December 16, 1998 - Use of ASRs (In-House Tests) to Monitor HIV/AIDS Drug Therapy

This letter is written on behalf of the American Society for Microbiology (ASM) regarding a matter of urgent health concern to HIV/AIDS patients. ASM requests your assistance in assuring the continued availability of clinical tests immensely valuable in the treatment of HIV/AIDS.

Regulations classifying certain Analyte Specific Reagents (ASRs) as Class III medical devices became effective on November 23, 1998. It has come to ASM's attention that FDA may intend to apply those regulations in a manner that would bar usage of in-house clinical laboratory tests that determine whether the HIV virus in specific HIV/AIDS patients is mutating in response to drug therapy.

The tests are not used for the diagnosis of HIV/AIDS. Indeed, they are not used until after a specific patient has commenced a drug regimen in response to a diagnosis. No suitable substitute tests are presently available for the important determinations made by these tests. Loss of such tests would severely undermine the treatment of numerous HIV/AIDS patients.

In addition, over the long term, the United States faces a broad array of infectious diseases. It is critically important that clinical laboratories develop tests to identify, on a patient-specific basis, the response of disease mechanisms to evolving drug therapies. Use of in-house tests to provide early measurement of the reaction of infectious diseases to drug therapy should be encouraged rather than prohibited. Therefore, without detracting from the immediate resolution of the dilemma confronting clinical laboratories assisting HIV/AIDS patients, we also raise longer term considerations related to FDA's enforcement of the ASR regulations.


The American Society For Microbiology has a significant interest in the regulation of Analyte Specific Reagents (ASR's).

ASM is the largest single life science society in the world representing over 42,000 members who work in clinical, public health, research and industrial laboratories. ASM publishes over a dozen scientific journals in discrete areas of the microbiological sciences. Further, ASM hosts numerous educational meetings, conferences, and programs throughout the nation for the purpose of advancing education in, and understanding of, the microbiological sciences. For example, ASM annually sponsors the Inter-Science Conference on Antimicrobial Agents and Chemotherapy, which is the largest annual conference in the world for scientific discussion of infectious diseases.

Many of ASM's members work in clinical laboratories regulated under the Clinical Laboratory Improvement Amendments of 1988 (CLIA '88) that are at the front line of the battle against infectious diseases. These laboratories develop and perform hosts of tests associated with the combat of infectious diseases ranging from initial diagnosis to monitoring the effectiveness of treatment. CLIA-regulated laboratories develop and use ASRs and, of course, are directly affected by FDA's interpretation of the ASR.

The ASR Regulations were based upon the sale of ASRs and an understanding of the proper role of clinical laboratories in developing in-house tests.

In response to the trend for sophisticated clinical laboratories to develop in-house tests using ASRs, FDA held a meeting of the Immunology Devices Panel on January 22, 1996, to discuss a regulatory framework for ASRs. The broad overview proposed by FDA at the meeting was generally supported by the Panel and professional and industry organizations attending the meeting. That overview included classifying the majority of ASRs in Class I and exempting them from Pre-Market Notification requirements.

Subsequently, on March 14, 1996, FDA proposed ASR regulations for public comment. 61 Fed. Reg. 10484 (March 14, 1996) FDA's proposal recognized competing considerations in the development of regulations related to ASRs used by clinical laboratories for the development of in-house tests. FDA expressly noted the clinical importance of in-house tests as "a mechanism for providing novel, highly specialized tests in a relatively short time . . . ." 61 Fed. Reg. 10484, 10485 (March 14, 1996).

After receipt and review of comments, FDA promulgated final regulations for the restriction and classification of ASRs on November 21, 1997. 62 Fed. Reg. 62243 (1997). The effective date of the regulations was November 23, 1998.

The focus of the regulations is upon classification and regulation of ASRs that move in commerce, not tests developed in-house by clinical laboratories or ASRs created in-house and used exclusively by the clinical laboratory for testing services. In the preamble to the final regulation, FDA repeatedly expresses confidence in CLIA regulated laboratories, specifically finding that development of in-house laboratory tests is a complex process in which diagnostic performance may be assessed either through the medical practice associated with a given laboratory or scientific literature. 62 Fed. Reg. 62250 (Nov. 21,1997)

As promulgated, the final ASR regulations prescribe labeling requirements for in vitro diagnostic products. 21 CFR 809.10(e) ASRs used for diagnostic purposes are designated as "restricted devices," and specific restrictions are established for covered ASRs. 21 CFR 809.30 For example, the sale of covered ASRs is restricted to in vitro diagnostic manufacturers, clinical laboratories regulated under the Clinical Laboratory Improvement Amendments of 1988, as qualified to perform high complexity testing, or VHA Directive 1106, and organizations that use reagents for purposes other than providing diagnostic information. 21 CFR 809.30(b)

The restrictions include specific labeling requirements (21 CFR 809.30(c)) and require a disclaimer by laboratories developing in-house tests using an ASR. 21 CFR 809.30(e) The disclaimer provision requires a laboratory using an in-house test to notify the person ordering the test that the test has not been approved by the FDA through a specific written disclaimer appended to the test results.

Finally, the regulations define and classify ASRs. Generally, ASRs are classified as Class I and are exempt from requirements for Pre-Market Notification. ASRs are designated as Class II when used in blood banking tests that have been classified as Class II devices. For purposes of this letter the key provision of the regulations is 21 CFR 864.4020(b)(3)(i) which classifies certain ASRs as Class III medical devices.

The subset of ASRs placed within class III was defined by FDA to be a narrow group of ASRs related to the blood supply or used in diagnoses protecting the public health against the spread of contagious, fatal diseases.

In proposing the ASR regulations, FDA stated that the Immunology Devices Panel agreed with the viewpoint that "a small number of ASR's presenting a high risk to public health would be placed in Class III." 61 Fed. Reg. 10485 (March 14, 1996). Working from this suggestion, the proposed regulations suggested classifying ASRs under Class III when:

The analyte is used to develop a test intended to diagnose a contagious condition and the condition is highly likely to result in a fatal outcome and prompt accurate diagnosis offers the opportunity to mitigate the public health impact of the condition (e.g., human immunodeficiency virus (HIV) or tuberculosis (TB);

A number of comments upon the proposed regulations objected to classifying ASRs in Class III on grounds such as: stricter regulation would impair the ability of clinical laboratories to respond to outbreaks of new or emerging infectious diseases; the population of patients is small and classification in Class I would be sufficient; and, such classification would cause confusion. FDA responded to these comments in the preamble to the final ASR regulations, asserting that the inclusion of ASRs in Class III would be narrow and would apply only when the diagnosis of a fatal, contagious disease could allay risks to the public health. FDA stated:

ASR's will be identified as class III devices only when they are intended to be used in tests that establish or safeguard the safety of the blood supply or in tests that diagnose contagious fatal diseases when prompt, accurate diagnosis can mitigate risks to the public health. 62 Fed. Reg. 62249 (Nov. 21, 1997).

Another comment upon the proposed ASR regulations suggested that classification of an ASR as Class III on the basis of the type of test for which it is used would create confusion. FDA replied that: "[T]hrough a narrow definition of the class II and class III identification, the exceptions to the general ASR classification [Class I] have been limited to a manageable number." 62 Fed. Reg. 62248 (Nov. 21, 1997).

The final ASR regulations regarding Class III ASRs are virtually identical to the proposed regulations. An ASR is in Class III when:

(i) The analyte is intended as a component in a test intended for use in the diagnosis of a contagious condition that is highly likely to result in a fatal outcome and prompt, accurate diagnosis offers the opportunity to mitigate the public health impact of the condition (e.g., human immunodeficiency virus (HIV/AIDS) or tuberculosis (TB). 21 CFR 864.4020(b)(3)(i)

These requirements focus upon two facets of the protection of public health: the nature of the disease and the opportunity to mitigate public health impacts through a prompt accurate diagnosis. Thus, Section 864.4020(b)(3)(i) is divided into two phrases.

First, the ASR must be a component of a test for: (1) "diagnosis" of; (2) a "contagious condition" that is; (3) "highly likely" to result in; (4) a "fatal outcome." Notwithstanding inevitable definition questions regarding such terms, the language clearly is aimed at determining a particular type of disease threat -- diagnoses of contagious, fatal diseases.

Second, the express language of the ASR regulation links the diagnosis of the contagious, fatal disease to protecting the public from the spread of such diseases by including the requirement that "prompt, accurate diagnosis offers the opportunity to mitigate the public health impact of the condition." Thus, the ASR regulations recognize a unique public health danger from contagious, fatal diseases and includes as a requirement for inclusion in Class III that the test must occur in situations in which: (1) a "prompt, accurate diagnosis" may; (2) "mitigate the public health impact of the condition."

FDA recognized the unique public interest in timely and correctly identifying that an individual has a disease posing a "public" threat through the possible transmission to others of a contagious, fatal disease. From the express language of Section 864.4020.(b)(3)(i) as well as FDA's comments in the preface to its promulgation, therefore, it is manifest that the section is aimed at promoting prompt accurate diagnoses of diseases to avoid the spread of fatal infectious diseases.

Recent developments may indicate that FDA intends to broaden the scope of class III ASRs beyond the "manageable number" contemplated in the Preamble of the ASR regulations.

ASM understands that FDA may now view the ASR regulations as including in Class III ASRs used as components of in-house tests that determine genetic mutations of the HIV virus infecting a specific patient. As a result, FDA may assert that such ASRs must receive Pre-Market Approval and may not be used by the laboratories that developed them without such approval.

The tests, however, occur after diagnosis of HIV/AIDS. Further, the tests are specific to the particular patient and play little or no role in mitigating the public health danger of spread of HIV/AIDS.

If ASM's understanding of FDA's position is correct, therefore, it appears FDA may view the definitions of key terms more broadly than indicated by FDA prior to the promulgation of the ASR regulations or may have lost sight that the purpose of the assurance of a prompt, accurate diagnosis was to mitigate the unique public health risk of the spread of contagious, fatal diseases. Application of the ASR regulations to require Pre-Market Approval of ASRs developed in-house by CLIA-regulated laboratories to determine genetic mutations of HIV in specific patients, as a practical matter, would cause the abandonment of such tests. Such a broadened interpretation of Section 864(b)(3)(i) would raise two concerns.

In the near term, such a position would threaten the health of HIV/AIDS patients. In-house tests are now being used by clinical laboratories to determine at the earliest possible stage the reaction of the HIV virus to specific drug therapies for specific patients. No substitute or alternative test is commercially available. Discontinuance of such tests would endanger the health of HIV/AIDS patients.

Over the longer term, an interpretation of 21 CFR 864.4020(b)(3)(i) that bars the in-house tests used to evaluate mutations of HIV in specific patients creates serious implications regarding FDA's approach to in-house tests for the entire spectrum of infectious diseases. Obviously, given the number of infectious diseases prevalent in society and the possible threat of biological terrorism, these implications raise important issues for ASM and its members.


Treatment of HIV/AIDS patients is presently enhanced by in-house tests of the patient's reaction to drug therapy.

At the present time, there are commercially available tests for the diagnosis of HIV positive status using Pre-Market Approved ASRs. Such tests for diagnosis of HIV/AIDS have been available since the mid-1980s. These tests are used to detect antibodies to the HIV virus and, therefore, a history of exposure to the virus. Clearly, those tests are, and should be, included within the express language of Section 864.4020(b)(3)(i).

Additionally, tests have been developed and commercially distributed to monitor the "viral load" of the HIV virus. A declining or constant viral load suggests that the antiviral drugs are doing their job of holding multiplication of the virus in check. These commercially available tests also use Pre-Market Approved ASRs and are distributed with FDA approval.

However, there are newer tests that have even greater efficacy than does the viral load tests in measuring drug effectiveness by taking the analysis to a stage preceding measurement of the viral load. This test is used after diagnosis of HIV positive status and after commencement of drug therapy. The test does not measure the level of HIV virus in the patient's body but rather screens for the appearance of viral genes that contain mutations that render the virus resistant to antiviral drugs.

Detection of such viral genes is important. When these genes are detected early, antiviral drugs can be changed to drugs for which mutated genes have not been detected. Thus, the drug therapy may stay ahead of viral mutation, and the multiplication of the virus may be avoided. Physicians and their patients have come to rely upon the results of these in-house tests to determine when resistance appears and then rapidly change the drug "cocktail." This contributes to maximizing the length and quality of life.

These tests for resistant viral genes and the reagents used in them are not available from a commercial source and do not use Pre-Market Approved ASRs. Instead, they have been developed in-house by CLIA-regulated laboratories as components of in-house tests to provide the earliest possible detection of the reaction of the HIV virus to particular drugs.

As FDA is aware, the Pre-Market Approval process is lengthy and demanding. As a practical matter, Pre-Market Approval requires an overall financial and administrative burden that most clinical laboratories cannot bear. While CLIA-regulated laboratories are well equipped to develop reagents to be used effectively in such in-house tests, they are neither financially nor administratively equipped to obtain Pre-Market Approval of specialized, narrowly-focused reagents.

Finally, clinical laboratories performing this type of testing are not engaged in marketing kits outside of their institution. These important tests are now being developed on an "in-house" basis rather than through use of ASRs distributed in commerce by commercial manufacturers to determine genetic mutations of viruses in order to anticipate possible loss of effectiveness of particularized drug regimens.

FDA should not take the position that the ASR regulations bar CLIA-regulated laboratories from using ASRs for in-house tests of the reaction of the HIV virus in specific patients to drug therapy.

As set forth above, 21 CFR 864.4020.(B)(3)(i) consists of two phrases. The first phrase is directed at the nature of the illnesses covered - contagious, fatal diseases and requires a "diagnosis" that such a condition exists. The second phrase is directed at the potential public harm through a prompt, accurate diagnosis that permits mitigation of the spread of the contagion. The in-house tests discussed in this letter are not within the letter or spirit of either the first or second phrases of the regulation.

1. Tests for genetic changes in HIV in specific patients do not constitute the "diagnosis" of HIV/AIDS.

The "diagnosis" of the HIV/AIDS condition that is significant for public health occurs well before administration of the tests discussed in this letter. Such tests, therefore, do not fall within the first phrase of the Section that applies to the "diagnosis" of the contagious condition.

Obviously, there are a number of tests that are employed post-diagnosis that are important for patient care, but they are not the singular diagnosis of the contagious condition that triggers recognition of, and permits response to, the potential public consequences of the illness. Treatment regimens certainly are not the diagnosis of the contagious disease and neither are tests that measure the success of the treatment regimen and evaluate the prognosis for the specific patient.

ASM is aware that there is one phrase in the preamble to the ASR regulations in which FDA asserts that it believes ASRs falling within the Class III exception include tests "for evidence and monitoring for levels of HIV/AIDS and tuberculosis." 62 Fed. Reg. 62249 (Nov. 21, 1998). The meaning of this somewhat cryptic terminology is not entirely clear, especially as it falls within FDA's response to a comment in which FDA states its belief it has established a "narrow definition" for the Class II and Class III exceptions and the Class II and Class III exceptions "have been limited to a manageable number." 62 Fed. Reg. 62248 (Nov. 21, 1997).

In any event, it is clear that the tests described in this letter do not in any sense "monitor" or measure levels of HIV/AIDS. Instead, they detect the genetic reaction of the HIV virus to drug therapy. Therefore, even if the reference to "evidence or monitoring levels" were intended to expand the term "diagnosis" beyond the logical, public health meaning of the determination of the existence of the contagious condition, it would not apply to the tests discussed in this letter.

Finally, if the term "diagnosis" in the ASR regulation were intended to apply to the tests described in this letter, then virtually every test used in the treatment of specific HIV/AIDS patients (and any other patient with a fatal, contagious disease) would constitute a "diagnosis" for purposes of Section 864.4020(b)(3)(i). Such a sweep would be wholly inconsistent with the wording of the regulations, the preamble description of the intent of the regulation, the public/private interest in treating the specific patient, and the public health impact of contagious diseases.

2. Tests for genetic changes in HIV in specific patients do not serve to mitigate the public health threat of spread of contagious, fatal diseases addressed by Section 864.4020(b)(3)(i).

The vast majority of ASRs are classified as Class I medical devices. FDA found that controls associated with Class I devices generally are sufficient to protect the public welfare. Further, the CLIA regulations regarding in-house modifications or materials or methods provide an adequate safeguard in the development of in-house tests.

According to FDA, the focus of Section 864.4020(b)(3)(i) is "highly contagious and fatal diseases." 62 Fed. Reg. 62249 (Nov. 21, 1997). As set forth above, the very basis for the section is the reasonable decision by FDA that it is important for the public to obtain prompt and accurate diagnoses of highly contagious, fatal conditions. Through such diagnoses, measures may be taken to prevent the further spread of the contagion. Thus, the section links the diagnosis of a contagious, fatal disease with the mitigation of a public health risk.

If the section only pertained to a diagnosis of a potentially fatal contagious condition, then it need only provide for inclusion of an ASR in Class III when the analyte is intended "for use in the diagnosis of a contagious condition that is highly likely to result in a fatal outcome." However, the section does not stop at that point but instead adds the conjunctive "and" and continues "and prompt, accurate diagnosis offers the opportunity to mitigate the public health impact of the condition . . . ." Clearly, the mitigation envisioned by the second phrase in the section is the avoidance of spreading the fatal contagion.

Indeed, if the public health impact were simply the potentially fatal impact of the disease upon the individual then every analytic tool related to individual treatment is included within its scope. If that were the intent, there would be no reason for limiting it to contagious conditions. Tests that relate to the treatment of the individual HIV/AIDS patient are no more related to the public health at large than tests performed on desperately ill patients suffering from non-contagious illness clearly not covered by Section 864.4020(b)(3)(i). Just as the tests considered in this letter occur after the diagnosis of HIV/AIDS, they also occur after the potential to mitigate the public risk -- spread of the contagion -- has been identified. As a result, the tests do not fall within the scope of Section 864.4020(b)(3)(i).

3. To the extent a CLIA-regulated laboratory itself develops the ASR used in the test, the ASR is not distributed in commerce and is not subject to Pre-Market Notification Requirements.

The primary reasons the ASRs used in the described tests are not, and should not be, within Class III are set forth above. However, to ASM's knowledge most laboratories performing this type of testing do not purchase commercial reagents for use in the tests. The ASRs used in the tests are developed and produced in-house.

At no point does the ASR enter commerce and at no point in the process is an obligation to obtain Pre-Market Approval triggered. Therefore, absence of a Pre-Market Approval of an ASR is not a basis for banning in-house tests using such ASRs.

On a long term basis, there are numerous ambiguities in the ASR regulations that should be addressed if the regulation may be construed to limit in-house tests by clinical laboratories that are useful for the treatment of infectious diseases.

The ASR regulations state that the scope of coverage includes infectious diseases for which there is a high likelihood of a fatal outcome, listing infection with HIV or TB as examples. In light of the importance of the tests discussed in this letter and other tests beneficial to the well being of specific patients, ASM is concerned that the definition is imprecise.

ASM would like to know if it is FDA's intention to add other infectious agents at a later date. There are many other agents with a high likelihood of a fatal outcome. For example, the federal government is currently drafting a response plan to manage effective diagnosis and treatment of infectious agents due to acts of biological terror. Does the FDA intend to apply the ASR rule to such diagnostic testing? The ASM is concerned that an open-ended interpretation of the language in the regulation may allow for the capricious application on the local or state level and lead to critical shortcomings in our nation's security and health systems.


ASM seeks to cooperate with the FDA to assure the best possible care of HIV/AIDS patients and to act consistently with the important public interest in avoiding the spread of contagious diseases. ASM concurs that prompt and accurate diagnosis of fatal, contagious conditions and action to mitigate the public impact are important public health objectives. ASM further concurs that CLIA-regulated laboratories contribute importantly to the development of valuable clinical tests through in-house development of ASRs and tests related to contagious diseases.

Consequently, ASM desires to work constructively toward resolution of a situation in which ASM believes the FDA may be poised to interpret the ASR regulations overly broadly as they relate to in-house ASRs and in a manner that prevents uses of ASRs for in-house tests that contribute importantly to the effective treatment of specific HIV/AIDS patients. ASM, therefore, seeks clarification of FDA's views of the application of the ASR regulations to such tests.

ASM is not concerned with the manner in which clarity is achieved -- advisory opinion, interpretive letter, meeting, or some other approach. Our only concern is maintaining the availability of tests vitally important for the best possible treatment for HIV/AIDS patients.