The U.S. Food and Drug Administration (FDA) has notified Congress that it intends to issue draft guidance to propose a risk-based, phased-in framework for oversight of laboratory developed tests (LDTs) and has provided the anticipated details of the LDT guidance in the notification.
The notification sent on July 31 was required by the Food and Drug Administration Safety and Innovation Act (FDASIA), which requires notification to Congress at least 60 days prior to the issuance of draft or final guidance.
Shift in FDA Policy Started in 2013
As reported by Regulatory Focus: FDA marked a shift in policy in 2013 when Commissioner Margaret Hamburg announced that FDA would be pursuing a regulatory framework for LDTs. "[FDA will be] working to make sure that the accuracy and clinical validity of high-risk tests are established before they come to market," Hamburg said. Hamburg said FDA was aware of the need to preserve an environment for innovation, and that it would be pursuing a risk-based framework to balance the need for evidence with innovation and patient access.
But Hamburg's proposal received pushback from the LDT industry almost immediately. The American Clinical Laboratory Association (ACLA) filed a Citizen Petition with FDA arguing that the agency lacked the authority to regulate LDTs, which it said were regulated under the Clinical Laboratories Improvement Act (CLIA), which governs clinical laboratories and the standards they use to "assure consistent performance" and reliability. At the core of ACLA's argument is that it considers LDTs not to be devices, but rather procedures for performing diagnostic testing using reagents and equipment.
FDA finally rejected that petition on July 31 and on the same day announced the release of its new LDT regulation policy.
According to a report by the law firm Morgan Lewis: FDA's risk-based approach will rely on the existing medical device classification system (Class I, II, or III) to evaluate the risk of a category of LDTs and, informed by the expressed interest in participating in the discussion of the classification process, will use expert advisory panels to help classify devices not previously classified by FDA.
FDA intends to issue draft guidance to describe what it considers generally to be Class I, II, or III within 24 months of finalizing the LDT guidance. FDA anticipates that it will phase in enforcement of regulatory requirements for LDTs over the next 10 years.
The phased-in enforcement for the different device categories is summarized in the following table, also created by Morgan Lewis:
FDA Enforcement of Regulatory Requirements for Categories of LDTs—Time Frames
Notification or Registration and Listing/ Adverse Event Reporting Requirements
Premarket Review Requirements
Quality System Regulation Requirements
Low-risk devices, traditional LDTs, and LDTs for rare disease and unmet needs
Six months after guidance is finalized.
Phased-in enforcement will begin five years after guidance is finalized. FDA plans to announce priority list for class II within four years of finalized guidance.
Enforced once FDA issues a clearance order.
Six months after guidance is finalized.
Phased-in enforcement will begin 12 months after guidance is finalized. FDA plans to announce priority list within 24 months of finalized guidance.
Enforced once premarket approval application is submitted.
Immediate Concerns Raised By American Medical Association
"The American Medical Association (AMA) believes that laboratory developed testing (LDT) services offer patients access to safe and high quality diagnostic services that are essential to patient care.
"The draft FDA Framework for Oversight of Laboratory Developed Tests (LDTs) announced today, outlines a risk-based approach that raises a number of questions and concerns.
"The FDA proposal adds an additional layer of regulatory requirements which may result in patients losing access to timely life-saving diagnostic services and hinder advancements in the practice of medicine.
"The AMA is committed to ensuring that the proposal that is ultimately adopted by the FDA preserves rapid access to care and medical advancements."
Association for Molecular Pathology
"Laboratory developed molecular pathology procedures have made enormous contributions to patient care in areas as diverse as oncology, infectious diseases, and inherited disorders. We are deeply concerned that attempts to regulate providers of these vital medical services as manufacturers, will harm patients by reducing access, decreasing innovation, and substantially raising the costs of essential diagnostic testing," said Roger Klein, Chair of the Professional Relations Committee at AMP.
AMP recently published an updated position statement on the regulation of LDPs and believes that the current oversight mechanisms already in place are sufficient for the majority of tests currently in practice. Moreover, LDPs are often the standard-of-care, the highest quality test available, and at times, the only available testing option.
Congressman Michael C. Burgess, M.D. (R-TX)
Congressman Burgess, vice chairman of the House Energy and Commerce Subcommittee on Health, responded to the FDA notification to Congress that it will release draft guidance to regulate LDTs with the following statement:
"Applying FDA's regulatory approach to LDTs is redundant, will stifle innovation and will require additional taxpayer funding for the FDA. To the extent concerns about 'higher-risk' tests exist; these can be addressed at no cost to the government through a modernization of The Clinical Laboratory Improvement Amendments (CLIA).
"Given the negative impact these policies – if pursued – could have on innovation, I am glad I was able to secure this notification requirement within the Food and Drug Administration Safety and Innovation Act of 2012. LDTs are not medical device products sold through interstate commerce. They are services provided only to the ordering healthcare provider and offered only by labs that validate and develop them. Professional medical services are not regulated by FDA. More importantly, the question of agency jurisdiction over LDTs has never been legally clarified. LDTs neither constitute "medical devices" nor are commercially distributed among states – both requirements for FDA jurisdiction under the Federal Food, Drug, and Cosmetic Act (FFDCA).
"FDA is the subject of much criticism from industry groups who are already under their jurisdiction. As such, they are overburdened and take too long to approve products, which increases uncertainty for companies and negatively impacts innovation, as well as patient access to new treatments and devices. If LDTs were regulated as medical devices by FDA, it would significantly tax an already overtaxed agency and stifle access to these important tests.
"The Energy & Commerce Committee is continuing to develop the 21st Century Cures initiative and explore how we can encourage innovation. We are also looking into ways to increase our ability to detect, treat and cure disease. I fear today's move by the FDA moves in the opposite direction and I look forward to raising this issue often in the coming months."
We will continue to follow this story on Policy and Medicine in the months to come.
I. LDT Guidance Overview
A. Defining LDT and Scope of Guidance
FDA defines the term laboratory developed test (LDT) as an IVD that is intended for clinical use and designed, manufactured and used within a single laboratory. The following is an example of an LDT:
A laboratory uses peer reviewed articles to guide development of a new diagnostic device. The laboratory uses general purpose reagents and analyte specific reagents combined with general laboratory instruments and develops a testing protocol, that together constitute a test system which is then verified and validated within the laboratory. Once validated this device is used by the laboratory to provide clinical diagnostic results.
FDA does not consider devices to be LDTs if they are designed or manufactured completely, or partly, outside of the laboratory that offers and uses them. The following are some examples of devices that FDA does not consider to meet the definition of an LDT:
- An entity that owns several clinical laboratories develops a device in one of its clinical laboratories and then transfers the device to several clinical laboratories within its network.
- An academic institution develops a device, which it then licenses to or signs an exclusivity agreement with a private corporation that owns a CLIA-certified laboratory. The private corporation's CLIA-certified laboratory then begins manufacturing and using the device to provide clinical diagnostic results.
- A laboratory contracts with a third party manufacturer to produce a key component (e.g., coated microtiter plate, specialized specimen collection kit) used in its device.
- A laboratory contracts with a specification developer to design a new device. Once complete, the design is then transferred to the clinical laboratory for final validation prior to the device being manufactured and used by the laboratory to provide clinical diagnostic results.
B. Risk-Based Approach toward Oversight of LDTs
FDA believes it should no longer generally exercise enforcement discretion towards all LDTs. Once finalized and implemented, this guidance document is intended to provide an oversight framework that will assure that devices used in the provision of health care, whether developed by a laboratory or a conventional IVD manufacturer, comply with the appropriate levels of regulatory controls.
i. Risk-Based Classification
Medical devices are classified as Class I, II or III based upon the controls necessary to provide a reasonable assurance of the safety and effectiveness of the device, and factors relevant to this determination include the device's intended use, technological characteristics, and the risk to patients if the device were to fail. Class I devices, which are subject only to general controls, generally represent the lowest-risk category of devices, while Class III devices, which are subject to general controls and premarket approval, generally represent the highest-risk devices. Section 513(a)(1) of the FD&C Act (21 U.S.C. 360c(a)(1)).
FDA will rely upon the existing medical device classification system to evaluate the risk of a category of LDTs and, informed by the industry's expressed interest in participating in the discussion of the classification process, will use expert advisory panels to help classify devices not previously classified by FDA, as appropriate. In determining the risk an LDT poses to the patient and/or the user, FDA will consider several factors including whether the device is intended for use in high risk disease/conditions or patient populations, whether the device is used for screening or diagnosis, the nature of the clinical decision that will be made based on the test result, whether a physician/pathologist would have other information about the patient to assist in making a clinical decision (in addition to the LDT result), alternative diagnostic and treatment options available to the patient, the potential consequences/impact of erroneous results, number and type of adverse events associated with the device, etc. To provide additional clarity, FDA intends to issue draft guidance to describe what the Agency considers generally to be Class I, II or III within 18 months of finalization of this guidance.
ii. LDT Framework
FDA intends to continue to exercise enforcement discretion for all applicable regulatory requirements for:
- LDTs used solely for forensic (law enforcement) purposes.
- Certain LDTs for transplantation when used in CLIA-certified, high-complexity histocompatibility laboratories.
FDA intends to exercise enforcement discretion for applicable premarket review requirements and quality systems requirements, but enforce other applicable regulatory requirements including registration and listing (with the option to provide notification) and adverse event reporting, for:
- Low-risk LDTs (Class I devices).
- LDTs for rare diseases and "Traditional LDTs."16 These types of LDTs reflect the types of LDTs that existed when the enforcement discretion policy was initially implemented.
- "LDTs for Unmet Needs," when no FDA-approved or cleared equivalent device is available.
For other high and moderate risk LDTs, FDA intends to enforce applicable regulatory requirements, including registration and listing (with the option to instead provide notification), adverse event reporting, premarket review, and quality system requirements, as follows:
- High-risk LDTs (Class III medical devices): Registration and listing (with the option to provide notification) and adverse event reporting begin six months after this guidance is finalized. Premarket review requirements begin 12 months after this guidance is finalized for the highest risk devices and phase-in over 4 years for the remaining high-risk devices. Devices would remain on the market during review and FDA's consideration of applications. FDA's focus on high-risk devices begins with the following: a) LDTs with the same intended use as a cleared or approved companion diagnostic; b) LDTs with the same intended use as an FDA-approved Class III medical device; and c) certain LDTs for determining the safety or efficacy of blood or blood products.
- Moderate-risk LDTs (Class II medical devices): Registration and listing (with the option to provide notification) and adverse event reporting begin six months after this guidance is finalized. Premarket review requirements begin after the high-risk (Class III) LDTs are completed, meaning 5 years after the guidance is finalized, and phase- in over 4 years. FDA intends to utilize FDA-accredited third party review of premarket submissions as appropriate.
Where an LDT's analytes/markers that are measured/assessed have had their clinical validity already established in the literature, FDA believes it may not be necessary for sponsors to conduct extensive new studies to demonstrate clinical validity of the analytes/markers, but the sponsor will need to demonstrate that any changes in technology or methodology that differ from that used in the literature to assess the analyte/marker do not affect the clinical validity of the LDT. FDA intends to work with the laboratory community, the health care professional community, and other stakeholders to identify those LDTs for which the clinical validity of the analyte/marker has already been established in the literature.
In addition, for those LDTs that present moderate risk, FDA intends to work with interested parties to expand the Agency's third party review program to include these types of devices. If successful, FDA believes that most moderate-risk LDTs could be reviewed by a third party reviewer. Under this model, FDA would generally review high-risk LDTs subject to a premarket approval application (PMA) (i.e., Class III medical devices), while accrediting third parties to carry out review of most moderate-risk LDTs requiring a premarket notification (510(k)) submission (generally Class II devices). FDA intends to continue exercising enforcement discretion with respect to applicable premarket review requirements and quality system requirements for Class I devices, which present the lowest risk.
Registration and Listing/Notification and Adverse Reporting: Six months after this guidance becomes final, manufacturers of LDTs should notify FDA if they are developing LDTs and must begin to report significant adverse events to FDA, so that problems can be detected and corrected in a timely manner.
Premarket Review: FDA intends to phase-in enforcement of premarket review requirements for relevant LDTs over an extended period of time. LDT categories will be phased-in for enforcement based on risk, and the number and type phased-in at a given time will be commensurate with available agency resources. The phased-in enforcement, starting with the highest-risk, will begin 12 months after the guidance becomes final.
FDA will prioritize all other LDTs based on risk using a public process, including expert advisory panels as appropriate, and will provide advanced notice with respect to timing of enforcement to manufacturers of LDTs that fall into the high- and moderate- risk categories. Premarket review for the highest risk devices will begin 12 months after this guidance is finalized. FDA expects to announce the priority list for the remaining high-risk devices within 24 months from finalization of the guidance, with enforcement for the initial prioritized group on this list of LDTs beginning no less than 12 months after the announcement of the priority list. FDA intends to complete phased-in enforcement of premarket review requirements for Class III devices first (within a period of 5 years of finalization of the guidance). FDA intends to phase in enforcement of requirements for Class II devices once FDA has completed the phase-in of the Class III devices. FDA expects to announce the prioritization of moderate-risk devices within 4 years of finalization of the guidance and complete phased-in enforcement of premarket regulatory requirements for Class II devices within 9 years of finalization of the guidance.
Under the proposed framework, laboratories that manufacture LDTs would comply with appropriate quality controls in the FDA QS reg (21 CFR Part 820) when a PMA is submitted or FDA issues a 510(k) clearance order for the LDT.
II. Framework for Regulatory Oversight of LDTs
The framework for regulatory oversight of LDTs discussed below describes FDA's general enforcement priorities for LDTs. As a general matter, FDA proposes a risk-based, phased-in approach, in combination with continued exercise of enforcement discretion for certain regulatory requirements and certain types of LDTs.
A. Main elements
The main elements of FDA's framework for regulatory oversight include:
- Either notification to FDA of LDTs manufactured by a laboratory or Registration and Listing
- Medical Device Reporting Requirements (MDR) for LDTs (e.g., adverse event reporting)
- Continued enforcement discretion with respect to premarket review requirements for low-risk LDTs, "Traditional LDTs," LDTs used for rare diseases, and "LDTs for Unmet Needs"
- Risk-based, phased-in approach to enforcing the premarket review requirements for other high-risk and moderate-risk LDTs
- Use of clinical literature to support a demonstration of clinical validity, which FDA expects would reduce the need for additional clinical studies to show clinical validity for LDTs where the analytes/markers that are measured/assessed have had their clinical validity established in the literature
- Facilitation of third-party review for many moderate risk LDTs
- Phased-in approach to enforcing the Quality System regulation
- Continued enforcement discretion for premarket review of Class I LDTs
For those LDTs that are already FDA approved or cleared, it is FDA's expectation that manufacturers will continue to follow the regulations. Manufacturers of tests that are used solely for in-process quality control testing in the manufacture of FDA-regulated articles should consult with FDA to determine applicable regulatory requirements.
B. Continued Enforcement Discretion in Full for Certain Categories of LDTs
FDA intends to continue to exercise enforcement discretion in full for certain categories of diagnostic devices. For the following devices, FDA does not intend to enforce applicable registration and listing (nor is FDA requesting notification), adverse event reporting, premarket review, or quality system requirements: (a) LDTs Used Solely for Forensic (Law Enforcement) Purposes; (b) LDTs Used in CLIA-Certified, High-Complexity Histocompatibility Laboratories for Transplantation.
C. Notification to FDA of LDTs Manufactured by a Laboratory or Registration and Listing
With the exception of the categories of devices identified above in (forensic (law enforcement) LDTs and certain LDTs used in connection with organ, stem cell, and tissue transplantation), for laboratories that manufacture, prepare, propagate, compound, assemble, or process LDTs, FDA intends to continue to exercise enforcement discretion with respect to registration and listing requirements (21 CFR Part 807) provided that such laboratories notify FDA that they are manufacturing LDTs and provide basic information regarding each of these LDTs. Notification is expected to occur once for each LDT, although if significant changes are made to an LDT, additional notification should be provided.
Laboratories should provide notification information to the FDA within 6 months of the date of publication of the final version of this guidance document with respect to their LDTs on the market on the date of publication of the final version of this guidance document, and any new LDTs on the market in the 6 months following publication of this document. Starting 6 months after publication of the final version of this guidance, laboratories offering new LDTs should provide notification prior to offering the LDT for clinical use. It should be noted that when a laboratory makes a significant change to the marketed intended use of an LDT for which they have previously provided notification, the LDT will be considered by the FDA to be a new LDT. Therefore, a new notification should be provided prior to offering that LDT for clinical use; this is especially important for those changes in marketed intended use that increase the risk of the device. Additionally, following initial notification, FDA urges laboratories that make other significant modifications to LDTs after notification to re-submit notification data to FDA to communicate such changes of the guidance for additional information on significant device modifications). Given that notification data will be used to classify LDTs and prioritize enforcement of premarket review requirements based on risk, it will benefit laboratories to provide the most accurate information possible to ensure that appropriate classification is made.
D. Medical Device Reporting (MDR) Requirements
With the exception of the categories of tests identified above (forensic (law enforcement) LDTs and certain LDTs used in connection with organ, stem cell, and tissue transplantation), FDA intends to enforce the manufacturer reporting requirements of the Medical Device Reporting (MDR) regulation (21 CFR Part 803, Subpart E) for laboratories manufacturing LDTs. The MDR regulation requires the manufacturer of a medical device to submit reports to the FDA whenever they become aware of information that reasonably suggests that a device they market may have caused or contributed to a death or serious injury, or has malfunctioned and the malfunction would be likely to cause or contribute to a reportable death or serious injury should it recur. (21 CFR 803.50.)
One objective of the MDR regulation is to provide a mechanism for FDA and device manufacturers to identify and monitor significant adverse events involving medical devices so that problems may be detected and corrected in a timely manner. This information is particularly important in the case of LDTs, as many of these devices have not undergone premarket review. MDR reporting for LDTs will provide for an important risk mitigation measure to detect, track, and help address serious problems related to LDT performance should they occur.
Therefore, beginning six months following publication of the final version of this guidance document, FDA intends to cease its exercise of enforcement discretion with respect to the MDR reporting requirements in 21 CFR Part 803, Subpart E, for laboratories that manufacture LDTs. A description of the specific requirements in 21 CFR Part 803, Subpart E, as well as further information on how the MDR requirements apply to laboratories is described in the guidance document "FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs)."
E. Premarket Review Requirements
With the exception of the categories of devices identified above (forensic (law enforcement) LDTs and certain LDTs used in connection with organ, stem cell, and tissue transplantation) and those otherwise identified, FDA intends to phase in the enforcement of applicable premarket requirements over time based upon the risk associated with that device. FDA intends to focus its efforts on the highest risk devices first and gradually phase in enforcement for other devices over time. In this manner, it is FDA's intention to avoid undue disruption of medical testing while seeking to assure patient safety and to assure that health care practitioners are relying on device results that are meaningful and accurate when making medical decisions.
i. Continued Enforcement Discretion with Respect to Premarket Review Requirements for LDTs Used for Rare Diseases and "Traditional LDTs"
The FDA believes that it is appropriate to continue to exercise enforcement discretion with respect to premarket review requirements for the two categories of LDTs described below.
(a) LDTs Used for Rare Diseases
The Humanitarian Use Devices (HUD)/Humanitarian Device Exemption (HDE) provisions of the Act (21 U.S.C. 360j(m)) and regulations (21 CFR 814, Subpart H) provide an abbreviated regulatory pathway as an incentive for the development of devices for use in the treatment or diagnosis of rare diseases or conditions.
FDA recognizes that some LDTs may qualify as HUDs. An IVD device may qualify for HUD designation when the number of persons who may be tested with the device is fewer than 4,000 per year. FDA recognizes that one patient may be tested multiple times with the same device; when this occurs, the multiple uses are counted as one use for purposes of defining which devices may qualify as HUDs.
If an IVD 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 who would be subject to testing using the device, then the device does not qualify as a HUD (21 CFR 814.102(a)(5)).
While FDA encourages laboratories manufacturing LDTs for rare diseases to seek approval under the HDE provisions, FDA plans to continue to exercise enforcement discretion with regard to premarket review requirements for LDTs that meet the definition in this guidance and the definition of an HUD under 21 CFR 814.102(a)(5).
(b) Traditional LDTs
FDA intends to continue to exercise enforcement discretion with respect to premarket review requirements for "Traditional LDTs," which are those IVD devices that reflect the types of LDT available when FDA began its policy of generally exercising enforcement discretion over LDTs in 1976. In considering whether to exercise enforcement discretion for Traditional LDTs, FDA intends to consider the following factors:
(1) Whether the device meets the definition of LDT in this guidance (a device designed, manufactured and used by a single laboratory); and
(2) Whether the LDT is both manufactured and used by a health care facility laboratory (such as one located in a hospital or clinic) for a patient that is being diagnosed and/or treated at that same health care facility or within the facility's healthcare system; and
(3) Whether the LDT is comprised of only legally marketed components and instruments (e.g., analyte specific reagents (21 CFR 864.4020), general purpose reagents (21 CFR 864.4010), and various classified instruments); and
(4) Whether the LDT is interpreted by qualified laboratory professionals, without the use of automated instrumentation or software for interpretation.
ii, Continued Enforcement Discretion with Respect to Premarket Review Requirements for "LDTs for Unmet Needs" When No FDA-cleared or -approved Alternative Exists
FDA recognizes the role that LDTs can play in meeting urgent unmet healthcare needs. FDA believes it is important to maintain the availability of LDTs that serve unmet needs (but that are not LDTs for rare diseases or "Traditional LDTs") until a comparable FDA-cleared or -approved device becomes available. For this reason, FDA intends to exercise enforcement discretion with respect to premarket review requirements for "LDTs for Unmet Needs." In determining whether an LDT is an "LDT for Unmet Needs," FDA intends to consider the following factors:
(1) Whether the device meets the definition of LDT in this guidance (a device designed, manufactured and used by a single laboratory); and
(2) Whether there is no FDA cleared or approved IVD available for that specific intended use; and
(3) Whether the LDT is both manufactured and used by a health care facility laboratory (such as one located in a hospital or clinic) for a patient that is being diagnosed and/or treated at that same health care facility or within that facility's healthcare system.
For LDTs for Unmet Needs, FDA does not intend to consider factors such as whether the LDT is comprised of only legally marketed components and instruments or whether the LDT is interpreted by qualified laboratory professionals, without the use of automated instrumentation or software for interpretation. FDA believes that greater flexibility is appropriate for LDTs for Unmet Needs because there is no FDA-cleared or approved alternative for the device on the market.
iii. Enforcement of Premarket Submission Requirements for Companion Diagnostics and Other High-risk Diagnostic Device Category LDTs
FDA intends to initially focus its enforcement priorities by generally enforcing the premarket review requirements beginning 12 months after this guidance is finalized for the following LDTs: a) LDTs with the same intended use as a cleared or approved companion diagnostic; b) LDTs with the same intended use as an FDA-approved Class III medical device; and c) certain LDTs for determining the safety or efficacy of blood or blood products.
FDA believes that these diagnostic device categories are among the highest risk LDTs currently available on the market because the device either is used to direct patient therapy (as in the case of LDTs with the same intended use as a cleared or approved companion diagnostic) or has the same intended use as a device that FDA has already determined to be in the highest risk classification (Class III).
For 12 months following publication of this guidance document in final form, FDA intends to exercise enforcement discretion with respect to premarket review requirements for currently marketed LDTs. FDA intends to begin enforcing premarket review requirements for these categories of currently marketed LDTs at the end of that 12-month period. If the appropriate premarket submission (generally a PMA) is made within the 12-month period, FDA intends to continue to exercise enforcement discretion while the premarket submission is under FDA review, so as not to interrupt patient access. FDA intends to begin enforcing premarket review requirements immediately upon publication of this guidance document in final form for all new LDTs (i.e., those that become available for patient testing after final publication of this guidance document) in these categories. FDA will expect manufacturers of these new LDTs to make an appropriate premarket submission and obtain approval or clearance for their devices prior to use.
iv. Phased-In Enforcement of Premarket Requirements for Other LDT Categories
After FDA collects and analyzes notification data, it will prioritize the remaining device categories based on risk using a public process. FDA plans to utilize advisory panels to provide recommendations to the Agency on LDT risks and prioritization of enforcement of applicable regulatory requirements on certain categories of LDTs, as appropriate. FDA intends for there to be ample opportunity for public comment.
v. Modifications to FDA Cleared/Approved Devices
As in the case of any other entity, a clinical laboratory that modifies an FDA cleared/approved device in a way that affects device performance or intended use is considered to be a device remanufacturer (21 CFR 820.3(w)). Such modifications may include change in specimen type or sample matrix (e.g., saliva vs. whole blood), type of analysis performed (e.g., qualitative vs. quantitative), the purpose of the assay (e.g. screening, diagnosis, prognosis, monitoring, surveillance, and confirmation), the target population(s), etc. These modified devices must meet premarket submission requirements under 21 CFR 807.81(a)(3) and 21 CFR Part 814. FDA intends to begin enforcing premarket requirements for these modified devices as the Agency begins enforcing premarket requirements for the LDT category under which the modified device falls.
vi. Clinical Investigations
FDA intends to continue to enforce investigational device requirements under 21 CFR Part 812 for all clinical investigations of LDTs that are conducted under clinical protocols that require institutional review board approval. Before conducting an investigation, clinical laboratories must follow applicable requirements in 21 CFR Part 56 for institutional review board (IRB) approval as well as applicable requirements in 21 CFR Part 50 for informed consent from the study subjects at the time of their enrollment in the study.
vii. Evaluation of Clinical Validity of LDTs
FDA expects that for many LDTs, clinical validity has already been established in literature. FDA emphasizes that it is the Agency's practice to leverage such information from the literature in lieu of requiring additional studies to demonstrate clinical validity. In these cases FDA may still require studies demonstrating device performance (e.g., analytical evaluations) but generally intends to rely on the scientific literature to support clinical validity if appropriate. FDA intends to work with the laboratory community, the healthcare professional community and other stakeholders to determine whether an LDT's clinical validity has already been established in the literature.
viii. Third Party Review
For LDTs, FDA envisions that the Agency would generally review PMAs for high- risk (Class III) LDTs, whereas third parties would generally review the 510(k)s for lower risk (Class II) LDTs. FDA seeks to work with interested parties that have experience with laboratories and can meet FDA requirements for third party reviewers. FDA anticipates that inclusion of such groups will facilitate a more efficient review process for LDTs. If this approach is successful, most 510(k)s for LDTs could be reviewed by appropriate third parties.
F. Quality System Regulation Requirements
The Quality System Regulation (21 CFR Part 820) was developed to define the minimal quality system requirements that medical device manufacturers must implement in order to assure that the finished device will be safe and effective. FDA intends to continue to exercise enforcement discretion with respect to QS reg requirements, codified in 21 CFR Part 820, until a manufacturer of a given LDT submits a PMA or FDA issues a 510(k) clearance order for the LDT. Under this enforcement policy, the clinical laboratory manufacturing and using the LDT will be responsible for having a quality system in place that meets the minimum requirements codified in 21 CFR Part 820, either at the time of PMA submission (the facility that makes the device must pass an inspection as a condition of PMA approval as a matter of law (21 CFR 814.45(a)(3))), or prior to market launch for cleared devices, as applicable. This initial period of continued exercise of enforcement discretion for QS reg requirements is intended to allow time for laboratories to learn about their regulatory obligations under the Act, as well as to develop programs to comply with them. FDA intends to assist laboratories in understanding these and other applicable requirements prior to enforcing those requirements.