 

INVESTIGATIONAL STUDIES .............................................................................................. 39 

Appendix 2: Regulatory Framework for IVD Products ............................................................. 

Regulated as Class I, II, or III Devices...................................................................................... 42 

Appendix 3: Sponsor’s Responsibilities for Significant Risk Device Investigations............. 42 

Appendix 4: Investigator’s Responsibilities for Significant Risk Device Investigations...... 49 

Appendix 5: Suggested Format for IDE Final Report ............................................................ 53 
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Guidance for Industry and FDA Staff 

In Vitro Diagnostic (IVD) Device Studies 

Frequently Asked Questions 

This guidance represents 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. 

I. Background 

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 21 CFR 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. 

1 As explained below, even if a particular IVD study is exempt from most requirements of 21 CFR 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 Part 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. 

 
5

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, and blood donor and 

recipient compatibility are licensed as biological products under Section 351 of 

the Public Health Service Act and are subject to the applicable regulations in 21 

CFR Parts 600-680 . Examples of licensed biologics devices include blood donor 

screening tests for human immunodeficiency virus (HIV) and hepatitis B and C 

tests intended for blood screening and reagents used in blood grouping, antibody 

detection and identification, and crossmatching for pre-transfusion compatibility 

testing. This guidance is written to address only IVD devices that are approved or 

cleared under the Federal Food, Drug, and Cosmetic Act (the Act) and Part 800 of 

the device regulations, regardless of which Center reviews the submission. If you 

have questions about a device licensed by CBER, you may go to the CBER 

website for published guidance 

(http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInf

ormation/default.htm) or contact CBER for further information on applicable 

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. 

II. Introduction 

1. What is the purpose of this guidance document and how does it differ from other 

guidance documents related to IVD products? 

FDA prepared this comprehensive document as a resource for you and for its own 

staff to address issues concerning IVD studies. This guidance document contains 

information relevant to studies conducted during the development of a new IVD 

product, as well as other general considerations about applicable requirements and 

marketing of the new device. It addresses particularly those investigational studies 

that are exempt from the majority of requirements under 21 CFR Part 812. IVD 

study investigators and members of IRBs who review and approve such studies 

 
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may also find it helpful. There are also device-specific guidance documents 

available for specific IVD products that can be found at 

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfggp/search.cfm. The use of 

investigational IVD devices in clinical studies designed to evaluate new drug 

products falls outside the scope of this guidance. 

2. Why are in vitro diagnostics considered devices? 

In vitro diagnostics (IVDs) meet the definition of a device under the Act. Section 

201(h) of the Act defines a device as: 

“an instrument, apparatus, implement, machine, contrivance, implant, in 

vitro reagent, or other similar or related article, including any component, 

part, or accessory, which is— 

(1) recognized in the official National Formulary, or the United 

States Pharmacopeia, or any supplement to them, 

(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, or 

(3) 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.” 21 U.S.C. 321(h) (emphasis added). 

3. 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 specimens, or to prepare or examine specimens (e.g., blood, serum, 

urine, spinal fluid, tissue samples) after they are removed from the human body. 

4. Which Divisions at FDA are responsible for review of IVD products? 

Center for Devices and Radiological Health (CDRH)

• Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) 

• Division of Chemistry and Toxicology Devices – Phone: (301) 796-

5470 

• Division of Immunology and Hematology Devices – Phone: (301) 796-

5481 

• Division of Microbiology Devices – Phone: (301) 796-5461 

Center for Biologics Evaluation and Research (CBER)

• Office of Cell, Tissues, and Gene Therapy (OCTGT) – Phone: (301) 827-5102 

• Office of Blood Research and Review (OBRR) 

• Division of Blood Applications (DBA) – Phone: (301) 827-3524 

 
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DBA schedules all review-related meetings for OBRR 

• Division of Emerging and Transfusion Transmitted Diseases 

(DETTD) – Phone: (301) 827-3008 

• Division of Hematology (DH) – Phone: (301) 496-4396 

5. Whom should I consult when I have questions about the manufacturing 

regulations or the conduct of a study (e.g., human subject protection issues)? 

Center for Devices and Radiological Health (CDRH)

For questions regarding manufacturing regulations and IVD-specific conduct of 

studies, contact: 

Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) 

Regulatory Staff, Patient Safety and Product Quality – Phone: (301) 796-5450 

For questions regarding the conduct of studies, contact: 

Office of Compliance (OC) 

Division of Bioresearch Monitoring (DBM) 

Phone: (301) 796-5490 

or 

Investigational Device Exemptions (IDE) Staff 

Office of Device Evaluation 

Phone: (301) 796-5640 

Center for Biologics Evaluation and Research (CBER)

For questions regarding manufacturing regulations and IVD-specific conduct of 

studies, contact the appropriate reviewing division identified in the previous 

answer. 

For questions regarding the conduct of studies, contact: 

Office of Compliance and Biologics Quality (OCBQ) 

Division of Inspections and Surveillance (DIS) 

Bioresearch Monitoring Branch – Phone: (301) 827-6221 

III. General Regulatory Issues 

1. Which regulations contain provisions relevant to the IVD industry? 

Listed below are some of the regulations that implement the Act and that are 

relevant to IVDs covered by this guidance. See Table 1 (Appendix 1) for 

additional information. This is not an all-inclusive list. 

Title 21, Code of Federal Regulations (21 CFR) 

Part 11, Electronic Records; Electronic Signatures 

Part 50, Protection of Human Subjects 

 
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Part 54, Financial Disclosure by Clinical Investigators 

Part 56, Institutional Review Boards 

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 Devices 

In 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 

2. How do I determine the applicability of the IDE regulation to my IVD study? 

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 the following three categories: 

a. 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. 

b. 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. 

c. The IVD 

• is properly labeled in accordance with 21 CFR 809.10(c); 

• is noninvasive (see question #5 below); 

• does not require an invasive sampling procedure that presents 

significant risk (see question #4 below); 

• does not by design or intention introduce energy into a subject; 

and 

 
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• is not used as a diagnostic procedure without confirmation of the 

diagnosis by another, medically established diagnostic product or 

procedure (see question # 6 below). 

For your study to be exempt from most of the requirements of the IDE 

regulation under this third category, it must meet all of the conditions 

listed in “c” above. (See also the decision tree in Appendix 1.) You should 

refer to 21 CFR 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 begin your investigation, including any shipment of 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 nonsignificant 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 

21 CFR Parts 50 and 56, even if they are not subject to most requirements 

of 21 CFR Part 812. 

3. How do I determine if the study is a significant or non-significant risk study 

under 21 CFR 812.2(b)? 

 
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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/ScienceResearch/SpecialTopics/RunningClinicalTrials/Guida

ncesInformationSheetsandNotices/ucm113709.htm, particularly the one on 

“Significant Risk and Nonsignificant Risk Medical Devices” at 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo

cuments/ucm126622.htm.) 

4. How do I determine if an invasive sampling technique presents a significant risk 

under 21 CFR 812.2(c)(3)? 

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. 

5. What does noninvasive mean? 

A noninvasive device is one that does not, by design or intention: 

a. penetrate or pierce the skin or mucous membranes of the body, the 

ocular cavity, or the urethra; or 

 
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b. 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 noninvestigational purposes is also considered noninvasive (21 CFR 

812.3(k)). 

6. What does it mean to have “confirmation of the diagnosis by another, medically 

established diagnostic product or procedure?” 

For an investigational study to be exempt under 21 CFR 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 an investigational test uses a new technology or represents a significant 

technological advance, established diagnostic products or procedures may not be 

adequate to confirm the diagnosis provided by the investigational IVD. For 

example, if an investigational test is designed to identify an infection at the 

earliest stages of viral infection (before formation of antibodies), established 

diagnostic products or procedures that rely on the detection of antibodies to the 

virus would be inadequate to confirm diagnoses. Under these conditions the 

study would not meet the criteria for exemption under 812.2(c)(3) since the 

testing could not be confirmed with a medically established diagnostic product or 

procedure. You may consider whether the device is a non-significant risk device 

subject to abbreviated IDE requirements (21 CFR 812.2(b)). 

7. What if no medically established means for diagnosing the disease or condition 

exists? 

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. 

8. Can an investigational IVD device be used outside of the study protocol, in an 

 
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emergency situation? 

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: 

a. the patient has a serious disease or condition; 

b. no generally accepted alternative diagnostic device or treatment for the 

condition is available; and 

c. 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. 

Although prior FDA approval for emergency use of the investigational device is 

not required, 21 U.S.C. § 360bbb(a), if an IDE exists, the use shall 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. 

3

 This reference can be found at: 

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm0

80203.pdf.

 
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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. 

9. Can an unapproved or uncleared investigational IVD device ever be used for 

nonemergency treatment of patients who do not meet the inclusion criteria of an 

investigational study? 

Yes, in exceptional situations. FDA 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"/single patient use of the device may be appropriate. Section 561 of the Act. 

CBER refers to such situations as “single patient exemptions.” Appropriate 

patient protection measures are needed for these studies. 

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. 21 CFR 812.35(a). 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

If a study is being conducted according to an exemption under 21 CFR 

812.2(c)(3), or as a non-significant risk IDE under 21 CFR 812.2(b), the sponsor 

should obtain prior approval for the specific compassionate use/single patient 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 

U.S. Food and Drug Administration 

Center for Devices and Radiological Health 

WO66 Room G609 

10903 New Hampshire Avenue 

Silver Spring, MD 20993-0002 

4

 See Chapter III, "Expanded Access to Unapproved Devices," of the guidance document "IDE Policies and 

Procedures," 

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm0

80203.pdf. 

 
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Compassionate use information is available on FDA’s web site at 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarke

tYourDevice/InvestigationalDeviceExemptionIDE/ucm051345.htm#compassiona

teuse

For CBER regulated products, the required information should be submitted to the 

appropriate reviewing division (see section II above): 

Document Control Center (HFM-99) 

Center for Biologics Evaluation and Research 

Food and Drug Administration 

1401 Rockville Pike, Suite 200N 

Rockville, MD 20852-1448 

10. Are treatment IDEs and continued access available for investigational IVDs 

under an IDE? 

Yes, both are available. See 21 CFR 812.36 and the Glossary for definitions of 

treatment IDE and continued access. 

11. Can my IVD device be considered a humanitarian use device (HUD) and can I 

apply for marketing approval through a humanitarian device exemption (HDE)? 

Yes, it is possible for an IVD device to be approved for marketing under the 

HDE. See the Glossary for definitions, 21 CFR Part 814, Subpart H, and 

Appendix 1 for more information. 

12. Can an IVD device qualify for HUD designation if the affected patient 

population is fewer than 4,000 per year but each patient may need to be tested 

multiple times? 

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). 

13. Is there a regulation that specifically addresses labeling of IVD products? 

Yes. The regulation, “Labeling for in vitro diagnostic products,” (21 CFR 

 
15

809.10), specifies the information required on labeling and in package inserts of 

marketed products as well as products in development that are distributed for use 

in studies. We recommend that you design IVD studies so that the results will 

support the proposed indications for use in the package insert and labeling. 

14. Are there different goals for IVD studies compared to other device studies? 

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). 

15. What regulations describe the content requirements for IVD premarket 

submissions? 

Regulations that describe the basic content requirements by submission type 

include: 

• Investigational Device Exemption (IDE) – 21 CFR 812.20 

• Premarket Notification (510(k)) – 21 CFR 807.87 

• Premarket Approval (PMA) – 21 CFR 814.20 

• Humanitarian Device Exemption (HDE) – 21 CFR 814.104 

Currently, there is no regulation describing the contents for a Product 

Development Protocol (PDP). However, section 515(f)(1) of the Act and the 

CDRH website at 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarke

tYourDevice/PremarketSubmissions/PremarketApprovalPMA/ucm048168.htm#p

dp describe PDP requirements. 

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/MedicalDevices/ProductsandMedicalProcedures/InVitroDiag

nostics/LabTest/ucm126189.htm or for CBER products at 

http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProd

ucts/PremarketApprovalsPMAs/ucm089793.htm and 

http://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/510k

Process/ucm133429.htm. We recommend that the sponsor structure submissions 

 
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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. 

16. Can published literature be used to support an IVD premarket submission? 

FDA has developed a guidance document entitled “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/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo

cuments/ucm080183.htm. 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.) 

17. Can data from studies performed outside of the United States (U.S.) be used to 

support an IVD premarket submission? 

Yes. FDA recognizes that clinical investigations may be conducted outside of the 

U.S., for example, in order to find adequate numbers of subjects for certain 

disease states, conditions, or pathogens. The PMA regulation contains information 

regarding research conducted outside of the U.S. (21 CFR 814.15). FDA can also 

accept data from foreign studies in support of 510(k)s . 

18. Can foreign/international data be used as the sole support of a marketing 

application? 

Yes, but only if warranted. The PMA regulation, 21 CFR Part 814, allows foreign 

data to be used as the sole support of a marketing application but only if (1) the 

data are applicable to the U.S. population and to U.S. medical practices, including 

laboratory practices, (2) the studies have been performed by clinical investigators 

of recognized competence, and (3) the data may be considered valid without the 

need for an on-site FDA inspection or, if necessary, FDA can validate the data 

through an on-site inspection or other appropriate means (21 CFR 814.15(d)). 

For IVD devices, FDA would consider differences in population demographics, 

disease prevalence, disease presentation, laboratory practices, and medical 

standards of care. If the sponsor plans to submit an application based solely on 

foreign data, FDA recommends that the sponsor consult with the reviewing 

division prior to submission of the application. 

See Introduction, Section II, question # 4 of this guidance for a list of reviewing 

divisions in both CDRH and CBER. 

 
17

19. What is a master file and how is one submitted? 

A device 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) for use as a 

reference source in support of at least one application. 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: 

• facilities and manufacturing procedures and controls; 

• synthesis, formulation, purification and specifications for chemicals, 

materials (an alloy, plastic, etc.) or subassemblies for a device; 

• packaging materials; 

• contract packaging and other manufacturing (such as sterilization); 

• nonclinical study data; and 

• clinical study data. 

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 the CDRH website 

at 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarke

tYourDevice/PremarketSubmissions/PremarketApprovalPMA/ucm142714.htm 

20. How do I arrange to reference a MAF? 

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 

 
18

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 the CDRH website at 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarke

tYourDevice/PremarketSubmissions/PremarketApprovalPMA/ucm142714.htm.

IV. Investigational Studies 

1. What does FDA consider to be valid scientific evidence? 

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 its safety and 

effectiveness. For example, if you are studying an IVD device that uses a wellcharacterized 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 has 

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.) 

 
19

2. Why should I review the information regarding the conduct of device studies 

found in the IDE regulation even if, after considering the exemption criteria in the 

regulation, I determine that my proposed studies are exempt from most IDE 

requirements? 

Some studies are exempt from most of 21 CFR 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 21 CFR Part 812 will also be useful to sponsors and investigators 

of device studies exempt under 21 CFR 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 Parts 50 and 56. 

3. Should I review the “International Conference on Harmonization; Good Clinical 

Practice: Consolidated Guideline” ("ICHGCP") published in the Federal Register 

Vol. 62, No. 90, May 9, 1997, pp. 25691-25709 or the draft ISO 14155, “Clinical 

Investigation of Medical Devices for Human Subjects,” when developing studies for 

devices that fall within the exemption at 21 CFR 812.2(c)? 

Although the ICH document was written for studies of pharmaceuticals, sections 

of the guidance address study issues common to all investigational products. 

Thus, these sections of the ICH GCP provide a useful reference regarding the 

proper conduct of studies. 

The draft ISO document specifically states that it does not apply to IVD devices. 

The draft 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. 

4. Is FDA willing to review and discuss a study protocol even if the study is exempt 

from most of the 21 CFR Part 812 requirements? 

Yes. Both CDRH and CBER have developed processes that allow sponsors to 

obtain early FDA input and review of proposed studies by submission of the 

protocol and other study materials in the form of a “pre-IDE” document and/or a 

discussion in the form of a “pre-IDE” meeting. While we refer to this early input 

as a "pre-IDE" process, it is also available for studies that are exempt from most 

IDE requirements under 21 CFR 812.2(c)(3) or that will be conducted under the 

abbreviated IDE regulations for NSR studies (21 CFR 812.2). FDA encourages 

use of the pre-IDE submission and/or meeting whenever the sponsor desires early 

feedback for clinical studies, particularly those for novel or high risk (Class III) 

devices. If you (the sponsor) are interested in submitting a pre-IDE, we 

 
20

recommend that you contact the Division that will review your device before you 

initiate your studies (See Introduction, Section II, question # 4 of this guidance). 

Use of the pre-IDE process does not obligate you in any way to future submission 

of an IDE. FDA also encourages continued communication throughout the course 

of the study. This communication can be in the form of an informational 

meeting/telephone call or status reports to the pre-IDE file. 

5. Can I obtain a more formal evaluation of my study design or investigational plan 

through a determination and/or agreement meeting? 

Yes, for Class III IVDs. (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/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo

cuments/ucm073604.htm. CBER also follows this meeting guidance document 

when determination and/or agreement meetings are requested. 

6. Under 21 CFR Part 812, what are the sponsor’s and investigator’s responsibilities 

for studies of a non-significant risk device conducted under the abbreviated 

requirements in 21 CFR Part 812? 

The majority of the sponsor’s and investigator’s responsibilities in a study of a 

nonsignificant risk device are found in 21 CFR 812.2(b)(1) of the IDE regulation 

and are summarized below: 

a. Label the device in accordance with 21 CFR 812.5; 

b. 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. 

c. 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 21 

CFR 56.109(c). 

d. Comply with the requirements of 21 CFR 812.46 with respect to monitoring 

investigations; 

e. Maintain the records required under 21 CFR 812.140(b)(4) and (5) and make 

the reports required under 21 CFR 812.150 (b)(1) through (3) and (5) through 

(10); 

f. Ensure that participating investigators maintain the records required by 

21 CFR 812.140(a)(3)(i) and make the reports required under 21 CFR 

812.150(a)(1), (2), (5), and (7); 

 
21

g. Comply with the prohibitions in 21 CFR 812.7 against promotion and other 

practices. 

All studies should 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. 

All sites participating in the study should 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 able 

to be pooled 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/downloads/ICECI/EnforcementActions/BioresearchMonitorin

g/UCM133752.pdf

7. What are my responsibilities as the sponsor or the investigator of a study of a 

significant risk device subject to 21 CFR Part 812? 

The sponsor’s responsibilities for significant risk device investigations are 

described in Appendix 3 of this guidance. This information is also included as an 

enclosure in all IDE approval letters. 

The investigator’s responsibilities for significant risk device investigations are 

described in Appendix 4 of this guidance. This information is also included as an 

enclosure in all IDE approval letters. 

8. Is it appropriate to use a quality systems approach in the conduct of IVD studies? 

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 

 
22

devices, and some Class I devices, are required to 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. 

9. If a sponsor’s ‘in-house’ laboratory participates in the study of an IVD is the 

laboratory considered to be a study site? 

Yes. All locations involved in an IVD study are considered study sites whether 

they are located at a sponsor-owned facility or at an independently-owned 

laboratory. The sponsor should list the laboratory as a study site, and the study 

should be conducted under the same investigational plan. As a study site, this 

laboratory can be inspected as part of the FDA’s bioresearch monitoring (BIMO) 

inspection program. 

V. Human Subject Protection 

1. When does an IVD study involve human subjects? 

Under FDA’s regulations governing the conduct of IVD device studies, the 

definition of "subject" includes individuals on whose specimens an investigational 

device is used [see 21 CFR 812.3(p)]. As a result, an IVD study using human 

specimens involves human subjects. 

2. Am I required to follow the “Good Laboratory Practice for Nonclinical Studies” 

regulation (21 CFR Part 58) in my IVD study? 

Part 58 applies only to nonclinical laboratory studies, which are defined as 

in vivo or in vitro experiments in which test articles are studied prospectively in 

test systems under laboratory conditions to determine their safety. The term does 

not include studies utilizing human subjects or clinical studies or field trials in 

animals. The term does not include basic exploratory studies carried out to 

determine whether a test article has any potential utility or to determine physical 

or chemical characteristics of a test article (21 CFR 58.3(d)). 

Moreover, because the safety of IVDs is related to the accuracy of the result, most 

IVD studies that are intended to establish safety would necessarily use human 

specimens. As noted above, an IVD study using human specimens involves 

human subjects and thus is excluded from the definition of nonclinical laboratory 

studies. Such studies to establish safety are subject to 21 CFR Parts 50 and 56 and 

21 CFR Part 812 as applicable, dealing with human subject research, rather than 

to 21 CFR Part 58. 

3. What regulations apply regarding human subject protection in investigational 

IVD studies? 

 
23

FDA regulations on “Protection of Human Subjects” and “Institutional Review 

Boards” (21 CFR Parts 50 and 56) apply to all clinical investigations 

(investigations involving human subjects) regulated by FDA under section 520(g) 

of the Federal Food, Drug and Cosmetic Act, as well as other clinical 

investigations that support applications for research or marketing permits for 

products regulated by FDA. (21 CFR 50.1, 56.101). As described above, any 

study using human specimens involves human subjects. FDA has expressed an 

intent to exercise enforcement discretion regarding informed consent for certain 

IVD studies, in the guidance entitled, "Guidance on Informed Consent for In 

Vitro Diagnostic Device Studies using Leftover Human Specimens that are not 

Individually Identifiable." 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo

cuments/ucm078384.htm

Some research studies involving human subjects that are conducted or supported 

by a federal department or agency will be required to follow the Federal Policy 

for the Protection of Human Subjects (the “Common Rule”). The Department of 

Health and Human Services (HHS) has codified the Common Rule at 45 CFR 

Part 46, subpart A. Research involving human subjects that is conducted or 

supported by HHS and that is not otherwise exempt must comply with 45 CFR 

Part 46, which contains additional protections for specific populations. For further 

information about the applicability of 45 CFR Part 46 to your study, refer to 

http://www.hhs.gov/ohrp/. 

FDA regulation and the Common Rule contain some differing requirements. 

Although FDA and HHS seek to harmonize requirements related to informed 

consent where possible, certain requirements of the FDA regulation and the 

Common Rule are different. The same study may be subject to both sets of 

requirements, either one, or neither. It is the responsibility of sponsors and 

investigators to comply with all applicable requirements. 

4. How do FDA regulations for protection of human subjects, 21 CFR Parts 50 and 

56, differ from HHS regulations in 45 CFR Part 46 subpart A? 

A general comparison appears in the FDA’s Good Clinical Practice program 

website, Comparison of FDA and HHS Human Subject Protection Regulations 

found at 

http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/Educa

tionalMaterials/ucm112910.htm. For additional information on 45 CFR Part 46 

subpart A refer to the Office for Human Research Protections at 

http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. 

5. Can investigational IVD studies receive expedited review (see Glossary for 

definition) by an IRB? 

 
24

Yes, in many cases an investigational IVD study is eligible for IRB expedited 

review (see 21 CFR 56.110), for both initial approval and continuing review. The 

categories of research that may be reviewed by the IRB through an expedited 

review procedure are described in the Federal Register notice on expedited 

review, found at 

http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/Guida

ncesInformationSheetsandNotices/ucm118099.htm. As stated in a Federal 

Register notice, however, sponsors and investigators may not use the expedited 

review procedure where identification of the subjects and/or their responses 

would reasonably place the subjects at risk of criminal or civil liability or be 

damaging to the subjects’ financial standing, employability, insurability, 

reputation, or be stigmatizing, unless reasonable and appropriate protections will 

be implemented so that risks related to invasion of privacy and breach of 

confidentiality are no greater than minimal. (63 FR 60353, November 9, 1998).

6. Can leftover specimens be used in IVD studies without informed consent? 

The document entitled, "Guidance for Industry, Institutional Review Boards, 

Clinical Investigators, and Food and Drug Administration: Guidance on Informed 

Consent for In Vitro Diagnostic Device Studies using Leftover Human Specimens 

that are not Individually Identifiable," 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo

cuments/ucm078384.htm, describes the limited circumstances in which FDA 

intends to exercise enforcement discretion regarding requirements for informed 

consent. (See Glossary for definition of "leftover specimens".) 

7. Can those who routinely conduct studies with IVDs (e.g., research hospitals) use a 

general informed consent to address future studies using samples collected in their 

own facility? 

To fulfill FDA informed consent requirements for studies of IVDs, a site may 

develop an informed consent process to address the use of samples collected at 

the facility (see the Glossary for definition) in a specific study or for a broader 

category of future studies. This general informed consent process may be used for 

subjects seen at and/or admitted to a specific facility. The informed consent 

document must contain all of the required elements found in 21 CFR 50.25. 

8. Can a human specimen that was initially collected in a study with the informed 

consent of the subject be used in a later study without a new consent process? 

If the original informed consent document contains a statement that excess 

specimen(s) will be stored for future use in specified types of studies and the new 

study meets the criteria stated in that consent document, it is possible that no 

further consent is necessary. This assumes that the original informed consent 

document contains all of the other essential elements, including notice to the 

subject that FDA may review their files and an explanation of the purposes and 

 
25

benefits of the research. (See 21 CFR 50.25.) We recommend sponsors and 

investigators consult with the IRB regarding the need for a new informed consent 

process in such a case. The IRB decision should include consideration of any state 

and/or local requirements regarding informed consent and patient rights. If new 

testing could expose the subject to previously unanticipated risks (e.g., privacy 

concerns for the subject and/or his family related to testing for a genetic marker), 

a new consent may be needed. In addition, if the original informed consent did not 

address future research use at all, or did not cover the type of study now under 

consideration, it is likely a new consent will be needed. 

Under certain circumstances, for human specimens leftover from specimens 

originally collected for a previous study, FDA intends to exercise enforcement 

discretion regarding informed consent requirements. See "Guidance for Industry, 

Institutional Review Boards, Clinical Investigators, and Food and Drug 

Administration: Guidance on Informed Consent for In Vitro Diagnostic Device 

Studies using Leftover Human Specimens that are not Individually Identifiable," 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo

cuments/ucm078384.htm, 

VI. Data Considerations 

1. What information should the protocol include to ensure that the investigational 

IVD study will be scientifically sound? 

We recommend that the protocol include a clear description of study design; 

objectives, estimation of performance goals (e.g., desired confidence interval 

widths) that are directly related to the intended claims for the IVD device, or 

hypotheses; and a statistical plan to be applied to the data. (See the Glossary for 

definitions of protocol, statistical hypothesis, and confidence interval.) 

2. Is it acceptable to develop new or to revise existing study hypotheses as the study 

progresses? 

We generally believe it would be inappropriate to draw conclusions from afterthe-fact hypotheses. We recommend that changes in study protocols be carefully 

documented and explained. FDA encourages sponsors to contact the appropriate 

review division to discuss studies before they are initiated and to consult FDA 

before changes in protocols are made mid-study. (For the FDA divisions 

responsible for review of IVD products, see Introduction, Section II, of this 

guidance.) 

3. How should I determine appropriate sample size for a study? 

The sponsor should formulate sample size based on standard statistical techniques 

and the sample size should account for any unique issues related to intended 

use(s), device technologies, and/or the biology of the condition being studied. 

 
26

4. What guidance is available for sponsors to determine how to estimate IVD 

performance in terms of sensitivity and specificity, how to handle discrepant results, 

and what to do when a study is performed without a truth standard (“gold 

standard”) (see the Glossary for definitions)? 

FDA has recognized a number of Clinical and Laboratory Standards Institute 

[(CLSI), formerly National Committee on Clinical Laboratory Standards 

(NCCLS)] standards related to these issues. A list of these standards, but not the 

standards themselves, can be found through the database on the CDRH web page 

http://www.accessdata.fda.gov/scrIpts/cdrh/cfdocs/cfStandards/search.cfm

National Committee on Clinical Laboratory Standards 

The agency’s guidance entitled “Statistical Guidance on Reporting Results from 

Studies Evaluating Diagnostic Tests” can be viewed at 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo

cuments/ucm071148.htm

5. How much leeway is there in deciding on the populations from which human 

specimens are collected and under what conditions are data on simulated specimens 

(see the Glossary for definition) acceptable? 

Studies should be performed in a representative sample of the intended use 

population (i.e., representation of both diseased and non-diseased cases, and 

controlling for subject demographics and morbidity factors that may affect the 

level of device performance). When a disease is rare or samples are needed 

specifically to challenge cut-off points, sponsors may use enriched samples, 

panels of credentialed samples (e.g., Center for Disease Control and Prevention 

(CDC) panels), and/or spiked or contrived samples. The acceptance of simulated 

specimens depends on how well they represent specimens from the intended-use 

population and whether their performance accurately reflects what the IVD device 

user can expect. 

6. Is it acceptable to eliminate data that appear to be out of line with the main body 

of the dataset (i.e., “outliers”)? 

An outlier, an observation that lies an unexpected distance from other values, does 

not in itself prove that an error or violation has occurred. Therefore, the primary 

data analysis should include all such observations, including “outliers”. A sponsor 

may perform some specific supplemental analyses on subsets of the data, if 

clinically and scientifically justified, that may exclude outlying data points. 

Excluding large amounts of data, regardless of the reasons for exclusion, will 

seriously bias the results. 

7. Can I add additional testing on the same subject to the dataset, particularly when 

it is hard to find study subjects? 

 
27

In most studies the sponsor should avoid multiple testings of the same subject 

because it may skew performance statistics and under-estimate standard 

deviations. When multiple testing is done, the sponsor should explain why it is 

necessary and choose methods of statistical analysis that allow adjustment for 

within-subject correlation. 

It is appropriate to conduct repeated testing of the same sample to evaluate test 

reproducibility – i.e., the ability of the test to yield the same or similar readings 

when expected. 

8. How much precision (see the Glossary for definition) is needed for measurement 

data, e.g., in terms of decimal places? 

Study data should contain no more decimal places than the precision of the 

instrument allows, i.e., if the instrument is only precise to the second decimal 

place the sponsor should not analyze the data using three decimal places. 

9. What records should help to ensure scientific soundness of an IVD investigational 

study? 

Unless a study falls within the exemption at 21 CFR 812.2(c), specific record 

requirements are listed in 21 CFR 812.140. In general, the records that are needed 

are those that provide the data for testing the study hypotheses. Records should 

contain sufficient detail to allow the study to be reproduced when the same 

protocol is followed. We recommend that investigators maintain detailed records 

because a review of the study may indicate the need for other analyses of the 

collected data. 

We also recommend that investigators: 

a. Maintain records of all data elements captured in the study, including 

raw measurements and subject co-variables in the form of demographic 

and morbidity factors; 

b. Link every observation recorded to the subject and that person’s covariable data; 

c. Preserve information obtained for all subjects enrolled and for all 

specimens collected. 

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/downloads/Drugs/GuidanceComplianceRegulatoryInformatio

n/Guidances/ucm072322.pdf. There is also a more general guidance document 

 
28

available on electronic records for clinical studies that is entitled “Computerized 

Systems Used in Clinical Trials,” which can be found at 

http://www.fda.gov/RegulatoryInformation/Guidances/ucm126402.htm. 

10. 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). 

The suggested format for the IDE final report, which FDA includes as an enclosure in all 

IDE approval letters, is found in Appendix 5 of this guidance. 

It should be noted that FDA will consider submission of a marketing application (510(k), 

PMA, or HDE) to serve as the final report for the IDE. When a study sponsor submits a 

marketing application in lieu of the final report, the sponsor should still submit a 

supplement to the IDE stating that the marketing application should be considered the 

final report for the study. 

The final report for significant risk device investigations must be submitted to the IRBs 

and/or FDA within six months after termination or completion of the study. 21 CFR 

812.150(b)(7). 

VII. Glossary 

Note: this glossary is written in plain language and is for use exclusively with this 

guidance document. 

Definitions that have been taken from the Act, other pertinent laws, or in Federal 

regulations include the relevant citation. 

510(k) – See Premarket Notification.

Agreement meeting – a meeting, under section 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. 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 

 
29

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/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocument

s/ucm073604.htm. 

Analyte specific reagent (ASR) - ASRs are defined as “antibodies, both polyclonal and 

monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and similar 

reagents which, through specific binding or chemical reactions with substances in a 

specimen, are intended for use in a diagnostic application for identification and 

quantification of an individual chemical substance or ligand in biological specimens." 21 

CFR 864.4020(a). ASRs are medical devices that are regulated by FDA. They are subject 

to general controls, including current Good Manufacturing Practices (cGMPs), 21 CFR 

Part 820, as well as the specific provisions of the ASR regulations (21 CFR 809.10(e), 

809.30, 864.4020).

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 862.9, 864.9, and 866.9. IVD examples of Class II devices include 

glucose test systems (21 CFR 862.1345), 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 

 
30

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/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYour

Device/InvestigationalDeviceExemptionIDE/ucm051345.htm. 

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/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocument

s/ucm080260.htm . 

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 section 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 

 
31

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/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocument

s/ucm073604.htm. 

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 a) recognized in the official 

National Formulary, or the United States Pharmacopeia, or any supplement to them; b) 

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 c) 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 

 
32

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 used 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 used 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 21 CFR 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). 

 
33

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 U.S.C. 

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/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYour

Device/PremarketSubmissions/PremarketApprovalPMA/default.htm. 

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) device advice page is available at 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYour

Device/PremarketSubmissions/PremarketNotification510k/default.htm. 

Product Development Protocol (PDP) – FDA process of approval for marketing of 

medical devices, usually reserved for Class III devices (see definitions of device classes 

 
34

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: 

1. is intended as an implant; 

2. is purported or represented to be for use in supporting or sustaining human life; 

3. is for a use of substantial importance in diagnosing, curing, mitigating, or 

treating disease, or otherwise preventing impairment of human health; or 

4. otherwise presents a potential for serious risk to the health, safety, or welfare of 

a subject. 

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)). 

 
35

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. 

VIII. References 

Note: this listing is presented in the order that the documents are first referred to in this 

guidance document. 

1. 21 CFR Part 812, Investigational Device Exemptions, found at 

 
36

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/ShowCFR.cfm?CFRPar

t=812. 

2. 21 CFR Part 312, Investigational New Drug Application, found at 

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/ShowCFR.cfm?CFRPar

t=312. 

3. 21 CFR Part 809, In Vitro Diagnostic Products for Human Use, found at 

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRP

art=809

4. 21 CFR 820.30, Subpart C of the Quality System Regulation, found at 

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=820.3

0

5. 21 CFR 860.7, Determination of safety and effectiveness, in Medical Device 

Classification Procedures, found at 

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/ShowCFR.cfm?FR=86

0.7. 

6. 21 CFR Part 54, Financial Disclosure by Clinical Investigators, found at 

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/ShowCFR.cfm?CFRPar

t=54

7. “Expanded Access to Unapproved Devices,” Chapter III, of the guidance 

document IDE Policies and Procedures. Guidance document found at 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo

cuments/ucm080202.htm. 

8. “Test Requirements,” (21 CFR 610.40), found at 

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=610.

40 and the “Restrictions on Use for Further Manufacture of Medical Devices, “ 

(21 CFR 610.42), found at 

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=610.

42

9. Information concerning Master Files for Devices (MAFs) is found on the 

CDRH website at 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarke

tYourDevice/PremarketSubmissions/PremarketApprovalPMA/ucm142714.htm

10. “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/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo

cuments/ucm080183.htm. 

 
37

11. Guidance regarding Product Development Protocol (PDP) applications, found 

at 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarke

tYourDevice/PremarketSubmissions/PremarketApprovalPMA/ucm048168.htm

12. FDA premarket final review summaries and FDA PMA summaries of safety 

and effectiveness, found at 

http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiag

nostics/LabTest/ucm126189.htm

and 

http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProd

ucts/PremarketApprovalsPMAs/ucm089793.htm. 

13. Guideline for the Monitoring of Clinical Investigations, found at 

http://www.fda.gov/ICECI/EnforcementActions/BioresearchMonitoring/ucm1350

75.htm

14. “Preparing Notices of Availability of Investigational Medical Devices and for 

Recruiting Study Subjects” found at 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo

cuments/ucm073568.htm. 

15. International Conference on Harmonization: “Good Clinical Practice” 

Guideline published in the Federal Register Vol.62, No.90, May 9, 1997, pp. 

25691-25709, found at 

http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.p

df. 

16. “Early Collaboration Meetings Under the FDA Modernization Act (FDMA); 

Final Guidance for Industry and for CDRH Staff,” is available at 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo

cuments/ucm073604.htm

17. 21 CFR 814.15, Research conducted outside of the United States, in 

Premarket Approval of Medical Devices, found at 

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/ShowCFR.cfm?FR=81

4.15

18.FDA’s Good Clinical Practice program website, Comparison of FDA and HHS 

Human Subject Protection Regulations found at 

http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/Educa

tionalMaterials/ucm112910.htm. 

 
38

19. “Expedited Review of Premarket Submissions for Devices,” found at 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo

cuments/ucm089643.htm

20. 21 CFR Part 50, Protection of Human Subjects, found at 

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRP

art=50

21. 21 CFR Part 56, Institutional Review Boards, found at 

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRP

art=56

22. 21 CFR 50.25, Elements of informed consent, in Protection of Human 

Subjects, found at 

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/ShowCFR.cfm?FR=50.

25

23. “Statistical Guidance on Reporting Results from Studies Evaluating 

Diagnostic Test” found at 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo

cuments/ucm071148.htm

24. 21 CFR Part 11, Electronic Records; Electronic Signatures, found at 

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/ShowCFR.cfm?CFRPar

t=11. 

25. Guidance for Industry: Part 11, Electronic Records; Electronic Signatures – 

Scope and Application, guidance document found at 

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio

n/Guidances/ucm072322.pdf. 

26. Draft Guidance for Institutional Review Boards, Clinical Investigators, and 

Sponsors: Exception from Informed Consent Requirements for Emergency 

Research at http://edocket.access.gpo.gov/2006/E6-14262.htm. 

27. The PMA information, found at 

http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceAppr

ovalsandClearances/PMAApprovals/default.htm

28. Food and Drug Administration Modernization Act of 1997; List of Documents 

Issued by the Food and Drug Administration That Apply to Medical Devices 

Regulated by the Center for Biologics Evaluation and Research (4/26/99; 64 

FR20312) found at http://www.fda.gov/ohrms/dockets/98fr/042699d.pdf. 

 
39

Appendix 1: REGULATORY DECISION TREE (21 CFR 

PART 812) for IVD INVESTIGATIONAL STUDIES 

Is it a Pre-amendments device (other than transitional) used according to the labeling in 

effect at the time, or is it a device, determined by FDA as substantially equivalent (SE) to 

a preamendments device, used according to the labeling reviewed as part of the SE 

determination? 

 Yes 

 

Study is exempt from 21 CFR Part 812, except for 21 CFR 

812.119 

No 

 

Is it a noninvasive device? 

 No 

Significant risk? 

 Yes 

 Apply to FDA for IDE

 No 

Follow 21 CFR 812.2(b) – abbreviated IDE 

requirements 

 Yes 

Does the study involve invasive sampling? 

 No 

 Yes 

 Significant risk? 

 Yes 

Apply to FDA for 

IDE 

No 

Will it be used as a diagnostic procedure without confirmation by a medically established 

product or procedure? 

Yes

 No Significant risk? 

 Yes 

Apply to FDA for IDE 

No 

 

 

 

 

 

 
 

40

Follow 21 CFR 812.2(b) – abbreviated IDE 

requirements 

If the sponsor complies with the applicable requirements of 21 CFR 809.10(c), the 

study is exempt from 21 CFR Part 812, with the exception of 21 CFR 812.119. 
41

Registration 

& Listing Application 

Applicable

Labeling 

801-Subpart A &

801.119 to all 

Limitations QSRs 

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) 

 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) 

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: 

 Significant Risk (SR) 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) 

 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 

 investigational devices

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* 

Research Use No 807.65(f) No 809.10(c)(2)(i) ‘Research Use Only’ 809.10(c)(2)(i) No* 

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) 

 Premarket Notification* 

(Class I, II, or III) 

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) 

*See 21CFR 862-866 (generic device class regulations) for specific-device exemptions 

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) 

814.104(b)(5)

Yes 

809.20(b) 

Appendix 2. Table 1. Regulatory Framework for IVD Products Regulated as Devices+
42

investigations of the device. (21 CFR 812.45) 

+ All references in table are to Title 21 of the Code of Federal Regulations. * While investigational IVDs exempt from most of the provisions of 21 CFR Part 812 are not exempt from the QSR requirem

to enforce such requirements for investigational IVDs that are exempt from most 21 CFR Part 812 requirements; except for d

Appendix 3: Sponsor’s Responsibilities for Significant Risk Device 

Investigations 

Sponsors are required to comply with all applicable duties under the regulations. We summarize them be1. 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 

properly d. Ensuring proper monitoring of the investigation e. Ensuring that any reviewing IRB and FDA are promptly informed of significant new informatioinvestigation 

2. Selection of Investigators (21 CFR 812.43) 

a. Assuring selection of investigators qualified by training and experience b. Permitting only participating investigators to use the investigational device 

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 ty(3) if an investigator was involved in an investigation or other research that was terminatedthe circumstances that led to the termination (4) statement of the investigator's commitment to: 

• conduct the investigation in accordance with the agreement, the investigational pl

and other applicable regulations, and any conditions of approval imposed by the IR• supervise all testing of the device involving human subjects 

• ensure that the requirements for obtaining informed consent are met (21 CFR Par

d. Selecting monitor(s) qualified by training and experience to monitor the progress of the investig

with FDA regulations. e. Providing investigators with the investigational plan and report of prior 

3. Monitoring (21 CFR 812.46) 
43

a. Securing compliance of all investigators in accordance with the signed investigator's agreement, the investigational plan, the requirements of 21 CFR Part 812 or other applicable FDA regulations, or any condition of approval imposed by the reviewing IRB or FDA. If compliance cannot be secured, use of the device by 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 that are Shipped 

Although investigators are responsible for ensuring that investigational devices are made available only to legally authorized to receive them (see 21 CFR 812.110(c)), sponsors also bear responsibility for taking pensure that devices are not diverted outside of legally authorized channels. Sponsors may ship investigati

qualified investigators participating in the clinical investigation (21 CFR 812.43(b)). Sponsors must also current, and accurate records pertaining to the shipment and disposition of the investigational device (21 Records of shipment shall include the name and address of the consignee, type and quantity of device, da

batch number or code mark. Records of disposition shall describe the batch number or code marks of any the sponsor, repaired, or disposed of in other ways by the investigator or another person, and the reasons 

disposal. To further ensure compliance with these requirements, sponsors should take appropriate measures to instr

regarding their responsibilities with respect to recordkeeping and device disposition. The specific recordkfor investigators are set forth at 21 CFR 812.140(a). Upon completion or termination of a clinical investiginvestigator's part of an investigation), or at the sponsor's request, an investigator is required to return to tremaining supply of the device or otherwise to dispose of the device as the sponsor directs (21 CFR 812.1
44

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 cleamarketing by FDA. This prohibition is applicable to sponsors and investigators (or any person acting on b

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 c

research, development, and handling c. Unduly prolonging an investigation beyond the point needed to collect data required to determi

is safe and effective, and d. Representing that the device is safe or effective for the purposes for which it is being investigat

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 situati

a. Changes in the investigational plan: FDA approval is required for any change that may affect thsoundness of the investigation or the rights, safety or welfare of the subjects. IRB approval is also that may affect the rights, safety or welfare of the subjects. The change in the investigational plan 

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 investigatio

next page): 

a. Correspondence (including reports) with another sponsor, monitor, investigators, an IRB or FDb. Records of any shipment, including: 

(1) name and address of consignee (2) type and quantity of device 
45

(3) date of shipment (4) batch numbers or code marks 

c. Records of disposition, describing: 

(1) Batch number or code mark of devices returned, repaired, or disposed of by the investi(2) Reasons for and method of disposal 

d. 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 

particular investigation 
46

 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 

Minutes of Meetings - - 

8. Submitting Reports (21 CFR 812.150(b)) 

A sponsor shall prepare and submit the following complete, accurate, and timely reports (also see Table I

a. Unanticipated adverse device effects (with evaluation) to FDA, all IRBs, and investigators with

after notification by the investigator. Subsequent reports on the effect may be required by FDA b. Withdrawal of IRB approval 
47

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 ni. Significant risk determinations by the IRB when sponsor had proposed nonsignificant risk withireceipt 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 
48

Type of Report Prepared by Investigators for Prepared by Sponsors 

for 

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 mannewhere devices are held (including any establishment where devices are manufactured, processed, packed, 

implanted or where records or results from use of devices are kept). FDA may also inspect and copy all reinvestigation including, in certain situations, records which identify subjects. 
49

Appendix 4: Investigator’s Responsibilities for Significant Risk Device Investigations Investigators are required to comply with all applicable duties under the regulations. We summarize them 

1. General Responsibilities of Investigators (21 CFR 812.100) 

a. Ensuring that the investigation is conducted according to the signed agreement, the investigatio

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 5

2. Specific Responsibilities of Investigators (21 CFR 812.110) 

a. Awaiting IRB approval and any necessary FDA approval before requesting written informed cosubject 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, a(4) any conditions of approval imposed by an IRB or FDA 

c. Supervising the use of the investigational device. An investigator shall permit an investigationaonly with subjects under the investigator's supervision. An investigator shall not supply an investiperson not authorized under 21 CFR Part 812 to receive it. d. Financial disclosure. A clinical investigator shall disclose to the sponsor sufficient accurate fina

allow the applicant to submit complete and accurate certification or disclosure statements under P

e. Disposing of the device properly. Upon completion or termination of a clinical investigation or 

of an investigation, or at the sponsor's request, an investigator shall return to the sponsor any rema

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 thparticipation in an investigation: 
50

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 (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 

reason(s) therefore 

c. 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 invinformed consent, any written concurrence of a licensed physician and a brief desc

circumstances (2) justifying the failure to obtain informed consent (3) document all relevant observations, including records concerning adverse devicanticipated or not), information and data on the condition of each subject upon ente

course of, the investigation, including information about relevant previous medical results of all diagnostic tests (4) a record of the exposure of each subject to the investigational device, including 

each use, and any other therapy 

d. The protocol, with documents showing the dates of and reasons for each deviation from e. Any other records that FDA requires to be maintained by regulation or by specific requi

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 i

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 e

(2) Progress reports on the investigation. (These reports must be provided at regular intervless often than yearly. If there is a study monitor, a copy of the report should also be sent t
51

(3) Any deviation from the investigational plan made to protect the life or physical well-beemergency. (Report is due as soon as possible but no later than 5 working days after the emExcept in emergency situations, a protocol deviation requires prior sponsor approval; and 

affect the scientific soundness of the plan or the rights, safety, or welfare of subjects, prior 

approval are required.) (4) Any use of the device without obtaining informed consent. (Due within 5 working day(5) A final report. (Due within 3 months following termination or completion of the investinvestigator's part of the investigation. For additional guidance, see the discussion under th

"Annual Progress Reports and Final Reports.") (6) Any further information requested by FDA or the IRB about any aspect of the investiga

b. To the Sponsor: 

(1) Withdrawal of IRB approval of the investigator's part of an investigation. (Due within such action). 

6. Investigational Device Distribution and Tracking 

The IDE regulations prohibit an investigator from providing an investigational device to any persoreceive it (21 CFR 812.110(c)). The best strategy for reducing the risk that an investigational devi

improperly dispensed (whether purposely or inadvertently) is for the sponsor and the investigators 

the shipping, use, and final disposal of the device(s). Upon completion or termination of a clinical investigator's part of an investigation), or at the sponsor's request, an investigator is required to ret

any remaining supply of the device or otherwise to dispose of the device as the sponsor directs (2Investigators must also maintain complete, current and accurate records of the receipt, use, or disp

investigational devices (21 CFR 812.140(a)(2)). Specific investigator recordkeeping requiremen

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 fapproved for marketing by FDA. This prohibition is applicable to sponsors and investigators (or abehalf 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 recov

manufacture, research, development, and handling 
52

c. Unduly prolonging an investigation beyond the point needed to collect data required to d

device is safe and effective, and d. Representing that the device is safe or effective for the purposes for which it is being in

8. Annual Progress Reports and Final Reports 

The IDE regulations do not specify the content of the annual progress or final reports. With respe

IRB, the IRB itself may specify what information it wishes to be included in these reports. Becausthe information listed below, it is suggested that, at a minimum, the annual progress and final repo

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 
53

Appendix 5: Suggested Format for IDE Final Report 

1. The Basics 

a. IDE Number b. Device name and indication for use c. Sponsor's name, address and phone number d. Contact person 

2. Study Progress 

(Data from beginning of the study should be reported, unless otherwise indicated.) 

a. Brief summary of study progress in relation to investigational plan b. Number of investigators/investigational sites (attach list of investigators) c. Number of subjects enrolled (by indication or model) d. Number of devices shipped e. Disposition of all devices shipped f. Brief summary of results g. Summary of anticipated and unanticipated adverse effects h. Description of any deviations from the investigational plan by investigators (since last progress 

3. Risk Analysis 

a. Summary of any new adverse information (since last progress report) that may affect the risk an

preclinical data, animal studies, foreign data, clinical studies, etc. b. Reprints of any articles published from data collected from this study 

4. Other Changes 

a. Summary of any changes in manufacturing practices and quality control (including changes not reported in a supplemental application) b. Summary of all changes in investigational plan not required to be submitted in a supplemental a

5. Marketing Application or Future Plans 

a. Progress toward product approval, with date (or projected date) of PMA or 510(k) submission; 

marketing of device is not planned. b. Any plans to submit another IDE application for this device or a modification of this device.