FDA advises blood centers on phase-in of AIDS test.

The nationhs blood banks and commercial blood product producers have entered a new era with the approval early last month of the first kits to test for antibodies to the human T-cell lymphotropic virus III, the agent believed to cause AIDS.

In announcing approval of the first test, Health and Human Services Secretary Margaret Heckler called it "the answer to the prayers of thousands of Americans" needing blood transfusions. She termed it "an additional insurance policy" for preventing transmission of the disease through the nation's blood supply.

Although the vast majority of the nation's blood product suppliers are expected to add the test to their procedures quickly, compliance will be voluntary while the Food and Drug Administration completes the time-consuming steps necessary to mak testing mandatory. The agency estimates that it will be several months at best before regulations establishing the test as a requirement are proposed and finalized--even with the rules on a fast track.

Meanwhile, though, "Laboratories should begin immediately to acquire the necessary equipment and to train personnel to assure accurate, routine test performance," said Dr. Elaine Esber, director of the FDA's Office of Biologics Research and Review, in a letter to all registered blood establishments.

The test and FDA's urgings come as the latest Federal figures show 8,597 AIDS cases in the U.S. and 4,145 deaths. Some 119 deaths are transfusion-related, with 15 of those children.

Abbott Laboratories was the first of five competitors to receive the agency go-ahead for marketing. The North Chicago, Ill., firm, which said each kit would sell for $2 to $3, signed acontract with the American Red Cross the day of Heckler's announcement. The Red Cross estimated that the test will cost about $5 per unit to administer, thus adding about 10 per cent to the cost of blood.

Electro-Nucleonics, Inc., of Fairfield, N.J., won the second approval on March 7, and HHS officials said the other three were not far off. The nation's 2,300 blood facilities are expected to need more than 1.5 million tests monthly, creating what industry analysts calculate to be a $60 to $80 million market.

Reportedly, the agency postponed its original mid-February product approval date while attempting to satisfy the concerns of local public health officials and organizations representing highrisk individuals. These groups raised numerous issues related to test accuracy, confidentiality, and public perception of its purpose and value. By early March, most of them appeared satisfied with plans worked out in meetings with FDA Commissioner Frank Young and Centers for Disease Control officials. For instance, the Government agreed that labeling should emphasize that the test is for blood screening, not disease diagnosis. The officials also said they would cooperate with local efforts to establish alternative testing sites for high-risk individuals who might otherwise donate blood to learn about possible exposure to the AIDS virus.

At the same time, the agency prepared a memorandum for physicians and other health workers, and a second detailed document for blood banks and laboratories likely to use the test. The first underscores that the test is a screen, that it has imperfections, and that retesting, confidentiality, and follow-up are critical. The second is designed to answer questions the agency believes will arise in applying the new test. Additionally, the agency has formed a working group whose members are to serve as contacts for centers needing more assistance.

The agency recommends that each facility conduct preliminary testing, and then enter an "essential" phase-in period. "It is very important that staff are adequately trained and that consistently reproducible results are assured before any positive results are communicated to donors," Dr. Esber's letter noted.

During the phase-in, "It will best serve public health goals to discard products with unvaliadated positive test results, although concomitant donor notification may not be appropriate" due to the test's uncertainties, she wrote. Product labeling for the HTLV-III antibody should begin only after a center is routinely testing "all of its blood supply." Any reactive samples identified before then "may be frozen and retested" after the test becomes routine. In that case, donor notification forms should explain that test results will not be available until that later time. Once the test system is up and running, donors are to be informed from the outset.

Other FDA testing recommendations include:

* Medical follow-up. HHS will offer suggestions for medical evaluation and counseling of reactive donors, but the major blood and plasma collecting organizations will "also be good resources for guidance in developing information for donors and notification procedures," the agency said. The FDA is advising attention to a donor's preference on notification since "many donors will respond best to a personal interview." Moreover, each center will want to assign responsibility for donor information to individuals "who understand the need for confidentiality and the severe psychological stress reactive tests will cause for some individuals.

* Alternative mechanisms for obtaining HTLV-III testing. FDA recommends that these be set up locally before testing is mandated. "Ideally, clear instructions concerning this alternative should be available to every prospective donor," the letter said, reiterating that those seeking the test should understand that the test is not diagnostic, and can yield false positives and negatives. At s least one report found that 4 of 96 individuals carried the virus for six months without developing detectable antibodies.

* Donor information and deferral registers. When a facility tests for HTLV-III routinely, all donors should be informed that 1) their blood will be tested; 2) after the phase-in, they will be notified if the test is positive initially; 3) they will be deferred from future donations if they test positive when repeated; and 4) they will be part of donor deferral registers as required by law if they have tested positive.

"We recommend that...information be put in the context of explaining which required lab tests are routinely performed on all blood products before distribution for use, and that donors be given a choice as to how the blood establishment will notify them of reactive test results," said Dr. Esber. "The analogy to HBsAg test requirements and deferral policies may be useful."

The agency also "strongly" recommends that the donor's signature acknowledging receipt of pre-donation information be part of each establishment's records. For testing on blood already in inventory during the phase-in period, donor consent "may not be feasible and is not required." In all cases, "it will be extremely important to protect the confidentiality of donor identity," the letter says. "The misuse of such information could have serious consequences for both donors and blood establishments because positive test results could result in loss of employment and insurability."

Donor deferral records do not s have to be available at the blood collection site, but there must be a mechanism for linking entries on the deferral list to individual donors and the reason for the deferral, the agency advised.

* Defining reactive results. The procedures required to determine that a sample is initially reactive for the HTLV-III antibody will be defined in each manufacturer's package insert. All initially reactive samples should be at least retested to assure accurate sample identification and reproducible results, FDA said. Also, the repeat test might be given on a sample integrally attached to the blood container. Donors should not be notified of positive test results until there "is clear agreement that theinitial and repeat tests are reactive; the test may be done with a single manufacturer's reagent." The agency also cautioned that "all blood products with an initial reactive test result must not be distributed for transfusion or further manufacturing into injectable products."

* Additional testing of reactive samples. Although blood and plasma centers' obligations end with repeating the manufacturer's prescribed HTLV-III test procedures in deciding that a sample is positive, the donor should be advised to consult a physician, clinic, or public health facility since a medical evaluation is recommended for individuals with repeatedly reactive results, FDA advised. and until a confirmatory test becomes available, additional testing for the HTLV-III antibody may be part of the medical evaluation. For that reason, the Western blot test for antibodies to HTLV-III--the technique used most extensively for HTLV-III antibody specificity in research--will be available through most of the licensed manufacturers.

Nevertheless, added the agency, the Western blot remains a research tool rather than a confirmatory test, so a negative result does not mean that antibody specific to HTLV-III is absent, because the relative sensitivity of both tests varies among laboratories.

* Standard operating procedure revisions. To comply with good manufacturing practices, each center will have to revise its procedure manual to include HTLV-III antibody testing, quarantine and disposition procedures for reactive units, procedures for notifying donors of reactive results, and record keeping procedures, including donor deferral registers. However, licensed establishments need not submit revised SOPs to FDA, Dr. Esber said.

Licensed facilities may use outside labs to perform the antibody testing, but only after prior approval of this shared responsibility. The collecting facility must maintain written records of all test results, with the records available before any product distribution occurs. Exception: source leukocytes or in emergency situations when the blood product is clearly labeled to indicate the test has not been performed.

* Blood product labeling. While information on the test should appear in the package insertS, the test results themselves must appear on the container label of source plasma, recovered human plasma, and other products intended solely for further manufacture, said FDA. Acceptable container statements are: "Nonreactive by serologic tests for HTLV-III" or "Nonreactive when tested for HBsAg and HTLV-III by FDA-required tests." Licensed centers should inform FDA (with file copies) of label notices to be used.

When HTLV-III testing becomes routine in a center, containers with untested blood will have to be so labeled. These products will generally be emergency shipments or old inventory of products with long dating periods, e.g., frozen red blood cells, plasma, and cryoprecipitated AHF. Label cautions to the effect that the reuired HTLV-III test has not been done, or that the product was prepared prior to the requirement and the status of the donor is not known or is nonreactive, must be affixed.

Prior FDA approval will be needed to collect reactive samples for research or further manufacturing into "special in vitro diagnostic products," Dr. Esber said.

She added that individual inquiries concerning the list of approved manufacturer licensees should be directed to the FDA Division of Product Certification at [phone].

Also, centers with further questions or problems in implementing HTLV-III test procedures can contact any major blood organization or the FDA's Office of Biologics Research and Review at [phone].