Threat to 'home brew' products angers labs.
The saga began last year, when officials at the Food and Drug Administration (FDA) said investigations found that a manufacturer was commercially marketing devices approved for research use only. The agency warned the firm that continued distribution would lead to regulatory action, and labs were notified that some of the company's diagnostic products would no longer be available.
That incident set off an alarm at the College of American Pathologists (CAP), where officials worried that a more widespread policy was in the making. True to those concerns, the FDA sent an October 1991 warning to six other manufacturers of in vitro diagnostic products on the implications of promoting tests for unapproved uses.
At the FDA's request, in February CAP submitted a list of 43 monoclonal antibodies that CAP said should be allowed to stay on the market since they had become the standard of care for diagnosing certain diseases. According to CAP, many of these products are currently approved as serum markers in flow cytometry or immunocytochemistry. For example, prostate-specific antigen is approved for monitoring prostate cancer but is not an accepted screening test for the disease.
In a draft compliance policy guide made available to laboratory groups late this summer, the FDA exempted 41 of the 43 products on CAP's list and added 19 others. The agency concluded that "immediate withdrawal of such products or severe restrictions on their access through limited investigational or research studies would not be in the best interests of public health."
The draft also noted that doctors and other medical professionals will be allowed to continue using products on the "accommodation list" because they are "considered the current standard of care essential to patient health and the practice of medicine."
William Hamlin, M.D., chairman of CAP's Council on Scientific Affairs, called the draft a "very positive sign that the FDA has heeded the College's advice and evidently plans to allow products that benefit patients to stay on the market."
Manufacturers of the listed monoclonal antibodies will have 30 months from the date of final policy notice to submit product approval applications in keeping with a 1976 medical device law. The products can remain on the market for that period, during which time manufacturers are to collect sufficient data for a product approval. Failure to gather such safety and efficacy data by the deadline will result in the product being removed from the market.
The overall objective of the policy guide, "Commercialization of Unapproved In Vitro Diagnostic Products for Research and Investigation," was to establish a certification program to prevent improper marketing, distribution, and use of such devices. It also was intended to create an audit trail of the use of the products from the manufacturer or importer to the end user.
According to the draft, the manufacturer or importer of products not on the accommodation list would need to create a program, in writing and before distribution, to show that labs and other providers are following appropriate guidelines on products labeled for investigational or research use only.
Laboratories that use those products would be required to attest that their application is limited to conducting tests for other laboratories or for researchers certified by the manufacturer or importer. Discontinuation of testing would be required for any other laboratory or researcher that the manufacturer/importer identifies as having failed to follow the certification program.
What has perplexed and angered the lab community is that the FDA has lumped home brew products in with all the other products to be regulated. Addressing the subject in just one paragraph, officials wrote:
"It has come to the attention of FDA that laboratories have been manufacturing 'home brew' products, either from products already on the market, or from components, and utilizing these unapproved products for diagnostic purposes. These products are subject to the same regulatory requirements as any unapproved medical device not identified" in the accommodation list of monoclonal antibodies.
Of course, product modification has become an accepted industry practice over the years; labs quickly mobilized to explain as much to the FDA. Some rushed to assert that the Clinical Laboratory Improvement Amendments of 1988 (CLIA '88), not the device premarket approval process, is the appropriate legal authority over home brew products.
The American Association for Clinical Chemistry (AACC) fired off a letter to the FDA stating that the group "believes the regulation of 'home brew' products is adequately addressed under CLIA '88, which requires verification of all performance specifications for modified or in-house developed tests."
Examples of home brew tests cited to the FDA by the AACC follow.
* Two-dimensional chromatography of amniotic fluid phospholipids is the gold standard for prenatal assessment of fetal pulmonary maturity. While the method is widely described in laboratory literature and has been used for more than 20 years, reagents for the test are not available in any FDA-approved form. The AACC says that without this test there would be an increase in perinatal deaths due to respiratory distress syndrome.
* HDL cholesterol is often measured by a complex method tied to the Centers for Disease Control's reference system. The dextran sulfate-magnesium sulfate precipitating reagent is not available in FDA-approved form.
* Total hemolytic complement is measured by a method involving sensitized sheep red blood cells that are usually made in a laboratory and are not available in FDA-approved form. The test is necessary to diagnose active autoimmune disease.
Similar comments were issued by the Clinical Laboratory Management Association (CLMA). A letter to the FDA said, "CLMA is concerned that imposition of additional regulatory requirements as outlined in the proposed compliance policy guide would drastically affect patient access to a wide range of laboratory services that are currently available, the list of which includes tests and methods far in excess of those listed on the FDA temporary exempt list."
Another CLMA letter being drafted for members of Congress at press time points out: "Development of new test methods by industry has been completely dependent historically on effective technology transfer from clinical and research laboratories in the hospital and academic sectors. We fear that the effect of further FDA certification requirements will undermine this process and thus potentially undermine the United States' predominance in this area of scientific advance."
The Washington law firm of Schwabe, Williamson & Wyatt suggests that a main problem posed by the FDA is one of semantics, since it seems to define labs that create home brew products as commercial manufacturers.
Writing to the FDA on behalf of several clinical reference laboratories, attorneys Jeffrey Boothe and Jeffrey Gibbs noted, "The situation would be different if the compliance policy guide merely meant to say FDA would regulate laboratories as 'manufacturers' only if they developed assay kits and shipped the kits to purchasers elsewhere. Regulating this activity as 'manufacturing' would not be objectionable."
Individual members of the lab industry are equally dismayed by the FDA policy guide and its potential impact on testing innovations.
According to Linda Bielitzki, a medical technologist and attorney with Rush-Presbyterian-St Luke's Medical Center, Chicago: "I question whether FDA truly appreciated the number of laboratories involved, and that brings up the question of the regulation's feasibility. We're not just talking about affecting a couple of large academic medical centers here."
Bielitzki says that even a modified policy guideline could place labs in regulatory limbo and stifle product innovations. If the FDA proceeds on its current tack, she says, "We'd see what an American lab would be. Laboratory A would look like laboratory B, which would look like laboratory C."
How could such a controversial--some would say naive--regulatory proposal find its way to daylight? Some Washington sources suspect the draft guideline was the work of a few overeager FDA staffers who inappropriately tied together the home brew issue with that of monoclonal antibodies. On the other hand, the draft was issued for comment from laboratory organizations, indicating it was not a loose-cannon project that received no formal clearance.
Two main questions have yet to be resolved. The first is whether the FDA has jurisdiction over home brew products under medical device statutes. If that authority holds true, the second question becomes whether the agency can publish its guidelines as final policy, much the way officials would instruct lab inspectors under CLIA. The alternative would be the formal notice of proposed rule making, which would open the proposal to a period of public comment.
At this writing, FDA officials were backpedaling, saying that it would be some time before any policy is finalized. But that was scant consolation to members of the lab community, who were left puzzling over how regulators could come up with a plan so lacking in understanding of common industry practices.
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|Title Annotation:||Food and Drug Administration draft policy guide|
|Publication:||Medical Laboratory Observer|
|Date:||Nov 1, 1992|
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