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Joint Comments to FDA on the Draft Guidance "Framework for Regulatory Oversight of Laboratory Developed Tests"

 

February 2, 2015

Division of Dockets Management (HFA—305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852

Re: Docket No. FDA-2011-D-0360 "Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs); Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories."


Dear Dockets Manager:

We appreciate the opportunity to provide comments on the Agency's proposed compliance policy contained in the "Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs); Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories." The FDA has grouped LDTs for platelets and red cell products together when describing the framework for transfusion compatibility. In recognition of this our comments concerning transfusion compatibility tests are relevant to all blood and blood products.

The agency has long recognized that traditional LDTs are critical in the search for compatible blood and blood products for patients with complex antibody issues. The reagents (primarily antisera and RBCs) used in these LDTs are often derived from rare donors and patients identified by the blood establishment and are applied to clinical problems too rare to support the development and approval of licensed materials. The methods are well documented in reference texts and peer-reviewed journals and have been in use for decades. The work is most frequently performed by the reference laboratory personnel at the blood center providing the blood products for transfusion rather than the transfusion service. This is due to expertise needed to perform and interpret the procedures, the availability of rare reagents for which no licensed alternatives exist, and the close relationship between blood centers and transfusion services working together to identify suitable products for the patients. This special relationship and the use of traditional LDTs should be recognized and allowed to continue either through exemption and/or enforcement discretion. See specific comments below: Continued Enforcement Discretion with Respect to Premarket Review Requirements — Traditional LDTs.

Our organizations have long supported, and in many instances, lead the industry in the search to provide compatible transfusions for difficult to serve patients. When FDA-approved (licensed or cleared) products are not available to meet the needs of these patients laboratories work within the regulations of the Clinical Laboratory Improvement Amendments (1988) to create the reagents and procedures needed. As such, these procedures are already highly regulated and we disagree with the designation of High Risk category assigned in the guidance document to LDTs used for transfusion compatibility. Given the oversight and inspection already in place for transfusion services and blood centers (e.g., CLIA, AABB, CAP, FDA) we believe these LDTs can be designated Low Risk.

Comments to specific recommendations in the guidance document are arranged in the following format:

Section — language from draft guidance reprinted.
Recommendation or Request for Clarification — recommendation or clarification request.
Rationale/Supporting Information — rationale in support of the recommendation /clarification request.


Section — D. Framework for Regulatory Oversight of LDTs

5. Premarket Review Requirements
(a) Continued Enforcement Discretion with Respect to Premarket Review Requirements — 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)."

Recommendation — The FDA should use the Rare Diseases Act of 2002 as a reference (200,000 patients) for "rare disease" rather than the HUD designation of 4,000 patients.

Rationale — The Rare Diseases Act of 2002 defines "rare disease" as any disease or condition that affects less than 200,000 persons in the Unites States. Much of the need for LDTs for compatibility testing is for chronically transfused and alloimmunized populations such as sickle cell patients that exceed the 4,000 patient limit of the HUD reference. http://history.nih.gov/research/downloads/PL107-280.pdf


Section — D. Framework for Regulatory Oversight of LDTs

5. Premarket Review Requirements
(a) Continued Enforcement Discretion with Respect to Premarket Review Requirements — 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 only of components and instruments that are legally marketed for clinical use (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."

Recommendation — Our organizations recommend that element 2 above be redefined such that blood center laboratories will explicitly be recognized as falling within the scope of continued enforcement discretion when working with transfusion services and performing various tests that are necessary, including the use of "Traditional LDTs", to provide compatible blood and blood products for patients being served by transfusion services.

Rationale — Blood center laboratories have a need to use "Traditional LDTs" that the agency has always recognized to be critical in the search for compatible blood and blood products for some patients. The reagents are often derived from rare donors and patients identified by the blood establishment for application to clinical problems too rare to support the development and approval of licensed materials.

In some/many instances the work is being performed by the reference laboratory services at the blood center rather than the transfusion service due to broader access to the reagents and the expertise needed to perform and interpret the procedures of a high complexity serological or molecular testing laboratory. We believe the special relationship between blood centers and transfusion services should be recognized. The relationship was recognized as recently as December, 2012 when FDA asked the Blood Products Advisory Committee to consider a similar topic, "Labeling of Red Blood Cell Units with Historical Antigen Results." http://www.fda.gov/AdvisoryCommittees/Calendar/ucm327394.htm

The nature of a healthcare system in the US is drastically different from that of the 1970s. Over the last ten years or more, bankruptcy and mega mergers have drastically decreased the number of healthcare systems. Whereas in 1975 there were 7000 hospitals in the US (ref), in 2012, that number was 5,723 (http://www.aha.org/research/rc/stat-studies/fast-facts.shtml). Additionally, independent hospitals, physician practices and healthcare systems have formed complex alliances and networks. In response to the concern that "the manufacture and use of LDTs within a facility's healthcare system ensures common responsibility for patient outcomes that may result from the clinical decisions informed by those device results," communication technology has removed barriers that may have impeded communication between the treating physician and the director of a laboratory located outside the hospital walls. In fact, many healthcare systems are geographically dispersed such that a stipulation for the laboratory to be within the healthcare system does not guarantee the laboratory and the patient to be within the same city or even within the same state.

Recommendation — Element 3 above should be expanded to include all reagents/material used in current LDTs, as allowed under CLIA. This would include Research Use Only materials.

Rationale — At times FDA-approved tests give ambiguous results and there is no approved test for confirmatory purposes. For example, the currently cleared PreciseType™ HEA Molecular BeadChip Assay gives ambiguous typing results with some genetic RBC antigen variants. In the absence of a cleared confirmatory test laboratories have developed molecular assays to discriminate between known variants contributing to ambiguous results. The reagents are oligonucleotide primers constructed based on knowledge of HEA sequence. This scenario is an example of the need to expand the definition of LDT to include all tests developed in a laboratory performing high complexity testing rather than limit the definition to those tests using in vitro diagnostic reagents. Laboratories currently incorporate the use of Research Use Only reagents as this is allowed under CLIA regulations. [42 CFR 493.1253 (b)(2)]

Recommendation — We recommend that element 4 above be amended so that "use of automated instrumentation or software for interpretation" is not a reason to withhold enforcement discretion with respect to premarket review.

Rationale — Technologic advances have increased the complexity of laboratory tests, resulting in more multi-analyte tests with software algorithm-based interpretation. Such tests are often performed in reference laboratories where laboratorians and pathologists are overseeing the testing.


Section — D. Framework for Regulatory Oversight of LDTs

5. Premarket Review Requirements
(c) Enforcement of Premarket Submission Requirements for Blood Donor, Transfusion Compatibility, and HCT/P Donor LDTs

Recommendation — We recommend that Transfusion Compatibility be removed from the title of this section and strike any reference to use of devices for this purpose from the paragraph within the section.

Rationale — We believe all devices necessary for transfusion compatibility tests (for all blood and blood products) should be allowed under the category of (b) Continued Enforcement Discretion with Respect to Premarket Review Requirements — Traditional LDTs (see above).


Section — D. Framework for Regulatory Oversight of LDTs

5. Premarket Review Requirements
(b) Continued Enforcement Discretion with Respect to Premarket Review Requirements — LDTs for Unmet Needs When No FDA-cleared or —approved Alternative Exists

"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.

As with Traditional LDTs, FDA believes that the manufacture and use of LDTs for Unmet Needs within a facility's healthcare system will help to mitigate risks because the healthcare system manufacturing and using the test is also responsible for treating the patient, and is thereby responsible for patient outcomes that may result from the clinical decisions informed by that device result.

Note: However, once FDA clears or approves an IVD for the same intended use, FDA will no longer consider the LDT to be an "LDT for Unmet Needs." Therefore, following FDA clearance or approval of a device with the same intended use as an LDT for Unmet Needs, FDA intends to enforce the premarket review requirements if the LDT falls within FDA's enforcement priorities."

Recommendation — Regarding element 3, please see our Recommendation/Rationale to element 2 in D.5. (a) Continued Enforcement Discretion with Respect to Premarket Review Requirements — Traditional LDTs. The element should be redefined such that blood center laboratories will explicitly be recognized as falling within the scope of continued enforcement discretion when working with transfusion services and performing various tests that are necessary, including the use of "LDTs for Unmet Needs," to provide compatible blood and blood products for patients being served by transfusion services.


Recommendation — Regarding LDTs that fall within FDA's enforcement priorities (see Note above): Prior to enforcing premarket review requirements for LDTs for Unmet Needs with the same intended use as a device that is cleared/approved, the FDA should issue a guidance document with "recommendations," or regulation with "requirements," for use of the device.

Rationale — The published regulatory document will provide a transparent opportunity for the agency to describe the scope of the newly cleared/approved device and why it will meet what has been up to that point a category of "Unmet Needs," and will provide users of similar LDTs an opportunity to review the data and respond if necessary.


AABB is an international, not-for-profit association representing individuals and institutions involved in the field of transfusion medicine and cellular therapies. The association is committed to improving health by developing and delivering standards, accreditation and educational programs that focus on optimizing patient and donor care and safety. AABB membership consists of nearly 2,000 institutions and 8,000 individuals, including physicians, nurses, scientists, researchers, administrators, medical technologists and other health care providers. AABB members are located in more than 80 countries.

Founded in 1962, America's Blood Centers is North America's largest network of community-based, independent blood programs. The network operates more than 600 blood donor centers providing over half of the U.S., and a quarter of the Canadian blood supply. These blood centers serve more than 150 million people and provide blood products and services to more than 3,500 hospitals and healthcare facilities across North America. America's Blood Centers' U.S. members are licensed and regulated by the U.S. Food and Drug Administration. Canadian members are regulated by Health Canada.

The American Red Cross shelters, feeds and provides emotional support to victims of disasters; supplies about 40 percent of the nation's blood; teaches skills that save lives; provides international humanitarian aid; and supports military members and their families. The Red Cross is a not-for-profit organization that depends on volunteers and the generosity of the American public to perform its mission. About 5.6 million units of whole blood are collected from roughly 3.3 million Red Cross volunteer donors, separated into 8 million transfusable blood products and supplied to approximately 2,700 hospitals and transfusion centers across the country for patients in need.

Thank you for the opportunity to offer these comments. We look forward to continuing to work with the FDA on patient and donor safety initiatives. Questions concerning these comments may be directed to acarrgreer@aabb.org.

Sincerely,

M. Allene Carr-Greer
Director, Regulatory Affairs