Allergenic Products Advisory Committee
25 October 2011
Non-standardized allergenic extracts were first licensed in the 1920s. While manufacturing standards have changed and non-standardized allergenic extracts are now subject to current good manufacturing practices, as well as adverse event reporting requirements, these products were licensed under a “safe, pure, and potent” standard that is now viewed as incomplete. Specifically, the manufacturers were not required to demonstrate efficacy, which was first required under the Drug Amendments of 1962, and is now required in order to obtain a license for a biological product. FDA first resolved to review efficacy data for older licensed biological products in the 1970s. Since that time our understanding of the data needed to demonstrate efficacy has changed. To call a biological product efficacious in 2011, FDA requires proof of efficacy related to individual products, and an individualized showing with respect to each product. Applying this standard of efficacy to existing licensed non-standardized allergenic extracts is difficult, in part because in many cases, manufacturers have not submitted data for each individual extract.
FDA recognized that older licensed biological products may not have undergone pre-approval, controlled, efficacy trials. Accordingly, the regulations governing FDA’s review of the efficacy of older biological products explained:
Proof of effectiveness shall consist of controlled clinical investigations…unless this requirement is waived on the basis of a showing that it is not reasonably applicable to the biological product or essential to the validity of the investigation, and that an alternative method of investigation is adequate to substantiate effectiveness. Alternate methods, such as serological response evaluation in clinical studies and appropriate animal and other laboratory assay evaluations may be adequate to substantiate effectiveness where a previously accepted correlation between data generated in this way and clinical effectiveness already exists. (21 CFR 601.25(d)(2))
FDA began to review the efficacy data supporting licensure of non-standardized allergenic extracts with its review of the 1981 report prepared by the Panel on Review of Allergenic Extracts, which was published in 1985 (50 FR 3082-3288). In 1983, an advisory panel prepared a second report that was not published in the Federal Register by FDA. That report is available at http://www.fda.gov/downloads/BiologicsBloodVaccines/Allergenics/UCM271333.pdf. FDA has continued to assess evidence of efficacy, and has not yet concluded that the data for non-standardized allergenic extracts establishes the efficacy of those products. As we have discussed in prior presentations to this advisory committee, we undertook a review of the scientific literature relating to these products. For purposes of this review, we continued to interpret the efficacy standard with considerable flexibility. Thus, for example:
- Non-standardized allergenic extracts were reviewed “generally,” without regard to specific manufacturer.
- For purposes of the review, we identified non-standardized allergenic extracts as meeting a working threshold for efficacy based on:
- two or more valid clinical reports from independent investigators;
- one valid clinical report, if it included supportive challenge data; and
- cross-reactivity data.
FDA’s review has identified some non-standardized extracts that appear to fall below the threshold used in our literature review, and below the standard set out in 21 CFR 601.25(d)(2).
FDA’s recent report released on 26 September 2011 (see http://www.gpo.gov/fdsys/pkg/FR-2011-09-26/pdf/2011-24598.pdf and http://www.fda.gov/BiologicsBloodVaccines/Allergenics/ucm272115.htm) provides an updated review of the literature of the non-standardized allergenic extracts that addresses their efficacy and safety, and that addresses issues of nomenclature. In the five tables that follow in this Briefing Document, non-standardized allergenic extracts are listed according to whether the use of the specific product for diagnosis and/or treatment of allergic disease are addressed in the scientific or medical literature, or whether any potential safety concerns were identified. This report is open for public comment until 25 November 2011.
FDA’s intent, as discussed at previous Allergenic Products Advisory Committee meetings on April 7, 2005 and September 13, 2006, had been to utilize this review, along with the deliberations described in both previous advisory panel reports, to implement 21 CFR 601.25 and 601.26 for non-standardized allergenic extracts. We are advising the Committee that applying these regulations to non-standardized allergenic extracts has presented significant challenges. FDA will discuss the nature of these challenges, as well as possible alternative approaches to this class of products, at the Allergenic Product Advisory Committee meeting at the Hilton Hotel in Silver Spring, MD, on October 25, 2011.