[Federal Register Volume 67, Number 35 (Thursday, February 21, 2002)]
[Proposed Rules]
[Pages 7982-7985]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-4208]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 862

[Docket Nos. 01P-0119 and 01P-0235]


Clinical Chemistry and Clinical Toxicology Devices; 
Reclassification of Cyclosporine and Tacrolimus Assays

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to 
reclassify cyclosporine and tacrolimus assays from class III (premarket 
approval) to class II (special controls). Cyclosporine and tacrolimus 
assays are intended for the quantitative determination of cyclosporine 
and tacrolimus concentrations and are used as an aid in the management 
of transplant patients receiving these drugs. FDA is proposing this 
action after reviewing reclassification petitions submitted by Dade 
Behring, Inc., and Microgenics, Inc. The agency is taking this action 
under the Federal Food, Drug, and Cosmetic Act (the act), as amended by 
the Medical Device Amendments of 1976 (the 1976 amendments), the Safe 
Medical Devices Act of 1990 (the SMDA), and the Food and Drug 
Administration Modernization Act of 1997 (FDAMA). Elsewhere in this 
issue of the Federal Register, FDA is announcing the availability of a 
class II special controls draft guidance entitled ``Class II Special 
Controls Guidance Document: Cyclosporine and Tacrolimus Assays; Draft 
Guidance for Industry and FDA.''

DATES: Submit written or electronic comments by April 22, 2002. See 
section XI of this document for the proposed effective date of a final 
rule based on this document.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Jean M. Cooper, Center for Devices and 
Radiological Health (HFZ-440), Food and Drug Administration, 9200 
Corporate Blvd., Rockville, MD 20850, 301-594-1243.

SUPPLEMENTARY INFORMATION:

I. Background (Regulatory Authorities)

    The act, as amended by the 1976 amendments (Public Law 94-295), the 
SMDA (Public Law 101-629), and FDAMA (Public Law 105-115), established 
a comprehensive system for the regulation of medical devices intended 
for human use. Section 513 of the act (21 U.S.C. 360c) established 
three categories (classes) of devices, depending on the regulatory 
controls needed to provide reasonable assurance of their safety and 
effectiveness. The three categories of devices are class I (general 
controls), class II (special controls), and class III (premarket 
approval).
    Under section 513 of the act, devices that were in commercial 
distribution before May 28, 1976 (the date of enactment of the 1976 
amendments), generally referred to as preamendments devices, are 
classified after FDA has: (1) Received a recommendation from a device 
classification panel (an FDA advisory committee); (2) published the 
panel's recommendation for comment, along with a proposed regulation 
classifying the device; and (3) published a final regulation 
classifying the device. FDA has classified most preamendments devices 
under these procedures.
    Devices that were not in commercial distribution prior to May 28, 
1976, generally referred to as postamendments devices, are classified 
automatically by statute (section 513(f) of the act) into class III 
without any FDA rulemaking process. Those devices remain in class III 
and require premarket approval, unless and until the device is 
reclassified into class I or II or FDA issues an order finding the 
device to be substantially equivalent, under section 513(i) of the act, 
to a predicate device that does not require premarket approval. The 
agency determines whether new devices are substantially equivalent to 
previously offered devices by means of premarket notification 
procedures in section 510(k) of the act (21 U.S.C. 360(k)) and part 807 
(21 CFR part 807).
    A preamendments device that has been classified into class III may 
be marketed, by means of premarket notification procedures, without 
submission of a premarket approval application (PMA) until FDA issues a 
final regulation under section 515(b) of the act (21 U.S.C. 360e(b)) 
requiring premarket approval.
    Reclassification of classified postamendments devices is governed 
by section 513(f)(3) of the act. This section allows FDA to initiate 
reclassification of a postamendments class III device under section 
513(f)(1) of the act, or the manufacturer or importer of a device to 
petition the Secretary of the Department of Health and Human Services 
for the issuance of an order classifying the device in class I or class 
II. FDA's regulations in Sec. 860.134 (21 CFR 860.134) set forth the 
procedures for the filing and review of a petition for reclassification 
of such class III devices. To change the classification of the device, 
it is necessary that the proposed new class have sufficient regulatory 
controls to provide reasonable assurance of the safety and 
effectiveness of the device for its intended use.

II. Regulatory History of the Device

    Cyclosporine assays are used for the quantitative determination of 
cyclosporine concentrations as an aid in the management of transplant 
patients receiving cyclosporine. Tacrolimus

[[Page 7983]]

assays are used for the quantitative determination of tacrolimus 
concentrations as an aid in the management of transplant patients 
receiving tacrolimus. These assays are postamendments devices 
classified into class III under section 513(f)(1) of the act, and 
cannot, therefore, be placed in commercial distribution unless they are 
reclassified under section 513(f)(3) of the act or are the subject of 
an approved PMA under section 515 of the act.
    In accordance with section 513(f)(3) of the act and Sec. 860.134, 
petitions were submitted by Dade Behring, Inc., on January 29, 2001, 
and by the Devices & Diagnostics Consulting Group, Inc. (on behalf of 
Microgenics, Inc.), on April 4, 2001, requesting reclassification of 
cyclosporine assays from class III to class II. On its own initiative, 
the agency is including tacrolimus assays, in addition to cyclosporine 
assays, in the proposed reclassification. Cyclosporine and tacrolimus 
are both calcineurin inhibitors. Tacrolimus assays have a similar 
intended use, as an aid in the management of transplant patients, as 
well as similar technological and performance characteristics to 
cyclosporine assays. The agency believes it is taking a least 
burdensome approach by including tacrolimus assays in the proposed 
reclassification.

III. Device Description

    Cyclosporine test systems are intended for the quantitative 
determination of cyclosporine concentrations as an aid in the 
management of transplant patients receiving cyclosporine. Tacrolimus 
test systems are intended for the quantitative determination of 
tacrolimus concentrations as an aid in the management of transplant 
patients receiving tacrolimus. Currently marketed cyclosporine and 
tacrolimus immunoassay test systems utilize monoclonal antibodies in 
order to enhance specificity of the assay for parent drug compound. FDA 
has also approved test systems based on chromatographic methods. 
Cyclosporine and tacrolimus test systems are typically used on 
automated laboratory analyzers. Whole blood is the matrix recommended 
for currently marketed test systems for cyclosporine and tacrolimus 
since these drugs are rapidly distributed into red blood cells and can 
be most reliably measured in this matrix.

IV. Proposed Reclassification

    The agency is proposing to reclassify cyclosporine and tacrolimus 
test systems from class III to class II and has developed a guidance 
document which, when final, will serve as the special control. 
Elsewhere in this issue of the Federal Register, FDA is announcing the 
availability of this draft guidance for comment in accordance with 
FDA's good guidance practices (GGPs) regulation (21 CFR 10.115). We 
have determined that there is adequate valid scientific evidence in the 
public domain to support this reclassification action and, therefore, 
it was unnecessary to refer the petitions to a classification panel for 
its review and recommendation. However, the agency did consult with 
certain Clinical Chemistry and Clinical Toxicology Devices panel 
members by mail regarding our revision of an existing 1993 guidance on 
cyclosporine and its adequacy as a special control for both 
cyclosporine and tacrolimus assays should the agency reclassify the 
cyclosporine and tacrolimus assays from class III to class II.

V. Risks to Health

    After considering the information in the petitions, including the 
published literature, FDA's own experience and knowledge with 
cyclosporine and tacrolimus assays, and the medical device reports 
(MDRs) filed on cyclosporine and tacrolimus assays, FDA has identified 
improper patient management as the only risk to health associated with 
these devices. Failure of the test to perform as indicated or error in 
interpretation of result may lead to improper patient management in one 
of three ways. First, a falsely low cyclosporine or tacrolimus 
measurement could contribute to a decision to raise the dose above that 
which is necessary for therapeutic benefit. This could result in 
increased risk of toxicity from an elevated drug level. Second, a 
falsely high cyclosporine or tacrolimus measurement could contribute to 
a decision to decrease the dose below that which is necessary for 
immunosuppression. This could result in increased risk of rejection of 
the transplanted organ. Third, no firm therapeutic range exists for 
cyclosporine or tacrolimus concentrations. Optimal concentration ranges 
for a patient depend upon many factors such as transplant type, 
sensitivity of patient, coadministered drugs, time post-transplant as 
well as metabolite cross-reactivity of the specific commercial assay 
used, age, and other patient conditions. Therefore, use of assay 
results to adjust a treatment regimen without considering other 
clinical factors, could result in improper patient management.

VI. Special Controls

    In addition to general controls, FDA believes that the draft 
guidance entitled ``Class II Special Controls Guidance Document: 
Cyclosporine and Tacrolimus Assays; Draft Guidance for Industry and 
FDA'' is an adequate special control to address the risk to health 
described above. The class II special controls guidance provides 
information on how to meet premarket (510(k)) submission requirements 
for the assays in sections that discuss performance characteristics and 
labeling. The performance characteristics section describes studies 
integral to demonstration of appropriate performance and control 
against assays that may fail to perform to current standards. The 
labeling section addresses factors such as specimen requirements, assay 
procedure, quality control, limitations, therapeutic ranges, and 
performance characteristics. Because no firm therapeutic range exists 
for cyclosporine or tacrolimus concentrations, labeling for the assay 
includes a discussion of additional clinical considerations involved in 
interpretation of assay results essential for proper patient 
management. In this way, the cyclosporine and tacrolimus assays can be 
used as an aid in establishing a treatment regimen for individual 
patients. FDA tentatively believes that complying with the act and 
special control guidance document will provide reasonable assurance of 
the safety and effectiveness of these devices and adequately address 
the risk to health identified in section V of this document.

VII. FDA's Tentative Findings

    The clinical efficacy of cyclosporine has been well-established 
over the past two decades. Monitoring of cyclosporine levels in blood 
plays a key role in patient management because of unpredictable 
pharmacokinetics, variable absorption, distribution, elimination and 
narrow therapeutic index unique to each patient (Ref. 1).
    FDA has considered issues that could potentially complicate use or 
interpretation of cyclosporine assay results. One issue is that no firm 
therapeutic ranges have been established (Ref. 2). While some patients 
may show signs of cyclosporine toxicity even with blood levels in the 
recommended therapeutic range, others may show signs of inadequate 
immunosuppression within that same therapeutic range. The guidance 
document therefore recommends cautionary labeling and explanation for 
the user concerning therapeutic ranges.

[[Page 7984]]

    Another issue is that the various immunoassays available differ in 
their accuracy and specificity for measurement of the parent 
cyclosporine compound (Refs. 3, 4, and 5). Average differences between 
two methods can be as high as 57 percent. In general, there is a 
positive bias of immunoassays compared with high performance liquid 
chromatography (HPLC) methods, as a result of metabolite cross-
reactivity. HPLC methods are currently the only methods considered to 
be capable of measuring specifically parent compound. The biases 
observed are not constant and can vary, depending on factors such as 
transplant type and time post-transplant (Ref. 6). In addition, inter-
individual differences, which can exceed the influence of the organ 
transplanted or hepatic function, have been observed (Ref. 3). 
Therefore, assay bias cannot be predicted for individual samples. 
Variability is less well-documented for samples collected in the early 
period after cyclosporine dosing, although some results indicate 
metabolite interference is less significant for these types of samples 
(Ref. 7). In light of the wide variability in cyclosporine assays, the 
guidance document recommends comparison of new test systems to a 
candidate reference HPLC method.
    FDA believes clinicians are familiar with the need to tailor an 
individual patient's dose based on overall allograft function along 
with any clinical signs of toxicity, in conjunction with the blood 
level. That is, the calcineurin inhibitor blood level is one measure 
that could be used as an adjunct to the care of transplant patients. 
Physicians managing the care of transplant patients also have resources 
for advice on the use of cyclosporine blood levels, and appropriate 
target ranges for blood levels in the early post-transplant (induction) 
stage as well as in the maintenance stage. These resources include the 
American Society of Transplantation, registries such as the North 
American Pediatric Renal Transplant Cooperative Study, and literature 
on the use and potential toxicities of this agent. FDA believes that 
these resources, in conjunction with appropriate labeling of the 
device, will sufficiently address the risks discussed above.
    In conjunction with the downclassification of cyclosporine tests, 
FDA proposes to include tacrolimus test systems. Tacrolimus was first 
cleared for clinical use in 1994, and like cyclosporine, is a 
calcineurin inhibitor. The immunosuppressive properties and molecular 
mechanisms of the two drugs are very similar (Ref. 8). Likewise, the 
toxicity profiles are very similar, although not identical. Tacrolimus 
raises the same issues as cyclosporine, related to the need for 
individual tailoring of dosing that is not solely dependent on blood 
drug levels. Similar issues to those discussed above also exist with 
regard to immunoassays for tacrolimus showing a positive bias compared 
with HPLC methods. FDA expects that the approach to validating 
analytical performance for test systems for these two drugs should be 
similar, as outlined in the draft guidance document.

VIII. Environmental Impact

    The agency has determined under 21 CFR 25.34(b) that this 
reclassification action is of a type that does not individually or 
cumulatively have a significant effect on the human environment. 
Therefore, neither an environmental assessment nor an environmental 
impact statement is required.

IX. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612) (as 
amended by subtitle D of the Small Business Regulatory Fairness Act of 
1996 (Public Law 104-121), and the Unfunded Mandates Reform Act of 1995 
(Public Law 104-4)). Executive Order 12866 directs agencies to assess 
all costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). The agency believes that this proposed rule is consistent with 
the regulatory philosophy and principles identified in the Executive 
order. In addition, the reclassification action is not a significant 
regulatory action as defined by the Executive order and so is not 
subject to review under the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Reclassification of the device from class III to 
class II will relieve manufacturers of the cost of complying with the 
premarket approval requirements in section 515 of the act. Because 
reclassification will reduce regulatory costs with respect to this 
device, it will impose no significant economic impact on any small 
entities, and it may permit small potential competitors to enter the 
marketplace by lowering their costs. The agency therefore certifies 
that this proposed rule, if finalized, will not have a significant 
economic impact on a substantial number of small entities. In addition, 
this reclassification action will not impose costs of $100 million or 
more on either the private sector or State, local, and tribal 
governments in the aggregate, and therefore a summary statement of 
analysis under section 202(a) of the Unfunded Mandates Reform Act of 
1995 is not required.

X. Paperwork Reduction Act of 1995

    FDA concludes that this proposed rule contains no new collections 
of information. Therefore, clearance by the Office of Management and 
Budget under the Paperwork Reduction Act of 1995 is not required.

XI. Request for Comments and Proposed Dates

    Interested persons may submit to the Dockets Management Branch 
(address above) written or electronic comments regarding this proposed 
rule by April 22, 2002. Two copies of any comments are to be submitted, 
except that individuals may submit one copy. Comments are to be 
identified with the docket number found in brackets in the heading of 
this document. Received comments may be seen in the Dockets Management 
Branch between 9 a.m. and 4 p.m., Monday through Friday. FDA proposes 
that any final regulation that may issue based on this proposal become 
effective 30 days after its date of publication in the Federal 
Register.

XII. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Shaw, L. M. et al., ``Current Opinions on Therapeutic Drug 
Monitoring of Immunosuppressive Drugs,'' Clinical Therapeutics, 
21:1632-1652, 1999.
    2. Oellerich, M. et al., ``Therapeutic Drug Monitoring of 
Cyclosporine and Tacrolimus,'' Clinical Biochemistry, 31:309-316, 
1998.
    3. Steimer, W., ``Performance and Specificity of Monoclonal 
Immunoassays for Cyclosporine Monitoring: How Specific Is 
Specific?,'' Clinical Chemistry, 45:371-381, 1999.
    4. Schutz, E. et al., ``Cyclosporin Whole Blood Immunoassays 
(AxSYM, CEDIA, and EMIT): A Critical Overview of Performance 
Characteristics and Comparison With HPLC,'' Clinical Chemistry, 
44:2158-2164, 1998.
    5. Holt, D. W. et al., ``New Approaches to Cyclosporine 
Monitoring Raise Further Concerns About Analytical Techniques,'' 
Clinical Chemistry, 46:872-874, 2000.

[[Page 7985]]

    6. Hamwi, A. et al., ``Cyclosporine Metabolism in Patients After 
Kidney, Bone Marrow, Heart-Lung, and Liver Transplantation in the 
Early and Late Posttransplant Periods,'' American Journal of 
Clinical Pathology, 114:536-543, 2000.
    7. Fernandez-Marmiesse, A. et al., ``Comparison of Predose vs 2-
h Postdose Blood Metabolites/Cyclosporine Ratios in Kidney and Liver 
Transplant Patients,'' Clinical Biochemistry, 33:383-386, 2000.
    8. Halloran, P. F., ``Molecular Mechanisms of New 
Immunosuppressants,'' Clinical Transplantation, 10:118-123, 1996.
    9. Braun, F. et al., ``Clinical Relevance of Monitoring 
Tacrolimus: Comparison of Microparticle Enzyme Immunoassay, Enzyme-
Lined Immunosorbent Assay and Liquid Chromatography Mass 
Spectrometry in Renal Transplant Recipients Converted From 
Cyclosporine to Tacrolimus,'' Transplantation Proceedings, 28:3175-
3176, 1996.
    10. Jusko, W. J. et al., ``Consensus Document: Therapeutic 
Monitoring of Tacrolimus (FK-506),'' Therapeutic Drug Monitoring, 
17:606-614, 1995.

List of Subjects in 21 CFR Part 862

    Medical devices.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 862 be amended in subpart B as follows:

PART 862--CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES

    1. The authority citation for 21 CFR part 862 continues to read as 
follows:

    Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 371.

    2. Section 862.1235 is added to subpart B to read as follows:


Sec. 862.1235  Cyclosporine test system.

    (a) Identification. A cyclosporine test system is a device intended 
to quantitatively determine cyclosporine concentrations as an aid in 
the management of transplant patients receiving therapy with this drug. 
This generic type of device includes immunoassays and chromatographic 
assays for cyclosporine.
    (b) Classification. Class II (special controls). The special 
control is ``Class II Special Controls Guidance Document: Cyclosporine 
and Tacrolimus Assays; Guidance for Industry and FDA.''
    3. Section 862.1678 is added to subpart B to read as follows:


Sec. 862.1678  Tacrolimus test system.

    (a) Identification. A tacrolimus test system is a device intended 
to quantitatively determine tacrolimus concentrations as an aid in the 
management of transplant patients receiving therapy with this drug. 
This generic type of device includes immunoassays and chromatographic 
assays for tacrolimus.
    (b) Classification. Class II (special controls). The special 
control is ``Class II Special Controls Guidance Document: Cyclosporine 
and Tacrolimus Assays; Guidance for Industry and FDA.''

    Dated: February 11, 2002.
Linda S. Kahan,
Deputy Director, Center for Devices and Radiological Health.
[FR Doc. 02-4208 Filed 2-20-02; 8:45 am]
BILLING CODE 4160-01-S