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Bioresearch Monitoring Inspections of In Vitro Diagnostics Devices






Introduction . . Pg 1


Nature, Scope, & Purpose . . Pg 1


Definition . . Pg 1


Exemptions from 21 CFR 812 . . Pg 1


Labeling Requirements. . .Pg 2


Prohibited Labeling Information . . Pg 2


Specimen Testing & Sampling Reqmnts. . .Pg 2


The Sponsor's Investigational Plan . . Pg 3


Proposed Intended Use of the IVD and


Clinical Data . . Pg 4


Performance Characteristics and the


Clinical Data . . Pg 5


Factors Affecting the Quality of the Results of


the Clinical Investigation . . Pg 5


Conclusion . . Pg 5


References . . Pg 6





The purpose of this document is to provide


a written reference for Food and Drug


Administration (FDA) Investigators conducting


bioresearch monitoring (BIMO) inspections


involving in vitro diagnostic (IVD) devices. The


following material presents key aspects of


existing compliance approaches to BIMO IVD




This guide was prepared by the FDA, Office


of Regulatory Affairs (ORA) and the Center for


Devices and Radiological Health (CDRH) with


input from the Center for Biologics Evaluation


and Research (CBER).





The purpose of bioresearch monitoring


inspections is to ensure that data and


information contained in premarket applications


are scientifically valid and accurate. Another


objective of the program is to ensure that


human subjects are protected from undue


hazard or risk during the course of scientific


investigations. Legal authority for these


inspections is found in Section 704 of the


Federal Food, Drug and Cosmetic Act (the Act)


which gives FDA authority to inspect facilities


where devices are "held."





IVD products are 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. These products are devices as


defined in section 201(h) of the Act.





Section 21 CFR 812.2(c)(3) exempts


investigations of IVD devices from the specific


regulations of 21 CFR 812, Investigational


Device Exemptions, under certain conditions.


Furthermore, because these are clinical


investigations, good laboratory practices (GLP)


regulations do not apply and should not be


used as a basis for citations on the form


FDA-483. Although the design control section


of the Quality System Regulation applies to


investigational devices, Quality System


Regulation deviations should only be cited


during Quality System Regulation inspections.


In order to be exempt from 21 CFR 812 the


sponsor must comply with the labeling


requirements of 21 CFR 809.10(c) and the


testing requirements of 21 CFR 812.2(c)3).





IVDs shipped solely for research purposes


must be labeled: "For Research Use Only, Not


for use in diagnostic procedures." If an IVD is


labeled "For Research Use Only," the research


that may be performed is limited to the


laboratory research phase needed to identify


test kit methods, components, and analytes to


be measured. An IVD labeled for research use


as described above is mislabeled if used for a


clinical study for even one patient if the results


are reported to the patient's physician or to


the patient's medical records. Research use


devices are not to be used to assess the


patient's condition regardless of whether or not


a confirmatory test or procedure is used.


IVDs shipped for clinical investigations must


be labeled: "For Investigational Use Only. The


performance characteristics of this product


have not been established. The regulations


define an investigation as a clinical investigation


or research involving one or more subjects to


determine the safety or effectiveness of a


device. (See draft CPG Commercialization of


In Vitro Diagnostic (IVD) Devices Labeled for


Research Use Only or Investigational Use Only,


dated January 5, 1998. This CPG will not be


implemented until finalized).





Labeling cannot include any representation


that the IVD is safe or effective because this is


a determination that only the FDA can make


based on the review of data gathered through


the clinical investigation and supplied by the


sponsor to FDA.


Labeling cannot include performance


characteristics or expected range because they


will be established by the research and/or


clinical investigation.





The testing must be noninvasive, must not


require an invasive sampling procedure that


presents significant risk, must not introduce


energy into the patient, and must not be used


as a diagnostic procedure without confirmation


of the diagnosis by an established diagnostic


product or procedure.


21 CFR 812.3(k) defines noninvasive devices


or procedures as those that do not penetrate


or pierce the skin, mucous membranes, ocular


cavity or urethra or do not enter body orifices


beyond specified limits. However, the


regulation defines simple venipuncture to obtain


blood specimens and the use of surplus samples


of body fluids or tissues left over from samples


taken for non-investigational purposes as




Procedures like amniocentesis, lumbar


puncture, and tissue biopsy, are examples of


invasive sampling procedures that present


significant risk. If they are performed solely for


the investigation, then the IVD would not be


exempt from the IDE regulations. If samples


from these procedures are left over from


samples originally taken for non-investigative


purposes, then the sampling is considered


noninvasive. However, the initial procedure


should have been indicated for the patient's


condition by current medical practice and not


performed to obtain specimens surreptitiously


for the clinical investigation.


In order to be exempt from 21 CFR 812,


the investigational device cannot be used as a


diagnostic procedure without confirmation of


the diagnosis by another, medically established


diagnostic product or procedure. Disease


diagnosis usually involves a number of


observations and factors including signs and


symptoms, medical history, and a battery of


tests. There are few tests that are


pathognomonic, i.e., are considered "gold


standards," for diagnosis of a disease and,


therefore, the diagnosis is established from a


number of factors. Moreover, a sponsor or


investigator may consider the investigational


IVD to be more accurate, precise, sensitive,


specific, etc., than current medically established


products or procedures. This is generally the


goal for producing a new product.


Nevertheless, the diagnosis itself must be


confirmed in the established way to meet the


requirements for exemption from the IDE







In order to obtain valid scientific data to


support its submission to the FDA and to


maintain the integrity of that data, the sponsor


should have an investigational plan including a


protocol or other effective means to


communicate procedures, etc., to its


investigators. Non-adherence to such a


protocol should be noted on an FDA 483.




The purpose of the plan is to establish and


support claims and information in proposed


labeling, including intended use; statements


about reagents, instruments, and specimens; the


procedure; limitations of the procedure;


expected values; and specific performance


characteristics; and to support a determination


of safety and effectiveness and/or substantial






Such a study must be carried out in a


scientifically sound manner. Therefore, to


assure useful results and the integrity of the


data and to be able to present their plan to an


Institutional Review Board (IRB), the sponsor


should develop an investigational plan. A good


plan will include all information, procedures,


reporting forms, etc., required by the clinical


investigator to gather valid data for the sponsor


to submit to FDA. These would include such


things as a statement of purpose, a protocol, a


description of the device, monitoring


procedures, labeling, consent materials, IRB


information, and additional records and reports.


Additional records could include a certification


program that ensures that the sponsor is


controlling the distribution of the investigational


and/or research device and is using it in


scientifically sound research and investigations.


The investigator should sign an investigator's


agreement acknowledging his/her




At this phase there should be no


promotional/advertising material.


Advertisements to recruit subjects should be


reviewed by the IRB to ensure that information


is not misleading and that patient's rights and


welfare are protected.


IRB and Informed Consent:


The IRB must review and approve the


protocol and consent materials before the


study can begin. 21 CFR 56, Institutional


Review Boards, and 21 CFR 50, Informed


Consent, do not specifically exempt IVDs and,


therefore, are applicable.


Because most IVD research and


investigations do not require an IDE and are


minimal risk, the IRB may use expedited review


procedures to review most IVD research and


investigational proposals. The IRB must


document why expedited review was used for


approving the IVD investigation.


The IRB may exempt the study from


informed consent if it finds that the research


presents no more than minimal risk of harm to


subjects and involves no procedures for which


written consent is normally required. For


example, an IRB may exempt a study from


informed consent if left-over specimens will be


used, provided that patient confidentiality is






While the protocol does not need FDA


approval, it is an essential tool for the sponsor


to communicate accurately to the IRB and the


clinical investigator. Although the sponsor is


exempt from labeling requirements if it meets


the requirements of 21 CFR 809.10(c), the


labeling or its equivalent supplies the clinical


investigator with important information about


the test procedure. Without a protocol, or


similar tool, the sponsor runs the risk of getting


invalid results from the investigation.


The protocol and the labeling should reflect


all the steps the clinical investigator must take


to obtain useful information for the sponsor.


They should describe such things as specimen


collection, instrumentation, reagents,


calibration, quality control, step-by-step


procedures, calculations, storage conditions,


stability of various components both before and


after opening and/or reconstituting, reporting


procedures, and the necessary reporting forms,


etc., for obtaining accurate and precise results


and communicating them to the sponsor.





For Diagnosis or Differential Diagnosis of a


Disease or Medical or Physiological Condition:


The sponsor may use the data to establish


expected values or ranges and cut-off values.


The sponsor's proposed labeling will designate


concentrations that characterize the healthy


and affected populations. These are usually


expressed as diagnostic cut-off values. This


information will determine the clinical


usefulness of the test results and will affect the


rates of true and false results. Since treatment


may be based on a diagnosis from an IVD,


expected values should be established with


accurate information. For example, an IVD to


measure blood glucose levels will have a normal


range for healthy individuals. Values outside


the normal range will be used in the diagnosis


of diabetes.


In many cases, the sponsor may simply


compare the performance of the investigational


device to a device already cleared with the


same intended use, using left-over patient


specimens. When the patient's diagnosis is


necessary, it must have been established by


some medically acceptable scientific method. In


those cases, the sponsor and investigator must


record enough of the patient's medical history


to determine the diagnosis and any other


conditions that might impinge on the


performance of the IVD.


To Monitor a Patient's Therapy or to Follow


Their Progress After Treatment:


Records should establish which patients are


on the therapy or have had the treatment. For


example, if the IVD measured a tumor marker


to assure total removal of the tumor and/or


monitor its reoccurrence, then records should


reflect the patient's diagnosis and treatment and


the pre-treatment levels of the marker.


Screening and Prognosis:


Screening is performed to identify risk


factors in health promotion and disease


prevention. For example, cholesterol screening


may be performed on a random population to


identify individuals with this risk factor for heart




Prognosis means determining the intensity


or stage of a disease and predicting the


expected course of a disease.


Generally firms do not develop an IVD


specifically for screening or prognosis. IVDs


intended to diagnose or monitor are used


instead and the results translated into screening


or prognostic terms. If the intended use is, or


includes screening, then the investigation should


reflect the anticipated screening population,


generally healthy adults. If it is for prognosis,


then the screening population should consist


almost exclusively of those with the disease.


Prognostic claims should be established with


patient outcome data.


Home Use and Physician Office Lab Devices


Versus Professional Lab Devices:


If a device is intended for use outside the


professional laboratory setting, the Office of


Device Evaluation may require other types of


studies, e.g., analyses performed by the actual




The FDA investigator should be alert to any


special instructions, e.g., patient instruction and


preparation, when he or she is inspecting such









The sponsor may use the investigational


data to support the performance characteristics


section of the product's proposed labeling. This


section of the labeling describes how well the


device performed during the clinical


investigation and describes such things as the


accuracy, precision, sensitivity, and specificity of


the IVD. The sponsor is establishing the


purported quality of the device and therefore


should assure that the data are valid.


Accuracy or bias describes how well the


IVD result compares to the actual


concentration in the patient's specimen.


Precision describes how well the IVD


repeats test results on the same material.


Sensitivity describes the lowest


concentration at which the IVD gives


acceptable results.


Specificity is the ability of the IVD to


accurately measure the analyte of interest in


the presence of potential interfering substances.


The performance characteristics should be


related to a generally accepted method and use


biological specimens from normal and abnormal


populations. The sponsor should define these


populations. Too few patients in any one


group may not provide the sponsor with the


statistical power to make a claim in their









There are many factors that may affect the


quality and validity of the data collected to


support the claims and statements discussed


above. The sponsor and investigator should


control these factors using QC and QA


methods applicable to diagnostic and analytical


laboratories. These factors are usually


categorized as pre-analytical, analytical, and






Pre-analytical considerations center around


the patient, his or her preparation, and the




Analytical considerations include everything


surrounding the actual measurement process.


Post-analytical considerations center around


the proper calculation and reporting of results.


Although elements of QC and QA


principles outlined in FDA's Good Laboratory


Practices or Quality Systems GMP Regulation


may apply, the regulations themselves do not.


FDA Investigators should base any inspectional


observations on whether the sponsor or clinical


investigator followed the protocol and labeling


specified for the investigation.


Although 21 CFR Part 812, Investigational


Device Exemptions (IDE), is used as guidance


when reviewing inspectional reports, the IDE


regulations themselves do not apply to in vitro


diagnostic devices and should not be used as a


reference when documenting observations on


the FDA-483.





In summary, IVDs for clinical investigations


or research must meet the labeling


requirements in 21 CFR 809.10(c). Labeling


must not contain performance claims,


diagnostic ranges, indications of safety and


effectiveness, etc. The sponsor must control


the distribution of the device to avoid the


appearance of commercializing an uncleared or


unapproved medical device. They must also


meet the requirements of 21 CFR 56,


Institutional Review Boards, and 21 CFR 50,


Protection of Human Subjects. Additionally, if a


protocol or its equivalent exists, the FDA


Investigator should assure that the clinical


investigator has followed it. The clinical


investigator should have followed the specific


inclusion and exclusion criteria for patients


assuring that the diagnosis for each patient is


accurate by a cleared IVD or other standard of


diagnosis. They should assure the integrity of


the data, specifically, that the analyses were


actually performed according to instructions


that accompany the kit and that the data were


recorded and reported accurately. Raw data


should exist to support the data submitted in


reports and applications to the Agency.


Although many of these requirements resemble


GLPs, the observations should be in terms of


adherence to the sponsor's protocol.


Should you have comments or questions


regarding In Vitro diagnostic bioresearch


monitoring inspections or this guide, please


contact Robert Fish at: Center for Devices and


Radiological Health Office of Compliance


Division of Bioresearch Monitoring Program


Enforcement Branch II, HFZ-312 28 Gaither


Road Rockville, MD 20850 (301) 594-4723





This reference is intended to be used in


conjunction with the:


-Compliance Program Guidance Manuals for


Institutional Review Boards; Sponsors,


Contract Research Organization and


Monitors; and Clinical Investigators (CP


7348.809; 7348.810; and 7348. 811),


-21 CFR Part 809 - In Vitro Diagnostic


Products for Human Use


-21 CFR Part 812.2 (c)(3), 812.3(k) - IVD




-21 CFR Part 50 - Protection of Human




-21 CFR Part 56 - Institutional Review




-Investigations Operations Manual (IOM),




-Applicable Compliance Policy Guides


(CPG) for devices (beginning with the


numbers 7124 and 7133).


Guidances are posted to the CDRH and


ORA Internet World Wide Web Home Pages


at http://www.fda.gov. See IOM Chapter 10,


References, for additional information.

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