Draft Guidance for Industry and 

FDA Staff 

In Vitro Diagnostic (IVD) Device 

Studies – Frequently Asked 

Questions 

This guidance document is being distributed for comment purposes only. 

Document issued on: October 25, 2007

Comments and suggestions regarding this draft document should be submitted within 90 days of 

publication in the Federal Register of the notice announcing the availability of the draft guidance. 

Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug 

Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Alternatively, electronic 

comments may be submitted to http://www.fda.gov/dockets/ecomments. All comments should be 

identified with the docket number listed in the notice of availability that publishes in the Federal 

Register. 

For questions regarding this document contact Sally Hojvat, Ph.D. in CDRH at (240) 276-0496 or 

Leonard Wilson in CBER at (301) 827-0373. 

When final, this document will supersede "Guidance for FDA Staff: Regulating In Vitro 

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

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Devices and Radiological Health 

 Center for Biologics Evaluation and Research 

CB

ER
Contains Nonbinding Recommendations 

Draft - Not for Implementation 

Preface 

Additional Copies 

Additional copies are available from the Internet at: 

http://www.fda.gov/cdrh/oivd/guidance/1587.pdf, or to receive this document via your fax 

machine, call the CDRH Facts-On-Demand system at 800-899-0381 or 301-827-0111 from a 

touch-tone telephone. Press 1 to enter the system. At the second voice prompt, press 1 to order a 

document. Enter the document number (1587) followed by the pound sign (#). Follow the 

remaining voice prompts to complete your request. 

Or, contact: 

Office of Communication, Training, and Manufacturers Assistance, HFM-40 

Center for Biologics Evaluation and Research 

Food and Drug Administration 

1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448 

Internet: http://www.fda.gov/cber/guidelines.htm 

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

ii 
Contains Nonbinding Recommendations 

Draft - Not for Implementation 

Table of Contents 

I. Background .................................................................................................................... 1 

II. Introduction .................................................................................................................... 2 

III. General Regulatory Issues.............................................................................................. 4 

IV. Investigational Studies ................................................................................................. 13 

V. Human Subject Protection............................................................................................ 16 

VI. Data Considerations ..................................................................................................... 19 

VII. Glossary........................................................................................................................ 23 

VIII. References.................................................................................................................... 30 

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

INVESTIGATIONAL STUDIES ................................................................................ 33 

Appendix 2: Regulatory Framework for IVD Products Regulated as Class I, II, or III Devices. 34 

Appendix 3: Sponsor’s Responsibilities for Significant Risk Device Investigations................... 37 

Appendix 4: Investigator’s Responsibilities for Significant Risk Device Investigations............. 42 

Appendix 5: Suggested Format for IDE Final Report .................................................................. 46 

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Draft Guidance for Industry and FDA Staff 

In Vitro Diagnostic (IVD) Device Studies – 

Frequently Asked Questions 

This draft guidance, when finalized, will represent the Food and Drug Administration's 

(FDA's) current thinking on this topic. It does not create or confer any rights for or on any 

person and does not operate to bind FDA or the public. You can use an alternative approach 

if the approach satisfies the requirements of the applicable statutes and regulations. If you 

want to discuss an alternative approach, contact the FDA staff responsible for implementing 

this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number 

listed on the title page of this guidance. 

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 Part 812 (21 CFR 812.2(c)(3)).1 This guidance document, written in 

question and answer format, is intended to assist you2 (the manufacturer, sponsor, applicant, 

investigator and the IVD device industry in general) in the development of IVD studies, 

particularly those exempt from most of the requirements of the IDE regulation and to provide 

you with a broad view of the regulatory framework pertaining to the development phase of IVD 

devices. The information in this guidance document is also pertinent to investigators who 

participate in IVD studies and to institutional review boards (IRB) that review and approve such 

studies. The document is intended to facilitate the movement of new IVD technology from the 

investigational stage to the marketing stage. 

This guidance document outlines FDA regulations applicable to studies for investigational IVD 

devices, including those regulations related to human subject protection. The guidance also 

explains data considerations that ultimately will affect the quality of the premarket submission. 

This document includes a glossary, a reference list with related web addresses, and a quickreference table. 

 

1

 As explained below, even if a particular IVD study is exempt from most requirements of Part 812, studies that will 

support applications to FDA are subject to 21 CFR 812.119 (Disqualification of a Clinical Investigator), 21 CFR 

Part 50 (Informed Consent), and 21 CFR 56 (Institutional Review Boards). 

2

 For the purpose of this document, “you” refers to the manufacturer, sponsor, applicant, investigator and the IVD 

device industry in general. If the text refers only to one or some of these entities, the appropriate entity is referenced 

by its name. 

1

 
The Center for Devices and Radiological Health (CDRH) and the Center for Biologics 

Evaluation and Research (CBER) each have regulatory responsibilities for IVD devices; 

information included in this document applies to Class I, II, and III IVD devices regulated by 

either Center. 

Note: Some devices used to test blood donor suitability are regulated as biologics and 

licensed under biologic regulations (600 series of 21 CFR) rather than under device 

regulations (800 series of 21 CFR). Examples of biologics IVD devices include licensed 

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

C tests intended for blood screening. This guidance is written to address only IVD 

devices that are approved or cleared under device regulations (800 series of 21 CFR), 

regardless of which Center reviews the submission. If you have questions about a device 

regulated by CBER, you may go to the CBER website for published guidance 

(http://www.fda.gov/cber/guidelines.htm) or contact CBER for further information on 

applicable biologic guidance and regulations. (See Introduction, Section II, question # 

4, of this guidance for a listing of CBER contact numbers). 

FDA's guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 

be viewed only as recommendations, unless specific regulatory or statutory requirements are 

cited. The use of the word should in Agency guidances means that something is suggested or 

recommended, but not required. 

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 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. 

2. Why are in vitro diagnostics considered devices? 

In vitro diagnostics (IVDs) meet the definition of a device under the Federal Food, Drug, and 

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

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

2

 
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, prepare, and 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: (240) 276-0443

• Division of Immunology and Hematology Devices – Phone: (240) 276-0493

• Division of Microbiology Devices – Phone: (240) 276-0496

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 

•

•

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: (240) 276-0484 

3

 
For questions regarding the conduct of studies, contact: 

Office of Compliance (OC) 

Division of Bioresearch Monitoring (DBM) 

Phone: (240) 276-0125 

or 

Investigational Device Exemptions (IDE) Staff 

Office of Device Evaluation 

Phone: (240) 276-4040 

Center for Biologics Evaluation and Research (CBER)

For questions regarding manufacturing regulations, 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 (BIMO) Branch – Phone: (301) 827-6347 or (301) 827-8221 

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. 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 

Part 54, Financial Disclosure by Clinical Investigators 

Part 56, Institutional Review Boards 

Part 99, Dissemination of Information on Unapproved/New Uses for Marketed 

Drugs, Biologics, and Devices 

Part 801, Labeling 

Part 803, Medical Device Reporting 

Part 807, Establishment Registration and Device Listing for Manufacturers and 

Initial Importers of Devices 

Part 809, In Vitro Diagnostic Products for Human Use 

Part 810, Medical Device Recall Authority 

Part 812, Investigational Device Exemptions 

Part 814, Premarket Approval of Medical Devices 

Part 820, Quality System Regulation 

Part 860, Medical Device Classification Procedures 

Part 862, Clinical Chemistry and Clinical Toxicology Devices 

4

 
Part 864, Hematology and Pathology Devices 

Part 866, Immunology and Microbiology Device 

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 #4 below); 

• does not require an invasive sampling procedure that presents significant risk (see 

question #5 below); 

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

• 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 category, it must meet all of the conditions listed in “c” above. (See also 

the decision tree in Appendix 1.) You should refer to Parts 50 and 56 for applicable 

requirements relating to IRBs and informed consent, including for device studies that 

meet the criteria described in 21 CFR 812.2(c). Additionally, investigators for those 

studies are still subject to 21 CFR 812.119 (the provision entitled “Disqualification of 

a clinical investigator.”). 

5

If your proposed study does not fit into one of the three categories listed above, you, the 

sponsor, must have an approved IDE (21 CFR 812.2) before you may ship your 

investigational IVD. (Note: A device that is approved under a premarket approval application 

 
(PMA) or cleared under a 510(k) and then used in a study in accordance with the approved or 

cleared labeling is not investigational and, therefore, is not subject to the IDE regulation.) 

The requirements for an IDE depend on the level of risk that the study presents to subjects. 

For a significant risk device (see the Glossary for definition), the sponsor must apply to FDA 

for an IDE approval (see 21 CFR 812.1, 812.20). For a non-significant risk device (see the 

Glossary for definition), the sponsor must meet the abbreviated requirements of 21 CFR 

812.2(b), including review and approval of the investigation by an institutional review board 

(IRB) and compliance with informed consent requirements. A non-significant risk study is 

considered to have an approved IDE when the abbreviated requirements are met. 

Note: The requirements of the “Protection of Human Subjects” and “Institutional Review 

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

FDA under section 520(g) of the Act, as well as other clinical investigations that support 

applications for research or marketing permits. (21 CFR 50.1, 56.101; see also Section V, 

Human Subject Protection, of this guidance.) Therefore, all studies of investigational IVDs

that will support applications to FDA are subject to Parts 50 and 56, even if they are not 

subject to most requirements of Part 812. 

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

I determine if an invasive sampling technique presents a significant risk under 21 CFR 

812.2(c)(3)? 

A significant risk IVD device is generally one that is for a use of substantial importance in 

diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of 

human health and presents a potential for serious risk to the health, safety, or welfare of a 

subject or otherwise presents a potential for serious risk to health, safety, or welfare of a 

subject. 21 CFR 812.3(m). 

For IVDs, we interpret "potential for serious risk" in relation to the nature of the harm that 

may result to the subject. Misdiagnosis and/or error in treatment caused by inaccurate test 

results would be considered a significant risk if the potential harm to the subject could be 

life-threatening, or could result in permanent impairment of a body function or permanent 

damage to the body structure. 

False positive results can lead to unnecessary confirmatory testing, unnecessary treatment 

that can be invasive or have harmful side effects, and/or unnecessary psychological trauma 

when serious or life-threatening diseases or conditions are involved. False negative results 

can lead to a delay in establishing the correct diagnosis, failure to start or continue needed 

treatment, false security that may prevent timely follow-up and retesting, and contribute to 

the potential spread of infectious agents to others. If the potential risk does not rise to the 

level described above, the study is not considered to pose a significant risk. FDA 

recommends the sponsor consider all these factors when determining the risk associated with 

your investigational IVD. (See 21 CFR 812.3(m) and also "Information Sheet Guidance for 

IRBs, Clinical Investigators, and Sponsors," available at http://www.fda.gov/oc/ohrt/irbs/, 

particularly the one on “Significant Risk and Nonsignificant Risk Medical Devices” at 

http://www.fda.gov/oc/ohrt/irbs/devrisk.pdf.) 

6

 
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. 

4. 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 

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)). 

5. 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 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. 

6. 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. 

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

emergency situation? 

Yes. (See also Chapter III, “Expanded Access to Unapproved Devices,” of the guidance 

7

 
8

 

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. 

While prior FDA approval for shipment for emergency use of the investigational device is 

not required, 21 U.S.C. § 360bbb(a), if an IDE exists, the use should be reported to FDA in a 

supplemental IDE by the IDE sponsor within 5 working days from the time the sponsor 

learns of the use (21 CFR 812.35(a)(2)). The IDE supplement should contain a summary of 

the conditions constituting the emergency, patient outcome information, and the patient 

protection measures that were followed. If no IDE exists, the physician should follow the 

above procedures and report the emergency use to the sponsor and to CDRH or CBER, as 

appropriate. 

For additional information on the procedures physicians and IRBs should follow in an 

emergency use situation, please see Chapter III, "Expanded Access to Unapproved Devices" 

of the guidance entitled, IDE Policies and Procedures. 

8. 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. CDRH recognizes that there are circumstances when an 

unapproved or uncleared IVD is the only available option for a patient or small group of 

patients who do not meet the inclusion criteria and "compassionate use" of the device may be 

3

 This reference can be found at: www.fda.gov/cdrh/ode/idepolcy.html

 
appropriate. Federal Food, Drug, and Cosmetic Act, Section 561. CBER has a similar 

program termed “single patient exemption.” FDA requires for compassionate use the same 

patient protection measures required for emergency use, noted above. 

Use of an investigational IVD device for one or a small group of patients who do not meet 

the study inclusion criteria would require a change to the investigational plan. If the study is 

being conducted under an approved IDE, the sponsor should submit a supplement to the IDE 

requesting a change to the investigational plan for “compassionate use”. 21 CFR 812.35(a). 

The review of this supplement can be facilitated by a phone call to the reviewing division and 

by the submission by facsimile of an advanced copy of the supplement. If the investigational 

IVD device would require an FDA-approved IDE, but one has not yet been submitted or 

approved, FDA intends to exercise enforcement discretion where the sponsor submits a 

compassionate use request to CDRH or CBER, as appropriate, and follows the patient 

protection measures listed above for emergency use.4

 

Whether the study is being conducted according to an exemption under 21 CFR 812.2, or a 

significant or non-significant risk IDE, the sponsor should obtain prior approval for the 

specific compassionate use for the individual(s) in question from the FDA and the reviewing 

IRB at the site where the physician proposes to use the device. For CDRH regulated 

products, the required information can be submitted to the Director of the IDE Program: 

Attn: Director, IDE Program 

Food and Drug Administration 

Center for Devices and Radiological Health 

HFZ-403 

9200 Corporate Blvd 

Rockville, MD 20850 

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

http://www.fda.gov/cdrh/devadvice/ide/early.shtml#compassionateuse . 

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

appropriate reviewing division. 

9. 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. 

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

marketing approval through a humanitarian device exemption (HDE)? 

 

4

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

Policies and Procedures," http://www.fda.gov/cdrh/ode/idepolcy.html. 

9

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

Glossary for definitions, 21 CFR 814 Subpart H, and Appendix 1 for more information. 

11. 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). 

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

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

13. 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). 

10

•

•

•

•

•

•

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). 

14. 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/cdrh/pdp/pdp.html 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/cdrh/oivd/index.html or for CBER products at 

http://www.fda.gov/cber/efoi/pma.htm

11

 and http://www.fda.gov/cber/dap/devlst.htm. 

We recommend that the sponsor structure submissions according to the relevant regulations 

and provide sufficient detail to give the reader an understanding of the scientific data and 

information supplied. OIVD has issued many device specific guidances that describe FDA’s 

recommendations for premarket submissions for particular types of IVDs. 

 

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

CDRH has developed a guidance document entitled “Guidance for Industry; Supplements to 

Approved Applications for Class III Medical Devices: Use of Published Literature, Use of 

Previously Submitted Materials, and Priority Review,” which can be found on the CDRH 

website at http://www.fda.gov/cdrh/modact/evidence.html. CDRH and CBER believe that 

the principles outlined in this guidance are applicable to other submissions, specifically those 

for a 510(k), PMA, and HDE. (See the Glossary for definitions of these submission types.) 

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

an IVD premarket submission? 

Yes. FDA recognizes there may be a need to go outside of the U.S. 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 . 

17. Can foreign/international data be used as the sole support of a marketing application? 

Yes. 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 on site (21 CFR 814.15(d)). For IVD devices, this may include 

consideration of 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. 

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

12

•

•

•

•

•

•

A master file (MAF) is a reference source that a person submits to FDA. In general, it is a 

file of trade secret or confidential commercial/financial information submitted by a third 

party (i.e., someone other than the applicant) in support of the application as a reference 

source. FDA will accept MAFs from organizations or persons who have not submitted or 

will not directly submit the information in a PMA, IDE, 510(k), or other device-related 

submission to FDA. MAFs may include information on the following: 

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 Appendix C of the Premarket Approval Manual, which is found on 

the CDRH website at http://www.fda.gov/cdrh/dsma/pmaman/appdxc.html#P7_2

19. 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 premarket 

submission to FDA is not already in a master file, you should request that the company that 

owns this information submit a master file to FDA. 

For more information on referencing MAFs, see Appendix C of the Premarket Approval 

Manual, which is found on the CDRH website at 

http://www.fda.gov/cdrh/dsma/pmaman/appdxc.html#P7_2

 
 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 the safety and effectiveness. For example, if you are 

studying an IVD device that uses a well-characterized technology and has an intended use 

that falls within a type of device that has been classified into Class I or Class II, the study 

may consist of a comparison of analytic performance to that of a legally marketed (i.e., 

predicate) device. On the other hand, if your IVD uses novel or unproven technology or if 

there is a new intended use, you may need to conduct a well-planned clinical study of the 

device in the target population defined by your intended use. You may contact the Division 

in the appropriate Center if you have questions regarding the type of study you need to 

conduct for your device. 

We recommend that sponsors and investigators of all studies, including exempt studies under 

21 CFR 812.2(c)(3), conduct the studies with the following goals in mind: producing valid 

scientific evidence of the product’s safety and effectiveness and protecting the rights and 

welfare of study subjects. Sponsors and investigators of significant and non-significant risk 

studies must comply with the regulation requirements in 21 CFR Part 812. FDA 

recommends that sponsors and investigators of studies exempt from the majority of 

requirements under 21 CFR Part 812 use the relevant sections of 21 CFR Part 812 regarding 

the general conduct of device studies as guidance. (General Regulatory Issues, Section III 

of this guidance, discusses how 21 CFR Part 812 may apply to a particular IVD study.) 

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 

decide that my proposed studies are exempt from most IDE requirements? 

13

Some studies are exempt from most of Part 812 because of the low risk they pose to study 

subjects. However, studies that will support a PMA or other premarket submission should 

have the same goals as all other device studies: 1) to produce valid scientific evidence to 

support reasonable assurance of a product’s safety and effectiveness, and 2) to protect study 

subjects. Therefore, the information in Part 812 will also be useful to sponsors and 

 
investigators of device studies exempt under 812.2(c). In addition, all studies that will 

support applications to FDA are subject to 21 CFR 812.119(c) as well as to 21 CFR Part 50 

and 21 CFR Part 56. 

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)? 

You may use the ICH GCP as a reference regarding the proper conduct of studies. Although 

the ICH document was written for studies of pharmaceuticals, sections discussing study 

conduct common to all investigational products are appropriate references. 

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

proposed ISO document is an international document intended to reflect basic practices 

appropriate to clinical trials worldwide. It does not include all of FDA’s specific 

requirements for clinical studies and is not presently a standard that FDA has officially 

recognized; therefore, we do not recommend that you rely on it. 

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

most of the 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 “preIDE” meeting. While we refer to this early input as a "pre-IDE" process, it is also available 

for studies 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 

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 preIDE 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. (See the Glossary for definition of terms.) A guidance document regarding these 

meetings, “Early Collaboration Meetings Under the FDA Modernization Act (FDAMA); 

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

http://www.fda.gov/cdrh/ode/guidance/310.pdf. CBER also follows this meeting guidance 

document when determination and/or agreement meetings are requested. 

14

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

that are not exempt from most of the Part 812 requirements? 

The majority of the sponsor’s and investigator’s responsibilities in a study of a nonsignificant risk device are found in section 812.2(b)(1) of the IDE regulation and are 

summarized below: 

a. Label the device in accordance with 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 56.109(c). 

d. Comply with the requirements of 812.46 with respect to monitoring investigations; 

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

required under 812.150 (b)(1) through (3) and (5) through (10); 

f. Ensure that participating investigators maintain the records required by 

812.140(a)(3)(i) and make the reports required under 812.150(a)(1), (2), (5), and (7); 

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

We recommend that all studies have a written protocol as described in 21 CFR 812.25 (b) 

and a risk analysis as described in 21 CFR 812.25 (c), regardless of the status of the study 

under 21 CFR Part 812. 

We also recommend that all sites participating in the study use identical copies of the 

protocol and receive protocol amendments simultaneously so that data is collected in a 

consistent manner. Data collected from different sites otherwise may not be poolable in the 

final analysis due to inconsistencies in how it was collected. We recommend that protocols 

describe the study objectives, design, methodology, subject populations, types of specimens, 

data to be collected and planned data analysis. (See also Data Considerations, Section VI, 

of this guidance). For information on how to monitor the study, you may refer to the FDA 

guidance document entitled “Guideline for the Monitoring of Clinical Investigations,” which 

is available at http://www.fda.gov/ora/compliance_ref/bimo/clinguid.html. 

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.

15

 
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 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. Should a sponsor's own “in-house” laboratory (e.g., Research and Development (R&D) 

sections) that participates as a study site in an IVD study conduct the study as an 

external/independent study site? 

Yes. FDA regards all study sites as equivalent 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 current 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 

16

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 Parts 50 and 56 dealing with human subject research, rather than to Part 

58. 

3. What regulations apply regarding human subject protection in investigational IVD 

studies? 

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 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/cdrh/oivd/guidance/1588.pdf)

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 are independent of one another. 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 Appendix E of the FDA Information Sheets, Guidance for 

Institutional Review Boards and Clinical Investigators found at 

http://www.fda.gov/oc/ohrt/irbs/appendixe.html. For additional information on 45 CFR Part 

46 subpart A refer to the Office for Human Research Protections at 

17

 
http://ohrp.osophs.dhhs.gov/. 

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

by an IRB? 

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/oc/ohrt/irbs/expeditedreview.pdf . As stated in that 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) 

http://www.fda.gov/oc/ohrt/irbs/expeditedreview.pdf

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/cdrh/oivd/guidance/1588.pdf, 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 do 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? 

Under certain circumstances, FDA intends to exercise enforcement discretion regarding 

informed consent requirements for use of human specimens leftover from specimens 

originally collected for a previous study. 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/cdrh/oivd/guidance/1588.pdf. 

18

 
If the new study does not fall within the scope of the guidance on leftover human specimens 

but 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 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. 

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 after-the-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 that FDA be consulted when 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. 

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 

19

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

standards themselves, can be found on the OIVD web page http://www.fda.gov/cdrh/oivd/. 

The agency’s Statistical Guidance on Reporting Results from Studies Evaluating Diagnostic 

Tests; Guidance for Industry and FDA reviewers can be viewed at 

http://www.fda.gov/cdrh/osb/guidance/1428.pdf. 

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 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 readings on the same subject to the dataset, particularly when it is 

hard to find study subjects? 

In most studies the sponsor should avoid multiple testing 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, 

20

 
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 co-variable 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/cder/guidance/5667fnl.htm. There is also a more general guidance 

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

Systems Used in Clinical Trials,” which is in draft format and can be found at 

http://www.fda.gov/cder/guidance/6032dft.htm. However, because this document is still in draft 

form, it is not currently in effect. 

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). 

21

 
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). 

22

 
VII. Glossary 

Note: this glossary is written in plain language and is for use with this guidance document. 

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

include the relevant citation. 

Accuracy – the closeness of agreement between the result of a measurement and the true value 

of the measurand, where the measurand is a particular quantity subject to measurement. For 

additional information, refer to the Harmonized Technology Database, Clinical and Laboratory 

Standards Institute, available at http://www.clsi.org. 

510(k) – See Premarket Notification. 

Agreement meeting – a meeting, under § 520(g)(7) of the act 21 U.S.C. § 360j(g)(7) that is 

available to anyone planning to investigate the safety or effectiveness of a class III device (see 

definition below) or any implant. Unlike the Determination Meeting, the Agreement Meeting is 

available to submitters of 510(k)s for eligible devices. The purpose of the meeting is to reach 

agreement on the key parameters of the investigational plan, including the study protocol. The 

meeting is to be held within 30 days of the receipt of a written request. FDA will document in 

writing any agreement reached and make it a part of the administrative record. The agreement is 

binding on FDA and can only be changed with the written agreement of the applicant or when 

there is a substantial scientific issue essential to determining the safety or effectiveness of the 

device. See 21 U.S.C. 360j(g)(7). A guidance document regarding these meetings, “Early 

Collaboration Meetings Under the FDA Modernization Act (FDAMA); Final Guidance for 

Industry and for CDRH Staff,” is available at http://www.fda.gov/cdrh/ode/guidance/310.pdf. 

Class I devices – devices for which the general controls of the Act are sufficient to provide 

reasonable assurance of their safety and effectiveness. They typically present minimal potential 

for harm to the user and the person being tested. They are subject to general controls, which 

include registration and listing, labeling, and adverse event reporting requirements (section 

513(a)(1)(A) of the Act). Most Class I devices are exempt from premarket notification (see 

definition below), subject to certain limitations found in section 510(l) of the Act and in 21 CFR 

§ 862.9, 864.9, and 866.9. Some are also exempt from the “Quality Systems Regulation” found 

in 21 CFR Part 820. IVD examples of Class I devices include complement reagent, phosphorus 

(inorganic) test systems (21 CFR 862.1580), and E. coli serological reagents (21 CFR 866.3255). 

Class II devices – devices for which general controls alone are insufficient to provide reasonable 

assurance of their safety and effectiveness and for which establishment of special controls can 

provide such assurances. Special controls may include special labeling, mandatory performance 

standards, risk mitigation measures identified in guidance, and postmarket surveillance (section 

513(a)(1)(B) of the Act). Some Class II devices are exempt from premarket notification (see 

definition below), subject to limitation in 21 CFR § § 862.6, 864.9, and 866.9. IVD examples of 

Class II devices include glucose test systems (21 CFR 1345), antinuclear antibody 

immunological test systems (21 CFR 866.5100), and coagulation instruments (21 CFR 

864.5400). 

23

 
Class III devices – devices for which insufficient information exists to provide reasonable 

assurance of safety and effectiveness through general or special controls. Class III devices are 

usually those that support or sustain human life, are of substantial importance in preventing 

impairment of human health, or which present a potential, unreasonable risk of illness or injury 

(section 513(a)(1)(C) of the Act). Most Class III devices require premarket approval (PMA, see 

definition below). IVD examples of these include automated PAP smear readers, nucleic acid 

amplification devices for tuberculosis, and total prostate specific antigen (PSA) for the detection 

of cancer. A limited number of Class III devices that are equivalent to devices legally marketed 

before enactment of the Medical Device Amendments of 1976 may be marketed through the 

premarket notification (510(k)) process (see definition below), until FDA has published a 

requirement for manufacturers of that generic type of device to submit PMA data. 

Compassionate use – The compassionate use provision allows access for patients with a serious 

disease or condition who do not meet the requirements for inclusion in the clinical investigation 

but for whom the treating physician believes the device may provide a benefit in treating and/or 

diagnosing their disease or condition. There must be no feasible alternative therapies/diagnostics 

available. Compassionate use is typically available only for individual patients but also may be 

used to treat a small group. Prior FDA approval is needed before compassionate use occurs. 

Further information can be found at 

http://www.fda.gov/cdrh/devadvice/ide/early.shtml#compassionateuse. 

Confidence interval – the range of plausible values for a statistical parameter, consistent with 

the observed data, which is computed with a sample estimate parameter (e.g., mean) and its 

standard deviation. For example, a “95% Confidence Interval” is computed such that, if the 

parameter was determined for repeated experiments, the resulting values would include the true 

parameter value 95% of the time. 

Continued access to investigational devices – FDA may allow sponsors to continue to enroll 

subjects under an IDE, after the trial has been completed, while a marketing application is 

prepared by the sponsor and/or reviewed by FDA. To continue enrolling subjects, a sponsor 

should show that there is a public health need for the device, that preliminary evidence indicates 

that the device is likely to be effective for the indications proposed, and that no significant safety 

concerns have been identified for the proposed indication. A guidance document, entitled 

“Continued Access to Investigational Devices During PMA Preparation and Review,” can be 

found at http://www.fda.gov/cdrh/d961.html. 

Co-variables – data elements relating to a subject that might affect how well a diagnostic test 

works, such as demographic status (age, gender, etc.), morbidity, or concurrent therapy. 

24

Determination Meeting – A Determination meeting under § 513(a)(3)(D) of the Act is available 

to anyone anticipating submitting a PMA or PDP and is intended to provide the applicant with 

the FDA’s determination of the type of valid scientific evidence that will be necessary to 

demonstrate that the device is effective for its intended use. As a result of this meeting, FDA 

will determine whether clinical studies are needed to establish effectiveness and, in consultation 

with the applicant, determine the least burdensome way of evaluating device effectiveness that 

has a reasonable likelihood of success. The applicant can expect that FDA will determine if 

 
concurrent randomized controls, concurrent non-randomized controls, historical controls, or 

other types of evidence will be acceptable. FDA’s determination is to be written, shared with the 

applicant within 30 days following the meeting, and is binding upon the FDA, unless it could be 

contrary to public health. 21 U.S.C. § 360c(a)(3)(D). A guidance document regarding these 

meetings, “Early Collaboration Meetings Under the FDA Modernization Act (FDAMA); Final 

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

http://www.fda.gov/cdrh/ode/guidance/310.pdf. 

Device – as defined in the Act, section 201(h): 

an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other 

similar or related article, including any component, part, or accessory, which is 

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 

25

 
CFR Part 814, Subpart H. If a device receives a designation as an HUD, a Humanitarian Device 

Exemption request (HDE) can be submitted. HUDs that are approved for marketing under an 

HDE have specific labeling requirements. IRB approval is required for use of a HUD (21 CFR 

814.124). 

Investigation – a clinical investigation or research involving one or more subjects to determine 

the safety or effectiveness of a device (21 CFR 812.3(h)). It is often referred to as a clinical trial 

and is sometimes referred to as a field trial. 

Investigational Device Exemption (IDE) – application which, when approved, allows the 

device to be shipped lawfully for the purpose of conducting studies regarding the safety and 

effectiveness of the device, without complying with certain requirements of the Act. (See 21 

CFR 812.1 for specific exemptions.) For significant risk (SR) device studies (see definition 

below), a sponsor must apply to FDA to obtain approval for an IDE. (See 21 CFR 812.20.) For 

non-significant risk (NSR) device studies (see definition below), an IDE is considered approved 

when a sponsor meets the abbreviated requirements found in 21 CFR 812.2(b), which include 

approval from the reviewing Institutional Review Board(s) (IRB(s)). 

Investigational plan – sponsor’s overall plan regarding the conduct of an investigational study. 

It includes, but is not limited to, the purpose of the study, a written protocol, a risk analysis, 

device description, labeling, written monitoring procedures, informed consent materials, and 

Institutional Review Board (IRB) information. (21 CFR 812.25.) For IVD studies, protocols 

should describe the study objectives, design, methodology, subject populations, types of 

specimens, data to be collected and planned data analysis. 

Investigational Use in vitro diagnostic (IVD) product – an IVD product being shipped or 

delivered for product testing prior to full commercial marketing (e.g., for use on specimens 

derived from humans to compare the usefulness of the product with other products or procedures 

in current use or recognized as useful). These products must be labeled according to 21 CFR 

812.5 for non-significant risk or significant risk devices and according to 21 CFR 

809.10(c)(2)(ii) for devices that are exempt under 812.2(c). 

Investigator – an individual who actually conducts a clinical investigation, i.e., a person under 

whose immediate direction the investigational product is administered, dispensed, or used, 

provided that the investigation involves a subject. In the event of an investigation conducted by a 

team of individuals, the investigator is the responsible leader of that team (21 CFR 812.3(i)). 

In vitro diagnostic (IVD) products – those reagents, instruments, and systems intended for use 

in the diagnosis of disease or other conditions, including a determination of the state of health, in 

order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for 

use in the collection, preparation, and examination of specimens taken from the human body. 

IVD products are devices as defined in section 201(h) of the Act and may also be biological 

products subject to section 351 of the Public Health Service Act. The regulatory definition of in 

vitro diagnostic products is found in 21 CFR 809.3(a). 

Leftover specimens -- remnants of specimens collected for routine clinical care or analysis that 

26

 
would otherwise have been discarded, or remnants of specimens previously collected for other 

unrelated research. These specimens may be obtained from a specimen repository -- a common 

site for storage of collections of human biological specimens available for study. See also Excess 

samples. 

Non-significant risk (NSR) device – a device that does not meet the definition of significant 

risk (SR) device (see definition below). An IDE is considered approved for a NSR 

investigational device study once sponsors meet the abbreviated requirements found in the 

“Investigational Device Exemptions” regulation at 21 CFR 812.2(b). The risk determination for 

an investigational device study should be based on the proposed use of the device in the 

investigation in addition to the characteristics of the device. 

Outlier – a data observation whose value appears to be out of line with the main body of data 

that has been collected. 

Pre-amendment in vitro diagnostic (IVD) tests – IVD tests that were in commercial 

distribution before May 28, 1976. 

Precision – the closeness of agreement between independent diagnostic test results obtained 

under stipulated conditions. For additional information refer to the Harmonized Technology 

Database, Clinical and Laboratory Standards Institute, available at http://www.clsi.org. 

Premarket Approval Application (PMA) – the application for approval required prior to the 

marketing of most Class III medical devices (section 515 of the Act, 21 USC 360e). (See 

definitions of Class I, II, and III devices above.) PMA approval is based on a determination by 

FDA that the applicant’s submission provides sufficient valid scientific evidence to provide 

reasonable assurance that the device is safe and effective for its intended use(s). The PMA 

regulation is 21 CFR Part 814. PMA information is available at 

http://www.fda.gov/cdrh/devadvice/pma/. 

Premarket Notification – also referred to as a 510(k), is a submission to FDA that contains 

information to demonstrate that a device is substantially equivalent (SE) to a legally marketed 

(predicate) device. Governing regulations regarding premarket notification procedures are found 

in Subpart E of the “Establishment Registration and Device Listing for Manufacturers and Initial 

Importers of Devices” regulation (21 CFR Part 807). The 510(k) manual is available at 

http://www.fda.gov/cdrh/manual/510kprt1.html. 

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

devices, usually reserved for Class III devices (see definitions of device classes above), by which 

the sponsor and FDA agree on the product design and testing early in the concept and planning 

stages of a product (section 515(f) of the Act). 

Protocol – a document that contains a description of the objectives and design of an 

investigational study, methodology(s) to be used, and data to be collected. It may also contain 

information regarding the planned data analysis and study monitoring. For most studies in the 

development of an IVD product, it also contains information regarding types of specimens and 

27

 
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)). 

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). 

28

 
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. 

29

 
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 

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/ShowCFR.cfm?CFRPart=812. 

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

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/ShowCFR.cfm?CFRPart=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?CFRPart=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=820.30

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=860.7. 

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

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/ShowCFR.cfm?CFRPart=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/cdrh/ode/idepolcy.html. 

8. “Requirements for Testing Human Blood Donors for Evidence of Infection Due to 

Communicable Disease Agents,” (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 MAFs, see Appendix C of the Premarket Approval Manual, 

which is found on the CDRH website at 

http://www.fda.gov/cdrh/dsma/pmaman/appdxc.html#P7_2

10. “Guidance for Industry Supplements to Approved Applications for Class III Medical 

Devices: Use of Published Literature, Use of Previously Submitted Materials, and 

Priority Review,” which can be found on the CDRH website at 

http://www.fda.gov/cdrh/modact/evidence.html. 

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

http://www.fda.gov/cdrh/pdp/pdp.html

30

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

effectiveness, found at http://www.fda.gov/cdrh/oivd/index.html and

http://www.fda.gov/cber/efoi/pma.htm.

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

http://www.fda.gov/ora/compliance_ref/bimo/clinguid.html. 

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

Study Subjects found at http://www.fda.gov/cdrh/comp/2229.html and 

http://www.fda.gov/cdrh/comp/2229.pdf. 

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/cder/guidance/959fnl.pdf. 

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/cdrh/ode/guidance/310.pdf. 

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=814.15

18. Appendix E of the FDA Information Sheets, Guidance for Institutional Review Boards 

and Clinical Investigators

31

, found at http://www.fda.gov/oc/ohrt/irbs/appendixe.html. 

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

www.fda.gov/cdrh/mdufma/guidance/108.html

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

http://www.fda.gov/oc/ohrt/irbs/appendixb.html

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

http://www.fda.gov/oc/ohrt/irbs/appendixc.html

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; 

Draft Guidance for Industry and FDA Reviewers,” found at 

http://www.fda.gov/cdrh/osb/guidance/1428.html and 

http://www.fda.gov/cdrh/osb/guidance/1428.pdf. 

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

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/ShowCFR.cfm?CFRPart=11. 

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

Application, guidance document found at http://www.fda.gov/cder/guidance/5667fnl.htm. 

26. Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: 

Exception from Informed Consent Requirements for Emergency Research found at 

http://www.fda.gov/ora/compliance_ref/bimo/err_guide.htm. 

32

27. The PMA information, found at http://www.fda.gov/cdrh/devadvice/pma/. 

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. 

 

 
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 

 

33

Study is exempt from 21 CFR Part 812, except for 812.119 

No 

 

 

 Yes Yes 

Is it an invasive device? Significant risk? Apply to FDA for IDE

 No No 

Follow 812.2(b) – abbreviated IDE requirements 

 Yes Yes 

Does the study involve invasive sampling? Significant risk? Apply to FDA for 

IDE 

 

 

 No No 

 

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

product or procedure? 

 

Yes 

 

 Yes 

 No Significant risk? Apply to FDA for IDE 

 

No 

 

Follow 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 812.119. 

 
 

34

Appendix 2: Regulatory Framework for IVD Products 

Regulated as Class I, II, or III Devices 
Regulatory Framework for IVD Products Regulated as Devices Draft - Not for Im

Registration 

& Listing 

Applicable 

Limitations QSRs Labeling Application 

801-Subpart A & 

801.119 to all 

Only 820.180 and 820.198 General Purpose (if not sterile) No No ‘For Laboratory Use’ 

809.10(d) 

Reagents (Class I) 807.65(c) 864.4010(b) 809.10(d)(1)(iv) 

864.4010(b) 

 ASR's Class I Yes No 807.20(a) 864.4020(b)(1) 

Restrictions on sale, use,

Yes 510(k) 809.10(e) distribution, & Yes 

 Class II 807.20(a) 807.81 

864.4020(b)(2)

809.30(c) reporting 809.20(b) 

809.30 

Yes PMA, 814.1

Class III 807.20(a) 

864.4020(b)(3) 

 Investigational Use: No 

• Significant Risk (SR) No 812.1 IDE 812.20 (except for Prohibition on promotion and commercialization 812.5 

820.30) [exempt from 

809.10(a)&(b)] 812.1 812.7 

• Non-Significant Risk (NSR) No 812.1 No 812.2(b) But see 812.20(b)(3) • Exempt from most 

requirements of Part 812

‘For investigational Use 

Only. The performance 

characteristics of this 

product have not been 

established’ 

809.10(c)(2)(ii)

No 

807.20(a) No 

809.10(c)(2)(ii) No* (investigational devices are not in 

commercial distribution) 

812.2(c)(3) 

 Note: 21 CFR 812.119 applies to all  investigational devices

No ‘Research Use Only’ 

809.10(c)(2)(i) 

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

No 

Yes 

807.20(a) 

[unless 807.81(a)(3) 

and unless rule requires 

PMA, 21 U.S.C. 

360e(b)] 

Yes 

809.20(b) 

Yes 

807.20(a) 

510(k) 

807.81 

(Exemptions subject to 

limitations in 862.9, 

864.9 & 866.9) 

Yes. 

809.20(b) 

Yes 

807.20(a) 

PMA 

814.20 

809.10 

“For In Vitro 

Diagnostic Use” 

809.10(a)(4)

 See "labeling" 

Yes 

809.20(b) 

For non investigational 

commercially marketed in vitro diagnostic devices: 

• Pre-Amendment device • Premarket Notification* 

(Class I, II, or III) 

• PMA/PDP (Class III) 

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

809.10 

• HDE Yes 814.102 Yes 

814.104(b)(4)(ii) 814.104(b)(4)(ii) 

807.20(a) HDE 809.20(b) 

814.104(b)(5) 814.104 
* While investigational IVDs exempt from most of the provisions of 812 are not exempt from 

requirements, we generally do not intend to enforce such requirements for investigational exempt from most Part 812 requirements; except for design controls.
Appendix 3: Sponsor’s Responsibilities for Significant Risk Device 

Investigations 

1. General Duties (21 CFR 812.40)

a. Submitting the IDE application to FDA 

b. Obtaining both FDA and IRB approval for the investigation 

c. Selecting qualified investigators and providing them with the information they 

need to conduct the investigation properly 

d. Ensuring proper monitoring of the investigation 

e. Ensuring that any reviewing IRB and FDA are promptly informed of significant 

new information about an investigation 

2. Selection of Investigators (21 CFR 812.43)

a. Assuring selection of investigators qualified by training and experience 

b. Shipping the investigational device only to participating investigators 

c. Obtaining a signed investigator's agreement from each investigator containing: 

(1) investigator's curriculum vitae 

(2) statement of investigator's relevant experience, including dates, location, 

extent, and type of experience 

(3) if an investigator was involved in an investigation or other research that 

was terminated, an explanation of the circumstances that led to the 

termination 

(4) statement of the investigator's commitment to: 

• conduct the investigation in accordance with the agreement, the 

investigational plan, Part 812 and other applicable regulations, and 

any conditions of approval imposed by the IRB or FDA 

• supervise all testing of the device involving human subjects 

• ensure that the requirements for obtaining informed consent are 

met (21 CFR Part 50) 

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

of the investigation in accordance with FDA regulations. 

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

investigations of the device. (21 CFR 812.45) 

3. Monitoring (21 CFR 812.46)

a. Securing compliance of all investigators in accordance with the signed 

investigator's agreement, the investigational plan, the requirements of Part 812 or 

other applicable FDA regulations, or any condition of approval imposed by the 

reviewing IRB or FDA. If compliance cannot be secured, shipment of the device 

to the investigator and the investigator's participation in the investigation must be 

discontinued 

b. Evaluating all unanticipated adverse device effects and terminating the 

37

 
investigation, or portions of it, as soon as possible if that effect presents an 

unreasonable risk to subjects (Reporting requirements are listed below.) 

c. Resuming terminated investigations only after IRB and/or FDA approvals are 

obtained, as required by this regulation. 

4. Controlling Distribution and Disposition of Devices 

Although investigators are responsible for ensuring that investigational devices are made 

available only to persons who are legally authorized to receive them (see 21 CFR 

812.110(c)), sponsors also bear responsibility for taking proper measures to ensure that 

devices are not diverted outside of legally authorized channels. Sponsors may ship 

investigational devices only to qualified investigators participating in the clinical 

investigation (§ 812.43(b)). Sponsors must also maintain complete, current, and accurate 

records pertaining to the shipment and disposition of the investigational device (§ 

812.140(b)(2)). Records of shipment shall include the name and address of the consignee, 

type and quantity of device, date of shipment, and batch number or code mark. Records of 

disposition shall describe the batch number or code marks of any devices returned to the 

sponsor, repaired, or disposed of in other ways by the investigator or another person, and 

the reasons for and method of disposal. 

To further ensure compliance with these requirements, sponsors should take appropriate 

measures to instruct investigators regarding their responsibilities with respect to 

recordkeeping and device disposition. The specific recordkeeping requirements for 

investigators are set forth at § 812.140(a). Upon completion or termination of a clinical 

investigation (or the investigator's part of an investigation), or at the sponsor's request, an 

investigator is required to return to the sponsor any remaining supply of the device or 

otherwise to dispose of the device as the sponsor directs (§ 812.110(e)). 

5. Prohibition of Promotion and Other Practices (21 CFR § 812.7)

The IDE regulation prohibits the promotion and commercialization of a device that has not 

been first cleared or approved for marketing by FDA. This prohibition is applicable to 

sponsors and investigators (or any person acting on behalf of a sponsor or investigator), 

and encompasses the following activities: 

a. Promotion or test marketing of the investigational device 

b. Charging subjects or investigators for the device a price larger than is necessary to 

recover the costs of manufacture, research, development, and handling 

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

required to determine whether the device is safe and effective, and 

d. Representing that the device is safe or effective for the purposes for which it is 

being investigated. 

6. Supplemental Applications (21 CFR 812.35(a) and (b)) 

Supplemental applications are required to be submitted to, and approved by, FDA in the 

38

 
following situations: 

a. Changes in the investigational plan: FDA approval is required for any change 

that may affect the scientific soundness of the investigation or the rights, safety or 

welfare of the subjects. IRB approval is also required for changes that may affect 

the rights, safety or welfare of the subjects. The change in the investigational plan 

may not be implemented until FDA approval (and IRB approval, if required) is 

obtained. 

b. Addition of new institutions: IRB approval is also required for new institutions. 

The investigation at the new institution(s) may not begin until both FDA and IRB 

approval(s) are obtained, and certification of IRB approval is submitted to FDA. 

7. Maintaining Records (21 CFR 812.140(b))

A sponsor shall maintain the following accurate, complete, and current records relating to 

an investigation (also See Table I, next page): 

a. Correspondence (including reports) with another sponsor, monitor, investigators, 

an IRB or FDA 

b. Records of shipment, including: 

(1) name and address of consignee 

(2) type and quantity of device 

(3) date of shipment 

(4) batch numbers or code marks 

c. Records of disposition, describing: 

(1) Batch number or code mark of devices returned, repaired, or disposed of 

by the investigator or other persons 

(2) Reasons for and method of 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 investigation or a particular investigation 

39

 
 TABLE I 

 RESPONSIBILITIES FOR MAINTAINING RECORDS

FOR A SIGNIFICANT RISK DEVICE STUDY

 Records Maintained by Maintained by 

 Investigator Sponsor 

All Correspondence Pertaining to the Investigation X X 

Shipment, Receipt, Disposition X X 

Device Administration and Use X - 

Subject Case Histories X - 

Informed Consent X - 

Protocols and Reasons for Deviations from Protocol X - 

Adverse Device Effects and Complaints X X 

Signed Investigator Agreements - X 

Membership/Employment/Conflicts of Interest - X 

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

A sponsor shall prepare and submit the following complete, accurate, and timely reports 

(also see Table II, next page): 

 

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

investigators within 10 working days after notification by the investigator. 

Subsequent reports on the effect may be required by FDA 

b. Withdrawal of IRB approval 

c. Withdrawal of FDA approval 

d. Current 6-month investigator list 

e. Progress reports (at least annual) - see attached suggested format for IDE progress 

report 

f. Recall and device disposition (within 30 working days after the request was 

made) 

g. Final report - see attached suggested format for progress reports 

h. Use of device without obtaining patient informed consent within 5 working days 

of receipt of notice of such use 

i. Significant risk determinations by the IRB when sponsor had proposed 

nonsignificant risk within 5 working days of receipt of such IRB determination 

j. Other reports requested by the IRB or FDA about any aspect of the investigation 

40

 
 TABLE II 

 RESPONSIBILITIES FOR PREPARING AND SUBMITTING REPORTS

FOR SIGNIFICANT RISK DEVICE STUDIES

Type of Report Prepared by Investigators for Prepared by Sponsors 

for 

Unanticipated Adverse Effect Evaluation Sponsors and IRBs FDA, IRBs and 

Investigators 

Withdrawal of IDE Approval Sponsors FDA, IRBs, and 

Investigators 

Progress Report Sponsors, Monitors and IRBs FDA and IRBs 

Final Report Sponsors and IRBs FDA, IRBs, and 

Investigators 

Emergencies (Protocol Deviations) Sponsors and IRBs FDA 

Inability to Obtain Informed Consent Sponsors and IRBs FDA 

Withdrawal of FDA Approval N/A IRBs and Investigators 

Current Investigator List N/A FDA 

Recall and Device Disposition N/A FDA and IRBs 

Records Maintenance Transfer Sponsors FDA 

Significant Risk Determinations N/A FDA 

9. Inspections (21 CFR 812.145)

Sponsors are required to permit FDA to enter and inspect (at reasonable times and in a 

reasonable manner) any establishment where devices are held (including any establishment 

where devices are manufactured, processed, packed, installed, used, or implanted or where 

records or results from use of devices are kept). FDA may also inspect and copy all 

records relating to an investigation including, in certain situations, records which identify 

subjects. 

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Appendix 4: Investigator’s Responsibilities for Significant Risk Device 

Investigations 

1. General Responsibilities of Investigators (21 CFR 812.100)

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

the investigational plan and applicable FDA regulations 

b. Protecting the rights, safety, and welfare of subjects under the investigator's care 

c. Controlling devices under investigation 

d. Ensuring that informed consent is obtained from each subject in accordance with 

21 CFR Part 50 

2. Specific Responsibilities of Investigators (21 CFR 812.110)

a. Awaiting IRB approval and any necessary FDA approval before requesting 

written informed consent or permitting subject participation 

b. Conducting the investigation in accordance with: 

(1) the signed agreement with the sponsor 

(2) the investigational plan 

(3) the regulations set forth in 21 CFR Part 812 and all other applicable 

FDA regulations, and 

(4) any conditions of approval imposed by an IRB or FDA 

c. Supervising the use of the investigational device. An investigator shall permit an 

investigational device to be used only with subjects under the investigator's 

supervision. An investigator shall not supply an investigational device to any 

person not authorized under 21 CFR Part 812 to receive it. 

d. Financial disclosure. A clinical investigator shall disclose to the sponsor 

sufficient accurate financial information to allow the applicant to submit complete 

and accurate certification or disclosure statements under Part 54. 

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

investigation or the investigator's part of an investigation, or at the sponsor's 

request, an investigator shall return to the sponsor any remaining supply of the 

device or otherwise dispose of the device as the sponsor directs. 

3. Maintaining Records (21 CFR 812.140)

An investigator shall maintain the following accurate, complete, and current records 

relating to the investigator's participation in an investigation: 

a. Correspondence with another investigator, an IRB, the sponsor, a monitor, or 

FDA 

b. Records of receipt, use or disposition of a device that relate to: 

(1) the type and quantity of the device, dates of receipt, and batch numbers 

or code marks 

(2) names of all persons who received, used, or disposed of each device 

(3) the number of units of the device returned to the sponsor, repaired, or 

42

 
otherwise disposed of, and the 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 investigator without informed consent, any written concurrence of a 

licensed physician and a brief description of the circumstances 

(2) justifying the failure to obtain informed consent 

(3) document all relevant observations, including records concerning 

adverse device effects (whether anticipated or not), information and data 

on the condition of each subject upon entering, and during the course of, 

the investigation, including information about relevant previous medical 

history and the results of all diagnostic tests 

(4) a record of the exposure of each subject to the investigational device, 

including the date and time of each use, and any other therapy 

d. The protocol, with documents showing the dates of and reasons for each deviation 

from the protocol 

e. Any other records that FDA requires to be maintained by regulation or by specific 

requirement for a category of investigations or a particular investigation. 

4. Inspections (21 CFR 812.145)

Investigators are required to permit FDA to inspect and copy any records pertaining to 

the investigation including, in certain situations, those which identify subjects. 

5. Submitting Reports (21 CFR 812.150)

An investigator shall prepare and submit the following complete, accurate, and timely 

reports: 

a. To the sponsor and the IRB: 

(1) Any unanticipated adverse device effect occurring during an 

investigation. (Due no later than 10 working days after the investigator 

first learns of the effect.) 

(2) Progress reports on the investigation. (These reports must be provided 

at regular intervals, but in no event less often than yearly. If there is a 

study monitor, a copy of the report should also be sent to the monitor.) 

(3) Any deviation from the investigational plan made to protect the life or 

physical well-being of a subject in an emergency. (Report is due as soon 

as possible but no later than 5 working days after the emergency occurs. 

Except in emergency situations, a protocol deviation requires prior 

sponsor approval; and if the deviation may affect the scientific 

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

FDA and IRB approval are required.) 

(4) Any use of the device without obtaining informed consent. (Due within 

5 working days after such use.) 

(5) A final report. (Due within 3 months following termination or 

completion of the investigation or the investigator's part of the 

investigation. For additional guidance, see the discussion under the 

43

 
section entitled "Annual Progress Reports and Final Reports.") 

(6) Any further information requested by FDA or the IRB about any aspect 

of the investigation. 

 

b. To the Sponsor: 

(1) Withdrawal of IRB approval of the investigator's part of an 

investigation. (Due within 5 working days of such action). 

6. Investigational Device Distribution and Tracking

The IDE regulations prohibit an investigator from providing an investigational device to 

any person not authorized to receive it (21 CFR 812.110(c)). The best strategy for 

reducing the risk that an investigational device could be improperly dispensed (whether 

purposely or inadvertently) is for the sponsor and the investigators to closely monitor the 

shipping, use, and final disposal of the device(s). Upon completion or termination of a 

clinical investigation (or the investigator's part of an investigation), or at the sponsor's 

request, an investigator is required to return to the sponsor any remaining supply of the 

device or otherwise to dispose of the device as the sponsor directs (21 CFR § 

812.110(e)). Investigators must also maintain complete, current and accurate records of 

the receipt, use, or disposition of investigational devices (21 CFR § 812.140(a)(2)). 

Specific investigator recordkeeping requirements are set forth at 21 CFR § 812.140(a). 

7. Prohibition of Promotion and Other Practices (21 CFR § 812.7) 

The IDE regulations prohibit the promotion and commercialization of a device that has 

not been first cleared or approved for marketing by FDA. This prohibition is applicable 

to sponsors and investigators (or any person acting on behalf of a sponsor or 

investigator), and encompasses the following activities: 

a. Promotion or test marketing of the investigational device 

b. Charging subjects or investigators for the device a price larger than is necessary to 

recover the costs of manufacture, research, development, and handling 

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

required to determine whether the device is safe and effective, and 

d. Representing that the device is safe or effective for the purposes for which it is 

being investigated. 

8. Annual Progress Reports and Final Reports

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

With respect to reports to the IRB, the IRB itself may specify what information it wishes 

to be included in these reports. Because FDA does require the information listed below, it 

is suggested that, at a minimum, the annual progress and final reports to the sponsor and 

the IRB also include the following items: 

a. IDE number 

44

 
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 

45

 
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 report) 

3. Risk Analysis

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

affect the risk analysis; this includes 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 application 

5. Marketing Application or Future Plans

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

submission; or indication that marketing of device is not planned. 

b. Any plans to submit another IDE application for this device or a modification of 

this device. 

46